Human Malformations and Related Anomalies

Human Malformations and Related Anomalies

OXFORD MONOGRAPHS ON MEDICAL GENETICS GENERAL EDITORS

Arno G. Motulsky Martin Bobrow Peter S. Harper Charles Scriver Charles J. Epstein Judith G. Hall 16. C. R. Scriver and B. Child: Garrod’s inborn factors in disease 18. M. Baraitser: The genetics of neurological disorders 21. D. Warburton, J. Byrne, and N. Canki: Chromosome anomalies and prenatal development: an atlas 22. J. J. Nora, K. Berg, and A. H. Nora: Cardiovascullar disease: gentics, epidemiology, and prevention 24. A. E. H. Emery: Duchenne muscular dystrophy, second edition 25. E. G. D. Tuddenham and D. N. Cooper: The molecular genetics of haemostasis and its inherited disorders 26. A. Boue´: Foetalmedicine 30. A. S. Teebi and T. I. Farag: Genetic disorders among Arab populations 31. M. M. Cohen, Jr.: The child with multiple birth defects 32. W. W. Weber: Pharmacogenetics 33. V. P. Sybert: Genetic skin disorders 34. M. Baraitser: Genetics of neurological disorders, third edition 35. H. Ostrer: Non-mendelian genetics in humans 36. E. Traboulsi: Genetic diseases of the eye 37. G. L. Semenza: Transcription factors and human disease 38. L. Pinsky, R. P. Erickson, and R. N. Schimke: Genetic disorders of human sexual development 39. R. E. Stevenson, C. E. Schwartz, and R. J. Schroer: X-linked mental retardation 40. M. J. Khoury, W. Burke, and E. Thomson: Genetics and public health in the 21st century 41. J. Weil: Psychosocial genetic counseling 42. R. J. Gorlin, M. M. Cohen, Jr., and R. C. M. Hennekam: Syndromes of the head and neck, fourth edition 43. M. M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth syndromes 44. R. A. King, J. I. Rotter, and A. G. Motulsky: The genetic basis of common diseases, second edition 45. G. P. Bates, P. S. Harper, and L. Jones: Huntington’s disease, third edition 46. R. J. M. Gardner and G. R. Sutherland: Chromosome abnormalities and genetic counselling, third edition 47. I. J. Holt: Genetics of mitochondrial disease 48. F. Flinter, E. Maher, and A. Saggar-Malik: The genetics of renal disease 49. C. J. Epstein, R. P. Erickson, and A. Wynshaw-Boris: Inborn errors of development: the molecular basis of clinical disorders of morphogenesis 50. H. V. Toriello, W. Reardon, and R. J. Gorlin: Hereditary hearing loss and its syndromes, second edition 51. P. S. Harper: Landmarks in medical genetics 52. R. E. Stevenson and J. G. Hall: Human malformations and related anomalies, second edition

Human Malformations and Related Anomalies EDITED BY

Roger E. Stevenson

Judith G. Hall

Greenwood Genetic Center

University of British Columbia

Greenwood, South Carolina

Vancouver, British Columbia

ASSOCIATE EDITORS:

Kathleen K. Sulik

Edith Gilbert-Barness

University of North Carolina

Tampa General Hospital

School of Medicine

Tampa, Florida

Chapel Hill, North Carolina

ASSISTANT EDITOR:

Karen Kiernan Buchanan Greenwood Genetic Center Greenwood, South Carolina

1 2006

Second Edition

1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Copyright # 2006 by Oxford University Press, Inc. Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Human malformations and related anomalies / editors, Roger E. Stevenson . . . [et al.].—2nd ed. p. ; cm.—(Oxford monographs on medical genetics ; no. 52) Includes bibliographical references and index. ISBN-13: 978-0-19-516568-5 ISBN-10: 0-19-516568-3 1. Abnormalities, Human. I. Stevenson, Roger E., 1940–. II. Series. [DNLM: 1. Abnormalities. 2. Genetics, Medical. QS 675 H918 2005] QM691.H88 2005 616'.043—dc22 2004061661

The science of medicine is a rapidly changing field. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy do occur. The authors and publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is accurate and complete, and in accordance with the standards accepted at the time of publication. However, in light of the possibility of human error or changes in the practice of medicine, neither the authors, nor the publisher, nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete. Readers are encouraged to confirm the information contained herein with other reliable sources, and are strongly advised to check the product information sheet provided by the pharmaceutical company for each drug they plan to administer.

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Preface

O

ver a decade has separated the first and second editions of Human Malformations and Related Anomalies. This interval has been eventful from many standpoints. A major birth defects prevention strategy—periconceptional folic acid utilization—has proved effective in large-scale studies in several countries. New understandings of the genetic basis for malformations and malformation syndromes have emerged and made possible prenatal and postnatal laboratory diagnostic technologies. While molecular advances may be considered the most spectacular, significant advances in the biochemical and cytogenetic bases for malformations have also been impressive. The interval has brought us to the threshold of recognition of potential roles that epigenetic mechanisms, genomic changes, and disruption of molecular pathways exert on human development. During this interval, birth defects have maintained their position as the leading cause of infant mortality and a major contributor to childhood morbidity. The number and scope of birth defects surveillance programs have expanded, and collaboration among the programs is providing a picture of the epidemiology of birth defects worldwide. Increased understanding of the developmental biology of malformations and related anomalies has come primarily from the various branches of genetics. Recognition that inborn errors of cholesterol synthesis are associated with embryodysgenesis is but one of a number of contributions from biochemical genetics. The long biochemical pathway from mevalonic acid to cholesterol can be interrupted at virtually every step by enzyme errors, which leads to an astonishing array of birth defects. Smith-Lemli-Opitz syndrome (caused by a deficiency of 7-dehydrocholesterol reductase), congenital hemidysplasia and ichthyosiform erythroderma and limb defects (deficiency of sterol D8 D7 isomerase), and the Conradi-Hunermann type of chondrodysplasia punctata (deficiency of sterol D8 D7 isomerase) are the most common of the inborn errors of cholesterol metabolism. These biochemical deficiencies and others in the cholesterol pathway were all delineated during the past decade. Application of emerging laboratory technologies has permitted many malformations and malformation syndromes to be explained at the molecular level. Recognition that mutations in the sonic hedgehog gene (SHH) cause holoprosencephaly is typical. The discovery process involved a series of accomplishments.

First came putative localization of a holoprosencephaly gene on 7q36 based on chromosomal rearrangements found in some patients with holoprosencephaly. This localization permitted construction of a yeast artificial chromosome (YAC) contig across the 7q36 locus and definition of a critical region containing the holoprosencephaly gene. Testing of genes within and adjacent to the critical region identified SHH to be the causative gene. Less common, but of equal importance, has been the subsequent identification of other genes on other chromosomes that can also cause holoprosencephaly. This approach to positional cloning of genes that are associated with malformations has been repeatedly successful. Witness the identification of the mutations in several FGF receptors in association with craniosynostosis, mutations in FGFR3 in achondroplasia and related chondrodysplasias, mutations in the NIPBL gene in Cornelia de Lange syndrome, and mutations in the FGD1 gene in Aarskog syndrome, among others. The assignment of genes or gene loci has been most successful perhaps in relation to malformations and malformation syndromes involving the brain and skeleton. Mutations in five genes are associated with the craniosynostoses, mutations in 47 genes are associated with skeletal dysplasias, and mutations in 14 genes are associated with various malformations of the brain. Mutational analysis of many of these genes is currently available in clinical laboratories. Identification of the genes associated with cardiac, respiratory, gastrointestinal, and renal malformations has been less successful. Knowledge that microdeletion syndromes occur throughout the genome, and technologies to detect these microdeletions, have been major contributions from cytogenetics. These advances have permitted better delineation of the structural and neurobehavioral manifestations of many common syndromes such as velocardiofacial/DiGeorge, Williams, Smith-Magenis, Miller-Dieker, and other syndromes. Deletions and duplications in the chromosomal subtelomeric regions have become recognized as important causes of severe mental retardation. These subtelomeric alterations are in some cases accompanied by malformations. In 1993, the only laboratory diagnostic technology relevant to malformations was cytogenetics. And, while cytogenetics has maintained an important and expanding role in the study of malformations, biochemical genetics and molecular genetics have

vi

Preface

become more equal contributors. Numerous are the malformations caused by perturbations of well known (e.g., disorders of cholesterol synthesis) and newly delineated (e.g., congenital disorders of glycosylation) metabolic pathways. In similar fashion, molecular studies are now essential components of the armamentarium of diagnostic and management teams. As the second edition of Human Malformations and Related Anomalies goes to press, the influences of epigenetic phenomena on human development are just being explored. The apparent increased risk for Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Russell-Silver syndrome, and bladder/cloacal exstrophy in infants conceived by assisted reproductive technologies (ARTs) raises suspicion that adverse epigenetic influences may be responsible. To be sure, imprinting defects may underlie alterations in growth and childhood development, but the role as a cause of specific malformations is not clear. Fortunately, no new environmental disasters of the magnitude of prenatal rubella infection or thalidomide exposure have occurred in recent years. Initial concern that transplacental HIV infection might produce maldevelopment has not been realized. Still, on a lesser scale, the recognition of teratogenicity of misoprostol (a prostaglandin inhibitor), fluconazole (an antifungal agent), parvovirus (B19), and early chorionic villus sampling reminds us that hazards to the unborn infant lurk in the environment. Clearly, the most effective birth defects prevention strategy of the past decade has been the use of folic acid during the periconceptional period to prevent neural tube defects. Although the protective effect of folic acid against NTDs was reported by Richard Smithells as early as 1981, it took randomized case-control studies by Great Britain’s Medical Research Council and by Andrew Czeizel in Hungary to convince medical and scientific communities of its efficacy. Increased folic acid concentration in the periconceptional period is now widely advocated for prevention of neural tube defects, and the recommendation has been advanced by decisions in several countries to fortify cereal grain flours. Evidence that folic acid also has a protective effect against other birth defects has been reported, although the magnitude of the protective effect appears to be less than for NTDs. To date, no compelling explanation for the mechanism by which folic acid conveys its protective effect against birth defects has been found. Equally obvious are the disappointments of the past decade. Additional prevention partners to take their places with folic acid have not been identified. Nor has an educational or other strategy been implemented to make significant progress in preventing pervasive teratogen exposures such as alcohol and other drug use during pregnancy. A litany of genes associated with malformations in lower animals has not been relevant to the same malformations in humans. For example, over 60 gene mutations that led to neural tube defects in mice have been identified, and in not a single instance has the homologous gene in humans been found to harbor mutations that cause human neural tube defects. Neither have examples of the much touted concept of gene—environment interactions as the basis for birth defects been found. And most disappointing, as mentioned before, has been the persistence of malformations as the leading cause of infant mortality. As we anticipated during the writing of Edition 1, the application of emerging technologies of molecular biology and developmental genetics would significantly advance the understanding

of normal and abnormal embryonic and fetal development during the ensuing decade. These research advances, continuing observations by clinicians, more comprehensive and accurate epidemiology, and new diagnostic and prevention capabilities related to birth defects called for a substantially revised edition. Human Malformations and Related Anomalies is intended to provide a body of information on individual anomalies and to connect the anomalies to malformation syndromes, primarily through the use of differential diagnostic tables. A central goal is to consider each significant human anomaly from the perspective of the clinician and in the context of the current understanding of embryonic and fetal development. What is the nature of the anatomical defect? What related anomalies and syndromes must be considered? What are the appropriate treatment and prevention strategies? Edition 2 of Human Malformations and Related Anomalies is presented in a single volume. A portion of the information in Volume 1 of Edition 1 has been condensed into an introductory chapter. Thereafter follow 34 chapters that provide detailed accounts of anomalies arranged by anatomical systems, as in Edition 1. The format of these chapters has been revised somewhat to more consistently reflect the relevant embryology, epidemiology, molecular insights, and animal studies. The occurrence of each anomaly in various associations and syndromes is documented. The natural history, approaches to treatment, and prevention strategies are given in the final subsection of each entry. Acknowledgments

Edition 2 of Human Malformations and Related Anomalies has had the benefit of the editorial touches of associate and assistant editors. Kathy Sulik took responsibility for giving a consistent and contemporary view of the human embryology relevant to each section. Enid Gilbert-Barness edited the entries from a pathology perspective. Karen Buchanan attended to the myriad details necessary to facilitate communications between the authors and editors, organize the contents, and adhere to the schedule. To these colleagues and to each of the 42 contributing authors, we are indebted. Rachel Collins, Librarian at the William A. Klauber and Betty Jane Klauber Genetics Library, has provided searches, citation verification, and reprints. Patti Broome assisted in preparation and organization of the final manuscript copy. Preparation of Edition 2 of Human Malformations and Related Anomalies has given us the pleasure of working again with Jeffrey House and Edith Barry at Oxford University Press. They have been helpful, encouraging, and accessible throughout the process. Similar support has come from our clinical and laboratory colleagues at the Greenwood Genetic Center and the University of British Columbia. Appreciation is expressed to the host of clinicians and researchers worldwide who, through their observations and laboratory findings, have contributed new knowledge and insights sufficient to warrant production of the current edition. Participants in the David W. Smith Workshop on Malformations and Morphogenesis have been continual sources of information and insight. Their innumerable contributions to this edition are gratefully acknowledged. R. E. S. J. G. H.

Contents

Contributors

3. Systemic Vasculature

xiii

121

Lynne M. Bird and Kenneth Lyons Jones

Part I—Overview 1. Human Malformations and Related Anomalies

3

Roger E. Stevenson

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8

Nomenclature 6 Classification and Coding 13 Genetic Causes of Malformations 14 Gene Mutations and Malformations 22 Environmental Causes of Malformations 33 Human Anomalies with Unknown Causes 58 Detection, Diagnosis, Evaluation, Management 58 Discussions with the Family 71

Part II—Cardiorespiratory Organs

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.15

Interrupted Aortic Arch 121 Right Aortic Arch 123 Cervical Aortic Arch 125 Double Aortic Arch 125 Double-Lumen Aortic Arch 126 Incidental Anomalies of the Aortic Arch 127 Innominate Artery Variants 128 Subclavian Artery Variants 129 Patent Ductus Arteriosus 130 Coarctation of the Aorta 133 Persistent Left Superior Vena Cava 136 Inferior Vena Cava Variants 137 Miscellaneous Venous Variants 138 Deep Vein Abnormalities 139 Vascular Malformations 140

4. Lymphatic System

145

Judith E. Allanson

2. Heart

85

Angela E. Lin, John Belmont, and Sadia Malik

2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14

Heterotaxy 93 Single Ventricle 96 Conotruncal Defects 97 Atrioventricular Septal Defects 101 Right Ventricular Outflow Tract Obstructive Defects 103 Left Ventricular Outflow Tract Obstructive Defects 106 Atrial Septal Defects 112 Ventricular Septal Defects 113 Anomalies of the Pulmonary Veins 115 Abnormal Systemic Venous Connections 117 Anomalies of the Ductus Arteriosus 118 Aortopulmonary Window (Aortopulmonary Septal Defect) 119 Anomalies of the Coronary Arteries 119 Anomalies of the Pericardium 120

4.1 4.2 4.3 4.4 4.5

Primary Lymphatic Anomalies 146 Pulmonary Lymphangiectasia 161 Fetal Cystic Hygroma 163 Lymphangioma 169 Lymphangioleiomyomatosis 180

5. Spleen

183

Arthur S. Aylsworth

5.1 5.2 5.3

Polyasplenia 185 Positional Alterations of the Spleen 195 Accessory Spleens, Structural Variation, and Fusion to Other Organs 196

6. Lower Respiratory Organs

201

Laurie H. Seaver

6.1 6.2 6.3 6.4 6.5

Bifid Epiglottis 201 Laryngeal Atresia, Webs, and Stenosis Laryngotracheoesophageal Cleft 205 Tracheal Agenesis 206 Tracheal Stenosis 207

202

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Contents

6.6 6.7 6.8 6.9 6.10 6.11 6.12

Congenital Tracheal Cartilaginous Sleeve 209 Tracheoesophageal Fistula 209 Pulmonary Agenesis/Aplasia 209 Congenital Cystic Adenomatoid Malformation 211 Congenital Lobar Emphysema 213 Primary Pulmonary Hypoplasia 213 Congenital Diaphragmatic Hernia 214

9.11 Congenital Cataracts 316 9.12 Persistent Hyperplastic Primary Vitreous or Persistence of the Fetal Vasculature 318 9.13 Optic Nerve Hypoplasia 320 9.14 Morning Glory Disc Anomaly 322 9.15 Optic Pit 324 10. Ear

327

John C. Carey

Part III—Craniofacial Structures External Ear 7. Skull

221

John M. Graham, Jr.

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22

Craniosynostosis 221 Kleeblattscha¨del 235 Wide Cranial Sutures 237 Anomalies of Fontanels 238 Cranial Dermal Sinus 242 Parietal Foramina (Includes Cranium Bifidum) 243 Wormian Bones 245 Scalp Vertex Aplasia 246 Thin Cranial Bones 248 Undermineralization of the Skull 248 Craniotabes 249 Thick Cranial Bones 251 Sclerosis and Hyperostosis of the Skull 254 Vertex Birth Molding 254 Breech Head (Bathrocephaly) 257 Other Cranial Deformations Due to Abnormal Fetal Presentation 258 Anomalies of the Sella Turcica 259 Anomalies of Foramen Magnum 260 Anomalies of the Other Basal Foramina and Canals 261 Basilar Impression 261 Cephalhematoma and Caput Succedaneum 262 Miscellaneous Anomalies of the Skull 264

8. Facial Bones

267

Karen Gripp and Luis Fernando Escobar

8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 9. Eye

Premature Metopic Sutural Synostosis 268 Orbital Hypotelorism 270 Orbital Hypertelorism 273 Midline Facial Skeletal Clefting 278 Absence and Hypoplasia of the Zygoma 280 Midface Retrusion and Hypoplasia 283 Agnathia 287 Micrognathia 288 Congenital Asymmetry of the Facial Skeleton 292

Anophthalmia 299 Microphthalmia and Typical Uveal Coloboma Cyclopia and Synophthalmia 302 Cryptophthalmos 303 Blepharophimosis 305 Other Anomalies of the Eyelids 306 Congenital Corneal Anomalies 309 Anterior Segment Dysgenesis 311 Peters Anomaly 313 Hypoplasia of the Iris (Aniridia) 314

10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 10.21

Microtia/Anotia 331 Small Ear 335 External Auditory Canal Stenosis and Atresia Without Microtia 336 Cryptotia 338 Large Ear (Macrotia) 338 Polyotia 339 Duplication of the External Auditory Meatus 340 Synotia/Otocephaly 340 Low-set Ears 342 Posteriorly Rotated Ears 344 Lop/Cup Ear Anomaly 344 Protruding Ear 346 Stahl Ear 348 Mozart Ear 349 Darwinian Tubercle 350 Prominent Crus of the Helix 350 Lobular Defects 350 Auricular Tags 351 Auricular Pits 353 Ear Lob Creases/Pits 355 Deformation of the Auricle 356

Middle Ear

356

John C. Carey and Albert H. Park

10.22 Hypoplasia/Aplasia/Malformation of the Malleus 358 10.23 Fusion Defects of the Malleus 359 10.24 Hypoplasia/Aplasia/Malformation of the Incus 361 10.25 Fusion Defects of the Incus 362 10.26 Hypoplasia/Aplasia/Malformation of the Stapes 362 10.27 Congenital Fixation of the Stapes 363 10.28 Absence of the Oval Window 364 10.29 Congenital Cholesteatoma 364 10.30 Persistence of the Stapedial Artery 365 10.31 Highly Placed Jugular Bulb 365 Inner Ear 366 Daryl A. Scott and John C. Carey

297

Elias I. Traboulsi

9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10

329

John C. Carey, Albert H. Park, and Harlan R. Muntz

10.32 Vestibular Dysplasias 366 10.33 Prelingual Hearing Loss 369 300

11. Nose

373

M. Michael Cohen, Jr.

11.1 11.2 11.3 11.4 11.5 11.6

Arhinia 374 Unilateral Arhinia, Heminasal Aplasia Small Nose 375 Nostril Coloboma 376 Bifid Nose 376 Nostril Atresia 377

374

Contents

11.7 11.8 11.9 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 12. Lips

Choanal Atresia 377 Polyrrhinia 378 Proboscis 378 Noses of Distinction 381 Deviation of the Nasal Septum 386 Turbinate Deformity 386 Arrhinencephaly 386 Hemangioma of the Nose 386 Dermoid Cyst of the Nose 388 Glioma of the Nose 388 Encephalocele Involving the Nose 388 391

Marilyn Jones

12.1 12.2 12.3

Median Cleft Lip 393 Cleft Lip With or Without Cleft Palate (CL/P) 394 Cleft Palate 400

13. Tongue

ix

14.6 14.7 14.8 14.9 14.10

13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13

13.14 13.15 13.16 13.17 13.18 13.19 13.20 13.21 13.22 14.

Teeth

425

Rena N. D’Souza, Hitesh Kapadia, and Alexandre R. Vieira

14.1 14.2 14.3 14.4 14.5

Tooth Agenesis 431 Supernumerary Teeth 444 Microdontia 446 Macrodontia 451 Abnormalities of Tooth Shape 452

469

15. Brain

Alasdair G. W. Hunter

15.1 15.2 15.3 15.4 15.5

405

Aglossia, Hypoglossia, Microglossia 406 Absence of Lingual Frenulum 406 Macroglossia 407 Bifid Tongue 408 Fissured Tongue, Scrotal Tongue, Lingua Plicata 408 Glossopalatine Ankylosis (Ankyloglossum Superius) 409 Ankyloglossia: Tongue-tie, Partial Ankyloglossia, Total and Lateral Ankyloglossia 410 Median Rhomboid Glossitis 411 Double Tongue 412 Lingual Thyroid 413 Choristoma of Tongue: Enterogenous Cyst of Tongue 414 Choristoma of Tongue: Epidermoid Cyst of Tongue 416 Choristoma of Tongue: Cyst Lined with Respiratory Epithelium or Nonciliated Columnar Epithelium 416 Choristoma of Tongue: Brain Tissue in Tongue 416 Choristoma of Tongue: Chondroma and Osteoma 417 Congenital Dermoid Cyst 418 Hamartoma: Lymphangioma of the Tongue 419 Hamartoma of the Tongue: Hemangioma 420 Hamartoma of the Tongue: Mixed Type (Mesenchymoma) 420 Congenital Teratoma 421 Abnormal Tongue Movements and Excessive Mobility of the Tongue 421 Pigmented Fungiform Papillae and Other Lingual Pigmentations 423

463

Part IV—Neuromuscular Systems

Robert J. Gorlin

13.1 13.2 13.3 13.4 13.5

Dental Malocclusion 456 Enamel Dysplasia 458 Dentin Dysplasia 461 Cementum Dysplasia 463 Abnormalities of Tooth Eruption

15.6 15.7 15.8 15.9 15.10 15.11 15.12 15.13 15.14

Microcephaly 470 Megalencephaly 511 Aprosencephaly/Atelencephaly 525 Holoprosencephaly 528 Malformations of Cortical Development: Disorders of Neuronal and Glial Formation, Migration, and Maturation; Lissencephaly, Pachygyria, Polymicrogyria, Heterotopias, Ectopias, and Cortical Dysplasias 546 Agenesis of the Corpus Callosum 581 Cavum, Cysts, and Absence of the Septum Pellucidum and Cavum Vergae 604 Hydrocephalus 610 Colpocephaly 636 Hydranencephaly 639 Porencephaly 645 Cerebellar Anomalies 654 Cystic Malformations 677 Chiari Malformations 700

16. Brain and Spinal Cord

715

Alasdair G. W. Hunter

16.1

Disorders of Neural Tube Closure

17. Spinal Cord

715

757

Alasdair G. W. Hunter

17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8

Primary Tethered Cord 757 Neurenteric Malformations 762 Intraspinal (Nonneurenteric) Cysts 764 Syringomyelia 768 Split Cord Malformation (Diastematomyelia) and Diplomyelia 773 Myelocystocele 776 Anterior and Lateral Meningoceles 778 Tailgut Cyst 782

18. Muscle

783

Judith G. Hall

18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9

Generalized Abnormalities of Muscle Mass: Increased Muscle Mass 786 Generalized Abnormalities of Muscle Mass: Decreased Muscle Mass 788 Localized Abnormalities of Muscle 790 Aglossia 791 Facial Muscle Deficiency 791 Asymmetric Crying Facies 791 Deficiency of Eye Muscles 792 Deficiency of Esophageal Muscles 792 Defects of Pectoralis Muscles and Other Muscles of the Shoulder Girdle 793

x

Contents

18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 18.18

Poland Anomaly 794 Poland-Mo¨bius Syndrome 795 Poland-Like Gluteal-Lower Leg Anomaly 796 Prune Belly Syndrome 797 Isolated Deficiency of Abdominal Muscles 799 Diaphragmatic Defects 799 Variations with Accessory Muscle Tissue 800 Muscle Atavisms 800 Muscle Abnormalities Associated with Chromosomal Disorders 801

21. Hands and Feet

935

David B. Everman

21.1 21.2 21.3 21.4

The The The The

Polydactylies 937 Syndactylies 954 Brachydactylies 968 Oligodactylies 984

22. Skeletal Dysplasias

997

Ju¨rgen Spranger

Part VI—Gastrointestinal and Related Structures Part V—Skeletal System 23. Ventral Wall of the Trunk 19. Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

805

Louanne Hudgins and Keith Vaux

19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 19.19 19.20 19.21 19.22 20. Limbs

Clavicular Hypoplasia/Aplasia 806 Clavicular Pseudarthrosis 807 Altered Shape and Other Abnormalities of the Clavicle 807 Sprengel Anomaly 807 Glenoid Hypoplasia 809 Anomalies of the Sternum 810 Pectus Excavatum/Pectus Carinatum 811 Rib Anomalies 812 Cervical Rib 813 Occipitalization of the Atlas 813 Aplasia/Hypoplasia of the Odontoid Process of the Axis 818 Segmentation/Formation Defects of the Vertebrae 819 Klippel-Feil Anomaly 821 Altered Vertebral Body Contour 823 Sagittal Clefts of the Vertebrae 825 Coronal Clefts of the Vertebrae 826 Spondylolysis and Spondylolisthesis 827 Sacral Agenesis 829 Anomalies of the Pelvic Bones 830 Developmental Dysplasia of the Hip 830 Coxa Vara 833 Coxa Valga 833 835

23.1 23.2 23.3

23.4 23.5 23.6 23.7 23.8

Sternal Defects 1025 Ectopia Cordis, Including Cantrell Pentalogy The Umbilicus: Congenital Anomalies and Variations in Configuration and Placement 1028 Umbilical Hernia 1031 Omphalocele 1034 Gastroschisis 1038 Exstrophy of the Bladder 1042 Exstrophy of the Cloaca 1046

Breasts

1049

23.9 23.10 23.11 23.12 23.13 23.14 23.15

Amastia and Hypomastia 1051 Enlarged Breasts 1053 Symmastia 1055 Supernumerary Breasts and Nipples Widely Spaced Nipples 1058 Gynecomastia 1059 Premature Thelarche 1063

24. Upper Gastrointestinal System

Pharynx 24.1

1065

24.2

1067

Fistulas, Sinuses, and Cysts: Branchial Clefts and Pouches 1069 Congenital Pharyngeal Diverticula 1071

Esophagus 24.3

Judith G. Hall

1055

H. Eugene Hoyme

20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 20.9 20.10 20.11 20.12 20.13 20.14

1027

Ellen Boyd and Roger E. Stevenson

Roger E. Stevenson

Limb Deficiencies 839 Synostosis 856 Constriction Rings 871 Duplications, Excessive Partitions, and Accessory Bones 876 Bowing of Long Bones 882 Short Stature 894 Tall Stature 900 Limb Overgrowth 902 Increased Bone Density 910 Decreased Bone Density 914 Osteolysis 916 Anomalies of the Patella 919 Hypermobile Joints 922 Arthrogryposis (Multiple Congenital Contractures) 925

1023

Cynthia Curry, Ellen Boyd, and Roger E. Stevenson

1071

Esophageal Stenosis, Atresia, and Tracheoesophageal Fistula 1073 24.4 Esophageal Webs and Rings 1076 24.5 Tubular Esophageal Duplications 1077 24.6 Enterogenous Cysts 1077 24.7 Esophageal Diverticula 1078 24.8 Heterotopic Gastric Mucosa in the Esophagus 1079 24.9 Congenital Short Esophagus 1079 24.10 Achalasia 1079 24.11 Chalasia 1080 Stomach 24.12 24.13 24.14 24.15

1081

Infantile Hypertrophic Pyloric Stenosis 1082 Microgastria 1084 Atresia and Stenosis of the Stomach 1084 True Diverticula of the Stomach 1085

Contents

24.16 24.17 24.18 24.19

Duplication of the Stomach 1086 Defects of Gastric Musculature 1086 Malposition of the Stomach 1087 Mucosal Heterotopia 1088

Duodenum

1089

24.20 24.21 24.22 24.23 24.24 24.25

Malrotation of the Duodenum 1090 Duodenal Stenosis and Atresia 1090 Duodenal Duplications 1092 Duodenal Diverticula 1093 Congenital Aganglionic Duodenum 1094 Extrinsic Vascular Obstruction of the Duodenum 1095 24.26 Congenital Paraduodenal Hernia through a Peritoneal Defect 1095

xi

28.6 28.7 28.8 28.9 28.10 28.11 28.12 28.13 28.14 28.15 28.16 28.17

Renal Dysplasia 1205 Familial Nephronophthisis/Medullary Cystic Disease 1215 Medullary Sponge Kidney 1217 Renal Cystic Disease Secondary to Obstruction Supernumerary Kidney 1222 Renal Ectopia 1223 Horseshoe Kidney 1228 Anomalies of the Bladder and Ureters 1232 Urachal Anomalies 1234 Urethral Agenesis or Atresia 1237 Posterior Urethral Valves and Urethral Stenosis 1241 Urethral Duplication 1247

29. Male Genital System 25. Small and Large Intestines

1097

Intestinal Agenesis 1099 Intestinal Atresia/Stenosis 1099 Duplications and Cysts 1103 Megacolon 1105 Malrotation 1109 Meckel Diverticulum 1111 Polyps 1111 Vascular Anomalies 1114

26. Rectum and Anus

1115

Cathy A. Stevens

26.1 26.2

Atresia of the Rectus and Anus Rectal Duplication 1122

27. Liver, Gallbladder, and Pancreas

1116

1123

Ian D. Krantz and Arthur S. Aylsworth

27.1 27.2 27.3

Anomalies of Liver Shape and Lobation 1127 Liver Dysplasia/Ductal Plate Malformations 1131 Intrahepatic Biliary Duct Atresia and Hypoplasia 1136 27.4 Agenesis of the Gallbladder 1139 27.5 Extrahepatic Biliary Atresia 1142 27.6 Cysts of the Biliary System 1145 27.7 Structural Variation and Miscellaneous Anomalies of the Gallbladder and Extrahepatic Ducts 1147 27.8 Pancreatic Agenesis 1150 27.9 Structural Variation and Anomalies of the Pancreas 1150 27.10 Pancreatic Cysts and Dysplasias 1154 27.11 Pancreatic Ectopia and Heterotopia 1157 Part VII—Urogenital System Organs 28. Urinary Tract

1161

Jane A. Evans

28.1 28.2 28.3 28.4 28.5

1251

Rick A. Martin

Eberhard Passarge and Roger E. Stevenson

25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8

1219

Renal Agenesis 1184 Renal Hypoplasia 1190 Cystic Diseases 1194 Autosomal Recessive (Infantile) Polycystic Kidney Disease 1197 Autosomal Dominant Polycystic Kidney Disease 1200

29.1 29.2 29.3 29.4 29.5 29.6 29.7 29.8 29.9 29.10 29.11 29.12 29.13 29.14 29.15 29.16 29.17 29.18

Micropenis 1255 Hypospadias 1258 Epispadias 1261 Hidden or Concealed Penis 1262 Megalourethra 1263 Diphallia 1264 Aphallia 1265 Penoscrotal Transposition 1265 Ectopic/Accessory Scrotum 1267 Cryptorchidism 1267 Microorchia/Anorchia/Agonadism 1268 Polyorchidism (Supernumerary Testes) 1271 Ectopic Testis 1272 Male Pseudohermaphroditism and 46,XY Sex Reversal 1272 Wolffian Duct Malformations 1276 Persistent Mu¨llerian Ducts 1276 Splenogonadal Fusion 1277 Inguinal Hernia 1277

30. Female Genital System

1279

Leah W. Burke

30.1 Ovarian Dysgenesis 1281 30.2 Mixed Gonadal Dysgenesis 1284 30.3 Hermaphroditism 1286 30.4 Ambiguous Genitalia 1287 30.5 Mu¨llerian Aplasia 1291 Isolated Anomalies of the Mu¨llerian Structures 1294 30.6 Absence of the Fallopian Tube 1294 30.7 Incomplete Mu¨llerian Fusion 1294 30.8 Cervical Atresia 1297 30.9 Vaginal Atresia 1298 30.10 Transverse Vaginal Septum 1299 30.11 Longitudinal Vaginal Septum 1300 30.12 Agenesis of the Clitoris 1300 30.13 Isolated Hypertrophy of the Clitoris/Clitoromegaly 1301 30.14 Duplication or Bifidism of the Clitoris/Female Epispadias 1302 30.15 Labial Fusion 1303 30.16 Imperforate Hymen 1303 30.17 Absence/Hypoplasia of External Genitalia 1303 30.18 Hyperplasia, Duplication, and Inversion of External Genitalia 1304

xii

Contents

Part VIII—Other Systems and Structures 31. Cutaneous Structures

1307

Julie S. Prendiville

31.1

Skin Cysts, Sinuses, Dimples, Tags, Tails, and Clefts 1309 31.2 Aplasia Cutis Congenita 1311 31.3 Mosaicism and the Lines of Blaschko 1312 31.4 Cutaneous Hamartomas 1315 31.5 Disorders of Keratinization 1319 31.6 Epidermolysis Bullosa 1319 31.7 Developmental Disorders of Connective Tissue 1321 31.8 Vascular Malformations 1322 31.9 Pigmentation Anomalies 1329 31.10 Malformations of the Epidermal Appendages 32. Endocrine Organs

1333

35. Umbilical Cord

1339

32.3 32.4 32.5 32.6 32.7 32.8 32.9

Congenital Adrenal Hyperplasia 1346 Anterior Pituitary, Hypothalamus, and Disorders of Short Stature 1349 Parathyroid Gland: Calcium Sensing Receptor Defects 1353 Parathyroid Gland: Albright Hereditary Osteodystrophy 1353 Posterior Pituitary and Water Metabolism 1354 Thyroid and Thyroid Biosynthetic Defects 1354 Endocrine Tumor Syndromes 1355 Mendelian Disorders with Endocrine Abnormalities 1356 Chromosomal Disorders with Endocrine Features 1357

33. Asymmetry and Hypertrophy

1359

Omar Abdul-Rahman and H. Eugene Hoyme

33.1 33.2

Laterality Sequences 1361 Kartagener Syndrome 1363

Patterns of Asymmetric Growth 33.3 33.4 33.5 34. Twins

1413

Will Blackburn and Nelson Reede Cooley, Jr.

Amy Potter and John A. Phillips III

32.1 32.2

Incidence of Twinning 1382 Causes of Twinning 1383 Sex Ratio 1383 Growth 1384 Spontaneous Abortions 1385 Vanishing Twin 1385 Fetus Papyraceus 1388 Perinatal Morbidity and Mortality 1389 Vascular Anastomoses in Twin Placentas 1390 Twin–Twin Transfusion Syndrome 1391 Acardia 1394 Conjoined Twins 1396 Structural Defects 1401 Mirror Image Twinning 1404 Discordance 1404 Caution for Complex Disorders 1404

1365

Hemihyperplasia (Hemihypertrophy) 1366 Hemihypoplasia and Hemiatrophy 1369 Generalized Overgrowth 1372 1377

Mary C. Phelan and Judith G. Hall

Zygosity and Placentation 1377 Polar Body Twinning 1380 Animal Models of Twinning 1380 Determination of Zygosity 1381

35.1 35.2 35.3 35.4 35.5 35.6 35.7 35.8 35.9 35.10 35.11 35.12 35.13 35.14 35.15 35.16 35.17 35.18 35.19 35.20 35.21

Umbilical Cord Calcifications 1417 Umbilical Cord Amnion (Inclusion) Cysts 1418 Umbilical Cord Cysts and Remnant Anomalies of Allantoic Duct Origin 1419 Umbilical Cord Cysts and Remnants of Vitelline (Omphalomesenteric Duct) Origin 1421 Umbilical Cord Pseudocyst (Cystic Mucoid Degeneration) 1424 Umbilical Cord Disruption (Linear) 1425 Umbilical Cord Dimensional Abnormalities 1426 Umbilical Cord-to-Cord Entanglements 1434 Umbilical Cord Hematoma 1436 Umbilical Cord Hernia 1437 Anomalies of Umbilical Cord Insertion 1439 Umbilical Cord Knots 1441 Umbilical Cord Loops (‘‘Encirclement’’) 1443 Umbilical and Umbilical Cord Polyp 1445 Abnormalities of Umbilical Cord (Abdominal Wall) Position 1448 Antenatal Separation of the Umbilical Cord 1449 Abnormalities of Postnatal Umbilical Cord Separation 1450 Umbilical Cord Torsion (Twist) Abnormalities 1451 Umbilical Cord Helical Ulceration 1453 Umbilical Cord Neoplasms 1454 Vascular Anomalies of the Umbilical Cord 1457

Index to Tables of Malformations and Associated Syndromes 1473 Subject Index

1477

Contributors

Omar Abdul-Rahman, M.D. Division of Medical Genetics Department of Pediatrics Stanford University School of Medicine Stanford, California Judith E. Allanson, M.D. Children’s Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario, Canada Arthus S. Aylsworth, M.D. Department of Pediatrics University of North Carolina Chapel Hill, North Carolina John Belmont, M.D., Ph.D. Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas Lynne M. Bird, M.D. Department of Dysmorphology and Genetics Children’s Hospital San Diego, California

M. Michael Cohen, Jr., D.M.D., Ph.D. Oral and Maxillofacial Sciences Dalhousie University Halifax, Nova Scotia, Canada Cynthia Curry, M.D. Genetic Medicine Central California Fresno, California Department of Pediatrics University of California, San Francisco San Francisco, California Rena N. D’Souza, D.D.S., Ph.D. Department of Orthodontics, Dental Branch University of Texas Health Science Center Houston, Texas Luis Fernando Escobar, M.D. Medical Genetics and Developmental Pediatrics St. Vincent Hospital of Indianapolis Indianapolis, Indiana

Will Blackburn, M.D. Fairhope, Alabama

Jane A. Evans, Ph.D. Department of Biochemistry and Medical Genetics University of Manitoba Winnipeg, Manitoba, Canada

Ellen Boyd, M.D. Fullerton Genetics Center Asheville, North Carolina

David B. Everman, M.D. Greenwood Genetic Center Greenwood, South Carolina

Leah W. Burke, M.D. Division of Clinical Genetics University of Vermont College of Medicine Burlington, Vermont

Robert J. Gorlin, D.D.S., D.Sc. University of Minnesota School of Dentistry Minneapolis, Minnesota

John C. Carey, M.D. Division of Medical Genetics University of Utah Salt Lake City, Utah

John M. Graham, Jr., M.D., Sc.D. Medical Genetics Institute Steven Spielberg Pediatric Research Center David Geffen School of Medicine at UCLA Cedars Sinai Medical Center Los Angeles, California

xiii

xiv

Karen Gripp, M.D. DuPont Hospital for Children Wilmington, Delaware Judith G. Hall, M.D. Departments of Medical Genetics and Pediatrics UBC and Children’s and Women’s Health Centre of British Columbia Vancouver, British Columbia, Canada H. Eugene Hoyme, M.D. Division of Medical Genetics, Department of Pediatrics Stanford University School of Medicine Stanford, California Louanne Hudgins, M.D. Division of Medical Genetics, Department of Pediatrics Stanford University School of Medicine Stanford, California Alasdair G.W. Hunter, M.D. Children’s Hospital of Eastern Ontario Ottawa, Ontario, Canada Kenneth Lyons Jones, M.D. Division of Dysmorphology/Teratology University of California San Diego, California Marilyn Jones, M.D. Children’s Hospital San Diego, California Hitesh Kapadia, D.D.S. Department of Orthodontics University of Texas Health Science Center Houston, Texas Ian D. Krantz, M.D. Division of Human Genetics and Molecular Biology The Children’s Hospital of Philadelphia The University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Angela E. Lin, M.D. Genetics and Teratology Unit Massachusetts General Hospital Boston, Massachusetts Sadia Malik, M.D. Department of Cardiology Arkansas Children’s Hospital Little Rock, Arkansas

Contributors

Eberhard Passarge, M.D. Institit fu¨r Humangenetik Universita¨tklinikum Essen, Germany Mary C. Phelan, Ph.D. T.C. Thompson Children’s Hospital Chattanooga, Tennessee John A. Phillips III, M.D. Division of Medical Genetics Department of Pediatrics Vanderbilt University School of Medicine Nashville, Tennessee Amy Potter, M.D. Division of Endocrinology and Metabolism Department of Medicine Vanderbilt University School of Medicine Nashville, Tennessee Julie S. Prendiville, M.B. British Columbia’s Children’s Hospital University of British Columbia Vancouver, British Columbia, Canada Daryl A. Scott, M.D., Ph.D. Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas Laurie H. Seaver, M.D. Greenwood Genetic Center Greenwood, South Carolina Ju¨rgen W. Spranger, M.D. Greenwood Genetic Center Greenwood, South Carolina Cathy A. Stevens, M.D. Department of Pediatrics University of Tennessee College of Medicine Chattanooga, Tennessee Roger E. Stevenson, M.D. Greenwood Genetic Center Greenwood, South Carolina Elias I. Traboulsi, M.D. Division of Ophthalmology Cleveland Clinic Foundation Cleveland, Ohio

Rick A. Martin, M.D. St. Louis Children’s Hospital, Medical Genetics Washington University St. Louis, Missouri

Keith Vaux, M.D. Department of Pediatrics Division of Dysmorphology University of California, San Diego San Diego, California

Harlan R. Muntz, M.D. Department of Otolaryngology University of Utah Health Sciences Center Salt Lake City, Utah

Alexandre R. Vieira, D.D.S., Ph.D. Department of Pediatrics University of Iowa Iowa City, Iowa

Albert H. Park, M.D. Department of Otolaryngology University of Utah Health Sciences Center Salt Lake City, Utah

Part I Overview

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1 Human Malformations and Related Anomalies Roger E. Stevenson

M

alformations result from pathologic processes during the embryonic period. The pathologic processes may be inborn, extrinsic, or some combination of the two. There is a narrow period of vulnerability during which developmental processes may be affected adversely, since most human body structures are formed between the second and the eighth weeks of development. Some organs, such as the brain, continue to develop throughout fetal life and even after birth. The small period of vulnerability notwithstanding, a remarkably large number of conceptuses, perhaps the majority, fall victim to disturbances in normal developmental processes. In most instances, the malformed conceptuses or embryos fail to implant or die following implantation.1–17 A minority of these conceptuses continue to develop, but will result in infants born with malformations. In this book, the phrase ‘‘malformations and related anomalies’’ encompasses all types of fetal and embryonic processes that lead to the presence of structural anomalies at birth. In addition to those processes that interfere with normal formation of structures (malformations), there are disruptions (in which normally developing structures are damaged by in utero forces such as vascular accidents or amniotic bands), deformations (in which a normal structure is misshaped by internal or external mechanical forces), and dysplasias (in which cell structure, cell arrangement in tissue, or tissues are disorganized). Among liveborn infants, 2–3% will have major malformations that are detected at birth or in the initial weeks or months of life (Tables 1-1 and 1-2).18–29 Some major malformations escape early detection, but these covert malformations are usually found by age 5 years and equal the number (2–3%) found at birth.30 Some internal malformations fail to cause physiologic disturbance and may be found only incidentally during surgery, scans, radiographs, or autopsy. Among stillborn infants, 15–20% will have major malformations.31–34 An even higher rate of malformations is to be found among spontaneous abortions. All anatomic structures appear to be susceptible to malformations. The frequency with which different structures are The author gratefully acknowledges the contributions of Judith G. Hall, Patrick M. MacLeod, Dagmar Bauer-Hansmann, Mitchell S. Golbus, Richard J. Schroer, Robert A. Saul, and Golder N. Wilson to volume 1 of the first edition of Human Malformations and Related Anomalies, on which this Introduction is based.

found postnatally to be malformed varies significantly, depending to a significant degree on the physiologic impact of the malformation prenatally. Table 1-1 gives the birth prevalence for malformations of the major anatomic structures.22,23,35 Certain birth defects appear to be increasing (e.g., hypospadias and coarctation of the aorta), whereas others are declining in prevalence (e.g., neural tube defects and renal agenesis). Wide fluctuations in prevalence are seen in different locations around the world.35 Nowhere in medicine is a sympathetic and discerning ear more important than in the evaluation of the infant with a birth defect. The family may be devastated by the announcement that the anticipated ‘‘perfect baby’’ has or may have a significant defect. More and more often the anomaly is recognized prenatally. The evaluation must begin at the time the defect is recognized or suspected, although full evaluation may be postponed in some infants until birth or until the infant can be evaluated at a tertiary center if the anomaly is not life threatening. The ideal situation with non– life-threatening defects is that parent–infant bonding proceed without interruption and the infant be discharged from the hospital with the mother. In other circumstances, evaluation must be carried out more urgently. Certain anomalies, particularly cardiac and gastrointestinal anomalies, are potentially lethal if not treated immediately. Other lethal conditions for which no treatment is available need urgent diagnosis to plan appropriate management with the family. Some anomalies may not be life threatening, but evaluation is no less urgent. Notable among these is ambiguous genital development. Malformations have emerged as the most common cause of death during the first year of life in developed countries.36–38 With a preplanned protocol, evaluation of the infant with anomalies who dies can be carried out efficiently and with sensitivity to the family. The protocol should include complete examination, storage of appropriate samples (serum, urine, tissues), photographs, radiographs, and necropsy.39,40 Abortuses and stillborn infants can be evaluated under a similar protocol. Only with knowledge of the nature of the anomalies can accurate information on the cause of death and risk of recurrence be provided for the family. Clinicians attempt to assign causation in all human anomalies for the purpose of gaining a secure foundation for counseling and consideration of future preventive efforts. As desirable 3

Table 1-1. Prevalence of selected major malformations USA: Atlanta*

USA: California{

Canada{

High Prevalence Regionsx

Low Prevalence Regionsx

Rate

Trend

Rate

Rate

Trend

Anencephaly

3.6

;

3.7

2.1

;

Mexico South America

Italy South Africa

Spina bifida

3.8

;

4.3

6.3

;

Mexico South America

Spain England/Wales

Encephalocele

1.6

;

0.9

1.4

Mexico South America

Spain Norway

Hydrocephaly

8.1

;

3.5

7.1

South America France

England/Wales Spain

Anophthalmia/Microphthalmia

2.9

;

1.2

1.1

USA (Atlanta) Ireland (Dublin)

England/Wales Hungary

Anotia/Microtia

1.5

Mexico South America

Australia England/Wales

USA (Atlanta) Ireland (Dublin)

England/Wales

N. Netherlands France

Mexico England/Wales

USA (Atlanta) France

England/Wales South America

Ireland (Dublin) USA (Atlanta)

England/Wales Spain

Neural Tube Defects

;

3.3

Cardiac Defects Atrial septal defect

25.1

19.7

23.0

:

Ventricular septal defect

37.8

16.0

30.4

:

Tetralogy of Fallot

4.2

2.6

4.2

:

Transposition of great vessels

5.4

4.2

4.2

Truncus arteriosus

0.9

0.6

1.2

Hypoplastic left heart syndrome

3.0

2.5

2.9

Coarctation of aorta

5.1

:

4.0

4.8

Cleft Lip With or Without Cleft Palate

9.0

;

10.4

10.7

Norway Japan

South Africa Canada

Cleft Palate Without Cleft Lip

6.8

4.9

6.3

Malta Finland

South Africa

Esophageal Atresia/Stenosis With or Without Fistula

2.0

1.2

3.4

South America Ireland (Dublin)

England/Wales

Rectal and Large Intestinal Atresia/Stenosis

3.7

2.5

4.5

:

33.7

:

2.3

24.2

Israel Czech Republic

Australia Italy

Renal Agenesis/Hypoplasia

4.5

;

0.5

4.2

Canada Ireland (Dublin)

Hungary Mexico

Diaphragmatic Hernia

2.3

2.5

France Ireland (Dublin)

South Africa Mexico

Bladder Exstrophy

0.1

0.0

Mexico France

England/Wales Japan

Omphalocele

2.6

France South America

Spain England/Wales

Gastroschisis

2.2

4.2

Mexico South America

Spain South Africa

Limb Reduction Defects (Upper)

4.1

3.7

Limb Reduction Defects (Lower)

1.7

1.7

Canada France

South Africa Japan

Hypospadias/Epispadias

;

1.3

g g

: 6.6

4.6

(continued)

4

Human Malformations and Related Anomalies

5

Table 1-1. Prevalence of selected major malformations (continued) USA: Atlanta* Rate

USA: California{

Trend

Canada{

Rate

Rate

Trend

High Prevalence Regionsx

Low Prevalence Regionsx

Chromosome Aneuploidies Trisomy 13

1.5

1.1

1.2

:

Ireland (Dublin)

Hungary

Trisomy 18

2.5

1.8

2.1

:

Ireland (Dublin)

Hungary

Trisomy 21

12.5

10.1

12.4

Ireland (Dublin)

Hungary

*Malformation rates (1996–2000) birth to age 6 years per 10,000 livebirths reported by Metropolitan Atlanta Congenital Defects Program (5 Metropolitan Atlanta counties).22 { Malformation rates (1996–2000) birth to age 1 year per 10,000 livebirths reported by California Birth Defects Monitoring Program (8 counties).22 { Malformation rates (1991–1993) birth to age 1 year per 10,000 births reported by Canadian Congenital Anomalies Surveillance System (Alberta, Manitoba, and Ontario provinces).23 x

High and low prevalence regions from International Clearinghouse for Birth Defects Monitoring Systems.35

Additional prevalence information on specific malformations may be found in the appropriate chapters.

Table 1-2. Incidence of major and minor anomalies Location 18

Sample Size

Major Anomalies (%)

Minor Anomalies (%)

14.7

Marden et al., 1964

USA

4412

2.1

Myrianthopoulos and Chung, 197420

USA

53,257

7.1

Mehes, 198350

Hungary

4589

2.2

Merlob et al., 198529

Israel

3762

1.6

21.0

Leppig et al., 198951

USA

4305

3.8

40.7

CBDMP, 1994*26

USA

>500,000

2.9

–

Stoll, 199525

Europe

291,126

2.2

–

Queisser-Luft et al., 200224

Germany

30,940

6.9

35.8

7.26 17.2

*California Birth Defects Monitoring Program.

as that goal may be, it is not attainable in every case. The causes of many malformations and recognized syndromes simply are not known. This is the case for approximately 40% of malformations.41,42 Of the 290 malformation syndromes included in Jones’ Smith’s Recognizable Patterns of Human Malformations, 40 (14%) have unknown etiology.43 Assignment of causation of a malformation in one individual may not be possible although the cause of the same malformation is readily determined in other individuals. Lethality has posed a barrier to determining causation of certain malformations and patterns of malformations; sirenomelia and Proteus syndrome are examples (Fig. 1-1).44,45 These conditions generally occur as isolated cases within a family. Affected individuals either die early (sirenomelia) or fail to reproduce (Proteus syndrome). The possibilities that either represents a dominant phenotype caused by a new mutation, a multifactorial phenotype with a low recurrence rate, or a chromosomal disorder caused by submicroscopic deletion that has not been detected with current technology cannot be excluded. Hence, the causes of these conditions will remain unknown until one of these possibilities or another alternative is confirmed and the possible cause or causes can be sorted out.

If heritable factors, environmental factors, or some combination of the two are accepted as the only etiologic possibilities for human anomalies, then one assumes that birth defects of unknown etiology will eventually be explained in terms of one of these three possibilities. Should factors other than hereditary and environmental be identified, the new influence must be woven into the causation schema. Kurnit et al. have suggested that chance may play a significant role in the occurrence of major malformations.46 The field of developmental biology is advancing in remarkable ways. Many of the genes involved in organ formation have been identified in lower animals; these same genes turn out to be important and thus conserved in human development.194 These developmental genes are expressed in a hierarchical manner much like the clotting cascade. Complex controls cause transcription to occur in tissue-specific and time-specific manner during development. Although the precise roles for various molecular phenomena (e.g., alternative splicing, regulatory elements, polymorphisms, receptors, affectors, epigenetic modifications of DNA and histones, processing of RNA) in development are unknown, it is clear that current investigations are directed at delineating a complete molecular embryology. Specific defects in

6

Overview

Fig. 1-1. Sirenomelia (A) and Proteus syndrome (B), a malformation and malformation syndrome of unknown causation. Note that a minority of cases of sirenomelia occurs in infants of diabetic mothers, and some possible cases of Proteus syndrome have had PTEN mutations.

molecular pathways and networks of pathways are now recognized and give greater insight into the etiology of structural anomalies observed at birth. 1.1 Nomenclature Meaningful terminology is fundamental to communication and to most educational processes. The plethora of terms used to describe human morphologic alterations sometimes promotes but often complicates these processes. Understandably, students may be confused by the admixture of commonly used terms. Some provide true descriptions of the alteration (macrocephaly); some bear ethnic, rank, or national connotations (Roman nose); some are colored with mythological imagery (sirenomelia, cyclopia); some imply a specific pathogenesis (oligohydramnios sequence); some imply a specific etiology (warfarin embryopathy); and some give tribute to a discoverer (Meckel diverticulum). The same term can be used in a very restricted sense by one group while having a more generic meaning for the total scientific community. Terms most removed from description of the anatomic alteration are most variable and carry the greatest prospect for continued change in the future. A universally acceptable and permanent terminology for anomalies would appear utopian. No previous system has met with full acceptance. One problem is that the priorities of different groups dealing with congenital anomalies are not the same. Anthropologists, anatomists, radiologists, and pathologists focus on the description of the change; therapists, on the functional implications; embryologists and teratologists, on the mechanisms; and clinicians, on the diagnosis, cause, treatment, and prevention. In each of these areas, a jargon has arisen to serve the perceived requirements of the group. Sometimes the terms used by one group coincide with those used by colleagues with other emphases. In

other situations, the terms used by one group meet indifference or rejection by others. Exclusive claim cannot be placed on any terms, and no group can prohibit use beyond a specified definition. Anatomically based nomenclature for malformations and related structural anomalies emphasizes topography and morphology. The purposes are to identify the anatomic part involved and to describe the alteration of that part. In this system, the development of new terms to describe human malformations would appear unnecessary. Human anatomy does not change, and timehonored terms for each structure are available.47 Morphologic alterations of individual structures can also be defined with simple, biologically correct terms. Should new descriptive terms become desirable, they can be introduced without necessitating revision of the entire system. Because anatomic terms are the least likely to change, they are used in this book. Anatomic alterations include size, shape, symmetry, consistency, density, continuity, patency, color, and position changes. Some are readily determined by gross inspection. Others fall into a continuum nearer the normal than the extreme. Indeed, some can be separated from the normal only by arbitrary convention. As part of the evaluation of an infant or child with malformations, careful measurements of normal and abnormal structures are essential. Norms for every age from embryo to adult are available. Not infrequently disharmonic growth between structures exists in association with congenital malformations. For those structural changes that fall along a continuum, one expects 5% to fall outside 2 standard deviations (SD) of the mean for the population, 2.5% below 2 SD of the population norm, and 2.5% above 2 SD of the norm. It is of interest that this definition of normality results in an incidence of abnormal members among the continuous traits similar to the incidence of major malformations in the newborn population (Tables 1-1 and 1-2). Some continuous traits (e.g., color, density, and consistency) have no standardized measurements from which their norms and standard deviations can be determined. In the clinical setting, assessment of these features is almost invariably subjective. In an anatomically based nomenclature, no consideration is given to causation and pathogenesis, although in certain instances they may be coincidentally accommodated. Macrocephaly is used generically to describe large head of unknown cause and also to describe large head with large brain. Hydrocephaly is used to describe a large head due to ventricular enlargement. Hydrocephaly, however, does not necessarily imply head enlargement, since hydrocephaly can coexist with normal or even small head sizes. This type of duplicity and nuance is to be expected in any system of nomenclature and can be tolerated to some degree. Macrohydrocephaly or hydromacrocephaly to identify large head due to enlarged ventricles becomes too cumbersome. The terminology for anomalies based on morphologic alterations is derived from the Greek language, as introduced by Malacarne in 1798,48 but an increasing drift toward the use of Anglicized terms is evident. With English now being considered the universal scientific language, this trend will likely continue. A mix of English, Latin, and Greek terms will be found in the present text, with the choice of the term being based on familiarity and ease of flow. Malformations, Disruptions, and Deformations

Distinction between pathogenetically different types of structural abnormalities is indicated by the terms malformation, disruption, and deformation.49 Anomalies can be placed into one of these

Human Malformations and Related Anomalies

categories on the basis of the developmental stage during which the alteration took place, the process that caused the change, or the end result. Using these distinctions, malformations arise during the initial formation of a structure. The structure can have a faulty configuration, can be incompletely formed, or can fail to form altogether. Malformations are caused by genetic or environmental influences or by a combination of the two. They result from abnormal processes during the formation of the structures (i.e., during organogenesis). For most structures, organogenesis is complete by 8 weeks postfertilization. However, teeth, brain, and genitalia are notable among the many structures whose formation extends beyond 8 weeks. Disruptions result from abnormal processes that alter normally forming structures during or after formation. A wide range of morphologic changes can occur secondary to disruptions, including alterations of shape and configuration, division of parts not usually divided, fusion of parts not usually fused, and loss of parts previously present. The causes of disruptions are usually environmental, but genetic causes (e.g., genetically programmed loss of blood supply and inherited thrombophilias) are also possible. Mechanical forces can cause compression, hemorrhage, thrombosis, emboli, and other vascular impairments that damage formed structures. The term deformation indicates molding of a part through mechanical forces, usually over a prolonged period of time. Deformations result in loss of symmetry, altered alignment, abnormal positioning, and distorted configuration. They usually occur after organogenesis, often involve musculoskeletal tissues, and require no obligatory underlying tissue defect. Abnormal tissues may, however, be more susceptible to deformation. Deformations are usually reversible postnatally, depending on how long-standing they are and how much growth has occurred subsequent to the initial compressive effects. Deformations are usually due to external forces but can result from edema, which can exert intrinsic compressive forces. These criteria for designating a malformation or disruption have been modified from those set forth by Spranger et al., who represented an International Working Group on Nomenclature of Errors of Morphogenesis.49 According to their definitions, malformations are all genetic in etiology; disruptions occur during or after organogenesis; and deformations are caused only by extrinsic forces. The restriction of malformation to structural defects of genetic origin would appear unwarranted and contrary to historical usage. For instance, it seems entirely appropriate to consider the limb anomalies caused by teratogens such as thalidomide to be malformations since they occur during the period of morphogenesis. Although this tripartite schema was thoughtfully devised and allows for meaningful communication among many who work with human congenital anomalies, universal usage should not be anticipated. The term malformation will be used in a generic sense by many to indicate any structural alteration that occurs during the prenatal period. In defense of this general usage, both scientists and the public understand the general nature of the problem when the term is used. Likewise, the term deformity is used by orthopedists to indicate any anomaly of the skeleton often including problems arising during embryologic development. The value to geneticists of using malformation, disruption, and deformation according to the foregoing definitions is that it allows certain generalizations to be made about the causation, pathogenesis, prognosis, and recurrence of different types of anomalies. It also allows for a more accurate categorization of the structural

7

abnormalities, which improves the prospect of a correct diagnosis. Spranger et al.,49 also described a fourth category of dysplasias in which cellular or tissue disorganization is present. Major and Minor Anomalies

Major structural anomalies have medical and social consequences. The incidences of major defects appear highest among abortions, intermediate in stillborn infants, and lowest among liveborn infants. The incidence of major anomalies recognized at birth among liveborn infants is 2–3% in most series (Table 1-1).18–29 An equal number of additional major anomalies will be recognized by age 5 years (e.g., cardiac defects, absent kidney). This means that by 5 years of age, 1 in 20 or 5% of individuals are found to have a major defect in structural development. Considering the complexity of the developmental processes, it is surprising that the frequency of anomalies is not higher. An evolving understanding of prenatal (and postnatal) human development indicates that the biochemical basis of development and growth changes during different stages of development. A specific gene’s product may have quite different effects in different tissues and at different times in development. Furthermore, a gene, possibly with alternative splicing, is reused in different tissues at different times in development. This suggests that susceptibilities and predispositions to detrimental influences both intrinsic and extrinsic may be very different at different times in development and that the potential for curative or corrective measures will need to be time-in-development sensitive. The control of these processes (e.g., the switch from embryonic to fetal and adult hemoglobin) is still poorly understood. No individual major anomaly has a sufficiently high incidence in the population for it to be considered a structural polymorphism; that is, none has an incidence of greater than 1%. The monopodic, cyclopic, and other malformed races that exist in noncritical accounts of ancient writers must be viewed with skepticism. Minor anomalies are relatively frequent structural alterations that pose no significant health or social burdens (Tables 1-2 to 1-4).18,49–52 They are nonetheless important because their presence prompts a search for coexistent, more important structural anomalies. The presence of two or more minor anomalies is an indication that a major defect or syndrome may be present as well. Minor anomalies often provide critical clues that permit the diagnosis of a specific syndrome or a specific disorder having multiple anomalies. They can also provide a clue to the timing of an insult during prenatal development. Approximately 15% of newborn infants have one or more minor structural anomalies.18,20,24,29,50,51 A higher incidence may be found among premature infants, while babies with intrauterine growth retardation have an even higher rate. The risk of having a major birth defect increases with the number of minor defects present (Table 1-4). Infants free of minor defects have a low incidence (approximately 1%) of major malformations. Infants with one minor defect have a 3% risk of a major defect; those with two minor defects have a 10% risk of a major malformation; and those with three or more minor defects have a 20% risk of a major defect.18,50,51 No clear distinction exists between normal variation and minor anomalies or between minor anomalies and major anomalies. The determinations are often arbitrary. Holmes separates minor anomalies from normal variants by considering as normal those features that occur in 4% or more of the population.52 This is a fourfold greater incidence than the 1% usually required for a

8

Overview Table 1-3. Minor anomalies Cranium and Scalp

Face and Neck

Horizontal palmar crease (single)

Triple hair whorl

Synophrys

Bridged palmar crease

Absence of hair whorl

Flat bridge of nose

Single crease, finger V

Patent metopic suture

Prominent bridge of nose

Metopic fontanel

Hypotelorism

Skin tags (preauricular, ear lobe, others)

Sagittal fontanel

Hypertelorism

Parietal foramen

Nostrils anteverted

Flat occiput

Long nasal septum

Prominent occiput

Epicanthal fold

Frontal bossing

Iris freckles

Flat brow

Upward palpebral slant

Pigmented spots Hypopigmented spots Trunk

Short palpebral fissures

Extra nipples Single umbilical artery Umbilical hernia

Microtia

Cleft uvula

Darwinian point

Cleft lip microform

Darwinian tubercle

Cleft gum

Lack of helical folding

Long philtrum

Bridged concha

Short philtrum

Ear lobe crease

Smooth philtrum

Ear lobe notched

Microstomia

Ear lobe bifid

Macrostomia

Lop ear

Macroglossia

Cup-shaped ear

Microglossia

Retroverted ear

Broad alveolar ridge

Thickened helix

Micrognathia

Helix excessively folded

Webbed neck

Helix attached to scalp

Redundant neck skin

Sinuses

Ptosis

Branchial

Skin

Overlapping digits

Preauricular

Shoulder dimples

Prominent heel

Ear lobe

Sacrum dimples

Helical

Dimples over other bones

Pilonidal

Sole crease

Diastasis rectus Glandular hypospadias Shawl scrotum Vaginal tag Limbs

Cubitus valgus Tapered fingers Overlapping fingers Broad thumb, great toe Clinodactyly Nails hypoplastic Nails hyperconvex Increased space, toes Syndactyly, toes 2–3

Table 1-4. Concurrence of minor and major anomalies at birth in three series Percent With Major Malformations Marden et al., 196418 USA

Mehes, 198350 Hungary

Leppig et al., 198751 USA

0

1.4

1.2

2.3

1

2.9

3.8

3.7

2

10.8

12.5

6.7

90

26


3

Nevi

Downward palpebral slant

Ears

Number of Minor Malformations

Hemangioma

19.6

human polymorphism. The level of sensitivity to minor anomalies is set differently by different observers. The difference may partially explain the low incidence of minor defects (7.26%) reported by Myrianthopoulos and Chung for the Collaborative Study in the

United States and the high incidence (39%) reported by Leppig et al.20,51 Minor morphologic features give the most consistent clues to the diagnosis of many multi-anomaly syndromes. Prenatal alcohol syndrome and prenatal hydantoin syndrome, for example, are more commonly diagnosed by a pattern of minor morphologic features than on the basis of major malformations. Mehes50 has found the number of minor anomalies detected to be greatest at the time of birth, with a decrease in the detection of many features by age 1 year. This suggests that certain minor anomalies resolve or become obscured with growth and function. Downslanting palpebrae, horizontal palmar creases, asymmetric ears, preauricular skin tags, and clinodactyly are among those features with similar incidences at birth and at 1 year. A 50% or greater reduction in the prevalences of high-arched palate, low-set ears, and upslanting palpebral fissures occurs by 1 year. This contrasts with the increased detection of major defects during the first year of life.20

Human Malformations and Related Anomalies

Connectional Terms

Because multiple structural anomalies often occur together, a terminology that relates the components has developed.49,53–57 In connectional terminology, anatomic description of the anomalies has been largely abandoned because listing each anatomical feature of the composite becomes cumbersome. Greater emphasis is given to pathogenesis and causation. The terminology relating multiple anomalies has little consensus and great liability for change and perhaps for confusion. These problems have prompted attempts to develop a uniform nomenclature. Over several years, beginning in 1974, a series of workshops were held to construct a classification and nomenclature of congenital anomalies and other human morphologic changes.49,53,58 As new rules regarding nomenclature were published, there was disagreement, and the scientific community became embroiled in a debate.59–61 It would be premature to suggest that this debate has resulted in widely accepted terminology. An equivalent meeting dealing with terminology is reported to have been held among persons themselves affected with congenital anomalies, in London, in 1898.62 The term prodigies, which the participants are said to have found acceptable, has never been adopted in the medical field. Syndrome, association, complex, spectrum, sequence, field defect, and phenotype have all been used to describe some composite of anatomic features. Johannsen63 coined the term phenotype to encompass the outward manifestations produced by an individual gene. The nature of the gene itself was termed genotype. Genotype and phenotype can refer to a single gene and its manifestations (anatomic, biochemical, physiologic), to a related group of genes and their manifestations, or to the entire genetic constitution and all resulting hereditary features. In current usage, phenotype has become a general term for describing a composite of features without regard to the underlying cause. Consistent with this usage, environmental as well as genetic factors can contribute to the phenotype. This more general use of phenotype in many cases suggests that the cause of the features is uncertain or that multiple causes might produce this composite of manifestations. In some cases a modifier is added to indicate pathogenesis, for example, akinesia phenotype to indicate those features that are produced by absence of prenatal movement from any cause. Complex is a general term that is also used to indicate a composite of manifestations. Spectrum is sometimes used to describe entities with multiple features, particularly those in which prominent features can be expressed with considerable variation. Greater specificity is suggested by the term syndrome, which means a group of features seen together in multiple individuals, but it also implies that the composite of features has a common, specific etiology. Use of the term indicates that a specific diagnosis has been made and that the natural history and recurrence risk are known. A well-recognized exception is use of the term to include the multiple features found in several well-delineated disorders, such as Proteus syndrome and Sturge-Weber syndrome.45,64 While the etiologies of these two disorders have not been identified, a single specific etiology is suspected for each. In some branches of medicine, syndrome is used without the specificity suggested previously when used to describe structural anomalies. Association has been used in clinical genetics to identify the nonrandom concurrence of two or more anomalies that occur more frequently than expected by chance alone but for which no etiology has been demonstrated. VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies) association

9

is a well-known example in which the first letters of the anomalies are used to make an acronym. Use of association does not imply a specific diagnosis. Recognition of such statistically related anomalies prompts the search for other defects when one component of an association is noted. It also helps to develop a differential diagnosis for specific entities (in the case of VACTERL: trisomy 18, thrombocytopenia and absent radius, Fanconi anemia, etc). Empiric risks for recurrence may also be given for an association even though no cause for the association has been determined. Furthermore, it may allow for prognosis if no specific diagnosis is achieved. For example, the prognosis for intellectual development for individuals with VACTERL association is generally favorable. Sequence has been used by some to indicate a pattern of anomalies that results from a single primary anomaly or single mechanical factor.43,49 The anomaly or mechanical factor that initiates the sequence may produce multiple secondary anomalies or may produce a secondary anomaly that leads to a tertiary anomaly, and so forth, in cascade fashion. For example, in Pierre Robin sequence, severe micrognathia is the primary anomaly that causes secondary glossoptosis which obstructs palatal shelf closure resulting in a cleft palate. Furthermore, oligohydramnios sequence and fetal akinesia sequence have overlapping features and both are actually deformational processes. Although proposed to identify a pattern of anomalies having uniform pathogenesis (oligohydramnios sequence), in use sequence sometimes implies causation (athyreotic hypothyroidism sequence). Redundancy in using the term sequence when applied to specific disease states such as athyreotic hypothyroidism is obvious. Further confusion can arise because of the longstanding use of sequence for the arrangement of nucleotides and codons in the genome. Finite areas of embryonic tissue develop into multiple and hence related morphologic structures. Damage to or defects in the genes underlying these finite areas or developmental fields can result in multiple structural anomalies. Use of the developmental field concept helps to explain why certain malformations occur together. Designation and understanding of developmental fields require considerable knowledge of embryonic topography and the fate of the component cells, as well as the timing of gene expression and their gene products. To use the concept, an arbitrary time during embryogenesis must be selected at which the dimensions of the developmental field are established and from which the developmental potential of the field is predicted. A polytopic field defect is a pattern of multiple anomalies often in different body areas resulting from disturbance of a single developmental field. This suggests that a specific gene (which is defective) is expressed in multiple body areas, perhaps even at different times. The term monotopic field is used when the repertoire of a developmental field is limited to a single body area; monotopic field defect is used to describe the malformation (usually of a single anatomic structure) that results from a disturbance to that field.54,65,66 Holoprosencephaly with midline cleft palate represents one classical monotopic field defect. Many difficulties arise with the actual use of developmental field to define structural anomalies. Many who work with human anomalies are not facile in linking various anomalies to their precursor embryonic cells and the genes they express. Considerable overlap of developmental fields occurs, depending on the dimensions selected and on the embryonic age at which the field is thought to be established. If the concept were pushed to the ultimate, the zygote would have to be considered the primary field from which the entire embryo develops.

10

Overview

Multiple anomalies can also be related through the time period during which they develop. A single insult during embryogenesis may affect multiple unrelated structures that are forming at the time. Without evidence linking the pathogenesis of diverse and seemingly unrelated components of conditions with multiple features, these components have been considered ‘‘pleiotropic effects’’ of the underlying cause. Pinsky55 has advocated the grouping of discrete syndromes that share a large portion of major features into communities and classes. It was suggested that grouping on the basis of multiple features could assist recall of the member syndromes, bibliographic retrieval, and computer analysis. At the same time the grouping could stimulate ideas about pathogenesis that might apply to a group of disorders sharing similar morphologic features and biochemical developmental pathways. This system could further permit collective statements that would then apply to the group as a whole and more clearly define the similarities and differences of member syndromes. Merits aside, this polythetic system has been slow to gain popularity, in part because it has been presented more as a theoretical system than as a practical system to be readily understood and utilized. However, reexamination may be useful in light of key developmental genes and their pathways such as sonic hedgehog and the fibroblast growth factors and their receptors (e.g., hedgehog community, FGFR community). Naming

The naming of composite entities (syndromes, associations, phenotypes) follows no fixed rules nor has any committee assumed authority for naming. Authors and editors often designate a name in the initial description of an entity, or one arises in a subsequent review. For conditions of known etiology, names that acknowledge the cause would seem to be most appropriate (e.g., trisomy 13 syndrome, prenatal alcohol syndrome). This is not possible for many syndromes caused by single genes, several genes, or for conditions of unknown etiology. Several different approaches have been used in these cases. If the major components are few, their enumeration in the name is possible (hypertelorism–hypospadias syndrome). This can be misleading, however, when the identifying features are not present (e.g., absence of cryptophthalmos in the cryptophthalmos syndrome or absence of camptomelia in camptomelic dysplasia). When the major components are numerous, the name can become tiresome. Use of the first letters of the major features to form a unique acronym has been successful in several instances (e.g., LEOPARD syndrome, CHARGE syndrome).This approach offers the user assistance in recalling the primary features of the entities. Perhaps the most widely accepted practice in naming composite entities has been to use eponyms. Eponymic designation attempts to credit the individual(s) who first described an entity or who first recognized it to be a specific entity. Not uncommonly, earlier reports of an entity are overlooked or not recognized to be that entity, leading to competing names or to compound eponyms (e.g., de Lange syndrome versus Brachmann–de Lange syndrome). Problems are also encountered when a prolific investigator describes more than one entity (e.g., Fanconi anemia syndrome and Fanconi renotubular syndrome). When heterogeneity is found to exist in an established name, renaming becomes necessary (Lawrence-Moon-Bardet-Biedl syndrome now divided into Lawrence–Moon syndrome and Bardet–Biedl syndrome with several subtypes of Bardet–Biedl). These difficulties aside, the use

of eponyms appears well established and will likely be replaced only by naming according to etiology (based on the gene or the environmental insult responsible). The possessive form of eponyms has been dropped in this book in keeping with McKusick’s suggestion. One international committee has published reasonable guidelines regarding the naming of human anomalies.53 Their suggestions include the use of etiologic agents when known (e.g., trisomy 18 syndrome), and eponyms (e.g., Down syndrome) that are well established. Use of the initials of the patient’s family (e.g., BBB syndrome, FG syndrome) and acronyms (e.g., EMG syndrome) that bear no relation to clinical feature was discouraged by this committee. Timing of Structural Alterations

The timing at which an anomaly arises has some importance in descriptive terminology. Postnatal alteration of an anatomic part should be distinguished from prenatal alteration, and prenatal alteration during organogenesis should be distinguished from alteration after organogenesis. Congenital means present at birth. It gives no clue to pathogenesis and causation, nor does it imply development at any particular time during prenatal life. Hence, use of congenital with malformation, disruption, or deformation in the sense described here would be redundant. Congenital anomaly, congenital defect, or congenital abnormality would be more appropriate term combinations since their use would restrict the general terms anomaly, defect, and abnormality to those present at birth. These terms imply a structure problem without specifying the etiology—which can be useful at times. Embryonic staging as set forth by Mall,67 Streeter,68,69 and O’Rahilly70,71 use arbitrary subdivisions of the period from fertilization to the start of fetal life to provide a description of the topographic, morphologic, and cytologic changes that take place during human development. The stages are defined by the composite of morphologic features and hence show some variability in size and chronologic age and in the progress of any single anatomic feature. They infer nothing about the gene expression and flow of biochemical events underlying the morphologic events. The age of an embryo is given in days following ovulation. Embryonic (postovulation) age is thus 2 weeks less than menstrual age (days or weeks following onset of last menstrual period), which is commonly used to date pregnancies in obstetrics and neonatology. Fertilization generally occurs within 24 hours after ovulation, usually in the outer reaches of the fallopian tubes. The initial four stages of human development take place over the first 5 to 6 days and span the early series of divisions of the free-floating conceptus up to and including the early implantation process. In the latter half of this period the conceptus is called a blastocyst, a mass of cells with an internal cavity. The period is called the preimplantation period. Interest in the specific nature of human preimplantation has been highlighted by the increasing use of assisted reproductive technologies (ARTs). Implantation occurs during stages 4–5, which span the period 5.5 to 12 days. The embryonic disc becomes bilaminar (ectoderm and endoderm), with the amniotic cavity developing on the epidermal surface and the yolk sac developing on the endodermal surface during these stages. The phenotypic description of the developing embryo often ignores the placenta which is

Human Malformations and Related Anomalies

simultaneously going through significant morphologic and metabolic change. Stage 23 (56–60 days, or 8 weeks, postfertilization) was considered arbitrarily to end the embryonic period.70,71 The beginning of marrow formation in the humerus was a developmental landmark used to assist in identifying this stage. The first 8 weeks after fertilization, or weeks 2 to 8, are generally considered the period of embryogenesis. The embryo has taken the human form, and most organs are fully formed and located in their final position by the end of this time. Exceptions are external genitalia, abdominal wall, heart, and dental structures and, of course, the brain, which continues its development (partly in response to utilization of neuronal pathways) into childhood. The fetal period begins with week 9 and extends to delivery, usually 40 weeks from the last menstrual period and 38 weeks from fertilization. Growth and maturation of function are the major processes that occur during this period. However, as noted previously, formation of some structures continues into this time and may be influenced by mechanical and flow considerations as well as gene expression (e.g., the heart and joints). External genitalia do not complete differentiation until week 12; hair follicles do not form until week 12; the midgut does not return to the abdominal cavity from the body stalk until week 10; and teeth do not gain their definitive morphology until much later in fetal life. An interesting new field related to fetal determinants of adult health suggests that events during fetal life can have long lasting effects on metabolism later in life. For instance, intrauterine growth retardation is associated with the development of diabetes, coronary artery disease, and hypertension in adulthood. Prematurity is associated with hypertension in adulthood. The mechanisms by which fetal events influence adult health are not yet known.71a In the strict sense, malformations, as previously defined, occur during the period of organ formation. Most will occur during the first 8 weeks of embryogenesis, but exceptions to this are not uncommon in those structures that are still forming after 8 weeks. In general, disruptions and deformations occur following morphologic development and, hence, usually after 8 weeks postconception. Some terms are particularly useful in defining environmental influences that act during gestation and that alter morphology, function, or growth. Teratogen has been used with widely variable meanings.72–74 In this text a teratogen has three features. First, as its derivation (teratos ¼ monster, gen ¼ produce) suggests, the end result of a teratogenic influence will be a morphologic abnormality rather than a functional one (however, of course, both morphologic and functional changes can be expected). Second, teratogens are environmental rather than genetic influences (however, maternal inherited metabolic disorders can have a detrimental effect on the embryo/fetus as in maternal phenylketonuria). Third, teratogens exert their influence following fertilization and before delivery (although the effects may not be obvious at birth as in the case of prenatal diethylstilbestrol exposure). Teratogens have an effect primarily during the first 8 weeks of embryogenesis, causing malformations, but may act at a later point in pregnancy, causing disruptions or deformations as well (e.g., as is seen with maternal warfarin use). These late effects of teratogens can also include malformation of structures that gain their morphology after the usual 8 weeks of embryogenesis. Etiology and Pathogenesis

Etiology simply means cause. For all human anomalies, the etiologic possibilities are limited to genetic (single gene, multiple genes,

11

chromosomal) or environmental (mechanical, infectious, chemical) causes, or some combination of the two. Little regard for etiology is given when naming individual structural anomalies. Etiology can be found, however, in the names of many syndromes (e.g., trisomy 13 syndrome, prenatal alcohol syndrome, X-linked hydrocephaly syndrome). More recently epigenetic influences (not resulting from changes in the structure of DNA, but rather in the control and expression of the genes) have been recognized to play a role in embryonic and fetal development. Pathogenesis indicates the mechanism or process by which a feature is produced. Again, little indication of pathogenesis is incorporated into the names of individual structural anomalies, but considerable emphasis is given in the naming of entities with multiple features (e.g., early amnion rupture, oligohydramnios sequence). As more is learned about the role of gene expression (e.g., alternative splicing, control of genes by RNA and transcriptions factors) as well as specific types of mutations, new nomenclature may emerge as illustrated by McKusick’s new organization of OMIM.101 Histologic Modifiers

Histologic analyses permit the description of the cellular and tissue processes underlying certain morphologic alterations. When known, these processes can be used as descriptive modifiers or to imply pathogenesis75 as in the chondrodysplasias. Aplasia, Hypoplasia, Hyperplasia, and Dysplasia

Aplasia indicates absence of cellular proliferation, hence the absence of tissue mass and, consequently, of an organ or morphologic feature. Hypoplasia indicates insufficient cell proliferation, resulting in a deficiency of tissue mass and ultimately undergrowth of an organ or morphologic feature. Similarly, hyperplasia means excessive proliferation of cells, accumulation of excessive tissue mass due to the increased cell number, and overgrowth of an organ or morphologic feature. Dysplasia as used in clinical genetics implies disorganization of cell structure, disordered cell arrangement in tissues, and faulty tissue organization in an organ or morphologic feature. At the tertiary (organ) level, these terms are best used only when the underlying histology is known. ‘‘Hyperplasia of (an anatomic part)’’ has greatest meaning when it implies that the excessive mass is due to an excessive number of otherwise normal cells. Regrettably, hyperplasia is often used as a mere description of overgrowth without regard to or knowledge of the histology. Worse yet, it is sometimes used to identify the larger of two parts of apparent unequal size without knowledge of the histology of either. At some point in their natural history, many cells become aplastic, that is, they cease to proliferate. Such cells (and tissues) can respond to injury, numerical depletion, hormone stimulation, and increased workload only by increasing their size. Muscle hypertrophy is a well-known example. Other cells retain the ability to divide actively. Endothelium, epithelium, mucosa, cartilage, bone, and connective tissues contain cells that are being constantly replenished by mitosis. The ability to repair damage can be an important cellular response during embryogenesis.72 The point in development at which paralysis of the various human cell types occurs is unknown, as are the signals that deprive cells of their ability to divide. Presumably most cells retain the ability to divide throughout embryogenesis and for variable periods of time thereafter. Hence embryos have the ability to repair and recover from certain insults

12

Overview

as long as the entire anlage is not damaged and as long as there are adequate time and resources to complete the repair before further differentiation is required. Dysplastic cells have altered sizes, shapes, and cytostructures. To the pathologist, these abnormal cells are regressive, often induced by chronic inflammation or irritation, and may progress in a neoplastic direction. No such connotations accompany the term dysplastic when used to describe the cellular, tissue, and organ disorganization found in congenital structural anomalies. These forms of dysplastic change arise during development, are usually genetically determined, and do not progress to neoplasia. The inborn errors of the chondroosseous skeleton constitute a large group of disorders called dysplasias.76,77 Multiple bones are involved, showing microscopic and radiographic evidence of disturbed growth and structure. Chondrocytes, osteocytes, connective tissue, or noncellular matrix can be abnormal, and the transition from cartilage to bone is often disorganized.78 Clinically these skeletal dysplasias are manifested by short stature; abnormal alignment, growth, or symmetry of body segments; or, less commonly, specific malformations (e.g., cleft palate, polydactyly). Agenesis has been used to indicate the failure of an organ to form, and in general it implies aplasia rather than loss through atrophy or disruption. Dysgenesis can be used in a similar fashion to indicate anomalous structure due to disorganization of the component cells and tissues. Atrophy, Hypotrophy, Hypertrophy, and Dystrophy

Atrophy means the degeneration of cells, usually resulting in shrinkage of tissue mass and diminished size of the affected organ or morphologic feature. Like the -plasia terms, atrophy and other -trophy terms are applied at the cellular (primary), tissue (secondary), and organ (tertiary) levels. Atrophy can be characterized by smaller than normal cell size, accumulation of intracellular pigment granules, and replacement of parenchymal cells by fat or connective tissue. Hypotrophy indicates that cells fail to achieve a normal size, and hence tissues, organs, and morphologic features are under grown. Hypertrophy is the enlargement of cells and consequent enlargement of tissue masses, organs, or morphologic features. Dystrophy means a disturbance in cell or tissue growth caused by faulty nutrition. The term has been used most widely, however, for certain heritable conditions of muscle, eye, or nails (e.g., myotonic dystrophy, lattice dystrophy of the cornea, nail dystrophy). In these conditions dystrophy is used without implying that defective nutrition is the underlying pathogenesis. Again, at the tertiary (organ or gross morphology) level, it may not be possible to distinguish enlargement due to hypertrophy from enlargement due to hyperplasia or to distinguish small size due to hypotrophy from small size due to atrophy, hypoplasia, or dystrophy. These distinctions require knowledge of the histologic structure. Accumulation of intracellular or extracellular fluid may alter size without affecting any of the cellular processes. In the absence of histologic information, general terms can be used to describe alterations in tissue bulk; for example, enlarged muscle to incorporate both muscle hyperplasia and hypertrophy or small muscle to encompass the possibilities of atrophy, hypotrophy, hypoplasia, dystrophy, and dysplasia. For practical reasons, the structural anomalies included in this discussion are those that can be detected by clinical observation and gross measurement. It is acknowledged that there exist

domains of microscopic and submicroscopic structural anomalies that are no less important than those mentioned. Histologic appearance is discussed only when those findings appear fundamental to understanding the gross structural alteration. Terms with Negative Impact

In general, structural anomalies are viewed negatively by medical practitioners, affected individuals, and society. Insensitive terminology can further stigmatize those affected and can separate caretakers from affected individuals, those affected from family, and family from society. Terminology should be as neutral as possible while correctly identifying or defining the structural anomaly. The care needed in choosing words when dealing with families or affected members may be obvious. However, terms employed internally in science should also be chosen carefully since these terms find their way to families via medical records, news articles, and courtrooms. It should be acknowledged that some morphologic abnormalities are not viewed negatively by affected individuals. An example is an alteration in size caused by achondroplasia. In this circumstance it is not unusual to find affected persons who want achondroplasia to recur in their biologic offspring, because normal size is less desirable in these particular families.79 Terminology does not remain constant; the nuances and implications of terms change with the generations. Until the early 1900s monster and monstrosity were widely used terms in medical circles to describe malformations or other morphologic changes. Monster has now gained a different nuance, primarily because of its use in movies to depict scary creatures. The new usage does not adhere to either of the word’s origins (to show or to warn), but suggests that those who look abnormal may also act in destructive, frightening, and otherwise offensive ways. Although monster and monstrosity have been used from the first written records of human malformations and into the twentieth century, they have in this century disappeared entirely from medical terminology. Other terms have had only brief life spans. Examples from the five editions of Smith’s Recognizable Patterns of Human Malformations will suffice to illustrate.43,80 In a period of less than 30 years (edition 1, 1970 to edition 5, 1997), repeated changes can be found in the preferred terminology for morphologic entities. Potter’s syndrome (edition 1) changed to oligohydramnios tetrad (edition 2) and then to oligohydramnios sequence (editions 3–5). The preferred term for amniotic bands changed with each edition. Initially, amniotic band syndrome changed to amniotic band anomalads, then to early amnion rupture spectrum, then to early amnion rupture sequence, and finally to amnion rupture sequence. These changes arose from the attempt to add a pathogenetic implication to the identification of the entity. Social sensitivity demands discretion in terminology. Terms that are divisive, derogatory, negative, or degrading should be abandoned. Happy puppet syndrome has been replaced by Angelman syndrome; fetal face syndrome by Robinow syndrome; and elfin facies syndrome by Williams syndrome. A term in common use in the middle of this century, mongolism, or mongoloid idiot, as assigned by Langdon Down for a specific mental retardation syndrome, is discouraged in favor of trisomy 21 syndrome or Down syndrome.81 The designation funny-looking kid (FLK) may be viewed as derogatory by an affected child, family members, and care-takers. The term dwarfism to identify persons with disproportionate skeletal dysplasias has been discouraged for the same reason. Special child or special needs child has been used to indicate children with handicaps. Since

Human Malformations and Related Anomalies

all children are special, the use of this term for a child with a malformation appears inappropriate and patronizing. The designation of syndromes by the initial of the proband (G syndrome, BBB syndrome) has been advocated by Opitz et al.54 While intended to be neutral, this naming schema offers nothing to assist the user in remembering the syndrome, is liable for duplication, and has not found wide acceptance. Anomalad was suggested by Fraser and advocated by Smith53 to indicate a cascade of structural anomalies that derived from a single preceding anomaly or mechanical force. The term was debated for several years and has now disappeared, being replaced by some users with sequence. Polyanomaly has also been suggested to indicate multiple anomalies, specifically those that arise from the same pathogenesis. There is nothing to recommend this term over multiple congenital anomalies, and the term does not flow well. In the last decade, the field of developmental biology has made considerable progress in understanding embryologic development by using animal models. Yeast, flies, worms, and fish have contributed to defining the molecular pathways involved in development of various structures. The conservation of the genes (and gene families) involved is remarkable. This work has a direct effect on understanding human development, which for ethical reasons cannot be studied directly. However, most animal models do not have a fetal period similar to that in humans. The application of these new discoveries of developmental biology to human in utero development and to the historic systems of phenotypic descriptive classification has been relatively slow and will undoubtedly be challenging.

1.2 Classification and Coding Classification

The systematic arrangement of structural anomalies on the basis of morphologic, anatomic, etiologic, or other criteria has been attempted by many observers. The number of classification schemas attests to the likelihood that no system has been entirely satisfactory. Nonetheless, finding some order among human congenital anomalies has utility in assisting human memory and giving insights into the range and nature of human anomalies. A growing utility is now being found for computer retrieval of information. Some admixture between the classification schemas is to be expected in a brief accounting of the types of classifications used in the past. Classification by Cause

One of the oldest classification schemas, that set forth by Empedocles,82 was based on causation. Five causes for human anomalies were recognized: excess semen, deficiency of semen, slowness of movement of semen, abnormal movement of semen, and division of semen into separate parts. Pare´’s classification83 had 13 causes, including abnormalities of semen as well as mechanical injury, uterine compression, maternal impressions, and the supernatural. Cleland’s system, published in 1889, had six causation categories, three leading to anomalies with morphologic deficiencies and three leading to anomalies of excess.84 Classification by Morphologic Alteration

Eight types of morphologic alterations were the major entries in the system of St. Isidore in AD 60085: large size, small size, transformation

13

of a part, transformation of the whole body, transposition of a part, adhesion of parts, mixture of sexes, and the coexistence of multiple anomalies. These types were supplemented by two entries based on the precocious or delayed appearance of features. To this type of classification, Huber86 added union of parts usually separated and closed state of canals usually open. Isidore and Etienne St. Hilaire set forth an extensive classification schema based on alterations of morphology.87 All anomalies were assigned to a kingdom, and the kingdom was subdivided into four divisions, each of which was further subdivided into classes, orders, tribes, families, and genera. Classification by Regional Anatomy

Use of regional anatomy to arrange anomalies first appeared in the 1600s.88,89 The systems used by Taruffi,90 Lowne,91 and Ballantyne92 at the end of the nineteenth century utilized regional anatomy as well. These systems often incorporated subclassifications based on morphologic alteration (e.g., excess or deficiency of parts). Classification by System

Closely related to schemas based on regional anatomy is the use of anatomic systems to organize human anomalies. This variation is the basis of classifications used by Warkany93 in the classic Congenital Malformations, in the International Classification of Diseases (ICD), in the Cardiff and Centers for Disease Control modifications of the ICD, and in the Systematized Nomenclature of Medicine (SNOMED).94–97 Other Classifications

Several additional schemas are of historical interest. The earliest known system separated malformations into those that affected ordinary citizens and those that affected royal families. This was the only arrangement of anomalies to be found in the enumerations of human anomalies in the teratologic records of the Chaldeans.98 Other systems have used viability of affected individuals, time of occurrence during embryogenesis, and various mixtures of the several foregoing schemas.94,96,99,100 The ICD is now undergoing its tenth revision.94 The currently available clinical modification (ICD-9-CM, 2004) as published by the U.S. Government allots 20 categories with accompanying numerical codes for congenital anomalies. Considerable inconsistency has crept into this schema. Initially oriented to systems, there occur drifts into regional anatomy and major divergence into causation (chromosome anomalies) in the nineteenth category. An admixture of systems, specific diseases, specific syndromes, and processes appears in the twentieth category. The system, although having lost its consistency, is widely used because of its acceptance for epidemiologic studies and for insurance categorization; but it does not accommodate a listing of rare but specific anomalies. The British Pediatric Classification modifies the ICD system for anomalies by adding two additional numbers to the code, permitting a further specific subdivision of an ICD category.95 The Centers for Disease Control (CDC) has further modified the ICD and British systems by adding a sixth digit to the code.96 The addition of digits in the British and CDC modifications allows categories of defects to be subdivided into individual anomalies but fails to correct the admixing of causation, pathogenesis, regional anatomy, organ system, syndromes, and diseases in the original ICD system. The Systematized Nomenclature of Medicine has been produced by the American College of Pathologists97 based on their

14

Overview

Systematized Nomenclature of Pathology. This schema utilizes seven sections to permit access from numerous perspectives: topography, morphology, etiology, function, disease, procedure, and occupation. Most useful in relation to structural anomalies are the topographic, morphologic, and etiologic fields. Other systems that deal with certain individual anomalies and syndromes include McKusick’s alphabetical listing of single gene disorders101,102 and Shepard’s alphabetical enumeration of environmental agents.103 Several computerized databases have been developed to assist the clinician in recalling information about entities having one or more morphologic characteristic. The two major systems, London Dysmorphology Database104 and POSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations),105 require entry of the anatomic description (topography and morphology) of individual features and search for entities in which the feature(s) occur.

Table 1-5. Causes of anomalies among liveborn infants Cause

Percent Incidence

Genetic

15–25

Chromosome

10–15

Single gene

2–10

Multifactorial

20–25

Environmental

8–12

Maternal diseases

6–8

Uterine/placental

2–3

Drugs/chemicals

0.5–1

Twinning

0.5–1

Unknown

40–60

Coding

At present there is no comprehensive coding system that is specific for structural anomalies that occur in humans. A five-digit system would be required to assign a unique number to each of the numerous structural variants and anomalies. To add an indicator of the major etiologies would require an additional digit. A further multidigit hindcode would be necessary to link individual anomalies to the various syndromes, diseases, or associations of which they might be a feature. Development of a uniform coding system for human anomalies will undoubtedly be encouraged by the increasing reliance on electronic systems for storage, retrieval, and manipulation of data. 1.3 Genetic Causes of Malformations Current clinical and technological methods can determine the cause of approximately one-half of the anomalies found in newborn infants (Table 1-5). One-half of the identifiable causes are either wholly or partially genetic. The genetic content of egg and sperm brings to the conceptus all instructions necessary for the formation and function of a new life. Disturbances in the amount of genetic material (aberrations in chromosome number or structure) or in the nature of this material (mutations or epigenetic alterations of genes) may preclude normal formation, causing a wide range of malformations or other morphologic changes and an equally broad range of functional impairments. Experience in mammalian cloning and in human in vitro fertilization has indicated that the genetic content of the gametes (DNA) must go through an epigenetic process called ‘‘reprogramming.’’ This process involves methylation of the DNA and its histones, and possibly other epigenetic measures, in order for the early development of a zygote to occur in a normal way before implantation. Without this ‘‘reprogramming,’’ disorders involving genomic imprinting may occur with increased frequency. Chromosome Aberrations and Malformations

Over 75 years passed between Flemming’s observations of chromosomes in the epithelium of the human cornea (1882)106 and the first demonstration (by Lejeune in 1959107) of the chromosomal basis for a human malformation syndrome, although the link between chromosomes and malformations had been suggested in the interim. As early as the 1930s, Waardenburg and Bleyer independently predicted that nondisjunction of chro-

mosomes during meiosis, resulting in abnormal chromosome number, might be the cause of Down syndrome.108,109 Rapid refinement in tissue culture and metaphase preparation and agreement on nomenclature followed Tjio and Levan’s discovery in 1956 that the correct number of human chromosomes was 46.110 Within 3 years chromosome analysis became commonplace in laboratories throughout the world. The discovery of numerical chromosome aberrations followed (Table 1-6), opening an era when an answer to nearly all human maladies, but especially malformations and malformation syndromes, was sought in the chromosomes. A rich yield rewarded investigators who sought the explanation of spontaneous abortion in chromosome analysis.5,13,111–114 In 1961, Penrose and Delhanty demonstrated triploidy in a macerated fetus.112 In reports that followed, chromosome aberrations were found in approximately one-half of early spontaneous abortions. The 45,X karyotype was found most frequently, but tetraploidy, triploidy, and numerous other trisomies not seen in liveborn infants constituted a major portion of chromosomally abnormal abortuses (Table 1-7). Prenatal diagnosis of chromosome aberrations became possible in 1966, when Steele and Breg combined the technique of amniocentesis with culture of amniotic fluid cells.115 The reliability and safety of the combined procedures contributed to rapid acceptance of the techniques for pregnancies determined to be at increased risk of chromosome abnormalities and certain biochemical defects. The utility of chromosomes in expanding the understanding of malformation syndromes reached a plateau in the late 1960s. Table 1-6. Sequence of discovery of chromosome aberrations Year

Chromosome Aberration

1959

Trisomy 21; 45,X; 47,XXY

1960

Trisomy 18; trisomy 13

1961

47,XYY

1963

Del 5p

1965

Del 4p

1969

Fragile X

1971

Trisomy 8

1973

Trisomy 9

Human Malformations and Related Anomalies Table 1-7. Prevalence of chromosomal aberrations among spontaneous abortions Type of Aberration

Percent

All Chromosome Aberrations

40

Trisomies

20

T-16

8

T-13,15,21,22

2*

T-2,7,8,14,18

1*

T-4,9,10,20

0.5*

T-3,5,6,12,7

0.1*

T-1,11,19

<0.1*

Sex chromosome

<0.5

Monosomy X Autosomal monosomy

8 <0.1

Polyploidies

9

Triploidy

7

Tetraploidy Other Rearrangements Mosaicism Unbalanced rearrangement Balanced rearrangement

2 3 2 1 <0.5

*Approximate rate for each of the trisomies named.

Excitement was returned to the field of cytogenetics with the introduction of banding techniques by Caspersson et al. in 1971, demonstration of fragile sites by Sutherland in 1977, and analysis of prophase and prometaphase (high resolution) chromosomes in the early 1980s. The introduction of fluorescence in situ hybridization in the 1990s, and comparative genomic hybridization in the 2000s permitted the detection of deletions and duplications that were beyond the resolution of the light microscope.116–120 Chromosome watching provides only a crude view of genetic events. Best regarded as carrier structures, the chromosomes keep the genes together in a limited number of packets, perhaps maintain the genes in some necessary sequence, and provide for the orderly transmission of the genes they contain to daughter cells through mitotic division and to new offspring through meiotic division. Errors can occur and in fact are commonplace in each of these processes. Nondisjunction or anaphase lag can occur in mitosis or meiosis, resulting in an abnormal chromosome number in daughter cells or gametes.121,122 Translocation, inversion, deletion, and duplication may occur because of faulty crossing-over during meiotic division and result in imbalanced chromosome complement of gametes.123 In at least four circumstances, regions of chromosomes can become altered, rendering the involved region functionally inert. The phenomenon is called ‘‘inactivation,’’ involves no change in nucleotide sequence, and is reversed in gametogenesis prior to meiosis. Inactivation involving most of the X chromosome is a well-documented phenomenon.124 One X chromosome in normal females and all but one X chromosome in individuals with multiple X chromosomes become inactivated during the 1000–2000 cell stage of embryogenesis. Inactivation appears random; that is, either the maternal or the paternal chromosome can be inactivated, but once this is established it remains fixed for all descendants of the initially inactivated cell. With the exception of

15

certain small segments of distal short arm and distal long arm (pseudoautosomal regions 1 and 2), and specific loci elsewhere, all of the X chromosome participates in the inactivation (Fig. 1-2).125 Because of this phenomenon, normal females are genetically mosaic, a portion of their cells having one ‘‘active’’ X chromosome and the remaining cells having the alternative X chromosome active. At the molecular level, X chromosome inactivation is thought to be achieved by methylation of DNA. Inactivation of segments of other chromosomes is presumed to be responsible for partitioning of gene activity temporally (genes that are active during embryogenesis may become inactive thereafter) and by cell type (genes that are transcribed in hepatic cells may not be transcribed in muscle cells and vice versa). Considerable attention has recently been given to the potential of certain genes to be expressed differently depending on whether they were inherited from the mother or the father. This special type of altered gene activity has been called imprinting. As with other types of nonpermanent DNA modification, genomic imprinting may involve methylation of DNA and its histones and generally persists for life, although it may be reversible during gametogenesis and early embryogenesis.126–128 Epigenetic phenomena not only partition gene expression to appropriate tissue types, conserve gene expression for appropriate times in the life cycle, balance the male and female genomes, and perpetuate the requirement for paternal and maternal contributions to offspring, but these phenomena have the capacity to be significant causes of developmental disease and disability. Epigenetic influences are mediated through changes in chromatin structure.129–131 Although the repertoire of epigenetic phenomena

Fig. 1-2. Pseudoautosomal regions of the X chromosome in distal Xp22 and distal Xq28 and loci elsewhere on the X chromosome that escape X inactivation.

16

Overview

that influences gene expression is incompletely known at this time, modification of DNA and histones by methylation or deacetylation have received most attention. Whether epigenetic phenomena will give rise to malformations remains for the moment an intriguing but unanswered question. In the end analysis, chromosome changes of consequence cause an imbalance in a number of genes. Assuming equal size of genes and even distribution along the chromosome, the smallest resolvable chromosome change (one band of a 1000-band microscopic preparation) would affect 30 to 40 genes. Of course, genes are not of equal size, nor are they evenly distributed along the chromosomes. Genes appear to be more concentrated in the guanine-cytosine–rich regions of the chromosome, that is, regions that appear as light bands in giemsa–trypsin preparations and in the telomeres.122 Certain large genes, such as the dystrophin gene, which contains 2300 kb of DNA and spans 2.3 cM of the genome, would occupy most of an average band.132 More than 500 small genes the size of b-globin could crowd into a single average band. Deletion of a representative chromosomal band would leave the individual with only a single copy (hemizygosity) for 30 to 40 genes rather than the normal two copies of each (Fig. 1-3). Deleterious recessive characteristics, if encoded on the normal homolog, could be uncovered and expressed by such a deletion. Phenotype alterations different from those found in the heterozygous state might also accompany the hemizygous state for genes coding for dominant characteristics. Duplication of a ‘‘typical’’ band would, in effect, cause partial trisomy for 30 to 40 genes, allowing for a triple dose of each gene within the duplicated band (Fig. 1-3). Three genes for each locus

over even such a small region appear to be accommodated no more harmoniously than would three partners in a marriage. With the advent of fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) technologies, it has become much easier to identify small, submicroscopic deletions and duplications. It may be anticipated that equal numbers of deletions and duplications occur because of mismatched crossing over during meiosis. This prediction notwithstanding, the number of deletions identified far exceeds the number of duplications. It appears that repeated occurrence of similar sized deletions and duplications occur because there are similar LINE or repeat elements at each end of the segment that leads to mismatching. It is possible for all the genes on a duplicated chromosome or a duplicated chromosome band to be ‘‘normal’’ and yet cause structural and functional abnormalities. This suggests that quantitative expression of genes may be an important determinant of structure and function. In fact, all of human variability may owe more to variation in quantitative expression at each gene locus than to the quality of the gene expression controlled by its nucleotide sequence. Further augmentation or reduction of gene expression may be produced by inactivation or imprinting of genes, chromosome regions, or entire chromosomes.126–128 Chromosome abnormalities of all types exert their influence from conception onward. The possibility that they also influence function and survival of the gametes cannot be dismissed. A great variety of chromosome abnormalities can cause substantial disorganization of the conceptus, embryodysgenesis, and fetal pathology. Malformations, disturbances in growth, mental impairment,

Fig. 1-3. Human female metaphase (left) and karyotype (right). In each, trypsin Giemsa banding is used, and the resolution is 400–500 bands.

Human Malformations and Related Anomalies

and other features usually accompany even the most minute change in the chromosomes.123 Numerical Abnormalities

Reproduction in humans depends on the production of gametes through the process of reduction division, or meiosis. The number of chromosomes in the primordial cell must be reduced by onehalf during maturation of the gametes in the ovary and testis. It is during this process of meiosis that most numerical chromosome abnormalities arise, due mostly to failure of normal disjunction of homologous chromosomes (nondisjunction). When a gamete with other than 23 chromosomes participates in fertilization, the resulting zygote has an abnormal number of chromosomes. The consequence of this is that the pregnancy is usually lost, the conceptus either failing to implant or aborting during the early weeks of formation.9,13–17,123,133–140 With few exceptions, those conceptuses that are maintained are destined to be born with malformations and disturbances of growth and mental function.123,135,136 Trisomies

Aneuploidies are tolerated poorly in humans. Most produce such disorganization of the conceptus that implantation cannot be accomplished and maintained. Trisomy for each autosome has been detected in conceptuses (Table 1-7). Trisomy 16 is the most common autosomal trisomy and one with near total loss during pregnancy.13,138 Trisomy 1 has only recently been found and is the least common autosomal trisomy in abortion tissue.139,140 Although trisomies 13, 18, and 21 regularly cause abortion, they constitute the most common autosomal trisomies among liveborn infants (Table 1-8). Full trisomies for most other autosomes uniformly cause abortions.13,123,132,135,136 Each autosomal trisomy produces a more or less characteristic pattern of malformations.123,135,136 It is well known that the risk for trisomies increases with advancing maternal age, which has led to the availability of prenatal diagnosis for women over 35 years of age and the development of maternal serum screening.

Table 1-8. Prevalence of chromosomal aberrations among liveborn infants Chromosomal Aberration

Prevalence

Trisomy 21

1/700

Trisomy 13

1/7000

Trisomy 18

1/8000

Trisomy 8*

<1/100,000

Trisomy 9

<1/100,000

Monosomy X

1/2500 (females)

47,XXX

1/1200 (females)

47,XXY

1/1000 (males)

47,XYY

1/1000 (males)

Fragile X

1/4000 (males)

48,XXYY

1/25,000 (males)

48,XXXX

<1/100,000 (females)

48,XXXY

<1/100,000 (males)

49,XXXXX

<1/100,000 (females)

49,XXXXY

<1/100,000 (males)

*Usually mosaic.

17

Extra sex chromosomes are among the most common chromosome abnormalities in liveborn infants (Table 1-8). In general, malformations do not accompany the presence of one or more additional X or Y chromosomes. This is due in part to routine inactivation of all except one X chromosome in each cell and the paucity of active genes located on the Y chromosome. Extra sex chromosomes can produce alterations of growth (XXY, XYY, XXX), habitus (XXY), sexual maturation (XXY), and behavior (XXY, XYY). Monosomies

Full monosomies for other than the X chromosome do not exist in liveborn infants.123,135,136,139,140 Autosomal monosomies leave the organism at such risk for imbalance of all gene products in pathways for which genes are carried on the involved chromosome as well hemizygous expression of deleterious genes that they cannot survive the formative and fetal months. Likewise, monosomy for the Y chromosome is lethal in humans since numerous genes on the X chromosome are required for even the rudiments of embryonic development. In contrast, X monosomy is one of the most commonly observed aneuploidies. While highly lethal prenatally (95% of affected conceptuses spontaneously abort), X monosomy has an incidence of 1 in 2500 liveborn females. Probably, Turner syndrome pregnancies that survive to birth are mosaic with some chromosomally normal cells, at least in the placenta. Affected girls show growth impairment, ovarian dysgenesis with failure of sexual maturation, and anomalies of the skeleton, heart, kidneys, and craniofacies.135,136,141 Mosaicism

Numerical chromosome abnormalities can also occur by nondisjunction or anaphase lag subsequent to fertilization, leading to mosaicism.142 The affected individual has two or more chromosomally different cell lines, all derived from a single zygote. One cell line is usually normal. The timing of the misdivision after fertilization, the lineage of the initiating cell, and the viability of the aberrant cell line(s) determine the proportion and type of tissue(s) affected and the impact. Nondisjunction or anaphase lag occurring during the preimplantation and embryonic period can lead to malformations. Misdivision at a later time would not cause malformations, but could cause a mosaic pattern of skin or hair pigmentation, segmental dyssymmetry, and other growth disturbances.143 Mosaicism can be demonstrated in a single cell type (e.g., lymphocytes) or may require examination of different tissues. Cultured lymphocytes and skin fibroblasts are generally used for this purpose.144–146 Mosaicism confined to other tissues cannot be excluded with this approach. Mosaicism for numerical chromosome aberrations occurs sporadically, and transmission to the next generation is uncommon. Only if the germinal cells (oogonia or spermatogonia) are affected with the aneuploidy would there be risk of full aneuploidy in the offspring. Juberg et al.147 have suggested that a predisposition to anaphase lag may explain the recurrence of chromosomal mosaicism within a family. Mosaicism arising during the first few days after fertilization may affect the embryo, the extraembryonic tissues, or both. This phenomenon complicates the use of extraembryonic tissues such as chorionic villi for prenatal diagnosis and may explain survival of fetuses with certain severe trisomies. Kalousek et al.148 have demonstrated that trisomy 13 and trisomy 18 fetuses who survive pregnancy have placentas that are euploid, at least in part. Alternatively, aneuploidy confined to the placenta may explain

18

Overview

growth retardation or spontaneous abortion of chromosomally normal fetuses.149–151 Structural Chromosomal Abnormalities

Structural chromosomal abnormalities presumably arise during meiosis through abnormal pairing of homologous sequences and interchange of genetic material between chromosomes or between parts of the same chromosome. The same mechanism may underlie all types of structural rearrangements: translocations, deletions, duplications, inversions, and insertions. Certain structural rearrangements may remain balanced and nondisruptive, that is, resulting in no total loss or gain of genetic material, occurring between genes, and failing to interrupt the regulatory sequences of adjacent genes. In this circumstance no phenotypic consequence results from the rearrangement. Carriers of balanced rearrangements, however, have a 50% probability of producing unbalanced gametes. Other chromosome rearrangements are balanced but disruptive. A rearrangement of this type bisects a gene, preventing transcription, or disturbs the gene’s regulatory sequence and may be accompanied by phenotypic consequences. Unbalanced rearrangements result in a loss or a gain of chromosome material, or both. They can occur de novo or can result from unbalanced segregation of a balanced rearrangement in one of the parents. Deletions

A deletion is the loss of a portion of a chromosome (Fig. 1-4). Deletions can affect a single gene, being submicroscopic and requiring molecular techniques for detection, or may be large enough to be seen under the microscope.123,152–157 Deletion of a region of a chromosome has the same effect as monosomy. It leaves the involved region of the chromosome unpaired, a situation permitting deleterious genes to be expressed with no possibility of compensation by the missing allele. Table 1-9 gives the most common microdeletions currently recognized.

Fig. 1-4. Deletion. Top: idiograms and photomicrographs of a normal chromosome 5 (left) and a terminal deletion of the short arm of chromosome 5 (right) in a patient with the cri du chat syndrome. Bottom: idiograms and photomicrographs of a normal chromosome 17 (left) and an interstitial deletion of a portion of band p11.2 from the short arm of chromosome 17 (right).

A ring chromosome is formed by fusion of the two ends of a chromosome after deletion of the two telomeres and variable segments of juxtatelomeric genes (Fig. 1-5). Ring chromosomes are unstable, can vary considerably in size in different cells, and tend to be lost during cell division, leading to mosaicism.158 Phenotypic consequences are quite variable, depending on the genetic material deleted. It is unusual for ring chromosomes to persist for more than one generation. Duplications

A portion of a chromosome can become duplicated by unequal crossover involving a normal chromosome, by a cross-over between the breakpoints of a pericentric inversion, or by unbalanced segregation of a translocation (Fig. 1-6).123,159 Trisomy for the duplicated region of the chromosome results in phenotypic changes. Although anticipated with the same frequency as microdeletions, microduplications are recognized less commonly. This may be due to the production of less severe phenotypes, the difficulties of detection with current technologies, or other factors. Translocations

Several types of translocations occur in which chromosome material is interchanged between two chromosomes or transferred from one chromosome to another.160–164 Robertsonian translocations, the most common type, involve only the acrocentric chromosomes (13–15, 21, and 22) and arise by fusion of two chromosomes at the centromere, forming a single composite (compound) chromosome (Fig. 1-7).160 Residual fragments of the short arms of the two chromosomes are lost in subsequent divisions. Loss of the short arms, known to contain redundant ribosomal RNA genes, does not appear to influence health. Carriers of Robertsonian translocations between homologous acrocentric chromosomes produce only abnormal gametes, either containing the compound chromosome or missing one acrocentric altogether. Resulting pregnancies are trisomic or monosomic. Carriers of Robertsonian translocations between different acrocentric chromosomes produce normal gametes (25%), gametes lacking the homolog of one of the acrocentrics involved in the translocation (25%), gametes having the translocation (25%), or gametes that have the translocation plus the homolog of one of the acrocentrics involved (25%). Theoretically, an offspring has an equal chance of being a normal, balanced carrier, trisomic, or monosomic. Empirical observations document the risk for trisomy in offspring to be less than 25% and to differ depending on whether the mother or father is the translocation carrier.164 The risk for Down syndrome among offspring of mothers with balanced 14;21 translocations is 15%. When the father has a balanced 14;21 translocation, the risk decreases to 2–3%. Monosomy 14 and monosomy 21 fetuses are uniformly lost to spontaneous abortion. Reciprocal translocations involve exchange of material between two chromosomes, resulting in the formation of two abnormal composite (compound) chromosomes (Fig. 1-8).161 Balanced and nondisruptive translocations cause no phenotypic effects. One-half of the gametes produced by carriers of a balanced reciprocal translocation will be unbalanced. An insertion is a rare type of nonreciprocal translocation in which a segment of a donor chromosome is inserted into a nonhomologous chromosome.162 In the process, the donor chromosome becomes deleted. The phenomenon requires three breakpoints, one in the recipient chromosome and two in the donor. As with other translocations involving non-homologous chromosomes, this rearrangement can lead to abnormal gametes

Human Malformations and Related Anomalies

19

Table 1-9. Microdeletions associated with malformations and malformation syndromes Syndrome

Location

Findings

Alagille (JAG1)*

20p11.23-p12.2

Dysmorphic facial features, chronic cholestasis, vertebral arch defects, pulmonic stenosis

Albright hereditary osteodystrophy-like syndrome

2q37

Short stocky build, abnormal facies, brachymetaphalangism, seizures, developmental delay

Alpha-thalassemia and mental retardation (ATR-16)

16p13.3

Dysmorphic facial features, alpha-thalassemia, mental retardation

Angelman (UBE3A)*

15q11-q13

Hypotonia, microcephaly, hypopigmentation, ataxic gait, inappropriate laughter, seizures, mental retardation

Cat eye

22q11.2

Coloboma, choanal atresia, learning disabilities, mental retardation

Cri du chat

5p13-p15.2

Microcephaly, hypertelorism

DiGeorge 2

10p13

Dysmorphic facies, conotruncal heart defects, T-cell immune defects

Greig cephalopolysyndactyly (GLI3)*

7p13

Craniosynostosis, polysyndactyly, mental retardation

Langer-Giedion

8q24.1

Trichorhinophalangeal syndrome (sparse hair, bulbous nose, cone-shaped phalangeal epiphyses), multiple exostoses, mental retardation

Miller-Dieker (LIS1)*

17p13.3

Type I lissencephaly, dysmorphic facies

NF1 microdeletion

17q11.2

Neurofibromatosis, early age onset of cutaneous neurofibromas, facial dysmorphism, learning disabilities, mental retardation

Prader-Willi

15q11-q13

Hypotonia, obesity, short stature, small hands and feet, hypopigmentation, hyperphagia, mental retardation

Rubinstein-Taybi (CBP)*

16p13.3

Dysmorphic facial features, broad thumbs and first toes, mental retardation

Smith-Magenis

17p11.2

Dysmorphic facial features, behavioral abnormalities, self-destructive behavior, peripheral neuropathy, mental retardation

Velo-Cardio-Facial (proximal 22q microdeletion, diGeorge)

22q11

Abnormal facies, cleft palate, thymic hypoplasia, hypocalcemia, heart defect

WAGR (PAX6)*

11p13

Wilms tumor, aniridia, genitourinary anomalies, mental retardation

Williams (LIMK1)*

7q11.23

Dysmorphic facial features, infantile hypercalcemia, congenital heart disease, premature aging of the skin, gregarious personality, mental retardation

Wolf-Hirschhorn

4p16.3

Abnormal facies, cleft lip/palate, heart and renal malformations, brain anomalies, genital anomalies, mental retardation

1p36 Deletion

1p36

Hypotonia, growth abnormalities, craniofacial dysmorphism, minor cardiac malformations, developmental delay

Distal 22q microdeletion (ProSAP2 ?)

22q13-qter

Mild facial dysmorphism, hypotonia, severe language delay

Xp22.3 Deletion

Xp22.3

X-linked ichthyosis, epilepsy, ocular albinism, Kallmann syndrome, mental retardation

Xp21 Deletion

Xp21

Muscular dystrophy, glycerol kinase deficiency, congenital adrenal hypoplasia, mental retardation

*Gene in the microdeletion which may be responsible for some or all of syndrome manifestations. Modified from Schwartz and Graf 2002,156 Brewer et al. 1998.154

depending on the segregation of the two chromosomes involved and their homologs. Inversions

In pericentric inversions, a chromosome has breakpoints on both arms, with reversal of the intervening centromeric segment Fig. 1-5. Ring chromosome. Idiograms and photomicrographs of normal chromosome 22 (left) and a ring chromosome 22 (right). The satellites and the telomere of 22q have been lost.

(Fig. 1-9). When balanced and nondisruptive, the rearrangement is benign.165,166 During meiosis I, the inverted chromosome is required to form a loop to pair with its noninverted homolog. If an uneven number of crossovers occurs within the loop, the gamete will be unbalanced, having one part of the chromosome duplicated and another part deleted. Gametes formed with the duplication-deletion chromosomes are unbalanced. Theoretically, one-half of gametes formed by a parent with a pericentric inversion will be unbalanced if crossing-over occurs in the inverted segment. In paracentric inversions, a segment of genes on one arm of a chromosome is reversed.167,168 In the absence of a bisected gene or disrupted regulation of adjacent genes, this rearrangement is benign. As with pericentric inversions, paracentric inversions must form a loop for pairing of sequences along the inverted segment during meiosis. An unequal number of crossovers during this

20

Overview

Fig. 1-6. Duplication. Idiograms and photomicrographs of normal chromosome 1 (left) and duplication of most of the long arm of chromosome 1 (right). The duplicated region extends from the heterochromatic region (stippled) to the terminal band (q44).

pairing can produce two different types of duplication-deletion chromosomes, one of which is acentric and one dicentric. Theoretically, one-half of the gametes produced by a carrier of a balanced paracentric inversion would be unbalanced, having one of these two duplication-deletion chromosomes if crossing-over occurred in the inverted segment. Isochromosomes

Cleavage of the centromere perpendicular to the plane of usual cleavage results in isochromosome formation (Fig. 1-10). This misdivision occurs at metaphase (meiosis or mitosis), leaving the anaphase chromosome with two long arm (q) chromatids or two short arm (p) chromatids rather than one of each. The resulting isochromosome has two identical arms and functionally represents duplication of one arm of the chromosome and deletion of the

Fig. 1-7. Robertsonian translocation. Top: idiograms and photomicrographs of normal chromosomes 14 and 21 (left and middle) and a Robertsonian (centromeric) translocation involving chromosomes 14 and 21 (right). The combined chromosome retains all the active genes on chromosomes 14 and 21. The short arms are genetically inactive and presumed to be lost from most cells. Balanced translocation carriers have the combined chromosome in addition to one normal 14 chromosome and one normal 21 chromosome. A small percentage of patients with Down syndrome have the combined chromosome in addition to one normal 14 and two normal 21 chromosomes. Bottom: idiograms and photomicrographs of normal chromosomes 13 and 14 (left and middle) and a Robertsonian translocation involving these two chromosomes. This is the most common translocation in humans.

other. Autosomal isochromosomes are unusual, but Xq isochromosomes occur not infrequently.169,170 Fragile Sites

Heritable regions of chromosomes that show a tendency to separation, breakage, or attenuation under certain cell conditions have been termed ‘‘fragile sites.’’171,172 Numerous rare and common fragile sites have been identified (Fig. 1-11). Fragile sites vary in

Fig. 1-8. Reciprocal translocation. Idiograms and photomicrographs of normal 9 and 10 chromosomes (left and left center) and the derivative 9 and 10 chromosomes formed reciprocal translocation between the two chromosomes at breakpoints 9q21.2 and 10q21.1 (right center and right).

Human Malformations and Related Anomalies

Fig. 1-9. Pericentric inversion. Idiograms and photomicrographs of normal chromosome 2 (left) and pericentric inversion involving the segment p11 to q13 of chromosome 2 (right). The resulting inversion chromosome 2 has reduced short arm length and increased long arm length.

21

Fig. 1-10. Isochromosome. Idiograms and photomicrographs of normal X chromosome (left) and an isochromosome for the long arms of the X chromosome (right). The original chromosome is presumed to have divided horizontally rather than longitudinally, resulting in a long arm isochromosome shown here and a short arm isochromosome lost from this cell line.

Other Chromosome Aberrations

appearance under the microscope and are enhanced by folate or thymidine depletion of the culture media or by the addition of bromodeoxyuridine, distamicin A, or aphidicolin.172 The fragile site located at q27.3 of the X chromosome has been associated with human dysmorphism and mental retardation, the so-called fragile X syndrome (Fig. 1-12).

Breakage and rearrangement of chromosomes occur in a small group of autosomal recessive disorders. The number of breaks can be increased over the spontaneous number found in cell cultures by exposure to radiation, mitomycin-C, or diepoxybutane.173,174 Chromatid breaks are typically found in Fanconi anemia; breaks, triradial and quadriradial associations between chromosomes,

Fig. 1-11. Schematic of human chromosomes showing locations of major heritable fragile sites. Closed arrows indicate folate-sensitive sites, including the fragile X site Xq27.3. Open arrows indicated sites that are induced by bromodeoxyuridine (BrdU) and distamycin A. Bars indicate

common constitutive fragile sites that are folate sensitive and induced by aphidicolin. (After Jacky P: Fragile X and other heritable fragile sites on human chromosomes. In: The ACT Cytogenetics Laboratory Manual, ed 2. Barch MJ, ed. Raven Press, New York, 1991, p 489.)

22

Overview

Uniparental Disomy

The mechanism underlying these phenotypic changes is unknown, but it appears possible that some parts of the maternal and paternal chromosomes are modified (imprinted) differently during gametogenesis, and the contribution from both parents is necessary for normal growth and development.126 Heterodisomy exists when the homologous chromosomes are different but both inherited from one parent. In isodisomy, both members of a chromosome pair are identical and the individual is homozygous for all genes on the chromosome involved. Both types of uniparental disomy have been identified in humans. Maternal disomy has been found in 10–25% of individuals with Prader-Willi syndrome and paternal disomy in 3–4% of individuals with Angelman syndrome.128,177 Uniparental disomy has also been documented in some cases of Beckwith-Wiedemann syndrome (paternal UPD 11p15.5), Russell-Silver syndrome (maternal UPD 7), and in individuals with short stature, mental retardation, and multiple anomalies.178–180 Uniparental disomy is rare and may result in most cases from trisomy rescue. Isodisomy has been documented to lead to autosomal recessive disorders.181

1.4 Gene Mutations and Malformations

Fig. 1-12. Fragile X chromosome. Idiograms and photomicrographs of normal X chromosome (top left) and fragile site at q27.3 of the X chromosome (top right). Photographs show facial features of males with the fragile X syndrome. Child at age 3 years (bottom left) shows prominent forehead but little other distinctive facial changes. In adulthood (age 37 years, bottom right) the typical facies, with long face, prominent forehead, large ears, and large lower jaw is apparent.

and sister chromatid exchanges in Bloom syndrome; breaks and nonrandom rearrangements of chromosomes 7 and 14 in ataxia– telangiectasia; and breaks in progeria and Werner syndrome. Whether the growth impairment, malformations, and other dysmorphic features in these conditions can be attributed to the influence of these chromosomal changes during development or represent pleiotropic effects of the underlying mutation is unknown. Centromere separations (chromosome puffs), primarily involving the acrocentric chromosomes and chromosomes 1, 9, and 16, have been found in numerous patients with Roberts syndrome (SC phocomelia).175 The centromeric constriction of these chromosomes is lost, and two distinct centromeres in alignment with the two chromatids can be demonstrated with C-banding (Fig. 1-13). Although centromere separation has been noted in normal individuals, those with a variety of hematologic disorders, and in aging women, it is a useful marker to distinguish Roberts syndrome from other limb reduction syndromes. A second type of premature centromeric division that involves all or most of the chromosomes has been described in a syndrome of microcephaly, Dandy-Walker malformation, Wilms tumor, and mosaicism for several different aneuploidies (mosaic variegated aneuploidy).176

Genes are the physical units of heredity by which characteristics are transmitted from generation to generation in all living organisms. They are the functional units of inheritance. Genes constitute the primary elements of the chromosomes along the length of which they are irregularly distributed. An understanding of the function of genes preceded knowledge of the physical nature of genes. To Gregor Mendel, an Augustinian monk from Moravia (present-day Czech Republic), must go credit for discovery of the principles of heredity.182 Working with Pisum hybrids, Mendel found that hereditary characters were transmitted as units that retained their integrity generation to generation, even when their expression was masked by another character. Those characters expressed in the hybrid (heterozygote) he called dominant and those whose expression could be masked in the hybrid recessive: Those characters which are transmitted entire, or almost unchanged in the hybridization, and therefore in themselves constitute the characters of the hybrid, are termed dominant, and those which become latent in the process, recessive. The expression ‘‘recessive’’ has been chosen because the characteristics thereby designated withdraw or entirely disappear in the hybrids, but nevertheless reappear in their progeny. On this basis Mendel could predict the behavior of selected characteristics generation to generation and express the predictions in mathematical terms. His findings were contrary to the prevailing view that hereditary characteristics were blended in each new generation, and his work went unnoticed by the scientific community for 30 years.183–185 Shortly after 1900, examples of Mendel’s dominant and recessive inheritance were suggested as the basis for human disorders. Farabee186 attributed the malformation brachydactyly, found in five generations of a Pennsylvania family, to a dominant hereditary factor (Fig. 1-14). At the same time, Garrod187,188 described three inborn errors of metabolism: alkaptonuria,

Human Malformations and Related Anomalies

23

Fig. 1-13. Roberts syndrome patient showing limb reduction defects and premature separation of the centromere in metaphase chromosome preparation. (Courtesy Dr. G. S. Pai, Medical University of South Carolina, Charleston.)

cystinuria, and albinism. On the advice of Bateson, Garrod indicated that they could be caused by rare recessive factors. He further believed that these conditions and a fourth, pentosuria, which he added later, resulted from blocks in normal enzyme activities, anticipating the relationship between genes and enzymes that would be elucidated some 40 years later.

In 1911, Johannsen189 suggested the term gene be used for a hypothetical unit of heredity, acknowledging that no structure or specific mechanism of action for the unit could at the time be assigned. He also used the terms phenotype to indicate the features caused by a gene and genotype for the gene basis for a given phenotype.

24

Overview

Fig. 1-14. Pedigree of brachydactyly transmitted as an autosomal dominant trait published by Farabee in 1905. This trait was the first recognized to demonstrate that the laws of Mendel applied to humans as well as to plants and the lower animals.

Dysmorphologists, clinical geneticists, endocrinologists, and specialists in metabolism generally focus their studies on the functional and structural consequences of mutant genes. Such genes underlie no small portion of human dysmorphology. They are responsible for 70% of the 290 entries in Jones’ Smith’s Recognizable Patterns of Human Malformations.43 Malformations or other morphologic features are found in 2534 (17%) of the 15,262 entries in Mendelian Inheritance in Man. In 977 of these entries, the responsible gene has been identified or regionally mapped (Table 1-10).102 Because gene ascertainment has depended predominantly on phenotype, it might be anticipated that a significant portion of genes associated with human dysmorphism have already been identified. Molecular techniques developed during the past two decades have revised concepts of gene structure and regulation.190–196 Individual genes have been isolated, cloned, and sequenced. Genes have been shown to vary remarkably in size, to be configured of variable numbers of translated sequences (exons) separated by noncoding intervening sequences (introns), and to be closely flanked by regulatory sequences at the upstream (5') and downstream (3') ends (Fig. 1-15). Messenger RNA, formed of exons spliced together after the introns have been removed from precursor nuclear RNA (Hn RNA), provides the template for polypeptide assembly. It has now been estimated that humans may have as many as 30,000–40,000 gene pairs distributed along the 46 chromosomes.102,197–200 For the most part, genes have come to light only if they produce some distinctive change—morphologic or functional—within an individual. Other than acknowledging the existence of the gene that causes such a distinctive phenotype, little more can be said about most genes. The exact functions of relatively few genes have been determined. With the advent of large-scale mapping and sequencing projects, the capacity to localize gene expression in developing and mature tissue, and the technologies to alter gene expression in experimental animals, this situation will rapidly change.197–200 Molecular pathways, which link genes that influence each other and control the metabolism necessary for structural development, growth, and maintenance, are beginning to emerge.195,196 Extensive characterization of a gene and its chromosomal location, sequence, and gene product may be accomplished before a link between the gene and the human phenotype is recognized. Chromosome rearrangements and linkage analyses have allowed a number of genes that cause human anomalies to be localized

on various chromosomes.101,201 Table 1-10 lists the genes associated with malformations and malformation syndromes and gives the chromosome locations of other genes known to be involved in human anatomical development. Mutations are alterations in the coding sequence or regulatory apparatus of a normal gene. They result in altered amino acid sequences in the polypeptide gene product or in the amount of polypeptide produced. For each gene, the number of possible mutations is great. Many, perhaps most, do not cause phenotypic effects and exist as innocuous molecular polymorphisms in the population. Other mutations interfere with normal biologic processes sufficiently to prevent survival of the organism. Intermediate between these extremes are mutations that produce nonlethal changes in the phenotype. These constitute the single gene disorders that provide diagnostic and research challenges for the dysmorphologists and clinical geneticists. Most genes exist in pairs, or alleles, one located on each member of a pair of homologous chromosomes. The exceptions occur in males, in whom most genes on the X and Y chromosomes are unpaired, or hemizygous. Unless inactivated by one of the mechanisms described previously, all genes are expressed within the metabolic machinery of the cell. This metabolic expression, however, may not be reflected in discernible features (phenotype) of the individual. For this reason, the terms recessive and dominant are useful in the clinical setting to describe the phenotypic consequences of gene mutations. In the strict sense, use of these terms in reference to genes may be considered inappropriate, since expression can be equally evident at the cellular level for genes that produce no phenotypic changes as for those that produce dramatic change. However technically incorrect, common usage permits one to speak of recessive or dominant genes and gene mutations. Dominant Phenotypes

Phenotypic changes produced by a single dose of a given gene are termed dominant or, as noted above, the terms dominant genes and dominant mutations are commonly used to characterize genes that can produce phenotypic manifestations when present in a single dose. To date, dominant phenotypes outnumber recessive phenotypes, a finding likely related to easier ascertainment of the former.101 There is no a priori reason to suspect that the mutations leading to dominant phenotypes occur more frequently than those leading to recessive phenotypes, and work with experimental animals and plants indicates that most mutations are recessive (require a double dose for manifestation).

Table 1-10. Selected malformations and malformation syndromes for which the gene has been identified or localized Disorder

Gene/Locus/OMIM

Disorder

Gene/Locus/OMIM

ADULT (Acro-dermatoungual-lacrimal-tooth

p63, 3q27, 103285

Atrioventricular septal defect, partial, with heterotaxy

CRELD1, 3p25.3, 606217

Aarskog-Scott

FGD1, Xp11.21, 305400

Bamforth-Lazarus

FOXE1, 9q22, 241850

Acheiropody

C7orf2, 7q36, 205000

Bannayan-Riley-Ruvalcaba

PTEN, 10q23.31, 153480

Achondrogenesis

XLC26A2, 5q32-q33.1, 600972

Bardet-Biedl

209900

Achondrogenesishypochondrogenesis, type II

COL2A1, 12q13.11-q13.2, 200610

Type 1

11q13

Achondroplasia

FGFR3, 4p16.3, 100800

Type 2

16q21

Acrocallosal

GL13, 7p13, 200990

Type 3

3p13-p12 15q22.3-q23

Acrocapitofemoral dysplasia

IHH, 2q33-q35, 607778

Type 4

Acrofacial dysostosis, Nager type

9q32, 154400

Type 5

2q31

Acromesomelic dysplasia, HunterThompson type

CDMP1, 20q11.2, 201250

Type 6

20p12

Type 7

4q27

Acrorenalocular

SALL4, 20q13.13-q13.2, 102490

Type 8

14q32.1

Agenesis of the corpus callosum with peripheral neuropathy

SLC12A6, 15q13-q14, 218000

Barth

Xq28, 302060

Beare-Stevenson cutis gyrata

FGFR2, 10q26, 176943

Aicardi

Xp22, 304050

Alagille

JAG1, 20p12, 118450

Beckwith-Wiedemann

KIP2, 11p15.5, 130650

Allan-Herndon

Xq21, 309600

9q34.3, 269700

Albright hereditary osteodystrophy

GNAS, 20q13.2, 174800

Berardinelli-Seip congenital lipodystrophy

FOXL2, 3q23, 110100

Alopecia universalis

8p21.2, 203655

Blepharophimosis, epicanthus inversus, and ptosis, type 1

Alpha-thalassemia/mental retardation

XNP, Xq13, 301040

Borjeson-Forssman-Lehmann

PHF6, Xq26.3, 301900

Amelogenesis imperfecta

Xp22.3-p22.1, 301200

Type A1

IHH, 2q33-q35, 112500

Angelman

UBE3A, 15q11-q13, 105830

Type B1

ROR2, 9q22, 113000

Aniridia, type II

PAX6, 11p13, 106210

Type C

CDMP1, 20q11.2, 113100

Anophthalmia 3

SOX2, 3q26.3-q27

Types D and E

HOXD13, 2q31-q32, 113200

Anophthalmos-1

Xq27-q28, 301590

Anterior segment anomalies and cataract

EYA1, 8q13.3, 601653

Anterior segment mesenchymal dysgenesis

FOXC1, 6p25, 601090

Anterior segment mesenchymal dysgenesis and cataract

FOXE3, 1p32, 107250

Brachydactyly

Branchiooto

EYA1, 8q13.3, 601653

Branchiootorenal and branchiootorenal with cataract

EYA1, 8q13.3, 113650

Campomelic dysplasia

SOX9, 17q24.3-q25.1, 114290

Camurati-Engelmann disease

TGFB1, 19q13.1, 131300 9p21-p12, 250250

Antley-Bixler

PITX3, 10q25, 107250

Cartilage–hair hypoplasia

Apert

POR, 7q11.2, 124015

Cat eye

22q11, 115470

Arthrogryposis multiplex congenita, distal, type 1

FGFR2, 10q26, 101200

Cerebellar hypoplasia

OPHN1, Xq12

Cerebropalatocardiac

PQBP1, Xq11.2

Arthrogryposis multiplex congenital, distal, type 2B (see Freeman-Sheldon)

9p13.2-p13.1, 108120

Char

TFAP2B, 6p12, 169100

CHARGE

CHD7, 8q12, 214800

Arthrogryposis multiplex congenita, neurogenic

5q35, 208100

Chondrodysplasia punctata, X-linked recessive

ARSE, Xp22.3, 302950

Arthrogryposis, X-linked (spinal muscular atrophy, infantile, Xlinked)

Xp11.3-q11.2, 301830

Chondrodysplasia, Grebe type

CDMP1, 20q11.2, 200700

Chondrodysplasia, HunterThompson type

CDMP1, 20q11.2, 201250

Asphyxiating thoracic dystrophy (Jeune)

15q13, 208500

Cleft lip/palate, nonsyndromic

MSX1, 4p16.1, 119530

Atelosteogenesis I, III

FLNB, 3p14.3, 108720

Cleft palate with ankyloglossia

TBX22, Xq12-q21, 303400

Cleidocranial dysplasia

CBFA1, 6p21, 119600

Coffin-Lowry

RSK2, Xp22.2-p22.1, 303600

Colonic aganglionosis, total, with small bowel involvement

RET, 10q11.2, 164761

Atelosteogenesis II

SLC26A2, 5q32-q33.1, 256050

Atrial septal defect with atrioventricular conduction defects

NKX2E, 5q34, 108900

(continued)

25

Table 1-10. Selected malformations and malformation syndromes for which the gene has been identified or localized (continued) Disorder

Gene/Locus/OMIM

Disorder

Gene/Locus/OMIM

Conotruncal anomaly face

TBX1, 22q11.2, 217095

Type 2

COL9A2, 1p33-p32.2, 600204

Contractural arachnodactyly, congenital

FBN2, 5q23-q31, 121050

Type 3

COL9A3, 20q13.3, 600969

COL9A1-related

COL9A1, 6q13, 120210

Myopathy-related

COL9A3, 20q13.3, 120270

Cornelia de Lange (see de Lange) Costello

22q13.1, 218040

Cowden disease

PTEN, 10q23.31, 601728

Craniofrontonasal dysplasia

EFNB1, Xq12, 304110

Craniometaphyseal dysplasia

5p15.2-p14.1, 123000

Craniosynostosis, nonspecific

FGFR2, 10q26, 176943

Crouzon

FGFR2, 10q26, 123500

Crouzon with acanthosis nigricans

FGFR3, 4p16.3, 134934

Currarino

HLXB9, 7q36, 176450

Cutis laxa, AD

ELN, 7q11.2, 123700 FBLN5, 14q32.1, 123700

Cutis laxa, neonatal

ATP7A, Xq12-q13, 300011

De Lange

NIPBL, 5p13.1, 122470

DiGeorge

TBX1, 22q11.2, 188400

Exostoses, multiple, type 1

EXT1, 8q24.11-q24.13, 133700

Exostoses, multiple, type 2

EXT2, 11p12-p11, 608210

FG syndrome

Xq12-q21.31, 305450 Xq28, 300321 Xp22.3, 300406

Fanconi anemia Complementation group A

227650 16q24.3, 227650

B

BRCA2, 13q12.3, 227660

C

9q22.3, 227645

D1

BRCA2, 13q12.3, 605724

D2

3p25.3, 227646

E

6p22-p21, 600901

F

11p15, 603467

Diastrophic dysplasia

SLC26A2, 5q32-q33.1, 222600

Duane-radial ray

SALL4, 20q13.13-q13.2, 607323

G

FANCG, 9p13, 602956

FLJ90130, 18q12-q21.1, 223800

L

2p16.1, 608111

Dyggve-Melchior-Clausen Dyschondrosteosis (see Leri-Weill) Dyskeratosis congenita

DKC1, Xq28, 305000

Dyssegmental dysplasia, Silverman-Handmaker type

HSPG2, 1p36.1, 224410

EEC (Ectrodactyly-ectodermal dysplasia-clefting)

p63, 3q27, 129900

Ectodermal dysplasia, anhidrotic

Fibrodysplasia ossificans progressiva

FOP, 4q27-q31, 135100

Fragile X syndrome

FMR1, Xq27.3, 309550

Frasier, pseudohermaphroditism

WT1, 11p13, 136680

Freeman-Sheldon

11p15.5, 191043

Frontometaphyseal dysplasia

FLNA, Xq28, 304120

ED1, Xq12-q13.1, 305100

GM1-gangliosidosis

GLB1, 3p21.33, 230500

Ectodermal dysplasia, hidrotic

GJB6, 13q12, 129500

Greig cephalopolysyndactyly

GLI3, 7p13, 175700

Ectodermal dysplasia, hypohidrotic with immune deficiency

NEMO, Xq28, 300291

Hand-foot-uterus

HOXA13, 7p15-p14.2, 140000

Ectopia pupillae

PAX6, 11p13, 129750

Hay-Wells

p63, 3q27, 106260

Heterotaxy, X-linked visceral

ZIC3, Xq26.3, 306955

COL1A1, 17q21.31-q22, 130000

Heterotopia, periventricular

FLNA, Xq28, 300049

COL5A1, 9q34.2-q34.3, 130000

Hirschsprung disease

RET, 10q11.2, 142623

Ehlers-Danlos syndrome Type I

COL5A2, 2q31, 130000 Type II

COL5A1, 9q34.2-q34.3, 130010

Type III

COL3A1, 2q31, 130020

Type IV

COL3A1, 2q31, 130050

Type VI

1p36.3-p36.2, 225400

Type VII

COL1A1, 17q21.31-q22, 130060

Type VIIA2

COL1A2, 7q22.1, 130060

Type VIIC

5q23, 225410

Type X

2q34, 225310

Holoprosencephaly 1

HPE1, 21q22.3, 236100

2

SIX3, 2p21, 157170

3

SHH, 7q36, 142945

4

TGIF, 18p11.3, 142946

5

ZIC2, 13q32, 603073

6

HPE6, 2q37.1-q37.3, 236100

7

PTCH, 9q22.3, 601309

Holt-Oram

TBX5, 12q24.1, 142900

Hutchinson-Gilford progeria

LMNA, 1q21.2, 176670

Hydrocephalus due to aqueductal stenosis

L1CAM, Xq28, 307000

Hydrolethalus

11q23-q25, 236680

Ellis-van Creveld

4p16, 225500

Emery-Dreifuss muscular dystrophy

LMNA, 1q21.2, 181350

Epidermolysis bullosa dystrophica, AD

COL7A1, 3p21.3, 131750

Epiphyseal dysplasia, multiple

SLC26A2, 5q32-q33.1, 226900

Hyperostosis, endosteal

LRP5, 11q13.4, 144750

COMP, 19p13.1, 132400

Hypochondroplasia

FGFR3, 4p16.3, 146000

Type 1

(continued)

26

Table 1-10. Selected malformations and malformation syndromes for which the gene has been identified or localized (continued) Disorder

Gene/Locus/OMIM

Disorder

Gene/Locus/OMIM

Microcephaly, autosomal recessive, type 1

MCPH1, 8p23, 251200

Hypodontia

PAX9, 14q12-q13, 106600

Hypodontia with orofacial cleft

MSX1, 4p16.1, 106600

Incontinentia pigmenti Type II

NEMO, Xq28, 308300

Type 2

19q13.1-q13.2

FGFR1, 8p11.2-p11.1, 123150

Type 3

9q34

FGFR2, 10q26, 123150

Type 4

15q15-q21

11q23, 147791

Type 5

1q31

Type 6

13q12.2

Jackson-Weiss Jacobsen Jeune (see asphyxiating thoracic dystrophy)

Miller-Dieker lissencephaly

LIS1, 17p13.3, 247200

Xp22.3, 308700

Milroy lymphedema

VEGFR3, 5q34, 153100

Kallmann 2

FGFR1, 8p11.2-p11.1, 147950

Morning glory disc anomaly

PAX6, 11p13, 607108

Klippel-Trenaunay

5q13.3, 149000

Mowat-Wilson

SMADIP1, 2q22, 235730

Kneist dysplasia

COL2A1, 12q13.11-q13.2, 156550

Mucolipidosis II

GNPTA, 4q21-q23, 252500

Langer mesomelic dysplasia

SHOX, Xpter-p22.32, 249700

Mucopolysaccharidosis

Langer-Giedion

TRPS2, 8q24.11-q24.13, 150230

Ih, Ih/s, Is (Hurler, Scheie)

IDUA, 4p16.3, 252800

Laron dwarfism

GHR, 5p13-p12, 262500

II (Hunter)

IDS, Xq28, 309900

Larsen, autosomal dominant

FLNB, 3p14.3, 150250

IIIA (Sanfilippo A)

SGSH, 17q25.3, 252900

Lenz microphthalmia

Xq27-q28, 309800

IIIB (Sanfilippo B)

NAGLU, 17q21, 252920

LEOPARD

PTPN11, 12q24.1, 151100

IIIC (Sanfilippo C)

MPS3C, Chr. 14, 252930

Leprechaunism

INSR, 19p13.2, 246200

IVA (Morquio)

GALNS, 16q24.3, 253000

Leri-Weill (dyschondrosteosis)

SHOX, Xpter-p22.32, 127300

IVB (Morquio B)

GLB1, 3p21.33, 230500

Limb-mammary

p63, 3q27, 603543

VI (Maroteaux-Lamy)

ARSM, 5q11-q13, 253200

Lipodystrophy, familial partial

LMNA, 1q21.2, 151660

VII (Sly)

GUSB, 7q21.11, 253220

Lissenephaly-1

LIS1, 17p13.3, 607432

Kallmann

Lissencephaly

Muenke

FGFR3, 4p16.3, 602849

MULIBREY nanism

17q22-q23, 253250

Norman-Roberts type

RELN, 7q22, 257320

Multiple endocrine neoplasia I

MEN1, 11q13, 131100

X-linked

DCX, Xq22.3-q23, 300067

Multiple endocrine neoplasia IIA

RET, 10q11.2, 171400

X-linked with ambiguous genitalia

ARX, Xp22.13, 300215

Multiple endocrine neoplasia IIB

RET, 10q11.2, 162300

Lowe

Muscle-eye-brain disease

POMGNT1, 1p34-p33, 253280

OCRL, Xq26.1, 309000

Nail-patella

LMX1B, 9q34.1, 161200

Nance-Horan

NHS, Xp22.13, 302350

Lymphedema and ptosis

FOXC2, 16q24.3, 153000

Lymphedema-distichiasis

FOXC2, 16q24.3

Neurofibromatosis, type 1

NF1, 17q11.2 162200

MASA (Mental retardation, aphasia, shuffling gait, adducted thumbs)

L1CAM, Xq28, 303350

Noonan

PTPN11, 12q24.1, 163950

Norrie disease

Xp11.4, 310600

Oculodentodigital dysplasia

GJA1, 6q21-q23.2, 164200

MASS

FBN1, 15q21.1, 604308

Mandibuloacral dysplasia

LMNA, 1q21.2, 248370

OSMED

COL11A2, 6p21.3, 215150

Marfan

FBN1, 15q21.1, 154700

Oligodontia

PAX9, 14q12-q13, 604625

Marshall

COL11A1, 1p21, 154780

Opitz BBB

CXorf5, Xp22.3-p22.2, 311200

McCune-Albright

GNAS, 20q13.2, 174800

Osteogenesis imperfecta

McKusick-Kaufman, polydactyly

20p12, 236700

Type I

COL1A1, 17q21.31-q22, 166200

Type II

COL1A1, 17q21.31-q22, 166210

17q22-q23, 249000

Type III

COL1A1, 17q21.31-q22, 259420

Type 2

11q13, 603194

Type IV

COL1A1, 17q21.31-q22, 166220

Type 3

8q24, 607361

Meckel Type 1

Melnick-Needles

FLNA, Xq28, 309350

Menkes

ATP7A, Xq12-q13, 309400

Metaphyseal chondrodysplasia, Murk Jansen type

PTHR1, 3p22-p21.1, 156400

Metaphyseal chondrodysplasia, Schmid type

COL10A1, 6q21-q22.3, 120110

Osteopetrosis, autosomal dominant Type I Type II Osteopetrosis, autosomal recessive

IRP5, 11q13.4, 607634 CLCN7, 16p13, 166600 GL, 6q21, 259700 CLCN7, 16p13, 259700 TCIRG1, 11q13.4-q13.5, 259700 (continued)

27

Table 1-10. Selected malformations and malformation syndromes for which the gene has been identified or localized (continued) Disorder

Gene/Locus/OMIM

Gene/Locus/OMIM

Sjogren-Larsson

17p11.2, 270200

OPD1, Xq28, 311300

Smith-Fineman-Myers

XNP, Xq13, 309580

Otopalatodigital Type I

Disorder

FLNA, Xq28, 311300

Smith-Lemli-Opitz, type I

11q12-q13, 270400

PPM-X (mental retardation with psychosis, pyramidal signs and macroorchidism)

MECP2, Xq28, 300055

Smith-Lemli-Opitz, type II

11q12-q13, 268670

Pallister-Hall

GLI3, 7p13, 146510

Parietal foramina 1

MSX2, 5q34-q35, 168500

Peutz-Jeghers

19p13.3, 175200

Pfeiffer

FGFR1, 8p11.2-p11.1, 101600

Type II

FGFR2, 10q26, 101600 Piebaldism

KIT, 4q12, 164920

Polycystic kidney and hepatic disease

PKHD1, 6p21.1-p12, 263200

Polycystic kidney disease, adult type I

PKD1, 16p13.3-p13.2, 173900

Polycystic kidney disease, adult type II

PKD2, 4q21-q23, 173910

Polydactyly, postaxial Type A3

19p13.2-p13.1, 607324

Types A1 and B

GLI3, 7p13, 174200

Polydactyly, preaxial Type II

7q26, 174500

Type IV

GLI3, 7p13, 174700

Prader-Willi

15q11, 176270

Progeria

LMNA, 1q21.2, 176670

Pseudoachondroplasia

COMP, 19p13.1, 177170

Pycnodysostosis

CTSK, 1q21, 265800

Refsum

PEX7, 6q22-q24, 266500

Robinow, autosomal recessive

ROR2, 9q22, 268310

Rubinstein-Taybi

CREBBP, 16p13.3, 180849

SED congenita (spondyloepiphyseal dysplasia)

COL2A1, 12q13.11-q13.2, 183900

SEMD, Pakistani type (spondyloepimetaphyseal dysplasia)

10q22-q24, 603005

SMD (spondylometaphyseal dysplasia)

COL2A1, 12q13.11-q13.2, 184252

SMED, Strudwick type (spondyloepimetaphyseal dysplasia)

COL2A1, 12q13.11-q13.2, 184250

Saethre-Chotzen

Smith-Magenis

17p11.2, 182290

Smith-McCort dysplasia

18q12-q21.1, 607326

Sotos

NSD1, 5q35, 117550

Split hand/foot malformation Type 1 with deafness

7q21.2-q21.3, 605617

Type 1

7q21.2-q21.3, 183600

Type 2

Xq26, 313350

Type 3

10q24, 600095

Type 4

p63, 3q27, 605289

Type 5

2q31, 183600

Spondylocostal dysostosis, autosomal recessive, 1

19q13, 277300

Spondyloepiphyseal dysplasia tarda

Xp22.2-p22.1, 313400

Stickler Type I

COL2A1, 12q13.11-q13.2, 108300

Type II

COL11A1, 1p21, 604841

Type III

COL11A2, 6p21.3, 184840

Supravalvar aortic stenosis

ELN, 7q11.2, 185500

Sutherland-Haan

POBP1, Xp11.23, 309470

Symphalangism, proximal

NOG, 17q22, 185800

Synostoses, multiple, 1

NOG, 17q22, 186500

Synpolydactyly with foot anomalies

HOXD13, 2q31-q32, 186000

Synpolydactyly, 3/3’4, associated with metacarpal and metatarsal synostoses

FBLN1, 22q13.3, 608180

Synpolydactyly, type II

HOXD13, 17q22, 186000

Tarsal-carpal coalition

NOG, 17q22, 186570

Tetralogy of Fallot

JAG1, 20p12, 187500 NKX2E, 5q34, 187500

Thanatophoric dysplasia, types I and II

FGFR3, 4p16.3, 187600

Townes-Brocks

SALL1, 16q12.1, 107480 TCOF1, 5q32-q33.1, 154500

FGFR2, 10q26, 101400

Treacher Collins mandibulofacial dysostosis

TWIST, 7p21, 101400

Trichorhinophalangeal

Schwartz-Jampel, type 1

HSPG2, 1p36.1, 255800

Septooptic dysplasia

3p21.2-p21.1, 182230

Type I

8q24.12, 190350

Type III

8q24.12, 190351

EDN3, 20q13.2-q13.3, 277580

Ulnar-mammary

TBX3, 12q24.1, 181450

Shprintzen-Goldberg

FBN1, 15q21.1, 182212

Van Buchem disease

17q11.2, 239100

Sialic acid storage disorder, infantile

6q13-q15, 269920

Van Buchem disease, type 2

LRP5, 11q13.4, 607636

Van der Woude, Type 1

IRF6, 1q32-q41, 119300

Silver-Russell

7p11.2, 180860

Van der Woude, Type 2

1p34, 606713

Simpson-Golabi-Behmel, type 1

GPC3, Xq26, 312870

Velocardiofacial

22q11.2, 192430

Situs ambiguous

NODAL, Chr. 10, 601265

Shah-Waardenburg

28

(continued)

Human Malformations and Related Anomalies

29

Table 1-10. Selected malformations and malformation syndromes for which the gene has been identified or localized (continued) Disorder

Gene/Locus/OMIM

Disorder

Vohwinkel with ichthyosis

1q21, 604117

Williams-Beuren

ELN, 7q11.2, 194050

WAGR (Wilms tumoraniridia-genitourinary anomalies-mental retardation)

WT1, 11p13, 194072

Wolf-Hirschhorn

4p16.3, 194190

X-linked hydrocephalus spectrum

L1CAM, Xq28, 303350

Zellweger

PEX1, 7q21-q22, 214100

Waardenburg

Gene/Locus/OMIM

PEX2, 8q21.1, 170993

Type I

PAX3, 2q35, 193500

Type IIA

MITF, 3p14.1-p12.3, 193510

Type III

PAX3, 2q35, 148820

PEX5, 12p13.3, 214100

Waardenburg-Shah

SOX10, 22q13, 277580

PEX10, Chr. 1, 214100

Walker-Warburg

9q31, 236670

PEX13, 2p15, 214100

Weaver

NSD1, 5q35, 277590

PEX16, 11p12-p11.2, 603360

Weill-Marchesani

ADAMTS10, 19p13.3-p13.2, 277600

PEX19, 1q22, 214100

It is anticipated that mutations leading to dominant phenotypes will in most cases affect genes coded for structural proteins. Examples include mutations of collagen genes resulting in Stickler syndrome and osteogenesis imperfecta.202,203 Mutation of Fig. 1-15. The repertoire of DNA in somatic cells is shown in this schematic. Through the process of replication (1), DNA duplicates itself prior to cell division so that identical genetic information can be transmitted to daughter cells. Through the processes of transcription, RNA processing, and translation (2–8) the genetic information is utilized within the cell to synthesize polypeptides or proteins. (Reprinted with permission from Miller WL: J Pediatr 99:1, 1981.)

PEX3, 6q23-q24, 214100 ABCD3, 1p22-p21, 170995

a single gene controls the amount or structure of 50% of the gene product produced, which in the case of structural protein can be sufficient to cause phenotypic changes. For this reason, these mutations are good candidates to cause structural abnormalities during embryogenesis. The study of rare pathologic phenotypes in the population allows certain generalizations about the mode of inheritance to be made. The implications of dominant phenotypes differ depending on whether the responsible gene is located on an autosome or on the X chromosome (Figs. 1-16, 1-17). Characteristics common in autosomal dominant phenotypes include the following. 1. 2. 3. 4.

Males and females are affected in equal proportions. Male-to-male inheritance does occur. Only one parent is usually affected. Each offspring of an affected parent has a 50% risk of being affected. 5. Normal children of an affected parent will not transmit the condition to their children. Characteristics common in X-linked dominant phenotypes include the following. 1. 2. 3. 4.

Males and females are affected in a 1:2 ratio. Male-to-male inheritance does not occur. Affected males transmit the phenotype to all of their daughters. Offspring of affected females have a 50% risk of being affected whether male or female. 5. Only one parent is usually affected. 6. Heterozygous females are affected less severely than are hemizygous males.

Pleiotropy

The mutation of a single gene can produce multiple effects (pleiotropism) in the phenotype. These effects may appear unrelated; but in some cases the underlying metabolism or the developmental process by which the features arise during embryogenesis provides an explanation for the pleiotropism. In other cases the explanations remain obscure. Genetic Heterogeneity

Identical or similar phenotypic disturbances can be caused by different gene mutations or chromosome imbalances. When

30

Overview

Fig. 1-16. Autosomal dominant inheritance. Top: pedigree showing autosomal dominant inheritance. Note that males and females are affected and that male-to-male transmission occurs. Middle: segregation of an autosomal dominant trait when one parent is affected. Each child, male or female, has a 50% chance of being affected. Bottom: segregation of an autosomal dominant trait when both parents are affected. Each child has a 50% chance of being affected (receiving the trait from one or the other parent), a 25% chance of being normal, and a 25% chance of being severely affected (receiving trait from both parents).

genetically determined phenotypes mimic each other, they are termed genocopies (e.g., Marfan syndrome and homocystinuria). Environmentally caused mimics of a genetically determined phenotype can occur as well and are termed phenocopies (e.g., the limb malformation condition produced by thalidomide exposure during pregnancy is a phenocopy of the genetic entity

Fig. 1-17. X-linked dominant inheritance. Top: pedigree showing X-linked dominant inheritance. Note males and females are affected, but male-to-male transmission does not occur. Middle: segregation of X-linked dominant trait when the father is affected. All daughters are affected, and all sons are normal. Right: segregation of X-linked dominant trait when the mother is affected. Each son or daughter has a 50% risk of being normal and a 50% risk of being affected.

SC phocomelia). For this reason, precise ascertainment of the cause of a given phenotypic change is fundamental to accurate counseling and rational preventive efforts. Penetrance

The frequency with which evidence of a mutant gene can be found in the phenotype is called penetrance. Usually used in reference to

Human Malformations and Related Anomalies

31

dominant phenotypes, full or complete penetrance describes phenotypic effects found in every individual possessing a given gene mutation. Incomplete or reduced penetrance occurs when some proportion of persons possessing a gene mutation show no phenotypic effect. Expressivity

Expressivity indicates the degree to which a mutant gene is manifest in the phenotype. Some degree of variable expressivity can be expected in most phenotypes depending in part on the influence of other genes, various types of inactivation, and environmental forces. Recessive Phenotypes

Phenotypes that require a double dose of a given gene are termed recessive. The abnormal gene product is usually an enzyme or transport protein. In the individual homozygous for these mutations, the structure of all of the gene product or the quantity produced is affected by the mutation. Individuals who have only one mutant gene are called carriers or heterozygotes, have 50% of their gene product affected by the mutation, and generally exhibit no phenotypic consequences. Because of the nature of the gene product affected by these mutations, the recessive phenotypes are often metabolic disturbances that impair function rather than morphology. Morphologic changes, if they occur, usually develop after embryogenesis or even postnatally. Exceptions to this generalization include extra digits in Carpenter syndrome, radial aplasia in Fanconi pancytopenia syndrome, marked prenatal growth impairment in achondrogenesis, and brain malformations seen in the congenital disorders of glycosylation and cholesterol metabolism. Implications of recessive phenotypes also depend on whether the responsible gene is located on an autosomal or a sex chromosome (Figs. 1-18, 1-19). Characteristics of autosomal recessive phenotypes include the following. 1. Males and females are affected in equal proportions. 2. Both parents must be carriers of a single copy of the responsible gene for a child to be affected. 3. Parents (heterozygous carriers) are usually normal. 4. Each child of carrier parents has a 25% risk of being affected, a 50% risk of being a carrier, and a 25% risk of being a nonaffected noncarrier. 5. The rarer the mutant gene is in the population, the greater the likelihood that parents of affected children will be consanguineous. Characteristics of X-linked recessive phenotypes include the following: 1. Only males are fully affected. 2. Sons of carrier females have a 50% risk of being affected. 3. Daughters of carrier females have a 50% risk of being carriers. 4. Male-to-male transmission does not occur. 5. All daughters of affected males will be carriers. 6. Unaffected males cannot transmit the phenotype. 7. A small percentage of females may show mild abnormalities. Carrier detection using biochemical or molecular techniques (linkage or gene analysis) has become possible for many autosomal and X-linked recessive phenotypes (Table 1-10). Such testing will become increasingly important in the prevention of birth defects and functional impairments.

Fig. 1-18. Autosomal recessive inheritance. Top: pedigree showing autosomal recessive inheritance. Note that both parents must be carriers, and the affected offspring may be male or female. Bottom: segregation of autosomal recessive trait in offspring when both parents are carriers. Each offspring has a 25% risk of being normal noncarrier, a 50% risk of being a carrier, and a 25% risk of being affected (inheriting the trait from both parents).

Mosaicism

When mutations occur after fertilization of an egg, a mosaic condition results in which the lineage of one cell harbors the mutation and one cell line remains normal.204 Depending on the type of gene affected, on the timing of the mutation, and on the lineage and viability of the cells bearing the mutation, phenotypic disturbances of various magnitudes can result. Certain conditions of unknown causation have been identified as candidates for single gene mosaicism, primarily because of the clonal or segmental nature of their phenotypic changes. Among these are Proteus syndrome, various pigmentary disturbances, McCune-Albright syndrome, Klippel-Trenaunay-Weber syndrome, and tumors. Germ line mosaicism describes the presence of a mutant germ line that is not found in the individual’s somatic cells. Although rarely documented, this phenomenon may explain the occurrence of several offspring affected with a dominant phenotype born of normal parents. Such has been suspected in some cases of achondroplasia and has been demonstrated by molecular techniques in

32

Overview

reaction (at the cellular level), can shape the entire individual. The power of such mutations to malform if expressed during embryogenesis or to otherwise disturb morphology if expressed later is not ordinarily offset by other genes or by the environment; that is, the penetrance of such abnormal genes is often very high. Polygenic Phenotypes

Although no example of a polygenic phenotype related to human anomalies can be given, it must be surmised that in some cases mutations of more than one gene may collaborate to produce phenotypic changes. Fingerprint patterns appear to be determined polygenically.206,207 It is most appropriate to consider polygenic inheritance in its role as the genetic component of multifactorial causation (see Multifactorial Causation of Human Anomalies, following). Contiguous Gene Phenotypes

Local groupings of separate genes that can be simultaneously affected by microdeletions and possibly by mutations have been termed contiguous gene complexes.152–155 The phenomenon, also termed segmental aneusomy, has been helpful in localizing genes to a specific chromosomal region and in determining their order. It provides a basis for phenotypic variability that might otherwise be attributed to variable expressivity or pleiotropism of a single gene. The phenotypes produced may have diverse components, each of which may be caused by alteration of a separate gene (Table 1-9). Alternatively, mutations can occur independently in any single gene in a contiguous gene complex without disturbing adjacent genes. Multifactorial (Bifactorial) Causation of Human Anomalies

Fig. 1-19. X-linked recessive inheritance: Top: pedigree of X-linked recessive inheritance. Note that males can be affected in multiple generations and that they inherit the X-linked trait from their mothers. Middle: segregation of X-linked recessive trait when the father is affected. All daughters are carriers, and all sons are normal noncarriers. Bottom: segregation of X-linked trait when the mother is a carrier. Each son has a 50% risk of being affected and each daughter is a 50% risk of being a carrier.

the case of osteogenesis imperfecta.205 When the mutation is known, it may be possible to look at sperm from a phenotypically normal father to determine whether he has germ line mosaicism. Alteration of a single gene can have a profound phenotypic effect, indeed as great as adding or deleting an entire chromosome. The effect of a mutation, while limited to a single metabolic

At the interface of genetic etiology and environmental etiology is multifactorial (bifactorial) causation, which requires the combined influences of both. Hereditary and environmental factors collaborate to cause certain malformations, other morphologic characteristics, and functional disabilities. Implicit in the multifactorial concept is the notion that the individual genetic or environmental factors involved lack the power to produce an abnormal phenotype but that multiple factors, heritable and environmental, can do so through their additive influence.208,209 By definition, if genes from two or more loci participate, the genetic component is polygenic. Multifactorial causation is broadly accepted, the evidence for it based on the recurrence risks for certain phenotypes within a family being greater than that for the general population but significantly lower than Mendelian expectation, the high but incomplete concordance in monozygotic twins, and the significantly lower but not negligible concordance in dizygotic twins. Isolated neural tube defects, cleft lip/palate, and certain cardiac defects meet these criteria and are considered to be malformations with multifactorial causation (Table 1-11). No example can be given, however, in which the genetic components and the environmental components have been fully elucidated, although there are suggestions that the combination of maternal smoking and certain predisposing genes may markedly increase the risk for facial clefting. Multifactorial causation is also considered responsible for phenotypes found in the extremes of continuous morphologic variation and for phenotypes found only beyond a developmental threshold. Continuous Traits

Human characteristics that vary by measurable increments across a broad spectrum are called continuous traits. Morphologic features

Human Malformations and Related Anomalies Table 1-11. Incidence of selected malformations which often have multifactorial causation Malformation

Incidence per 10,000 births

Neural tube defects Anencephaly

5

Spina bifida

5

Encephalocele

1

Cleft lip/palate

10

Congenital dislocation of the hip

10

Club foot

12

Pyloric stenosis

30

Cardiac defects

70

included among the continuous traits are head circumference, height, and interpupillary measurement. No abrupt change separates normal from abnormal (Fig. 1-20). Abnormalities of these characteristics are arbitrarily defined as those variations that fall beyond 2 SD in either direction from the mean for a given population. Hence, macrocephaly can be defined as head circumference or volume greater than 2 SD above the mean, microcephaly as head circumference or volume less than 2 SD below the mean, short stature as height less than 2 SD below the mean, and so forth. It should be cautioned that phenotypes defined as abnormal in this system should not be considered absolute, fixed for all time and all populations.210 Rather, they should be considered abnormal only for a given subpopulation, at a given point in time, and in relationship to parental background. Threshold Traits

Traits that do not vary continuously but appear only above a given threshold are called discontinuous or threshold traits. Several of the more common human malformations, notably neural tube defects and cleft lip and palate, are included among these traits (Table 1-11). Characteristics that can be expected in multifactorial causation are as follows.

Fig. 1-20. Distribution curve for height, a trait with continuous variation; 95% of individuals will have measurements between the two arrows (mean ± 2 SD).

33

1. Males and females are affected but often with unequal frequencies. 2. There is an increased risk for recurrence in first-, second-, and third-degree relatives of an index case: 2–5% for firstdegree relatives, about one-fourth as high for second-degree relatives and one-tenth as high for third-degree relatives. (Edward’s approximation211 states that the recurrence risk for first-degree relatives is Hp, where the incidence in the population is p.) 3. The recurrence risk doubles after a second first-degree relative is affected. 4. The recurrence risk increases with severity of the phenotype in the index case. 5. The recurrence risk increases if the index case is of the sex less frequently affected. The nature and number of genes and environmental factors involved in the production of any multifactorial malformation cannot be given. The concept that a vast number of genes and environmental factors must be operative is probably incorrect. Assuming equal environmental and genetic contributions to a hypothetical malformation with a recurrence risk of 2–5%, the number of genes involved in producing the malformation can be as few as three. The only requirement of the environmental factor is that it be operative during the period of embryogenesis. One might suspect nutritional variations to be a strong environmental contributor prenatally, as they are in many multifactorial phenotypes postnatally. 1.5 Environmental Causes of Malformations The uterus serves to shelter, nourish, and protect the conceptus until maturity sufficient for extrauterine viability is reached. When any of these basic functions fails, the organism can suffer pathologic consequences. The available safe-guards are simply insufficient to protect against every environmental exposure that may be imposed through the maternal host.212–217 Noxious insults from the environment usually reach the developing organism by way of the vascular system and placenta, less commonly by direct penetration through the uterine wall, and rarely by ascent through the os cervix. Environmental insults after fertilization that produce structural defects are termed teratogens, from the Greek word teratos (monster) and gen (producing). Because of this derivation, it seems inappropriate to classify influences as teratogenic unless they can cause structural defects. However, many teratogens are known to lead to functional as well as structural abnormalities. Agents that cause visual impairments, hearing impairments, or mental retardation are not teratogens unless (in the process) they malform the eyes, ears, or brain. Nor should chromosome aberrations or mutations be considered teratogenic. The term is reserved for environmental insults. Teratogenic potential is largely limited to the period of organogenesis, although certain insults, primarily ones mechanical in nature, can produce deformation or destruction of tissues after the embryonic period. Certain chemicals (e.g., alcohol, warfarin, mercury) and infections (e.g., rubella, herpes, varicella, syphilis) may disturb growth and tissue maturation after the period of organogenesis. By and large, environmental exposures are sporadic events with a low likelihood of recurrence. However, they are likely to

34

Overview

interact with the genotype of both mother and embryo/fetus. Teratogenic effects recur in successive pregnancies only if the environmental exposure and genetic susceptibility recurs. Environmental insults can indirectly affect the conceptus by causing ill health in the mother. General systemic toxicity may accompany radiation exposure or certain infections, leading to abortion although no specific damage has been caused to the tissues of the conceptus. Alternatively, environmental insults can produce chromosome damage or mutation in the developing conceptus that in turn leads to abortion, malformation, or other injury. Radiation and certain chemicals have this potential. Occurring after fertilization, such induced genetic damage will affect only a portion of the cells, will become heritable only if germ cells are involved, and should not be considered teratogenic or hadegenic. Teratogens directly influence development by interfering with cellular metabolism, altering timing, placing pressure on developing parts, disturbing regional vascular supply, and killing cells. Metabolism may be disturbed by altering the availability of essential nutrients, inhibiting enzyme activities, blocking mitosis, interfering nonmutationally with nucleic acid function, and impairing membrane function, osmolar balance, and energy production.215,217 A certain degree of protection against prenatal environmental insults may be afforded by the genetic constitution of a conceptus. This can be surmised from the variable rates at which identical insults induce malformations in different strains of experimental animals218 and in dizygotic twins. It explains in part the variable rates of specific malformations among the different human races.219 However, some teratogens have sufficient potency that they cannot be neutralized by genomic protection. Thalidomide apparently represents such a teratogen. It must be suspected that the genotype of the mother can also diminish or enhance the susceptibility to teratogenic influences as well. The time during pregnancy when the environmental exposure occurs greatly influences the effects. An insult that produces teratogenic effects during organogenesis may have no apparent later effects or may influence subsequent growth and physiologic function. For example, prenatal rubella infection during the first 2 months produces cardiac defects; infection after the fourth month produces deafness; and infection at any time causes growth impairment. For teratogenic effects to occur, the environmental agent must gain access to the conceptus or induce disturbances in the mother that are then reflected in the conceptus. Certain chemical agents, because of their size, transport, or binding properties, do not reach the conceptus even though they may be present in the maternal circulation. Many hormones are typical of this phenomenon. They exert their influence via metabolic changes in the mother that can then be imposed transplacentally. Most teratogenic influences are dose dependent: the greater the exposure, the greater the likelihood of adverse effects and the greater the severity of the effects produced. Radiation

Radiation, a ubiquitous environmental influence, has the potential to produce fetal death, growth impairment, somatic abnormalities, mutation, chromosome fragmentation, and malignancy. Ionizing radiation from any source—natural, conventional x-ray machines, isotopes, or nuclear explosions—carries this potential. Radiation-induced pathology in the conceptus presumably arises because of impairment of cell division, cell death, mutation, and chromosome damage.220

All persons are inescapably exposed to low doses of naturally occurring radiation. At the surface of the earth the magnitude of this exposure is about 125 mrad per person per year, but can vary several fold in different locations around the world. A rad is the unit of absorbed energy equivalent to 100 ergs per gram of tissue. For example, from a chest radiograph, an individual receives onethirtieth of a rad of radiation to the chest wall. Nearly one-half of naturally occurring radiation derives from the land, the structures thereon, and the air; 30% from cosmic sources; and 20% from ingested radionuclides. Less than 5% of radiation in the general environment derives from nuclear-powered reactors or residual fall-out from nuclear explosions. The discovery of x-rays in 1895 and subsequent efforts to exploit the properties of ionizing radiation for diagnostic and treatment purposes have increased the average exposure 50–100% over the natural background radiation. An approximation of the radiation dosage to the fetus or embryo from diagnostic radiographic examinations of the mother can be deduced from the ovarian dosages given in Table 1-12.221 Although the total human exposure to intrauterine radiation fortunately is limited, sufficient data have been gained from medical radiation and from the nuclear explosions at Hiroshima and Nagasaki to delineate the major effects on the conceptus. By the time of birth, the usual infant will have received about 90 mrad of radiation from the natural environment and possibly an equal amount from medical procedures. The effects from this low level of radiation exposure are not measurable. Although the low level of radiation exposure may contribute in some minor way to mutation rate, it does not make a discernible contribution to the abortion, congenital malformation, and growth impairment rates or to any other measure of ill health in the embryo or fetus. Much higher exposures are required to reach the threshold of overt effects. Each year approximately 15–20% of women between ages 15 and 35 years will have abdominal or pelvic radiographs. The radiation dosage from such exposures is usually low, but always causes alarm if the woman is subsequently found to be pregnant. The radiation doses received by the uterus during various medical procedures are listed in Table 1-12.221 The most commonly encountered exposure is a dose of 0.5 to 2 rads from intravenous pyelography, barium enema, or pelvic computerized tomography. With these levels of exposure no gross defect or growth impairment is to be expected in the offspring regardless of the time of the exposure; however, the possibility of intrauterine growth retardation has recently been raised.221a The possibility of mutational injury must be considered, but no practical means of detecting such injury currently exists.222 Mutations to the germ line of the in utero embryo or fetus can lead to a transgenerational effect. Progressively greater resistance to the lethal effect of radiation is gained as the conceptus passes through the preimplantation, embryonic, and fetal periods. Exposure during the preimplantation period either kills the conceptus or leaves no overt trace of injury, suggesting that the teratogenic and lethal doses do not differ significantly during this time. Radiation doses in excess of 10 rads may be lethal during the first week postfertilization. The minimum lethal dosage steadily increases from 25 to over 100 rads between the first and last weeks of embryogenesis. In the early decades of this century x-rays were used to induce abortion. In the majority of cases (96%), a single dose of 360 rads to the uterus prior to 14 weeks gestation resulted in abortion.223 Impairment of growth is the most sensitive measure of radiation effect on the embryo and fetus.220 During embryogenesis,

Human Malformations and Related Anomalies

Table 1-12. Estimated ovarian radiation dose from various diagnostic radiographic procedures

Examination

Estimated Ovarian Radiation Dose (millirads)

Barium Enema Total

805

Radiography

439

Fluoroscopy

366

Upper Gastrointestinal Series Total

558

Radiography

360

Fluoroscopy

198

Intravenous or retrograde pyelography

407

Hip

309

Abdomen

289

Lumbar spine

275

Cholecystography

193

Pelvis Thoracic spine

41 9

Chest Radiography Photofluorography Fluoroscopy

8 8 71

Skull

4

Cervical spine

2

Upper extremity (excluding shoulder)

1

Shoulder

<1

Lower extremity (excluding hip)

<1

Penfil RL, Brown ML: Genetically significant dose to the United States population from diagnostic medical roentgenology, 1964. Radiology 90:209, 1968.

35

dosage and less concentration in the thyroid gland. Diagnostic procedures with isotopes other than 131I are unlikely to expose the fetus to hazardous levels of radiation. Microwaves, Shortwaves, and Radiowaves

Radiation from exposure to radiowaves, shortwaves, and microwaves can produce tissue heating, and, hence, may disturb embryonic development. Shortwave radiation can penetrate deeply enough into solid tissues to reach the human fetus and, thus, is a greater potential hazard than microwaves.231,232 Microwaves have limited penetration power, reaching 3–4 cm below the skin surface, and thus have limited access to the human embryo and fetus. Microwave ovens and diathermy machines produce radiation in this wave length (2450 mHz). There is no current evidence indicating that radiowaves, shortwaves, or microwaves can cause nonthermal injury to the developing embryo. Magnetic Fields

Human exposures to magnetic fields result primarily from video display terminals and magnetic resonance imaging (MRI) machines. Neither type of exposure has caused malformations, but the risk for pregnancy loss may be increased.233 Ultrasound

Diagnostic ultrasound is used in the majority of pregnancies during the first and second trimesters. Although usually performed to determine fetal age, ultrasound is also used to document fetal movement, placental location, number of fetuses, number of corpus luteum, growth increments, and certain malformations. Such examinations use ultrasound in microsecond pulses separated by 1–2 sec pauses and have not been associated with any adverse effect on the fetus.234 Continuous wave ultrasound can, of course, disrupt cellular structure and can generate tissue destruction through thermal effects. McLeod and Fowlow235 described growth impairment, microcephaly, sacral dysgenesis, and developmental impairment in an infant born following therapeutic ultrasound to the psoas bursa of the mother at days 6 to 29 postovulation. Hyperthermia and Hypothermia

25 rads or more are required to impair growth. Some degree of recovery from growth impairments caused during embryogenesis may be anticipated postnatally. Fifty or more rads are required to impair fetal growth. Growth impairment during this period is less likely to improve during the postnatal period. The brain and eyes sustain the brunt of radiation injury during embryogenesis.224–228 Dosages in excess of 25 rads are required for discernible damage. Microcephaly, hydrocephaly, microphthalmia, optic atrophy, retinal dysplasia, and cataracts have all been reported, usually following exposures to 100 rads or more.224–226 Skeletal, visceral, and genital abnormalities have been noted less commonly. Growth impairments always accompany these more specific abnormalities. Isotopes

Radiation from radionuclide use during pregnancy occurs much less commonly than radiation from x-rays. Various 131I preparations commonly used before the 1970s for isotopic scanning have the disadvantage of concentration in the thyroid gland. If administered to a pregnant woman after 10 weeks gestation in sufficiently high doses, 131I can ablate the fetal thyroid gland, resulting in hypothyroidism.229,230 131I has been largely replaced by technetium pertechnetate, which causes less total radiation

Elevation of maternal temperature, primarily from sauna or hot tub bathing and from infection, has been implicated as a hazard to the human embryo.236–238 Although much of the information on this subject has been retrospectively collected, its consistency with results from animal experiments makes hyperthermia a plausible teratogen. Abnormalities have been experimentally induced in a variety of species by raising the core temperature of pregnant dams with pyrogens, external heat sources, microwaves, and shortwaves. Abortion can result from heating prior to implantation, and abortion, resorption, malformation, growth impairment, perinatal death, and functional impairments can result from heating after implantation. Early in embryogenesis, the central nervous system appears most vulnerable, presumably because of its rapid rate of mitosis. Heat injury to this target tissue is manifested by temporary interruption of mitosis and cell death of periventricular cells and, to a lesser extent, of deeper mesenchymal cells.239 Depending on the timing, duration, and degree of hyperthermia, growth impairment and various structural changes can be produced. Smith and associates provided suggestive evidence that in humans 11% of pregnancies resulting in anencephaly and 7% of those resulting in spina bifida had a history of temperature elevation during the first few weeks of gestation.236–238 They subsequently found that a maternal temperature elevation of 1.58C or

36

Overview

more, prolonged for 1 day or longer between weeks 4 and 14, could result in more subtle damage to the conceptus. All infants born after such exposures were mentally retarded, usually showing other evidence of neurologic insult, including hypotonicity, hypertonicity, contractures, and seizures. Microcephaly was found in two patients and neuronal heterotopias were present in the two patients at autopsy. Facial changes, predominantly seen in those exposed prior to 7 weeks’ gestation, included microphthalmia, micrognathia, midface hypoplasia, abnormal pinnae, and cleft lip and/or palate. Maternal hyperthermia has also been noted in the pregnancy history of infants born with Mo¨bius syndrome (oromandibulo-limb hypogenesis syndrome).240,241 In light of these findings, it is reasonable to treat elevation of maternal body temperatures to avoid potential damage to the fetus while also determining the cause of fever in the mother. Prolonged and limited periods of hypothermia have been associated with fetal death and malformations in experimental animals as well. Damage from gestational hypothermia has not been reported in humans.

Infectious processes influence the developing organism through a number of well-defined and theoretical mechanisms.212–214,242,247 Cell death and depletion result in tissue or organ hypoplasia and generalized growth impairment. Continuing nonlethal infection of cells can impair mitosis, which again inhibits local and overall growth. Vasculitis can lead to microinfarcts, calcium deposition, and cavitation of tissues. Suppressed hematopoiesis and hemolysis can cause anemia and increased cardiac burden. Cytokines associated with maternal infections may have very different effects in the developing conceptus. With the exception of T. pallidum, organisms that cause septicemia can cross the placenta at any stage during pregnancy. The time of infection to some degree influences the effects on the fetus, as does the fetus’ immunologic response to the infection. Infectious processes can further influence pregnancy maintenance and development of the conceptus by causing hyperthermia, general toxicity in the mother, or mutation or chromosomal damage in the conceptus.247 Viruses

Prenatal Infections

A substantial dichotomy often exists between the severity of infection in the maternal and prenatal organisms. Covert maternal infection is the rule. In contrast, the embryo or fetus may sustain devastating injury to all organ systems. Not uncommonly, the first evidence that the mother has harbored an infection comes with the birth of the affected infant. A wide spectrum of microbial organisms can adversely affect the embryo or fetus.212,242–246 It must be suspected, in fact, that any organism that can gain access to the conceptus can act as a pathogen. Women acquire certain important infections, including syphilis, gonorrhea, herpesvirus, cytomegalovirus, human immunodeficiency virus (HIV), and chlamydia, through venereal transmission. Other infections can be acquired through respiratory spread (rubella, varicella, coxsackievirus, parvovirus), through contact with infected blood products (HIV, hepatitis virus, malaria), through cat litter exposure (toxoplasma), or through uncooked meat (toxoplasma).212,242–246 In virtually all circumstances the conceptus becomes infected through hematogenous spread. Organisms causing maternal septicemia cross the placenta and reach fetal tissues through the fetal circulation. In some cases a placentitis may become established as an intermediate state that seeds the umbilical vessels. Less commonly, organisms from the genital tract may reach the placenta and fetal membranes by retrograde migration. Early postnatal infections can be established through direct contact with microorganisms in the lower genital tract during birth; this mode is responsible for many newborn herpes simplex virus, chlamydial, monilial, streptococcal, and other bacterial infections. Both the maternal cytokines that are a response to the infection and the infectious agent may lead to abnormalities in the embryo or fetus. Twenty-five percent of women between ages 15 and 35 years lack immunity for viral organisms known to be embryopathic or fetopathic. A primary infection by these organisms can result in maternal septicemia and the accompanying risk for transplacental spread. Recurrence in subsequent pregnancies should not be anticipated. Since prior infection with certain organisms, including Treponema pallidum, gonococcus, streptococcus, and herpesvirus does not confer immunity, all women are susceptible to infection or reinfection during pregnancy. All women as well are susceptible to HIV infection. Recurrence or persistence of infection through several pregnancies is possible for organisms of this type.

Cytomegalovirus

Once considered a uniformly fatal process, prenatal cytomegalovirus infection is now known to cause remarkably diverse pathology.247–252 In its most severe form, cytomegalovirus causes intrauterine growth retardation, hepatitis, meningoencephalitis, and pneumonitis. Growth impairment continues postnatally. The necrotizing meningoencephalitis results in microcephaly, periventricular calcification, mental retardation, seizures, deafness, and motor deficits (Fig. 1-21). Uncommonly, obstructive hydrocephalus occurs. Optic atrophy and chorioretinitis can leave residual visual impairment. Other findings include hepatosplenomegaly, thrombocytopenia, localized purpura, and hemolytic anemia. Morphologic features, inguinal hernias, microcephaly, hydrocephaly, and microphthalmia result from the continuing infectious damage rather than from developmental disturbance during the period of organogenesis. Milder infections can cause functional deficits without morphologic changes. Subclinical cases with neither morphologic nor functional changes have been documented with serologic testing. Herpesvirus

Type I herpes simplex virus generally infects the cornea, the skin of the face and upper trunk, and the oral mucosa; type II usually infects the genitalia. The type can be determined by serologic and virologic methods. Type II herpesvirus (genital type) appears to be the more important in prenatal infections. Antibodies against the two types cross react, but the antibody of one type does not prevent infection by the other type, although spread of the virus may be limited. It has been suggested that transplacental infection might occur only in the absence of prior maternal infection by either type. Of the few case reports of herpes simplex virus infection during early gestation, only the reports of Schaffer253 and South et al.254 can be accepted without reservation. In both infants the virus significantly involved the central nervous system with residual microcephaly, cerebral calcifications, microphthalmia, retinal dysplasia, tone disturbance, and seizures. Vesicles containing the virus were present on the limbs of both infants at birth. Late infection is usually contracted at birth rather than prenatally. Severe infection occurs, nonetheless, with most cases

Human Malformations and Related Anomalies

37

Fig. 1-21. Prenatal cytomegalovirus infection. Left and middle: dense periventricular calcification in severely microcephalic infant. Right: marked microcephaly, spasticity, and mental retardation in a 30-month-old male with prenatal cytomegalovirus infection. (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Institute, Wilmington, DE.)

being fatal during the first year of life. The cutaneous vesicle is a hallmark of infection and may be present at birth if infection occurred transplacentally or may develop during the first 2 weeks of life if infection occurred during birth. Widespread infection with tissue necrosis involves most organs, particularly the brain and liver. Varicella-Zoster Virus

Varicella can be transmitted transplacentally at any time during pregnancy. First-trimester varicella can cause meningoencephalitis, cutaneous lesions, and diffuse visceral involvement.254–256 Such infections are usually fatal; those who survive may have residual optic atrophy, microphthalmia, chorioretinitis, cortical atrophy, seizures, or motor disabilities. Similar features have been observed following herpes-zoster infection during the first trimester. Infection with varicella late in pregnancy may cause fetal infection, which is manifest by cutaneous vesicles at birth or during the initial weeks of life.257 Rubeola

While there is no doubt that rubeola virus can reach the conceptus during the phase of maternal viremia, malforming and destructive effects on the fetus have not been recognized. Abortion and stillbirth rates following maternal rubeola are not excessive. Scattered reports of congenital defects have documented no consistent pattern, and the defects should not be considered rubeola defects. Influenza

Following the 1957 influenza pandemic, Coffey and Jessop258 reported an increased incidence of central nervous system malformations among infants born of Irish mothers who had influenza during pregnancy. An increased incidence of malformations was not found in other studies that utilized serologic evidence to confirm influenza virus infection. There is no compelling evidence that points to influenza virus infection as a cause of malformations. Maternal fever and increased drug use often accompany influenza and must be taken into account in cases of malformations following infection during pregnancy.236–238

Mumps Virus

Infection with mumps during pregnancy does not cause malformations but may result in abortion or stillbirth. Patients with endocardial fibroelastosis have been noted to have a positive mumps antigen skin test, but the relationship of mumps virus infection to this cardiomyopathy is obscure.259 The long-term fertility of the male conceptus does not seem to be effected. Rubella

In the decades since Gregg’s report of cataracts in infants born of mothers who had a rubella infection during the first trimester, a vast body of information on the embryopathy caused by this virus has accumulated.260–264 The risk of fetal involvement resulting from maternal infection during the first month is 50% or greater and decreases with each successive month. Infection following the 8 weeks of organogenesis can cause deafness, microcephaly, and mental retardation. Rubella infection during the first trimester is accompanied by abortion (10%) and stillbirth (4%), with higher rates of fetal death during the first 2 months. Characteristically, rubella virus infection during the first trimester affects the developing eye, ear, and heart. Over one-half of infants have unilateral or bilateral hearing loss, primarily the sensorineural type. Likewise, retinopathy, nuclear cataract, glaucoma, microphthalmia, and myopia affect over one-half of infants (Fig. 1-22). Defects of the major arteries far outnumber the intracardiac lesions caused by rubella. Patent ductus arteriosus and pulmonary artery stenosis are the two most common cardiovascular defects. Intracardiac lesions, although less frequent, may be more significant in terms of hemodynamic disturbance. Pulmonary valvular stenosis, aortic valvular stenosis, and ventricular septal defects are the most common intracardiac lesions. Continuing infection impairs growth, interrupts bone growth and maturation, causes pancytopenia, and produces widespread visceral involvement. Surviving infants have residual growth and neurologic impairments. The degree of postnatal growth impairment parallels the degree of mental deficit, presumably reflecting the duration and severity of infection.263 Rarely, some women do not mount a normal immunologic reaction to rubella

38

Overview

tion usually occurs transplacentally, although intrapartum infection may account for some cases. During the first year of life, infected infants exhibit growth retardation, microcephaly, seborrheic dermatitis, adenopathy, and recurrent infections.266–268 Anemia, reversal of the T4:T8 lymphocyte ratio (<1), and hypergammaglobulinemia usually accompany the clinical findings. Mortality is high, with the majority of deaths occurring during the first 2 years of life. Malformations as a part of prenatal HIV infection have not been reported. Facial features consisting of a box-like cranial configuration with frontal bossing, prominent eyes, oblique palpebral fissures, hypertelorism, depressed nasal root, triangular philtrum, and patulous lips have been described in two cohorts of infants and children with prenatally acquired AIDS.269,270 Prudence requires further observation before these morphologic features can be attributed to HIV infection rather than to other environmental or ethnic influences. Other Viruses

Prenatal infections from a number of other viruses have also been documented. They have not resulted in malformations, but they have resulted in significant fetal pathology. Coxsackievirus infections have been associated with fetal pancarditis and meningoencephalitis; poliovirus with abortion, stillbirth, and meningomyelitis; echovirus with disseminated viremia; variola and vaccinia with necrotizing cutaneous and visceral infection; and hepatitis viruses with neonatal hepatitis.212,271–278 The effects of SARS and West Nile virus during pregnancy are not yet known. Chlamydia

Fig. 1-22. Prenatal rubella. Cataracts (top; left removed) and glaucoma (bottom) in prenatally infected children.

Infection with Chlamydia trachomatis is considered to be the most prevalent venereally transmitted disease among pregnant women. While some studies have found infection to be associated with premature rupture of fetal membranes, premature delivery, and perinatal mortality, no association with malformations has been documented.279 Mycoplasma

and may harbor the virus, leading to repeated infection of offspring. Parvovirus

Human parvovirus B19 causes erythema infectiosum in children and a nonspecific arthropathy in children and adults. The virus can also cause erythrocyte aplasia in patients with chronic hemolytic anemias or immunological impairments. As many as one-third of the fetuses born to women who have a primary B19 infection during pregnancy become infected.265 Fetal infection generally results in nonimmune hydrops fetalis and death. The pathogenesis has not been clarified, but presumably involves impairment of erythrocyte production, hemolysis, or direct infection of cardiac muscle alone or in some combination. Malformations do not result from human parvovirus B19 infection. Human Immunodeficiency Virus

In the decade since its introduction into the United States, HIV infection has become the most common serious infection during pregnancy and the most common prenatal infection. From 30% to 50% of infants born to HIV seropositive women will develop AIDS or HIV-mediated disease.266–270 It is thought that prenatal infec-

Placental colonization with Mycoplasma is commonly found at delivery.280 Prematurity and low birth weight may be associated with genital mycoplasmic colonization.281 Malformations are not known to be caused by Mycoplasma. Bacteria

Sepsis from a number of bacterial organisms can cause abortion or stillbirth, but does not cause malformations.212,282 Bacterial infections are of greater concern as a cause of perinatal or newborn infections. Sepsis, pneumonitis, and meningitis can be caused by Eschericha coli and other coliform organisms, Listeria monocytogenes, Campylobacter fetus, non-group A b-hemolytic streptococcus, and Staphylococcus. Neisseria gonorrhea is an important cause of generalized ophthalmitis in the newborn. Tuberculosis can be transmitted transplacentally or postnatally. Spirochetes T. Pallidum

Syphilis is the major spirochetal infection of significance to the fetus. Always one of the most prevalent and devastating fetal infections, it has not disappeared with the advent of effective therapy.283,284 For

Human Malformations and Related Anomalies

unknown reasons, the syphilis spirochete usually does not reach the conceptus during the first trimester; hence, it is not an important cause of abortion or malformation.285 Malformations of the permanent teeth may occur and include abnormal tapering of the incisors, enamel-covered notching of the central incisors, and crowding of the cusps of the first molars (Fig. 1-23).286 These malformations are caused by infection after the period of organogenesis. T. pallidum is disseminated through hematogenous spread to every organ system, but with predilection for skin, mucous membranes, liver, central nervous system, and bones. Most severely involved fetuses die from widespread tissue damage. Hydrops fetalis is a well recognized but uncommon presentation.287 Less severe infection can produce intrauterine growth retardation with or without active signs of syphilitic involvement at birth.212 Scarring or destruction of tissues and incomplete resolution of proliferative processes produce certain morphologic changes after the active infectious stage of prenatal syphilis.288 These predominantly facial changes include frontal or frontoparietal bossing, saddle nose, rhagades, and mandibular overgrowth. Chorioretinal

39

lesions can also occur. Perforation of the palate or nasal septum can result from gummatous tissue reaction and destruction. Saber shins and hydrarthrosis can result from skeletal involvement. Most of these morphologic changes can be prevented or made less severe by early detection and treatment. Leptospirosis and Lyme Disease

Fatal leptospirosis, presumably acquired in utero, has been described in a newly born infant, but was not associated with congenital anomalies.289 Transplacental passage of the Lyme spirochete has been documented, and it has been associated with a variety of adverse pregnancy outcomes.290 A causal relationship between infection during pregnancy and malformations has not been established. Fungi

One-third or more of pregnant woman harbor Candida species in the genital tract. In most instances these organisms are nonpathogenic, existing in a saprophytic relationship with the host. By virtue of their location in the birth canal, they can contaminate the infant during birth and, in rare instances, have reached the

Fig. 1-23. Prenatal syphilis. Four stigmas of prenatal infection with syphilis: Top left: corneal scarring from interstitial keratitis. Top right: enamel-covered notching of permanent central incisors. Bottom left: perforation of the palate from gummatous involvement. Bottom right: saber shins from incomplete resorption of periosteal bone formation. (Courtesy of Dr. James Millar, Centers for Disease Control, Atlanta, GA.)

40

Overview

fetus during intrauterine life. Candida species have not been implicated as a cause of malformations. Chorioamnionitis uncommonly occurs, often related to a retained contraceptive device or to cerclage.291 Extension to the fetus can cause death or early delivery of an infant with disseminated infection. Protozoa Toxoplasma Gondii

Primary maternal infection with T. gondii occurs in 1 per 1000 pregnancies in the United States.212,292 Higher incidences can be found in other countries, notably Mexico and France. Infection is disseminated to the fetus in 40% of the cases. The organisms gain access to the fetal circulation from foci in the placenta and become widely distributed to all tissues. The clinical signs of toxoplasmosis result from chronic destructive infection of the tissues. The height of the tissue reaction occurs during the first few months of life. Thereafter the signs of active infection may not be discernible, even on pathologic examination. However, the consequences, generally cerebral and ocular, may continue to appear over a number of years. Organisms have been recovered from the brain of a congenitally infected infant at age 5 years. Malformations are not a part of the pathology of prenatal toxoplasmosis. Hydrocephaly and microcephaly result from chronic destructive meningoencephalitis and should not be considered teratologic effects of the parasite. Little evidence has been accumulated to demonstrate fetal involvement during the period of organogenesis. The classic triad of congenital toxoplasmosis— chorioretinitis, hydrocephaly, and cerebral calcifications—has become accepted as the most common presentation of infants infected prenatally. This is unfortunate in that it encourages the observer to dismiss the diagnosis if cerebroocular signs are lacking. Signs and symptoms vary considerably in different infants and can change over time in the same infant.292–294 Regardless of the predominant signs in a particular infant, significant residual damage to the central nervous system may become apparent after a period of years. This can occur even in children who show no signs of infection during infancy. The most common residual findings are chorioretinitis, blindness, and impaired intellect (Fig. 1-24).

Malaria

Although placental infection with malaria is a common event, prenatal infection of the fetus is decidedly rare. Infected fetuses can be growth impaired, and the infection usually results in stillbirth or in continuing infection in the neonatal period that is usually fatal.295 Although sickle cell hemoglobin heterozygosity and being a carrier for glucose-6-phosphate dehydrogenase confer resistance to death from malaria, they do not seem to have any protective effect for the fetus. Prion Diseases

Although prion diseases can be inherited, as in the case of Creutzfeldt-Jakob disease, there are no reports of transplacental infection from bovine encephalopathy or scrapi. Prenatal Drug and Chemical Influences

The intimate intraplacental relationship between maternal and fetal circulations that permits the exchange of essential chemical substances also allows chemical disturbances to be reflected transplacentally.212–216 Most soluble constituents of maternal serum cross the placenta by simple or facilitated diffusion. Substances that diffuse poorly because of molecular size, degree of ionization, lipid insolubility, or adverse concentration gradient may be delivered to the fetus by active transport or by pinocytosis. Small leaks in the villous membrane would allow gross cross contamination of maternal and fetal circulations, but this leakage is probably not an important mechanism in the transfer of physiologically active substances. In any given case, the transport of a substance across the placenta may be altered by pathologic changes in the placenta, disturbances in maternal or fetal blood flow, or aberrant metabolism by the mother, fetus, or placenta. Transport is facilitated late in pregnancy by a thinning of the villous membrane. Disorders of fetal metabolism are in most cases compensated for by the mother. Hence the fetus with phenylketonuria or hypothyroidism is protected, at least in part, during intrauterine life. Conversely, the limited metabolic capabilities of the fetus may be insufficient to sustain homeostasis in the face of chemical disturbances imposed by the mother. Both exogenous substances,

Fig. 1-24. Prenatal toxoplasmosis. Left and middle: microcephaly and diffuse cerebral calcifications in a mentally retarded adult with prenatal toxoplasma infection. Right: punched out chorioretinal lesion in macular region. (Courtesy of Dr. David Knox, Johns Hopkins Hospital, Baltimore, MD.)

Human Malformations and Related Anomalies

Table 1-13. Teratogenic drugs and chemicals Teratogenicity Proven/Likely

ACE inhibitors

Lithium

Alcohol (ethyl)

Methimazole

Aminopterin, methotrexate

Methyl mercury

Androgens

Methylene blue

Busulfan

Misoprostol

Carbamazepine

Penicillamine

Carbimazole

Propylthiouracil

Chlorobiphenyls

Tetracycline

Cocaine

Thalidomide

Coumarin

Toluene

Cyclophosphamide Diethylstilbestrol

Trimethadione, paramethadione

Diphenylhydantoin

Valproic acid

Fluconazole

Vitamin A

41

cephaly, neural tube defects, urogenital abnormalities, hemangiomas, and radial ray deficiencies.299 Frank mental retardation occurs in one-half of children with prenatal alcohol syndrome. Mental retardation can be accompanied by muscle weakness, poor coordination, tremors, hyperactivity, reduced attention span, speech impairment, strabismus, and sensorineural and conduction hearing deficits. Structural and functional impairments occur in up to one-half of infants born of alcoholic women who drink heavily (
3 oz absolute alcohol daily) during pregnancy. Functional and growth disturbances without other morphologic changes can occur in infants whose mothers drink moderately (1–2 oz absolute alcohol daily). No adverse effects have been documented in infants of mothers who drink less than 1 oz absolute alcohol daily. The possibility that subclinical damage may be reflected later in school and work performance cannot be excluded. Because of our limited understanding of the effects of prenatal exposure to alcohol, total abstinence from alcohol during pregnancy is a wise precaution. Cocaine

Iodides Isotretinoin, etretinate Teratogenicity Controversial/Doubtful

Agent Orange

Metronidazole

Aspartame

Oral contraceptives

Aspirin

Retinoids (topical)

Bendectin

Rubella vaccine

Cigarette smoking

Spermicides

Corticosteroids

Streptomycin

Lead

Vitamin D

Marijuana

Zinc deficiency

usually in the form of drugs, and metabolic deficiencies and excesses reflecting maternal disease states are important in this regard. Drugs and chemicals known to have teratogenic potential are given in Table 1-13. Alcohol

In 1973, Jones et al.296 called attention to the effects of prenatal exposure to alcohol, renewing concerns about alcohol use during pregnancy that had existed since the early Greek city-states.297,298 They described a pattern of malformations and other morphologic changes, growth impairment, and cognitive defects among infants of chronic alcoholics. This prenatal alcohol syndrome is now recognized as one of the most common causes of birth defects among patients with mental retardation. Reduced head circumference, length, and weight present at birth persist postnatally. Facial characteristics, largely reflecting impaired brain growth, consist of small eyes and short palpebral fissures, ptosis, epicanthus, midface hypoplasia, long and smooth philtrum, and thin upper lip (Fig. 1-25). Atrial and ventricular septal defects are the most common of a wide variety of cardiac defects. Radioulnar and cervical vertebral fusions, camptodactyly and other joint contractures, hip dislocation, deformations of the feet, hypoplastic distal phalanges and nails, and altered palmar creases are skeletal components of the full syndrome. Less common defects include protuberant ears, cleft lip/palate, hydro-

During the 1980s, cocaine became one of the most commonly used recreational street drugs among pregnant women. One in 10 women in the United States use cocaine during pregnancy. Among the wide range of abnormalities now being reported in infants of cocaine users, most appear related to the propensity of the drug to affect the cardiovascular system.216,300–303 A 10-fold increased risk of stillbirth relates almost exclusively to abruptio placenta. Vascular-based disruptions, skull defects, cutis aplasia, porencephaly, ileal atresia, visceral infarcts, genitourinary abnormalities, and limb reductions constitute most of the structural defects. Intrauterine growth impairment and cardiac defects have also been reported. Collectively these defects affect less than 10% of infants. A similar low percentage of infants exhibit withdrawal symptoms during the neonatal period. Necrotizing enterocolitis has been reported as a possible postnatal vascular complication. The incidence of sudden infant death syndrome appears to be increased. Cigarette Smoking

Increased pregnancy loss accompanies maternal cigarette smoking.216,304,305 Abruptio placenta and placenta previa account for most fetal and neonatal deaths, although the specific mechanism by which smoking causes fetal loss is unknown. Uterine ischemia with secondary decidual necrosis results from smoking and offers a plausible explanation for the increased risk of abruptio placenta. The fetus grows more slowly when the mother smokes.216,304,306,307 The growth impairment parallels the amount of smoking. Infants of mothers who smoke more than one pack (20 cigarettes) per day weigh up to 300 g less than expected. The growthretarding properties of smoking probably act throughout pregnancy. Certainly weight reduction can be seen in infants born at any time during the third trimester. Altered caloric distribution to the fetus, placental dysfunction, fetal hypoxia, and direct chemical toxicity of compounds in tobacco smoke can contribute to prenatal growth impairment. Postnatal catch-up growth occurs during the first year of life. Marijuana

Although a dose-related reduction in birth weight has been found in infants of mothers who used marijuana, neither major malformations nor patterns of malformations have been identified among these infants.308

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Overview

Fig. 1-25. Prenatal alcohol syndrome. The 3-year-old boy at left has microcephaly, left ptosis, short palpebral fissures (<3rd percentile), smooth philtrum, thin upper lip, fingernail hypoplasia, and developmental delay. The 27-month-old girl at right has short stature, microcephaly, midface hypoplasia, short palpebral fissures (<3rd percentile), smooth philtrum, thin upper lip, and developmental delay. Lysergic Acid Diethylamide (LSD)

Chromosome breakage of leukocytes has been induced in vitro and in vivo by LSD.212,309 The breakage appears transitory and has not been implicated as a cause of malformations or other ill health in infants of mothers who ingested LSD during pregnancy. Several infants of mothers who used LSD have had malformations.212 Although these infants have had no single characteristic malformation, limb and other skeletal anomalies have predominated. The evidence remains insufficient to implicate LSD as a cause of human malformations. Anticonvulsant Drugs Diphenylhydantoin (Dilantin)

Seizure disturbances affect 1 in 300 pregnant women. The majority of affected women require continuous anticonvulsant therapy during pregnancy. Diphenylhydantoin, the anticonvulsant used most commonly, was the first to be suspected of causing intrauterine damage.310 After initial studies linked diphenylhydantoin with cleft lip and palate, a broader syndrome of malformations, other morphologic changes, and functional impairments were attributed to prenatal exposure.311–315 Affected infants have some combination of intrauterine and postnatal growth impairments, microcephaly, hypertelorism, depressed nasal bridge, ptosis, wide mouth, hypoplasia of the distal phalanges and nails, and developmental impairment (Fig. 1-26). Cleft lip and palate and cardiac defects are the most common major malformations. Colobomas, glaucoma, and other ocular abnormalities have been reported, as have diaphragmatic, umbilical, and inguinal hernias. It has been suggested that about 10% of exposed infants will have significant malformations or mental defect, with a somewhat higher percentage having one or more minor features.315 Exposed

infants may also have an increased risk of developing tumors of neural tissue during childhood. Trimethadione, Paramethadione (Triodine, Paradione)

Of the anticonvulsants, trimethadione and paramethadione pose the greatest prenatal hazard.316 One-fourth of pregnancies of women who use trimethadione and paramethadione are spontaneously aborted. One-third of those born die during the first year of life. The majority of liveborn infants have prenatal and postnatal growth deficiency, developmental delay, malformations, and distinctive facies. The distinctive facial features include Vshaped eyebrows with or without synophrys, broad nasal bridge, arched or cleft palate, cleft lip, and malpositioned ears, with anterior cupping and/or excessive folding of the superior helices (Fig. 1-27). A wide variety of major and minor defects in virtually all systems has been reported. Cardiovascular defects, renal malformations, tracheoesophageal anomalies, hernias, and hypospadias are most common. Survivors often have mild to moderate mental retardation and speech impairment. Valproic Acid (Valproate, Depakene)

Reports of an association between valproic acid and spina bifida prompted concern that this anticonvulsant might be an important teratogen.317 The risk for meningomyelocele, primarily lumbar or lumbosacral, appears to be about 1–2% following first-trimester exposure (two- to fourfold higher than the population frequency). Intrauterine growth proceeds normally, but developmental delay, a pattern of craniofacial features, and other malformations have been described.318,319 Bitemporal narrowing, tall forehead with metopic prominence, shallow orbits with epicanthus and infraorbital creases, small nose with flattened bridge, long and flat philtrum, small mouth with thin upper vermilion, rotated pinnae, and micrognathia form a more or less distinctive craniofacial

Human Malformations and Related Anomalies

43

Fig. 1-26. Prenatal hydantoin exposure. A 7-year-old female with prenatal exposure to hydantoin. Fingernails and toenails show marked hypoplasia. Facial appearance and school performance in first grade were normal.

morphology. Cardiovascular defects, oral clefts, inguinal hernias, hypospadias, clubfoot, long thin digits, strabismus, and nystagmus occur in a minority of infants. An overall risk cannot yet be given. Carbamazepine (Tegretol)

Once considered to be the drug of choice for seizure management during pregnancy, carbamazepine has recently been found as the cause of minor facial and skeletal abnormalities.320 In retrospective and prospective observations, Jones et al.320 have found a small percentage of exposed infants to have growth retardation, abnorFig. 1-27. Prenatal trimethadione exposure. Facial appearances of two brothers aged 10 years (left) and 13 years (right) exposed prenatally to trimethadione. Both have V-shaped eyebrows, broad nasal bridge, epicanthus, and low-set retroverted ears with excessively folded superior helices. Both have borderline intellectual function. (Courtesy of Dr. Elaine Zackai, Children’s Hospital of Philadelphia, Philadelphia, PA.)

mal facies, nail hypoplasia, and developmental delay. Craniofacial features include microcephaly, narrow bitemporal diameter, up slanted palpebral fissures, epicanthus, short nose, and long philtrum. Cardiac defects were found in 2 of 8 cases ascertained retrospectively and 1 of 35 cases ascertained prospectively. Methotrexate, Aminopterin

The folic acid antagonists are used primarily in the treatment of psoriasis and certain malignant diseases. Their potent teratogenic properties have been known since the 1950s, when the drug was also used as an abortifacient.321 The folic acid antagonists produce cranial and skeletal malformations (Fig. 1-28).322,323 Bony malformations of the skull include absent or defective ossification, misshapen bones, sutural synostosis, and anencephaly. The globular head, wide-spaced and prominent eyes, depressed nasal bridge, micrognathia, malformed ears, and underdeveloped supraorbital ridges compose a somewhat characteristic facies. Cleft lip and/or cleft palate have been present in several cases. Further skeletal anomalies, including mesomelic shortening of the limbs, dislocated hips and elbows, coalescence of carpals and tarsals, clubfoot, and delayed bone maturation, have been reported. Prenatal and postnatal growth have been severely impaired, but mental development in survivors is only mildly affected.324 Misoprostol

A synthetic analog of prostaglandin E1, misoprostol has been used alone or in combination with mifepristone or methotrexate as an abortifacient, predominantly in South America.325–329 Anomalies, plausibly related to vascular disturbances induced by misoprostol, have been reported in cases where abortion did not occur. They include Mo¨bius facies with cranial nerve palsies, terminal transverse limb defects and other amniotic band-like limb defects, equinovarus foot deformation, arthrogryposis, and hypoplasia of various muscles.

44

Overview

Misoprostol does not appear to cause major malformations, and the overall risk for vascular insults to the fetus following maternal use of misoprostol appears to be low. Thalidomide

Fig. 1-28. Prenatal aminopterin exposure. Photographs at birth and at age 18 months of a girl exposed to aminopterin during the first trimester. Features included globular skull with deficient calcification, low-set ears, ocular hypertelorism, micrognathia, cleft palate, dislocated hips, short forearms, and other minor skeletal anomalies. (Reprinted with permission from Shaw EB, Steinbach HL: Am J Dis Child 115:477, 1968, American Medical Association, copyright 1969.322)

More than any other event, the thalidomide tragedy alerted the world to the teratogenic potential of drugs. A chemical with sedative properties, thalidomide was marketed alone or in various compounds for a wide variety of ailments beginning in 1956. The most extensive distribution was in West Germany, but substantial use occurred throughout Europe and in certain Asian and American countries.330 Thalidomide was available for only 4 years before its teratogenicity was recognized and distribution was halted. Only the unusual and dramatic nature of the malformations accounts for the drug’s teratogenic properties being recognized that quickly. Over 4000 infants are known to have been injured by prenatal exposure. Thalidomide produced malformations limited to tissues of mesodermal origin, primarily limbs, ears, cardiovascular system, and gut musculature.331,332 The types of malformations could be related to the age of the embryo at the time of ingestion. Malformations resulted from repeated use and from single ingestions during the critical period of 20 to 40 days postovulation. Abnormal development of the long bones produced an almost endless and striking variety of limb reduction malformations (Fig. 1-29). Typically the upper limbs were more severely involved than the lower limbs. Of the long bones of the upper limbs, the radius was most frequently involved. However, any of the bones could be defective or, in severe cases, totally absent. The hands in some cases were normally formed; in other cases, the hands lacked thumbs or other fingers; and in still other cases, hands were absent.

Fig. 1-29. Prenatal thalidomide exposure. Left: midline facial hemangioma and upper limb reduction malformation. Middle: microtia. Right: upper limb reduction malformation. (Courtesy of Dr. Helen Taussig, Johns Hopkins Hospital, Baltimore, MD.)

Human Malformations and Related Anomalies

Oligodactyly, syndactyly, and polydactyly occurred. Lower limbs could be similarly affected, but less frequently and less severely. The head and neck escaped gross malformation, and mentation appeared normal. Characteristically, a midline hemangioma extended from the frontal area over the tip of the nose and ended on the upper lip. Ear malformations ranging from agenesis to preauricular tags occurred in one-fifth of cases. Some infants had facial or abducens palsy, usually unilateral. A wide variety of cardiovascular defects were seen, affecting about 10% of infants. Visceral anomalies included agenesis of spleen, gallbladder, and appendix and atresias or stenoses of the esophagus, duodenum, and anus. The mechanism by which thalidomide produced malformations is entirely unknown. Isotretinoin, Vitamin A

Within 1 year of the release of isotretinoin for the treatment of cystic acne, malformations were linked to its use during pregnancy.334 That isotretinoin would affect the developing human was not unexpected because of its known teratogenicity in animals and because of the teratogenicity of the related compounds etretinate and vitamin A in humans. Isotretinoin (Accutane) used during the embryonic period causes an increased risk for spontaneous abortion (40%) and for malformations (25%) among survivors.335–337 Anomalies of the central nervous system, cardiovascular system, and craniofacial structures predominate (Fig. 1-30). Most affected infants have central nervous system defects. Hydrocephaly with or without other structural abnormalities of the cerebrum and cerebellum occurs. The ears are usually small, malformed, or misplaced with atresia of the external auditory canal and underdevelopment of the middle ear. Less common alterations of the craniofacial structures include sloping or narrow forehead, accessory parietal sutures, depressed and wide nasal root, micrognathia, and cleft palate. One-third of the affected infants have cardiovascular anomalies, usually affecting the aortic arch or conotruncal area of the heart. Thymic agenesis, hypogenesis, and/or ectopia may accompany these cardiovascular defects. Isotretinoin defects have been attributed to a disturbance of the migration and influence of the cranial neural crest cells. Lammer et al.338 have also found craniofacial alterations in fetuses exposed only after 60 days postovulation. These infants have prominent metopic sutures, epicanthus, and dimples or creases on the posterior aspect of the ears. Since isotretinoin has a serum

45

half-life of 16 to 20 hr and is not stored in tissue, use prior to conception carries little if any risk during a subsequent pregnancy. Vitamin A intake in excess of 25,000 IU daily during the first trimester has been associated with malformations. Malformations of the central nervous system, facial structures, heart, skeleton, and genitourinary system have been reported.339,340 Although these are insufficient data to conclude that vitamin A is teratogenic, there exists no compelling reason for use of such extraordinary doses during pregnancy. Etretinate

Like its congener isotretinoin, etretinate can cause central nervous system, cardiovascular, and skeletal malformations. It is used primarily in the treatment of psoriasis. In contrast to isotretinoin, etretinate is predominantly bound to lipoproteins and persists in the circulation for years after use. Grote et al.341 have reported unilateral limb defects in a fetus conceived 4 months after the mother’s last dose of etretinate. Vitamin D

Although circumstantial evidence has linked excessive maternal Vitamin D intake and the idiopathic hypercalcemia syndrome (Williams syndrome), most infants born after vitamin D supplementation during pregnancy showed no evidence of the hypercalcemia syndrome. Additionally, excessive pregnancy intake could not be documented in those infants with features present at birth. Williams syndrome is now known to be a genetic disorder, and the possibility that abnormal maternal, fetal, or placental metabolism of vitamin D, calcitonin, or calcium plays a contributory role is considered unlikely. Androgens

Masculinization of the female infant results from exposure to excessive androgens during pregnancy.342–346 Androgens have been used during pregnancy for a variety of reasons, including prevention of abortion. There are currently no acceptable uses of androgens during pregnancy. Contemporary exposures to androgens are more likely to be from endogenous production by maternal tumors or from the use of progestational agents having androgenic activity. Masculinization due to prenatal androgen exposure does not progress after birth, and some measure of regression may occur. Enlargement of the clitoris and labia majora results from androgen

Fig. 1-30. Malformation in an infant exposed to retinoic acid during the first 18 weeks of gestation. Features include hypertelorism, downslanting palpebral fissures, microtia, cleft palate, hydrocephalus, hypoplasia of the cerebellum, and a heart defect. (Courtesy of Dr. Paul M. Fernhoff, Emory University School of Medicine, Atlanta, GA.)

46

Overview

and enlargement of the clitoris and labia majora. The incidence of masculinization varies with the drug, dosage, timing, and duration of usage. The frequency of masculinization following norethindrone (Norlutin) exposure has been reported to be 18%; following ethisterone (Pranone) exposure, 13%; and following medroxyprogesterone (Provera) exposure, 1%.212,343,344 Considerable controversy has surrounded the question of whether progestins cause other malformations.349–354 Several studies have demonstrated an association between progestins and conotruncal cardiac defects,349,350,352,353 neural tube defects,355 limb reduction defects,349,351,356 esophageal atresia,354 and the VACTERL malformations.353 In general, these studies have shown a twofold to fourfold increase in these malformations among infants born of pregnancies in which progestins were used as a pregnancy test, as protection against abortion, or as a birth control measure. Other studies have failed to find such associations.357–359 Further experience is required to determine if there is a causal relationship between progestins and any malformation or whether the associations found in some studies are due to other factors. Diethylstilbestrol Fig. 1-31. Virilization of a female fetus caused by an androgenproducing maternal tumor.

stimulation following formation of the genitalia; labial fusion and inhibition of uterovaginal descent to the perineum requires exposure prior to 10 weeks postfertilization (Fig. 1-31). The severity of these changes depends on the potency of the androgens and on the duration and period of gestation when used. Females exposed to androgen prenatally do not generally experience excessive growth but they may have advanced bone age. The possibility that changes in genital development and bone maturation occur in males has not been investigated. Corticosteroids

Long-standing concern has existed regarding two potential prenatal effects of exogenous corticoids: cleft palate and adrenal atrophy.347,348 One percent or less of infants of mothers receiving corticosteroids will have either of these effects. Importance must be attached, however, to even a low incidence of adrenal atrophy, since it may be life-threatening in the neonatal period. Additionally, the risk of stillbirth appears increased several fold, perhaps to an adverse effect of corticoids on placental function. Progestins

Exogenous sex hormones have been used purposely and inadvertently during pregnancy. Progestin–estrogen combinations have been administered for several days in early gestation as a pregnancy confirmation test, and progesterone and various synthetic progestins have been given on a prolonged basis in an attempt to protect against abortion. Neither use is currently recommended. Estrogen and progestins, used sequentially or in combination as oral contraceptives, may be used for variable periods of time before pregnancy is recognized. While progesterone lacks androgenic properties, certain synthetic progestins have sufficient androgenic activity to cause mild virilization in the user and, when used in pregnancy, to masculinize the female fetus.343,344 Prenatal masculinization is not unlike that caused by maternally administered androgens; that is, manifested by labial fusion, persistence of the urogenital sinus,

As many as 2 to 3 million pregnant women received the synthetic estrogen diethylstilbestrol over a 25-year period prior to 1971.360 In early pregnancy it was used primarily as prophylaxis against pregnancy loss in women who had experienced recurrent abortions. Alarm about prenatal diethylstilbestrol exposure came with the Herbst and Scully361 report of vaginal adenocarcinoma in young women whose mothers had received the drug. Further studies have documented structural changes in the genital tract and abnormalities of menses; reproductive impairment may also be related to prenatal diethylstilbestrol exposure. Over one-half of women exposed prenatally to diethylstilbestrol will have vaginal adenosis in which mu¨llerian mucosa persists over the cervix and upper vagina. Disorganization of the fibromuscular structure of the cervix produces irregular surface anatomy with ridges, protuberances, and sulci. The uterus may be hypoplastic with abnormal configuration and synechiae of the cavity. The fallopian tubes are short and narrow, with short ostia and absent fimbria. These abnormalities contribute in part to excessive menstrual irregularities, impaired fertility, ectopic pregnancies, and preterm deliveries. Approximately one-third of males exposed prenatally to diethylstilbestrol have some abnormality of the reproductive system.362 These abnormalities include small penis with hypospadias or meatal stenosis, cryptorchidism, small testes with induration of the capsule, and epididymal cysts. Impaired sperm production accompanies these structural changes. Angiotensin-Converting Enzyme Inhibitors

Hypoplasia of the skull and renal dysgenesis have been reported among infants exposed during the second and third trimesters to angiotensin-converting enzyme (ACE) inhibitors.363,364 Oligohydramnios and neonatal anuria have been attributed to the renal dysgenesis. Thioureas

Propylthiouracil and other thiourea compounds interrupt thyroxin production by blocking both the iodination of tyrosine and the coupling of diiodotyrosine. They are widely and effectively used in the therapy of hyperthyroidism. Niswander and Gordon365 found hyperthyroidism in 1 of every 500 pregnancies. Thioureas readily cross the placenta and can cause goiter and hypothyroidism

Human Malformations and Related Anomalies

in the fetus.365–367 Thiouracil goiters are usually mild to moderate in size and do not compromise the respiratory and alimentary tracts in otherwise normal infants. With the exception of umbilical hernias, any of the signs of hypothyroidism can be present. Goiter and other signs of hypothyroidism spontaneously regress over a 2to 6-week period, and regression can be hastened by thyroxin supplements.366 Limited follow up has not shown residual growth or mental impairments. Carbimazole, Methimazole

Eighteen cases of embryopathy have been noted among infants exposed to carbimazole or methimazole prenatally.368–370 Distinctive findings were scalp aplasia cutis, choanal atresia, esophageal atresia/tracheoesophageal fistula, and athelia/hypothelia. Facial findings included short flared eyebrows, short upslanting palpebral fissures, broad nasal bridge, hypoplastic alae nasi, and small ears. A minority had heart defects and delayed development. Iodides

Inorganic iodides have been used as a mucolytic agent for various respiratory ailments and to suppress hyperfunction of the thyroid gland. Iodides readily cross the placenta and in excess can interfere with fetal thyroid function. Inhibition of organification, coupling of iodotyrosines, and release of thyroxin by the thyroid gland all contribute to the iodides’ goitrogenic effect. The massive fetal thyromegaly produced by iodides is unequaled by any other goitrogenic agent or disease.371 The goiter may be sufficiently large to cause polyhydramnios prenatally and respiratory and alimentary obstruction postnatally (Fig. 1-32). Although no permanent thyroid dysfunction should be anticipated, transient hypothyroidism or, less commonly, hyperthyroidism can occur in the neonatal period.

Babies prior to 1976), 18 (10.8%) had malformations.372 Thirteen of the malformed infants had cardiovascular malformations, and four of these were the Ebstein anomaly. Additionally, one of six stillborn infants in the series had tricuspid atresia. Subsequent study has concluded that the overall risk for malformations is only slightly increased, and there is no increased risk for Epstein anomaly.373 Infants exposed to lithium may experience transient lethargy, hypotonia, cyanosis, poor feeding, and poor respiratory efforts during the early neonatal period.

Mercury

Two serious incidents of food contamination with alkylated mercury, a potent neurotoxin, have occurred during the past three decades.374,375 In both instances disturbances of neurologic function were documented in infants who were exposed prenatally. In the 1950s, methylmercury sulfide and methylmercury chloride were discharged in the Minamata Bay (Japan) by a vinylchloride and acetaldehyde plant.374 Residents of the area who consumed large amounts of fish and shellfish from the polluted waters accumulated toxic levels of mercury and suffered neurologic impairments. Similar wide-spread exposure occurred in 1972 among rural Iraqis who ingested bread prepared from wheat treated with the fungicide methylmercury.375 Prenatally exposed infants exhibited a wide range of neurologic abnormalities: mental retardation, speech and language delays, visual and hearing impairments, weakness, ataxia, gait disturbance, involuntary movements, swallowing dysfunction, hyperreflexia, and emotional lability (Fig. 1-33). Morphologic changes of the central nervous system included microcephaly, heterotropias, and other abnormalities of

Lithium

The major use of lithium salts in medicine is in the treatment of manic-depressive illness. Of 166 infants exposed to lithium during pregnancy (cases reported to the international Registry of Lithium

Fig. 1-32. Immense goiter (left) in infant born of mother taking iodides during pregnancy. The firm goiter compromised respiration. The infant also had hypothyroidism and cardiac failure but responded to thyroxin therapy. Goiter had greatly resolved by age 2 months (right). (Reprinted with permission from Senior B, Chernoff HL: Pediatrics 47:510, 1971.371)

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Fig. 1-33. Infant with marked neurologic impairment following prenatal exposure to the fungicide methylmercury. (Courtesy of Dr. Sami Elhassani, Mary Black Hospital, Spartanburg, SC.)

48

Overview

cytostructure. Irregular tooth size and malocclusions were also found in affected children. Warfarin

Anticoagulants are used prophylactically following cardiac valve transplantation and in the treatment of thrombophlebitis, thrombosis, embolus, and polycythemia. Warfarin and other related vitamin K antagonists cross the placenta and can cause spontaneous abortion, malformations, and fetal anticoagulation.376–378 The sentinel signs of embryonic pathology, nasal hypoplasia, and skeletal stippling depend on exposure during the critical period of 4 to 6 weeks postovulation (Figs. 1-34, 1-35). Mid-trimester exposure can result in optic atrophy, brain anomalies, and mental impairment. Third-trimester exposure can anticoagulate the fetus, predisposing to perinatal hemorrhage. In warfarin embryopathy, the nose appears small, with depression of the nasal bridge and accentuated demarcation between the alae nasi and the tip of the nose. Choanal stenosis may coexist. Prenatally, the restricted nasal airway may contribute to the increased frequency of polyhydramnios and postnatally to respiratory embarrassment and death. Calcific stippling occurs primarily in the tarsals, proximal femurs, and paravertebral processes but may be present in other areas of the skeleton and in the laryngeal and tracheal cartilages. Brachydactyly and small nails, with greater severity in the upper limbs, have been present in about one-half of affected infants. Optic atrophy, microphthalmia, and blindness can result from exposure during the first or second trimester. Mortality is high (20%) among affected infants, and one-third of survivors will be mentally retarded. A variety of structural anomalies of the brain (e.g., DandyWalker malformation, agenesis of the corpus callosum), microcephaly, optic atrophy, visual impairment, seizures, hypotonia, and mental retardation have been noted among infants exposed to warfarin throughout pregnancy and among infants exposed only after the first trimester. Others with intracranial hemorrhage in the perinatal or postnatal periods have developed hydrocephaly and mental retardation. Chlorobiphenyls

Epidemics of reversible skin eruptions due to the ingestion of cooking oil contaminated with polychlorinated biphenyls have occurred in Japan and Taiwan.379,380 The persistence of these chemicals in tissues for a number of years has resulted in the

Fig. 1-34. Prenatal warfarin exposure. Infant was exposed throughout pregnancy. He has marked nasal and midface hypoplasia, narrow nasal passages, brachydactyly, and nail hypoplasia. Development was normal at age 7 months. (Courtesy of Dr. J.M. Pettifor, Johannesburg, South Africa.)

prenatal exposure of many infants. Affected infants have lower birth weights, cutaneous and mucosal hyperpigmentation, gum hypertrophy, natal teeth, hepatomegaly, nail dystrophy, acne, and conjunctivitis. The generalized increase in mucocutaneous pigmentation (cola-colored babies) appears accentuated over the face and gums, digits, nails, and genitals. Neonatal acne resolves with or without scarring, but the hyperpigmentation persists. A minority of affected infants have ocular hypertelorism, flaring of the eyebrows, cranial chair loss, scalp calcifications, hirsutism, chipping of the teeth, clinodactyly, chronic respiratory infections, and developmental delay.

Fig. 1-35. Prenatal warfarin exposure. Radiographs show irregular ossification (stippling) of the tarsal bones (left) and articular or periarticular calcification along the vertebral column (right).

Human Malformations and Related Anomalies

Fluconazole

Fluconazole is an antifungal agent which in chronic high doses (
400 mg/d) during pregnancy has been associated with craniofacial, cardiac, and skeletal malformations.381–384 Craniofacial anomalies included brachycephaly, craniosynostosis, frontal cranioschisis, trigonocephaly, shallow orbits, hypoplasia of the midface and nose, cleft palate, and micrognathia. Tetralogy of Fallot, atrial and ventricular septal defects, and hypoplasia of the pulmonary artery have been reported. Among the wide variety of skeletal anomalies are shortening of the limbs, digit hypoplasia, thinning the bowing of the long bones, fractures, and humeroradial synostosis. The craniofacial findings and humero-radial synostosis have prompted comparisons to Antley-Bixler syndrome. Aleck has pointed out that Fluconazole inhibits lanosterol 14 alphademethylase, an enzyme that has been found deficient in patients with Antley-Bixler syndrome.384 Other Drugs

Questions about the safety during pregnancy of a number of other drugs and chemicals have been raised by retrospective studies and isolated case reports.213,216,385–390 Further investigations have failed to confirm any association between certain of these substances and adverse pregnancy outcome. For other substances, the body of information remains insufficient to form reliable conclusions. Prenatal Hormonal Influences Diabetes Mellitus

Distinguished as being the most common hormone deficiency during pregnancy, diabetes mellitus is the prototypic maternal metabolic disease that influences the health of the embryo and fetus. The maternal disease varies considerably in its severity and its impact on the conceptus. The chemical imbalance inherent in diabetes is readily reflected transplacentally, placing stress on fetal homeostatic mechanisms. Diabetic pregnancies are subject to secondary complications that can further jeopardize the fetus. Since diabetes mellitus can exist throughout pregnancy, prenatal consequences include malformations, growth disturbances, stillbirth, and homeostatic derangements that can persist into the newborn period. Infants born of mothers with diabetes mellitus types 1 and 2 grow excessively before birth, presumably because of excessive glucose availability and fetal hyperinsulinism.391–393 The macrosomia is generalized, affecting linear growth and weight, and with the notable exception of the brain it is shared by most internal organs (Fig. 1-36). In contrast, infants born of diabetic mothers with vascular complications can be growth impaired during fetal life. In neither case does the altered growth rate continue postnatally. Gestational diabetes that does not develop into type I or II diabetes probably poses little risk to the conceptus; but because it is difficult to distinguish what type the mother has, all diabetes during pregnancy is treated with caution. An overall threefold increase in malformations occurs among infants of diabetic mothers, with a direct correlation between the severity of malformations and the degree of control of maternal diabetes.394–401 Defects of the heart, central nervous system, kidneys, and skeleton predominate. Abnormalities of the major arteries, particularly transposition of the great vessels and conus arteriosus, ventricular septal defects, and dextrocardia occur with

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greatest frequency, but a variety of cardiovascular defects have been reported. Anencephaly, spina bifida, hydrocephaly, and holoprosencephaly are the major central nervous system malformations that occur in infants of diabetic mothers. A spectrum of malformations involving the lower spine has been associated with diabetes mellitus. Collectively termed ‘‘caudal regression syndrome,’’ the spine may have faulty segmentation or may terminate altogether in the lumbar or sacral region with disturbance in neurologic function below the level of spine disruption (Fig. 1-37). Anal and urethral sphincters may be incompetent, and motor function of the lower limbs may be impaired. Defective development of the long bones, joint dislocations, and malpositions can result as well. Sirenomelia occurs as a part of this spectrum of defects, and malformations of the lower and upper extremities can occur independently of the caudal regression syndrome. Femoral hypoplasia (usually proximal) can occur with or without caudal regression. A characteristic proximally placed large toe is a rare anomaly most often associated with maternal diabetes. Although an overall increase in many types of malformations occurs among infants of diabetic mothers, holoprosencephaly and caudal regression syndrome in particular might be considered ‘‘diabetic malformations’’ because they occur with several hundredfold increase in these infants. Yet it is appropriate to remember that most cases of these uncommon malformations occur in nondiabetic pregnancies.212,394 Other significant difficulties encountered by the infants of diabetic mothers include hyperbilirubinemia, hypocalcemia, hypoglycemia, cardiomyopathy, vascular thromboses, respiratory distress syndrome, and birth injury . Hypothyroidism

Since thyroxin fails to cross the placenta in early pregnancy and fetal synthesis of thyroxin begins after the first trimester, it may be surmised that organogenesis and early fetal growth proceed independently of thyroid hormone. Further evidence that thyroid hormone is not necessary for early development is the birth of normally formed infants to untreated cretinous and myxedematous women.402 Later in pregnancy thyroid hormone does become important to fetal growth, osseous development, and neuronal maturation. However, the fetus should be capable of supplying its own hormone by the time the hormone is needed. Thyroid hormone may have some function in the maintenance of the placenta as demonstrated by an increased risk of abortion in pregnant women who have low thyroxin levels.403 The exact relationship between hypothyroxemia and abortion in these pregnancies has not been clearly delineated. Pregnancies in women with frank and untreated hypothyroidism do not consistently terminate in abortion. Only in cases in which the fetal thyroid gland has been impaired by antithyroid drugs (e.g., propylthiouracil, carbimazole, iodides), radioactive iodine, or possibly maternal antibodies does one expect effects on the fetus.367,404 Hyperthyroidism

Transfer of maternal thyroxin to the fetus is negligible during early pregnancy. Free thyroxin can cross the placenta, but the relative thyroid-binding globulin capacity favors the mother. During the final weeks of pregnancy, fetal thyroid-binding globulin may compete more favorably and thyroxin may be transferred to the fetus. Triiodothyronine is less bound by thyroidbinding globulin and can more freely cross the placenta in all stages of pregnancy. Thyroid-stimulating hormone does not cross

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Fig. 1-36. Infants of diabetic mothers. Left: general appearance of infants of mothers with class A, B, or C diabetes mellitus. They appear excessively nourished and pass the initial extrauterine hours in a limp and quiet manner unless disturbed by stimuli from the environment or by their own respiratory distress, hypoglycemia, or hypocalcemia, Right: plethoric and cushingoid facies.

Fig. 1-37. Caudal deficiency in a 3-year-old child whose mother had diabetes mellitus. The spine ends at L2, and the ilia are fused in the midline.

the placenta. Immunoglobulins that stimulate the thyroid gland do cross the placenta and may potentially stimulate the fetal thyroid gland.405–407 Most cases of hyperthyroidism during pregnancy are due to Graves disease. In untreated state, fetal death often follows. The

presence of thyroid-stimulating globulins in Graves disease places the fetus at risk for thyrotoxicity regardless of the treatment status of the maternal disease. When maternal hyperthyroidism is treated, two contrasting influences can affect the fetus. If thyroidstimulating globulins are present, hyperthyroidism can be induced

Human Malformations and Related Anomalies

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Hyperparathyroidism

Since most hormones and tropic substances cross the placenta with difficulty, if at all, hyperfunctioning endocrine glands exert their influence indirectly. Fewer than 100 cases of maternal hyperparathyroidism, usually due to parathyroid adenomas, have been reported.413 The excessive production of parathyroid hormone results in maternal hypercalcemia, which is reflected transplacentally in fetal hypercalcemia that in turn depresses the fetal parathyroid gland. This simplistic schema may in fact be much more complicated, involving 1,25-dihyroxyvitamin D3 synthesis, hypomagnesemia, and/or end-organ responsiveness to parathyroid hormone as well. Maternal hyperparathyroidism results in excessive abortion and stillbirth and, because of suppression of the fetal para-thyroid gland, predisposes the newborn to hypocalcemia and tetany. Cushing Syndrome

Hyperfunction of the adrenal gland during pregnancy may be caused by tumor or hyperplasia.414 One-half of the pregnancies will result in abortion or perinatal death. Maternal overproduction of adrenocortical steroids can suppress the fetal adrenal gland, which becomes manifest in the neonatal period as adrenal insufficiency. Overproduction of Sex Hormones Fig. 1-38. Small for gestational age infant born of a mother with hyperthyroidism. Infant had transient signs of hyperthyroidism: agitation, tachycardia, tachypnea, and excessive hunger.

in the fetus. Alternatively, the fetal gland can be suppressed by transplacental passage of antithyroid medications. Neonatal thyrotoxicosis induced by transplacental thyroidstimulating globulins usually is a transient phenomenon, commonly lasting several months.408,409 Most affected infants have goiter, exophthalmos, restlessness, and tachycardia (Fig. 1-38). They may have excessive length, but are thin. Less than one-half will show periorbital edema, ravenous appetite, temperature elevations, cyanosis or cardiac failure, and hepatosplenomegaly. Craniosynostosis has been reported in several infants.410 In some instances the neonatal thyrotoxicity persists, suggesting in these cases a heritable thyroid dysfunction rather than a transient influence of exposure to thyroid-stimulating globulin(s).411 Goiter, hypothyroidism, and scalp defects have resulted from the use of antithyroid medications during pregnancy.

During pregnancy, the serum concentrations of progesterone and estrogen are higher than at any other time during life. Transplacental hormones can cause breast engorgement, neonatal vaginal bleeding, and the cutaneous eruption herpes gestationis. Breast engorgement occurs in male and female fetuses during the final 4 to 6 weeks of gestation. At term the usual breast nodule measures 5 mm more and regresses over the first postnatal months. Some infants have excessive breast enlargement and may produce a few drops of milk. Vaginal bleeding related to estrogen and progesterone withdrawal may occur during the neonatal period, beginning in the first week of life and rarely lasting beyond a couple of days. Androgens produced by arrhenoblastoma or luteoma of pregnancy can masculinize female fetuses. The full extent of masculinization, usually some degree of clitoral hypertrophy and labial adhesion, will be apparent at birth. Androgen-secreting adrenocortical adenomas have also resulted in masculinization of female fetuses. Although overproduction of androgens also occurs in the adrenogenital syndrome, fetuses born of such pregnancies have not shown masculinization or other ill effects. Herpes Gestationis

Hypoparathyroidism

Infants of mothers with untreated hypoparathyroidism may have transient hyperparathyroidism during the fetal and neonatal periods.412 The fetal parathyroid hyperplasia occurs in response to low maternal and fetal serum calcium concentrations mediated by the maternal parathyroid dysfunction. Excessive fetal parathyroid hormone predominantly affects the skeletal system, but other systemic effects of fetal hypercalcemia may result as well. All bones show demineralization, and subperiosteal reabsorption occurs in the long bones. Long bones may also show considerable bowing, and fractures may be present. Intrauterine growth retardation, pulmonary artery stenosis, ventricular septal defects, and muscle hypotonia have been described in individual cases.212

A curious erythematobullous eruption associated with pregnancy, herpes gestationis causes intense pruritis as its major symptom.212,415 The natural confinement of the condition to pregnancy and the artificial induction of lesions with progestational steroids provide justification for considering it a hormonally induced entity. The name herpes gestationis is inaccurate since it incorrectly suggests that the eruption is somehow associated with herpesvirus. Herpes gestationis occurs once in every 10,000 pregnancies and can recur in consecutive or nonconsecutive pregnancies. Lesions usually erupt at 4 to 5 months’ gestation but can appear as late as 2 weeks after delivery. About 10–20% of infants born of affected mothers will have lesions at birth or will develop lesions within the first 48 hours of life. The bullous lesions clear

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Overview

spontaneously within 1 week. These lesions may be related to fetal maternal microchimerism.415a Maternal Phenylketonuria

Before treatment with a phenylalanine-limited diet was practiced, most people with phenylketonuria became severely mentally retarded during childhood and few went on to reproduce. The offspring of those women who did become pregnant were also mentally impaired. Substantial experience with pregnancy in phenylketonuric women has confirmed that the metabolic derangements in untreated maternal phenylketonuria almost invariably injure the offspring.416–419 Infants born of mothers with untreated phenylketonuria have intrauterine and postnatal growth retardation, microcephaly, mental retardation, and cardiac defects, the frequencies of these impairments being directly related to the maternal phenylalanine level (Fig. 1-39). When the maternal phenylalanine level exceeds 20 mg/d1, 92% of infants have mental retardation; 73%, microcephaly; 40%, intrauterine growth retardation; and 12%, cardiac malformations. One-fourth of pregnancies are spontaneously aborted. Rigid compliance with dietary treatment beginning before conception offers the only hope of decreasing this high incidence of malformation and other impairments among the offspring of phenylketonuric women. Other Aminoacidopathies

Only limited data exist concerning pregnancies in women with various aminoacidopathies other than phenylketonuria. With the Fig. 1-39. Three-year-old male with microcephaly, mental retardation (IQ 55), short stature, and seizures. Infant was born of a woman with phenylketonuria who received no treatment during pregnancy. Her three other pregnancies resulted in one abortion and two microcephalic infants.

exception of hydrocephaly in two infants born to mothers with homocystinuria and Hartnup aminoaciduria, adverse affects on pregnancy outcome have not been reported.420–422 Phytoestrogens

Concern has been expressed because of an increasing occurrence of hypospadias that environmental estrogens as well as phytoestrogens may be responsible; however, the correlation of hypospadias with intrauterine growth retardation seems more likely. Prenatal Nutrient Deficiencies Folic Acid

Insufficient availability of folic acid and/or other vitamins has been suggested as a cause of defects in neural tube closure as well as other birth defects.423–425 On the basis of this suggestion, the effects of supplementation of high-risk pregnancies with a folic acid–containing multivitamin, or folic acid alone, in the periconceptional period (4 weeks before conception until 8 weeks after) was studied in Great Britain. Smithells et al.424,425 used a multivitamin supplement (Pregnavite), and Laurence et al.426 used a supplement of folic acid alone. In both studies, supplementation was found to protect against recurrence of neural tube defects (NTDs) in infants of mothers who had previously had an infant with an NTD, reducing the recurrence rate to less than 0.5%. A number of retrospective studies have supported the British findings.427,428 One retrospective study in the United States failed to find any protection against NTDs from preconceptional vitamin usage.429 Conclusive evidence that the use of periconceptional folic acid (alone or in multivitamins) lowered the risk of recurrence of NTDs was provided by the Medical Research Council study in 1991.430 Similar protection against the initial occurrence of NTD cases using a multivitamin with folic acid was found by Czeizel and Dudas one year later.431 The successful use of folic acid supplementation to lower the occurrence of NTDs has been reported from the Americas, Australia, and China.432–435 Fortification of cereal grain flours with folic acid has been required in the United States since January 1998.436 A large number of breakfast cereals have also been fortified with 400 mcg folic acid per serving. The combination of supplement use, flour fortification, and consumption of fortified cereals has resulted in a twofold to threefold increase in serum and erythrocyte folate levels in the United States.437 These combined measures have resulted in an overall reduction of 19% in the rates of NTDs.438 A number of studies have suggested that folic acid may protect against other malformations.439–442 Reduction in the risks for the occurrence of cleft lip with/without cleft palate, conotruncal heart defects, limb reduction defects, and urinary tract defects has been reported in several studies. It should be noted that infants born of women frankly folate deficient during pregnancy have not been found to show any measure of ill health, including intrauterine growth retardation, neural tube defects or other malformations, or hematologic abnormalities.443 Several infants born after exposure to the folic acid antagonist aminopterin have, however, had neural tube defects.212 Oxygen

Chronic intrauterine hypoxia occurs in a number of circumstances. Cigarette smoking and certain pulmonary, cardiovascular, and hematologic disorders prevent the mother’s blood from being consistently and completely oxygenated.444–447 Chronic

Human Malformations and Related Anomalies

hypoxemia also occurs in women who live at altitudes greater than 2000 m.448–449 These situations limit adequate oxygen delivery to the fetus. Chronic fetal hypoxia can also result from placental dysfunction, preeclampsia, and nontoxemic hypertension. Impairment of intrauterine growth results from chronic mild hypoxemia, regardless of the cause. In several circumstances a direct correlation has been demonstrated between the degree of hypoxia and the severity of growth impairment. For pregnancies at high altitude, birth weights decrease 100–200 g for every 1000 m above sea level. Alzamora et al.450 also found an increased incidence of patent ductus arteriosus and atrial septal defects among infants born at high altitudes. A progressive decrease in birth weight has also been directly correlated with diastolic blood pressure in hypertensive mothers and with the degree of oxygen desaturation in mothers with cyanotic heart disease.451 Neill et al.446 noted dramatic intrauterine growth retardation among infants of mothers with cyanotic heart disease whose hemoglobin level was greater than 18 g/dl, hematocrit greater than 65%, and oxygen saturation less than 65%. Infants of mothers with less severe cyanotic heart disease had less severe intrauterine growth retardation. Neill et al. also noted an increased risk of abortion, fetal death, and preterm delivery of pregnancies complicated by maternal cyanotic heart disease.446 Acute intrauterine hypoxemia can cause fetal death or neurologic impairment. This outcome may follow umbilical cord occlusion and premature placental separation.

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Fig. 1-40. Coarse facies, anteverted nostrils, large tongue, umbilical hernia, and muscular appearance of male infant with hypothyroidism. (Courtesy Dr. Charles I. Scott, Jr, A.I, du Pont Institute, Wilmington, DE.)

Vitamin D

Rickets has been present in newborn infants of mothers with osteomalacia and of women not overtly vitamin D deficient.452 Clinical signs of rickets—rachitic rosary, Harrison groove, delayed maturation of skull bones with large fontanels, and expansion of the osteochondral junctions—may be obvious at birth. Alternatively, radiographic histologic evidence may be found in the absence of physical findings. Dental enamel deposited during the period of intrauterine deficiency will be hypoplastic, dentin will be unevenly calcified, and the predentin will be excessively wide. The fetus may be endangered by hypocalcemic tetany in utero or by uterine tetany or dystocia secondary to pelvic contracture. Calcium

Maternal hypocalcemia can result from hypoparathyroidism, inadequate dietary calcium or vitamin D, and heritable vitamin D deficiencies. Although there is a calcium gradient favoring the fetus, fetal hypocalcemia can occur and result in osteopenia, rickets, or osteitis fibrosa, depending on the degree of calcium deficiency and other compensatory homeostatic hormonal changes.453 Iron

The fetus effectively parasitizes the mother’s iron stores regardless of the state of her iron homeostasis. At birth the hemoglobin level of the fetus appears to be unrelated to anemia in the mother. In maternal iron deficiency, the placenta is often large, apparently to try to compensate for the maternal anemia. Studies done in South America suggest that the higher the level of anemia in the mother, the lower the intelligence of her offspring.453a Iodine

The iodine-deficient woman who is pregnant may fail to provide sufficient mineral to the fetus.454 The fetus suffers the same pathologic consequences of the deficiency as the mother and can be

born with goiter and signs of cretinism (Fig. 1-40). Features of cretinism, retarded bone growth and ossification, epiphyseal dysgenesis, myxedema, constipation, umbilical hernias, and cutaneous mottling will be present at birth or soon after in the untreated infant. If the condition is untreated, mental retardation is the most important sequela. Prenatal Mechanical Influences

The maternal pelvis, abdominal wall, uterus, and amniotic fluid participate in protecting the conceptus against mechanical injury. Each becomes less protective as pregnancy advances. By midtrimester, the fetus lies outside the safety of the pelvis. The abdominal wall and the uterus become progressively thinner as the conceptus grows, and the ratio of amniotic fluid to mass of fetus decreases steadily. Prior to 8 weeks postfertilization, amniotic fluid makes up 95% of intraamniotic volume. The amniotic fluid component of intraamniotic volume decreases to one-half by 14 weeks and to one-third by 36 weeks. Some degree of intrinsic protection against mechanical injury may also be provided by the plasticity of embryonic and early fetal tissues and by their capacity to repair local damage. Mechanical forces can alter prenatal development by direct trauma to tissues, by interruption of blood supply, by constraint, and by damaging the placenta or cord. About 6–7% of women sustain physical injury during pregnancy.455,456 Vehicle accidents account for the majority of such injuries, with falls, gunshots, stabbings, and physical abuse constituting other significant causes. Little role has been demonstrated for these external forces as a cause of malformation except in the case of attempted termination of pregnancy where congenital contractures have been reported.456a Penetrating and blunt trauma can cause death by damaging the fetus, placenta, or cord. Rare instances of similar injury have resulted from amniocentesis.

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Fig. 1-41. Deformations caused by intrauterine mechanical forces. Cephalic molding (A) and nasal deformation (B) can occur from prolonged constraint in a malformed uterus or from the forces of delivery. Clubfoot and other limb deformations (C) occur from prolonged constraint. Fetuses with neuromuscular impairments are at greater risk for such deformations.

A greater potential for mechanical alteration of morphology comes from within the mother. The same structures that surround and protect the conceptus against mechanical injury can, in certain circumstances, impose constraints detrimental to development.

craniofacial and limb deformations in twins. Although there is increased risk of malformations and disruptions in twins, these have been related to other factors, usually vascular, rather than mechanical, forces.

Malformations of the Uterus

Vascular Compromise

The size of the intrauterine cavity and its ability to accommodate the growing conceptus may be limited by malformations of the uterus. Uterine malformations are associated with greater risks of spontaneous abortion, malpresentation, stillbirth, and premature delivery. One-third of liveborn infants have craniofacial or limb deformations, evidence of late intrauterine constraint (Fig. 1-41).457,458 Craniofacial asymmetry, torticollis, scoliosis, excessive folding and flattening of the ears, flattening of the nose, joint contractures, and limb edema have been reported. Compression earlier in pregnancy can impair peripheral circulation, particularly in the limbs. Graham and associates458 have attributed limb hypoplasia and various limb reduction abnormalities to early constraint caused by malformations of the uterus.

Either inherited abnormalities of vascular formation or thrombophilias can predispose to in utero vascular accidents. Hunter’s preliminary study suggests that thrombophilias may predispose to limb anomalies, terminal transverse limb deficiencies in particular,461a Shalev and Hall’s study of familial vascular compromise suggests that inherited hypoplasia of blood vessels may affect growth of the shoulders.461b

Fibroids

Fig. 1-42. Growth curves from 24 weeks to term for singletons, twins, triplets, and quadruplets. (Adapted from McKeown and Record.461)

Because they occupy space in the uterine cavity, fibroids limit space for placentation and growth of the conceptus. Growth deficiency, deformations, and disruption of the limbs similar to those caused by compression in the malformed uterus have been reported. Twins

The human uterus has a limited capacity to accommodate twins and other multiple pregnancies. Mechanical forces undoubtedly contribute in some measure to the increased risk of growth deficiency, prenatal and postnatal mortality, malformations, disruptions, deformations, and premature delivery in such pregnancies (see also Chapter 34).459,460 However, changes in maternal metabolism in twin pregnancy also undoubtedly have effects on fetal growth and outcome. Fetal growth is influenced by the number of fetuses present. The growth deceleration that occurs at about 36 weeks in singletons takes place at about 30 weeks in twins, 27 weeks in triplets, and 26 weeks in quadruplets (Fig. 1-42).461 Some contribution to growth deficiency in twins may be related to mechanical constraint, but the greater influence must be assigned to placental function. Constraint is likely the major contributor to

Amnion Disruption and Amniotic Bands

The amniotic system provides the innermost and perhaps the most substantial of the safeguards against prenatal mechanical injury. Within the amniotic membrane, the developing organism

Human Malformations and Related Anomalies

55

Fig. 1-43. Facial features of a 23-week-old fetus with Potter syndrome secondary to type IIB cystic dysplasia. Note the prominent lower palpebral folds (arrows), flattening of the nose, and low-set and flattened ears (E). (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

is suspended in an aqueous medium by a mobile and elastic cord, free of impingements that could impair symmetric growth or limit movement. Failure of this system can be catastrophic, causing a striking array of structural anomalies. Inadequate production or chronic loss of amniotic fluid allows the uterus to compress the more pliable parts of the external fetal anatomy. Typically the facies are flattened, with depression of the tip of the nose and abnormal folding of the ears (Potter facies), the feet and hands are malpositioned, and the skin is excessively wrinkled (Fig. 1-43).462–465 In the absence of amniotic fluid, the lungs remain underdeveloped and ill-prepared for neonatal respiratory function.

The amniotic membrane participates directly in the production of abnormalities through several mechanisms.463–465 Strips, strands, or sheets of amnion may separate partially or completely from the amniotic membrane and become suspended in the amniotic fluid. These amniotic ‘‘bands’’ may encircle digits or entire limbs, eventually compromising blood supply to the distal part. Growth and development of limbs thus entangled may become disrupted, with residual constriction rings, syndactyly, and amputations (Fig. 1-44). Bands of amnion may also be swallowed. If the band is attached to the amniotic membrane, the fetus becomes tethered and through continued swallowing efforts pulls itself to the point of

Fig. 1-44. Amniotic bands. Left and middle: fetus with ring constrictions, digital fusions, and amputations secondary to amniotic bands. Note string of amnion attached to dorsal aspect of digits. Right: ring constrictions and amputations in a 27-year-old man.

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Overview

Fig. 1-45. Amniotic rupture and bands in two fetuses. Left: unusual cranial lobation, fusion of cranium to placenta, and omphalocele. Right: cleft lip, cranial fusion to placenta, and digital amputations with amniotic bands between right hand and placenta.

attachment. The strong amniotic tether can cut into orofacial structures, leaving clefts unrelated to lines of embryonic fusion (Fig. 1-45). Bizarre lobation of the cranium can result from twisting of the fetus, and cranial tissues can fuse to the amnion and placenta. In other circumstances, the amnion may rupture, collapsing more or less in toto about the embryo or fetus. This blanket of amnion deprives the developing organism of free movement and holds it close to its placental attachment. Anomalies related to amnion rupture depend on the time of rupture, the presence of amniotic bands, the degree of compression exerted by surrounding structures, and the occurrence of adhesions. Amnion rupture during the period of embryogenesis presumably causes malformations through adhesions and compression of the gelatinous embryonic tissues. Later amnion rupture disrupts structures already formed through direct compression and vascular compromise of exposed parts. Graham and associates458 include limb reduction defects, body wall deficiencies, neural tube defects, postural deformations, scoliosis, and growth deficiency among the effects of acute or prolonged compression related to amnion rupture. Affected infants may also have band-related anomalies and short umbilical cords. The etiology of amnion disruption is unknown, but does not appear to be genetic. It occurs more often in young primagravidas and in pregnancies that follow miscarriage. Prenatal Immunologic Influences

The extent to which immunologic processes influence human development is unknown. A growing body of information implicates immune mechanisms as an important cause of infertility.466–468 Certain maternal immunologic diseases, notably lupus

erythematosus, are associated with excessive pregnancy wastage. The possibility that subclinical disease contributes in some substantial way to pregnancy loss overall cannot be dismissed. Maternal antibodies transferred transplacentally can interfere with a wide variety of systemic functions in the fetus and continue for variable periods postnatally. The role of immune processes in causing congenital anomalies is less clear. Prenatal immunologic influences may be mediated by direct attack on tissues of the conceptus, particularly the placenta, by transplacental transfer of globulins that may attack fetal cells from within, and by transfer of immunocompetent cells that provide a nidus for initiating graftversus-host disease. It is now known that fetus and mother regularly exchange cells, and that if these cells are stem cells, they may take up ‘‘permanent’’ residence. It is unclear what role such cells play in either maternal, newborn, or later autoimmune disorders.415a Rh Isoimmunization

Hydrops fetalis is the end result of severe fetal involvement by Rh isoimmunization. The preceding cascade of events is initiated by Rh-positive fetal erythrocytes gaining entry into the circulation of a previously sensitized Rh-negative mother (Fig. 1-46).469 Maternal IgG antibodies to the Rh antigens cross the placenta and attach to fetal erythrocytes. Destruction of these erythrocytes, primarily by the spleen, causes anemia. When the fetal hematopoietic response cannot compensate for the anemia, cardiac failure and universal edema ensue (Fig. 1-47). Fetomaternal incompatibility for erythrocyte antigens other than the Rh and ABO antigens can also cause hemolytic disease, but prenatal hemolysis sufficient to produce hydrops fetalis is distinctly uncommon.470

Human Malformations and Related Anomalies

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Platelet Isoimmunization

Maternal antibodies against fetal platelets can lead to prenatal and transient postnatal thrombocytopenia.471 The hazard of hemorrhage, particularly intracranial, appears to be greatest during the perinatal period. Prenatal hemorrhage and infarction can occur, however, with residual hydrocephaly and porencephaly. Thyroid Antibodies

Fig. 1-46. Schematic showing events leading to Rh disease of the fetus (erythroblastosis fetalis).

A number of thyroid antibodies have been described and are widely used for diagnostic purposes.472,473 At least two types of thyroid antibodies can influence fetal thyroid function. Thyroidstimulating immunoglobulins bind the thyroid-stimulating hormone receptor and stimulate thyroid function. These antibodies are present in Graves disease, are 7S in size, cross the placenta, and can stimulate the fetal thyroid. Affected fetuses develop goiter and hyperthyroidism, which may persist for several weeks or months postnatally. A second type of thyroid antibody is inhibitory in nature. This antibody also binds to the thyroid-stimulating hormone receptor but blocks thyroid function, producing hypothyroidism. This blocking immunoglobulin also crosses the placenta and may cause cretinism in the fetus. Although the thyroid gland may not be visible on radioactive scanning during the early months of life, thyroid function will return once the antibodies have dissipated, generally a matter of several months. Lupus Erythematosus

A potentially serious disorder may be seen at birth or soon thereafter in a minority of infants of mothers with systemic lupus erythematosus. Congenital heart block, hepatosplenomegaly, lupus erythematosus rash, pancytopenia, and stippled epiphysis are the major features.474,475 The hematologic findings resolve over the first couple of months, and the rash resolves by 6 months. Heart block becomes manifest by bradycardia before or after delivery and is permanent. One-third of infants with heart block also have cardiac malformations and endocardial fibroelastosis. An excessive frequency of abortion and stillbirth has also been reported. Although two-thirds of mothers of affected infants are asymptomatic, Ro antibodies (antibody to Sjo¨gren syndrome A antigen) will usually be present in mothers and infants. Antinuclear antibody and La antibody (antibody to Sjo¨gren syndrome B antigen) may be present as well. Some individuals with this selflimited syndrome in the neonatal period develop other signs of systemic lupus erythematosus in adolescence or early adulthood. Pemphigus Vulgaris Fig. 1-47. Newborn infant with hydrops fetalis secondary to Rh incompatibility.

ABO Incompatibility

Fetomaternal incompatibility for ABO antigens is the most common blood group incompatibility, occurring in 20% of pregnancies.212 Only a small percentage of ABO incompatible pregnancies results in fetal hemolysis, this occurring most commonly in A or B fetuses of mothers with blood group O. Fetal hemolysis is rarely sufficient to stress the cardiovascular system and lead to hydrops fetalis.

Infants of mothers with pemphigus vulgaris may have bullous or erosive lesions at birth, presumably the result of transplacentally acquired pemphigus antibodies.476 Skin lesions are typical of pemphigus vulgaris, having acantholytic cells, neutrophils, eosinophils, and blisters above the basal layer and leukocyte infiltrates deeper in the dermis. IgG and C3 are deposited in the intercellular spaces of the dermis. Some infants are small for gestational age, and the risk of stillbirth appears to be increased. Liveborn infants generally have a benign course, with spontaneous and permanent resolution of the skin lesions within the first couple of weeks of life. Myasthenia Gravis

Ten percent of infants born of mothers with myasthenia gravis will exhibit signs of myasthenia during the first weeks of life.212,477 These infants are inactive, have hypotonia, and suck, cry, and

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Overview

swallow poorly. Although the face is expressionless due to the temporary myopathy, ptosis and ocular motor palsies do not usually occur. Most infants have no structural anomalies, although deformations due to fetal inactivity have been reported. Transplacental passage of antimuscle antibodies or other humoral factors have been suspected but not proven to be the cause of transient neonatal myasthenia gravis. Engraftment of Foreign Cells

Three possibilities exist for fetal exposure to foreign immunocompetent cells. Maternal cells may gain access to the fetal circulation through leaks in the villous membrane or through fetomaternal vascular anastomoses. In twin pregnancies, vascular anastomoses in the placenta may allow sharing of blood cells. This sharing usually occurs only in monozygotic twins; therefore, the admixing of cells is with the same genotype. Intrauterine transfusion in the treatment of fetal anemia can also be the source of foreign cells. Establishment of the viable grafts from each of these sources has occurred.477–482 Although immunodeficiency of the fetal host has been documented or suspected in most cases of intrauterine engraftment with foreign cells, viable grafts have occurred in apparently normal fetuses. Graft-versus-host disease has occurred only in instances of intrauterine engraftment of maternal cells. Ill effects from graft-versus-host disease usually develop after birth, but some affected infants are growth deficient, with pancytopenia and scaling dermatitis at birth. Malformations have not been associated with intrauterine engraftment of foreign cells. 1.6 Human Anomalies with Unknown Causes The era of molecular medicine promises to bring additional insights into the mechanisms by which malformations occur. A number of molecular pathways in development are now partially understood, showing that interruption of various components of the genetic–metabolic machinery that supports normal embryonic development can lead to malformations. While none of the pathways is fully and incontestably delineated, at least the skeletons of a number of pathways are known.196 The major molecular players, the anatomical correlates, and the embryological timing are known for limb development, for example (see Chapters 20–22). A role for chance in the causation of morphological characteristics and malformations has been proposed by Kurnit et al.46 For example, chance variations in the way early embryonic cells migrate, divide, or adhere may be magnified as anatomical defects or functional impairments in the fully formed individual. 1.7 Detection, Diagnosis, Evaluation, Management Prenatal Diagnosis

Long before the era of pregnancy imaging and invasive diagnostics, physicians depended on auscultation, palpation, and measurement to determine the growth and well-being of the fetus. No means were available in early pregnancy to detect malformations, although certain phenomena, such as excessive or deficient pregnancy size, polyhydramnios or oligohydramnios, or breech presentation, might have suggested the possibility of malformations in the fetus. Late in pregnancy, radiographs were useful in

identifying some birth defects, specifically those that affected the skeleton. The combination of amniocentesis (aspiration of amniotic fluid) and cytogenetic analysis of cultured amniocytes by Steele and Breg in 1966 ushered in an era that utilized invasive techniques to identify malformation syndromes in the fetus during the midtrimester.115 The reliability and safety of amniocentesis coupled with cytogenetic and biochemical analysis led to rapid acceptance of these procedures for high-risk pregnancies. Noninvasive testing using maternal blood (early 1970s) and ultrasonography (late 1970s) added to the prenatal screening and diagnostic armamentarium. Development of transvaginal and transabdominal chorionic villus sampling (CVS) and amniocentesis at 10 to 14 weeks permitted prenatal testing earlier in gestation, often before the pregnancy was recognized by those beyond the family. CVS and early amniocentesis were accompanied by greater risk of pregnancy loss than was traditional amniocentesis. Advances in molecular technologies greatly expanded the number of malformations and malformation syndromes that could be diagnosed prenatally. The possibility that many fetal defects could be diagnosed based on testing of fetal cells retrieved from the mother’s blood has been extensively investigated, but as of this writing is not sufficiently reliable for routine prenatal diagnosis.483–485 Ultrasonography

Although available for obstetrics use since the 1950s, ultrasound imaging for the purpose of identifying malformations came into widespread use only in the 1970s and 1980s. The absence of side effects for the mother or fetus has led to the use of ultrasonographic examination of nearly all pregnancies in developed countries. Although used routinely to assess a number of pregnancy parameters (number of fetuses, amount of amniotic fluid, placental position, fetal cardiac activity, gestational age, presence of uterine or pelvic abnormalities), obstetric ultrasonography also is useful for detection of gross malformations. Ultrasonography has also become an indispensable tool to guide aspiration and biopsy needles for obtaining amniotic fluid, placental, and fetal samples. Transvaginal ultrasound appears to give even higher resolution, particularly early, than transabdominal ultrasound. High resolution ultrasonography can be used for high-risk pregnancies and for followup of suspicious findings on lower resolution ultrasound.486–487 Real-time ultrasound can be used to access normal fetal behavior and movement (e.g., swallowing, breathing and limb movement). Maternal Serum Screening

Elevated maternal serum levels of alpha-fetoprotein were found in the 1970s to be a reliable indication of open neural tube defects and certain other malformations.488 Maternal serum alphafetoprotein screening became the primary method for identifying neural tube defects until replaced by ultrasonography in the mid1990s. Other tests, such as human chorionic gonadotropin, UE3, PAPP-A, and INH, have now been added to maternal serum screening to expand its utility in detecting fetal defects.489 Amniocentesis

Since the late 1960s, amniocentesis coupled with cytogenetic, biochemical, and molecular analyses has been the major method of prenatal diagnosis of malformations and malformation syndromes. The safety of mid-trimester amniocentesis (0.5% or less pregnancy loss over that of control pregnancies not undergoing amniocentesis; near absence of severe maternal complications or fetal injury) and accuracy has led to its widespread acceptance and availability.

Human Malformations and Related Anomalies

Malformations that have a cytogenetic, molecular, or biochemical basis may be prenatally diagnosed via amniocentesis.490 Early amniocentesis (14 weeks or earlier) has become possible with the support of high-resolution ultrasound. A higher rate of procedure-related pregnancy loss and limb anomalies than with transabdominal CVS (vide infra) or traditional amniocentesis (15 weeks or later) has been reported.490,491 Chorionic Villus Sampling (CVS)

The acquisition or biopsy of placental tissue at 10 to 12 weeks can be accomplished by transcervical or transabdominal CVS techniques. Cell cultures established from CVS can be used for cytogenetic, biochemical, and molecular studies. The collective literature gives the impression of a marginally higher rate of pregnancy loss following CVS; a greater risk of mosaicism (involving the placenta), especially involving chromosome 20; and the possibility that the procedure may be causally related to transverse terminal limb reduction defects.492,493 Percutaneous Umbilical Blood Sampling

Fetal blood may be obtained late in pregnancy by ultrasounddirected acquisition of umbilical cord blood. Cultured lymphocytes can be subjected to chromosome or molecular analysis and whole blood/plasma/serum for a variety of hematological, immunological, microbiological and other assays. Biopsies of solid tissues (e.g., skin, muscle) for microscopic examination has been performed in the second and third trimester via catheter or fetoscope.494

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Assessment of Embryonic and Fetal Growth

Measurements become important very early in pregnancy. The general well-being of the embryo or fetus is often judged by size alone. Most insults to the rapidly growing prenatal organism will impair growth. The embryonic period (especially weeks 2–8) has been divided into stages on the basis of size (greatest length or crown– rump length) and progress of morphologic development.495 These stages, arbitrarily assigned, provide an orderly reference against which the growth and morphology of individual embryos can be compared. The changes in proportion and scale of different body segments are among the most remarkable of prenatal events. Growth in the prenatal period is truly phenomenal, from a single-celled organism weighing approximately 0.0000006 g at conception to a differentiated human being with billions of cells that weighs close to 3500 g at birth. Crown–rump length progresses from 0.4 mm at stage 7 (about 16 days postovulation) to 30 mm at stage 23 (end of embryonic period, about 56 days) to 51 cm at birth (about 280 days). During the previable fetal period (8–24 weeks postovulation), a dramatic weight gain occurs in comparison to the length gain (weight increases approximately 164 times, and crown–rump length increases approximately 7 times; Fig. 1-48).495,496 Once viability is possible (accepted as approximately 24 weeks’ postovulation or 26 weeks’ gestation as calculated by the first day of the last menstrual period), linear growth and weight are roughly

Fig. 1-48. Fetal weight, crown–rump (CR) length, and crown–heel (CH) length for days 56–168 postovulation. (From Saul et al.496)

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Overview

Fig. 1-49. Comparison of third-trimester fetal growth (length, right; weight, left) showing proportionate (3rd, 50th, and 97th percentile) changes over time. (From Saul et al.496 based on data from Usher and McLean.525)

parallel (Fig. 1-49), with proportionate growth continuing until birth. Scammon and Calkins497 have published measurements of numerous external features of more than 400 fetuses. These measurements can be used to assess anomalous growth in relation to gestational age or crown–heel length. Measurements of skeletal structures and of certain soft tissues and viscera have been made in utero during ultrasound examination.498 Standard curves have been constructed from the measurements and provide a basis for prenatally identifying overall growth impairments or specific anomalies. Postnatal Diagnosis

The goal of evaluation of the infant with a structural anomaly is to arrive at a specific diagnosis, following which the prognosis can be projected, a management plan formulated, and recurrence risks discussed with the family. If the pathogenesis can be determined, it may be helpful in understanding the anomaly and explaining the defect to the family. History

The agenda in evaluating the infant with a birth defect is little different from that used in general medical evaluations. In most medical diagnoses, history-taking plays an extraordinarily powerful role. The diagnosis is suggested by the history more often than by any other diagnostic adjunct. In the case of anomalies, the diagnosis may be immediately obvious to parents and physician alike because of prior occurrence in the family. Often, however, the history is less revealing. Nevertheless, attention must be given for clues in the history that help establish a diagnosis. Advanced

maternal age suggests an increased risk of a chromosomal cause for the anomaly; advanced paternal age suggests an increased risk for a new dominant single gene defect; kinship between the parents signals the possibility of an autosomal recessive gene defect. A history of abortions or stillbirths suggests the possibility of recurrence of a heritable defect—chromosomal, single gene, or multifactorial. Pregnancy history may likewise yield subtle clues to diagnosis. Fetuses that move poorly in utero may signal brain anomalies, other neuromuscular defects, limb malformations, or short limb skeletal dysplasias. Breech position may indicate constraint or a neuromuscular abnormality that impaired the ability to achieve cephalic presentation. Excessive low back pain associated with lack of movement may indicate constraint. Polyhydramnios indicates lack of fetal swallowing or gastrointestinal absorption of the amniotic fluid because of central nervous system or gastrointestinal anomalies. Oligohydramnios may signal obstructive urinary tract anomalies or anomalies of the kidneys. Certain maternal diseases and exposures during pregnancy alert the clinician to the possibility of particular anomalies; maternal diabetes and alcohol ingestion are the two most frequently encountered. When evaluation for congenital anomalies is requested, the defect may be obvious or there may be circumstances that only suggest the possibility of an anomaly. The latter is often the case in the neonatal period. Table 1-14 lists findings in the newborn that may prompt a search for occult anomalies. The manner in which the newborn adapts to postnatal life often suggests the possibility of an occult anomaly. The infant who has difficulty with breathing, feeding, or with maintenance of

Human Malformations and Related Anomalies Table 1-14. Findings in the newborn that prompt a search for occult anomalies Older parents Family history of anomalies, abortions, or stillbirths History of teratogenic exposures History of oligohydramnios or polyhydramnios History of decreased fetal movement Prematurity or postmaturity Breech presentation Overgrowth or undergrowth for gestational age Discordance of measurements Three or more minor anomalies Failure of neonatal adaptation Persistent hypotonia or hypertonia

muscular tone is particularly suspect. Anomalies of the central nervous system, other neuromuscular impairments, and cardiac defects may create problems in transition to postnatal life. In the older infant and child, developmental progress becomes a more important clue to the possibility of occult anomalies, particularly those involving the nervous system and special senses. In spite of the powerful role of history taking in establishing a diagnosis, the clinician must be aware that historical clues and familial features may be misleading. The history of prenatal distress may incline one to think of hypoxia or physical injury but may occur in the fetus with an intrinsic defect as well. Facial features that appear unusual may be familial rather than a sign of a syndromic complex. A negative history of drug exposure does not preclude drug ingestion during the pregnancy. Likewise, a history of exposure to a chemical during pregnancy does not mean that the exposure caused the fetal defect. Only when the pregnancy history is congruous with the physical defects can one accept the cause-and-effect relationship. Examination

Major anomalies that affect topographic anatomy become obvious on physical examination. Minor anomalies may require more careful attention, including measurements and comparisons to normal growth charts, but can provide equally important clues to diagnosis. Photographs of various anomalies are part of the documentation and are useful over time to document a changing natural history. Evaluation of the volar dermal ridges and creases may be helpful in certain syndromes. Both the nature of the anomalies and the composite of anomalies have diagnostic importance. The presence of three or more minor anomalies should prompt a search for occult major malformations. Childhood is marked by rapid changes in topographic features, growth, and developmental abilities. Features diagnostic at birth may not have been apparent in the mid-trimester fetus, and they will not remain the same throughout childhood and adolescence.499–503 Many conditions with diagnostic facial features in late childhood, adolescence, or adult life can appear entirely normal at birth. Numbered among these are individuals affected with Williams syndrome, fragile X syndrome, storage disorders, Angelman syndrome, Prader-Willi syndrome, and muscular dystrophy (Figs. 1-12, 1-50). Conversely, distinctive features in an infant may become less distinctive as the years pass, as is the case with Aarskog syndrome and Kabuki syndrome (Fig. 1-51).

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At different ages, diagnosis depends on different features (Figs. 1-52, 1-53). At birth, infants with 45,X Turner syndrome have lymphedema, excess nuchal skin, and coarctation of the aorta; during childhood they have stunted growth; and at adolescence they fail to mature sexually.504 In fragile X syndrome, the infant is generally large at birth; delayed developmentally, particularly in speech, during the early years; displays facial characteristics of the syndrome in mid-childhood; and has macroorchidism in the postpubertal years.503 Infants with certain storage diseases may exhibit excessive growth, umbilical hernia, and hepatosplenomegaly at birth. During childhood they develop contractures or other skeletal abnormalities, eye abnormalities, developmental impairment, and slowing of growth. Physical observations should include detection of major anomalies, notation of minor defects and variations, assessment of growth (head circumference, weight and height or length), measurement of individual features that appear abnormal, and an estimate of developmental status. Unusual or repetitive behaviors should be noted. Repeated observations over a period of years may ultimately lead to a diagnosis not initially obvious or to revision of an incorrect diagnosis. Comparison of minor features, particularly facial characteristics, with those of the parents and siblings often permits separation of family features from those that may be of diagnostic importance. Review of photographs of family members taken at the same age as the patient can be helpful. Dysmorphology

The study of abnormal morphology is in large part the study of disharmonic growth.505–507 Individual morphologic features become distinctive because of their size in relation to other features around them. Downslanting palpebral fissures result from undergrowth of the malar region (zygoma) in relation to the frontal region (frontal bone). Micrognathia results from undergrowth of the mandible in relation to the maxilla. Macroglossia is overgrowth of the tongue in comparison to the oral cavity. This is not to say that absolute undergrowth or overgrowth does not occur in these circumstances, but only that the disharmony of growth is the phenomenon that provokes identification of features as dysmorphic. A large tongue accommodated in a large mouth in a large craniofacies will not likely be singled out as a dysmorphic feature. Dysmorphology employs both gestalt and measurements in assessing patients with anomalous development. Major anomalies pose little difficulty and in general do not require measurement. More subtle alterations of morphology may be discerned by the eye, but confirmation by measurement substantiates the clinical observation. Standards of Measurement

The establishment of normal values for traits that vary continuously is based on the measurement of the trait in a large number of individuals. Unbiased estimates may be obtained by randomly sampling the population in question. In many cases, if sufficient data are accumulated, continuous variables are distributed in a manner that approximates a normal distribution curve. The distribution can be further described by two parameters, the mean and the standard deviation.508 Data that describe normal distributions have been well characterized mathematically and are available in tabulated and graphics forms, allowing generalizations to be made about the distributions of the traits. For example, for a trait exhibiting a normal distribution, two-thirds or 68% of the observations will

Fig. 1-50. A–D: Williams syndrome showing evolution of facial features at 6 months (A), 12 months (B), 4 years (C), and 20 years (D). E–H: Prader-Willi syndrome with 15q interstitial deletion. (E) 9-month-old female with hypotonia and feeding difficulties requiring tube feedings. Slight cupid’s bow configuration to the upper lip is present but the facies appear normal otherwise. (F) 3-year-old male with history of hypotonia, feeding difficulties requiring tube feedings until age 6 months, and developmental delay. He has esotropia, cupid’s bow configuration to upper lip, and short stature. (G) 9-year-old girl with moderate obesity, short stature, small hands and feet, and (H) same girl at age 16 years showing morbid obesity.

Human Malformations and Related Anomalies

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Fig. 1-51. Aarskog syndrome in 3 males at ages 2 years, 18 years, and 60 years. The triangular facial configuration with prominence of the forehead and hypertelorism becomes less apparent with increasing age.

Fig 1-52. Turner syndrome (45,X karyotype) at ages 3 months and 3 years. In infancy, this girl appeared normal except for epicanthal folds and puffiness of the hands and feet. By age 3 years she had short stature and webbing of the neck had become prominent.

fall within ± 1 SD of the mean, and 95% will fall within ± 2 SD (Fig. 1-20). In many cases, abnormal physical measurements are arbitrarily considered to be those values that lie in the upper and lower 2.5% of the distribution or that are greater than 2 SD from the mean. Microcephaly is defined as a head circumference less than 2 SD below the mean; macrocephaly as greater than 2 SD

above the mean. Functional deficits can be defined in these terms as well. Scores of less than 2 SD on standardized intelligence tests arbitrarily define mental retardation within our population. A formidable body of human anatomic measurements (taken during the prenatal period and during infancy, childhood, and, to a lesser extent, adult life) has been accumulated.496–498,509–511 It might be assumed that the growth standards were derived from

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Overview

Fig. 1-53. Four males with fragile X syndrome at ages 3 years (A), 7 years (B), 23 years (C), and 41 years (D). Prominence of the forehead is evident from early childhood, but enlargement of the lower jaw develops in late adolescence or adulthood.

data collected with rigidly controlled protocols, which entails placing the subject in a natural and relaxed position, having measurements taken by an experienced observer, and using the most precise instruments. Calipers are used for taking measurements less than 30 cm, and rigid measuring devices (measuring table or stadiometer) are used for measuring length or height. Certainly many of the standards were prepared in this optimal fashion. However, that is not always the case. It is advisable for the users of growth

standards to become familiar with the population from which the data were collected, with the method of data collection, and with the number and experience of individuals collecting the data. Ethnic differences occur in many measurements; however, well established ethnic norms are rarely available. Growth references for certain uncommon populations may derive from pooled data. This applies particularly to growth references for skeletal dysplasias and syndromes.496,512,513 The data

Human Malformations and Related Anomalies

may come from many sources, collected over a period of many years, and are usually collected by a number of different observers in a number of different settings. Unfortunately, heterogeneity of the subject population may not be rigidly excluded. While such standards are not optimal, they may be the only reference available for certain populations. Many genetic texts contain standards for growth during the childhood years but lack information on mature measurements. This deficiency is removed in part by the data in the Natick Anthropometric Survey.511 In the latest (1988) survey, 132 different measurements were taken of 2208 females ages 18 to 50 years and of 1774 males ages 17 to 51 years. Seventy-eight percent of all subjects were ages 20 to 35 years. The sample was composed of persons in the U.S. Army. Among the men, 66.1% were white, 25.8% were black, and 3.8% were Hispanic. Among the women, 51.6% were white, 41.8% were black, and 2.6% were Hispanic. Obtaining accurate measurements is not easy. Features with clearly defined boundaries can be measured relatively precisely. Human topography is characterized by curvilinear structures and hence provides a greater challenge. Curvature of body surfaces, tone difference, and subject cooperation also influence the accuracy of measurements. Often the setting in which the person is evaluated does not permit the use of the most accurate instruments and may be compounded by insufficient lighting, lack of cooperation, and insufficient time to achieve the accuracy desired. These difficulties aside, the clinician is called upon in a variety of settings to obtain measurements for use in diagnosis. Usually straight rulers, flexible tapes, and scales are the only measuring devices available. With knowledge of the proper anatomic landmarks and care in taking measurements, the clinician can make reliable observations under less than ideal circumstances. That there is some limitation of comparison of these values with those carefully collected in the research setting must, however, be acknowledged. Other Methods of Measurement

Photogrammetry has been used as an alternative to direct measurement. Standardized photographs are taken to depict features of interest. A scale is included to permit various features to be measured on the photograph. With the features converted into a two-dimensional image, measurements are easily made by hand or by computer. This method requires a standardized photographic assembly, is costly, and does not provide measurements immediately for the clinician. More recently, computer programs can simulate three dimensions and volumes. Radiocephalometry provides another method for assessment of craniofacial anomalies.514–516 Based on standardized positions and radiographic techniques, various landmarks of the craniofacial skeleton are identified and measurements taken. Radiocephalometry has utility in defining the anatomy in craniofacial syndromes and in planning reconstructive surgery. It requires standardized equipment, is tedious, and is not readily adaptable to most clinical settings. Radiographs are necessary for the measurement of most components of the skeleton. They permit individual bones to be measured for comparison to age-specific population data and permit one skeletal feature to be compared with others in the same individual. The latter use detects disharmonic growth. Radiography has been most successfully employed in comparisons of the tubular bones of the hand, a procedure termed metacarpophalangeal profile analysis.517 Most syndromes with abnormalities of the hands will have a more or less distinctive profile.

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Fig. 1-54. Computed three-dimensional reconstruction of cranial tomography demonstrating skull with left coronal synostosis. (Courtesy of Dr. Michael W. Vannier, Washington University Medical Center, St. Louis, MO.)

Computed tomography and magnetic resonance imaging can be used for two-dimensional viewing and for three-dimensional reconstruction of most anatomic parts (Figs. 1-54, 1-55).518–522 The imaging systems give the clinician a view of many features that are normally hidden. Three-dimensional reconstructions are helpful in planning surgery and in projecting the results anticipated from surgery. Growth in Infancy and Childhood

Growth is a complex phenomenon, largely determined by the genetic constitution but also easily influenced by many environmental insults. Growth is mediated through hormonal stimulation of various tissues, particularly the chondroosseous skeleton. Nonspecific impairments of growth can be caused by a wide range of environmental influences, including nutrition, oxygen supply, infection, systemic disease, numerous drugs and chemicals, and emotional deprivation. Unlike prenatal environmental insults to growth, postnatal insults generally affect growth overall rather than that of isolated features. An exception to this generalization is the coarsening of lower facial features and gum hypertrophy caused by prolonged postnatal exposure to the hydantoins.523 Growth during infancy and childhood is expected to proceed at an orderly and predictable pace. Standards for growth of most anatomic features are available.496,498,509,510,524–532 Feingold and Bossert513 studied over 2400 individuals, newborn to age 14 years, and constructed growth curves for many different anatomic features. These and other growth references have been published as monographs.496,509 Most growth curves are prepared from measurements of a cross section of the population and with few exceptions are referenced against age. Growth in Individuals with Skeletal Dysplasias and Malformation Syndromes

Growth in many malformation syndromes, skeletal dysplasias, and metabolic disorders proceeds at a rate different from that of the general population. For most of these disorders, insufficient cross-sectional or longitudinal data have been collected to permit the construction of growth curves.496,512,513 For those conditions for which curves are available, growth can be monitored and the success of various treatments analyzed. Growth curves for children with achondroplasia, the most common form of short-limb dwarfism, have been available since 1978 and are immensely useful in evaluating such patients. Horton et al.512 collected growth data on over 400 patients with achondroplasia and constructed growth curves for stature, growth

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Overview

Fig. 1-55. Three-dimensional reconstruction of computed tomography imaging of cranium of infant with osteogenesis imperfecta. Anteroposterior view (left) and vertex view (right) show marked deficiency of cranial ossification.

velocity, upper/lower segment ratios, and head circumference. The curves for stature and head circumference in Fig. 1-56 demonstrate the marked discrepancy between the expected growth in achondroplasia and the normal growth in the general population. Following the growth of achondroplastic children using normal growth curves is of limited benefit, but comparisons with the growth curves of other children with achondroplasia can be very instructive. Individuals with achondroplasia usually have significant macrocephaly. Comparing their head growths to those of other individuals with achondroplasia can often reassure the family and thus avoid unnecessary diagnostic tests. Furthermore, if any growth-promoting intervention is used, the change in growth should be compared with that expected in achondroplasia without the intervention. Meaney and Farrer513 have cataloged the information available on growth in a number of different genetic and congenital disorders. Their exhaustive tabulation reveals that all too often insufficient data are available to prepare clinically useful growth curves such as those available for achondroplasia. Table 1-15 lists those conditions for which growth information has been compiled and charts have been adapted for clinical use. The most

useful curves are available in the collected works of Saul et al.496 and Hall et al.509 In many cases the available growth data must be considered preliminary because the studies did not include as many observations as broad collaborative studies have provided. Such broad studies are needed to understand the natural history of pathologic states and to provide the necessary information for counseling patients with abnormal growth and their families. Laboratory Testing and Imaging

Diagnostic technology has received considerable attention during the past few decades. Radiographs and other imaging procedures are used to define anomalies; cytogenetic, molecular, and biochemical testing screen for underlying chromosomal and gene errors; and computer data banks synthesize information. It may seem that the clinician’s role in the evaluation may be displaced by these techniques. To the contrary, the physician geneticist remains central to the evaluation process. Of equal importance to the clinician’s roles in arriving at a correct diagnosis and providing information for the family, is the development of a long-term relationship with the family. This has particular importance because of the pace at which new knowledge, diagnostic techniques,

" Fig. 1-56. Composite of growth curves for individuals with achondroplasia: stature (top) and head circumference (bottom). Females, left; males, right. Shaded areas represent normal growth; mean ± 2 SD are shown for achondroplasia. (From Saul et al.496 based on data of Horton et al.512)

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Overview Table 1-15. Conditions for which growth curves are available Achondroplasia

Table 1-16. Indications for chromosome analysis Individual with

Features of recognizable chromosomal syndrome

Amyoplasia

Mental retardation of unknown cause

de Lange syndrome

Unexplained major and minor anomalies

Diastrophic dysplasia

Multiple congenital anomalies

Distal arthrogryposis Fragile X syndrome

Abnormalities of sexual development, including ambiguous or hypoplastic genitalia and failure of sexual maturation at puberty

Marfan syndrome

Unexplained abnormalities of growth

Multiple pterygium syndrome

Certain malignancies

Noonan syndrome

Unexplained failure of neonatal adaptation

Prader-Willi syndrome

Features of mosaicism (hypomelanotic spots, streaky pigmentary disturbance, asymmetry)

Pseudoachondroplasia Rubinstein-Taybi syndrome Sickle cell disease

Couples with

Spondyloepiphyseal dysplasia

Repeated spontaneous abortions

Trisomy 13

Infertility

Trisomy 18

Offspring with a chromosomal duplication, deletion, or other rearrangement

Trisomy 21 (Down syndrome) Williams syndrome

Family Members of 496

From Saul et al. 1998.

and prevention strategies are being devised. The sensitive clinician also orchestrates the evaluation in such a manner as to be most efficient and least stressful to the emotions and finances of the family. Laboratory and imaging technologies play important roles in the diagnosis of the infant with anomalies. These roles will likely increase as an understanding of the molecular basis for anomalies is gained. Testing is appropriately used, first, to confirm a suspected diagnosis and, second, as a diagnostic probe. Most genetic testing is noninvasive. Selection of tests should be made judiciously, nonetheless, if for no other reason than the costs involved. In most cases laboratory testing involves blood samples, urine specimens, or tissue biopsy. The ability to perpetuate genotypically stable cell lines (as fibroblasts or lymphoblasts) has been of great utility in the study of infants with anomalies and other heritable disorders. Cells from these cultures may be frozen and later thawed and subcultures reestablished for analysis. This has been particularly helpful in those cases in which the patient has died and in situations where there is the need to transport diagnostic materials to some distant site. Chromosome Analysis

Chromosome aberrations, in particular aneuploidies and deletions, cause a number of malformation syndromes.123 Less commonly, chromosome abnormalities may be found in apparently isolated malformations. Chromosome preparations may be made from cultures of lymphocytes, skin and other solid tissues, amniotic fluid cells, and chorionic villi. Chromosome preparations can also be made on bone marrow and chorionic villus cells without culture. The quality of such preparations is less satisfactory than that of preparations from cell culture. Table 1-16 lists many conditions in which chromosome analysis may be indicated. None of these conditions has a consistent chromosomal etiology, but this possibility may need to be excluded when another etiology has not been established.

An individual with inherited chromosome duplication, deletion or other rearrangement Pregnancy Products

Abortions Unexplained stillborns Hydropic placentas

Biochemical Tests

Biochemical testing of infants with structural anomalies is not very helpful in identifying causes of the anomalies. Usually, infants and children with metabolic disorders do not have structural anomalies or other dysmorphic features. Important exceptions do occur. Metabolic disorders are an important cause of nonimmune and noninfectious hydrops fetalis (Table 1-17).533 Some infants with metabolic disorders have structural anomalies or distinctive anatomic features at birth (Tables 1-18 and 1-19), and others develop distinctive features with the progression of the metabolic disorder.533–539 Defects of neuronal migration and other structural abnormalities of the brain have been noted in a number of inborn errors of metabolism (Table 1-18). Disorders of cholesterol metabolism, fatty acid oxidation, glycoprotein glycosylation, and peroxisomal metabolism in particular may be accompanied by anomalies at birth. Persons with lysosomal storage diseases typically develop abnormal features with the passage of time. Hence, infants with Hurler disease (MPS 1-H) may have excessive weight, macrocephaly, hernias, macroglossia, and hepatosplenomegaly at birth or during the very early months of life. During childhood they develop gibbus deformation, stiffness of the joints, corneal clouding, and short stature. Other storage diseases appear entirely normal at birth but develop many of the same features during early childhood. A large and complex group of metabolic disorders—the congenital disorders of N-glycosylation (CDGIa-g, CDGIIa-d) and O-glycosylation (Walker-Warburg syndrome, muscle-eye-brain disease, progeroid type of Ehlers-Danlos syndrome, hereditary

Human Malformations and Related Anomalies Table 1-17. Heritable metabolic causes of hydrops fetalis Mucopolysaccharidoses Sly disease: MPS VII Morquio disease: MPS IV Mucolipidoses II: I-cell disease GM1 gangliosidosis Galactosialidosis Sialidosis: neuraminidase deficiency Infantile sialic acid storage disease Nieman-Pick Farber Gaucher Congenital disorders of glycosylation Hematologic disorders a-thalassemia G6PD deficiency Pyruvate kinase deficiency Glucose phosphate isomerase deficiency

multiple exostosis), which may have variable structural anomalies (Table 1-18)—is currently being delineated at the biochemical and molecular level. Traditionally the study of hormones and enzymes, metabolism has expanded to the study of gene products that are involved in the structure of various tissues. These structural proteins— collagen, fibrillin, elastin, and others—have proven important in the pathogenesis of a number of syndromes.540–546 Defects in different collagens have been demonstrated in a number of skeletal dysplasias (see Chapter 22); defective fibrillins have been found in Marfan syndrome and Beals syndrome; defective elastin has been found in supravalvular aortic stenosis and Williams syndrome.540–545 A battery of simple biochemical tests can be performed on urine specimens to screen for a variety of metabolic disorders.547 These tests are not specific and should be used only as screening tests. Most laboratories include the following tests: Benedict’s test (detects reducing sugars), dinitrophenylhydrazine (detects ketoacids), toluidine blue spot test (detects mucopolysaccharides), the nitroprusside test (detects cystine and homocystine), nitrosonaphthol test (detects tyrosine metabolites), and ferric chloride (detects phenylalanine and histidine metabolites). These tests have only limited use in the evaluation of the child with congenital anomalies. With the exception of the mucopolysaccharidoses, the conditions detected by these screening tests do not commonly have anomalies. Some laboratories include an oligosaccharide screen in the urine metabolic screen.548 This test may be positive in several lysosomal storage diseases (mucolipodosis II, GM1 gangliosidosis, GM2 gangliosidosis, fucosidosis, mannosidosis, glycogen storage disease type II, galactosialidoses, sialic acid storage diseases, and aspartylglucosaminuria), conditions that, like the mucopolysaccharidoses, may have hernias, hepatosplenomegaly, and excessive intrauterine growth. Urine screening tests may be performed on random specimens or timed collections. Other inborn errors of metabolism associated with malformations or dysmorphic features (Table 1-18) may require specific testing of blood, urine, or cultured cells.

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Molecular Analysis

A vast number of conditions with structural anomalies have now been associated with mutations in specific genes; others have been localized to more or less discrete regions of the genome (Table 1-10). Molecular technologies can be employed in the diagnosis, carrier testing, and prenatal detection of many of these conditions. The pace of gene discovery and linkage to developmental anomalies has been quickened by the Human Genome Project and related research. As one consequence, molecular diagnostics and molecular cytogenetics have become formidable components of current overall laboratory testing technologies. The addition of microarray technologies promises to expand the utility of these technologies. Molecular Chromosomal Studies

Techniques to identify specific sequences of DNA have led to an ever expanding suite of diagnostic tests.549–551 Fluorescence probes have been developed, using a wide range of colors (flors), to identify unique sequences. These can be utilized directly on interphase nuclei or chromosome preparations (e.g., fluorescent in situ hybridization—FISH) to visually identify deletions, duplications, and translocations (Fig. 1-57). They are also used to order genes along the chromosome. Comparative genomic hybridization utilizes a normal reference panel of DNA to identify missing or extra DNA.550 Since it is done utilizing chromosomes, the molecular mapping of these abnormalities determines which chromosome(s) is affected. It is more accurate than analysis of extended chromosome preparations, but less accurate than targeted fluorescent probes. However, it is a useful screening technique. Microarrays of multiple DNAs, RNAs, and proteins allow testing for multiple sequences simultaneously. These have enormous potential for identifying specific mutations in a pathway, expression of specific genes in a time specific tissue, specific manner and defining differences between normal and pathologic states. Imaging

Sonographic and magnetic resonance imaging are to the soft structures of the body what radiographs have been to the skeleton. The anatomy of internal soft tissues, previously hidden to a large degree, can now be studied with noninvasive techniques. Heart anatomy can be defined without catheterization; spine and brain anatomy can be outlined without pneumoencephalography or vascular imaging; the kidneys can be seen without contrast infusions. Most imaging of non-skeletal internal structures can now be done without radiation exposure by using sonography and magnetic resonance. Radiographs are necessary in the evaluation of the skeletal dysplasias. Functional imaging studies will help to define the differences in congenital anomalies and disorders involving behavioral abnormalities when compared to normal. Photography

Photography provides an easy means of documenting distinctive anatomic features and recording changes that take place over time. Features of interest should be photographed against a neutral backdrop. A scaled background can be used to give an estimate of size. Measurements of various features can be taken from photographs made under standardized conditions. Elimination of shadows that obscure details of various features may be achieved by indirect illumination. Clothing, jewelry, or makeup that cover the feature(s) of interest should be removed.

Table 1-18. Inborn errors of metabolism associated with brain malformations Defects of Neuronal Migration Metabolic Error

Lissencephaly/ Pachygyria

Polymicrogyria

Cortical Heterotopias

Dysgenesis of Corpus Callosum

Cerebellar Malformation/ Dysplasias

Holoprosencephaly

þ

þ

þ

þ

þ

þ

þ

Dysplasia of Olivary Nuclei

Hypoplasia of Temporal Lobes

Amino Acids Nonketotic hyperglycinemia

þ

þ

Cholesterol Smith-Lemli-Opitz

þ

þ

þ

Fatty Acid Oxidation þ

Carnitine palmitoyl transferase 2 Glutaric acidemia 2

þ

þ

þ

Glycosylation Congenital disorders of N-glycosylation Congenital disorders of O-glycosylation

þ

þ

Mitochondrial þ

Fumarase deficiency Pyruvate dehydrogenase deficiency

þ

þ

þ

þ

þ

þ þ

þ

þ

Respiratory chain enzyme deficiency Organic Acidurias Ethylmalonic acidemia*

þ

Glutaric acidemia 1 Peroxisomal Zellweger

þ

þ

þ

Infantile Refsum

þ

þ

þ

þ

Infantile adrenoleukodystrophy Functional enzyme deficiency

þ

þ

þ

þ

þ

þ

þ

þ þ

Chondrodysplasia punctata Others þ

Menkes Adenylate succinate lyase deficiency *Associated with neural tube defects Adapted from Nissenkorn et al., 2001.538

þ

þ

þ

þ þ

Human Malformations and Related Anomalies

71

Table 1-19. Inborn errors of metabolism associated with malformations and dysmorphic features Inborn Errors

Structural Anomalies

Biochemical Findings

Adenylate Succinate Lyase Deficiency

Lissencephaly, hypoplasia of cerebellar vermis

ADSL deficiency (urinary metabolites)

CDG I (a,d,e,f,g Subtypes)

Variable microcephaly, agenesis of corpus callosum, cerebellar hypoplasia, hypertelorism, colobomas, optic nerve atrophy, retinitis pigmentosa, short stature, short limbs, inverted nipples, abnormal fat disposition, joint contractures, ichthyosis, depending on subtype

Abnormal sialidation of serum transferrin (detected by isoelectric focusing)

CDG II (a–d Subtypes)

Variable coarse facies, short stature, short limbs, large and low-set ears

Abnormal sialidation of serum transferrin in subtypes a and d (detected by isoelectric focusing)

Congenital Disorders of N-Glycosylation

Disorders of O-Glycosylation Walker-Warburg Syndrome

Lissencephaly, encephalocele, microphthalmia

–

Muscle-Eye-Brain Disease

Hydrocephaly, cerebellar hypoplasia, glaucoma, muscle dystrophy

–

Progeroid Type of Ehlers-Danlos Syndrome

Short stature, scant scalp hair, aged appearance, elastic skin, hypermobile joints, osteopenia

–

Short stature, exostoses

–

DOOR (deafness, onychodystrophy, onycholysis, mental retardation)

Hereditary Multiple Exostoses

Short broad nose, ptosis, absence of fingernails and toenails, triphalangeal thumbs

Elevated a-ketoglutarate

Errors of Cholesterol Synthesis (SmithLemli-Opitz, CHILD, Greenberg dysplasia, chondrodysplasia punctata, Antley-Bixler, desmosterolosis, lathosterolosis, mevalonic aciduria)

Craniofacial, brain, skeletal and genital anomalies

Low cholesterol with elevated precursors

Glutaric Aciduria 2

Large fontanel, agenesis of corpus callosum, renal cysts, lissencephaly, cerebellar dysgenesis

Acidosis, hypoglycemia, elevations of glutaric acid

Lysosomal Disorders (mucopolysaccharidoses, mucolipidoses, gangliosidoses, sialidoses)

Coarse facies, hernias, hepatosplenomegaly, dysostosis multiplex

Elevated urinary mucopolysaccharides, abnormal oligosaccharides

Menkes

Kinky hair with pili torti, cortical heterotopias, dysgenesis of the corpus callosum and cerebellum

Low serum copper and ceruloplasmin

Peroxisomal Disorders (Zellweger, infantile adrenoleukodystrophy, infantile Refsum)

Distinctive facies, brain anomalies including migration defects and dysgenesis of the cerebellum and corpus callosum, corneal clouding, hepatomegaly, renal cysts, stippling of epiphyses, joint contractures

Elevated very long chain fatty acids, plasmalogens

Note: Structural anomalies have also been reported in patients with nonketonic hyperglycinemia, fumarase deficiency, multiple acyl CoA dehydrogenase (MCAD) deficiency.

1.8 Discussions with the Family Communication of information to the affected individual and family is perhaps the most important responsibility of the physician. The physician must be comfortable explaining the heritable or environmental basis of anomalies when an etiology is established and must be knowledgeable about the potential for prevention through various pregnancy alternatives, including prenatal diagnosis. The accuracy of the information provided by the physician must be assured by careful attention to the details of the case and by a continual awareness of new knowledge. The physician responsible for determining the cause of anomalies must become accustomed to the use of the phrase, ‘‘I don’t know.’’ The search for the cause of human anomalies fails in about one-half of cases (Table 1-5).40–42 Even without knowing the cause, information gained during the evaluation may benefit the family. Based on experience with similar cases, the prognosis may be reasonably stated and the recurrence risk given. In the course of the evaluation, the physician and

coworkers develop an interest in the affected individual and family, gain a feeling for the impact that the defect may have on family members, and assume a position of trust and confidence from which continuing support can be given. Sensitivity assists the physician in relating to the family. Much has been said in favor of having a team of specialists from different disciplines participate in the evaluation and management of certain anomalies.552–554 One advantage is bringing the various medical, surgical, and paramedical personnel to one site. When the availability of specialists and the logistics make this impractical, it is optimal for one physician to assume responsibility for coordinating all aspects of the complex evaluation. Attention should be given to support of the family unit and amelioration of the guilt that often develops in one or both parents. Paramount among the questions asked by the affected individual or parents are what is the defect, why did it happen, and will it happen again? In the best of circumstances, all these questions can be answered. In the worst, none can be answered completely. In any circumstance, an approach to management of the anomaly must be worked out with the family. The family may

72

Overview

Fig. 1-57. Fluorescence in situ hybridization (FISH). Left: 2 interphase nuclei with FISH using probes specific for the alpha satellite region (D18Z1) of the centromere of chromosome 18, indicating trisomy 18. Right: 2 metaphase spreads with chromosome 17s identified by FISH using the RARA probe (17q21.1) (arrowheads) and presence of the Smith-Magenis region (7p11.2) on only one of the two chromosomes, diagnostic of the Smith-Magenis syndrome. (Courtesy of Dr. Barbara DuPont and Sydney Ladd, Greenwood Genetic Center, Greenwood, SC.)

elect to have the support and advice of family members, friends, clergy, or others. When appropriate, members of the extended family may also be brought into the evaluation. When a diagnosis cannot be made, the physician or family may wish to consult other geneticists and dysmorphologists. This may be accomplished by direct consultation in another center or by correspondence. If done by correspondence, the sharing of photographs of features is a tremendous asset to the consultant. Regular follow-up is critical to optimizing the potential of an eventual diagnosis. These follow-up visits also emphasize to the family that interest in their child’s welfare continues. References 1. Hertig AT, Rock J, Adams EC, et al.: Thirty-four fertilized human ova, good, bad and indifferent, recovered from 210 women of known fertility. Pediatrics 23:202, 1959. 2. Roberts CJ, Lowe CR: Where have all the conceptions gone? Lancet 1:498, 1975. 3. Wilcox AJ, Weinberg CR, O’Connor JR, et al.: Incidence of early loss of pregnancy. N Engl J Med 319:189, 1988. 4. Poland BJ, Miller JR, Harris M, et al.: Spontaneous abortion: a study of 1,961 women and their conceptuses. Acta Obstet Gynecol Scand Suppl 102:1981. 5. Boue J, Boue A, Lazar P: The epidemiology of human spontaneous abortions with chromosomal anomalies. In: Aging Gametes. RJ Blandau, ed. Karger, Basel, 1975, p 330.

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424. Smithells RW, Nevin NC, Seller MJ, et al.: Further experience of vitamin supplementation for prevention of NTD recurrences. Lancet 1:1027, 1983. 425. Smithells RW, Sheppard S, Wild J, et al.: Prevention of neural tube defect recurrence in Yorkshire: Final report. Lancet 2:498, 1989. 426. Laurence KM, James N, Miller MH, et al.: Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. Br Med J 282:1509, 1981. 427. Mulinare J, Cordero JF, Erickson JD, et al.: Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 260:3141, 1988. 428. Milunsky A, Jick H, Jick SS, et al.: Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 262:2847, 1989. 429. Mills JL, Rhoads GG, Simpson JL, et al.: The absence of a relation between the periconceptional use of vitamins and neural-tube defects. N Engl J Med 321:430, 1989. 430. MRC Vitamin Study Research Group: Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131, 1991. 431. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by preconceptional vitamin supplementation. N Engl J Med 327:1832, 1992. 432. Berry RJ, Li Z, Erickson JD, et al.: Prevention of neural tube defects with folic acid in China. N Engl J Med 341:1485, 1999. 433. Stevenson RE, Allen WP, Pai GS, et al.: Decline in prevalence of neural tube defects in a high-risk region of the United States. Pediatrics 106:677, 2000. 434. Chan A, Pickering J, Haan EA, et al.: ‘‘Folate before pregnancy’’: the impact on women and health professionals of a population-based health promotion campaign in South Australia. Med J Aust 174:631, 2001. 435. Martı´nez de Villarreal L, Pe´rez JZV, Va´zquez PA, et al.: Decline of neural tube defects cases after a folic acid campaign in Neuvo Leo´n, Me´xico. Teratology 66:249, 2002. 436. US Department of Health and Human Services, Food and Drug Administration: Food standards: amendment to the standards of identity for enriched grain products to require addition of folic acid. Federal Register 61:8781, 1996. 437. Jacques PF, Selhub J, Bostom AG, et al.: The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340:1449, 1999. 438. Honein MA, Paulozzi LJ, Mathews TJ, et al.: Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285:2981, 2001. 439. Botto LD, Olney RS, Erickson JD: Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet Part C (Semin Med Genet) 125C:12, 2004. 440. Scanlon KS, Ferencz C, Loffredo CA, et al.: Preconceptional folate intake and malformations of the cardiac outflow tract. BaltimoreWashington Infant Study Group. Epidemiology 9:95, 1998. 441. Shaw GM, O’Malley CD, Wasserman CR, et al.: Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 59: 536, 1995. 442. Tolarova M, Harris J: Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 51:71, 1995. 443. Pritchard JA, Scott DE, Whalley PJ, et al.: Infants of mothers with megaloblastic anemia due to folate deficiency. JAMA 211:1982, 1970. 444. Bureau MA, Shapcott D, Berthiaume Y, et al.: Maternal cigarette smoking and fetal oxygen transport: a study of P50, 2,3-diphosphoglycerate, total hemoglobin, hematocrit and type F hemoglobin in fetal blood. Pediatrics 72:22, 1983. 445. Gordon M, Niswander KR, Berendes H, et al.: Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol 106:421, 1970.

446. Neill CA, Swanson S, Hellegers AE: Cyanotic congenital heart disease in pregnancy. In: Intrauterine Development. AC Barnes, ed. Lea & Febiger, Philadelphia, 1968. 447. Anderson M, Went LN, MacIver JE, et al.: Sickle-cell disease in pregnancy. Lancet 2:516, 1960. 448. Ballew C, Haas JD: Hematologic evidence of fetal hypoxia among newborn infants at high altitude in Bolivia. Am J Obstet Gynecol 155:166, 1986. 449. Yip R: Altitude and birth weight. J Pediatr 111:869, 1987. 450. Alzamora V, Rotta A, Battilana G, et al.: On the possible influence of great altitudes on the determination of certain cardiovascular anomalies. Pediatr 12:259, 1953. 451. Johnson GT: Comments in Non-toxaemic Hypertension in Pregnancy. NF Morris, JCM Browne, eds. Churchill, London, 1958, p 60. 452. Maxwell JP: Further studies in adult rickets (osteomalacia) and foetal rickets. Proc R Soc Med 28:265, 1934. 453. Pitkin RM: Calcium metabolism in pregnancy and the perinatal period: a review. Am J Obstet Gynecol 151:99, 1985. 453a. Larkin EC, Rao GA: Importance of fetal and neonatal iron: adequacy for normal development of central nervous system. In: Brain, Behavior, and Iron in the Infant Diet. Dobbing J, ed. Springer-Verlag, London, 1990, p 43. 454. Held KR, Cruz ME, Moncayo F: Clinical pattern and genetics of the fetal iodine deficiency disorder (endemic cretinism): results of a field study in highland Ecuador. Am J Med Genet 35:85, 1990. 455. Stafford PA, Biddinger PW, Zumwalt RE: Lethal intrauterine fetal trauma. Am J Obstet Gynecol 159:485, 1988. 456. Franger AL, Buchsbaum HJ, Peaceman AM: Abdominal gunshot wounds in pregnancy. Am J Obstet Gynecol 160:1125, 1989. 456a. Hall JG: Arthrogryposis associated with unsuccessful attempts at termination of pregnancy. Am J Med Genet 63:293, 1996. 457. Miller ME, Dunn PM, Smith DW: Uterine malformation and fetal deformation. J Pediatr 94:387, 1979. 458. Graham JMJ, Miller ME, Stephen MJ, et al.: Limb reduction anomalies and early in utero limb compression. J Pediatr 96:1052, 1980. 459. Bryan EM: The intrauterine hazards of twins. Arch Dis Child 61:1044, 1986. 460. Phelan MC, Stevenson RE: Adverse outcomes of twin pregnancies. Proc Greenwood Genet Center 8:3, 1989. 461. McKeown T, Record RG: Observations and fetal growth in multiple pregnancies in man. J Endocrinol 8:386, 1952. 461a. Hunter AG: A pilot study of the possible role of familial defects in anticoagulation as a cause for terminal limb reduction malformations. Clin Genet 57:197, 2000. 461b. Shalev SA, Hall JG: Poland anomaly—report of an unusual family. Am J Med Genet 118A:180, 2003. 462. Thomas IT, Smith DW: Oligohydramnios, cause of the non-renal features of Potter’s syndrome, including pulmonary hypoplasia. J Pediatr 84:811, 1974. 463. Torpin R: Fetal Malformations Caused by Amnion Rupture During Gestation. Charles C Thomas, Springfield, IL, 1968. 464. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amnion rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 465. Miller ME, Graham JMJ, Higginbottom MC, et al.: Compressionrelated defects from early amnion rupture: evidence for mechanical teratogenesis. J Pediatr 98:292, 1982. 466. Gleicher N, El-Roeiy A: The reproductive autoimmune failure syndrome. Am J Obstet Gynecol 159:223, 1988. 467. Sargent IL, Wilkins T, Redman CWG: Maternal immune responses to the fetus in early pregnancy and recurrent miscarriage. Lancet 2:1099, 1988. 468. McIntyre JA, Faulk WP: Recurrent spontaneous abortion in human pregnancy: results of immunogenetical, cellular, and humoral studies. Am J Reprod Immunol 4:165, 1983. 469. Cohen F, Zuelzer WW, Gustafson DC, et al.: Mechanisms of isoimmunization. I. The transplacental passage of fetal erythrocytes in homospecific pregnancies. Blood 23:621, 1964.

Human Malformations and Related Anomalies 470. Scanlon JW, Muirhead DM: Hydrops fetalis due to anti-Kell isoimmune disease: survival with optimal long-term outcome. J Pediatr 88:484, 1976. 471. Palchak AE, Aster RH, Gottschall J, et al.: Effect of maternal-fetal platelet incompatibility on fetal development. Pediatr 74:570, 1984. 472. Matsuda T, Momoi T, Akaishi K, et al.: Transient neonatal hyperthyroidism and maternal thyroid stimulating immunoglobulins. Arch Dis Child 63:205, 1988. 473. Connors MH, Styne DM: Transient neonatal ‘‘athyreosis’’ resulting from thyrotropin-binding inhibitory immunoglobulins. Pediatrics 78:287, 1986. 474. Doshi N, Smith B, Klionsky B: Congenital pericarditis due to maternal lupus erythematosus. J Pediatr 96:699, 1980. 475. Olson NY, Lindsley CB: Neonatal lupus syndrome. Am J Dis Child 141:908, 1987. 476. Merlob P, Metzker A, Hazaz B, et al.: Neonatal pemphigus vulgaris. Pediatrics 78:1102, 1986. 477. Oosterhuis HJGH, Feltkamp TEW, van der Geld HRW: Muscle antibodies in myasthenic mothers and their babies. Lancet 2:1225, 1966. 478. Borzy MS, Magenis E, Tomar D: Bone marrow transplantation for severe combined immune deficiency in an infant with chimerism due to intrauterine-derived maternal lymphocytes: donor engraftment documented by chromosomal marker studies. Am J Med Genet 18:527, 1984. 479. Stevenson RE, Sorell M, Kapoor N, et al.: Chimerism in an infant with severe combined immunodeficiency. Proc Greenwood Genet Center 3:30, 1984. 480. Bastian JF, Williams RA, Ornelas W, et al.: Maternal isoimmunization resulting in combined immunodeficiency and fatal graft-versus-host disease in an infant. Lancet 1:1435, 1984. 481. Turner JH, Hutchinson DL, Petricciani JC: Chimerism following fetal transfusion. Scand J Haematol 10:358, 1973. 482. Parkman R, Mosier D, Umansky I, et al.: Graft-versus-host disease after intrauterine and exchange transfusions for hemolytic disease of the newborn. N Engl J Med 290:359, 1974. 483. Elias S, Simpson JL: Prospects for prenatal diagnosis by isolating fetal cells from maternal blood. Centemp Rev Obstet Gynecol 7:135, 1995. 484. Bianchi DW: Fetal cells in the maternal circulation: feasibility for prenatal diagnosis. Fr J Haemotol 105:574, 1999. 485. Hall JM, Williams SJ: Isolation and purification of CD34þ fetal cells from maternal blood. Am J Hum Genet 51:A257, 1992. 486. Hafner E, Schucher K, Liebhart E, et al.: Results of routine fetal nuchal translucency measurement at weeks 10-13 in 4,233 unselected pregnanct women. Prenat Diagn 18:29, 1998. 487. Hata T, Manabe A, Aoki SW, et al.: Three-dimensional intrauterine sonography in the early first-trimester of pregnancy: preliminary study. Hum Reprod 13:740, 1998. 488. Platt LD, Feuchtbaum L, Filly R, et al.: The California maternal serum alpha-fetoprotein program: the role of ultrasonography in the detection of spina bifida. Am J Obstet Gynecol 166:1328, 1992. 489. Canick JA, Kellner LH: First trimester screening for aneuploidy: serum biochemical markers. Semin Perinatol 23:359, 1999. 490. CEMAT Group: Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis. The Canadian early and midtrimester amniocentesis trial (CEMAT) Group. Lancet 351:242, 1998. 491. Nicolaides K, Brizot ML, Patel F, et al.: Comparison of chorionic villus sampling and early amniocentesis for karyotyping in 1,492 singleton pregnancies. Fetal Diagn Ther 11:9, 1996. 492. Olney RS, Khoury MJ, Alo CJ, et al.: Increased risk transverse digital deficiency after chorionic villus sampling: results of the United States multistate case-control study, 1988-1992. Teratology 51:20, 1995. 493. Dolk H, Beatrand F, Lechat MF (Eurocat): Chorionic villus sampling and limb abnormalities. Lancet 339:876, 1992. 494. Evans MI, Hoffman EP, Cadrin C, et al.: Fetal muscle biopsy: Collaborative experience with varied indications. Obstet Gynecol 84:913, 1994.

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495. O’Rahilly R, Muller F: Developmental Stages in Human Embryos. Carnegie Institution of Washington, Washington, DC, 1987, Publication 637. 496. Saul RA, Geer JS, Seaver LH, et al.: Growth References: Third Trimester to Adulthood. Greenwood Genetic Center, Greenwood, SC, 1998. 497. Scammon RE, Calkins LA: The Development and Growth of the External Dimensions of the Human Body in the Fetal Period. University of Minnesota Press, Minneapolis, 1929. 498. Elejalde BR, de Elejalde MM: The prenatal growth of the human body determined by the measurement of bones and organs by ultrasonography. Am J Med Genet 24:575, 1986. 499. Morris CA, Demsey SA, Leonard CO, et al.: Natural history of Williams syndrome, physical characteristics. J. Pediatr 113:318, 1988. 500. Allanson JE, Hall JG, Hughes HE, et al.: Noonan syndrome: the changing phenotype. Am J Med Genet 21:507, 1985. 501. Butler MG, Meaney FJ, Palmer CG: Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am J Med Genet 23:793, 1986. 502. DeBusk FL: The Hutchinson-Gilford progeria syndrome: review of 4 cases and review of the literature. J Pediatr 80:697, 1972. 503. Stevenson RE, Prouty LA: Fragile X syndrome. VI. A subjective assessment of the facial features in blacks and whites. Proc Greenwood Genet Center 7:103, 1988. 504. Simpson JL: Disorders of Sexual Differentiation: Etiology and Clinical Delineation. Academic Press, New York, 1976, p 260. 505. Aase JM: Diagnostic Dysmorphology. Plenum Medical Book Co, New York, 1990. 506. Jones KL: Morphogenesis and dysmorphogenesis. In: Smith’s Recognizable Patters of Human Malformations, ed 5. WB Saunders, Philadelphia, 1997, p 695. 507. Wilson GN: Pediatric genetics, birth defects and syndromology. In: Clinical Genetics. A Short Course. Wiley-Liss, New York, 2000, p 251. 508. Snedecor GW, Cochran WG: Statistical Methods, ed 6. Iowa State University Press, Ames, 1967. 509. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 510. Brandt JM, Allen GA, Haynes JL, et al.: Normative standards and comparison of arthropometric data of white and black newborn infants. Dysmorph Clin Genet 4:121, 1990. 511. Gordon CC, Churchill T, Clauser CE: 1988 Anthropometric Survey of U.S. Army Personnel: Summary Statistics Interim Report. U.S. Army Natick Research, Development and Engineering Center, Natick, MA, 1989. 512. Horton WA, Rotter JI, Rimoin DL, et al.: Standard growth curves for achondroplasia. J Pediatr 93:435, 1978. 513. Meaney FJ, Farrer LA: Clinical anthropometry and medical genetics: a compilation of body measurements in genetic and congenital disorders. Am J Med Genet 25:343, 1986. 514. Broadbent BH:A new x-ray technique and its application to orthodontia. Angle Orthod 1:45, 1931. 515. Knott VB: Change in cranial base measures of human males and females from age 6 years to early adulthood. Growth 35:145, 1971. 516. Frias JL, King GJ, Williams CA: Cephalometric assessment of selected malformation syndromes. BDOAS XVIII(1):139, 1982. 517. Poznanski AK: The Hand in Radiological Diagnosis. WB Saunders, Philadelphia, 1984, p 31. 518. Vannier MW, Marsh JL, Warren JO: Three-dimensional CT reconstruction images for craniofacial surgical planning and evaluation. Radiology 150:179, 1984. 519. Vannier MW, Gutierrez FR, Laschinger JC, et al.: Three-dimensional magnetic resonance imaging of congenital heart disease. Radio Graphics 8:857, 1988. 520. Geist D, Vannier MW: PC-based 3-D reconstruction of medical images. Comput Graphics 13:135, 1989. 521. Vannier MW, Knapp RH, Offutt CJ, et al.: Computers in radiology. Curr Imaging 1:128, 1989.

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522. Vannier MW, Marsh JL: Three-dimensional reconstruction. In: Otolaryngology-Head and Neck Surgery: Update I. CW Cummings, et al., eds. CV Mosby, St. Louis, 1989, p 28. 523. Johnson JP: Acquired dysmorphic craniofacial features associated with chronic phenytoin therapy. Proc Greenwood Genet Center 3:114, 1984. 524. Lubchenco LO, Hansman C, Boyd E: Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 44 weeks. Pediatrics 37:403, 1966. 525. Usher R, McLean F: Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 74:901, 1969. 526. Merlob P, Sivan Y, Reisner SH: Anthropometric measurements of the newborn infant (27 to 41 gestational weeks). BDOAS XX(7):1, 1984. 527. Hamill PVV, Drizd TA, Johnson CL, et al.: Physical growth: National Center for Health Statistics Percentiles. Am J Clin Nutr 32:607, 1979. 528. Tanner JM, Davies PSW: Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 107:317, 1985. 529. Ogden CL, Kuczmarski RJ, Flegal KM, et al.: Centers for Disease Control and Prevention 2000 growth charts for the United States: Improvements to the 1977 National Center for Health Statistics Version. Pediatrics 109:45, 2002. 530. Nellhaus G: Head circumference from birth to eighteen years: practical composite international and interracial graph. Pediatrics 41:106, 1968. 531. Roche AF, Mukherjee D, Guo S, et al.: Head circumference reference data: birth to 18 years. Pediatrics 79:706, 1987. 532. Feingold M, Bossert WH: Normal values for selected physical parameters: an aid to syndrome delineation. BDOAS X(13):135, 141, 153, 1974. 533. Burin MG, Scholz AP, Gus R, et al.: Investigation of lysosomal storage diseases in nonimmune hydrops fetalis. Prenatal Diagn 24:653, 2004. 534. Leroy JG, Demars RI, Opitz JM: I-cell disease. BDOAS V(4):174, 1969. 535. Singh I, Johnson GH, Brown FR III: Peroxisomal disorders: biochemical and clinical diagnostic considerations. Am J Dis Child 142:1297, 1988. 536. Mitchell G, Saudubray JM, Gubler MC, et al.: Congenital anomalies in glutaric aciduria type 2. J Pediatr 104:961, 1984. 537. Marquardt T, Denecke J: Congenital disorders of glycosylation: review of their molecular bases, clinical presentations, and specific therapies. Eur J Pediatr 162:359, 2003. 538. Nissenkorn A, Michelson M, Ben-Zeev B, et al.: Inborn errors of metabolism: a cause of abnormal brain development. Neurology 56: 1265, 2001.

539. Kelley RI, Herman GE: Inborn errors of sterol biosynthesis. Ann Rev Genomics Hum Genet 2:299, 2001. 540. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development, ed 2. Oxford University Press, Oxford, 2002. 541. Loeys BL, Metthys DM, de Paepe AM: Genetic fibrillinopathies: new insights in molecular diagnosis and clinical management. Acta Clin Belg 58:3, 2003. 542. Biggin A, Holman K, Brett M, et al.: Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat 23:99, 2004. 543. Ades LC, Holman KJ, Brett MS, et al.: Ectopia lentis phenotypes and the FBN1 gene. Am J Med Genet 126A:284, 2004. 544. Donnai D, Karmiloff-Smith A: Williams syndrome: from genotype through to the cognitive phenotype. Am J Med Genet 97:164, 2000. 545. Metcalfe K, Rucka AK, Smoot L, et al.: Elastin: mutational spectrum in supravalvular aortic stenosis. Eur J Hum Genet 8:955, 2000. 546. Hakamori S, Fukuda M, Sekiguchi K, et al.: Fibronectin, laminin, and other extracellular glycoproteins. In: Extracellular Matrix Biochemistry. Picz KA, Reddi AH, eds. Elsevier, New York, pp 229–276. 547. Thomas GH, Howell RR: Selected Screening Tests for Genetic Metabolic Diseases. Year Book Medical Publishers, Chicago, 1973. 548. Sewell AC: Urinary oligosaccharides. In: Techniques in Diagnostic Human Biochemical Genetics. FA Hommes, ed. Wiley-Liss, New York, 1991, p 219. 549. De Vries BB, Winter R, Schinzel A, van Ravenswaaij-Arts C: Telomeres: a diagnosis at the end of the chromosomes. J Med Genet 40:385, 2003. 550. Vissers LELM, de Vries BBA, Osoegawa K, et al.: Array-based comparative genomic hybridization for the genomewide detection of submicrocopic chromosomal abnormalities. Am J Hum Genet 73: 1261, 2003. 551. Mantripragada KK, Buckley PG, de Stahl TD, Dumanski JP: Genomic microarrays in the spotlight. Trends Genet 20:87, 2004. 552. Thompson GH, Bilenker RM: Comprehensive management of arthrogryposis multiplex congenita. Clin Orthop Rel Res 194:6, 1985. 553. Salyer KE, Munro IR, Whitaker LA, et al.: Difficulties and problems to be solved in the approach to craniofacial malformations. BDOAS XI(7):315, 1975. 554. Lee PA, Mazur T, Danish R, et al.: Micropenis. I. Criteria, etiologies and classification. Johns Hopkins Med J 146:156, 1980.

Part II Cardiorespiratory Organs

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2 Heart Angela E. Lin, John Belmont, and Sadia Malik

I

n common practice, malformation of the heart refers to a defect of the intracardiac structures, that is, the atrial and ventricular chambers and septa, and the atrioventricular and semilunar valves. Beyond the heart itself are the great arteries which are frequently associated with abnormalities of outflow tract septation (conotruncal defects), and the systemic and pulmonary veins. Because intra-cardiac and extra-cardiac malformations cannot be easily separated, this chapter uses the broader term cardiovascular malformation (CVM), also known as a congenital heart defect. The term congenital heart disease is not employed since it connotes an active pathologic process. Caring for an individual with a CVM of any age can be a challenge even to an astute cardiac specialist. The number of individual CVMs is vast, the anatomy often complex, and the terminology likewise complex.1 An approach to the heart by sequential segmental analysis has had widespread appeal (Table 2-1).2 Naming complex CVMs has prompted vigorous discussion. Two recent systems of nomenclature are marvels of scope, but somewhat unwieldy in length.3,4 This chapter has been guided by the practical approach to classify CVMs based on mechanistic ‘‘families.’’5–7 Much has been learned about CVMs in the decade since the first edition of this book was published.8 This chapter has been substantially revised. Notably, the introduction now includes reviews of the embryology, epidemiology and molecular basis of CVMs. For selected defects, additional sub-sections have been added. As in the previous edition, several CVMs mentioned in this chapter are discussed elsewhere in the book. For example, patients with CVMs may have thoraco-abdominal malformations, including abnormal situs. Thus, laterality defects (also known as heterotaxy) span the content of the chapters on the Heart, the Spleen (Chapter 5), and Asymmetry and Hypertrophy (Chapter 33). Likewise, several CVMs involving the outflow tract, descending aorta, and great veins are also discussed in the chapter on Systemic Vasculature (Chapter 3). For additional information about the anatomy, diagnosis, and treatment of CVMs, the reader is referred to two excellent pediatric cardiology textbooks which themselves have been revised since the previous edition of this book.9,10 Chapters from these texts formed the core of the cardiology references. Rather than endorse a single

The authors acknowledge the contributions of Donald A. Riopel, author of this chapter in the first edition of Human Malformations and Related Anomalies.

system of cardiac nomenclature, we cited multiple sources and used cardiac terminology accordingly. The vast number of chromosome disorders, Mendelian gene mutations, and teratogens associated with CVMs have been listed elsewhere.11,12 We have added new tables listing many syndromes and conditions. These tables are not meant to be exhaustive compendia of the occurrence of a CVM in every possible syndrome. Instead, we emphasize CVMs with very frequent or very distinctive associations, omitting limited associations or private syndromes. A recurring dilemma in any review of the heart is narrowing the scope of the discussion. The spectrum of cardiac abnormalities extends from congenital malformations to complex acquired disorders. To maintain the focus on malformations and structural birth defects, we alert readers that this edition does not include sections on primary pulmonary hypertension, cardiomyopathy, and rhythm disturbances. Embryology

Cardiac development is among the most studied processes in vertebrate embryology, accompanied by a wealth of information from animal models. Yet there are considerable uncertainties with regard to the details of human heart development because of the difficulties inherent in studying early human embryos. The most extensively studied mammalian model of embryonic development is the mouse. However, the topology of the gastrulation and early somite stage embryos of this species compared to primates is somewhat different.13 The identity of morphogens, signaling cascades, and controlling transcriptional factors cannot be assumed to be identical when comparing species.14 In general, one could view abnormal cardiac development as a cascade of linked events in which there is an initial inciting event in a specific region or process (Fig. 2-1). This may be strongly suggested by some specific CVMs (e.g., dextrocardia and atrial isomerism) in which abnormalities in left–right axis patterning affect orientation of the inflow structures with respect to the midline or directionality of looping. But, for many CVMs the situation is ambiguous and they may be interpreted as arising from either an early event or a later and more specific process. This is particularly true of ventricular septal defects that may accompany either an early event (e.g., malalignment of the conal septum) or late disturbance (e.g., failure to close the muscular ventricular septum) in 85

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Cardiorespiratory Organs Table 2-1. Segmental analysis of the heart Anatomic Feature

Thoracoabdominal situs Cardiac position Atrial arrangement (atrial appendage) Atrioventricular connection Ventricular topology Conus Ventriculoarterial connection Great vessels From Anderson and Ho.2

cardiac morphogenesis. Given the large body of animal data that support mechanistic inferences about aberrant development in CVMs, there is a distinct lack of data from abnormal human embryos, particularly data reflecting on molecular mechanisms.

Commitment of Precardiac Mesoderm

Cells that will contribute to the heart arise from the anterior embryonic mesoderm. Their commitment to the cardiac lineage is established in the process of migration through the primitive streak.15,16 The activity of the transcription factor MesP1 is required for mesodermal cells to migrate out of the primitive streak.17 Anterior mesoderm cells are fated to contribute to the myocardium with the posterior boundary controlled by the Wnt family of growth factors.18 The precardiac mesoderm forms two lineages, myocardial and subjacent endocardial cells.19 Wnt inhibitory molecules, crescent and dickkoph, are expressed by the cardiac mesoderm; ectopic expression of these in posterior mesoderm is sufficient to induce heart formation.20 Wnt inhibi tion and BMP-type growth factors15,16 produced by adjacent neuroectoderm and foregut endoderm together induce cardiac mesoderm committment. In mice, the cardiogenic mesoderm expresses the transcription factor Nkx2.5, an NK homeobox family member with specific functions in both early and late cardiac development.21,22 Nkx2.5 is

Fig. 2-1. Schematic of heart development showing some key processes and mechanisms. The listed genes have been shown to play required roles in these processes (not exhaustive) or have been associated with syndromic or nonsyndromic cardiovascular malformations. See text for specific disease associations and gestational timing.

Heart

the vertebrate homologue of Drosophila tinman, which is required for the formation of the heart-like vessel in flies.23,24 The early cardiomyocytes express heart-specific differentiation markers including Mef-2C, cardiac actin, desmin, eHand, and cardiac-specific ankyrin protein (CARP), which probably act downstream of Nkx2.5.25,26 A second heart-forming field has recently been defined.27–29 This field arises from a more medial population of mesoderm cells just anterior to the cardiac crescent. Descendants of the precursors in the anterior heart-forming field will give rise to the common outflow tract or more cranially derived structures of the more mature heart. Cardiac organogenesis begins at day 18 as the cardiogenic mesoderm coalesces toward the midline. A pair of elongated mesenchymal strands canalize to form paired endothelial tubes which then fuse in the midline. The future cardiac myocytes are separated from the endothelial lining of the heart tube by cardiac jelly,30 a gelatinous connective tissue matrix which forms a subendocardial zone. GATA family transcription factors are necessary for the movements of cardiac mesoderm in forming the linear heart tube.31 GATA4 functions in endoderm underlying the myocardial precursors. OEP/cryptic32 and casanova33 mutations, which also affect endoderm development, lead to cardia bifida and, thus, demonstrate the importance of endoderm–mesoderm interaction. Heart Tube

By day 22, the single heart tube elongates, and segmentations define the truncus arteriosus, bulbus cordis, primitive ventricles, atrium, and sinus venosus. These structures indicate the cranialto-caudal patterning in the otherwise symmetric heart tube.34 At the cranial end, the truncus arteriosus is continuous with the aortic sac and aortic arch arteries. At the caudal end of the heart tube, the sinus venosus receives respectively the umbilical, vitelline, and common cardinal veins from the chorion (primitive placenta), yolk sac, and embryo proper.35 Shortly after coalescing into this heart tube, rhythmic contractions result from the intrinsic contractile and rhythmic properties of the myocardial cells. In the absence of valves, the flow of blood is directed from the inflow to the outflow by a kind of peristaltic action beginning in the sinus venosus. Normal flow is required for proper growth and remodeling of the heart such that obstruction leads to morphological abnormalities that are suggestive of human malformations like hypoplastic left-heart syndrome.36 Concomitant processes specify chamber identity. The transcription factors Mesp1 and Mesp217 also play a cell autonomous role in ventricular but not atrial chamber formation. Irx4 is also involved in ventricular specification.37,38 Irx4 seems to be regulated by Nkx2.5 and another transcription factor, dHand.39 dHand and eHand are both required for normal ventrical growth, although they exhibit generally complementary patterns of expression. eHand is predominantly expressed in the left ventricle and outflow tract. Right ventricle (RV) growth is specifically impaired in dHand mutant embryos leading to defective looping stage development.40 Another transcription factor, Mef2c, is also required for both left ventricle (LV) and RV growth,41 whereas COUP-TFII is required for atrial and sinus venosus precursor development.42 Looping

By day 23, a slight asymmetric growth of the left sino-atrial areas produces a ‘‘leftward jog’’ that is the first manifestation of the future left–right (LR) asymmetry of the mature heart.43 Because the bulbus cordis and the outer curvature of the RV grow faster than the other segments, the heart tube bends ventrally. This bending proceeds to a rightward folding of the ventricular seg-

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ment forming the C-looped heart. As growth continues, an Sshaped heart forms as the atrium and sinus venosus are pushed behind the future ventricles. The relative positions of the future LV and RV are also established at this stage. There is an extensive literature on the establishment of the left–right axis in the various animal model systems.44–46 There are several linked processes that mediate this cascade: (1) symmetry breaking; (2) formation of the node that will relay LR positional information from the organizer to the lateral plate mesoderm (LPM); (3) expression of the nodal-dependent signal transduction pathway in the left LPM; and (4) transfer of positional information to organ primordia. The node is a critical organizer that forms at the anterior most portion of the primitive streak.47,48 The node is composed of specialized epithelial cells with ventral monocilia. The monocilia exhibit a gyrorotatory motion leading to the ‘‘nodal flow hypothesis’’ in which the motion of the monocilia generates a morphogen gradient necessary to induce left side identity.49 Nodal, a growth regulator produced by the node, is a TGFb family signaling molecule that plays a variety of roles in the early embryo.50 Nodal expression in the node is required for proper left– right patterning. LeftyA is a nodal antagonist that is expressed in medial left LPM that is required to delimit the area of nodal activity and mutations that lead to left isomerism.51,52 Transfer of positional information to organ primordia is mediated in part by PitX2, a homeobox transcription factor that plays a central role in cardiac growth and development of the common outflow tract.53 PitX2 is directly regulated by nodal to mediate the left–right patterning inherent in the looping process. PitX2 is also directly regulated by the Wnt/b-catenin pathway to control development of the outflow tract via interaction with neural crest cells.54 Atrioventricular Canal and Atrial Septation

Blood flows from the sinus venosus to the common atrium and passes through the atrioventricular (AV) canal into the future ventricles. Partition of the AV canal at the common atrium and the ventricles begins about the middle of the 4th week. The endocardial cushions emerge from the subendocardial dorsal and ventral walls of the AV canal. By the 5th week the endocardial cushions fuse in the dorsal ventral midline to divide the AV canal into the right and left canals, preceding formation of the mature AV valves. The transcription factors, PitX2 and FOG-2,55,56 also are involved in the formation of the AV canal, and their mutation may lead to abnormal atrial septation. FOG2 specifically interacts with GATA4, and its deficiency leads to defects that resemble tetralogy of Fallot.57 AV canal defects are also observed in Tolloid-1 mutants.58 At the level of the common atrium, the septum primum grows from the wall of the atrial chamber. Before foramen primum (the gap in the incomplete septum) is completely closed, it becomes perforated to form another gap called the foramen secundum. Late in the 5th week, the septum secundum emerges to the right of the septum primum. The septum secundum grows toward the endocardial cushions and covers the foramen secundum. The septum secundum is incomplete, and its opening is called the foramen ovale. The septum primum forms a flap valve for the foramen ovale. Before birth, the foramen ovale lets most of the blood entering the right atrium from the inferior vena cava cross to the left atrium. After birth, the foramen ovale closes as a result of fusion of the septum primum and secundum. Much of the molecular information about these processes comes from the observation of mutations in families with dominant forms of atrial septal defects. Two genes, NKX2.559,60 and TBX5, have been implicated.61,62

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Cardiorespiratory Organs

Left Atrium and Pulmonary Veins

The primitive pulmonary venous plexus coalesces into the pulmonary veins, which in turn merge into the common pulmonary vein. This vein grows toward the primitive left atrium in a process of targeted growth. The venous wall is gradually incorporated into the wall of the left atrium. Later, the proximal branches of the pulmonary veins are incorporated into the dorsal wall of the chamber, resulting in four pulmonary veins with separate openings into the atrium. The left atrial appendage, which is a remnant derived from the primitive atrium, develops trabeculations reflecting its distinct embryonic origin compared to the remainder of the smooth-walled left atrium. At present, there are almost no molecular data from any of the animal model systems that reflect on these interesting processes despite their importance in human CVM. AV Canal–Ventricular Septation

Partitioning of the right and left ventricles begins with a muscular fold in the constriction (interventricular groove) between the primitive ventricles. The fold increases in prominence as a result of the differential growth of the ventricles on each side, as well as active upward growth of myocardium, forming the muscular interventricular septum. The wall between the ventricles remains incomplete through the 7th week. The final closure of the interventricular septum is coupled with the partitioning of the common outflow tract. Ridges from both the right and left side of bulbus cordis emerge, and these in turn fuse with the ridge produced by the endocardial cushions of the AV canal. The membranous interventricular septum derives from the right side of the endocardial cushions joining the aorticopulmonary septum and the muscular part of the interventricular septum. At closure of the interventricular septum, the pulmonary trunk connects with the right ventricle and the aorta with the left ventricle. Several transcription factors have been shown to play a role in ventricular septation,38,63 including a retinoic acid coreceptor (RXRa), TEF1, N-myc, and Sox4. Valvulogenesis

The semilunar (aortic and pulmonary) valves develop from three ridges of the endocardial tissue at the orifices of the aorta and pulmonary trunk. These swellings become hollowed out and reshaped to form the three thin-walled cusps. The AV valves (tricuspid and mitral) develop similarly from localized proliferation of subendocardial tissue around the AV canals. Mutation of mouse NFATc leads to defective semilunar valve formation.64,65 Double Egfr/Ptpn11 mutations in mice also lead to defective semilunar valve growth,66 highlighting the importance of EGFR activation in valvulogenesis. Neural Crest Contribution to Cardiac Development

At the time of formation of the neural tube, neurectodermal cells at the most dorsal ridge or crest migrate ventrally and there differentiate into a wide variety of neural and mesenchymal cell types. Two broad domains of neural crest cells may be defined—cephalic and truncal. In addition, related cells emerge from the cephalic placodes and give rise to craniofacial structures such as the inner ear. Neural crest cells provide autonomic innervation to the heart, with the sympathetic system arising from the truncal neural crest.67 The cardiac neural crest extends from the otic placode to the 3rd somite. These neural crest cells contribute to the heart and outflow tract. This same population of cells plays a critical role in the development of the thymus and parathyroid glands. Cardiac neural crest cells travel through the 3rd, 4th, and 6th pharyngeal

arches. They participate in the secondary heart field-related structures and are required for formation of the aorticopulmonary cushions. These cells also contribute to the walls of the aorta and pulmonary arteries distal to the outflow tract. Various mutant models,68–72 including Pax3,73 have been inferred to affect cardiac neural crest migrations or differentiation. Pathways such as that requiring semaphorin3C74,75 are directly involved in controlling neural crest cell migration. Other pathways, exemplified by the endothelin system, Tbx1, and Pitx2 may be involved in differentiation and growth or indirect mechanisms.76–79 Common Outflow Tract

During the 5th week, ridges of the subendocardial tissue form in the bulbus cordis. Similar ridges form in the truncus arteriosus and are continuous with those in the bulbus cordis. The spiral orientation of the ridges results in a spiral aorticopulmonary septum when these ridges fuse. This septum divides the bulbus cordis and the truncus arteriosus into two channels, the aorta and the pulmonary trunk. Blood from the aorta passes into the third and fourth pairs of aortic arch arteries (future aortic arch), and blood from the pulmonary trunk flows into the sixth pair of aortic arch arteries (future pulmonary arteries). Several mouse mutants including disheveled-2, semaphorin3C, and c-Jun exhibit failure of aorticopulmonary septation.75,80,81 Various combinations of the RARa1, RARb, and RXRa gene mutations also result in muscular ventricular septal defects, double-outlet right ventricle, transposition of the great arteries, and truncus arteriosus.82 In addition, mutations in Fgf8 and Tbx178,83,84 demonstrate CVMs that are suggestive of the type seen in DiGeorge syndrome. Moreover, mutation of the Pitx2c isoform provides functional evidence that the anterior heart field contributes to the common outflow tract and aortic arch remodeling.77 An important role for the notch signal transduction pathway in these processes can be inferred from human mutations in JAGGED1, a key notch receptor ligand in Alagille syndrome.85 Animal models have been less informative about notch in cardiac development, but progress is being made.86 Conduction System

At the heart tube and looping stages, the primitive common atrium acts as the pacemaker. As the chambers are formed, the AV constriction forms fibers that are specialized for conduction. These Purkinje fibers form the sinoatrial node, AV node, and AV bundle. They are innervated by making connections with neural crest–derived autonomic neurons that invade the subendocardial tissue. The sinoatrial node originates in the sinus venosus, later incorporating into the wall of the right atrium close to the entrance of the superior vena cava. The AV node develops in the lower part of the interatrial septum. The AV bundle in the interventricular septum consists of Purkinje fibers that extend from the AV node to the ventricles. A specific role for NKX2.5 in the development of the conduction system is demonstrated by both mouse and human mutations.87,88 Connexin40 is likely to be a key downstream target in that effect.89 In addition, mutation in the transcription factor HF-1b also leads to disrupted conduction system differentiation.90 Epidemiology

The frequency of CVMs is a fundamental and seemingly simple piece of epidemiologic information. Instead of incidence, which would require the inclusion of all conceptions (such as spontaneous abortions), most studies report live birth prevalence.91–93 However, determining the true prevalence of CVMs is difficult

Heart

since the diagnostic criteria used in a study may include cases recognized solely by clinical examination. More rigorous prevalence analyses require the use of echocardiography, cardiac catheterization, or autopsy data for confirmation. An exhaustive listing of 50 years of prevalence studies, including the diverse study designs and prevalence estimates, was provided by Rosenthal.93 Acknowledging great methodologic differences among the studies reviewed, a CVM was reported in about 2 to 8 per 1000 infants.93 The largest has been the Baltimore– Washington Infant Study (BWIS), a case-control analysis of CVMs that included echocardiographic diagnosis as a prerequisite.5,6,92 An impressive body of more recent data from a larger cohort has been derived from the ongoing Metropolitan Atlanta Congenital Defect Program (MACDP),94–99 much of it synthesized in a thoughtful review.95 In addition to liveborns up to age 1 year, stillborn infants and pregnancy terminations (that occurred at 20 gestational weeks or later) were identified. Table 2-2 summarizes the two programs, a comparison discussed in detail by Botto and Correa.94 Notably, rates for major CVMs have been similar, whereas rates for milder defects such as ventricular and atrial septal

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defects and patent ductus arteriosus were higher in more recent years. Despite the broad scope of the BWIS, the case ascertainment did not include the collection of all ventricular septal defects, only a sample, resulting in a relatively lower overall prevalence of heart defects and smaller contribution of ventricular septal defects compared to later studies. Over time, the overall prevalence of CVMs in comparable large population-based case-control studies has shown a steady increase from the 1970s (2.1%, New England) to the 1980s (4.8%, Baltimore–Washington area) and to the most recent estimate of 9.4 per 1000 in metropolitan Atlanta (1995–1997).92–94 This figure of almost 1% is due, in part, to increased echocardiographic detection of milder CVMs such as the small ventricular septal defects mentioned previously. Although there is general agreement about identifying severe CVMs, prevalence rates can vary based on the inclusion of mild CVMs, or cardiac problems which are not malformations (e.g., valve regurgitation and cardiomyopathy). In most studies, the overall CVM prevalence does not include mitral valve prolapse, patent ductus arteriosus of the preterm infant, and bicuspid aortic valves

Table 2-2. Prevalence of cardiovascular malformations: Baltimore–Washington Infant Study (BWIS) and the Metropolitan Atlanta Congenital Defect Program (MACDP) Prevalence per 10,000*

Cardiovascular Malformation

Ventricular septal defect (includes membranous, muscular, unspecified)

BWIS 1981–1989

MACDP 1968–1997

MACDP 1995–1997

11.2

16.6

24.0

Pulmonary valve stenosis

5.4

3.8

6.0

Peripheral pulmonic stenosis

NA

3.6

7.0

Atrioventricular septal defect (includes primum type atrial septal defect and canal-type ventricular septal defect)

3.3

2.7

3.4

With Down syndrome

2.3

1.5

2.4

Without Down syndrome

1.0

1.2

1.0 4.7

Tetralogy of Fallot

3.3

3.8

Atrial septal defect, secundum

3.2

10.0

4.6

d-Transposition of great arteries (includes d-TGA with intact ventricular septum, ventricular septal defect)

2.6

1.1

2.2

Hypoplastic left heart syndrome

1.8

2.1

2.1

Laterality(heterotaxy)/looping defect (includes L-transposition [corrected transposition])

1.4

1.3

1.6

Coarctation of the aorta

1.4

2.9

3.5

Patent ductus arteriosus

0.9

6.6

8.1

Aortic valve stenosis

0.8

1.0

0.8

Bicuspid aortic valve

0.7

NA

NA

Double-outlet right ventricle

0.7

1.1

2.2

Total anomalous pulmonary venous return

0.6

0.7

0.7

Pulmonary atresia with intact ventricular septum

0.6

0.6

0.6

Interrupted aortic arch

0.6

NA

NA

Ebstein anomaly

0.6

0.4

0.6

Common arterial trunk (truncus)

0.5

0.5

0.6

0.4

0.3

0.3

NA

6.4

9.7

Tricuspid atresia Other major CVMs

*Figures rounded. Listed in descending order as reported initially in the BWIS. CVM, cardiovascular malformation; NA, not available. Adapted from Botto et al.,94 Botto and Correa.95

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(present in 1–2% of adult series). Another important variable is birth status. The prevalence of CVMs is estimated to be higher among stillbirths (3–4%), and aborted fetuses (10–25%),93,100 although these estimates are based on rare studies. The small number of reports that include terminations in the broad definition of ‘‘birth’’ provide valuable information to assess temporal trends. Whether changes in the liveborn prevalence of CVMs are related to trends in prenatal diagnosis and elected termination will take on a greater role as prenatal vitamin therapy is assessed.94,96,101 Prevalence determination is also influenced by the period of ascertainment and the defect severity. The natural history may affect whether a CVM is detected. However, information about the natural history of a CVM may have limited utility by the time it is published since it was based on diagnostic techniques and treatment that have become outdated. With advances in both palliative and corrective surgery during the last 20 years, the number of children with a CVM surviving to adulthood has increased dramatically. Despite these advances, CVMs remain the leading cause of death in children with congenital malformations.94,95 The public health burden they represent is enormous.95 Gender differences in the occurrence of specific cardiac lesions have been well-documented. Transposition of the great arteries and left-sided obstructive lesions are slightly more common in boys, whereas atrial and ventricular septal defects are more common in girls.92 There are no racial differences in the occurrence of CVMs as a group; however, for specific lesions such as transposition of the great arteries, truncus arteriosus, coarctation of the aorta, and aortic stenosis, a higher occurrence may be seen in white versus black infants.6,94 Studying the ethnic variation of CVM prevalence is an even greater challenge than comparing racial groups. Prevalence figures about different ethnic groups derived from surveillance programs are sparse.93 Inferences might be drawn by comparing different countries, but such an approach would be unreliable because of different methodology. Almost all of the published studies of CVM prevalence have been conducted in the United States, the United Kingdom, and western Europe.92 Extracardiac anomalies occur in about 25% of infants with significant cardiac malformations, and their presence may significantly increase mortality.6 The extracardiac anomalies are often multiple; one-third of infants with both cardiac and extracardiac anomalies have an established syndrome. The cause of most CVMs is unknown. The proportion of patients with a CVM and a chromosome abnormality has been reported as approximately 12%6 to 13.4%.98 In the data from the MADCP,98 trisomy 21, 22q11.2 deletion and trisomy 18 were the most common chromosomal diagnoses (58.1%, 10.9%, and 10.3%, respectively, and 79.4% in total). In the BWIS, a CVM was found in over 90% of patients with trisomy 18, 50% of patients with trisomy 21, and 40% of those with Turner syndrome.6 Approximately 3% of patients with a CVM have an identifiable single gene defect, such as Marfan or Noonan syndrome. Two to four percent of CVMs are associated with known environmental or adverse maternal conditions and teratogenic influences, including maternal diabetes mellitus, phenylketonuria, rubella, and drugs (warfarin, thalidomide, antimetabolites, anticonvulsant agents).5,6,95 The BWIS also showed the association of CVMs with maternal exposure to solvents and pesticides.5,6,92 The impact of maternal alcohol ingestion, an extremely common exposure, in producing CVMs in humans has not been completely elucidated. A recent population-based case-control study reported an association between conotruncal CVMs and maternal alcohol use, especially with binge drinking.102

Evidence is growing to support the notion that CVMs can be prevented by using periconceptional multivitamins containing folic acid.95 A comprehensive review compared four major case-control studies and one clinical trial, and recommended a systematic, integrated research effort to answer the question definitively.103 In particular, several groups have noted a reduced risk of conotruncal heart defects.103 Two studies have shown that febrile illness with no multivitamin use was associated with an increased risk for certain CVMs.104,105 With concomitant multivitamin use, however, the risks associated with febrile illness were attenuated. In contrast to studies showing the risks associated with too little folic acid, excessive use of retinol (a specific vitamin A compound) has been implicated as a possible teratogen.106 A ninefold increased risk for transposition of the great arteries (d-TGA) was observed. Future investigations of the impact of prenatal vitamins, especially folic acid, will require meticulous study design, including classification of CVMs. To integrate the numerous clinical, laboratory testing, and research issues, the parents and extended family of a child with a CVM can be offered genetic counseling.108 The key to accurate genetic counseling for a family with a CVM is to determine whether the CVM is isolated or accompanied by additional malformations, and whether other families members are affected, especially the parents. One recent analysis estimates that about 75% of CVMs would not have an identifiable cause.11 A careful physical examination and detailed family history covering at least two generations must be performed. Additional studies, such as chromosome analysis, FISH analysis for 22q11 deletion, and familial echocardiograms would be recommended by the genetics specialist coordinating the evaluation. When a CVM appears to be an isolated sporadic occurrence associated with multifactorial inheritance pattern, the risk of recurrence is low. Compared to the background risk of 4 to 9 infants per 1000 having a CVM in the normal population, the risk increases to about 2–8% for a second pregnancy, depending on the type of CVM in the proband. This increased risk is discussed in more detail in the sections of each specific CVM. When providing genetic counseling to families, a detailed approach based on the type of CVM and other relevant factors is desirable.11,108 Diagnosis

Cardiovascular malformations can be detected at every age, and almost every CVM has been diagnosed prenatally at some point starting with the first trimester through the remainder of pregnancy.109,110 Diagnosis is accomplished using both the screening four-chamber view on obstetric ultrasound, as well as detailed fetal echocardiography. In addition to identifying the malformation of the heart itself, fetal echocardiography becomes a tool to predict a chromosome abnormality.111 In one study, approximately 25% of fetuses diagnosed at 20 to 24 weeks gestation with a CVM had an abnormal karyotype, including trisomy 21, 18, 21 and 9; 45,X, and 22q11 deletion.111 The results of this study reinforced the common practice that the detection of a CVM by fetal echocardiography should be an indication for karyotyping, usually by amniocentesis. Most CVMs present in the first year of life, with additional defects becoming symptomatic in the later years of childhood, and some escaping detection until adulthood. Obtaining a careful clinical history and performing a meticulous physical examination remain the mainstay of diagnosis.112 Advances in imaging techniques have

Heart

rendered a diagnosis based solely on auscultation, radiography, and electrocardiography incomplete. Because of the association of CVMs and malformation syndromes, patients undergoing cardiac evaluations should also be inspected for possible dysmorphic facial features or unusual body characteristics that might indicate an underlying syndrome. For example, a young girl with short stature and possible coarctation of the aorta should be examined for other features of Turner syndrome. This should be done initially by the primary care doctor and pediatric cardiologist who may decide that a referral to a dymorphologist is warranted. Two-dimensional echocardiography with Doppler examination has revolutionized cardiac diagnosis because of its noninvasiveness and ability to visualize cardiac structures with a high degree of accuracy.113–115 Transesophageal imaging provides additional views for patients with poor ultrasonic windows, intraoperative assessment, and for postoperative patients with limited access to the chest wall. Magnetic resonance imaging (MRI) offers superb imaging for vascular structures and elucidates the complex spatial relationships of some CVMs.116 Nuclear cardiology contributes complementary physiologic information such as ventricular function and myocardial perfusion.117 Cardiac catheterization with angiocardiography remains an important diagnostic procedure, with an ever increasing role in therapeutic intervention.118 References 1. Edwards WD: Classification and terminology of cardiovascular anomalies. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 118. 2. Anderson RH, Ho SY: Sequential segmental analysis—description and categorization for the millennium. Cardiol Young 7:98, 1997. 3. Association European Pediatric Cardiology (AEPC). Codes. http://www. aepc.org/code-com.htm 4. Mavroudis C, Jacobs JP: Congenital heart surgery nomenclature and database project: overview and minimum dataset. Ann Thorac Surg 69: S2, 2000. 5. Ferencz C, Rubin JD, Loffredo CA, Magee CA: Epidemiology of Congenital Heart Disease: The Baltimore-Washington Infant Heart Study 1981–1989. Futura, Mount Kisco, NY, 1993. 6. Ferencz C, Loffredo CA, Correa-Villasen˜or A, Wilson PD: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore–Washington Infant Study: 1981–1989. Futura Publishing Company, Inc., Armonk, NY, 1997. 7. Clark EB: Etiology of congenital cardiovascular malformations: Epidemiology and genetics. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 64. 8. Riopel DA: The Heart. In: Human Malformations and Related Anomalies, ed 1. Stevenson RE, Hall JG, Goodman RM. Oxford University Press, New York, 1993, p 237. 9. Allen HD, Clark EB, Gutgesell HP, et al.: Moss and Adams’ Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adult, vols 1 and 2, ed 6. Lippincott Williams and Wilkins, Philadelphia, 2001. 10. Garson A Jr., Bricker JT, Fisher DJ, Neish SR: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Williams and Wilkins, Baltimore, 1998. 11. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, et al., eds. Churchill Livingstone, London, 2002, p 1239. 12. Lin AE: Congenital heart defects in chromosome abnormality syndromes. In: Moss and Adams’ Heart Disease in Infants, Children, and

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39. Yamagishi H, Yamagishi C, Nakagawa O, et al: The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Dev Biol 239:190, 2001. 40. Srivastava D, Cserjesi P, Olson EN: A subclass of bHLH proteins required for cardiac morphogenesis. Science 270:1995, 1995. 41. Lin Q, Schwarz J, Bucana C, et al: Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276:1404, 1997. 42. Pereira FA, Qiu Y, Zhou G, et al: The orphan nuclear receptor COUPTFII is required for angiogenesis and heart development. Genes Dev 13:1037, 1999. 43. Manner J: Cardiac looping in the chick embryo: a morphological review with special reference to terminological and biomechanical aspects of the looping process. Anat Rec 259:248, 2000. 44. Yost HJ: Establishment of left-right asymmetry. Int Rev Cytol 203:357, 2001. 45. Mercola M: Embryological basis for cardiac left-right asymmetry. Semin Cell Dev Biol 10:109, 1999. 46. Boorman CJ, Shimeld SM: The evolution of left-right asymmetry in chordates. Bioessays 24:1004, 2002. 47. Tabin CJ, Vogan KJ: A two-cilia model for vertebrate left-right axis specification. Genes Dev 17:1, 2003. 48. Brennan J, Norris DP, Robertson EJ: Nodal activity in the node governs left-right asymmetry. Genes Dev 16:2339, 2002. 49. Nonaka S, Shiratori H, Saijoh Y, et al: Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418:96, 2002. 50. Hamada H, Meno C, Watanabe D, et al: Establishment of vertebrate left-right asymmetry. Nat Rev Genet 3:103, 2002. 51. Meno C, Shimono A, Saijoh Y, et al: lefty-1 is required for leftright determination as a regulator of lefty-2 and nodal. Cell 94:287, 1998. 52. Kosaki K, Bassi MT, Kosaki R, et al: Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am J Hum Genet 64:712, 1999. 53. Ryan AK, Blumberg B, Rodriguez-Esteban C, et al: Pitx2 determines leftright asymmetry of internal organs in vertebrates. Nature 394:545, 1998. 54. Kioussi C, Briata P, Baek SH, et al: Identification of a Wnt/Dvl/ beta-Catenin ! Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 111:673, 2002. 55. Tevosian SG, Deconinck AE, Tanaka M, et al: FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101:729, 2000. 56. Svensson EC, Huggins GS, Lin H, et al: A syndrome of tricuspid atresia in mice with a targeted mutation of the gene encoding Fog-2. Nat Genet 25:353, 2000. 57. Crispino JD, Lodish MB, Thurberg BL, et al: Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev 15:839, 2001. 58. Clark TG, Conway SJ, Scott IC, et al: The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development 126:2631, 1999. 59. Ikeda Y, Hiroi Y, Hosoda T, et al: Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease. Circ J 66:561, 2002. 60. Biben C, Weber R, Kesteven S, et al: Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res 87:888, 2000. 61. Hatcher CJ, Kim MS, Basson CT: Atrial form and function: lessons from human molecular genetics. Trends Cardiovasc Med 10:93, 2000. 62. Vaughan CJ, Basson CT: Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus. Am J Med Genet (Semin Med Genet) 97:304, 2000. 63. Cripps RM, Olson EN: Control of cardiac development by an evolutionarily conserved transcriptional network. Dev Biol 246:14, 2002. 64. Ranger AM, Grusby MJ, Hodge MR, et al: The transcription factor NFATc is essential for cardiac valve formation. Nature 392:186, 1998. 65. de la Pompa JL, Timmerman LA, Takimoto H, et al: Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392:182, 1998.

66. Chen B, Bronson RT, Klaman LD, et al: Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet 24:296, 2000. 67. Baptista CA, Kirby ML: The cardiac ganglia: cellular and molecular aspects. Kaohsiung J Med Sci 13:42, 1997. 68. Creazzo TL, Godt RE, Leatherbury L, et al: Role of cardiac neural crest cells in cardiovascular development. Annu Rev Physiol 60:267, 1998. 69. Hutson MR, Kirby ML: Neural crest and cardiovascular development: a 20-year perspective. Birth Defects Res Part C Embryo Today 69:2, 2003. 70. Jiang X, Rowitch DH, Soriano P, et al: Fate of the mammalian cardiac neural crest. Development 127:1607, 2000. 71. van den Hoff MJ, Moorman AF: Cardiac neural crest: the holy grail of cardiac abnormalities? Cardiovasc Res 47:212, 2000. 72. Waldo K, Miyagawa-Tomita S, Kumiski D, et al: Cardiac neural crest cells provide new insight into septation of the cardiac outflow tract: aortic sac to ventricular septal closure. Dev Biol 196:129, 1998. 73. Conway SJ, Henderson DJ, Kirby ML, et al: Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. Cardiovasc Res 36:163, 1997. 74. Maschhoff KL, Baldwin HS: Molecular determinants of neural crest migration. Am J Med Genet (Semin Med Genet) 97:280, 2000. 75. Feiner L, Webber AL, Brown CB, et al: Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 128:3061, 2001. 76. Yanagisawa H, Hammer RE, Richardson JA, et al: Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. J Clin Invest 105:1373, 2000. 77. Liu C, Liu W, Palie J, et al: Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development 129:5081, 2002. 78. Vitelli F, Morishima M, Taddei I, et al: Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Hum Mol Genet 11:915, 2002. 79. Sinning AR: Role of vitamin A in the formation of congenital heart defects. Anat Rec 253:147, 1998. 80. Hamblet NS, Lijam N, Ruiz-Lozano P, et al: Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 129:5827, 2002. 81. Eferl R, Sibilia M, Hilberg F, et al: Functions of c-Jun in liver and heart development. J Cell Biol 145:1049, 1999. 82. Lee RY, Luo J, Evans RM, et al: Compartment-selective sensitivity of cardiovascular morphogenesis to combinations of retinoic acid receptor gene mutations. Circ Res 80:757, 1997. 83. Frank DU, Fotheringham LK, Brewer JA, et al: An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development 129:4591, 2002. 84. Jerome LA, Papaioannou VE: DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 27:286, 2001. 85. Spinner NB, Colliton RP, Crosnier C, et al: Jagged1 mutations in alagille syndrome. Hum Mutat 17:18, 2001. 86. McCright B, Lozier J, Gridley T: A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129:1075, 2002. 87. Schott JJ, Benson DW, Basson CT, et al: Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281:108, 1998. 88. Kasahara H, Wakimoto H, Liu M, et al: Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/ Nkx2.5 homeoprotein. J Clin Invest 108:189, 2001. 89. VanderBrink BA, Sellitto C, Saba S, et al: Connexin40-deficient mice exhibit atrioventricular nodal and infra-Hisian conduction abnormalities. J Cardiovasc Electrophysiol 11:1270, 2000. 90. Nguyen-Tran VT, Kubalak SW, Minamisawa S, et al: A novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages. Cell 102:671, 2000. 91. Hoffman J: Incidence, mortality and natural history. In: Anderson RH, Baker EJ, et al eds., Pediatric Cardiology, ed 2. Churchill Livingstone, London, 2002, p 111–139. 92. Loffredo CA: Epidemiology of cardiovascular malformations: Prevalence and risk factors. Am J Med Genet (Semin Med Genet) 97:319, 2000.

Heart 93. Rosenthal G: Prevalence of congenital heart disease. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, et al., eds. Williams & Wilkins, Baltimore, 1998, pp 789–843. 94. Botto LD, Correa A, Erickson JD: Racial and temporal variations in the prevalence of heart defects. Pediatrics 107:e32, 2001. 95. Botto LD, Correa A: Decreasing the burden of congenital heart anomalies: an epidemiologic evaluation of risk factors and survival. Prog Pediatr Cardiol 18:111–121, 2003. 96. Cragan JD, Khoury MJ: Effect of prenatal diagnosis on epidemiologic studies of birth defects. Epidemiology 11:695, 2000. 97. Boneva RS, Botto LD, Moore CA, et al.: Mortality associated with congenital heart defects in the United States. Trends and racial disparities, 1979–1997. Circulation 103:2376, 2001. 98. Botto LD, Campbell RM, Rasmussen SA, et al. The current contribution of chromosomal anomalies to the occurrence of congenital heart defects: findings from population-based study. Am J Hum Genet 71(Suppl 4): 211A, 2002. 99. Botto LD, May K, Fernhoff PM, et al: A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101, 2003. 100. Chinn A, Fitzsimmons J, Shepard TH, et al.: Congenital heart disease among spontaneous abortuses and stillborn fetuses: prevalence and associations. Teratology 40:475–482, 1989. 101. Lin AE, Herring AH, Scharenberg KS, et al.: Changes in hospital-based birth prevalence of cardiovascular malformations. Am J Med Genet 84: 102,1999. 102. Carmichael SL, Shaw GM, Yang W, Lammer E. Maternal periconceptional alcohol consumption and risk for conotruncal heart defects. Birth Defects Res (Part A) 67:875, 2003. 103. Botto LD, Mulinare J, Erickson JD: Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps. Am J Med Genet 121:95, 2003. 104. Botto LD, Lynberg MC, Erickson JD: Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiology 12:485, 2001. 105. Shaw GM, Nelson V, Carmichael SL, et al: Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies. Epidemiology 13:625, 2002. 106. Botto LD, Loffredo C, Scanlon KS, et al.: Vitamin A and cardiac outflow tract defects. Epidemiology 12:491, 2001. 107. Towbin J, Greenberg F: Genetic syndromes and clinical molecular genetic. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, et al., eds. Williams & Wilkins, Baltimore, 1998, p 2627. 108. Hoess K, Goldmuntz E, Pyeritz RE: Genetic counseling for congenital heart disease: new approaches for a new decade. Curr Cardiol Reports 4:68, 2002. 109. Huhta JC, Tian Z-Y: Fetal echocardiography in the practice of perinatal cardiology. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, et al., eds. Williams & Wilkins, Baltimore, 1998, p 845. 110. Rowland DG, Wheller JJ: Congenital heart disease and arrhythmias in the fetus. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 569. 111. Raymond FL, Simpson JM, Sharland GK, et al.: Fetal echocardiography as a predictor of chromosomal abnormality. Lancet 350:930, 1997. 112. Duff DF, McNamara DG: History and physical examination of the cardiovascular system of the cardiovascular system. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, et al., eds. Williams & Wilkins, Baltimore, 1998, p 693. 113. Geva T: Echocardiography and Doppler ultrasound. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, et al., eds. Williams & Wilkins, Baltimore, 1998, p 789. 114. Kimball TR, Meyer RA: Echocardiography. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and

115.

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93 Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 204. Snider AR, Ritter SB: Doppler Echocardiography. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 234. Long, FR, Smith MA, Adler BH: Advanced imaging techniques In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 171. Wiles HB: Nuclear cardiology. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, et al., eds. Williams & Wilkins, Baltimore, 1998, p 889. Bridges ND, O’Laughlin MP, Mullins CE, et al.: Cardiac catheterization, angiography, and intervention. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, et al., eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 276.

2.1 Heterotaxy Definition

Heterotaxy includes defects of left–right axis patterning, laterality defects, cardiac malpositions, abnormalities of atrial and visceral situs, and looping defects including l-TGA and ventricular inversion. Heterotaxy is derived from the Greek root for ‘‘other arrangement’’ and refers to an abnormal left–right relationship of thoracic and/or abdominal organs in relationship to each other.1,2 Normal left–right anatomy is called situs solitus, whereas mirror image anatomy is called situs inversus. Normally, the arrangement of body organs is characterized by asymmetry. Heterotaxy is typified by symmetry (or loss of asymmetry) of otherwise unilateral structures. Situs ambiguus describes the indeterminate arrangement of the abdominal organs. Heterotaxy can be defined simply as an arrangement which is not clearly situs solitus or situs inversus. Heterotaxy ‘‘syndromes’’ are characterized by a wide variety of congenital anomalies of both midline structures as well as lateralized internal organs.3–8 The discussion on asymmetry (Chapter 33) by Hoyme provides further description of abdominal organ situs anomalies. Incomplete or failed left–right patterning may lead to cardiac segmental discordance, isomerism (e.g., right atrial appendage isomerism in which left atrial development is lost) and/or failure of normal vascular remodeling (e.g., persistent left superior vena cava). As a consequence of the uncertainties about embryological pathology, the nosology used to describe these conditions is not uniform. None of the classifications completely captures the full range of clinically important variants.3 Some useful distinctions include (1) dextrocardia, levocardia, and mesocardia, which describe the position of the heart in the thorax without reference to the intracardiac anatomy; (2) d-loop and l-loop, which refer to the normal rightward looping of the heart tube (in contrast to the leftward looping of situs inversus); and (3) arterial transpositions, which refer to the relative positions of the aorta and pulmonary trunk. There is general agreement that the segmental approach to the heart is the preferred method to describe complex heart defects, especially those with heterotaxy (Table 2-1). Chambers and vessels are identified by morphologic characteristics, position, and connections. Following the approach of Van Praagh1,2,6 six segments can be categorized by the (1) systemic and pulmonary

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veins; (2) atrial situs, which may be normal or solitus, inversus, or ambiguus and may include heterotaxy with or without isomerism; (3) AV connection with d- or l-looped ventricular looping, and concordant or discordant atrial connection; (4) ventricles and infundibulum; (5) ventriculo-arterial connection; and (6) great artery relationships, which may be normally related, side-byside, d-TGA, l-TGA, or otherwise malposed. Situs Inversus

Dextrocardia with situs inversus has a lower risk of intracardiac CVM than dextrocardia with situs solitus. However, when present, severe CVMs may include ventricular septal defect (60%), d-TGA or l-TGA (50%), double outlet right ventricle (30%), pulmonic stenosis (50%), and right aortic arch (80%).1 Levocardia with situs inversus is a rare complex discordance almost always associated with intracardiac anomalies including malposition and d-TGA, AV septal defect, pulmonic stenosis, and anomalous pulmonary venous return. Situs Ambiguus

Two clinical categories of situs ambiguus, polysplenia and asplenia, are discussed at length in Chapter 5. Asplenia represents a failure of left-sided patterning and suggests bilateral right-sidedness. Polysplenia suggests bilateral left-sidedness either because of a failure of the midline barrier or because of lack of right-side patterning.1,2 Heart defects seen in patients with asplenia tend to be more severe and complex than those seen with polysplenia.1,2,3–6 Cardiovascular malformations in heterotaxy with asplenia include d-transposition of the great arteries (80%), common atrium or atrial septal defect (90%), AV septal defect (80%), bilateral superior vena cava (50%), double outlet right ventricle, pulmonary atresia and stenosis (80%), single ventricle (50%), and total anomalous pulmonary venous connection (70%). Several CVMs are frequently associated with polysplenia-type anatomy but are rare in asplenia such as partial anomalous pulmonary venous return (40%), intrahepatic interruption of the inferior vena cava with connection to the azygous or hemiazygous vein (70%), and left ventricular outflow tract obstruction (40%). Two autopsy series showed atrial isomerism to be relatively common, occurring in 5.2% and 3.1% of cases, respectively.10,11 Ventricular Inversion—Corrected Transposition

With ventricular inversion or congenitally corrected transposition of the great arteries, there is AV and ventriculoarterial discordance. Assuming that the atria are normal, the anatomic left ventricle pumps the pulmonary circulation, and the anatomic right ventricle supports the systemic circulations.1,12–14 Ventricular inversion is almost always associated with l-TGA such that the aorta emerges from the anatomic right ventricle anterior or leftward to the pulmonary artery. A secondary consequence of ventricular inversion is that the AV node is also malpositioned and sometimes accompanied by an accessory AV node. The bundle of His and the right and left bundle branches are also inverted. Ventricular inversion may rarely be an isolated defect, but usually a ventricular septal defect (80%) or pulmonic stenosis (70%) are present. AV conduction defects are common with complete heart block occurring in at least one-third of cases.13 Other Associations with Heterotaxy

Heterotaxy includes pulmonary isomerism, vascular rings, midline liver, annular pancreas, right-sided stomach, biliary atresia, tracheo-esophageal fistula, omphalocoele, and intestinal malrota-

tion with obstruction or volvulus (vascular obstruction). Other midline malformations include central nervous system abnormalities such as encephalocele, neural tube defects, porencephalic cyst, and cerebellar agenesis. Axial skeletal defects (hemivertebra and sacral agenesis), hindgut abnormalities (anal atresia or stenosis), and genito-urinary tract anomalies (hypoplastic kidneys, hypospadias, duplicated uterus, vaginal atresia, fusion of adrenals in midline) have been reported. Craniofacial anomalies include cleft lip/palate agnathia, micrognathia, choanal atresia, and laryngeal cleft, occurring equally in asplenia and polyspenia phenotypes. In 160 autopsy cases of patients with heterotaxy, midline defects were found in 38%.5 Sacral dysplasia and anorectal anomalies have been reported in patients with X-linked heterotaxy caused by mutations in ZIC3.14 In pedigrees in which a ZIC3 mutation was identified, both carrier females as well as affected males were noted to have anal anomalies.14,15 Diagnosis

The evaluation of a child with heterotaxy requires much more than an evaluation of the heart. The anatomic investigation of the heart is accomplished primarily by meticulous echocardiography with attention to atrial situs, outflow tract, and inferior vena cava integrity.8,9 To further define distal pulmonary arteries or pulmonary venous connections, cardiac MRI or angiography may be needed. Catheterization is required to assess pulmonary vascular resistance. The electrocardiogram (ECG) is important for identification of AV conduction defects, and Holter monitor testing may be needed to assess AV block. It is essential to thoroughly investigate all organ systems at risk in each infant with suspected heterotaxy. An overpenetrated chest radiograph can be used to establish pulmonary situs. Abdominal organ situs should be investigated by ultrasonogaphy with attention to spleen size, number, and position, pancreas, and liver situs. Radionuclide studies can also be used to determine spleen activity. Intestinal contrast studies may be necessary if there is clinical concern for obstruction, volvulus, and malrotation. Genitourinary malformations may be investigated by ultrasonography with attention to the renal collecting system, adrenals, and internal reproductive organs. Radiographs of the spine allow examination of the axial skeleton and sacrum. Head ultrasound, computed tomography, and MRI may be used to look for heterotopias and hydrocephalus. The laboratory evaluation should include a complete blood count to look for Howell-Jolly bodies as a clue to the possibility of functional asplenia. Based on reports of chromosome abnormalities,8,9 karyotype, FISH analysis for deletion 22q11, and subtelomere analysis should also be considered. Etiology and Distribution

Situs inversus totalis occurs in about 1/10,000 healthy individuals. It is extremely difficult to estimate the birth incidence and prevalence of laterality defects because of the mechanistic ambiguity of some common birth defects. The hospital-based prevalence rate of heterotaxy in a well-defined cohort was 1 per 10,000 among non-transfer births (which approaches a population prevalence).8 Heterotaxy accounts for about 3% of CVM1 and ventricular inversion accounts for approximately 0.5%. However, d-TGA and related malposed great arteries accounts for 9–10% of heart defects.10,12 It is not yet clear whether the majority of TGA results from early patterning defects or disturbances in the septation of the

Heart

common outflow tract. Taken together with visceral and midline defects, the true incidence of birth defects related to anomalies of the embryonic left-right axis may be much higher than currently appreciated. Most cases of heterotaxy are sporadic and one might assume that Mendelian inheritance represents the exception. However, familial clustering of situs inversus and situs ambiguus is well recognized. Some of these defects might not have been interpreted as heterotaxy (e.g., hypoplastic left ventricle) outside the context of the index case. The occurrence of families with X-linked inheritance has been demonstrated by linkage analysis (HTX1, Xq26.2, OMIM #306955) and confirmed by mutant gene identification (ZIC3).14 The excess of males with heterotaxy cannot be fully accounted for by ZIC3 mutation, however. Some pedigrees are suggestive of autosomal dominant inheritance with incomplete penetrance. Familial clustering of d-TGA also recently has been reassessed, again pointing to the higher than expected occurrence of significant CVMs in relatives, although not always TGA. Mutations in the following genes have been associated with clinical heterotaxy and/or d-TGA in the literature: ZIC3,14 CRYPTIC/CFC1,17 LEFTYA,18 ACVR2B,19 NKX2.5,20 and CRELD1.21 It should be noted that only single patients with an NKX2.5 and CRELD1 mutations have been observed and so the contribution of gene defects in these loci remains to be further characterized. Functional studies of CRYPTIC mutations have been carried out but not for those observerd in LEFTYA, ACVR2B, NKX2.5, or CRELD1. Familiality of left-right defects is, therefore, complicated by lack of critical population-based data collection for family history, incomplete penetrance in families with apparent Mendelian inheritance, locus heterogeneity, allelic heterogeneity, and ambiguity as to the origin of atypical birth defects in close relatives. Other factors including occurrence of specific defects within more complex multisystem syndromes or chromosomal disorders, unknown environmental liability factors, sex differences, phenocopies, incomplete ascertainment due to fetal loss, and reduced family size due to burden of disease add to the difficulty in sorting our the etiologies of heterotaxy. Taken together, these are all typical of ‘‘complex traits’’. Heterotaxy can be associated with chromosome abnormalities. Only trisomy 13 has been seen in more than one patient with heterotaxy (Table 6 in Lin et al).8 Maternal insulin-dependent diabetes has been shown to be a risk factor which has clinical significance because of the potential for prevention.8,22 Interestingly, in the Baltimore-Washington Infant Study, cases of isolated dextrocardia shared similar risk factors as other heterotaxy malformations. The risk to twin probands applied to monozygous pairs in contrast to twin probands with other CVMs. Prognosis, Treatment, and Prevention

The outcome of patients with a laterality defect is an enormous spectrum ranging from an asymptomatic adult with dextrocardia or interrupted inferior vena cava, to a critically ill newborn with complex single ventricle, pulmonary atresia, cleft lip and asplenia. Cardiac complications can be related to cyanosis, congestive heart failure and arrhythmia. Arrhythmia can result from an absent sinoatrial node and intracardiac surgical scars. Despite improvement in prenatal detection and surgical management, the prognosis for children with complex heterotaxy-type cardiac lesions is poor.23,24 Risk factors for poor outcome include unobstructed pulmonary blood flow, obstructed pulmonary venous return, and major AV valve anomalies. Single ventricle heterotaxy with or without atrial isomerisms may be treated with the Fontan procedure where there is evidence of improving success.25

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Surgical management of associated birth defects like intestinal obstruction is also often necessary. The presence of functional asplenia increased the risk of overwhelming bacterial infection and appropriate antibiotic prophylaxis must be considered. References (Heterotaxy) 1. Gutgesell HP: Cardiac malposition and heterotaxy. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 789. 2. Hagler DJ, O’Leary PW: Cardiac malpositions and abnormalities of atrial and visceral situs. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001 p 1151. 3. Phoon CK, Neill CA: Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 73:581, 1994. 4. Ticho BS, Goldstein AM, Van Praagh R: Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. Am J Cardiol 85:729, 2000. 5. Peoples WM, Moller JH, Edwards JE: Polysplenia: a review of 146 cases. Pediatr Cardiol 4:129, 1983. 6. Van Praagh S KJ, Alday L, Van Praagh R: Systemic and pulmonary venous connections in visceral heterotaxy, with emphasis on the diagnosis of the atria situs: a study of 109 postmortem cases. In: Developmental Cardiology, Morphogenesis and Function. Takao A, ed. Futura, Mt. Kisco, NY, 1990, p 671. 7. Uemura H, Ho SY, Devine WA, et al.: Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both. Am J Cardiol 76:846, 1995. 8. Lin AE, Ticho BS, Houde K, et al.: Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med 2:157, 2000. 9. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001. 10. Sharma S, Devine W, Anderson RH, et al.: The determination of atrial arrangement by examination of appendage morphology in 1842 heart specimens. Br Heart J 60:227, 1988. 11. Hegerty AS, Anderson RH, Ho SY: Congenital heart malformations in the first year of life—a necropsy study. Br Heart J 54:583,1985. 12. Mullins CE: Ventricular inversion. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 789. 13. Freedom RM, Dyck JD: Congenitally corrected transposition of the great arteries. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1085. 14. Egloff L, Rothlin M, Schneider J, et al.: Congenitally corrected transposition of the great arteries: a clinical and surgical study. Thorac Cardiovasc Surg 28:228, 1980. 15. Gebbia M, Ferrero GB, Pilia G, et al.: X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305, 1997. 16. Casey B, Devoto M, Jones KL, et al.: Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1. Nat Genet 5:403, 1993. 17. Bamford RN, Roessler E, Burdine RD, et al.: Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26:365, 2000. 18. Kosaki K, Bassi MT, Kosaki R, et al.: Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am J Hum Genet 64: 712, 1999. 19. Kosaki R, Gebbia M, Kosaki K, et al.: Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 82:70, 1999. 20. Watanabe Y, Benson DW, Yano S, et al. Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD. J Med Genet 39:807, 2002.

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21. Robinson SW, Morris CD, Goldmuntz E, et al.: Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 72:1047, 2003. 22. Kuehl KS, Loffredo C: Risk factors for heart disease associated with abnormal sidedness. Teratol 66:242, 2002. 23. Gaynor JW, Collins MH, Rychik J, et al.: Long-term outcome of infants with single ventricle and total anomalous pulmonary venous connection. J Thorac Cardiovasc Surg 117:506, discussion 513, 1999. 24. Lin JH, Chang CI, Wang JK, et al.: Intrauterine diagnosis of heterotaxy syndrome. Am Heart J 143:1002, 2002. 25. Stamm C, Friehs I, Duebener LF, et al.: Improving results of the modified Fontan operation in patients with heterotaxy syndrome. Ann Thorac Surg 74:1967, discussion 1978, 2002.

2.2 Single Ventricle Definition

Single ventricle is also known as univentricular heart and univentricular AVconnection. A single ventricle defect is an AV connection completely or predominantly to a single ventricular chamber.1–3 Cardiac pathologists have debated whether to call such hearts single ventricle,3 common ventricle, univentricular heart, or to refer to such as a univentricular AV connection.1 This section will use the term single ventricle. In the BWIS, single ventricle does not appear as a distinct entity in the risk factor analysis. Instead, patients with single ventricle are listed in the ‘‘Spectrum of Laterality and Cardiac Looping Defects’’ because of their frequent association with Ltransposition of the great arteries and heterotaxy.4 A single ventricle heart is never an isolated defect. Hemodynamics dictate an atrial shunt, mixing in the ventricle and outlet chamber, and frequent great artery looping errors. Some hearts may be viewed as having functional single ventricles. These are defined as one ventricle with a single AV valve (due to AV valve atresia), or CVMs with two AV valves and two ventricles, one of which is very hypoplastic.2,3 Tricuspid atresia, pulmonary atresia, straddling tricuspid valve, unbalanced AV canal, hypoplastic left heart syndrome, unbalanced AV canal, and double outlet right ventricle with hypoplastic left ventricle are among those included in this category.3 Hearts with superior–inferior ventricles and crisscross AV relations are rare types of functional single ventricle. The morphology of the main ventricle determines how the heart is classified. The most common single ventricle is single left ventricle, which is more common in patients without heterotaxy.3 There is a morphologic left ventricle and a right ventricular remnant (outlet chamber) connected by the bulboventricular foramen or ‘‘ventricular septal defect.’’2 There is usually an L-loop, with concordance between the ventricular and great artery segment. In the ‘‘Holmes heart,’’ the aorta arises from the left ventricle and the pulmonary artery from the right ventricular outlet chamber.3 AV valve anomalies are common. Because the morphology of the AV valves does not correspond to the situation in biventricular hearts (i.e., bileaflet mitral valve, trileaflet tricuspid valve), they are usually referred to at the right or left AV valves.2 Double-inlet left ventricle is most common.2,3 Atresia of one AV valve or common AV valve may be present.2,3 Familiar variants include hypoplasia, stenosis, and overriding or straddling of the AV valve.2 The common-inlet ventricle has a common AV valve.2 Outflow obstruction includes subaortic narrowing due to subvalvar hypoplasia or accessory AV valve tissue, or a restrictive ventricular connection.3 Finally, conduction abnormalities can be present.2

Single right ventricle is strongly associated with heterotaxy, especially situs ambiguus and asplenia.3 Because there is no left ventricle, there is always double outlet right ventricle.3 Almost all cases have two AV valves.3 In some cases of single ventricle, the solitary ventricle has indeterminate morphology.1 Diagnosis

The majority of patients with single ventricle present in the newborn period with symptoms varying from cyanosis to congestive heart failure, depending on the presence or absence of pulmonic obstruction.2 Clinical status is also influenced by AV valve regurgitation and aortic obstruction. Segmental analysis of these complex hearts is accomplished by two-dimensional echocardiography.2 In addition to the primary role in assessing anatomy, ventricular function can be evaluated.5 Doppler interrogation evaluates pulmonic and subaortic obstruction, as well as AV valve regurgitation or stenosis, and coarctation.2 Transesophageal echocardiography is important for intra-operative and postoperative care.5 In the hands of experts, fetal echocardiography should be able to diagnose single ventricle. The ECG in all forms of single ventricle is often abnormal due to alterations of depolarization and asymmetric ventricular forces.2 Patients with common-inlet AV connection have ECG signs of AV canal defects, including left axis deviation.2 The chest radiograph is variable and depends on the specific abnormalities, which may increase pulmonary blood flow and heart size. MRI is useful to delineate extracardiac anomalies.2,5 It is also useful for adolescent patients. Cardiac catheterization is performed in anticipation of staged Fontan procedures with attention to pulmonary vascular resistance, systemic and pulmonary vein connections, pulmonary artery and aorta morphology, and aorto-pulmonary collaterals.2 Etiology and Distribution

There are scant data discussing the etiology of single ventricle. There are no consistent syndrome associations. One recent review included functional forms of single ventricle, although nonfunctional single ventricle could be sorted out.6 The monograph summarizing the results of the BWIS did not analyze single ventricle as a distinct entity; however, a subsequent paper reported its epidemiologic analysis.7 The regional prevalence was 6.1 per 100.000, a lower figure than what has been estimated,6 but perhaps more accurate because it was observed rather than estimated. None of the variables for maternal exposure was shown to have a significant association.7 Among paternal exposures, alcohol and cigarette smoking were reported possible risk factors.7 Prognosis, Treatment, and Prevention

Management is based on the specific anatomy.2 Surgery is performed to increase or decrease pulmonary blood flow, relieve subaortic obstruction, and correct AV valve regurgitation. The timing and specific technique of the pre-Fontan palliative procedures continue to be refined. The general approach is systemic pulmonary shunting or pulmonary artery banding in the first 6 months, with relief of subaortic obstruction as needed. A bidirectional cavopulmonary shunt can be performed, with a modified Fontan procedure between 2–3 years.2 Outcome studies about the Fontan procedure often incorporate tricuspid atresia, which is consistently associated with a higher 5- and 10-year survival rates (approaching 80%) compared with other forms of single ventricle (less than 70%).6 Alternatively, transplantation can be considered. Ventricular septation has been abandoned. In

Heart

general, long-term survival has been achieved, accompanied by complications that include developmental delay,8 arrhythmias, protein-losing enteropathy, and exercise intolerance.2,9 References (Single Ventricle) 1. Anderson RH: How should we optimally describe complex congenitally malformed hearts? Ann Thor Surg 62:710, 1996. 2. Hagler DJ, Edwards WD: Univentricular atrioventricular connection. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1129. 3. Weinberg PM: Morphology of single ventricle. Prog Pediatr Cardiol 16:1, 2002. 4. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study: 1981–1989. Futura, Armonk, NY, 1997. 5. Sherwood MC, Geva T: Noninvasive imaging of the single ventricle. Prog Pediatr Cardiol 16:11, 2002. 6. O’Leary PW: Prevalence, clinical presentation and natural history of patients with single ventricle. Prog Pediatr Cardiol 16:31, 2002. 7. Steinberger EK, Ferencz C, Loffredo CA: Infants with single ventricle: a population-based epidemiologic study. Teratol 65: 106, 2002. 8. Forbess JM, Visconti KJ, Hancock-Friesen C, et al.: Neurodevelopmental outcome after congenital heart surgery: results from an institutional registry. Circulation 106(suppl 1):I95, 2002. 9. Rychik J, Cohen MI: Long-term outcome and complications of patients with single ventricle. Prog Pediatr Cardiol 16: 89, 2002.

2.3 Conotruncal Defects Definition

Conotruncal defects may be described as abnormalities of outflow tract septation or ectomesenchymal tissue migration abnormalities. Abnormal septation of the outflow tract of the embryonic heart can occur with failure to separate the pulmonary artery and aorta completely, resulting from errors in conotruncal rotation. This large group of CVMs is attributed to abnormal migration of cranial neural crest cells to the outflow tract and pharyngeal derivatives.1,2 Different pathologists have used various terms to describe this portion of the heart tube, referring to it as the conotruncus, outlet segment, and outflow tract.2–4 Two defects that may be viewed as more than simple septation defects are d-transposition of the great arteries (which includes abnormal conotruncal cushion position) and type B interrupted aortic arch (which involves disruption of the descending aorta).3 Transposition of the Great Arteries

Transposition of the great arteries (TGA), or more precisely dextroTGA(d-TGA), is due to failure of the conotruncal septum to spiral, resulting in the aorta arising anteriorly from the right ventricle and the pulmonary artery posteriorly from the left ventricle.5,6 d-Transposition must be differentiated from l-transposition as discussed in the section on looping and laterality. The term ‘‘simple d-TGA’’ refers to the most common (80%) situation in which d-TGA is accompanied by patent foramen ovale (almost all), atrial septal defect, ventricular septal defect (VSD) (40%, one-third of which are small), patent ductus arteriosus (PDA), pulmonic stenosis or coronary artery anomaly.6 Some authors include double outlet right ventricle with subpulmonary VSD (which is within the spectrum of Taussig-Bing

97

anomaly) in the discussion of simple d-TGA because of similar anatomy, physiology, and treatment.6 Simple d-TGA contrasts with ‘‘complex d-TGA,’’ which may include AV valve atresia or straddling orifice, or single ventricle heart with d-TGA. Early onset cyanosis is the familiar presentation for d-TGA.5,6 The presence of a PDA or large VSD improves the degree of cyanosis. Because the chest radiograph and ECG may be normal in appearance in the immediate newborn period, a prompt echocardiographic examination is clearly indicated. In some centers, pre-operative catheterization is not performed, although it is still done for blade atrial septostomy.5,6 For patients with complex dTGA, catheterization with angiocardiography remains an important diagnostic tool.5,6 If untreated, 90% of infants die in the first year of life.5,6 Treatment in the immediate newborn period includes prostaglandin infusion, followed by emergency balloon atrial septostomy. The arterial switch procedure is the corrective surgery of choice for most patients, although the atrial switch procedures of Mustard and Senning remain an option for others.5,6 Patients with coronary artery anomalies, d-TGA/VSD, or pulmonic stenosis (left ventricular outflow tract obstruction) require special attention. Dysrhythmias are more common with atrial switch procedures.5,6 The quality of life in adulthood is usually excellent.5,6 Truncus Arteriosus

In persistent truncus arteriosus, failure of the aortopulmonary septum to septate results in a single arterial ‘‘trunk’’. All three circulations—systemic, pulmonary, and coronary—arise from this trunk. There is a single semilunar valve that may have 1 to 5 cusps and may be stenotic or insufficient.7 The ventricular septal defect is usually a large conoventricular defect; rarely is it small or absent.7 Three types of truncus arteriosus are defined on the basis of the pulmonary artery origin.7 In type I, the truncus gives rise to a short common pulmonary artery trunk, which gives rise to both pulmonary arteries. In type II, the posterior or dorsal wall of the truncus gives rise to both pulmonary arteries directly, which are close to one another. In type III, both pulmonary arteries arise independently from either side of the truncus some distance from one another Truncus is usually an isolated defect, but frequent abnormalities include right aortic arch, type B interrupted aortic arch, and absent ductus arteriosus. What had been called type IV truncus or pseudotruncus is now referred to as pulmonary valve atresia with VSD (described in this chapter in the section on tetralogy of Fallot). Also excluded from the definition of classic truncus is hemitruncus in which one pulmonary artery arises from the ascending aorta, and the other pulmonary artery arises from the right ventricle and has a normal valve. The findings on physical examination and chest radiography are related to the degree of pulmonary overcirculation modulated by pulmonary vascular resistance. Echocardiography reliably establishes the anatomy, and Doppler interrogation delineates the hemodynamics. Besides scanning the truncal root, the descending aorta must be imaged to ensure that interruption is not present.7 Cardiac catheterization with angiocardiography is used infrequently.7 It is helpful in patients with unusual arch anatomy and in patients who present at a later age and need assessment of the pulmonary vascular bed.7 Surgical correction at 6 weeks of age is recommended because of the risk of early onset pulmonary vascular obstructive disease.7 Continued technical improvements have helped reduce operative mortality and prolong survival. At present, the preferred

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conduit connecting the right ventricle to the pulmonary arteries is a cryopreserved porcine homograft.7 Tetralogy of Fallot

Normal conotruncal development requires proper rotation, septation, and alignment of the outlet septum with the ventricular trabecular septum.1,3 The defects in tetralogy of Fallot are attributed to incomplete rotation and partitioning of this process. In the familiar tetrad, the hallmark is the subpulmonic deviation of the conal septum superiorly and to the right, which results in right ventricular hypertrophy and aortic override.8,9 The muscular subvalvular narrowing may be accompanied by valvar and supravalvar stenoses, or focal or diffuse pulmonary artery narrowing. There may be anomalous muscle bundles within the right ventricle itself leading to the ‘‘double-chambered right ventricle.’’ Depending on the system of cardiac nomenclature, the VSD may be described as perimembranous, conoventricular, or infundibular. There is general agreement that this is an anteriorly malaligned defect, and usually nonrestrictive.8,9 An additional muscular VSD(s) may be present.8,9 Associated anatomic features include patent foramen ovale or secundum atrial septal defect, right aortic arch with mirror-image branching, left superior vena cava to coronary sinus, and coronary artery anomalies. In patients with Down syndrome, tetralogy of Fallot can be associated with AV canal.8,9 Although many discussions of tetralogy of Fallot include variant forms with absent/dysplastic pulmonary valve, or absent pulmonary valve, these will be discussed as separate entities. Because the degree of pulmonic obstruction and ventricular shunting is variable, the clinical presentation of tetralogy of Fallot is varied. Acyanotic ‘‘pink tet’’ patients may have symptoms, physical findings, and chest radiographs suggestive of pulmonary overcirculation. With progression of subpulmonic obstruction, patients present with cyanosis. The classic hypercyanotic or hypoxemic episodes (‘‘tet spells’’) are observed less frequently since the introduction of early surgical correction in infancy.8,9 Tetralogy of Fallot can be diagnosed by the classic findings of cyanosis, systolic murmur of valvar pulmonic stenosis, bootshaped heart on chest radiograph, and right ventricular hypertrophy on ECG.8,9 The clinical diagnosis can be confirmed with two-dimensional echocardiography. Doppler analysis can be used to define the location and severity of the pulmonic stenosis.8,9 The indication for cardiac catheterization has decreased, although a role for interventional techniques has grown. Angiocardiography is required in a minority of patients in whom the coronary artery cannot be defined adequately using echocardiography.9 Surgical repair in early infancy is desirable, and survival is generally excellent. There is general agreement that earlier repair diminishes postoperative arrhythmias, sudden death, and residual defects.8,9 Tetralogy of Fallot with Absent Pulmonary Valve

Despite the term ‘‘absent’’ pulmonary valve, the valve in this variant of tetralogy of Fallot is typically a primitive dysplastic ring of tissue.10 The intracardiac anatomy is otherwise similar. The distinguishing feature is the massive post-stenotic dilation of the central pulmonary arteries which compress the mainstem bronchi. Furthermore, there is a bizarre pulmonary arterial branching pattern.10 Infants with this CVM present with respiratory distress due to both large airway compression and reactive small airway disease. There is a highly distinctive heart murmur produced by the pulmonic stenosis and regurgitation.10 Called a ‘‘to and fro’’ murmur,

it occurs in systole and diastole and is heard at the upper left sternal border, but is widely transmitted. Unlike the chest radiograph of typical tetralogy of Fallot, congenital absence of the pulmonary valve produces cardiomegaly with dilated pulmonary arteries.10 Two-dimensional echocardiography defines the pulmonic annulus and distal arteries.10 Surgery must not only correct the cardiac defect, but also relieve the compression of the large airways.10 The severe respiratory obstructive disease is not always relieved because of the involvement of the more distal arterial and alveolar branches. Operative mortality has been high in infancy, with better results in those who are asymptomatic prior to surgery.10 Tetralogy of Fallot with Pulmonary Atresia

When tetralogy of Fallot is accompanied by pulmonary valve atresia, the combination is called tetralogy of Fallot with pulmonary atresia or pulmonary atresia with VSD. Involvement of the pulmonary trunk may be limited to an imperforate pulmonary valve or extend to absence of the pulmonary valve and proximal pulmonary trunk.11 A confluence of the right and left pulmonary artery branches may be present, giving the appearance of a seagull.8,11 Aorto-pulmonary collateral vessels provide the sole supply of blood to the lungs. Patients with tetralogy of Fallot with pulmonary atresia usually present in the newborn period with cyanosis.8,11 Some are adequately oxygenated due to adequate systemic collateral flow. In such patients, a characteristic continuous murmur is heard widely over the precordium and back.8,11 Although two-dimensional echocardiography can delineate the typical features of tetralogy of Fallot, cardiac catheterization is needed to outline the pulmonary arterial bed.8 This includes imaging the presence or absence of a confluence of the right and left pulmonary arteries, and systemically derived collateral arteries. In addition, stenoses and regions of hypoplasia should be demonstrated. Alternatively, MRI can be used. For the small number of patients who have a pulmonary artery confluence of reasonable size, complete repair can be performed using a valved conduit from the right ventricle and pulmonary artery, and closing the VSD.8,11 In most patients with hypoplastic pulmonary arteries, the preferred surgical treatment is single staged unifocalization, or a multi-staged repair.8 Double-Outlet Right Ventricle

This deceptively simple term refers to hearts in which the aorta and pulmonary artery arise from the right ventricle without mitral-aortic valve continuity and a double conus (infundibulum). The range of associated defects makes this an anatomically, hemodynamically, and clinically diverse CVM. Cardiac pathologists differ on the strictness of the definition. The interested reader is referred to excellent reviews in recent cardiology textbooks.12,13 Some insight may be gained from embryology. Double-outlet right ventricle is a relatively primitive condition, in which there is persistence of the posterior conus so that the aorta is not committed completely to the left ventricle.12,13 There is, in fact, a spectrum of defects ranging from double-outlet right ventricle that resembles tetralogy of Fallot to a form that approximates complete d-TGA.12,13 The classification of double-outlet right ventricle requires a description of the relationship of the great arteries, which can be normally related (NRGA), side-by-side, d-malposed, or l-malposed.12,13 Four types of VSD can be present in double-outlet right

Heart

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Table 2-3. Syndromes and conditions frequently associated with conotruncal defects Causation

Type of Conotruncal Defect

MIM #

Gene

Locus

179613

Unknown

Unknown

Chromosome Abnormality Recombinant 8 (partial trisomy 8q)

TOF, DORV Truncus

Deletion 17p11.2 (Smith-Magenis)

TOF

NA

Unknown

Unknown

Trisomy 13

VSD conoventricular

NA

Unknown

Unknown

NA

Unknown

Unknown

NA

Unknown

Unknown

TBX1

22q11

JAG1

20p12

DORV, TOF Trisomy 18

VSD conoventricular TOF, DORV

Trisomy 21 Deletion 22q11.2 spectrum

TOF Truncus

DGS 188400

DiGeorge sequence

IAA, type B

VCF 192430

Velocardiofacial syndrome

TOF, TOF/PA, DORV, VSD conoventricular

Autosomal Dominant Alagille

TOF

118450

CHARGE

Truncus, IAA, type B

214800

CHD7

8q12.1

Adams-Oliver

TOF

100300

Unknown

Unknown

Jones-Waldman

TOF

Unknown

Unknown

Unknown

Townes-Brocks

Truncus, TOF

107480

SALL1

16q12.1

Ritscher-Schinzel (3C)

TOF, DORV

220210

Unknown

Unknown

Thrombocytopenia-absent radius (TAR)

TOF

274000

Unknown

Unknown

Autosomal recessive

Teratogen Diabetes23

Truncus

NA

NA

NA

Retinoic acid

IAA, type B, TA

NA

NA

NA

Alcohol

TOF

NA

NA

NA

Thalidomide

TOF

NA

NA

NA

dTGA, TOF, DORV

Truncus Maternal phenylketonuria

TOF

NA

NA

NA

Trimethadione

TOF, d-TGA

NA

NA

NA

TOF

164210

Unknown

Unknown

Other Hemifacial microsomia FAVS, OAVD, Goldenhar Ectopia cordis

Heterogeneous TOF

NA

NA

NA

Compiled from Clark,2 Ferencz et al.,4 Burn and Goodship,20 Lofreddo.23 Italics indicate if the CVM is the most commonly associated defect(s). FAVS, facio-auriculo-vertebral spectrum; d-TGA, dextro-transposition of the great arteries; DORV, double outlet right ventricle; IAA, interrupted aortic arch; NA, not applicable; OAVD, oculo-auriculo-vertebral dysplasia; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

ventricle: (1) subaortic VSD, (2) subpulmonic VSD (supracristal), which is part of the Taussig-Bing complex, (3) doubly committed, and (4) remote location such as an AV canal or muscular VSD.13 According to one author,13 there could be 16 combinations of great artery relationships and VSD location, although not all have been observed. Additional types of double-outlet right ventricle incorporate variations in visceral situs and AV discordance. Associated cardiac defects include pulmonic stenosis, subaortic obstruction, mitral valve anomalies, and left ventricular hypoplasia.12,13 Not surprisingly, the clinical presentation varies greatly from double-outlet right ventricle patients with subaortic VSD

and pulmonic stenosis that resembles tetralogy of Fallot, to those with subpulmonary VSD with or without pulmonic stenosis that may mimic d-TGA.12,13 The patients with subaortic VSD without pulmonic stenosis have hemodynamics like patients with a large unrestrictive VSD. Diagnosis requires high quality two-dimensional echocardiography with Doppler examination. Surgical correction can be as simple as closure of a large VSD or as complex as the reconstruction of an essentially single ventricle heart with double-outlet right ventricle and left ventricular outflow tract obstruction.12,13

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Cardiorespiratory Organs

Conoventricular Ventricular Septal Defects

Conotruncal ventricular septal defects include outlet, malalignment, infundibular, and subpulmonary defects.14,15 This large, non-restrictive VSD is the most common anatomic type of VSD associated with truncus arteriosus, type B interrupted aortic arch, and tetralogy of Fallot. It may also occur as an isolated CVM. Conoventricular VSDs are typically associated with clinical, radiographic, and ECG features of pulmonary overcirculation, except when associated CVMs or subpulmonic obstruction are present14,15 (see the section on VSDs).

Type B Interrupted Aortic Arch

Aortic arch interruption refers to discontinuity between the ascending and descending aorta, aside from the blood supplied by a patent ductus arteriosus or a branch of the aortic arch.16,17 It is also discussed in Chapter 3 (Systemic Vasculature). Three anatomic types are widely used.16,17 Type A refers to interruption distal to the left subclavian artery, type B refers to interruption between the carotid and subclavian arteries, and type C involves the aorta between the innominate and carotid artery. Type B interrupted aortic arch is the most common type and is typically associated with a conoventricular VSD with posterior malalignment. Several hypotheses have been offered to explain interruption of the aorta. Depending on the location of the interruption, there may have been failure of formation, inappropriate regression, or altered blood flow.17 Type B is best explained by involution of the left fourth arch and a segment of dorsal arch between the fourth and sixth arches.17 The characteristic presentation for these patients is cardiovascular collapse or heart failure when the ductus closes.16,17 The diagnosis is made urgently by high quality two-dimensional echocardiography.17 An accurate diagnosis of the arch anatomy requires imaging from selected suprasternal views. Angiography is still used by some centers, whereas others use MRI with three-dimensional reconstruction.17 Surgical correction involves reconstruction of the aorta with homograft augmentation, patch closure of the VSD, and release of the subaortic obstruction.16,17 Associated cardiac anomalies such as truncus or dTGA require additional palliative techniques.

Etiology and Distribution

Although d-TGA is infrequently (10%) associated with noncardiac malformations, the other conotruncal CVMs are frequently associated with noncardiac malformations, with up to 40% occurring in patients with truncus.4 Like all CVMs, conotruncal defects are etiologically and genetically heterogeneous.4,18,19 Table 2-3 lists syndromes and conditions in which conotruncal CVMs are frequently associated. Table 2-1 also includes genes that have been identified in association with these conditions. In the past twenty years, this group of CVMs has been especially rewarding in clinical, cytogenetic, and molecular research. Prominent on Table 2-1 is chromosome 22q11 deletion. In large clinical and population-based studies, this deletion has been detected in about 50% patients with type B interrupted aortic arch, 25–35% of patients with truncus, and 10–15% patients with tetralogy of Fallot.20,21 Among patients with tetralogy of Fallot, some studies have shown that the deletion is more common in patients

who have additional vascular anomalies such as collateral vessels, right aortic arch, or aberrant subclavian artery.20 Among fetuses with prenatally imaged conotruncal CVMs, the frequency of 22q11 deletion in one study was higher (figures rounded), that is, interrupted aortic arch (89%), tetralogy of Fallot (79%), tetralogy of Fallot with pulmonary atresia (73%), tetralogy of Fallot with absent pulmonary valve (67%), truncus (67%), and complex transpositions (50%).22 In contrast to the high frequency associated with these conotruncal defects, 22q11 deletion is less common with double-outlet right ventricle, dTGA, and conoventricular VSD.20 Several teratogens are proven causes of conotruncal CVMs.2,4,18 The association between dTGA and maternal diabetes which had been reported in small clinical series, and reported for decades as a proven association, has not been demonstrated in larger epidemiologic surveys.23 However, diabetes is a proven risk factor for truncus arteriosus.4 References (Conotruncal Defects) 1. Maschhoff KL, Baldwin HS: Molecular determinants of neural crest migration. Am J Med Genet (Semin Med Genet) 97:280, 2000. 2. Clark EB: Etiology of congenital cardiovascular malformations: Epidemiology and genetics. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 64. 3. Colvin EV: Cardiac embryology. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 99. 4. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study: 1981–1989. Futura Publishing Company, Inc., Armonk, NY, 1997. 5. Neches WH, Park SC, Ettedgui JA: Transposition of the great arteries. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 789. 6. Wernovsky G: Transposition of the great arteries. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1027. 7. Mair DD, Edwards WD, Julsrud PR, et al.: Truncus arteriosus. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 910. 8. Neches WH, Park SC, Ettedgui JA: Tetralogy of Fallot and tetralogy of Fallot with pulmonary atresia. In: The Science and Practice of Pediatric Cardiology, volumes 1 and 2. Second Edition. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1383. 9. Siwik ES, Patel CR, Zahka KG, et al.: Tetralogy of Fallot. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 880. 10. Gutgesell HP, Goldmuntz E: Congenital absence of the pulmonary valve. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 903. 11. O’Leary PW, Mair DD, Edwards WD, et al.: Pulmonary atresia and ventricular septal defect. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 864.

Heart 12. Silka MJ: Double outlet ventricles. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1505. 13. Hagler DL: Double-outlet right ventricle and double-outlet left ventricle. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1102. 14. Gumbiner CH, Takao A: Ventricular septal defect. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1119. 15. McDaniel NL, Gutgesell HP: Ventricular septal defects. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ. Lippincott Williams and Wilkins, Philadelphia, 2001, p 636. 16. Morriss MJH, McNamara DG: Coarctation of the aorta and interrupted aortic arch. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 789. 17. Weinberg PM: Aortic arch anomalies. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 707. 18. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 19. Towbin JA, Greenberg F: Genetic syndromes and clinical molecular genetic. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 2627. 20. Goldmuntz E, Clark BJ, Mitchell LE, et al.: Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 34:492, 1998. 21. Botto LD, May K, Fernhoff PM, et al.: A population-based study of the 22q11.2 deletion: Phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101, 2003. 22. Boudjemline Y, Fermont L, Le Bidois J, et al.: Prevalence of 22q11 deletion in fetuses with conotruncal cardiac defects: A 6-year prospective study. J Pediatr 138:520, 2001. 23. Loffredo CA, Wilson PD, Ferencz, C: Maternal diabetes: An independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 64:98, 2001.

2.4 Atrioventricular Septal Defects Definition

Atrioventricular septal defects are a spectrum of defects caused by incomplete septation of the AV septum, usually accompanied by abnormalities of the AV valves. Because this group of CVMs is thought to be the result of persistence of the AV canal or faulty fusion of the anterior and posterior endocardial cushions, some cardiac pathologists refer to them by the embryologic stage they recall, that is, AV ‘‘canal’’ defects or endocardial ‘‘cushion’’ defects. The term ‘‘partial’’ AV septal defect refers to an atrial septal defect, although others use the term to indicate defects with distinct tricuspid and mitral valves.1,2 Thus defined, it may include a primum type atrial septal defect, mitral valve cleft, tricuspid valve cleft, and inlet (canal, subtricuspid) ventricular septal defect.1,2 Most commonly, partial AV septal defect refers to a primum ASD (located anteriorly and inferiorly to the fossa ovalis) and a cleft anterior mitral valve leaflet (which differs anatomically from isolated mitral valve clefts).1,2

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The ‘‘complete’’ AV septal defect is aptly named, consisting of both a large common atrial and ventricular component, and a common AV.1,2 The Rastelli classification based on the AV valve leaflets is widely used.3 In type A, the bridging leaflet is committed to the left ventricle; in type B, the anterior bridging leaflet is larger and overhangs the interventricular septum; and in type C, the large anterior bridging leaflet (‘‘free floating’’) relates to the anterior tricuspid papillary muscle. These distinctions are important for the surgeon planning operative repair. The term unbalanced AV septal defect refers to severe hypoplasia of one ventricle, usually the left ventricle. The ‘‘intermediate’’ (transitional) AV septal defect is rare, and the term itself is uncommonly used. It resembles the complete form.1,2 However, the anterior and posterior bridging leaflets are fused to the top of the ventricular septum, resulting in distinct mitral and tricuspid valve components. Common atrium is a simple term which provides a clear visual to the virtual lack of atrial septum. There may be as little as a residual band of muscle, or cord.1,2 The mitral valve is usually cleft. Additional anomalies include cleft in the anterior mitral leaflet, parachute mitral valve, double-orifice, subaortic stenosis, and tetralogy of Fallot.1,2 Anomalies of the conduction system, such as displacement of the AV node, are familiar and have clinical and surgical implications.1,2 Diagnosis

The clinical findings of a primum atrial septal defect are similar to those of other atrial septal defects with left-to-right shunts with the addition of a mitral insufficiency murmur.1,2 With common atrium, symptoms usually appear earlier due to the larger shunt. An inlet ventricular septal defect will have similar physical findings with a long harsh murmur along the left sternal border. A complete AV septal defect will produce a spectrum of all the previously mentioned findings, depending on the degree of pulmonary resistance. The lower the pulmonary resistance, the greater the pulmonary blood flow. Affected children may show signs of congestive heart failure and may have precordial overactivity, loud systolic murmurs, and gallop rhythms, as well as the loud and often single second heart sound of pulmonary hypertension. A few children with pulmonary hypertension will have an absent or soft systolic murmur. Cardiomegaly and an increase in the pulmonary vascularity are common to all these lesions.1,2 These defects produce the distinctive ECG finding of a superior axis with a counterclockwise loop in almost all cases.1,2 Depending on the severity of the shunt, there will usually be ventricular hypertrophy due to volume overload. The anatomy of all forms of AV septal defect is well defined by two-dimensional and Doppler echocardiography, supplemented by transesophageal imaging in patients needing additional views.1,2 Cardiac catheterization can be used to define the magnitude of left-to-right shunt and determine pulmonary vascular resistance.1,2 This is especially important for children with Down syndrome in whom accelerated pulmonary hypertension has been observed. Angiography shows a characteristic gooseneck deformity of the left ventricular outflow tract caused by the displacement of the mitral valve.1,2 Etiology and Distribution

The association of AV septal defects and noncardiac malformations, especially chromosome abnormality syndromes, is well known.4 In the BWIS, only 22.8% of AV septal defects were not associated with a noncardiac anomaly.5 Table 2-4 lists syndromes

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Cardiorespiratory Organs Table 2-4. Syndromes and conditions frequently associated with atrioventricular septal defects Causation

Type of Atrioventricular Canal Defect

MIM #

Gene

Locus

Complete AVC

606217

CRELD1

3q25

Chromosome Abnormality Deletion 3p25 Deletion 8p23

Complete AVC

NA

Unknown

Unknown

Trisomy 13

Complete AVC

NA

Unknown

Unknown

Trisomy 18

Complete AVC

NA

Unknown

Unknown

Down syndrome (Trisomy 21)

Complete AVC, ASD primum, VSD canal-type

NA

Unknown

Unknown

Trisomy 22

Complete AVC

NA

Unknown

Unknown

Complete AVC, ASD primum

142900

TBX5

12q2

Autosomal Dominant Holt-Oram Noonan

Partial AVC

163950

PTPN11

12q24

McKusick-Kaufman

Complete AVC, ASD primum, common atrium

236700

MKKS

20p12

Hydrolethalus

Complete AVC, AVC, NOS

236680

Unknown

11q24

Common atrium, ASD primum

225500

EVC

4p16

OFD, type II

ASD primum, AVC, NOS

252100

Unknown

Unknown

OFD, type IV

AVC, NOS

258860

Unknown

Unknown

OFD, type VI

AVC, NOS

277170

Unknown

Unknown

Smith-Lemli-Opitz

Complete AVC, ASD primum, common atrium

270400

DHCR7

11q12

Ritscher-Schinzel (3C)

Complete AVC

220210

Unknown

Unknown

Autosomal Recessive Ellis-van Creveld

Compiled from Pierpont et al.,4 Burn and Goodship,7 Marino.9 Italics indicate if the CVM is the most commonly associated defect(s). ASD, atrial septal defect; AVC, atrioventricular canal; NA, not applicable; NOS, not otherwise specified; OFD, oral-facial-digital; SRP, short rib polydactyly; VSD, ventricular septal defect.

and conditions in which AV septal defects are frequently associated.4,6–9 Aneuploidy, especially Down syndrome, is the most common and familiar syndrome association. However, there are several Mendelian syndromes in which complete AV septal defects are overrepresented, such as Smith-Lemli-Opitz syndrome (Fig. 2-2).8 AV septal defects are also common in patients with heterotaxy.10 Studies analyzing AV septal defects can be difficult to compare if the specific type of defect (e.g., complete, partial) is not specified. The frequent occurrence of AV septal defect in patients with trisomy 21 and other chromosome abnormalities (Table 2-4)4 has been viewed as a clue to possible mutant genes in patients without chromosome abnormalities.11 Recent discoveries extend those observations. CRELD1 (3p25) was the first mutant human gene to be implicated in the pathogenesis of isolated AV septal defect and AV septal defect in the context of heterotaxy.12 Prognosis, Treatment, and Prevention

The prognosis is directly related to the extent of the defect, associated malformations, and the presence of pulmonary vascular obstructive disease.1,2 Children with Down syndrome have an increased risk for pulmonary vascular obstructive disease. Therefore, prompt recognition and early surgical repair are essential in prevention of pulmonary vascular obstructive disease and other pulmonary complications.1,2

Fig. 2-2. Eight-year-old girl with velocardiofacial syndrome. She has an atrial septal defect and double aortic arch. (Courtesy of Dr. R. Curtis Rogers, Greenwood Genetic Center, Greenwood, SC.)

Heart

All forms of AV septal defect require surgical repair, which includes closure of the septal defect as well as repair of the abnormal valve. Because of improved results, the preferred approach for complete AV septal defect is total correction between 6 and 12 months of age.1,2 Repair must be done before 1 to 2 years of age because of the possibility of severe pulmonary vascular disease. For partial forms, the repair is done later in life. The role of pulmonary artery banding has diminished. Postoperative lesions requiring treatment include AV valve regurgitation, residual atrial or ventricular septal defect, and conduction defects.1,2

References (Atrioventricular Septal Defects) 1. Vick GW III: Defects of the atrial septum including atrioventricular septal defects. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1149. 2. Feldt RH, Edwards WD, Porter CJ, et al.: Atrioventricular septal defects. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 618. 3. Rastelli GC, Kirklin JW, Titus JL: Anatomic observations on complete form of persistent common atrioventricular canal with special reference to atrioventricular valves. Mayo Clinic Proc 41:296, 1966. 4. Pierpont MEM, Markwald RR, Lin AE: Genetic aspects of atrioventricular septal defects. Am J Med Genet (Semin Med Genet) 97:289, 2000. 5. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study: 1981-1989. Futura, Armonk, NY, 1997. 6. Towbin JA, Greenberg F: Genetic syndromes and clinical molecular genetic. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 2627. 7. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 8. Lin AE, Ardinger HH, Ardinger RH, et al.: Cardiovascular malformations in Smith-Lemli-Opitz syndrome. Am J Med Genet 68:270, 1997. 9. Marino B, DiGilio MC, Toscano A, et al.: Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr 135:703, 1999. 10. Digilio MC, Marino B, Ammirati A, et al.: Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. Am J Med Genet 84:350, 1999. 11. Digilio MC, Marino B, Toscano A, et al.: Atrioventricular canal defect without Down syndrome: a heterogeneous malformation. Am J Med Genet 85:140, 1999. 12. Robinson SW, Morris CD, Goldmuntz E, et al.: Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 72:1047, 2003.

2.5 Right Ventricular Outflow Tract Obstructive Defects Definition

Right ventricular outflow tract obstructive (RVOTO) defects are defined as congenital obstruction to right ventricular outflow. Broadly defined, this category includes atresia, stenosis, hypoplasia and dys-

103

plasia of the tricuspid and pulmonary valves, as well as subvalvar and supravalvar pulmonary stenoses. However, this section limits discussion to tricuspid atresia, Ebstein anomaly, pulmonary stenosis, and pulmonary atresia with intact ventricular septum. Tricuspid Atresia

Tricuspid atresia refers to complete absence of the tricuspid valve with no direct communication between the right atrium and the right ventricle. Cases can be classified by the presence or absence of, or size of, a ventricular septal defect, pulmonary stenosis, great artery relationships, or relationship to the right ventricle.1,2 The latter includes tricuspid atresia associated with Ebstein malformation or AV canal.1 The ventricular septal defect may be perimembranous, muscular, malalignment-type, or atrioventricular. Although most (75%) cases are associated with normally related great arteries, 25% of patients have d-TGA, and only 5% of patients have 1-TGA or malposed great arteries.1 An atrial level shunt is obligatory. Downstream obstruction may include pulmonary atresia, and left-sided obstruction with coarctation may be present. Because of the variable anatomic features of tricuspid atresia, there is no typical clinical presentation, murmur, or radiographic appearance.1,2 Some degree of desaturation is always present, though cyanosis may not be apparent. Infants with pulmonary stenosis or atresia in addition to tricuspid atresia have more severe cyanosis. Murmurs may be produced by a ventricular septal defect, pulmonic stenosis, or collateral vessel. Tricuspid atresia with d-TGA will have pulmonary overcirculation. The typical ECG includes right atrial enlargement; left axis deviation with decreased or absent right ventricular forces presents a distinctive ECG.1,2 The diagnosis of tricuspid atresia and associated defects (e.g., great artery relationship, atrial and ventricular septal defect, pulmonic stenosis) is readily made by echocardiography and Doppler techniques.1,2 The role of cardiac catheterization is greatly diminished, although a balloon atrial septostomy may be needed to improve atrial shunting. Catheterization retains a role in assessing pulmonary vascular resistance, refining pulmonary artery anatomy and other complex-associated CVMs such as anomalous pulmonary venous connection.1,2 Ebstein Anomaly

The tricuspid valve in Ebstein anomaly has variable morphology. Generally, the anterior leaflet is not displaced, but is sail-like.3 There is downward displacement of the septal and posterior leaflets to the right ventricular wall.3,4 The free portion of the valve leaflet is remote from the AV junction, and the upper part of the right ventricle becomes ‘‘atrialized.’’3,4 The right atrial enlargement can be severe. Associated defects include some form of an atrial communication.3,4 An Ebstein-like anomaly may occur with 1-TGA with ventricular inversion. There is tremendous variation in clinical presentation from a fetus diagnosed by fetal echocardiography, to a newborn with severe cyanosis, respiratory distress, tachycardia, and gross cardiomegaly, and finally to an asymptomatic adult.3,4 The so-called quadruple gallop on auscultation is common.4 The radiograph changes are, likewise, variable. In some cases the cardiac silhouette appears normal. In others there is massive cardiomegaly filling the entire chest cavity.3,4 The ECG may show only slight intraventricular delay to complete right bundle branch block. Features of preexcitation (Wolff-Parkinson-White) are seen in about 25% of patients.3,4

104

Cardiorespiratory Organs

Two-dimensional echocardiography is the superior technique for imaging the abnormal tricuspid valve.3,4 Doppler assessment can assess the obstruction to flow, and the atrial right-to-left shunt. Cardiac catheterization and angiography are rarely necessary for diagnosis and are accompanied by a higher risk for arrhythmia.3,4

valvotomy. However, patients with dysplastic valves and those with multiple levels of fixed obstructions still require surgical valvotomy.5,6 To define the sites of obstruction in the peripheral pulmonary arteries, MRI is superior to echocardiography and complementary to angiocardiography.5,6

Pulmonary Stenosis

In pulmonary atresia with intact ventricular septum, the pulmonary valve is imperforate and blood supply is maintained by a patent ductus arteriosus. This defect is linguistically similar to pulmonary atresia with ventricular septal defect (discussed in the section on conotruncal defects), but the entities differ markedly. There is a spectrum in the severity of involvement of the pulmonary valve, right ventricle, tricuspid valve, and coronary arteries that may be related to developmental onset.7 Thus, the right ventricle in pulmonary atresia with intact ventricular septum may range in severity from a diminuitive chamber to a well-formed ventricle.7,8 The tricuspid valve is usually abnormal with some degree of hypoplasia or dysplasia and, rarely, may have the form of Ebstein anomaly.7,8 Profound regurgitation may be present. Myocardial abnormalities are common with highly characteristic ventriculocoronary connections (‘‘sinusoids’’).7,8 Progressive cyanosis is the consistent clinical finding in pulmonary atresia with intact ventricular septum.7,8 A systolic murmur of tricuspid regurgitation or the continuous murmur of a patent arterial duct may be present. On chest radiograph, the heart size may be normal or severely enlarged depending on the size of the right atrium.7,8 There is a deficiency in the area usually occupied by the main pulmonary artery and ischemic lung fields. The consistent ECG findings include a QRS axis of þ30 to þ90, decreased or absent right ventricular forces, left ventricular dominance, and right atrial enlargement.8 Two-dimensional echocardiography can define the degree of right ventricular hypoplasia, the size of the tricuspid valve, and the size of the pulmonary valve and arteries.7,8 Doppler interrogation is needed to analyze ductal and interatrial flow, determine the degree of tricuspid regurgitation, and differentiate anatomic from functional pulmonary atresia.7,8 This may occur with Ebstein anomaly or other tricuspid anomalies in which severe regurgitation and right ventricular dysfunction are present. It is advised that angiocardiography be performed to supplement echocardiography to define ventriculocoronary artery connections.7,8

Pulmonary stenosis refers to obstructive defects primarily of the pulmonary valve itself, but may include obstruction in the subvalvar or supravalvar region, or along the length of the pulmonary arteries. When all levels and forms are considered, both isolated and complex, pulmonary stenosis is remarkably common, found in about one-fourth of all individuals with a CVM.5 The typical stenotic pulmonary valve is dome-shaped, with fusion along the edges of the valve leaflets.5,6 In contrast, dysplastic pulmonary valve stenosis is characterized by a lack of commissural fusion with thickened, myxomatous cusps. This is more common in Noonan syndrome.5–7 Infundibular pulmonary stenosis is rarely isolated.8 It is usually associated with other defects as in tetralogy of Fallot. A malformation related to infundibular pulmonary stenosis is double chambered right ventricle in which anomalous muscle bundles divide the right ventricle into two chambers.5,6 This unique entity may represent an embryologic arrest in the incorporation of the bulbus cordis into the body of the right ventricle. Pulmonary artery stenosis can be classified into four types: type I is single, central; type II is bifurcated; type III is multiple peripheral; and type IV is central and peripheral.5 It may take the form of supravalvar pulmonary stenosis immediately above the valve. Peripheral pulmonary stenosis may occur anywhere along the length of the pulmonary arteries as diffuse hypoplasia or focal narrowing. Pulmonary valve stenosis is usually accompanied by a characteristic systolic ejection murmur located at the upper left sternal border.5,6 When the leaflets are mobile, a systolic ejection click is present, but when the valve is dysplastic, the click is absent.5,6 Children with pulmonary stenosis are usually asymptomatic at presentation, though symptoms may progress with age. When severe pulmonary stenosis presents in the newborn period causing cyanosis due to atrial shunting, the term critical pulmonary stenosis is used.5,6 The diagnostic murmur and click are absent; instead, severe cardiomegaly may be the most remarkable finding. In contrast to valvar pulmonary stenosis, peripheral pulmonary stenosis lacks an ejection click and presents with a continuous murmur radiating widely in the pulmonary area, axilla, and back. With pulmonary valve stenosis, poststenotic dilation of the main pulmonary artery can be seen on radiograph. The pulmonary vascularity is generally normal unless there is right-to-left shunting, usually at the atrial level. Patients with pulmonary artery stenosis usually have a normal radiograph.5,6 The ECG shows a right axis and various degrees of right ventricular hypertrophy, depending on the severity of the pulmonary valve stenosis. In patients with Noonan syndrome, the axis is often oriented superiorly. With mild peripheral pulmonary stenosis, the ECG is usually normal.5,6 Two-dimensional echocardiography will easily demonstrate the anatomy of pulmonary valve and the regions below and immediately above it. Further imaging will define the proximal pulmonary arteries. Continuous wave Doppler is used to estimate the pressure gradient across the obstruction.5,6 Cardiac catheterization is primarily a therapeutic role. Percutaneous balloon valvuloplasty has become the preferred treatment over surgical

Pulmonary Atresia with Intact Ventricular Septum

Etiology and Distribution

Tricuspid atresia is rarely associated with malformation syndromes, and rarely familial. Of interest is the familiar possible teratogenic association between lithium and Ebstein anomaly which had been suggested by early biased retrospective clinical reports.9 However, more recent epidemiologic analyses concluded that there appears to be an only slightly increased risk of CVMs and other malformations to fetuses exposed to first-trimester lithium, but no specific Ebstein risk.9 Aside from a few reports of familial Ebstein anomaly, the most noteworthy association has been two cases with 1p36.3 deletion as mentioned in a recent review.10 Pulmonary valve stenosis may occur as an isolated defect or as part of numerous multiple malformation syndromes.11 Table 2-5 lists syndromes and conditions that are frequently associated with pulmonic stenosis, notably Noonan syndrome.11–17 The recent discovery that mutations in the PTPN11 gene cause Noonan syndrome, 15,16 as well as multiple lentigines/LEOPARD syndrome, led to the findings that PTPN11 mutations are associated with non-Noonan

Heart

105

Table 2-5. Syndromes and conditions frequently associated with pulmonic stenosis Causation

Type of Pulmonic Stenosis

MIM #

Gene

Locus

Chromosome Abnormality Deletion 4p (Wolf-Hirschhorn)

Valvar

194190

WHSC1

4p16.3

Deletion 4q31, 3212

Valvar

NA

?dHAND

4q33

Deletion 8p2317

Valvar

NA

Unknown

Unknown

Alagille22

Peripheral, valvar

118450

JAG1

20p12

Noonan15

Valvar

163950

PTPN11

12q24

Autosomal Dominant

16

Valvar

151100

PTPN11

12q24

Cardio-facio-cutaneous20

Valvar

115150

Unknown

Unknown

Costello14,21

Valvar

218040

Unknown

Unknown

Williams

Peripheral, valvar

194050

ELN

7q11.2

Peripheral

245150

MGP

12p13

Valvar

312870

GPC3

Xq26

Peripheral, valvar

NA

NA

NA

LEOPARD/Multiple lentigines

Autosomal Recessive Keutel X-Linked Simpson-Golabi-Behmel13 Teratogen Rubella

Compiled from Burn and Goodship11 and others specified. Italics indicate if the CVM is the most commonly associated defect(s). NA, not applicable.

dysplastic pulmonic valve stenosis,18 but not nonsyndromic non-dysplastic pulmonic stenosis,19 cardio-facio-cutaneous (CFC) syndrome,20 or Costello syndrome (Fig. 2-3).21 Peripheral pulmonary stenosis with or without other cardiac anomalies may also be seen in several malformation syndromes, also listed on Table 2-5.11 Along with patent ductus arteriosus, they are the most common vascular defects caused by prenatal rubella infection. Cardiovascular malformation occur in more than 90% of patients with Alagille syndrome or a JAG1 mutation, typically the entire spectrum of right-sided CVMs.22 Branch pulmonary artery and valvar pulmonic stenosis are most common.22 Although aortic stenosis, supravalvar and valvar, are most common in Williams syndrome, peripheral pulmonic stenosis has also been observed.11 Like tricuspid atresia, pulmonary atresia is rarely familial23,24 and has no consistent syndrome association. Prognosis, Treatment, and Prevention

Most patients with tricuspid atresia require one or more surgical procedures.1,2 Widespread use of the modified Fontan procedure has led to dramatic improvement in survival. In patients with decreased pulmonary blood flow, early palliative surgery may consist of a systemic to pulmonary artery shunt (such as a BlalockTaussig shunt).1,2 Although the classic Fontan procedure is rarely performed, the modified Fontan, preceded by various staging procedures, has improved prognosis.2 The prognosis for patients with Ebstein anomaly is highly variable and dependent on the severity of the defect.3,4 Survival is limited for the newborn with a severely abnormal valve, massive cardiomegaly, or associated defects unless surgery is offered.3,4 Cardiac transplantation can be considered, as can surgical repair

of the valve with plication of the atrialized portion of the right ventricle and plastic reconstruction of the valve leaflet. Valve replacement is often necessary. The surgical procedures are associated with a high mortality rate.3,4 Sudden death is common in older children and in adults with this defect, presumably due to arrhythmias. Medical management for Ebstein anomaly includes treatment of arrhythmias and right heart failure.3,4 Surgical treatment is reserved for severe right ventricular dysfunction and valvar insufficiency. In utero diagnosis is possible by fetal echocardiography. The prognosis of children with pulmonary valve stenosis depends on the severity of the obstruction. Mild stenosis rarely progresses in severity with time, and prognosis is good. More severe forms progress and require prompt treatment to minimize myocardial damage.5,6 Results from a multicenter registry following valvuloplasty and angioplasty confirm that this procedure is safe and effective in treating pulmonic stenosis in all age groups.5,6 Surgery may be preferred for selected cases of critical pulmonic stenosis and dysplastic pulmonic valves.5 Most children with untreated pulmonary atresia die in the first year of life.7,8 Despite continued advances and diverse surgical options, multiple procedures may be necessary. Prostaglandin infusions in the newborn period will keep the ductus open and allow adequate pulmonary blood flow. The goal is biventricular repair, which requires a right ventricle of adequate size.7,8 Usually, the infant needs a systemic to pulmonary shunt. To decompress the right ventricle and promote growth, options include surgical or balloon valvotomy, or outflow tract patching.7,8 Later in life more complete relief of the obstruction is possible. A Fontan-type procedure may be necessary if the right heart is too small.7,8 Patients with abnormal coronary artery anatomy or abnormal tricuspid valves require customized surgical approaches.7,8

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Cardiorespiratory Organs

Fig. 2-3. Eight-year-old boy with Costello syndrome. He has the typical facial appearance (hypertelorism, downslanted eyes, full nasal tip, broad mouth with full lips, small low-set ears with upturned lobules, broad forehead) and curly hair. A glimpse of his thumb demonstrates extreme joint laxity, spatulate finger pad, and ulnar deviation. He also has the most common cardiovascular malformation, i.e., valvar pulmonic stenosis. (Photograph was provided courtesy of his parents.)

References (Right Ventricular Outflow Tract Obstructive Defects) 1. Driscoll DJ: Tricuspid atresia. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, JT Bricker, DJ Fisher, SR Neish, eds. Williams & Wilkins, Baltimore, 1998, p 1579. 2. Epstein ML: Tricuspid atresia. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ. Lippincott Williams and Wilkins, Philadelphia, 2001, p 799. 3. MacLellan-Tobert S, Porter C: Ebstein anomaly of the tricuspid valve. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1303. 4. Epstein ML: Congenital stenosis and insufficiency of the tricuspid valve. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ. Lippincott Williams and Wilkins, Philadelphia, 2001, p 810. 5. Cheatham JP: Pulmonary stenosis. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1207. 6. Latson LA, Prieto LR: Pulmonary stenosis. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ. Lippincott Williams and Wilkins, Philadelphia, 2001, p 820.

7. Reddy VM, Ungerleider RM, Hanley FL: Pulmonary valve atresia with intact ventricular septum. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1563. 8. Freedom RM, Nykanen DG: Pulmonary atresia and intact ventricular septum. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 844. 9. Cohen LS, Friedman JM, Jefferson JW: A reevaluation of risk of in utero exposure to lithium. JAMA 271:146, 1994. 10. deVries BBA, White SM, Knight SJL, et al. Clinical studies on submicroscopic subtelomeric rearrangements: a checklist. J Med Genet 38:145, 2001. 11. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 12. Huang T, Lin AE, Cox GF, et al.: Cardiac phenotypes in chromosome 4q-syndrome with and without a deletion of the dHAND gene. Genet Med 4:464, 2002. 13. Lin AE, Neri G, Hughes-Benzie R et al.: Cardiac abnormalities in the Simpson-Golabi-Behmel syndrome. Am J Med Genet 83:378, 1999. 14. Lin AE, Grossfeld PD, Hamilton RM, et al.: Further delineation of cardiac abnormalties in Costello syndrome. Am J Med Genet 111:115, 2002. 15. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465, 2001. 16. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiple-lentigines/ LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389, 2002. 17. Digilio MC, Marino B, Guccione P, et al.: Deletion 8p syndrome. Am J Med Genet 75:534, 1998. 18. Chen B, Bronson RT, Klaman LD, et al.: Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nature Genet 24:296, 2000. 19. Sarkozy A, Conti E, Esposito G, et al.: Nonsyndomic pulmonary valve stenosis and the PTPN11 gene. Am J Med Genet 116A:389, 2003. 20. Ion A, Tartaglia M, Song X, et al.: Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet 111:421, 2002. 21. Tartaglia M, Cotter PD, Zampino G: Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes. Clin Genet 63:423, 2003. 22. McElhinney DB, Krantz ID, Bason L, et al.: Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation 106:2567, 2002. 23. Chitayat D, McIntosh N, Fouron JC: Pulmonary atresia with intact ventricular septum and hypoplastic right heart in sibs: A single gene disorder? Am J Med Genet 42:304, 1992. 24. Grossfeld PD, Lucas VW, Sklansky MS, et al.: Familial occurrence of pulmonary atresia with intact ventricular septum. Am J Med Genet 72:294, 1997.

2.6 Left Ventricular Outflow Tract Obstructive Defects Definition

Left ventricular outflow tract obstructive (LVOTO) defects are intracardiac and vascular defects of the systemic arterial circulation that lead to reduced outflow. Similar to the array of right heart obstructive defects, LVOTO defects can be grouped from proximal (mitral stenosis/atresia, subaortic stenosis, aortic valve

Heart

stenosis) to distal structures (supravalvar aortic stenosis, coarctation of the aorta, type A interrupted aortic arch). Many patients have combinations of these defects, which may be as simple as coarctation of the aorta with bicuspid aortic valve to a series of more severe defects such as hypoplastic left heart syndrome and Shone syndrome.1 Mitral Valve Stenosis/Atresia

Mitral valve atresia results from failure of mitral valve development with absence of the mitral orifice, whereas mitral stenosis is a restricted opening with compromised blood flow from left atrium to left ventricle.1–4 This hemodynamic obstruction may result from an abnormality of the mitral valve leaflets or the papillary muscle arcade. Congenital mitral stenosis may be classified into several types.1–4 A hypoplastic mitral valve is the most common form. One rare form of mitral stenosis is supravalvar mitral membrane, a ridge of abnormal connective tissue arising from the atrial surface of the mitral leaflets, usually associated with other defects. Usually the mitral valve itself is dysplastic and stenotic. The embryological origin of the membrane is not clear. Parachute mitral valve,5 double orifice mitral valve, and mitral valve atresia as part of hypoplastic left heart syndrome (see following) are also part of this spectrum. Subannular obstruction due to thickened leaflets, fibrous obliteration of interchordal spaces, absent or abnormal chordal insertion (called the mitral arcade), papillary muscle hypoplasia, decreased interpapillary spaces, and fused papillary muscles make the anatomy of mitral stenosis exceptionally complex. Shone syndrome (also known as Shone’s complex or anomaly) classically consists of supravalvar mitral membrane, parachute mitral valve, subaortic stenosis, and aortic coarctation.2,3 A clear unifying pathological mechanism has not been identified. Patients with mitral stenosis exhibit many of the same symptoms as in other forms of left ventricular outflow tract obstruction including tachypnea, diaphoresis, respiratory disease, and failure to thrive.2,3 The chest radiograph shows pulmonary venous congestion, and a large heart due mainly to enlargement of the right ventricle. With mitral stenosis the left atrium may be large, but with mitral atresia there is usually hypoplasia of the left atrium. The ECG findings are variable but usually include right ventricular hypertrophy. Left atrial enlargement may be seen with mitral stenosis. Echocardiography is the most sensitive diagnostic tool for assessing mitral valve stenosis or atresia. Cardiac catheterization is used for pressure measurements of gradients, often necessitating the transeptal technique.2,3 Aortic Stenosis

Aortic stenosis includes defects that cause outflow obstruction involving the aortic valve itself, or the region below or above it.6 The aortic valve is formed by three cusps of equal size. The valve leaflets emerge from two swellings at the septum of the truncus and one on the opposite wall of the outflow track. Fusion of two leaflets gives rise to bicuspid aortic valves, leaving straight rather semicircular free margins. This limits the valve aperture and mobility. Fusion of all three leaflets leads to unicuspid valve with restricted central opening. Supravalvar aortic stenosis accounts for about 10% of cases of aortic stenosis. The indentation is located above the sinuses of Valsalva with a constricting ridge (hourglass deformity), less commonly as a fusiform ascending aorta. These lesions may progress as

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the individual becomes older.6 Supravalvar aortic stenosis is apparently mechanistically distinct from processes that lead to aortic valve leaflet disease as demonstrated by its specific association with Williams syndrome and autosomal dominant supravalvar aortic stenosis7,8 (see Fig. 2-4). Aortic valvar stenosis is the most common hemodynamically severe lesion in this class. Associated lesions include aortic coarctation, VSD, and PDA. Congenital bicuspid aortic valve may also be associated with adult-onset calcific aortic stenosis9 and aortic aneurysm.10 In contrast to the familiar entity known as ‘‘absent’’ pulmonary valve in which there is actually a rim of a dysplastic pulmonary valve, absent aortic valve is an extremely rare defect.11 In the small number of reported patients, it was associated with very complex CVMs, and it was lethal. Fibromuscular subaortic stenosis is slightly more common than supravalvar aortic stenosis.6,12 About 80% of patients have a thin discrete collar or ridge with a muscular base up to 1 cm below the aortic valve.12 The remaining patients have a more diffuse or ‘‘tunnel’’ form of obstruction. Rarely, abnormal insertion of the mitral valve or accessory mitral leaflet may cause significant obstruction. The signs and symptoms of congenital aortic stenosis are highly variable and range from the shock-like presentation of an infant with critical aortic stenosis to the asymptomatic older child or adult with trivial involvement.6 Fatigue is a common complaint in older chidren. Angina and syncope are worrisome indicators of severe obstruction which occur in a small minority. The physical exam will correspondingly range from a hyperactive precordium and reduced pulses, with loud ejection murmur, click, and gallop to a mild-to-moderate systolic murmur. A minority of patients develop an early diastolic murmur of aortic insufficiency. Chest radiograph shows dilation of the ascending aorta, with eventual left ventricle enlargement in aortic stenosis.6 The ECG varies from normal to severe left ventricular hypertrophy, with strain depending on severity of obstruction.6 Two-dimensional echocardiography provides excellent imaging of aortic stenosis.6 Leaflet motion appears restricted, and the valve may appear thickened in the long axis view. A bicuspid aortic valve may appear to be tricuspid because of a prominent raphe, but the ‘‘fish mouth’’ appearance of the valve at systole is characteristic. Doppler echocardiography allows assessment of the presence of high-velocity jets in aortic stenosis and assessment of the instantaneous pressure gradient between the left ventricle and aorta.6 Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome is characterized by aortic valve atresia or severe hypoplasia, mitral valve atresia or severe hypoplasia, severe hypoplasia of the left ventricle, and hypoplasia of the ascending aorta.13,14 Associated lesions include mitral stenosis or atresia (85%), coarctation, or malaligned atrioventricular septal defect and common atrioventricular valve.13,14 Other associated lesions include atrial septal defect, anomalous pulmonary venous connection, coronary artery abnormalities, persistent left superior vena cava, and endocardial fibroelastosis. In utero, there is little or no restriction of fetal growth in the presence of hypoplastic left heart syndrome since the fetal circulation is adequate. Most neonates are born at term and initially appear normal. At birth, the open ductus arteriosus supplies blood to the systemic circulation. However, systemic desaturation is present because of pulmonary and systemic venous blood mixing in the right atrium via an ASD or through the foramen

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ovale. As the ductus arteriosus constricts, systemic blood flow is drastically decreased and, if untreated, cardiogenic shock ensues. Clinically, the infant presents with pallor, cyanosis, decreased pulses, cool extremities, tachypnea, respiratory distress, and lethargy. This presentation overlaps with severe inborn errors of metabolism, and a dramatic metabolic acidosis with lactic acidemia often accompanies critical outflow tract obstruction. Swift cardiac imaging resolves the diagnostic dilemma. Hypoplastic left heart syndrome can be readily detected by fetal echocardiography.13,14 In the symptomatic newborn, ECG shows right atrial enlargement with peaked P waves. Right ventricular hypertorophy occurs in almost all patients.13,14 The chest radiograph is nonspecific and may show cardiomegaly with increased pulmonary vascular markings. Two-dimensional and Doppler echocardiography are diagnostic. A critical feature is the presence or absence of tricuspid or common AV valve regurgitation, which is associated with decreased surgical survival. Noncardiac anomalies associated with hypoplastic left heart syndrome include diaphragmatic hernia and central nervous system anomalies, especially microcephaly, abnormal cortex, agenesis of the corpus callosum, and holoprosencephaly.15 Coarctation of the Aorta

Coarctation of the aorta consists of narrowing of the thoracic descending aorta caused by localized thickening of the aortic media.16 This defect is also discussed in Chapter 3, Systemic Vasculature. Coarctation of the aorta may occur as an isolated defect, or with another LVOTO. A common classification defines the coarctation based on the relationship to the ductus, that is, postductual, juxtaductal, or preductal. Practically speaking, most coarctations are considered juxtaductal. Coarctation should be distinguished from tubular hypoplasia of the aorta, which consists of a long uniformly narrow segment of the proximal or distal aortic arch and isthmus. The media of the aorta is normal in contrast to the thickened media of coarctation. The clinical presentation of coarctation is variable, but most patients are asymptomatic.16 The classic sign is elevated blood pressure of the upper limbs and decreased blood pressure of the lower limbs, with corresponding decreased pulses.16 Isolated coarctation may not be recognized in an infant. When it is associated with additional defects such as ventricular septal defect, diffuse hypoplasia of the aorta, and conotruncal or atrioventricular valve anomalies, it is more likely to be symptomatic and associated with early-onset heart failure.16 The chest radiograph and ECG are generally normal in most patients with coarctation, although evidence of left ventricular hypertrophy may be present with severe obstruction.16 Rib notching is highly characteristic of thoracic coarctation because of the gradual dilation of the intercostals collateral arteries. Visualization of the coarctation by two-dimensional echocardiography can be accomplished by systematic imaging using suprasternal notch views. Associated defects must also be sought. Doppler echocardiography helps define the degree of obstruction. MRI evaluation can be used in selected patients, especially for postoperative imaging.16 Type A Interrupted Aortic Arch

In Type A interrupted aortic arch, there is complete discontinuity between the ascending and descending aorta distal to the left subclavian artery.16 This CVM is also discussed in Chapter 3, Systemic Vasculature. Type A interrupted aortic arch can be compared to aortic atresia in which there is preservation of a nonpatent cord

of tissue, but without discontinuity. Frequent associated defects include bicuspid aortic valve, ventricular septal defect, and other left-sided obstructive defects. Similar to the presentation of type B interrupted aortic arch or severe coarctation, infants may be asymptomatic initially, but suffer catastrophic collapse with the onset of closure of the ductus.16 The diagnosis is similar to what is used to diagnose type B interrupted aortic arch. High-quality two-dimensional echocardiography, especially supra-sternal views, is the most frequent imaging tool. MRI can be used for cases in which the aorta cannot be adequately imaged. Etiology and Distribution

The familiality of LVOTO defects strongly suggests the action of genetic factors in their etiologies. In families with two affected individuals in which the proband had a left ventricular outflow tract obstruction malformation, there was a much greater likelihood of a concordant malformation (another LVOTO defect) in the relative.17 Based on a simple review of the published sibling recurrence risk estimates compared to the population birth prevalence, one can estimate the heritability of LVOTO defects to be 0.6–0.8. This estimate of heritability might be biased downward due to lack of relevant data on occurrence in second- and thirddegree relatives, and reproductive selection (differential abortion, cessation of reproduction after birth of affected infant, and decreased reproductive fitness in affected individuals). Siblings and parents of children with LVOTO defects may have a variety of mild defects including greatly increased risk of bicuspid aortic valve.18 Therefore, it has been recommended that echocardiography be performed on all first-degree relatives.19 It is unknown whether parents with bicuspid aortic valve have an increased offspring recurrence risk compared to unaffected parents. It is also unknown whether families with bicuspid aortic valve and other left heart anomalies represent a special biological subgroup among the broader group of sporadic LVOTO malformation. The assorted mitral, aortic valve, and aortic arch defects that comprise the family of LVOTO defects have been the subject of hypotheses concerning the role of altered in utero hemodynamics. Cardiac chamber, valve, and great vessel morphogenesis requires flow-directed remodeling. Primary defects that affect blood flow into the left ventricle may result in secondary hypoplasia as seen in chick and fetal lamb models where restriction of left ventricle inflow produces a phenotype similar to hypoplastic left heart syndrome. A recent elegant zebrafish model demonstrated reduction in endothelial markers in the developing heart tube after placement of a bead blocking inflow or outflow, providing evidence of epigenetic modification of ventricular development.20 This effect has been demonstrated in humans by serial prenatal ultrasounds in fetuses affected with hypoplastic left heart syndrome which have also shown worsening of left ventricle hypoplasia as the pregnancy progresses.21 The mechanisms for causing mitral valve stenosis/atresia are not well defined but may relate to the primary formation of the mitral apparatus. One factor is the volume of blood flow passing through the mitral orifice. Stenosis and atresia can be produced by obstructing the left atrium in the chick embryo. There are no specific syndrome associations or known disease genes for mitral valve stenosis/atresia, in particular, and little insight into familiality. Recurrence risk for isolated mitral stenosis/atresia has not been adequately addressed in the literature, but counseling similar to that provided for LVOTO defects in general seems warranted.

Heart

Numerous malformation syndromes are frequently associated with LVOTO (Table 2-6).8,22-30 Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are common in Williams syndrome (Fig. 2-4), as well as stenoses of systemic arteries such as the renal and cerebral arteries.26 Both Williams syndrome and dominant supravalvar aortic stenosis result from haploinsufficiency for elastin,26,27 although Williams syndrome has a more complex phenotype because of the loss of several other dosage-sensitive genes in the commonly deleted interval. Another familiar syndrome is Turner syndrome, associated with a CVM in about 30% of all patients, with coarctation and bicuspid aortic valve in 30% each. The entire spectrum of LVOTO may occur, as well as a small, but real, risk for aortic root dilation and rupture.28 Hypoplastic left heart syndrome is infrequently associated with an underlying syndrome, including Turner syndrome. Table 2-6 lists additional syndromes in which its occurrence is frequent enough to be noteworthy, for example, Jacobsen syndrome (11q23 deletion)29 (Fig. 2-5). An uncommon teratogenic cause of LVOTO is maternal phenylketonuria. Coarctation, hypoplastic left heart syndrome, and aortic stenosis were more common in the offspring of children born to mothers with maternal phenylketonuria.30

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Mouse models with mutation of HAND2, neuregulin, ERBB2, ERBB4, and retinoid X receptor-a have primary ventricular hypoplasia. The transcription factor NFATc is implicated in semilunar valve formation, whereas the zebrafish transcription factor gridlock/HEY2 is required for aortic arch formation. Mice heterozygous for eNos deficiency demonstrate bicuspid aortic valve.31 Prognosis, Treatment, and Prevention

The prognosis of LVOTO defects is related to the severity and specific type of obstruction. Although acquired mitral valve stenosis can be treated by balloon dilation, congenital stenosis is not relieved by this technique. Surgical treatment usually is necessary, sometimes with valve replacement.2,3 Supravalvar mitral membrane may require surgical excision if there is increasing obstruction.2,3 The treatment and ultimate prognosis of aortic valve stenosis depends on the severity and level of the obstruction.6 Early symptomatic obstruction and availability of surgical correction have a marked influence on survival. Sudden death is described in isolated aortic valve stenosis. Dysplastic aortic valves are very susceptible to bacterial endocarditis, with an annual incidence of about 1%. In general, aortic valve abnormalities increase in severity with time. Perhaps the high pressure and mechanical stress contribute to progressive calcification

Table 2-6. Syndromes and conditions frequently associated with left ventricular outflow tract obstruction (lvoto) Causation

Type of LVOTO

MIM #

Gene

Locus

HLHS

NA

Unknown

Unknown

Chromosome Abnormality Deletion 11q23 29

(Jacobsen syndrome)

COA

Trisomy 13

BAV, HLHS

NA

Unknown

Unknown

Trisomy 18

BAV, COA, HLHS

NA

Unknown

Unknown

Trisomy 21

COA

NA

Unknown

Unknown

BAV, COA, ASV

NA

Unknown

Unknown

194050

ELN

7q11.2

130160

ELN

7q11.2

146510

GLI3

7p13

100300

Unknown

Unknown

147920

Unknown

Unknown

ASV, COA, HLHS

270400

DHCR7

11q12

COA

606519

Unknown

Unknown

COA, HLHS, ASV

NA

NA

NA

28

Turner

MS, HLHS Autosomal Dominant Williams26

SVAS

Familial SVAS27

SVAS

Aortic stenosis, valvar Aortic stenosis, valvar Pallister-Hall

BAV

Adams-Oliver24

COA, BAV

MV anomalies Parachute MV Kabuki22

COA, Parachute MV

Autosomal Recessive Smith-Lemi-Opitz Autosomal Unknown PHACES25 Teratogen Maternal phenylketonuria30

Compiled from Burn and Goodship8 and others specified. Italics indicate if it is the most commonly associated defect(s). ASV, aortic stenosis valvar; BAV, bicuspid aortic valve, COA, coarctation; HLHS, hypoplastic left heart syndrome, MS, mitral stenosis, MV, mitral valve; NA, not applicable; SVAS, supravalvar aortic stenosis.

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Cardiorespiratory Organs

Fig. 2-4. Left: Aortography in a male with Williams syndrome showing supravalvar aortic stenosis (arrow). Middle and right: facial features in males at 19 months and 22 years showing epicanthal folds, anteverted nares, and prominent lips. Note stellate iris pattern in patient on right. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.)

Fig. 2-5. Two girls (16 and 13 years) with Jacobsen syndrome and deletion 11q. The photo was taken at the Third Biannual European 11q Conference in Pforzheim, Germany in 2002. (Photos are provided courtesy of Dr. Paul Grossfeld, University of California, San Diego.)

of the valve leaflets and eventual valve obstruction. Sudden death is a well-recognized complication of moderate-to-severe aortic stenosis. Patients with severe aortic stenosis are candidates for surgical or interventional catheterization procedures. Newborns with critical LVOTO may be treated with prostaglandin E1 infusion to open the ductus. Surgical correction of infantile aortic stenosis is accompanied by high mortality, making a palliative procedure with limited valvotomy preferred.6 Definitive surgery in older children involves open commissurotomy using cardiopulmonary bypass. However, aortic insufficiency is observed in two-thirds of patients postoperatively. Valve replacement in children is difficult. Mechanical valves are preferred

because of the high risk of bioprosthetic valve failure.6 Pulmonary valve autografts and aortic valve homograft conduits have also been used, but can be technically difficult.6 Balloon aortic valvotomy is an effective treatment in most patients.6 Surgical correction of supravalvar aortic stenosis by lateral aortotomy, resection of stenotic areas, and insertion of Dacron graft is effective. Surgical resection of the subvalvar membrane in subaortic stenosis is also possible in most patients, but the prognosis for the more severe and diffuse type is worse. Hypoplastic left heart syndrome is lethal if untreated. Surgical options include a 3-stage reconstruction in which the first stage (Norwood procedure) uses native tissue to enlarge the hypoplastic

Heart

aorta, accompanied by a modified Blalock-Taussig shunt. The second stage is currently a hemi-Fontan or bi-directional Glenn shunt, followed by the Fontan procedure as the third stage. The outcome following stage 1 continues to improve.32–34 Another option is orthotopic cardiac transplantation, although the scarcity of suitable donors makes this a therapeutic challenge.35 The current surgical strategies, succinctly summarized in a recent editorial, result in similar surgical outcomes at highvolume, lower-risk hospitals. Medical treatment alone (i.e., surgical nonintervention) is an option that may be chosen by some families and depends on regional preferences. Intrauterine diagnosis is possible for hypoplastic left heart syndrome and other LVOTO. The potential for ‘‘prevention’’ has been explored by the use of fetal interventional procedures.36,37 Overall mortality rates for most CVM have been dropping due to widespread improvements in medical and surgical care. However, mortality from hypoplastic left heart has not been decreasing as fast. Data from 1980–1995 reported hypoplastic left heart as the single largest contribution of any class of birth defects to infant mortality.38 References (Left Ventricular Outflow Tract Obstructive Defects) 1. Kitchiner D, Jackson M, Malaiya N, et al.: Incidence and prognosis of obstruction of the left ventricular outflow tract in Liverpool (1960-91): a study of 313 patients. Br Heart J 71:588, 1994. 2. Grifka RG, Vincent JA: Abnormalities of the left atrium and mitral valve, including mitral valve prolapse. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, JT Bricker, DJ Fisher, SR Neish, eds. Williams & Wilkins, Baltimore, 1998, p 1277. 3. Baylen BG: Mitral inflow obstruction. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1011. 4. Moore P, Adatia I, Spevak PJ, et al. Severe congenital mitral stenosis in infants. Circulation 89:2099, 1994. 5. Tandon R, Moller JH, Edwards JE: Anomalies associated with the parachute mitral valve: a pathologic analysis of 52 cases. Can J Cardiol 2: 278, 1986. 6. Latson LA: Aortic stenosis: Valvar, supravalvar, and fibromuscular subvalvar. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, JT Bricker, DJ Fisher, SR Neish, eds. Williams & Wilkins, Baltimore, 1998, p 1257. 7. Kim YM, Yoo SJ, Choi JY, et al.: Natural course of supravalvar aortic stenosis and peripheral pulmonary arterial stenosis in Williams’ syndrome. Cardiol Young 9:37, 1999. 8. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR. Churchill Livingstone, London, 2002, p 1239. 9. Ward C: Clinical significance of the bicuspid aortic valve. Heart 83:81, 2000. 10. Sabet HY, Edwards WD, Tazelaar HD, et al.: Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases. Mayo Clin Proc 74:14, 1999. 11. Lin AE, Chin AJ: Absent aortic valve: a complex anomaly. Pediatr Cardiol 11:195, 1990. 12. Oztunc F, Ozme S, Ozkutlu S, et al.: Fixed subaortic stenosis in childhood. Medical and surgical course in 90 patients. Jpn Heart J 33:327, 1992. 13. Barber G: Hypoplastic left heart syndrome. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, JT Bricker, DJ Fisher, SR Neish, eds. Williams & Wilkins, Baltimore, 1998, p 1625. 14. Freedom RJ, Black MD, Benson LN: Hypoplastic left heart syndrome. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1011

111 15. Glauser TA, Rorke LB, Weinberg PM, et al.: Congenital brain anomalies associated with the hypoplastic left heart syndrome. Pediatrics 85:984, 1990. 16. Morris MJH, McNamara DG: Coarctation of the aorta and interrupted aortic arch. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, JT Bricker, DJ Fisher, SR Neish, eds. Williams & Wilkins, Baltimore, 1998, p 1317. 17. Wollins DS, Ferencz C, Boughman JA, et al.: A population-based study of coarctation of the aorta: comparisons of infants with and without associated ventricular septal defect. Teratology 64:229, 2001. 18. Huntington K, Hunter AG, Chan KL: A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol 30:1809, 1997. 19. McBride KL, Lewin M, Pignatelli R, et al: Echocardiographic evaluation of parental and sibling risk associated with pediatric left ventricular outflow tract lesions. Am J Hum Genet 71:211A, 2002. 20. Hove JR, Koster RW, Forouhar AS, et al.: Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421:172, 2003. 21. Hornberger LK, Sanders SP, Rein AJ, et al.: Left heart obstructive lesions and left ventricular growth in the midtrimester fetus. A longitudinal study. Circulation 92:1531, 1995. 22. Digilio MC, Marino B, Toscano A, et al.: Congenital heart defects in Kabuki syndrome. Am J Med Genet 100:269, 2001. 23. Milunsky JM, Huang XL: Unmasking Kabuki syndrome: chromosome 8p22-8p23.1 duplication revealed by comparative genomic hybridization and BAC-FISH. Clin Genet 64:1399-1404, 2003. 24. Lin AE, Westgate MN, van der Welde ME, et al.: Adams-Oliver syndrome associated with cardiovascular malformations. Clin Dysmorphol 7:235, 1998. 25. Slavotinek AM, Dubovsky E, Dietz HC, et al. Report of a child with aortic aneurysm, orofacial clefting, hemangioma, upper sternal defect, and marfanoid features: Possible PHACE syndrome. Am J Med Genet 110:282, 2002. 26. Morris CA, Mervis CB: Williams syndrome and related disorders. Annu Rev Genomics Hum Genet 1:461, 2000. 27. Ewart AK, Jin W, Atkinson D, et al.: Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. J Clin Invest 93: 1071, 1994. 28. Saenger P, Albertsson Wikland K, Conway GS, et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 86:3061, 2001. 29. Grossfeld PD, Mattina T, Lai Z, et al.: The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A 129:51, 2004. 30. Levy HL, Guldberg P, Guldberg G, et al.: Congenital heart disease in maternal phenylketonuria: report from the maternal PKU collaborative study. Pediatr Res 49:636, 2001. 31. Lee TC, Zhao YD, Courtman DW, et al.: Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. Circulation 101:2345, 2000. 32. Pearl JM, Nelson DP, Schwartz SM, et al.: First-stage palliation for hypoplastic left heart syndrome in the twenty-first century. Ann Thorac Surg 73:331, 2002. 33. Andrews R, Tulloh R, Sharland G, et al.: Outcome of staged reconstructive surgery for hypoplastic left heart syndrome following antenatal diagnosis. Arch Dis Child 85:474, 2001. 34. Jenkins PC, Flanagan MF, Sargent JD, et al. A comparison of treatment strategies for hypoplastic left heart syndrome using decision analysis. J Am Coll Cardiol 38:1181, 2001. 35. Wernovsky G, Newburger J: Neurologic and developmental morbidity in children with complex congenital heart disease. J Pediatr 142:6, 2003. 36. Tworetzky W, Wilkins-Haug L, Jennings RW, et al.: Balloon dilation of severe aortic stenosis in the fetus: potential for prevention of hypoplastic left heart syndrome: candidate selection, technique, and results of successful intervention. Circulation 110:2125, 2004. 37. Marshall AC, van der Velde ME, Tworetzky W, et al.: Creation of an atrial septal defect in utero for fetuses with hypoplastic left heart syndrome and intact or highly restrictive atrial septum. Circulation 110:253, 2004.

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38. Trends in Infant Mortality Attributable to Birth Defects—United States, 1980–1995. Morbidity and Mortality Weekly Report 47:773, 1998.

2.7 Atrial Septal Defects Definition

Atrial septal defects are defects in the atrial septum other than the foramen ovale which connect the right and left atrium. These include the familiar secundum atrial septal defects (6–10% of all CVMs), as well as the less common sinus venosus atrial septal defects, and rare coronary sinus atrial septal defects.1,2 The secundum atrial septal defect and patent foramen ovale occur in the region of the fossa ovalis which may be a deficiency, perforation (fenestration) or absence of the septum primum.2 In contrast, primum atrial septal defects (discussed in the section on atrioventricular septal defects) are caudal, and sinus venosus defects are posterior to the fossa ovalis. The rare coronary sinus atrial communication is associated with an unroofed coronary sinus and usually accompanied by a persistent left superior vena cava to the left atrium.1,2 Secundum atrial septal defects are thought to be due to defective development or erosion of the flap valve of the foramen ovale.1,2 Sinus venosus atrial septal defects result from incomplete incorporation of the sinus venosus into the atrium and are frequently associated with partial anomalous pulmonary venous return of the right lung. Coronary sinus atrial septal defects are attributed to the incomplete absorption of the left sinus venosus. Diagnosis

Most of the following comments refer to secundum atrial septal defects. The clinical findings are consistent with a left-to-right atrial level shunt which is determined by the relative compliance of the two ventricles and not the size of the defect.1,2 Most children do not have symptoms, and many are probably undiagnosed. Diagnosis usually occurs when a child is evaluated for a systolic murmur which can mimic that of pulmonic stenosis. However, atrial septal defect is characterized by a fixed split-second heart sound, and with larger shunts, a mid-diastolic murmur across the tricuspid valve at the lower left sternal border.1,2 Radiographs show volume overload of the right side of the heart and increased pulmonary vascularity.1,2 On the ECG, there is right axis deviation, and right ventricular hypertrophy due to diastolic overload (incomplete right bundle branch block pattern).1,2 Occasional conduction defects of the sinus and atrioventricular node may be present. Two-dimensional echocardiography easily shows drop-out of the atrial septum where each defect is located. Anomalies of the pulmonary and systemic veins should be sought.1 Color flow Doppler imaging helps to identify the left-to-right shunting. Although surface echocardiography shows the atrial septal defect in pediatric patients, transesophageal echocardiography is necessary for adult patients.1,2 Cardiac catheterization is usually unnecessary for the diagnosis of most atrial septal defects. It may be used if there is a question about an associated defect or if pulmonary vascular disease is suspected.1,2 Angiocardiography is rarely needed to image the atrial defect itself. Catheterization is currently implemented therapeutically, primarily for implantation of occlusion devices.1,2 Etiology and Distribution

Secundum atrial septal defect usually occurs as an isolated malformation but is found in numeous malformation syndromes.

Table 2-7 lists the syndromes and conditions in which there is a strong association with atrial septal defect.3,4 Perhaps the most familiar is Holt-Oram syndrome, the prototypic ‘‘heart-hand syndrome’’ reviewed recently by Huang.5 Atrial septal defect occurs in over half of affected individuals, as well as other CVMs such as ventricular septal defects and complex CVMs. In the most recent and largest study, the genotype of the causative gene, TBX5, did not predict the clinical phenotype6 (Fig. 2-6). Gene mutations involving PTPN11 which causes Noonan syndrome is more familiar as a cause of pulmonic stenosis, but also results in atrial septal defect.7 Mutations in NKX2.5 produce atrial septal defects and conduction abnormalities,8 but no extracardiac anomalies. GATA4 (8p2223), a transcription factor essential for heart formation, causes CVMs, perhaps through its interactions with NKX2.5.9 In the two families studied, the most commonly observed CVM was an atrial septal; less common were ventricular septal defect and pulmonic stenosis (a single case of atrioventricular septal defect was also noted). Prognosis, Treatment, and Prevention

Most atrial septal defects are associated with a benign course, even when untreated.1,2 In fact, many are probably undiagnosed, leading to an underestimate of prevalence.1 Spontaneous closure occurs often in the first year of life. Unlike the vast majority of CVMs that are the therapeutic realm of pediatric cardiologists, this CVM poses a real concern to physicians caring for adults. Symptoms of congestive heart failure and atrial dysrhythmias may appear in the fifth decade of individuals with untreated atrial septal defects.1,2 Hemodynamically significant atrial septal defects can produce pulmonary vascular obstructive disease in 5–10% of these undiagnosed patients.2 A large atrial communication can increase the risk for paradoxical embolism. For large atrial septal defects, surgical closure is usually the accepted method of repair, regardless of symptoms or age. The issue of when and how to close them in adults remains the subject of ongoing research. However, the procedure of choice at many institutions for secundum atrial septal defects is catheter implantation using a clamshell occlusion device (one model is currently FDA approved).1 Atrial septal defects in other locations require surgical closure with direct suturing or patch. References (Atrial Septal Defects) 1. Vick GW III: Defects of the atrial septum including atrioventricular septal defects. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1141. 2. Porter CJ, Feldt RH, Edwards WD, et al.: Atrial septal defects. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 603. 3. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 4. Lin AE: Congenital heart defects in chromosome abnormality syndromes. In: Moss and Adams’ Heart Disease in Infants, Children, and Adolescents, including the Fetus and Young Adult, ed 5. Williams and Wilkins, Baltimore, 1994, p 633. 5. Huang T: Current advances in Holt-Oram syndrome. Curr Opin Pediatr 14:691–695, 2002. 6. Brassington AM, Sung SS, Toydemir RM, et al.: Expressivity of HoltOram syndrome is not predicted by TBX5 genotype. Am J Hum Genet 73:74, 2003.

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Table 2-7. Syndromes and conditions frequently associated with secundum atrial septal defect Causation

MIM #

Gene

Locus

4p16.3

Chromosome Abnormality Deletion 4p (Wolf-Hirschhorn)

194190

WHSC1

Deletion 4q

NA

Unknown

Unknown

Trisomy 13

NA

Unknown

Unknown

NA

Unknown

Unknown

Trisomy 21 4

Derivative (22),t(11;22)

NA

Unknown

Unknown

Trisomy 22

NA

Unknown

Unknown

Holt-Oram5

142900

TBX5

12q2

ASD and conduction defect8

108900

NKX2.5

5q34

Autosomal Dominant

7

Noonan

163950

PTPN11

12q24

Kabuki

147920

Unknown

Unknown

Rubinstein-Taybi

180849

CREBBP

16p13

Familial septal defects9

607941

GATA4

8p22-23

Autosomal Recessive Ellis-van Creveld

225500

EVC

4p16

Thrombocytopenia-absent radius (TAR)

274000

Unknown

Unknown

Toriello-Carey

217980

Unknown

Unknown

NA

NA

NA

Teratogens Alcohol

Compiled from Burn and Goodship3 and others specified. Italics indicate if it is the most commonly associated defect(s). NA, not applicable.

7. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet 29:465, 2001. 8. Schott JJ, Benson DW, Basson CT, et al.: Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281: 108, 1998.

Fig. 2-6. Radiograph of the hands of an infant with Holt-Oram syndrome. There is severe hypoplasia of the radius bilaterally with absence of the right thumb and hypoplasia of the left thumb. The patient had an atrial septal defect. There was a mutation of TBX5 which deleted a glutamine and caused a frame shift. (Radiograph courtesy of Dr. Taosheng Huang, University of California, Irvine.)

9. Garg V, Kathiriya IS, Barness R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443, 2003.

2.8 Ventricular Septal Defects Definition

Ventricular septal defects are defects in the closure of the ventricular septum resulting in an abnormal communication between the left and right ventricle. A variety of adjectives may be used to further characterize the defect, and the same defect may be described in many ways depending on the system of cardiac nomenclature. Ventricular septal defects may be described by their location in the septum, or by their relation to landmarks in the ventricle (crista, infundibulum), semilunar and atrioventricular valves, and inflow or outflow region of the ventricle.1,2 The viewpoint in naming the septal landmarks differs slightly whether based on autopsy or echocardiographic analyses.1,2 In contrast to the simplicity of an atrial septal defect, the numerous systems of cardiac nomenclature for a ventricular septal defect challenge even the astute cardiologist and baffle the general clinician. Populationbased surveillance systems that collect data from multiple reporting sources must translate an assortment of descriptions into epidemiologic codes. Often, the diagnostic terms are not synonymous, hampering epidemiologic and genetic studies. The membranous septum is an easily recognized landmark. Membranous septal defects (Type II, infracristal) are the most

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common (80%) in surgical and autopsy series, but are second to muscular defects in echocardiographic studies.3 They may extend into the surrounding inlet, outlet, and muscular septum and, thus, are often more broadly called perimembranous defects.2 Because the membranous septum lies in the crescent below the aortic valve in the left ventricle outflow tract, they are also known as infracristal defects. Small pieces of the septal leaflet of the tricuspid valve may form ‘‘aneurysms’’ that can lead to spontaneous closure over time.1,2 Less common (5–7%) are the defects which occur in the outflow tract of the right ventricle. Synonyms include Type I, outlet, subpulmonary, conoventricular (some with malalignment), conotruncal (as described also Section 2.3, Conotruncal defects), supracristal, infundibular, and doubly committed subarterial.1,2 Inlet defects (Type III) are also uncommon (5–8%). Although they are located beneath the septal leaflet of the tricuspid valve, some authors point out that they differ from atrioventricular canal defects.2 Muscular ventricular septal defects (Type IV) vary in size from pinhole to large central defects. They may be single or multiple (‘‘swiss cheese’’). Ventricular septal defects may require more than one term to adequately describe their origin and extension; for example, a large defect may begin in the membranous region and extend to the inlet septum. Aortic insufficiency may result from herniation of one of the aortic valve leaflets with an outlet or perimembranous defect. The size of a defect can vary from a serpiginous pinhole to a defect so large that the heart becomes a functional common ventricle. In general, defects that are the size of the aortic valve annulus are considered large. Diagnosis

The clinical presentation varies greatly with the size of the defect, pulmonary vascular resistance, and the presence of associated defects. Most small-to-moderate sized ventricular septal defects are diagnosed by the characteristic holosystolic murmur heard along the left sternal border in an otherwise asymptomatic child.1,2 A thrill may be present. With larger defects, high flow, and pulmonary hypertension, the second heart sound will be loud and narrowly split. A diastolic murmur may reflect aortic insufficiency. The term Eisenmenger complex refers to the physiology created by right-to-left shunt reversal across a ventricular septal defect. These patients have cyanosis and clinical deterioration. Likewise, abnormalities on chest radiograph and ECG depend entirely on the hemodynamic significance of the ventricular septal defect. Small defects are associated with normal chest radiographs. As the degree of left-to-right shunting increases, the left atrium and ventricle dilate, causing cardiomegaly. The pulmonary arteries and veins will also dilate, causing increased vascularity. If pulmonary vascular obstructive disease develops, then the vascularity becomes ‘‘pruned’’ and the heart becomes smaller.1,2 As the leftto-right shunt increases, the ECG manifests left atrial enlargement and left ventricular hypertrophy. High-flow, high-pressure situations will result in biventricular hypertrophy. If pulmonary vascular obstructive disease develops, the ECG will show pure right ventricular hypertrophy and right atrial enlargement. The anatomic location, shape, size, and shunt magnitude of ventricular septal defects can be seen by two-dimensional and Doppler echocardiography with color-flow mapping. Associated anomalies of the AV and semi-lunar valves, and inflow and outflow obstruction, can be delineated. The rapid ECG confirmation of ventricular septal defects diagnosed clinically has contributed to the increase in overall CVM prevalence.4

The role of cardiac catheterization is useful for infants with large shunts, patients with moderate shunts but increased pulmonary resistance, and patients with additional complex CVMs.1,2 When there is evidence of elevated pulmonary vascular resistance, the reactivity of the pulmonary bed can be assessed with oxygen, nitric oxide. and vasoactive drugs.1,2 Etiology and Distribution

Ventricular septal defects often occur in otherwise healthy children. They may be found in a large number of syndromes and conditions. Table 2-8 lists the ones in which there is a frequent association. As discussed for atrial septal defects, causative mutations in the TBX5 gene also produce ventricular septal defects, typically membranous and muscular, with a notable association with ‘‘swiss cheese’’ septum.6,7 GATA4 caused atrial septal defects and ventricular septal defects in the two families studied.8 The prevalence of muscular ventricular septal defects in the population-based BWIS was about 4.7 per 10,000. However, a more recent study using prospective color Doppler echocardiography in 1-week-old newborns reported a frequency of 53 per 1,000. Most of these defects were asymptomatic.9 This apparent increase in prevalence likely reflects increased detection of closing defects. Prognosis, Treatment, and Prevention

The prognosis is of ventricular septal defects is highly variable, depending on the size and location of the defect, and associated defects. Large defects with large left-to-right shunts lead to increased pulmonary blood flow and congestive heart failure. Small defects have excellent long-term prognosis and require no therapy, but have a risk for subacute bacterial endocarditis. Medical therapy (diuretics, digoxin) is offered to children with moderate or large ventricular septal defects who have symptoms of congestive heart failure. Although palliation with a pulmonary artery band was common practice in the past, direct surgical closure is now preferred.1,2 The technique for perimembranous and inlet defects is usually transatrial, with other approaches developed for defects located in other locations. Almost half of perimembranous ventricular septal defects, and up to 80% of muscular defects, will close spontaneously during infancy.1 For those patients requiring surgical repair, the mortality rate is less than 10% in most large medical centers. Most conoventricular ventricular septal defects occur in association with other defects of the outflow tract of the heart such as tetralogy of Fallot or truncus arteriosus. Isolated conoventricular ventricular septal defects rarely close spontaneously. This tissue is integral to the support of the aortic and pulmonary valve annuli, and there may be aortic valve leaflet prolapse. The conoventricular ventricular septal defect is often closed electively to reduce the aortic valve damage. AV ventricular septal defects rarely close spontaneously, and most require surgical repair. References (Ventricular Septal Defects) 1. Gumbiner CH, Takao A: Ventricular septal defect. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1119. 2. McDaniel NL, Graham TP, Gutgesell HP: Ventricular septal defects. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 636.

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115

Table 2-8. Syndromes and conditions frequently associated with ventricular septal defect (membranous, muscular, unspecified)* Causation

MIM #

Gene

Locus

Trisomy 13

NA

Unknown

Unknown

Trisomy 18

NA

Unknown

Unknown

Trisomy 21

NA

Unknown

Unknown

Holt-Oram4,5

142900

TBX5

12q2

Kabuki

147920

Unknown

Unknown

Townes-Brock

107480

SALL1

16q12.1

Rubinstein-Taybi

180849

CREBBP

16p13

Familial septal defects6

607941

GATA4

8p22-23

Fryns

229850

Unknown

Unknown

Ritscher-Schinzel (3C)

220210

Unknown

Unknown

Thrombocytopenia-absent radius (TAR)

274000

Unknown

Unknown

Toriello-Carey

217980

Unknown

Unknown

312870

GPC3

Xq26

Maternal hyperphenylalanine

NA

NA

NA

Diabetes

NA

NA

NA

Alcohol

NA

NA

NA

Valproate

NA

NA

NA

Thalidomide

NA

NA

NA

Trimethadione

NA

NA

NA

164210

Unknown

Unknown

Heterogeneous

Unknown

Heterogeneous

Unknown

Chromosome Abnormality

Autosomal Dominant

Autosomal Recessive

X-Linked Simpson-Golabi-Behmel Teratogen

Other Hemifacial microsomia FAVS, OAVD, Goldenhar VACTERL

NA

*Because a small muscular ventricular septal defect can occur in almost every syndrome, this table lists only the associations that are frequent. Compiled from Burn and Goodship3 and others specified. Italics indicate if it is the most commonly associated defect(s). FAVS, facio-auriculo-vertebral sequence; NA, not applicable; OAVD, oculo-auriculo-vertebral dysplasia.

3. Roguin, N, Du ZD, Barak M, et al.: High prevalence of muscular ventricular septal defect in neonates. J Am Coll Cardiol 26:1545, 1995. 4. Fixler DE, Pastor P, Chamberlin M, et al.: Trends in congenital heart disease in Dallas County births: 1971-1984. Circulation 81:137, 1990. 5. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 6. Sletten LJ, Pierpont ME: Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet 65:128, 1996. 7. Brassington AM, Sung SS, Toydemir RM, et al.: Expressivity of HoltOram syndrome is not predicted by TBX5 genotype. Am J Hum Genet 73:74, 2003. 8. Garg V, Kathiriya IS, Barness R, et al.: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443, 2003. 9. Roguin N, Du ZD, Barak M, et al: High prevalence of muscular ventricular defect in neonates. J Am Coll Cardiol 26:1545, 1995.

2.9 Anomalies of the Pulmonary Veins Definition

Anomalies of the pulmonary veins are abnormalities of the location, number, and patency of the pulmonary vein. Some authors use the terms anomalous pulmonary venous connection and anomalous pulmonary venous drainage (return) interchangeably. However, anomalous pulmonary venous connection is present when one or more of the pulmonary veins connect to a systemic vein.1 In contrast, anomalous pulmonary venous drainage denotes abnormal pulmonary venous flow (or return) either to a systemic vein or the right atrium.1 Anomalous pulmonary venous drainage with normal connection exists in patients with malposition of the atrial septum, common atrium, and sinus venosus defect.1 In these patients, the

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Cardiorespiratory Organs

orifice(s) of the pulmonary veins (usually on the right side) are located in their normal position in the posterior left atrial wall, but the flow of blood may enter the superior vena cava or the right atrium. Pulmonary venous anomalies may be further classified as total or partial, and may include pulmonary vein stenoses and abnormal numbers of pulmonary veins. An embryologic classification system based on abnormalities of common pulmonary vein development can be used to classify the wide array of anomalies.1 Partial Anomalous Pulmonary Venous Connection

The pulmonary veins arise from the splanchnic bed surrounding the developing lung buds and connect with the left atrium by the process of targeted growth. When one to three of the pulmonary veins connect to the systemic veins, partial anomalous pulmonary venous connection (PAPVC) is present. The most frequent anomalous connection is right pulmonary vein(s) into the superior or inferior vena cava. In rare circumstances, the left pulmonary veins drain via the innominate vein or a persistent left superior vena cava into the coronary sinus. Patients are often asymptomatic. Clinical signs of left-toright shunt at the atrial level may be present with a fixed, widely split second heart sound and systolic ejection murmur in the second left intercostal space.1 Radiographs may show cardiomegaly and an increase in pulmonary artery vascularity, depending on the size of the left-toright shunt.1 Variable right ventricular hypertrophy due to volume overload may be evident on ECG, again depending on the number of anomalous veins.1 A comprehensive echocardiographic examination is required to demonstrate each pulmonary vein from multiple views. An associated sinus venosus atrial septal defect may be difficult to visualize in older patients.1 Cardiac MRI, including the newer techniques of cine MRI and magnetic resonance angiography (MRA), are powerful tools to delineate pulmonary vein anatomy.2 Catheterization and angiography have a limited role, although interventional catheterization to occlude aortopulmonary collaterals may be indicated.1 A familiar anatomic variant of PAPVC is the scimitar syndrome. This may be viewed less as a true multiple malformation ‘‘syndrome’’ and more as a developmental field defect.3 All or some of the right pulmonary veins enter the inferior vena cava at or below the diaphragm. Associated anomalies include right lung hypoplasia or horseshoe lung, secondary dextrocardia (i.e., dextroposition), hypoplasia of the right pulmonary artery, and pul-

monary sequestration. Intracardiac malformations may coexist. Noncardiac malformations include vertebral anomalies, horseshoe kidneys, and rectovaginal fistula. The small number of syndromes which are frequently associated with anomalous pulmonary venous return are listed in Table 2-9.4,5 Males and females are equally affected. Surgical correction is the definitive treatment. Prognosis and treatment depend on the number of veins involved and magnitude of pulmonary overcirculation. With only one or two anomalous veins, the size of the shunt may be small and even go undetected. Untreated volume overload in the pulmonary circulation may rarely lead to pulmonary hypertension over a period of decades.

Total Anomalous Pulmonary Venous Connection

Absence of connections between the pulmonary veins and the left atrium defines total anomalous pulmonary venous connection (TAPVC). As noted previously, pulmonary veins arise from the splanchnic bed surrounding the developing lung buds and connect with the left atrium. When there is complete failure of the pulmonary veins to join the left atrium, the pulmonary veins may connect to the systemic venous circulation (total anomalous pulmonary venous connection) or into the right atrium (total anomalous pulmonary venous drainage).1 The pulmonary venous return to the systemic circulation may occur above the diaphragm, below the diaphragm, or intracardiac. When there is no obstruction to blood flow, patients present in infancy with evidence of a large left-to-right shunt.1 They may have mild systemic desaturation and frequently have systemic pressure in the pulmonary arteries. When obstruction is present, patients present with newborn cyanosis, pulmonary congestion, and congestive heart failure.1 Chest radiographs show a large heart with increased blood flow when no obstruction is present.1 With obstruction, the heart is small, the pulmonary veins are engorged, but the lung fields appear hyperlucent. Right ventricular hypertrophy and right atrial enlargement are present on ECG.1 Echocardiography shows evidence of a large right atrium with bowing of the atrial septum to the left.1 Likewise, the right ventricle encroaches on the left. Meticulous mapping of the number, size, course and patency of the pulmonary veins, confluence, and venous channel should be accomplished using twodimentional echocardiography with color flow Doppler mapping.1

Table 2-9. Syndromes and conditions frequently associated with anomalous pulmonary venous connection Causation

Type of Anomalous Venous Connection

MIM #

Gene

Locus

Chromosome Abnormality Cat eye

Total

NA

unknown

22q

Turner

Partial

NA

unknown

X

Partial

142900

TBX5

12q2

Total

270400

DHCR7

11q12

Autosomal Dominant Holt-Oram5 Autosomal Recessive Smith-Lemli-Opitz

Compiled from Burn and Goodship3 and Lacro et al.5 Italics indicate if it is the most commonly associated defect(s). NA, not applicable.

Heart

The interatrial commnication, intracardiac structures, and infradiaphragmatic venous structures should also be evaluated. As noted previously, MRI and the advanced modalities of cine MRI, 3-D MRI, and MRA provide enhanced imaging of all cardiovascular and noncardiac structures.2 The role of diagnostic cardiac catheterization and angiography has been greatly reduced and may become obsolete as MRI supplants imaging in the most challenging cases.1 Table 2-9 lists syndromes and conditions strongly associated with TAPVC. Omitted from the table are heterotaxy ‘‘syndromes,’’ which are more accurately viewed as developmental field defects. In particular, bilateral right sidedness (asplenia) is frequently associated with TAPVC of the mixed type. Although siblings with TAPVC have been reported, implying autosomal recessive inheritance, autosomal dominant inheritance with variable expressivity and reduced penetrance seems to be more likely. In a large Utah–Idaho kindred, a gene has been detected which maps to chromosome 4p13-q12.6,7 Infants without obstruction present in congestive heart failure in the first few weeks or months of life.1 Again, surgical correction is necessary and usually successful, with resolution of the pulmonary hypertension. Cor Triatriatum

There are several anatomic types of cor triatriatum,1 and a single embryologic explanation is not possible. In the ‘‘classic’’ form, an accessory chamber joins the left atrium directly and receives the pulmonary veins with egress through the opening in the ‘‘membrane.’’1 Alternatively, the pulmonary veins may return to the right atrium directly or indirectly via an anomalous venous channel. Cor triatriatum is attributed to incomplete incorporation of the common pulmonary vein into the embryonic left atrium.1 Although the specific mechanism is unknown, the embryonic error is thought to be related to that which causes anomalous pulmonary venous return. The clinical presentation of cor triatriatum depends on the degree of obstruction and on the presence or absence of collateral drainage. Patients may present with clinical evidence of pulmonary hypertension, with a loud pulmonary closure sound and right heart failure.1 The time of onset of symptoms depends on the specific anatomy present and the degree of obstruction to pulmonary venous blood return.1 Chest radiographs show pulmonary venous obstruction, a large pulmonary artery, and large left atrium.1 Right ventricular hypertrophy is present on ECG.1 Echocardiography can detect the membrane within the left atrial cavity, and Doppler interrogation with color-flow mapping may show a turbulent color jet through a small opening.1 The membrane in cor triatriatum must be distinguished from a supravalvar mitral ring. On cardiac catheterization and angiography there is pulmonary hypertension. Selective pulmonary arteriograms define the accessory chamber.1 Surgery is necessary to reverse pulmonary hypertension, and prognosis is excellent.1 Pulmonary Vein Stenosis

Pulmonary vein stenosis refers to obstruction of one or more pulmonary veins. There can be localized narrowing at the junction with the left atrium, or diffuse hypoplasia.1 The latter may be complicated by intimal proliferation of intraparenchymal pulmonary veins. Two possible mechanisms have been suggested. The first theory postulates that the stenosis is part of the spectrum of incomplete absorption of the veins into the left atrium. The

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second theory considers the possibility of intrauterine inflammation with secondary scarring. Signs and symptoms are those of pulmonary hypertension. The chest radiograph shows signs of pulmonary venous obstruction, and the ECG demonstrates severe right ventricular hypertrophy and possibly right atrial enlargement.1 The dilated pulmonary vein(s) may be seen on echocardiography, or, if not, a high-velocity jet is seen entering the left atrium.With cardiac catheterization and angiography, the elevated pulmonary pressures and elevated pulmonary wedge pressure can be measured.1 Angiography may show the individual obstructed vein(s).1 The prognosis is guarded because of continued pulmonary hypertension in the affected lobes, which eventually causes deterioration of those areas.1 Surgical correction is disappointing. Balloon dilation has been attempted, as well as stent placement, without consistent success.1 References (Anomalies of the Pulmonary Veins) 1. Geva T, Van Praagh S: Anomalies of the pulmonary veins. In: Moss and Adams Heart Disease in Infants, Children and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 736. 2. Greil GF, Powell AJ, Gildein HP, et al.: Gadolinium-enhanced 3dimensional MR angiography of pulmonary and systemic venous anomalies. J Am Coll Cardiol 39:335, 2002. 3. Ruggieri M, Abbate M, Parano E, et al.: Scimitar vein anomaly with multiple cardiac malformations, craniofacial, and central nervous system abnormalities in a brother and sister: Familial scimitar anomaly or new syndrome? Am J Med Genet 116A:170, 2003. 4. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 5. Lacro RV, Obler D, Smoot LB: Anomalous pulmonary venous connection (APVC) in Holt-Oram syndrome (HOS). Proc Greenwood Genet Center 22:100, 2003. 6. Bleyl S, Ruttenberg HD, Carey JC, et al.: Familial total anomalous pulmonary venous return: a large Utah-Idaho family. Am J Med Genet 52:462, 1994. 7. Bleyl S, Nelson L, Odelberg SJ, et al.: A gene for familial total anomalous pulmonary venous return maps to chromosome 4p13-q12. Am J Hum Genet 56:408, 1995.

2.10 Abnormal Systemic Venous Connections Definition

There are several abnormalities at systemic venous connection which are due to abnormal drainage or morphology of the superior and inferior vena cavae. There are three basic venous systems from which they are derived: (1) the cardinal veins which form the superior and inferior caval systems; (2) the umbilical, vitelline, and omphalomesenteric veins (discussed in Chapter 35) and (3) the pulmonary veins. Related to the formation of the superior vena cava is the creation of the coronary sinus from the coronary vein. Its orifice is an important landmark indicating the right atrium.1,2 Persistent Left Superior Vena Cava (Bilateral Superior Venae Cavae)

Persistence of the left superior vena cava involves drainage through the coronary sinus into the right atrium in over 90% of

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the cases. In the remaining cases, drainage occurs into the left atrium.1,2 It has been attributed to failure of obliteration of the left anterior cardinal vein. Left superior vena cava is a frequent occurrence with tetralogy of Fallot, mitral atresia, atrioventricular canal defects, and juxtaposed right atrial appendage.1,2 Although itself clinically asymptomatic, its association with other defects may create challenges during catheterization and surgery. The diagnosis is suspected by echocardiographic imaging of an enlarged coronary sinus, which is further delineated using Doppler flow mapping. Additional imaging techniques include magnetic resonance imaging and magnetic resonance angiography.1,2 A left superior vena cava must be identified preoperatively, especially in cases requiring a systemic venous to pulmonary artery anastomosis. Surgical ligation may be performed if there is an innominate vein.1,2 Another variation of persistent left superior vena cava occurs when there is partial or complete unroofing of the coronary sinus.1,2 This creates an interatrial communication but is not a true septal defect.2 This is common in heterotaxy, both asplenia (67%) and polysplenia (13%).3

2.11 Anomalies of the Ductus Arteriosus Definition

Anomalies of the ductus arteriosus include abnormal position, number, absence, or closure of the ductus arteriosus. The ductus arteriosus originates from the distal left sixth aortic arch, connecting the main pulmonary trunk with the descending aorta distal to the origin of the left subclavian artery.1,2 When there is a right aortic arch, the ductus arteriosus may be on the right, joining the right pulmonary artery and the right aortic arch just distal to the right subclavian artery; but more commonly it is on the left joining the left pulmonary artery and the proximal portion of the left subclavian artery. Rarely, the ductus arteriosus may be bilateral, tortuous, or aneurysmally dilated.2 Absent ductus arteriosus has been associated with tetralogy of Fallot and absent pulmonary valve.2 Premature closure of the ductus is considered to be a cause of congestive heart failure at birth.2 Patent Ductus Arteriosus (Patent Arterial Duct)

Anomalies of the Coronary Sinus

As mentioned above in the discussion about left superior vena cava, the coronary sinus may be unroofed. Coronary sinus orifice atresia, severe stenosis, aneurysm or diverticulum are extremely rare anomalies.1,2 Interrupted Inferior Vena Cava

Interruption of the inferior vena cava refers to absence, specifically, of the hepatic segment of the inferior vena cava with azygous continuation into the right or left superior vena cava. It is strongly associated with polysplenia (86%).3 The anomaly itself is asymptomatic, but its presence must be known before catheterization and surgical therapy.1,2 It is readily imaged by echocardiography, magnetic resonance imaging, magnetic resonance angiography and venous angiography. Bilateral Inferior Venae Cavae

Bilateral suprahepatic inferior vena cava occur in heterotaxy, rarely in patients with normal situs.3 References (Abnormal Systemic Venous Connections) 1. Huhta JC: Anomalies of systemic venous return. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1667. 2. Geva T, Van Praagh S: Abnormal systemic venous connections. In: Moss and Adams Heart Disease in Infants, Children and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 773. 3. Raghib G, Ruttenberg HD, Anderson RC, et al.: Termination of left superior vena cava in left atrium, atrial septal defect, and absence of coronary sinus: a developmental complex. Circulation 31:906, 1965. 4. Van Praagh S, Santini F, Sanders SP: Cardiac malpositions with special emphasis on visceral heterotaxy (asplenia and polysplenia syndromes). In: Nadas’ Pediatric Cardiology, ed 4. Nadas AS, Fyler DC, eds. Hanley & Belfus, Philadelphia, 1992, p 589.

This defect is also discussed in Chapter 9. Classically, the patent ductus arteriosus produces a ‘‘continuous’’ murmur.1,2 Small defects are asymptomatic, but large defects may cause congestive heart failure.1,2 If untreated, pulmonary vascular obstructive disease ensues. Large shunts will cause overcirculation of the lungs resulting in left atrial and left ventricular enlargement on both the ECG and chest radiograph. The echocardiogram with Doppler interrogation is an excellent method to diagnose patent ductus arteriosus.1,2 Cardiac catheterization is no longer necessary. The treatment for patent ductus arteriosus depends on whether the patient is a preterm or term infant. Patent ductus arteriosus may be closed with indomethacin in the premature infant. For most children more than a few months of age, transcatheter closure with a coil device is the treatment of choice.1 Currently, there are both FDA and non-FDA models available. For children with a very large patent ductus, and based on institutional preference for age (older than 12 months) or symptoms (heart failure), surgery may be offered.1,2 The true frequency of patent ductus arteriosus is unknown. Possibly more so than for any other CVM, prevalence estimates are highly dependent upon gestational age, ascertainment age, method of diagnosis, and associated extracardiac malformation, especially those that alter pulmonary vascular resistance. Of the many syndromes and conditions associated with a patent ductus arteriosus,1–5 notably the trisomies and fetal rubella, one mendelian syndrome is worth noting. In addition to patent ductus arteriosus, the Char syndrome includes distinctive facial appearance (i.e., flat nasal bridge, downturned eyes, patulous lips, short philtrum, flared eyebrows) and clinodactyly of the fifth finger. Recent studies of the causative TFAP2B mutation have provided genotype–phenotype correlation.5 References (Anomalies of the Ductus Arteriosus) 1. Mullins CE, Pagotto L: Patent ductus arteriosus. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1181. 2. Moore P, Brook MM, Heyman MA: In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 652.

Heart 3. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study: 1981-1989. Futura, Armonk, NY, 1997. 4. Burn J, Goodship J: Congenital heart disease. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, ed 4. Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Churchill Livingstone, London, 2002, p 1239. 5. Zhao F, Weismann CG, Satoda M, et al.: Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. Am J Hum Genet 69:695, 2001.

2.12 Aortopulmonary Window (Aortopulmonary Septal Defect) Definition

Aortopulmonary window is a defect in the aortopulmonary septum distal to the semilunar valves. Although aortopulmonary window resembles truncus arteriosus anatomically, it differs considerably from an embryologic and syndromic viewpoint.1,2 Unlike truncus, there is no strong association with the 22q11 deletion spectrum/DiGeorge syndrome. Associated defects include aortic origin of the right pulmonary artery, tetralogy of Fallot, anomalous origin of the right coronary artery from the pulmonary artery, and right aortic arch.1,2 Type A interruption of the aortic arch predominates in contrast to the type B seen with DiGeorge syndrome. The hemodynamic features are that of a large left-to-right shunt such as a large ventricular septal defect or patent ductus arteriosus. There are no specific radiographic or electrocardiographic abnormalities that are specific to aortopulmonary window.1,2 The defect is accurately imaged by echocardiography. Cardiac catheterization may be necessary to assess pulmonary vascular resistance or image the coronary arteries. Surgical correction must be performed early in life because of the pulmonary overcirculation. Prognosis is excellent assuming surgery is performed promptly and successfully. References (Aortopulmonary Window) 1. Wiggins JW Jr: Aortopulmonary septal defect. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1199. 2. Brook MM, Heymann MA: Aortopulmonary window. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 670.

2.13 Anomalies of the Coronary Arteries Definition

Anomalies of the coronary arteries include abnormal number, origin, or course.1,2 Omitted from this discussion are anomalies of the coronary sinus, aortic root (such as aortic dilation), and sinus of Valsalva. The right and left coronary arteries arise from the right and left sinus of Valsalva respectively and have a predictable course over the surface of the heart. From the epicardial surface, they branch intramurally to reach the endocardium.1,2 The venous drainage of the heart is collected by the coronary

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sinus, which runs in the posterior atrioventricular groove. One of the characteristics of the coronary system is the ability to form collateral vessels to compensate for congenital or acquired absence or stenosis.1,2 The presence or absence of symptoms in large part depends on the adequacy of collateralization. A right-dominant system is vastly more common in primates and swine. However, a left-dominant system is more common in patients with a bicuspid aortic valve or aortic stenosis. Diagnosis

Because of the variety of specific anatomic types, coronary artery anomalies can be associated with a wide range of clinical presentations ranging from no symptoms to chest pain, or even sudden death.1–3 For example, a single coronary artery is usually asymptomatic and diagnosed only in conjunction with other cardiac anomalies, or as a complication of atherosclerotic occlusion.1,2 The familiar anomalous origin of the left coronary artery from the pulmonary artery may cause anginal symptoms and myocardial infarction in infancy.1,2 Symptoms of congestive heart failure must be differentiated from dilated cardiomyopathy since anomalous origin of the left coronary artery from the pulmonary artery is surgically treatable. Anomalous course of the left coronary artery may be asymptomatic for many years. Angina or arrhythmia during exercise in young individuals should prompt evaluation for anomalies of the coronary arteries. The definitive diagnosis of a coronary anomaly had been angiography at cardiac catheterization.1,2 However, echocardiography with color flow Doppler mapping has become the standard of care. Visualization of the origin and length of the coronary artery should be seen in more than one view, confirmed by Doppler flow. Additional imaging will delineate the ventricular chambers dimensions, function, valve leaflets, and attatchments. Ventricular dilation, regional wall abnormalities, valvar regurgitation, and endocardial fibroelastosis signify damage to the heart muscle. With anomalous origin of the left coronary artery from the pulmonary artery, additional information can be obtained from the chest radiograph which shows moderate to severe cardiomegaly with pulmonary venous engorgement.1,2 Other anomalies of the coronary arteries will not cause an abnormal chest radiograph. The ECG may show evidence of an anterolateral myocardial infarction with deep Q waves. However, the abnormal ECG changes may appear only during exercise testing. Coronary artery anomalies can be associated with other CVMs,1,2 especially tetralogy of Fallot, d-TGA, 1-TGA (corrected transposition), single ventricle, truncus arteriosus, pulmonary atresia, and double outlet right ventricle.1,2 It is important for the cardiac surgeon that these anomalies are diagnosed preoperatively. When disrupted, these anomalies may be the source of postoperative complications causing ischemia and ventricular dysfunction. Etiology and Distribution

The course and pattern of the coronary arteries are highly preserved in phylogeny. The coronary bed develops as one of the last steps in primary cardiac morphogenesis. An epicardial origin for the coronary vascular system has been proposed replacing the previous theory in which myocardial sinusoids were believed to precede the actual vessels.1,2 Presumably, the mechanism involves morphoregulatory genes and local signals perhaps from growth factors. New experimental data implicate a complex genetic basis. The incidence of coronary artery anomalies is unknown, since many cases are asymptomatic.

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Prognosis, Treatment, and Prevention

Early diagnosis is critical. Prognosis depends on the amount of myocardial ischemia and damage that has occurred.1,2 Surgical intervention is available for anomalous origin of the left coronary artery from the pulmonary artery. This may include ligation, transplantation of the coronary artery to the aorta, saphenous vein graft, mammary artery graft, or tunnel procedure within the great arteries to reroute the coronary blood into the left coronary system, promoting normal prograde flow. Both acquired disorders (e.g., atherosclerosis, Kawasaki disease) and congenital coronary artery anomalies can cause sudden death in asymptomatic persons.3 Athletes, especially elite competitors, are at risk. Prospective ECG screening for coronary anomalies (and a variety of other cardiac abnormalities) is technically feasible. However, due to cost–benefit issues, ECG screening is not offered routinely as part of precompetition screening at the present time.3 References (Anomalies of the Coronary Arteries) 1. Herlong, JR: Congenital coronary artery anomalies. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1647. 2. Matherne GP: Congenital anomalies of the coronary vessels and the aortic root. In: Moss and Adams Heart Disease in Infants, Children and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 675. 3. Liberthson RR: Sudden death from cardiac causes in children and young adults. N Engl J Med 334:1039, 1996.

2.14 Anomalies of the Pericardium Definition

Anomalies of the pericardium include complete or partial absence of the pericardium, which may involve the left side, right side, or diaphragmatic surface.1–2

These rare defects are usually asymptomatic, but herniation of the left atrium or ventricle can cause strangulation of those portions of the heart, with serious consequences.2 A bulge in the area of the left atrial appendage can be seen on chest radiograph. Confirmation is made by computerized or magnetic resonance imaging of the heart. The ECG is usually normal unless ischemia occurs. Diseases with effusion or thickening of the pericardium have always been best diagnosed by echocardiography, but absence of a part of the pericardium may be difficult to detect with echocardiogram. Cardiac catheterization and angiography may be necessary if the defect cannot be confirmed by other imaging processes. A congenital pericardial defect may be associated with heterotaxy. A defect in the diaphragmatic pericardium is one of the hallmark defects of the pentalogy of Cantrell, together with supraumbilical abdominal wall defect, sternal cleft, CVM, and diaphragmatic hernia.1 Complete absence of the pericardium may be asymptomatic. When the defect is partial, the atrial appendage or another part of the heart may become engaged in the defect, resulting in strangulation and death. Constrictive pericarditis due to chronic pericardial inflammation is not a malformation. However, pericardial constriction is one of the key features of MULIBREY (muscle, liver, brain, eye) ‘‘nanism,’’ an autosomal recessive syndrome characterized by hypotonia, growth deficiency, triangular face with frontal bossing, decreased retinal pigment, and normal intelligence.3 References (Anomalies of the Pericardium) 1. Altman C: Pericarditis and pericardial diseases. In: The Science and Practice of Pediatric Cardiology, vols 1 and 2, ed 2. Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. Williams & Wilkins, Baltimore, 1998, p 1809. 2. Rheuban KS: Pericardial disease. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 1287. 3. Lapunzina P: MULIBREY nanism: three additional patients and a review of 39 patients. Am J Med Genet 55:349, 1995.

3 Systemic Vasculature Lynne M. Bird and Kenneth Lyons Jones

3.1 Interrupted Aortic Arch Definition

Interrupted aortic arch is discontinuity of the aortic arch in which either an aortic branch vessel or the ductus arteriosus supplies the descending aorta. Three anatomic forms have been described.1 In type A, interruption of the arch is distal to the origin of the left subclavian artery; in type B, interruption of the arch is proximal to the origin of the subclavian artery, between the origins of the left common carotid and left subclavian arteries; and in type C, interruption of the arch is proximal to the origin of the left common carotid artery, between the origins of the innominate and the left common carotid arteries (Fig. 3-1). Diagnosis

The vast majority of cases are detected in the newborn period through symptoms of respiratory distress and mild-to-severe cyanosis, with or without decreased peripheral pulses. Although differential cyanosis is a useful diagnostic sign, it occurs only rarely because of the frequent association of a ventricular septal defect (85%). Using echocardiography, most cases of type B and type C aortic arch interruption can be diagnosed accurately by identifying an ascending aorta with a straight course to its branches (‘‘V’’ sign), without the normal continuous curvature to the descending aorta. Type A cases show a ‘‘W’’ sign, formed from the three main branches arising from the aorta.2 Echocardiography may not distinguish clearly between type A interruption and coarctation of the aorta. Aortic arch interruption has been successfully detected in utero at 17 weeks’ gestation using fetal echocardiography.2

Two-thirds of patients with interrupted aortic arch have DiGeorge syndrome, a disorder due to a submicroscopic deletion of chromosome 22q11.2. If only type B interrupted aortic arch is considered, up to 80–90% have DiGeorge syndrome8; type A and type C interrupted aortic arch have rarely been seen in association with DiGeorge syndrome. Hemizygosity for 22q11.2 results in aberrant development of the fourth branchial arch and derivatives of the third and fourth pharyngeal pouches.9 Features include hypocalcemia due to parathyroid hypoplasia and thymic hypoplasia that reduces circulating T-cell numbers but usually does not impair cellular immunity. Other defects of the truncoconal area of the heart, including truncus arteriosus, tetralogy of Fallot, and malalignment ventricular septal defect, are seen frequently, as is aberrant subclavian artery creating a vascular ring. The fundamental defect caused by the 22q11.2 deletion is most likely defective neural crest cell development.9 Neural crest cells are important in the development of the parathyroid and thymus glands, the aortic arches and truncoconal region of the heart, and craniofacial structures.10 TBX1 may be the major determinant of the phenotype associated with the 22q11.2 deletion syndrome, as point mutations in this gene can produce nearly the full spectrum of abnormalities.11 Rarely, other syndromes have been associated with interrupted aortic arch (Table 3-1).7,8,12–18 Prenatal exposure to retinoic acid is frequently associated with type B aortic arch interruption and is also thought to disturb neural crest-derived structures.17,18 One patient out of 23 with interrupted aortic arch was found to have a point mutation in the NKX2.5 gene, which is capable of producing a wide variety of cardiovascular anomalies.19

Etiology and Distribution

Prognosis, Treatment, and Prevention

Interrupted aortic arch is an uncommon defect, with a frequency of 0.3 to 5.9 per 100,000 births.3–6 It accounted for 1.3% of the critical congenital heart defects ascertained through the New England Regional Infant Cardiac Program from 1968 to 1974,5 and 1.2% of total defects identified by the Baltimore–Washington Infant Study (1981–1989).6 In virtually all cases, interrupted aortic arch is associated with intracardiac abnormalities. Type B interruption is most frequent, accounting for 60–70%3–7 of cases.

Without surgery, most patients die in the first 2 weeks of life.3 Infusion of prostaglandin E1 is frequently used to maintain patency of the ductus arteriosus, ensuring adequate systemic blood flow prior to surgical intervention. One-stage operation has an improved mortality rate over multi-stage repairs, but early and late mortality rates continue to be substantial (12–14% and 20– 30%, respectively).20,21 Associated anomalies play an important role in outcome. 121

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Fig. 3-1. Schematic of types of interrupted aortic arch. Type A: interruption of aorta distal to the origin of the left subclavian artery. Type B: interruption between the origins of the left common carotid and left subclavian arteries. Type C: interruption between the innominate or right common carotid and the left common carotid arteries. PDA ¼ patent ductus arteriosus.

Table 3-1. Syndromes associated with interrupted aortic arch Syndrome

Prominent Features

Causation

Down syndrome12

Hypotonia, flat midface, upslanting palpebral fissures

Chromosomal

Trisomy 187

Clenched hands, short sternum, low arch dermal ridge patterning on fingertips

Chromosomal

Trisomy 1313

Cleft lip, cerebral malformations, polydactyly

Chromosomal

Trisomy 5q31.1q35.114

Growth retardation, microcephaly, facial dysmorphism (single case report)

Chromosomal

DiGeorge syndrome8

Hypoparathyroidism, thymic hypoplasia, aortic arch anomalies, conotruncal cardiac defects, cleft palate

Del 22q11.2

Cytogenetic Aberrations

Ring chromosome 2115

Chromosomal

46, XY, r(21)(p11q12) Genetic Syndromes

Townes-Brocks7

Imperforate anus, thumb abnormalities, ear anomalies, hearing loss

AD (107480) SALL1, 16q12.1

Perlman syndrome16

Macrosomia, nephroblastomatosis, facial dysmorphism

AR (267000)

Hydantoin7

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoin

Retinoic acid17,18

Microtia, craniofacial malformations, conotruncal cardiac defects, brain malformations, thymic hypoplasia

Prenatal exposure to isotretinoin

Teratogenic Abnormalities

References (Interrupted Aortic Arch) 1. Celoria GC, Patton RB: Congenital absence of the aortic arch. Am Heart J 58:407, 1959. 2. Marasini M, Pongiglione G, Lituania M, et al.: Aortic arch interruption: two-dimensional echocardiographic recognition in utero. Pediatr Cardiol 6:147, 1985. 3. Collins-Nakai RL, Dick M, Parisi-Buckley L, et al.: Interrupted aortic arch in infancy. J Pediatr 88:959, 1976.

4. Samanek M, Slavik Z, Zborilova B:. Prevalence, treatment, and outcome of heart disease in live-born children: a prospective analysis of 91,823 live-born children. Pediatr Cardiol 10:205, 1989. 5. Fyler DC, Buckley LP, Hellenbrand WE, et al.: Report of the New England Regional Infant Cardiac Program. Pediatrics 65(Suppl):375, 1980. 6. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations. The

Systemic Vasculature

7. 8.

9.

10.

11. 12.

13. 14.

15. 16. 17. 18. 19.

20. 21.

Baltimore-Washington Infant Study 1981-1989. Futura Publishing Co. Inc., New York, 1997. Loffredo CA, Ferencz C, Wilson PD, et al.: Interrupted aortic arch: An epidemiologic study. Teratology 61:368, 2000. Rauch A, Hofbeck M, Leipold G, et al.: Incidence and significance of 22q11.2 hemizygosity in patients with interrupted aortic arch. Am J Med Genet 78:322, 1998. Van Mierop LHS, Kutsche LM: Cardiovascular anomalies in DiGeorge syndrome and importance of neural crest as a possible pathogenetic factor. Am J Cardiol 58:133, 1986. Hutson MR, Kirby ML: Neural crest and cardiovascular development: a 20-year perspective. Birth Defects Res Part C Embryo Today 69:2, 2003. Yagi H, Furutani Y, Hamada H, et al.: Role of TBX1 in human del22q11.2 syndrome. Lancet 362:1366, 2003. McMahon CJ, Said HG, Clapp SK. Interrupted aortic arch type B in trisomy 21: repair with carotid artery interposition. Pediatr Cardiol 24:40, 2003. Sharma J, Saleh M, Das BB. Berry syndrome with trisomy 13. Pediatr Cardiol 23:205, 2002. Martin DM, Mindell MH, Kwierant CA, Glover TW, Gorski JL. Interrupted aortic arch in a child with trisomy 5q31.1q35.1 due to a maternal (20;5) balanced insertion. Am J Med Genet 116A:268, 2003. Johnson MC, Hing A, Wood MK, et al. Chromosome abnormalities in congenital heart disease. Am J Med Genet 70:292, 1997. Greenberg F, Copeland K, Gresik MV. Expanding the spectrum of the Perlman syndrome. Am J Med Genet 29:773, 1988. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid embryopathy. N Engl J Med 313:837, 1985. Rappaport EB, Knapp M: Isotretinoin embryopathy—a continuing problem. J Clin Parmacol 29:463, 1989. McElhinney DB, Geiger E, Blinder J, et al.: NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42:1650, 2003. Schreiber C, Eicken A, Vogt M, et al.: Repair of interrupted aortic arch: results after more than 20 years. Ann Thorac Surg 70:1896, 2000. Bailey WW: Interrupted aortic arch. Adv Card Surg 5:97, 1994.

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Fig. 3-2. Schematic of right aortic arch, with the major arteries arising as a mirror image of the normal order.

iosus. In one study of 57 cases, no ductus was found in 28%; in 19%, a right-sided ductus running between the proximal segment of the right arch just beyond the right subclavian branch and the right pulmonary artery was found; in 50%, a left-sided ductus running from the proximal segment of the left subclavian artery to the left pulmonary artery was found; and in one case, bilateral ducti arteriosi were found.1 Given that a retro-esophageal vessel is not present in any of these variations, neither the esophagus nor the trachea is compressed. However, very rarely the point of attachment of the ductus is to a retro-esophageal descending aortic diverticulum (Kommerell diverticulum).4 In this situation, a vascular ring is formed, made up of the right aortic arch to the right of the trachea and esophagus, the retroesophageal segment of the aorta posteriorly, the ductus arteriosus to the left, and the pulmonary arterial bifurcation anteriorly. Diagnosis

3.2 Right Aortic Arch Definition

Right aortic arch is an aortic arch that passes over the right mainstem bronchus and joins a right-sided proximal descending aorta that crosses to the left side to enter the abdomen through a normally positioned aortic hiatus of the diaphragm. This anomaly occurs in about 0.1% of individuals. This malformation has two major variants with respect to the origin of the brachiocephalic arteries: 1) mirror-image branching and 2) retro-esophageal left subclavian artery.1 In addition, rare types of aberrant brachiocephalic branching may exist in association with right aortic arch.2,3

3.2.1 Right Aortic Arch with Mirror-Image Branching Definition

In right aortic arch with mirror-image branching, the major arteries arise as a mirror image of the normal order. The first branch of the arch is the innominate artery; the second is the right carotid artery; and the third is the right subclavian artery (Fig. 3-2). Variations exist based on the presence and position of the ductus arter-

In a postnatally ascertained population, virtually all individuals with right aortic arch and mirror-image branching have an associated cardiac defect, the most common of which is tetralogy of Fallot.1 In a large population that was screened prenatally, an intracardiac anomaly was found in only one of 19 cases.5 Since a vascular ring occurs only rarely, respiratory symptoms are infrequently observed. In the rare case of retro-esophageal descending aortic diverticulum and left ductus, compression of the left main bronchus may lead to air trapping on the left. A combination of barium esophagraphy and two-dimensional echocardiography is usually sufficient to make a diagnosis.6 Angiography is seldom needed. Etiology and Distribution

A right aortic arch represents persistence of the right fourth pharyngeal arch artery as opposed to the normal situation, in which the aortic arch is fully formed from the left fourth pharyngeal arch artery. The interruption of the left arch leading to mirror-image branching is between the left ductus arteriosus and the descending aorta (Fig. 3-2). Mirror-image branching is the most common aortic arch pattern in patients with a right aortic arch. No male or female predominance has been documented. The vast majority of affected individuals are believed to have an associated congenital heart defect1,2; however, this may reflect ascertainment bias, since recent data from a population screened prenatally suggest that only a minority have an intracardiac anomaly.5 A right aortic arch has been seen in the 22q11.2 deletion syndrome (DiGeorge syndrome, Shprintzen syndrome, velo-cardio-facial

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syndrome)8 and CHARGE syndrome.9 The principal features of the 22q11.2 deletion syndrome (in addition to those noted in entry 9.1) are velopharyngeal insufficiency (with overt or submucous cleft palate), retruded mandible, prominent nose with squared nasal root and narrow alar base, and slender, tapered fingers. In adolescence and adulthood, the face is long with vertical maxillary excess and reduced expression. CHARGE syndrome (coloboma, heart defects, atresia choanae, retarded growth and development, genital anomalies, and ear defects) is due to haploinsufficiency of CHD7.10 The cardiovascular defects include right-sided aortic arch, ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of Fallot, patent ductus arteriosus (PDA), and double-outlet right ventricle, with an atrioventricular canal.9 Right aortic arch has been reported once in Kallman syndrome,11 Noonan syndrome,12 and PHACES (posterior fossa malformation, hemangioma, arterial anomalies, cardiac defect, eye anomalies, sternal malformation) association.13 Prognosis, Treatment, and Prevention

Prognosis depends on the underlying cardiac defect accompanying the right-sided aortic arch. Neither tracheal nor esophageal compression occurs unless the ductus attaches to an aortic diverticulum, in which case there can be severe respiratory difficulties. Division of the left-sided ligamentum arteriosum results in immediate and complete relief of symptoms. 3.2.2 Right Aortic Arch with Aberrant (Retro-Esophageal) Left Subclavian Artery Definition

In this variation, the left subclavian artery arises as the fourth branch from the left dorsal aspect of the upper descending aorta (Fig. 3-3). The branches from proximal to distal are the left common carotid, the right common carotid, the right subclavian, and the left subclavian, which crosses the midline behind the esophagus to supply the left arm. Variations of the defect depend on the presence and position of the ductus arteriosus: an absent ductus, a right-side ductus running between the proximal segment of the right aortic arch and the right pulmonary artery, and a left-side ductus running between the left subclavian artery and the left pulmonary artery.1 Fig. 3-3. Schematic of right aortic arch, with aberrant left subclavian artery arising proximal to the right subclavian artery.

Diagnosis

On barium esophagram, an oblique indentation running upward from right to left is present in the posterior wall of the esophagus.14 Its significance relative to symptoms of dysphagia and stridor depends on the position of the ductus arteriosus. Only in cases of a left-side ductus will symptoms occasionally occur due to the creation of a vascular ring, but even in this case most individuals are asymptomatic since the ring is usually loose. As with a right aortic arch with mirror-image branching, individuals with right aortic arch and aberrant left subclavian should be evaluated for the possibility of the 22q11.2 deletion (Shprintzen syndrome, velo-cardio-facial syndrome, DiGeorge syndrome) and CHARGE syndrome. Etiology and Distribution

This defect is less common than right aortic arch with mirrorimage branching. The vast majority of affected individuals have an associated cardiac defect, most of which include a VSD. Other defects have included transposition of the great arteries, tetralogy of Fallot, common atrioventricular canal, and cor triatriatum. Asplenia has not been noted, although it has been documented in right aortic arch with mirror-image branching.1 Sex ratio is equal. Like right aortic arch with mirror-image branching, this defect is due to a persistence of the right fourth pharyngeal arch artery; in this instance, however, the interruption of the left arch occurs between the left common carotid and the left subclavian. Prognosis, Treatment, and Prevention

When this defect is isolated, most affected individuals are asymptomatic, so treatment is rarely necessary. Prognosis is determined by the associated cardiac defect. Surgical division of the ligamentum arteriosum is recommended for patients with severe symptoms. Relief of symptoms frequently takes months following surgery. References (Right Aortic Arch) 1. Knight L, Edwards JE: Right aortic arch: types and associated cardiac defects. Circulation 50:1047, 1974. 2. Garti IJ, Aygen MM, Vidna B, et al.: Right aortic arch with mirrorimage branching causing vascular ring. A new classification of the right aortic arch patterns. Br J Radiol 46:115, 1973. 3. Moes CAF, Freedom RM: Rare types of aortic arch anomalies. Pediatr Cardiol 14:93, 1993. 4. van Son JA, Konstantinov IE: Burckhard F. Kommerell and Kommerell’s diverticulum. Tex Heart Inst J 29:109, 2002. 5. Achiron R, Rotstein Z, Heggesh J, et al.: Anomalies of the fetal aortic arch: a novel sonographic approach to in-utero diagnosis. Ultrasound Obstet Gynecol 20:553, 2002. 6. Celano V, Pieroni DR, Gingell RL, et al.: Two-dimensional echocardiographic recognition of the right aortic arch. Am J Cardiol 51:1507, 1983. 7. McElhinney DB, Hoydu AK, Gaynor JW, et al.: Patterns of right aortic arch and mirror-image branching of the brachiocephalic vessels without associated anomalies. Pediatr Cardiol 22:285, 2001. 8. McElhinney DB, Clark BJ III, Weinberg PM, et al.: Association of chromosome 22q11 deletion with isolated anomalies of aortic arch laterality and branching. J Am Coll Cardiol 37:2114, 2001. 9. Lin AE, Chin AJ, Devine W, et al.: The pattern of cardiovascular malformation in the CHARGE association. Am J Dis Child 14:1010, 1987. 10. Vissers L, Ravenswaaij C, Admiraal R, et al.: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36:955, 2004. 11. Cortez AB, Galindo A, Arensman FW, et al. Congenital heart disease associated with sporadic Kallmann syndrome. Am J Med Genet 46:551, 1993.

Systemic Vasculature 12. Kishnani P, Iafolla AK, McConkie-Rosell A, et al.: Hemangioma, supraumbilical midline raphe, and coarctation of the aorta with a right aortic arch: single causal entity? Am J Med Genet 59:44, 1995. 13. Lam J, Corno A, Oorthuys HW, et al.: Unusual combination of congenital heart lesions in a child with Noonan’s syndrome. Pediatr Cardiol 3:23, 1982. 14. Neuhauser EBD: The roentgen diagnosis of double aortic arch and other anomalies of the great vessels. AJR Am J Roentgenol 56:1, 1946.

3.3 Cervical Aortic Arch Definition

Cervical aortic arch is an aorta that ascends high in the mediastinum, above the clavicle and sometimes above the angle of the mandible. Sixty percent of cases are on the right side and connect either to a left-sided (80%) or right-sided (20%) descending thoracic aorta. Similarly, left-sided cervical aortic arch connects either to a left-sided (70%) or right-sided (30%) descending thoracic aorta.1 Depending on the laterality of the cervical aortic arch and the arrangement of the brachiocephalic vessels, Haughton classified cervical aortic arch into five main types.2 Diagnosis

This defect can present as a pulsatile mass in the cervical region, or with chest infection, headache, or murmur, or it can be discovered incidentally on chest radiograph.1 If the cervical arch and the thoracic aorta are contralateral, symptoms of tracheo-esophageal compression can occur because a vascular ring is formed by the retro-esophageal descending aorta, ligamentum arteriosum, and pulmonary artery. In those cases, a barium swallow reveals oblique compression posteriorly. The diagnosis is confirmed by computed tomography (CT), magnetic resonance imaging (MRI), or angiography. Etiology and Distribution

More than 125 cases have been reported in the world’s literature. There is a 2:1 female-to-male predominance in cases that come to medical attention. In the majority of cases, there is no associated intracardiac pathology, but when an intracardiac defect is present, it is almost always a VSD or conotruncal defect.3–5 There are several reports of cervical aortic arch, most of which are rightsided, in the 22q11.2 deletion syndrome.6–10 Right-sided cervical aortic arch is more likely to be associated with intracardiac pathology, whereas left-sided cervical aortic arch is more likely to be complicated by coarctation and/or aneurysm. There is a particularly striking association between Haughton’s class D cervical aortic arch and aneurysm. Various errors of morphogenesis of the pharyngeal arch arteries have been proposed to explain the development of the cervical aortic arch.11 Persistence of the right third pharyngeal arch artery and regression of the fourth pharyngeal arch arteries are presumed to account for most cases. Failure of inferior migration of the fourth pharyngeal arch artery12 and confluence of third and fourth pharyngeal arch arteries13 have been proposed to account for other cases. Prognosis, Treatment, and Prevention

Aneurysm formation14 and aortic dissection15 have been reported due to degenerative changes in the cervical aortic arch, even in

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children.16 The Haughton class D cervical aortic arch seems to be most prone to the development of aneurysmal dilation. Pathology of the aneurysmal tissue has shown cystic medial necrosis in several patients, including one known to have Marfan syndrome.15,17 Coarctation has occurred in several cases.18 References (Cervical Aortic Arch) 1. Bourdon JL, Hoeffel JC, Worms AM, et al.: The cervical aortic arch: a case with diffuse arterial dysplasia and neurocutaneous angiomatosis. Pediatr Radiol 10:143, 1981. 2. Haughton VM, Fellows KE, Rosenbaum AE: The cervical aortic arches. Radiology 114:675, 1975. 3. Takao R, Imamura H, Koga Y, et al.: Right-sided cervical aortic arch associated with tetralogy of Fallot and peculiar tortuosity of the descending aorta. Cardiovasc Radiol 2:51, 1979. 4. Patel KR, Hurwitz JL, Clauss RH: Cervical aortic arch associated with tetralogy of Fallot. Cardiovasc Surg 1:602, 1993. 5. Moncada R, Shannon M, Miller R, et al.: The cervical aortic arch. AJR Am J Roentgenol 125:591, 1975. 6. Kumar A, McCombs JL, Sapire DW: Deletions in chromosome 22q11 region in cervical aortic arch. Am J Cardiol 79:388, 1997. 7. Kazuma N, Murakami M, Suzuki Y, et al.: Cervical aortic arch associated with 22q11.2 deletion. Pediatr Cardiol 18:149, 1997. 8. Van Son JAM, Bossert T, Mohr FW: Surgical treatment of vascular ring including right cervical aortic arch. J Card Surg 14:98, 1999. 9. McElhinney DB, Thompson LD, Weinberg PM, et al.: Surgical approach to complicated cervical aortic arch: anatomic developmental and surgical considerations. Cardiol Young 10:212, 2000. 10. Walker T, Heinemann M-K, Nagy S, et al.: Right-sided cervical aortic arch with stenosis—treatment with an extra-anatomic bypass graft. Thorac Cardiov Surg 50:306, 2002. 11. DuBrow IW, Burman SO, Elias DO, et al.: Aortic arch in the neck. J Thorac Cardiovasc Surg 68:21, 1974. 12. Beavan TED, Fatti L: Ligature of aortic arch in the neck. Br J Surg 34:414, 1947. 13. D’Cruz IA, Cantez T, Namin EP, et al.: Right-sided aorta II: right aortic arch, right descending aorta, and associated anomalies. Br Heart J 28: 725, 1966. 14. Hirao K, Miyazaki A, Noguchi M, et al.: The cervical aortic arch with aneurysm formation. J Comput Assist Tomogr 23:959, 1999. 15. Cao P, Angelini P, Colonna L, et al.: Cervical aortic arch with mediocystic necrosis. Bull Texas Heart Inst 7:188, 1980. 16. Pearson GD, Kan JS, Neill CA, et al.: Cervical aortic arch with aneurysm formation. Am J Cardiol 79:112, 1997. 17. Wei C, Okabe M, Ooi T, et al.: Cervical aortic arch associated with aortic kinking and aneurysm. Nippon Kyobu Geka Gakkai Zasshi 31: 2202, 1983. 18. Tsukamoto O, Seto S, Moriya M, et al.: Left cervical aortic arch associated with aortic aneurysm, aortic coarctation, and branch artery aneurysm: a case report and review. Angiology 54:257, 2003.

3.4 Double Aortic Arch Definition

Double aortic arch is a splitting of the ascending aorta into two segments, which pass on either side of the esophagus and trachea and join together as a single descending aorta (Fig. 3-4). In the most common variation, both aortic arch segments are patent, the right (posterior) segment is larger than the left (anterior) segment, and the ductus and descending aorta are left-sided. Less frequently, one arch, usually the left (anterior) arch, is represented only by a cord.

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obstruction, and transection of the posterior arch (distal to the right carotid artery) with anterior translocation and end-to-side re-anastomosis to the ascending aorta has been required.14 When the dominant segment is anterior, division of the posterior arch and the ligamentum arteriosum is indicated. Prognosis is generally good. Dysphagia is often relieved immediately by the surgery; respiratory symptoms usually resolve within 1 month of surgery. However, frequent respiratory illness, persistent cough, stridor, and pneumonia occur intermittently in a significant number of patients. Twenty-seven percent of a group of 48 patients were hospitalized for respiratory distress 1 month to 3 years after surgery.15 Aorto-esophageal fistula is a rare and catastrophic complication.16 References (Double Aortic Arch)

Fig. 3-4. Schematic of a double aortic arch, with both segments patent and giving rise to major aortic arch arteries. Other variations occur in which one segment is atretic.

Diagnosis

Symptoms consisting of stridor, dysphagia, nonproductive cough, and hoarse cry develop soon after birth in the most severe cases.1 In one study of 24 patients, mean age of diagnosis was 1 year, with a range from 7 days to 10 years.2 The severity and onset of symptoms depend on the space between the aortic segments. Diagnosis has been delayed until adulthood, in which case dysphagia is the most common symptom.3–5 Stridor is usually worsened by eating. Bronchopneumonia secondary to aspiration is the major cause of death. The diagnosis can be made by chest radiography and barium esophagram6 and confirmed with CT and MRI.7,8 Rarely is angiography necessary. Etiology and Distribution

Double aortic arch arises because of persistence of the fourth right pharyngeal arch artery.9 The failure of dissolution of the right fourth pharyngeal arch artery leads to compression of the esophagus and trachea between the two segments of the split ascending aorta. Although the defect is most frequently seen as an isolated defect in an otherwise normal individual, it has been associated with 22q11.2 deletion syndrome10,11; the frequency of the 22q11.2 deletion is higher if there is an atretic left (anterior) segment.11 Prenatal diagnosis of this defect was recently accomplished for the first time.12 Shirali et al. reported the only case of double aortic arch with bilateral patent ducti arteriosi in a newborn who had transposition of the great arteries.13 Prognosis, Treatment, and Prevention

The goal of treatment is to alleviate tracheal obstruction and esophageal compression and prevent the long-term complications of aneurysmal dilation, traumatic rupture, and hemoptysis due to erosion into the esophagus or trachea. If, as is usually the case, the major arch is posterior, division of the anterior arch is usually performed between the left common carotid and left subclavian arteries or distal to the left subclavian artery. Occasionally, leaving the posterior arch in its native position does not correct airway

1. Wolman I: Syndrome of constricting double aortic arch in infancy. J Pediatr 14:527, 1939. 2. Lincoln J, Deverall P, Stark J, et al.: Vascular anomalies compressing the oesophagus and trachea. Thorax 24:295, 1969. 3. Ito K, Kogure T, Hayashi S, et al.: A case of the incomplete double aortic arch diagnosed in adulthood by MR imaging. Radiat Med 13:263, 1995. 4. Brockes C, Vogt PR, Roth TB, et al.: Double aortic arch: diagnosis missed for 29 years. Vasa 29:77, 2000. 5. Stoica SC, Lockowandt U, Coulden R et al.: Double aortic arch masquerading as asthma for thirty years. Respiration 69:92, 2002. 6. Neuhauser E: The roentgen diagnosis of double aortic arch and other anomalies of the great vessels. AJR Am J Roentgenol 56:1, 1946. 7. Jaffe RB: Radiographic manifestations of congenital anomalies of the aortic arch. Radiol Clin North Am 29:319, 1991. 8. Lowe GM, Donaldson JS, Backer CL: Vascular rings: 10-year review of imaging. Radiographics 11:637, 1991. 9. Gross R, Ware P: The surgical significance of aortic arch anomalies. Surg Gynecol Obstet 83:435, 1946. 10. Schreiber C, Tsang VT, Yates R, et al.: Common arterial trunk associated with double aortic arch. Ann Thorac Surg 68:1850, 1999. 11. McElhinney DB, Clark BJ III, Weinberg PM, et al: Association of chromosome 22q11 deletion with isolated anomalies of aortic arch laterality and branching. J Am Coll Cardiol 37:2114, 2001. 12. Achiron R, Rotstein Z, Heggesh J, et al.: Anomalies of the fetal aortic arch: a novel sonographic approach to in-utero diagnosis. Ultrasound Obstet Gynecol 20:553, 2002. 13. Shirali GS, Geva T, Ott DA, et al.: Double aortic arch and bilateral patent ducti arteriosi associated with transposition of the great arteries: missing clinical link in an embryologic theory. Am Heart J 127:451, 1994. 14. Sebening C, Jakob H, Tochtermann U, et al.: Vascular tracheobronchial compression syndromes: experience in surgical treatment and literature review. Thorac Cardiov Surg 48:164, 2000. 15. Marmon L, Bye M, Haas J, et al.: Vascular rings and slings: long-term follow-up of pulmonary function. J Pediatr Surg 19:683, 1984. 16. Hill JG, Munden M: Aorto-oesophageal fistula associated with double aortic arch. Clin Radiol 54:847, 1999.

3.5 Double-Lumen Aortic Arch Definition

Double-lumen aortic arch is a splitting of the ascending aorta into two parallel segments, both of which pass anterior to the trachea on their transverse course. Two anatomic variants have been described.1 In the first, a smaller additional channel runs inferiorly along the transverse aortic arch proper from the level of the innominate artery to the level of the left subclavian artery (systemic-to-systemic

Systemic Vasculature

connection), creating a double-lumen aorta with no functional significance. In the second variant, the additional channel connects to a derivative of the embryonic sixth arch, forming a systemic-topulmonary connection. In the setting of pulmonary atresia, this accessory lumen supplies blood to the lungs and may be misdiagnosed as the ductus arteriosus. Diagnosis

This defect is recognizable by echocardiography, MRI, or angiography, demonstrating two arches passing on the same side of the trachea in parallel. It is not uncommon for the double-lumen aortic arch to be missed by echocardiography and even surgical inspection. The diagnosis is often made in the course of evaluation of an associated cardiac defect. Histologically, the two lumina have separate adventitial layers, but on direct inspection the aortic isthmus can simply appear unusually wide, sometimes with a linear dimple in its center. Etiology and Distribution

Double-lumen aortic arch arises because of persistence of the fifth pharyngeal arch artery. Formerly the subject of much controversy, the existence of the fifth pharyngeal arch artery in humans is gaining acceptance as a growing number of cases without a plausible alternative embryologic basis accumulate. The apparent rarity of this defect is due to failure of recognition and may have a true incidence of 1 in 330 individuals.1 The first recognized case of double-lumen aortic arch was described in 1969.2 The vast majority of cases are discovered because of the presence of an associated cardiac defect (cor triatriatum,2 interrupted aortic arch type A,3 coarctation,4,5 transposition of the great arteries with pulmonary valve stenosis and VSD,6 truncus arteriosus,7 tetralogy of Fallot,1,8,9 pulmonary atresia and VSD,10 secundum atrial septal defect,11 and patent ductus arteriosus and aberrant right subclavian artery12). This defect can occur on the right side if the right fourth and fifth pharyngeal arch arteries persist.13 One case of bilateral persistent fifth pharyngeal arch arteries has been reported.14 Persistent fifth aortic arch has been reported in monosomy for 22q11.15,16 There is one report of this anomaly occurring in a patient who was exposed to trimethadione during gestation.12 This association may be spurious, as this patient, who had an aberrant subclavian artery and patent ductus arteriosus in addition to the double-lumen aortic arch, has facial characteristics suggesting the 22q11.2 deletion syndrome as a potential diagnosis. Persistence of the left fifth pharyngeal arch artery and regression of the left fourth pharyngeal arch artery was offered as the embryologic basis of a single arterial trunk arising from a left aortic arch observed by Pearl.17

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2. Van Praagh R, van Praagh S: Persistent fifth arterial arch in man: congenital double-lumen aortic arch. Am J Cardiol 24:279, 1969. 3. Da Costa AG, Iwahashi ER, Atik E, et al.: Persistence of hypoplastic and recoarcted fifth aortic arch associated with type A aortic arch interruption: surgical and balloon angioplasty results in an infant. Pediatr Cardiol 13:104, 1992. 4. Lambert V, Blaysat G, Sidi D, et al.: Double-lumen aortic arch by persistence of fifth aortic arch: a new case associated with coarctation. Pediatr Cardiol 20:167, 1999. 5. Gibbin CL, Midgley FM, Potter BM, et al.: Persistent left fifth aortic arch with complex coarctation. Am J Cardiol 67:319, 1991. 6. Herrera MA, D’Souza VJ, Link KM, et al.: A persistent fifth aortic arch in man: a double-lumen aortic arch (presentation of a new case and review of the literature). Pediatr Cardiol 8:265, 1987. 7. Lim C, Kim W-H, Kim S-C, et al.: Truncus arteriosus with coarctation of persistent fifth aortic arch. Ann Thorac Surg 74:1702, 2002. 8. Donti A, Soavi N, Sabbatani P, et al.: Persistent left fifth aortic arch associated with tetralogy of Fallot. Pediatr Cardiol 18:229, 1997. 9. Marinho-da-Silva AJ, Sa´-e-Melo AM, Provideˆncia LA: True double aortic lumen in tetralogy of Fallot. Int J Cardiol 63:117, 1998. 10. Yoo S-JY, Moes CAF, Burrows PE, et al.: Pulmonary blood supply by a branch from the distal ascending aorta in pulmonary atresia with ventricular septal defect: differential diagnosis of fifth aortic arch. Pediatr Cardiol 14:230, 1993. 11. Geva T, Ray RA, Santini F, et al.: Asymptomatic persistent fifth aortic arch (congenital double-lumen aortic arch) in an adult. Am J Cardiol 65:1406, 1990. 12. Lawrence T-YK, Stiles QR: Persistent fifth aortic arch in man. Am J Dis Child 129:1229, 1975. 13. Boothroyd AE, Walsh KP: The fifth aortic arch: a missing link? Pediatr Radiol 29:52, 1999. 14. Wang J-N, Wu J-M, Yang Y-J: Double-lumen aortic arch with anomalous left pulmonary artery origin from the main pulmonary artery—bilateral persistent fifth aortic arch: a case report. Int J Cardiol 69:105, 1999. 15. Lee M-L, Chiu I-S, Fang W, et al.: Isolated infundibuloarterial inversion and fifth aortic arch in an infant: a newly recognized cardiovascular phenotypes [sic] with chromosome 22q11 deletion. Int J Cardiol 71:89, 1999. 16. Lee M-L, Tsao L-Y, Wang B-T, et al.: Maternally inherited unbalanced translocation of chromosome 22 in a 5-day-old neonate with persistent fifth aortic arch and tetralogy of Fallot. Int J Cardiol 90:337, 2003. 17. Pearl WR: Single arterial trunk arising from the aortic arch: evidence that the fifth branchial arch can persist as the definitive aortic arch. Pediatr Radiol 21:518, 1991. 18. Gerlis LM, Dickinson DF, Wilson N, et al.: Persistent fifth aortic arch. A report of two new cases and a review of the literature. Int J Cardiol 16:185, 1987. 19. Einzig S, Steelman R, Pyles LA, et al.: Radiological case of the month. Arch Pediatr Adolesc Med 151:1259, 1997.

Prognosis, Treatment, and Prevention

3.6 Incidental Anomalies of the Aortic Arch

When there is no associated cardiac defect, persistent fifth aortic arch (systemic-to-systemic connection) is asymptomatic. Coarctation of one or both segments of the double-lumen aortic arch is often repaired by anastomosis of the two lumens to create a larger channel.4 Prognosis is determined by the associated cardiac defect, if any. Associated noncardiac malformations, including tracheo-esophageal fistula, imperforate anus, hemivertebrae, hypoplastic left thumb, absent kidney, and cystic kidney, have been reported in at least two cases.18,19

The usual sequence of branching from the aortic arch is the right innominate, left common carotid, and left subclavian arteries; but occasionally the innominate and left common carotid arteries arise together as a brachiocephalic trunk (Fig. 3-5). Origin of the left vertebral artery between the left common carotid and left subclavian arteries is another variation that typically causes no symptoms.1

References (Double-Lumen Aortic Arch)

Reference (Incidental Anomalies of the Aortic Arch)

1. Gerlis LM, Ho, SY, Anderson RH, et al.: Persistent fifth aortic arch—a great pretender: three new covert cases. Int J Cardiol 23:239, 1989.

1. Jaffe RB: Radiographic manifestations of congenital anomalies of the aortic arch. Radiol Clin N Amer 29:319, 1991.

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aortic arch, or aberrant branching with the left subclavian artery arising as the fourth main branch (see section 3.2). Rarely, the innominate artery arises aberrantly as the third branch, after the right common carotid and right subclavian arteries, from the distal right aortic arch, passing upward and to the left behind the esophagus before giving rise to the left common carotid and left subclavian arteries.4,5 The ductus arteriosus persists on the left, connecting the aberrant artery to the left pulmonary artery and creating a vascular ring. Dysphagia can result from the posterior compression on the esophagus. A lateral esophagram demonstrates a large posterior impression. 3.7.3 Isolated Innominate Artery Definition Fig. 3-5. Schematic of an anomalous innominate artery, with the left common carotid arising from a brachiocephalic artery, which is positioned to the left of the trachea.

3.7 Innominate Artery Variants

An isolated innominate artery is an innominate artery that does not originate from the aorta, but communicates with the pulmonary trunk via a patent ductus arteriosus. This rare anomaly was described first in 1966 by D’Cruz et al.6 and Levine et al.,7 and no more than 15 additional cases have been reported. Most isolated innominate arteries are left-sided with right-sided aortic arch. Diagnosis

3.7.1 Compression by the Innominate Artery Definition

Compression by the innominate artery, in which the trachea is compressed by the innominate (brachiocephalic) artery, is not a true anomaly, since the innominate artery originates partially or completely to the left of the trachea and crosses anteriorly to it in the majority of individuals. Diagnosis

Indentation of the trachea has been noted in 30% of normal children and in 71% of patients with congenital heart disease.1 In some cases, compression of the trachea leads to cough, stridor, and occasionally apnea, cyanosis, and pneumonia.1 A lateral plain chest film may show a curvilinear, constant, anterior tracheal narrowing midway between the carina and the sternal notch.2 However, in a series of 13 symptomatic patients with compression by the innominate artery, only four were identified with anterior tracheal indentation on chest radiograph and all had normal esophagrams; tracheobronchoscopy or aortography demonstrated the compression in the remainder.3 Prognosis, Treatment, and Prevention

In the past, symptomatic patients were treated with aortic suspension (suturing the aorta to the sternum without dissecting the vessel away from the trachea, thereby opening the lumen of the airway), but currently most patients are managed non-operatively. Symptoms resolve gradually, and patients are usually asymptomatic by age 1.5 years.1 Surgery should be reserved for those infants with severe stridor, wheezing, cyanosis, recurrent pneumonia, atelectasis, or any episode of apnea.3 3.7.2 Aberrant Left Innominate Artery

In the setting of a right aortic arch, the arterial branching pattern is usually mirror-image branching of that seen in normal left

Most cases have been discovered in the course of evaluating for co-existing intracardiac pathology. If the ductus arteriosus obliterates, the blood supply to the isolated artery is usually via vertebral and collateral arteries, and Doppler echocardiography may be able to demonstrate reversal of flow in the vertebral artery. When contrast is injected into the aortic arch during cardiac catheterization, the innominate artery shows delayed opacification via vertebral and collateral arteries. The diagnosis should be suspected in any patient with a right aortic arch and diminished pulses or blood pressure in the left arm. Patients can present with symptoms such as claudication of the left arm or syncope due to reversal of flow in the left carotid and vertebral arteries.8 Etiology and Distribution

Most cases are seen in association with other aortic arch or cardiac anomalies. At least one case of 22q11.2 deletion syndrome with right (cervical) aortic arch and isolated innominate artery has been reported.9 Isolated innominate artery has been seen once in Down syndrome,10 CHARGE syndrome,11 and with a complex cardiac defect accompanying a disturbance of laterality.12 Miyaji et al. have encountered a left aortic arch with isolated innominate artery that arose from the right pulmonary artery in a child with DiGeorge syndrome.13 Prognosis, Treatment, and Prevention

Patients with symptoms suggesting central nervous system vascular insufficiency or left arm claudication may require reimplantation of the isolated artery into the aorta to diminish steal from the cerebral circulation. If the innominate artery is connected to the pulmonary artery via a patent ductus arteriosus, ligation of the duct will prevent pulmonary steal and may be sufficient.10 References (Innominate Artery Variants) 1. Strife JL, Baumel AS, Dunbar JS: Tracheal compression by innominate artery in infancy and childhood. Pediatr Radiol 139:73, 1981.

Systemic Vasculature 2. Berdon WE, Baker DH, Borkink J, et al.: Innominate artery compression of the trachea in infants with stridor and apnea: method of Roentgen diagnosis and criteria for surgical treatment. Radiology 92: 272, 1969. 3. Bertolini A, Pelizza A, Panizzon G, et al.: Vascular rings and slings: diagnosis and surgical treatment of 49 patients. J Cardiovasc Surg 28: 301, 1987. 4. Grollman JH, Bedynek JL, Henderson HS, et al.: Right aortic arch with aberrant retroesophageal innominate artery: angiographic diagnosis. Radiology 90:782, 1968. 5. Garti IJ, Aygen MM: Right aortic arch with aberrant left innominate artery. Pediatr Radiol 8:48, 1979. 6. D’Cruz JA, Cantez T, Namin EP, et al.: Right aortic arch, right descending aorta, and associated anomalies. Br Heart J 28:725, 1966. 7. Levine S, Serfas LS, Rusinko A: Right aortic arch with subclavian steal syndrome (atresia of left common carotid and left subclavian arteries). Am J Surg 111:632, 1966. 8. Singh B, Satyapal KS, Moodley J, et al.: Right aortic arch with isolated left brachiocephalic artery. Clin Anat 12:47, 2001. 9. Duke C, Chan KC: Isolated innominate artery in 22q11 microdeletion. Pediatr Cardiol 22:80, 2001. 10. Kaku S, Pinto F, Lima M: Isolation of the left brachiocephalic artery associated with right aortic arch and left-sided arterial duct. Cardiol Young 6:239, 1996. 11. Fong LV, Venables AW: Isolation of the left common carotid or left innominate artery. Br Heart J 57:552, 1987. 12. Papagiannis J, Kanter RJ, Vander Heide RS, et al.: Isolated innominate artery in asplenia syndrome with aortic atresia: newly recognized cardiovascular complex. Am Heart J 131:1042, 1996. 13. Miyaji K, Hannan RL, Burke RP: Anomalous origin of innominate artery from right pulmonary artery in DiGeorge syndrome. Ann Thorac Surg 71:2043, 2001.

3.8 Subclavian Artery Variants 3.8.1 Aberrant Right Subclavian Artery Definition

Aberrant right subclavian artery is origination of the right subclavian artery below the left subclavian artery as the fourth main branch of the left-sided aortic arch (Fig. 3-6). Rarely, a common

Fig. 3-6. Schematic of an aberrant right subclavian artery arising distal to the left subclavian artery.

129

carotid trunk gives rise to both right and left common carotid arteries, in which case the aberrant right subclavian artery is the third main branch of the aortic arch.1 The aberrant right subclavian artery courses obliquely upward to the right and passes posterior to the esophagus in the majority of cases. Occasionally it passes anterior to the esophagus (as in the first case described in association with dysphagia by Bayford in 1794),2 between the trachea and esophagus, and very rarely it passes anterior to both structures. Diagnosis

The majority of individuals with aberrant right subclavian artery never develop symptoms. For those who do, difficulty in swallowing, referred to as dysphagia lusoria,2,3 generally has its onset in adulthood. Other presenting complaints include shortness of breath, chest pain, swelling of the right side of the neck, cough, hoarseness, vertigo, and Horner syndrome.4 However, children with a history of slow feeding, gagging, and vomiting since infancy5–7 and airway symptoms8 have been reported. Barium esophagram is the most helpful study in documenting this abnormality. The lateral view reveals a small posterior esophageal indentation, while the oblique course of the vessel is demonstrated in the frontal view. Echocardiography, CT, magnetic resonance angiography, and digital subtraction angiography have also been used to identify this defect. Etiology and Distribution

An aberrant right subclavian artery is the most common aortic arch anomaly, occurring in 0.5–1.8% of the general population.9 Usually it represents a single anomaly of the aortic arch, but can be combined with coarctation, interruption, or a right-sided arch. Females predominate over males in instances of isolated aberrant right subclavian artery and in cases of aortic coarctation with pre-stenotic aberrant right subclavian artery.9 Male predominance was found in cases of aortic coarctation with post-stenotic aberrant right subclavian artery. An equal sex distribution was observed for aberrant right subclavian artery with interruption of the aortic arch.9 Although usually the aberrant artery represents an isolated defect of the aortic arch, when it is associated with other aortic arch abnormalities or additional cardiovascular malformations, visceral anomalies should be sought. In an autopsy study, Molz and Burri documented noncardiac anomalies in one-third of cases, including esophageal atresia, tracheo-esophageal fistula, abnormalities of lung lobation, anal atresia, gall bladder agenesis, asplenia, double uterus and vagina, renal anomalies, and sacral spina bifida.9 As with other aortic arch abnormalities, 22q11.2 deletion syndrome should be considered in patients with aberrant right subclavian artery.10 Prognosis, Treatment, and Prevention

With a minimum incidence in 1 in 200 persons,11 aberrant right subclavian artery is asymptomatic in the vast majority. For symptomatic individuals, surgery is the treatment of choice for infants and children. Because coexistent esophageal pathology (motility disturbance, sliding hiatal hernia) is common in adults, a trial of prokinetic or antireflux medications is warranted.12 If symptoms persist, surgical correction should be considered. The majority of symptomatic patients will benefit from surgical correction.12 A case can be made for repair of incidentally discovered lesions because of the risk of aneurysm, rupture, or erosion into adjacent structures. Division of the subclavian artery can result in upper limb ischemia and subclavian steal, so techniques to maintain continuity of the

130

Cardiorespiratory Organs

right subclavian artery are preferred.4 The most common technique employed is end-to-side anastomosis to the right carotid artery.12 3.8.2 Aberrant Left Subclavian Artery

This anomaly is discussed in section 3.2.2. 3.8.3 Isolated Subclavian Artery Definition

An isolated subclavian artery is a subclavian artery that does not originate from the aorta. This anomaly can occur on the right with a left-side aortic arch or on the left with a right-side aortic arch.13 The isolated subclavian artery is connected to the ipsilateral pulmonary artery by a ductus arteriosus, which may or may not remain patent. There is a high frequency of bilateral ductus arteriosus, as in the first known report by Ghon.14 If the ductus arteriosus on the side of the isolated subclavian artery remains patent, once the pulmonary vascular resistance falls, flow reverses in the subclavian artery, and collateral supply develops. In the case of a closed ductus arteriosus on the side of the subclavian artery, the subclavian artery is supplied by collateral vessels, usually the vertebral artery. Diagnosis

Differential amplitude of upper limb pulses are a clue to the diagnosis, but this sign may not always be present.15 This anomaly can present in children with symptoms of airway or esophageal compression.8 Adults may have arm claudication if collateral supply is insufficient, or the subclavian steal phenomenon, in which the reversal of flow through the collateral vertebral–basilar arterial system results in syncope or transient cerebral ischemia. Barium esophagraphy is normal. Helical CT and MRI are both adequate to detect this anomaly.8 Definitive demonstration by aortography is the investigation of choice. Etiology and Distribution

Isolated subclavian artery is thought to be an uncommon anomaly, although true incidence is unknown because cases may go unrecognized. Most reported cases of left-sided isolation of the subclavian artery and right aortic arch have been associated with intracardiac malformations, most commonly tetralogy of Fallot.15,16 This anomaly has been seen with Goldenhar syndrome,15 disturbances of laterality,15 and in a patient with multiple anomalies that could have represented the 22q11.2 deletion syndrome.16 Prognosis, Treatment, and Prevention

Prognosis is usually determined by the associated intracardiac malformation. The anatomy of the subclavian artery is particularly significant if the cardiac malformation is being palliated with a Blalock-Taussig shunt, as shunting is usually performed on the side contralateral to the arch.15 When the ductus arteriosus is patent, there is potential for pulmonary overcirculation. References (Subclavian Artery Variants) 1. Moes CAF, MacDonald C, Mawson JB: Left innominate vein compression by a brachiocephalic artery anomaly. Pediatr Cardiol 16:291, 1995. 2. Bayford D: An account of a singular case of obstructed deglutition. Mem Med Soc London 2:274, 1794.

3. Asherson N: David Bayford. His syndrome and sign of dysphagia lusoria. Ann R Coll Surg Engl 61:63, 1979. 4. Austin EH, Wolfe WG: Aneurysm of aberrant subclavian artery with a review of the literature. J Vasc Surg 2:571, 1985. 5. Martin GR, Rudolph C, Hillemeier C, et al.: Dysphagia lusorum in children. Am J Dis Child 140:815, 1986. 6. Roberts CS, Othersen HB Jr, Sade RM, et al.: Tracheoesophageal compression from aortic arch anomalies: analysis of 30 operatively treated children. J Pediatr Surg 29:334, 1994. 7. Berdon WE, Baker DH: Vascular anomalies and the infant lung: rings, slings and other things. Semin Roentgenol 7:39, 1972. 8. Donnelly LF, Fleck RJ, Pacharn P, et al.: Aberrant subclavian arteries: cross-sectional imaging finding in infants and children referred for evaluation of extrinsic airway compression. AJR Am J Roentgenol 178: 1269, 2002. 9. Molz G, Burri B: Aberrant subclavian artery (arteria lusoria): sex differences in the prevalence of various forms of the malformation. Evaluation of 1378 observations. Virchows Arch A Pathol Anat Histol 380:303, 1978. 10. McElhinney DB, McDonald-McGinn D, Zackai EH, et al.: Cardiovascular anomalies in patients diagnosed with a chromosome 22q11 deletion beyond 6 months of age. Pediatrics 108:e104, 2001. 11. Stewart JR, Kincaid OW, Edwards JE: An Atlas of Vascular Rings and Related Malformations of the Aortic Arch System. Charles C. Thomas, Springfield, IL, 1964. 12. Janssen M, Baggen MGA, Veen HF, et al.: Dysphagia lusoria: clinical aspects, manometric findings, diagnosis and therapy. Am J Gastroenterol 95:1411, 2000. 13. Moes CAF, Freedom RM: Rare types of aortic arch anomalies. Pediatr Cardiol 14:93, 1993. 14. Ghon A: Uber eine seltene Entwicklungsstorung des Gefass-systems. Verh Dtsch Ges Pathol 12:242, 1908. 15. Nath PH, Castaneda-Zuniga W, Zollikofer C, et al.: Isolation of a subclavian artery. AJR 137:683, 1981. 16. McMahon CJ, Thompson KS, Kearney DL, et al.: Subclavian steal syndrome in anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries. Pediatr Cardiol 22:60, 2001.

3.9 Patent Ductus Arteriosus Definition

Patent ductus arteriosus (PDA) is lack of closure of the ductus arteriosus in full-term infants. The ductus arteriosus normally closes from a functional standpoint soon after birth, although anatomic obliteration does not take place until a few weeks postnatally. The ductus is usually on the left, connecting the main pulmonary trunk with the descending aorta just distal to the origin of the left subclavian artery. However, in cases of right aortic arch, it may be on the right side, and rarely it is bilateral. This discussion excludes persistent patency in premature infants due to normal physiologic delay in closure. As opposed to preterm ductus in which the structural anatomy is normal, PDA in the term infant shows deficiency of the mucoid endothelial layer and the muscular media.1 Diagnosis

Although a small ductus is not usually associated with symptoms, a large PDA results in distinctive clinical signs, which are usually diagnostic. These include a wide pulse pressure with water-hammer arterial pulses, and a machinery-like murmur, which begins soon after the first heart sound, reaches maximum intensity at the end of

Table 3-2. Syndromes associated with patent ductus arteriosus Syndrome

Prominent Features

Causation

Down6

Flat face with upward-slanting palpebral fissures, small ears, hypotonia, atrioventricularis communis

Chromosomal

Trisomy 187

Clenched hands, short sternum, low arch dermal ridge patterning on fingertips

Chromosomal

Trisomy 137

Defects of eye, nose, lip, and forebrain; holoprosencephaly; polydactyly; skin defects of posterior scalp

Chromosomal

XXXXX8

Upward-slanting palpebral fissures, small hands, fifth finger clinodactyly

Chromosomal

XXXY and XXXXY9

Hypogenitalism, limited elbow pronation, low dermal ridge count on finger tips

Chromosomal

Deletion 1p3610

Hypotonia, mental retardation, deeply set eyes, cardiomyopathy, sensorineural hearing impairment

Del 1p36

Deletion 4p11

Growth deficiency, microcephaly, ocular hypertelorism, short upper lip and philtrum, downturned corners of mouth, cleft lip/palate

Del 4p

Deletion 9p12

Craniosynostosis and trigonocephaly, upward-slanting palpebral fissures, hypoplastic supraorbital ridges

Del 9p

DiGeorge13

Hypoparathyroidism, thymic hypoplasia, aortic arch anomalies, conotruncal cardiac defects, cleft palate

Del 22q11.2

Alagille (arteriohepatic dysplasia)14

Cholestasis, peculiar facies, peripheral pulmonic stenosis

AD (118450) JAG1, 20p12

Carpenter15

Acrocephaly, polydactyly and syndactyly of feet, lateral displacement of medial canthi

AR (201000)

Char16

Broad forehead, ptosis, thick lips, short nose with broad tip, 5th finger clinodactyly

AD (169100) TFAP2B, 6p12

CHARGE27

Coloboma, choanal atresia, genital defects, ear anomalies

AD (214800) CHD7, 8q12.1

Hay-Wells15

Ankyloblepheron, ectodermal dysplasia, cleft lip/palate

AD (106260) TP73L, 3q27

Holt-Oram17

Upper limb defect, narrow shoulders, atrial septal defect

AD (142900) TBX5, 12q24.1

Lymphedema-distichiasis18

Lymphedema, double row of eyelashes, cleft palate

AD (153400) FOXC2, 16q24.3

Meckel-Gruber15

Encephalocele, polydactyly, cystic dysplasia of kidneys

AR (249000) 11q13, 8q24, 15q24

Mowat-Wilson19

Hirschsprung disease, microcephaly, seizures, pointed chin, deeply set eyes

AR (235730) SIP1, 2q22

Neu-Laxova15

Microcephaly/lissencephaly, exophthalmos, absent eyelids, subcutaneous edema, syndactyly

AR (256520)

Noonan20

Neck webbing, pectus excavatum, cryptorchidism, pulmonic stenosis

AD (163950) PTPN11, 12q24.1

Rubinstein-Taybi21

Short stature, mental retardation, broad thumbs and toes, downward slanting palpebral fissures

AD (180849) CREBBP, 16p13.3

Cytogenetic Abberrations

Genetic Syndromes

Teratogenic Abnormalities

Diabetes22

Various major malformations

Maternal diabetes

Hydantoin15

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoins

Rubella23

Microcephaly, deafness, cataracts

Prenatal rubella infection

Broad nasal bridge, short nose, meningomyelocele

Prenatal exposure to valproic acid

Valproate

24

(continued)

131

132

Cardiorespiratory Organs Table 3-2. Syndromes associated with patent ductus arteriosus (continued) Syndrome

Prominent Features

Causation

Coffin-Siris25

Hypoplastic finger and toenails, coarse facies, sparse scalp hair

Unknown AR (135900)

Facio-auriculo-vertebral spectrum26

Ear anomalies, mandibular hypoplasia, vertebral defects

Unknown

VACTERL association28

Vertebral anomalies, anal atresia, tracheo-esophageal fistula, renal anomalies, radial ray anomalies

Unknown

Syndromes of Unknown Cause

systole, and decreases in late diastole. A prominent pulmonary artery with increased pulmonary vascular markings is commonly seen on chest radiograph. An ECG shows evidence of left ventricular hypertrophy. An echocardiogram usually reveals an enlarged left atrium and ventricle in addition to the PDA. Cardiac catheterization is confirmatory.1 Etiology and Distribution

PDA is a relatively common defect, frequently occurring in association with other congenital heart defects. As an isolated defect, a clinically significant PDA occurs in about 1 in 10,000 live births.2,3 Silent PDA, a tiny ductus that is not detected by auscultation but found incidentally during echocardiography done for another purpose, may have an incidence of 1 in 500 to 1 in 1000 live births.3 In the New England Regional Infant Cardiac Program (1969–1974), there was a 2:1 female-to-male ratio,2 but the Baltimore–Washington Infant Study did not find a statistically significant deviation of the sex ratio.4 PDA is heterogeneous in etiology. It is often seen as an isolated defect in an otherwise normal individual. As an isolated defect, it has been seen in multiple generations of a family, suggesting autosomal dominant inheritance. However, for the majority of isolated cases, a multifactorial etiology is implied. In a population-based study of congenital heart defects,5 among 22 probands with PDA, 1 of 13 siblings (7.7%) also had a PDA. Frequently PDA is seen as one feature of a multiple malformation syndrome (Table 3-2).6–28 Teratogenic, chromosomal, and single-gene (both dominant and recessive) etiologies can be associated with PDA. For the majority of these syndromes, PDA is only an occasional defect. However, for some, such as rubella embryopathy, Char syndrome, or the XXXXX syndrome, PDA is the most common cardiac defect. The ductus arteriosus is derived from the sixth left aortic arch. The mechanisms responsible for normal postnatal closure of the ductus are not completely known, nor are the factors that maintain patency. However, its association with flow-related cardiac defects and its frequent association with intrauterine rubella, an agent that compromises development of arterial walls, indicate that patency of the ductus is significantly determined by blood flow. Prognosis, Treatment, and Prevention

Because of the pressure differential between the aorta and pulmonary artery, PDA is associated with high-velocity flow that poses a risk for bacterial endocarditis and pulmonary vascular occlusive disease. For five decades, the treatment of PDA has been surgical ligation and division through a posterolateral tho-

racotomy, with minimal morbidity and mortality in those patients who have not developed irreversible pulmonary vaso-occlusive disease. Small to moderately large PDAs are now routinely treated with trans-catheter coil closure,29,30 which has the advantages of being minimally traumatic and performed as an ambulatory procedure. Large PDAs, or those without a constricting area to trap the coil, can be approached with video-assisted thoracoscopic surgery. References (Patent Ductus Arteriosus) 1. Moore P, Brook MM, Heymann MA: Patent ductus arteriosus. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 652. 2. Fyler DC, Buckley LP, Hellenbrand WE, et al.: Report of the New England Regional Infant Cardiac Program. Pediatrics 65(Suppl):375, 1980. 3. Hoffman JIE, Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol 39:1890, 2002. 4. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations. The Baltimore-Washington Infant Study 1981-1989. Futura, New York, 1997. 5. Boughman HA, Berg KA, Astemborski JA, et al.: Familial risk of congenital heart defect assessed in a population-based epidemiologic study. Am J Med Genet 26:839, 1987. 6. Freeman SB, Taft LF, Dooley KJ, et al.: Population-based study of congenital heart defects in Down syndrome. Am J Med Genet 80:213, 1998. 7. Musewe NN, Alexander DJ, Teshima I, et al.: Echocardiographic evaluation of the spectrum of cardiac anomalies associated with trisomy 13 and trisomy 18. J Am Coll Cardiol 15:673, 1990. 8. Kassai R, Hamada I, Furuta H, et al.: Penta X syndrome: a case report with review of the literature. Am J Med Genet 40:51, 1991. 9. Karsh RB: Congenital heart disease in 49, XXXXY syndrome. Pediatrics 56:462, 1975. 10. Heilstedt HA, Ballif BC, Howard LA, et al.: Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am J Hum Genet 72:1200, 2003. 11. Su PH, Kuo PL, Chen SJ, et al.: De novo 4p-syndrome with oligohydramnios sequence. J Formos Med Assoc 102:647, 2003. 12. Huret JL, Leonard C, Forestier B, et al.: Eleven new cases of del(9p) and features from 80 cases. J Med Genet 25:741, 1988. 13. McElhinney DB, McDonald-McGinn D, Zackai EH, et al.: Cardiovascular anomalies in patients diagnosed with a chromosome 22q11 deletion beyond 6 months of age. Pediatrics 108:E104, 2001. 14. Harris M, Cao QL, Waight D, et al.: Successful combined orthotopic liver transplant and transcatheter management of atrial septal defect, patent ductus arteriosus, and peripheral pulmonic stenosis in a small infant with Alagille syndrome. Pediatr Cardiol 23:650, 2002.

Systemic Vasculature 15. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997. 16. Satoda M, Zhao F, Diaz GA, et al.: Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet 25:42, 2000. 17. Basson CT, Cowley GS, Solomon SD, et al.: The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 330:885, 1994. 18. Brice G, Mansour S, Bell R, et al.: Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet 39:478, 2002. 19. Mowat DR, Wilson MJ, Goossens M: Mowat-Wilson syndrome. J Med Genet 40:305, 2003. 20. Sanchez-Cascos A: The Noonan syndrome. Eur Heart J 4:223, 1983. 21. Stevens CA, Bhakta MG: Cardiac abnormalities in the RubinsteinTaybi syndrome. Am J Med Genet 59:346, 1995. 22. Abu-Sulaiman RM, Subaih B: Congenital heart disease in infants of diabetic mothers: echocardiographic study. Pediatr Cardiol 25:137, 2004. 23. Ushida M, Katow S, Furukawa S: Congenital rubella syndrome due to infection after maternal antibody conversion with vaccine. Jpn J Infect Dis 56:68, 2003. 24. Anoop P, Sasidharan CK: Patent ductus arteriosus in fetal valproate syndrome. Indian J Pediatr 70:681, 2003. 25. Fleck BJ, Pandya A, Vanner L, et al.: Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study. Am J Med Genet 99:1, 2001. 26. Nakajima H, Goto G, Tanaka N, et al.: Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J 62:617, 1998. 27. Tellier AL, Cormier-Daire V, Abadie V, et al.: CHARGE syndrome: report of 47 cases and review. Am J Med Genet 76:402, 1998. 28. Kairamkonda V, Thorburn K, Sarginson R: Tracheal bronchus associated with VACTERL. Eur J Pediatr 162:165, 2003. 29. Fox JM, Bjornsen KD, Mahoney LT, et al.: Congenital heart disease in adults: catheterization laboratory considerations. Catheter Cardiovasc Interv 58:219, 2003. 30. Jacobs JP, Giroud JM, Quintessenza JA, et al.: The modern approach to patent ductus arteriosus treatment: complementary roles of video-assisted thoracoscopic surgery and interventional cardiology coil occlusion. Ann Thorac Surg 76:1421, 2003.

3.10 Coarctation of the Aorta Definition

Coarctation of the aorta is a constriction of the thoracic aorta of varying length, almost always located just distal to the origin of the subclavian artery at the junction of the ductus arteriosus and the aorta (Fig. 3-7). The constriction can represent either a severe, long-segment narrowing of the aortic isthmus, in which case lower trunk blood flow is supplied by right ventricular output across the ductus arteriosus, or a discrete obstruction, in which case lower trunk blood flow is supplied by left ventricular output through the ascending aorta.1 Diagnosis

Symptomatic coarctation of the aorta is usually identified in infancy with the sudden onset of congestive heart failure prior to age 2 weeks. Although patients who have a very low cardiac output often have very weak but equal pulses in both the arms and legs, children with coarctation of the aorta who have normal cardiac output frequently have differential pulses as well as blood pressure between the arms and legs. In infancy, the ECG reveals right ven-

133

Fig. 3-7. Coarctation of the descending aorta (arrow) demonstrated by angiography. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston.)

tricular hypertrophy. An echocardiogram is helpful, particularly with respect to documenting coexistent cardiac defects.2 Twothirds of individuals with aortic coarctation in infancy have a PDA, approximately one-third have a VSD,1 and one-third have a bicuspid aortic valve.3 Left ventricular angiography is important to delineate the anatomy of the coarctation and to document whether blood flow to the lower trunk is supplied via the ascending aorta or the ductus arteriosus. Increasingly, MRI is being used to define collateral vessels.4 After infancy, coarctation of the aorta is rarely associated with symptoms. Although a bicuspid aortic valve is frequently an associated anomaly, most patients do not have associated intracardiac defects. Although the diagnosis often is not made before age 10 years, a difference in blood pressures between the arms and legs is a constant feature, elevated systolic blood pressure in the arms usually occurs, and absence of the femoral (40%) and pedal (77%) pulses is common.5 An ECG may show left ventricular hypertrophy, but is frequently normal. Chest radiograph in children older than 5 years reveals rib notching, variable alterations in the aortic arch, and prominence of the descending aorta.6 Etiology and Distribution

Coarctation of the aorta has a prevalence of 1.4 cases per 10,000 live births.3,7 It was the fourth most common cardiac defect noted in the New England Regional Cardiac Program, occurring in 7.5% of infants under age 1 year who had cardiac defects.7 There is probably a slightly higher number of males with coarctation of the aorta,7 although the male-to-female ratio of 1.4:1 was not statistically significant in the Baltimore–Washington infant study.3 However, for older patients, a 1.7:1 male predominance has been documented. There was a higher prevalence of coarctation of the aorta in white than nonwhites in the Baltimore–Washington Infant Study; the same observation was made for aortic valve stenosis, but not for

134

Cardiorespiratory Organs

other left-sided obstructive lesions (hypoplastic left heart, bicuspid aortic valve).3 Coarctation of the aorta occurs frequently among girls with 45, X Turner syndrome8 and much more rarely as one feature of the multiple malformation syndromes listed in Table 3-3.3,8–21 One patient aged 59 with coarctation of the aorta was found to have a point mutation in the NKX2.5 gene, which is capable of producing a wide spectrum of cardiovascular defects.22 In aortic coarctation, a flange or shelf of tissue extends into the aortic lumen from the posterolateral wall at a point opposite the orifice of the ductus arteriosus. Hutchins23 and Rudolph et al.24 suggested that the tissue shelf was formed by the division

of the ductal stream, with a portion flowing toward the head and neck vessels and the remainder coursing toward the descending aorta and placenta. In the normal fetus, total cardiac output is divided essentially in half between the pulmonary artery and the aorta. Although 50% of the total cardiac output leaves the heart through the pulmonary artery, the blood pumped to the lungs accounts for only 8–10% of the total cardiac output. Therefore, 40% of the total cardiac output flows across the ductus arteriosus to the descending aorta, most of which returns to the placenta. With respect to aortic blood flow, about 35% of total cardiac output provides the blood supply to the head and arms, leaving

Table 3-3. Syndromes associated with aortic coarctation Syndrome

Prominent Features

Causation

45,X Turner syndrome8

Edema over dorsum of fingers and toes, webbed neck, low posterior hairline, ovarian dysgenesis, short stature

Chromosomal

Down syndrome3,9

Hypotonia, flat midface, upslanting palpebral fissures

Chromosomal

Trisomy 1810

Clenched hands, short sternum, low arch dermal ridge patterning on fingertips

Chromosomal

Cleft lip, cerebral malformations, polydactyly

Chromosomal

Periorbital fullness, broad mouth, full lips, hoarse voice, friendly personality

Del 7q11.23

Arteriohepatic dysplasia12

Cholestasis, peculiar facies, peripheral pulmonic stenosis

AD (118450) JAG1, 20p12

Neurofibromatosis13

Cafe´ au lait spots, multiple neurofibromas, axillary freckling

AD (162200) NF1, 17q11.2

Meckel-Gruber syndrome14

Encephalocele, polydactyly, cystic dysplasia of kidneys

AR (249000) 11q13, 8q24, 15q24

Roberts syndrome3

Hypomelia, growth deficiency, midfacial defect

AR (268300)

Peters-Plus syndrome

Peters anomaly, disproportionate short stature, cleft lip

AR (261540)

Noonan syndrome15

Webbed neck, posteriorly rotated ears, sternal deformation, woolly hair

AD (163950) PTPN11, 12q24.1

Rubinstein-Taybi16

Short stature, mental retardation, broad thumbs and halluces, downward slanting palpebral fissures

AD (180849) CREBBP, 16p13.3

Alcohol14

Microcephaly, short palpebral fissures, long and smooth philtrum

Prenatal exposure to alcohol

Hydantoin14

Broad nasal bridge, short nose, nail hypoplasia

Prenatal exposure to hydantoin

Valproate17

Broad nasal bridge, short nose, meningomyelocele

Prenatal exposure to valproic acid

Maternal PKU18

Microcephaly, mental deficiency, prenatal-onset growth deficiency

Elevated maternal phenylalanine levels

Facio-auriculo-vertebral spectrum3,19

Ear anomalies, mandibular hypoplasia, vertebral defects

Unknown

VACTERL association3

Vertebral anomalies, anal atresia, tracheo-esophageal fistula, renal anomalies, radial ray anomalies

Unknown

PHACES association20

Posterior fossa malformation, hemangioma, arterial anomalies, cardiac defect, eye anomalies, sternal malformation

Unknown

Kabuki syndrome21

Long palpebral fissures, eversion of lateral third of eyelid, prominent ears, persistent fingerpads, short stature

Unknown

Cytogenetic Aberrations

Trisomy 133,10 11

Williams syndrome

Single-gene Conditions

3

Teratogenic Abnormalities

Syndromes of Unknown Cause and Associations

PKU, phenylketonuria.

Systemic Vasculature

only 15% of the total cardiac output to flow across the aortic isthmus. Because the embryonic heart is a parallel circuit, the proportion of blood flow between the aorta and pulmonary artery depends on the resistance in each limb of the circuit. Any cardiac defect that obstructs antegrade aortic blood flow will proportionately increase flow through the pulmonary artery and ductus arteriosus. Because of the metabolic needs of the head and arms, ductal blood is diverted to provide additional perfusion to the head and arm vessels. A spectrum of cardiac defects will result, depending on the degree of reduction in left heart blood flow: severe reduction leads to a hypoplastic left heart, whereas less severe reduction leads to coarctation of the aorta. Although the pathogenesis of aortic coarctation associated with 45, X Turner syndrome remains unknown, Clark25 hypothesized that increased lymphatic pressure associated with jugular lymphatic sac obstruction may compress the ascending aorta, leading to a decrease in blood flow through the left ventricle and an increase in blood flow to the pulmonary artery. Recurrence risk figures have been determined based on a population-based study of congenital heart defects. Fifty-four probands were ascertained with coarctation of the aorta. Three of 37 siblings (8.1%) had a cardiac defect (one coarctation, one PDA, and one VSD).26

Prognosis, Treatment, and Prevention

The major consequence of coarctation of the aorta is increased afterload on the left ventricle. Collateral vessels from the subclavian, internal mammary, intercostals, and spinal arteries may develop. Surgery is the treatment of choice for aortic coarctation in infancy. Prognosis depends on a variety of factors, including the age of the patient when surgery is performed and the severity of associated defects. Operative mortality figures are 4–32%.1 If the coarctation is found in infancy, elective surgical repair between ages 1 and 5 years has been recommended, because 20% of individuals with untreated coarctation die between the first and second decades. Spinal cord ischemia is a potential complication of coarctation repair.27 Transcatheter balloon angioplasty has emerged as an alternative to surgery for native coarctation, with delivery of an endovascular stent to maintain adequate vessel patency an option in older adolescents and adults.4 Balloon angioplasty is the preferred treatment in those who have developed a re-coarctation after surgical repair.28 Approximately one-third of patients experience long-term cardiovascular complications including re-coarctation, hypertension, aortic valve abnormalities, premature coronary artery disease, and aortic aneurysm.29

References (Coarctation of the Aorta) 1. Beckman RH III: Coarctation of the aorta. In: Moss and Adams Heart Disease in Infants, Children, and Adolescents, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 988. 2. Sahn DJ, Allen HD, McDonald G, et al.: Real-time cross-sectional echocardiographic diagnosis of coarctation of the aorta. Circulation 56: 762, 1977. 3. Ferencz C, Loffredo CA, Correa-Villasen˜or A, et al.: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations. The Baltimore-Washington Infant Study 1981–1989. Futura, New York, 1997. 4. McCrindle BW: Coarctation of the aorta. Curr Opin Cardiol 14:448, 1999.

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5. Strattford MA, Griffiths SD, Gersony WM: Coarctation of the aorta: a study in delayed detection. Pediatrics 69:159, 1982. 6. Martin EC, Strattford MA, Gersony WM: Initial detection of coarctation of the aorta: An opportunity for the radiologist. AJR Am J Roentgenol 137:1015, 1981. 7. Fyler DC, Buckley LP, Hellenbrand WE, et al.: Report of the New England Regional Infant Cardiac Program. Pediatrics 65(Suppl):375, 1980. 8. Sybert VP: Cardiovascular malformations and complications in Turner syndrome. Pediatrics 101:e11, 1998. 9. Papa M, Santoro F, Corno A: Spontaneous closure of inlet ventricular septal defect in an infant with Down’s syndrome and aortic coarctation. Chest 104:620, 1993. 10. Graham EM, Bradley SM, Shirali GS, et al.: Effectiveness of cardiac surgery in trisomies 13 and 18 (from the Pediatric Cardiac Care Consortium). Am J Cardiol 93:801, 2004. 11. Bruno E, Rossi N, Thuer O, et al.: Cardiovascular findings, and clinical course, in patients with Williams syndrome. Cardiol Young 13:532, 2003. 12. Kamath BM, Spinner NB, Emerick KM, et al.: Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 109:1354, 2004. 13. Lin AE, Birch PH, Korf BR, et al.: Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Am J Med Genet 95:108, 2000. 14. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed. 5. WB Saunders, Philadelphia, 1997. 15. Marino B, Digilio MC, Toscano A, et al.: Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr 135:703, 1999. 16. Stevens CA, Bhakta MG: Cardiac abnormalities in the RubinsteinTaybi syndrome. Am J Med Genet 59:346, 1995. 17. Arpino C, Brescianini S, Robert E, et al.: Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 41:1436, 2000. 18. Levy HL, Guldberg P, Guttler F, et al.: Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study. Pediatr Res 49:636, 2001. 19. Greenwood RD, Rosenthal A, Sommer A, et al.: Cardiovascular malformations in oculoauriculovertebral dysplasia (Goldenhar syndrome). J Pediatr 85:816, 1974. 20. Bronzetti G, Giardini A, Patrizi A, et al.: Ipsilateral hemangioma and aortic arch anomalies in posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta, and cardiac defects and eye abnormalities (PHACE) anomaly: report and review. Pediatrics 113: 412, 2004. 21. Digilio MC, Marino B, Toscano A, et al.: Congenital heart defects in Kabuki syndrome. Am J Med Genet 100:269, 2001. 22. McElhinney DB, Geiger E, Blinder J, et al.: NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42:1650, 2003. 23. Hutchins GM: Coarctation of the aorta explained as a branch-point of the ductus arteriosus. Am J Pathol 63:203, 1971. 24. Rudolph AM, Heymann MA, Spiznas U: Hemodynamic considerations in the development of narrowing of the aorta. Am J Cardiol 30:514, 1972. 25. Clark EB: Neck web and congenital heart defects: a pathogenetic association in 45, XO Turner syndrome? Teratology 29:355, 1984. 26. Mitchell SC, Korones SB, Bereudes HW: Congenital heart disease in 56,109 births: incidence and natural history. Circulation 43:323, 1971. 27. Serfontein SJ, Kron IL: Complications of coarctation repair. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 5:206, 2002. 28. Fox JM, Bjornsen KD, Mahoney LT, et al.: Congenital heart disease in adults: catheterization laboratory considerations. Catheter Cardiovasc Interv 58:219, 2003. 29. Toro-Salazar OH, Steinberger J, Thomas W, et al.: Long-term followup of patients after coarctation of the aorta repair. Am J Cardiol 89: 541, 2002.

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Cardiorespiratory Organs

3.11 Persistent Left Superior Vena Cava 3.11.1 Connecting to Right Atrium Definition

Persistent left superior vena cava (PLSVC) connecting to right atrium is origination of the left superior vena cava at the junction of the left subclavian and left internal jugular veins, and connecting to the coronary sinus, which joins the right atrium (Fig. 3-8).1 At least two-thirds of PLSVC occurs as part of a bilateral double superior caval system.2

remains patent, it becomes a PLSVC draining into the right atrium via a dilated coronary sinus.4 This is consistent with the observations of Jureidini et al. that when the left innominate vein is hypoplastic or absent, PLSVC is present.5 Prognosis, Treatment, and Prevention

In the absence of congenital heart defects, prognosis is excellent and treatment is unnecessary. The practical importance of the defect relates to increased difficulty in performing cardiac catheterization through the left arm. Coronary sinus dilation may be a risk for cardiac arrhythmia by stretching the atrioventricular node and His bundle.2,4 3.11.2 Connecting to Left Atrium

Diagnosis

Definition

In cases of isolated PLSVC connecting to the right atrium, patients are usually asymptomatic and diagnosis is incidentally made during other investigations.1 PLSVC is frequently associated with congenital heart defects, in which case symptoms reflect the underlying cardiac anomaly. Echocardiography shows an enlarged coronary sinus, and definitive diagnosis is made by angiography. The enlarged coronary sinus can interfere with the formation of the posterior wall of the left atrium, causing either a fenestration between the coronary sinus and left atrium (unroofing of coronary sinus) or an interatrial communication through the mouth of the coronary sinus (coronary sinus type atrial septal defect). In this situation, the PLSVC effectively drains into the left atrium, and symptoms of right-to-left shunt can occur.

PLSVC connecting to left atrium is origination of the left superior vena cava at the junction of the left subclavian and left internal jugular veins and connecting directly to the left atrium (Fig. 3-9).

Etiology and Distribution

The prevalence of PLSVC is approximately 0.3% in the unselected population.1 In patients with additional cardiac defects, the incidence is higher (2–4%)3 and particularly associated with laterality defects. In normal development, venous return from the rostral end of the embryo drains to the right atrium via paired left and right anterior cardinal veins. By the eighth week of gestation, the left innominate vein develops a bridge between the left and right anterior cardinal veins. As blood flow increases through the left innominate vein and decreases through the caudal portion of the left anterior cardinal vein, the latter vessel gradually becomes obliterated. If the caudal portion of the left anterior cardinal vein Fig. 3-8. Schematic showing persistence of the left superior vena cava, with connection into the right atrium.

Diagnosis

The majority of PLSVC connecting to the left atrium occurs in association with other cardiac defects.1 When it occurs as an isolated defect, patients can be asymptomatic or minimally symptomatic. Symptoms are usually those of a right-to-left shunt (mild peripheral cyanosis and polycythemia). Cardiovascular examination, chest radiography, and ECG results are usually normal. PLSVC is often an incidental finding during other diagnostic examinations. CT, MRI, or echocardiography with color Doppler can noninvasively diagnose. Etiology and Distribution

Only 8% of PLSVC connects to the left atrium.1 Bilateral superior vena cavae with the PLSVC draining into the left-sided atrium occurs with laterality defects. As in PLSVC connecting to the right atrium, this defect is due to failure of obliteration of the left anterior cardinal vein. The connection to the left atrium occurs when the normal invagination between the left sinus horn and the

Fig. 3-9. Schematic showing persistence of the left superior vena cava, with connection into the left atrium.

Systemic Vasculature

left atrium fails to occur; as a result, the coronary sinus fails to form, and the PLSVC drains into the left atrium. Prognosis, Treatment, and Prevention

Treatment is surgical, either simple ligation of the PLSVC or transposition to the right atrium. Prognosis depends on the associated cardiac defects. Because systemic venous return drains directly into the left atrium, there is a risk of paradoxical emboli to the central nervous system. PLSVC has been reported in Turner syndrome,6 Holt-Oram syndrome,7 Fryns syndrome,8 short-rib polydactyly (Beemer-Langer type),9 and once with Ellis van Creveld syndrome (in association with right isomerism).10 References (Persistent Left Superior Vena Cava) 1. Geva T, van Praagh S: Abnormal systemic venous connections. In: Moss and Adams Heart Disease in Infants, Children and Adolescents, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 773. 2. Sarodia BD, Stoller JK: Persistent left superior vena cava: case report and literature review. Respir Care 45:411, 2000. 3. Campbell M, Deucher DC: The left sided superior vena cava. Br Heart J 16:423, 1954. 4. Tak T, Crouch E, Drake GB: Persistent left superior vena cava: incidence, significance and clinical correlates. Int J Cardiol 82:91, 2002. 5. Jureidini SB, Hormann JW, Williams J, et al.: Morphometric assessment of the innominate vein in the prediction of persistent left superior vena cava. J Am Soc Echocardiogr 11:372, 1998. 6. Fuseini A, MacLoughlin P, Dewhurst NG: Dual-chamber pacing via a persistent left superior vena cava in a patient with Turner’s syndrome. Br J Clin Pract 47:333, 1993. 7. Cheng TO: Persistent left superior vena cava in Holt-Oram syndrome. Int J Cardiol 76:83, 2000. 8. Pinar H, Carpenter MW, Abuelo D, Singer DB: Fryns syndrome: a new definition. Pediatr Pathol 14:467, 1994. 9. Myong NH, Park JW, Chi JG: Short-rib polydactyly syndrome, Beemer-Langer type, with bilateral huge polycystic renal dysplasia: an autopsy case. J Korean Med Sci 13:201, 1998. 10. Digilio MC, Marino B, Ammirati A, et al.: Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. Am J Med Genet 84:350, 1999.

3.12 Inferior Vena Cava Variants The inferior vena cava (IVC) is formed between 4 and 12 weeks gestation through a process of development, anastomosis and regression of three sets of paired veins (cardinal, subcardinal, and supracardinal).1 The mature IVC evolves to a unilateral rightsided cava consisting of hepatic, prerenal, renal and postrenal segments. Anomalies are discovered in infants when evaluating cardiac or visceral malformations and in adults incidentally or because of thrombosis of the iliac veins. In a study of 97 consecutive patients with deep venous thrombosis, 31 had involvement of the iliac veins, and 5 of those were found to have an anomalous IVC.1 3.12.1 Left Inferior Vena Cava

An IVC that travels to the left of the aorta and crosses to the right at the level of the renal hila to assume the normal position. The IVC can cross either in front of or behind the aorta.2 This

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anomaly has a prevalence of 0.2–0.5%, and results from persistence of the left supracardinal vein with regression of the right supracardinal vein.2 There is no clinical significance to this anomaly unless abdominal surgery is needed; it can complicate surgical repair of abdominal aortic aneurysms. 3.12.2 Double Inferior Vena Cava

A double inferior vena cava (IVC) is formed from paired venae cavae that travel on either side of the aorta, joining at the level of the renal hila to form a single inferior vena cava on the right side. This anomaly has a prevalence of 1–3% and results from persistence of both supracardinal veins.2 Occasionally, the left-side components originate from persistence of the left subcardinal vein, rather than the left supracardinal vein, and in this case the left ureter is retrocaval and subject to compression.2 Double IVC with both cavae running on the right side is very rare and arises from the persistence of the right supracardinal and right subcardinal veins, which converge into a single vessel at the level of the renal hila. There is no clinical significance. 3.12.3 Interrupted Inferior Vena Cava with Azygous Continuation Definition

Interrupted inferior vena cava with azygous continuation is the absence of the IVC between the renal veins and the hepatic veins.3 The right supracardinal vein persists to connect the caudal IVC to the azygous vein, which courses to the right of the spine. The azygous vein enters the thorax through the aortic hiatus of the diaphragm and joins the superior vena cava just above its junction with the right atrium (Fig. 3-10). Diagnosis

This anomaly, asymptomatic by itself, can be a part of situs abnormalities (left isomerism, situs ambiguus), in which case symptoms are related to the presence of a cardiac defect (usually one producing cyanosis). Diagnosis is by sonography or venous angiography.4 Etiology and Distribution

The IVC is formed between the sixth and eighth weeks from the hepatic vein, right subcardinal vein, subcardinal anastomoses, and right supracardinal vein. Failure of the right subcardinal and hepatic veins to join results in a deficiency of the IVC above the renal veins. Anastomosis between the right subcardinal and right supracardinal veins allows blood from the lower part of the body to reach the azygous vein. Although once thought to be extremely rare in individuals with normal hearts, this defect is being discovered increasingly in asymptomatic individuals who are evaluated noninvasively for unrelated problems. Interrupted IVC has been noted in 0.6– 2.9% of patients with congenital heart disease studied by cardiac catheterization. Commonly associated cardiac defects include cor biloculare, atrioventricular canal, anomalous connections of pulmonary veins, double-outlet right ventricle, large ASD, pulmonary stenosis or atresia, abnormal cardiac position, and anomalies of the superior vena cava.5 Interrupted IVC has been reported in Hennekam syndrome.6

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Cardiorespiratory Organs 8. Basile A, Certo A, Ascenti G, et al.: Embryologic and acquired anomalies of the inferior vena cava with recurrent deep vein thrombosis. Abdom Imaging 28:400, 2003. 9. Castro FJ, Perez C, Narvaez FJ, et al.: Congenital absence of the inferior vena cava as a risk factor for pulmonary thromboembolism. An Med Interna 20:304, 2003. 10. D’Aloia A, Faggiano P, Fiorina C, et al.: Absence of inferior vena cava as a rare cause of deep venous thrombosis complicated by liver and lung embolism. Int J Cardiol 88:327, 2003.

3.13 Miscellaneous Venous Variants 3.13.1 Periureteral Venous Ring

Periureteral venous ring is persistent anastomosis between the right supracardinal and right posterior cardinal veins, forming a venous ring around the right ureter. Compression can lead to hydronephrosis.1 3.13.2 Left Renal Vein Compression

Fig. 3-10. Schematic showing interruption of the inferior vena cava between the renal veins and the hepatic veins. Blood returns to the heart via the azygous vein and the superior vena cava. Prognosis, Treatment, and Prevention

Prognosis is excellent in the absence of associated cardiac defects7; however, there may be an increased risk for recurrent deep vein thrombosis due to venous stasis.8 In those cases associated with laterality defects, prognosis is related to the severity of the associated cardiac anomaly. 3.12.4 Absence of Inferior Vena Cava

Complete absence of IVC has been reported in several patients presenting with deep vein thrombosis.1,9,10 References (Inferior Vena Cava Variants) 1. Obernosterer A, Aschauer M, Schnedl W, et al.: Anomalies of the inferior vena cava in patients with iliac venous thrombosis. Ann Intern Med 136:37, 2002. 2. Minniti S, Visentini S, Procacci C: Congenital anomalies of the venae cavae: embryological origin, imaging features and report of three new variants. Eur Radiol 12:2040, 2002. 3. Geva T, van Praagh S: Abnormal systemic venous connections. In: Moss and Adams Heart Disease in Infants, Children and Adolescents, vols 1 and 2, ed 6. Allen HD, Clark EB, Gutgesell HP, Driscoll DJ, eds. Lippincott Williams and Wilkins, Philadelphia, 2001, p 773. 4. Stackelberg B, Lind J, Wegelius C: Absence of inferior vena cava diagnosed by angiocardiography. Cardiologia 21:583, 1952. 5. Anderson RC, Adams P, Burke B: Anomalous inferior vena cava with azygous continuation (infrahepatic interruption of the inferior vena cava). J Pediatr 59:370, 1961. 6. Al-Gazali LI, Hertecant J, Ahmed R, et al.: Further delineation of Hennekam syndrome. Clin Dysmorphol 12:227, 2003. 7. Effler DB, Greer AE, Sifers EC: Anomaly of the vena cava inferior: report of fatality after ligation. J Am Med Assoc 146:1321, 1951.

Left renal vein compression results in hypertension, producing the so-called nutcracker syndrome. Two forms have been described: anterior nutcracker syndrome due to compression of the left renal vein between the superior mesenteric artery and the aorta, and posterior nutcracker syndrome due to retro-aortic position of the left renal vein and compression between the aorta and the spine.2 The resulting left renal venous hypertension can cause left flank or abdominal pain, hematuria, and/or orthostatic proteinuria.3 Left renal vein entrapment (nutcracker phenomenon) should be considered in children with nonglomerular hematuria or proteinuria.4 Other presentations include varicocele, left leg varicose veins, pelvic congestion syndrome, and vulval varices.5 Diagnosis can be made with Doppler sonography, magnetic resonance angiography, or selective left renal venography. Treatment has included transposition of the left renal vein, renal autotransplantation, nephropexy, and stenting.5 3.13.3 Congenital Absence of the Portal Vein Definition

Congenital absence of the portal vein results in the enteric blood bypassing the liver and draining directly into the systemic circulation. Normally the splenic vein and superior mesenteric vein join to form the portal vein; in this anomaly, either each anastomoses directly with the systemic circulation (usually the infrahepatic inferior vena cava or left renal vein) or each forms a confluence that connects directly to the inferior vena cava.6 Diagnosis

This abnormality is typically discovered fortuitously in children while evaluating for another problem. Discovery in adolescents and adults being evaluated for liver pathology has also been reported.7 Diagnosis is suggested by color Doppler sonography demonstrating a portocaval shunt, and confirmed with CT or MRI. Angiography is rarely necessary since the improvement in noninvasive imaging.8 Prenatal diagnosis has been made once.9

Systemic Vasculature

Etiology and Distribution

The portal vein develops between the 4th and 10th gestational weeks from portions of the right and left vitelline veins, and receives flow from the splenic and superior mesenteric vein primordia. Approximately 50 cases of congenital portal vein absence have been reported, and females predominate.7–20 Nodular hyperplasia,7,10–12 hepatocellular adenoma,7 hepatocellular carcinoma,7,13,14 and hepatoblastoma7 have been seen in association. Absence of the portal vein occurs with biliary atresia (usually accompanied by polysplenia)7,15,16 and cardiac defects (ASD, VSD, PDA).7 It has been reported once with oculo-auriculo-vertebral spectrum,17 once with a congenital choledochal cyst,11 and in two patients with Down syndrome.18 Despite the porto-systemic shunt, hepatic encephalopathy is rare.7

Prognosis, Treatment, and Prevention

Long asymptomatic intervals are possible, but serious sequelae have been reported, including hepatic encephalopathy,7,8 liver tumors,7,13,14 and brain abscess.12 Liver transplantation is the only definitive therapy.

References (Miscellaneous Venous Variants) 1. Minniti S, Visentini S, Procacci C: Congenital anomalies of the venae cavae: embryological origin, imaging features and report of three new variants. Eur Radiol 12:2040, 2002. 2. Ali-El-Dein B, Osman Y, Shehab El-Din AB, et al.: Anterior and posterior nutcracker syndrome: a report on 11 cases. Transplant Proc 25:851, 2003. 3. Lee SJ, You ES, Lee JE, et al.: Left renal vein entrapment syndrome in two girls with orthostatic proteinuria. Pediatr Nephrol 11:218, 1997. 4. Ekim M, Bakkaloglu SA, Tu¨mer N, et al.: Orthostatic proteinuria as a result of venous compression (nutcracker phenomenon)—a hypothesis testable with modern imaging techniques. Nephrol Dial Transplant 14:826, 1999. 5. Little AF, Lavoipierre AM: Unusual clinical manifestations of the Nutcracker syndrome. Australas Radiol 46:197, 2002. 6. Morgan G, Superina R: Congenital absence of the portal vein: two cases and a proposed classification system for portasystemic vascular anomalies. J Pediatr Surg 29:1239, 1994. 7. Tanaka Y, Takayanagi M, Shiratori Y, et al.: Congenital absence of portal vein with multiple hyperplastic nodular lesions in the liver. J Gastroenterol 38:288, 2003. 8. Niwa T, Aida N, Tachibana K, et al.: Congenital absence of the portal vein: clinical and radiologic findings. J Comput Assist Tomogr 26:681, 2002. 9. Venkat-Raman N, Murphy KW, Ghaus K, et al.: Congenital absence of portal vein in the fetus: a case report. Ultrasound Obstet Gynecol 17:71, 2001. 10. Arana E, Marti-Bonmati L, Martinez V, et al.: Portal vein absence and nodular regenerative hyperplasia of the liver with giant inferior mesenteric vein. Abdom Imaging 22:506, 1997. 11. Kinjo T, Aoki H, Sunagawa H, et al.: Congenital absence of the portal vein associated with focal nodular hyperplasia of the liver and congenital choledochal cyst: a case report. J Pediatr Surg 36:622, 2001. 12. Alvarez AE, Ribeiro AF, Hessel G, et al.: Abernethy malformation: one of the etiologies of hepatopulmonary syndrome. Pediatr Pulmonol 34:391, 2002. 13. Lundstedt C, Lindell G, Tranberg KG, et al.: Congenital absence of the intrahepatic portion of the portal vein in an adult male resected for hepatocellular carcinoma. Eur Radiol 11:2228, 2001. 14. Pichon N, Maisonnette F, Pichon-Lefievre F, et al.: Hepatocarcinoma with congenital agenesis of the portal vein. Jpn J Clin Oncol 33:314, 2003.

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15. Andreani P, Srinivasan P, Ball CS, et al.: Congenital absence of the portal vein in liver transplantation for biliary atresia. Int J Surg Investig 2:81, 2000. 16. Taoube KA, Alonso Calderon JL, Yandza T, et al.: Congenital absence of portal vein in a girl with biliary atresia treated with liver transplant. Cir Pediatr 12:38, 1999. 17. Morse SS, Taylor KJW, Strauss EB, et al.: Congenital absence of the portal vein in oculoauriculovertebral dysplasia (Goldenhar syndrome). Pediatr Radiol 16:437, 1986. 18. Pipitone S, Garofalo C, Corsello G, et al.: Abnormalities of the umbilico-portal venous system in Down syndrome: a report of two new patients. Am J Med Genet 120A:528, 2003.

3.14 Deep Vein Abnormalities 3.14.1 Aplasia/Hypoplasia of the Deep Venous System

Aplasia/hypoplasia of the deep venous system is deficiency of the deep veins, including iliac, femoral, popliteal, and axillary veins. Superficial veins are the routes for venous drainage from the limbs, and their ligation or excision is contraindicated.1 Symptoms of swelling and aching of the limbs, venous claudication, cyanosis, and varicosities are generally mild unless thrombosis occurs. Acute thrombosis is treated with rest, elevation, and anticoagulation. Both antegrade and retrograde phlebography are most useful in confirming the diagnosis, although great difficulty is often encountered in documenting the extent of the defect.1 Deep vein anomalies occur in 20–50% of patients with Klippel-Trenaunay-Weber syndrome.2,3 Hypoplasia of the deep venous system of the lower limbs has been reported once in association with phakomatosis pigmentovascularis.4 3.14.2 Congenital Vein Valve Aplasia

Congenital vein valve aplasia is a virtually complete lack of valves in all deep and superficial veins. Affected individuals generally present in adolescence with orthostatic leg edema and dilation of superficial veins. The arms are less commonly symptomatic. Although varicose veins and leg swelling leading to significant disability are common, leg ulcers and claudication occur only rarely. Prevention of edema can be achieved by avoiding long periods of standing and use of compressive stockings. Surgery on the incompetent superficial venous system can ameliorate some symptoms, but since there are no competent valves to use for reconstruction, surgical procedures are generally not helpful.5 Autosomal dominant inheritance is well documented.6,7 3.14.3 Iliac Vein Compression

Iliac vein compression occurs when the left common iliac vein is compressed by the overlying right common iliac artery. It was first described in 1851 by Virchow8 and further detailed by May and Thurner9 in the pathology literature and Cockett and Thomas10 in the surgical literature. May-Thurner syndrome and Cockett syndrome are synonyms for iliac vein compression syndrome, which indicates symptomatic left leg venous outflow obstruction. At least one case occurring on the right side has been described.11 At one time, ‘‘spurs’’ or synechiae in the vein were thought to be congenital, but now are believed to represent progressive fibrosis secondary to irritation from chronic pulsatile trauma.12 Two-thirds of patients with Iliac vein compression are female. Most patients present with an acute iliofemoral deep vein

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Cardiorespiratory Organs

thrombosis, or with chronic left leg edema. Diagnosis has been problematic in the past because of difficulty in visualizing the iliac veins by sonography. Lower limb venography is frequently unrevealing if injection of contrast is made in the dorsum of the foot rather than in the popliteal or femoral vein. Magnetic resonance venography is the noninvasive imaging modality of choice.12 Thrombolytic therapy is indicated for an acute iliofemoral deep vein thrombosis of less than 10 days’ duration. Anticoagulant therapy or surgery were formerly the only treatments for chronic obstruction, but endovascular stent placement has gained popularity.12 Early treatment to avoid vein valve incompetence is advisable.

spongy masses that are easily compressed and lack pulsations. Complex lesions may infiltrate soft tissues or bones and present with swelling or asymmetry. One subtype, glomuvenous malformations (venous malformations with glomus cells, glomangioma) are raised, blue-purple lesions with a cobblestone surface, and are painful on palpation. Glomangiomas are more likely to be inherited and are rare in mucosae. Distinction is usually simple based on clinical presentation; the pathognomonic histopathologic finding in glomuvenous malformations is endothelial channels lined by glomus cells, which probably derive from smooth muscle.1

References (Deep Vein Abnormalities)

The incidence of vascular malformations is probably between 1/5000 and 1/10,000 births.1 Most cases are sporadic, but familial occurrence is well described, in which case multiple lesions are common. Activating mutations of the gene TIE2, encoding an endothelial-specific receptor tyrosine kinase, the angiopoietin receptor, have been reported in at least four families with cutaneomucosal venous malformations.1,2 Glomuvenous malformations are usually familial, and a single gene locus, VMGLOM, on the short arm of chromosome 1, encodes a novel protein designated glomulin, which could be involved in the TGF-beta pathway.3 Venous vascular anomalies constitute an important component of the following three syndromes.

1. Gorenstein A, Shifrin E, Gordon RL, et al.: Congenital aplasia of the deep veins of lower extremities in children: the role of ascending functional phlebography. Surgery 99:414, 1986. 2. Servelle M: Klippel and Trenaunay’s syndrome. Ann Surg 201:365, 1985. 3. Dogan R, Faruk Dogan O, Oc M, et al.: A rare vascular malformation, Klippel-Trenaunay syndrome. Report of a case with deep vein agenesis and review of the literature. J Cardiovasc Surg (Torino) 44:95, 2003. 4. Park JG, Roh KY, Lee HJ, et al.: Phakomatosis pigmentovascularis IIb with hypoplasia of the inferior vena cava and the right iliac and femoral veins causing recalcitrant stasis leg ulcers. J Am Acad Dermatol 49:S167, 2003. 5. Plate G, Brudin L, Eklof B, et al.: Physiologic and therapeutic aspects in congenital vein aplasia of the lower limb. Ann Surg 198:229, 1983. 6. Leu HJ: Familiar congenital absence of valves in the deep leg veins. Humangenetik 22:347, 1974. 7. Lodin A, Lindvall N, Gentele H: Congenital absence of venous valves as a cause of leg ulcers. Acta Chir Scand 116:256, 1958-1959. 8. Virchow R: Uber die Erweiterung kleiner Gefasse. Arch Path Anat 13:427, 1851. 9. May R, Thurner J: The cause of the predominately sinistral occurrence of thrombosis of the pelvic veins. Angiology 8:419, 1957. 10. Cockett FB, Thomas ML: The iliac compression syndrome. Br J Surg 52:816, 1965. 11. Molloy S, Jacob S, Buckenham T, et al.: Arterial compression of the right common iliac vein; an unusual anatomical variant. Cardiovasc Surg 10:291, 2002. 12. O’Sullivan GJ, Semba CP, Bittner CA, et al: Endovascular management of iliac vein compression (May-Thurner) syndrome. J Vasc Interv Radiol 11:823, 2000.

3.15 Vascular Malformations Definition

Vascular malformations are developmental defects consisting of abnormal vascular channels, probably caused by dysregulation in signaling that regulates proper formation of the vascular tree. Depending on clinical appearance, natural history, and histopathology, they can be divided into arteriovenous, capillary, lymphatic, venous, and combined lesions. 3.15.1 Venous Malformation Diagnosis

Most venous malformations are cutaneous and/or intramuscular, but they can occur in any organ. They can be flat or raised and are typically violaceous or bluish in color. Simple lesions are non-painful

Etiology and Distribution

Klippel-Trenaunay-Weber Syndrome

The principal features of this disorder are capillary and cavernous vascular malformations, varicosities and deep vein anomalies, and asymmetric limb hypertrophy (Fig. 3-11).4,5 Although the type of vascular defects is variable, venous malformations predominate. Deep vein abnormalities occur frequently. Occasional vascular abnormalities include lymphatic vascular malformations and lymphectasia; vascular malformations of the gastrointestinal tract, urinary system, mesentery, and pleura; and arteriovenous fistulae. Almost all cases are sporadic. There is an equal incidence of males and females, and intelligence is normal. Proteus Syndrome

The principal features of this condition are disproportionate overgrowth (limbs and organs); capillary, venous, and lymphatic vascular malformations; lipomas; and connective tissue nevi. Lesions are distributed in a random, mosaic fashion, and the course is progressive.6 All cases are sporadic, and the sex ratio is equal. The connective tissue nevus presents as a cerebriform growth on the plantar surface, abdomen, hands, or nose; it is almost pathognomonic for Proteus syndrome. Some patients have a characteristic facial phenotype and mental deficiency. Death from pulmonary embolus appears to be a significant risk.7 Maffucci Syndrome

The principal features of this disorder are venous vascular malformations and enchondromas that typically occur in proximity. Lymphatic vascular malformations occasionally occur. The risk for sarcomatous change of the enchondromas is approximately 30%.8,9 Intelligence is normal. All cases are sporadic, and the sex ratio is equal. Prognosis, Treatment, and Prevention

Growth is slow and commensurate with the growth of the individual. If the lesion can be excised in its entirety, surgery is curative. Recurrence after incomplete resection is common. For those lesions not amenable to surgery, sclerotherapy can reduce

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Fig. 3-11. Capillary, venous, and cavernous malformations of the central nervous system may occur in (A) Sturge-Weber syndrome and (B) Klippel-Trenaunay-Weber syndrome.

their bulk; however, redirection of blood to other channels and recurrence are common.1 3.15.2 Arteriovenous Malformation

An arteriovenous malformation is a direct connection between arterioles and venules without an intervening capillary network. Superficial lesions appear pink or red and are warm and pulsatile. These lesions can cause congestive heart failure and are common in the central nervous system, where they can have a catastrophic presentation. Intracranial Arteriovenous Malformation Diagnosis. The majority of AVMs of the brain are supratentorial, most occurring along the middle cerebral artery.10 Some have been observed in the posterior fossa, spinal cord, and choroid plexus. Intracranial bleeding is the most common presentation, with subarachnoid hemorrhage as the initial symptom in 30–60% of patients, followed by seizures. Recurrent headaches prior to hemorrhage occur frequently in adults but rarely in children. Focal neurologic deficits such as hemiplegia/hemiparesis usually occur with large malformations. Although cranial or carotid bruits can be heard in normal children, it has been suggested that over 50% of children with an AVM have a bruit over the cranial vault or eyeball. Definitive diagnosis requires cerebral angiography, CT, or MRI. It is particularly important to rule out multiple intracerebral AVMs, though this is rare. Etiology and Distribution. Brain AVMs occur in approximately 0.14% of the population. Males have a higher incidence than females. The onset of symptoms varies from 1 month to adulthood, and is commonly in the third decade. Most brain AVMs are sporadic, but familial predisposition is well described.11 Both autosomal dominant and autosomal recessive inheritance are implied. Prognosis, Treatment, and Prevention. The natural history demonstrates a 1–2% bleeding rate, and 2–4% annual risk of re-

bleeding.12 The annual risk of death (1%), disability (1%), and developing epilepsy (1%) leads most authors to recommend treatment.12 Small lesions are more likely to rupture than large AVMs.12 To control seizures and reduce the chance of hemorrhage, the treatment of choice for intracranial AVMs is gamma knife irradiation or surgery,11 with adjuvant embolization and radiotherapy in some cases.12 A long-term follow-up study (spanning 31 years) of 68 affected individuals who had not undergone surgery showed that 68% led normal lives, 15 patients died at ages ranging from 14–64 years, 3 were mentally retarded, and 6 were invalids.13 Spontaneous regression of cerebral AVMs, presumed due to thrombosis, has been well documented, but there are no clinical or angiographic features that aid in predicting those lesions that will regress.14 AVMs have been documented in families with dominantly inherited capillary malformations (see 3.15.3) and constitute an important component of the following three conditions. Hereditary Neurocutaneous Vascular Malformation

These central nervous system AVMs are often located in the spinal cord and are also seen in association with cutaneous vascular lesions occurring in the same or adjacent dematome.15 The inheritance is autosomal dominant (MIM 106070). Lymphedema and Cerebral Arteriovenous Anomaly

This autosomal dominant disorder is characterized by idiopathic lymphedema of the lower limbs, pulmonary hypertension, and AVMs (MIM 152900).16 Hereditary Hemorrhage Telangiectasia (HHT, Osler-Weber-Rendu)

This is an autosomal dominant disorder (MIM 187300) characterized by AVM and telangiectases (focal dilations of postcapillary venules) in skin and mucosa.17 Arteriovenous fistulae affect

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the lung, brain,18 and gastrointestinal tract in HHT. The most consistent clinical symptom is epistaxis. Two gene loci for HHT have been identified (ENG encoding endoglin and ALK-1 encoding activin receptor-like kinase 1), and mutations cause loss of function of the encoded proteins.19 Intra- and interfamilial variability is common, but in general mutations in ALK-1 are associated with milder disease.19 Both proteins interact with the TGF-beta receptor complex in vascular endothelial cells. The likely mechanism involves defective TGF-beta signaling and progressive disappearance of the capillary bed. 3.15.3 Capillary Malformations

Capillary malformations are flat, red cutaneous lesions typically located in the head and neck region. Commonly occurring on the eyelids, forehead, and nape of the neck, capillary malformations make up the vascular stains that are present in up to 40% of newborns and fade during infancy. A more prominent ‘‘port-wine stain’’ is present in 0.3% of newborns and can thicken with age and darken from pink to red-purple. Histologically, capillary malformations are composed of numerous dilated capillary-like vessels with decreased neuronal markings, leading some investigators to propose that lack of innervation may cause dilation of cutaneous capillaries.2 The gene locus for dominantly inherited multiple capillary malformations was mapped to chromosome 5q14-21 in several families,2 some of which subsequently were shown to have mutations in RASA1.20 At least one family member in all of the mutation-positive families had an AVM or arteriovenous fistula or soft- and skeletal-tissue hypertrophy. Sturge-Weber Syndrome

An important disorder presenting with a facial port-wine stain is Sturge-Weber syndrome. Vascular eye abnormalities and ipsilateral occipital leptomeningeal angioma accompany the port-wine stain, which does not conform to a dermatomal or vascular distribution. There is one report of a contralateral occipital leptomeningeal angioma in Sturge-Weber syndrome.21 Glaucoma occurs frequently. Seizures occur in 80% of patients and are often intractable; cortical resection or hemispherectomy can provide good long-term seizure control in the majority of these patients.22 The incidence of mental retardation is high (75%), and a small study indicated that the incidence is lower in patients receiving prophylactic antiepileptic treatment.23 There is no correlation between the extent of the facial port-wine stain and the severity of neurologic involvement.24 Neurologic deterioration occurs in some patients.25 Pulsed dye laser can safely fade cutaneous lesions by up to 70%.26 3.15.4 Capillary-Venous Malformation

Capillary-venous malformations are dilated capillary-like vessels and large cavernous channels arranged in a lace-like structure. They have a predilection for the brain (cerebral cavernous malformations, formerly known as cavernomas or cavernous angiomas),1 where they account for 5–13% of all vascular malformations of the brain.27 Diagnosis

Cerebral cavernous malformations (CCMs) can cause various neurologic problems including seizures and headaches. Based on a study by Fortuna et al.28 of 56 children with CCM, the most frequent presentations are seizures, hemorrhage, intracranial

hypertension, and focal neurologic deficits. Diagnosis is most accurately made by MRI. Etiology and Distribution

CCMs occur in 0.5% of the population.2 They have been described in all age groups with no sex predilection.29 CCMs can occur sporadically as single lesions; multiple lesions are more likely to be familial. Autosomal dominant inheritance with reduced penetrance has been well documented.30 Loss-of-function mutations in KRIT1 (encoding a protein that interacts with a member of the RAS family of GTPases involved in signal transduction) are responsible for some familial and sporadic cases.29,31 Other families have mutations in MGC4607, encoding a novel protein, malcavernin,32 or in PDCD10 involved in apoptotic pathways.33 Prognosis, Treatment, and Prevention

Although the natural history of CCMs is not entirely clear, they grow over an extended period of time by progressive ectasia of vascular channels and budding of capillaries from the cavernous spaces, leading to seizures, hemorrhage, or mass effect. The treatment of choice is excision for symptomatic lesions.34 The benefit of intervention for asymptomatic lesions is less clear. References (Vascular Malformations) 1. Vikkula M, Boon LM, Mulliken JB: Molecular genetics of vascular malformations. Matrix Biology 20:327, 2001. 2. Brouillard P, Vikkula M: Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340, 2003. 3. Brouillard P, Boon LM, Mulliken JB, et al.: Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘‘glomangiomas’’). Am J Hum Genet 70:866, 2002. 4. Baskerville PA, Ackroyd JS, Thomas ML, et al.: The KlippelTrenaunay-Weber syndrome: clinical, radiological and haemodynamic features and management. Br J Surg 72:232, 1985. 5. Servelle M: Klippel and Trenaunay’s syndrome. Ann Surg 201:365, 1985. 6. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 7. Slovotinek AM, Vacha SJ, Peters KF, et al.: Sudden death caused by pulmonary thromboembolism in Proteus syndrome. Clin Genet 58:386, 2000. 8. Kaplan RP, Wang JT, Amron DM, et al.: Maffucci’s syndrome: two case reports with a literature review. J Am Acad Dermatol 29:894, 1993. 9. Albregts AE, Rapini RP: Malignancy in Maffucci syndrome. Dermatol Clin 13:73, 1995. 10. Warkany J, Lemire RJ: Arteriovenous malformations of the brain: a teratologic challenge. Teratology 29:333. 1984. 11. Herzig R, Burval S, Vladyka V, et al.: Familial occurrence of cerebral arterio-venous malformation in sisters: case report and review of literature. Eur J Neurol 7:95, 2000. 12. Mattle HP, Schroth G, Seiler RW: Dilemmas in the management of patients with arteriovenous malformations. J Neurol 247:917, 2000. 13. Svein HJ, McRae JA: Arteriovenous anomalies of the brain. Fate of patients not having definitive surgery. J Neurosurg 23:23, 1965. 14. Lee SK, Vilela P, Willinsky R, et al.: Spontaneous regression of cerebral arteriovenous malformations: clinical and angiographic analysis with review of the literature. Neuroradiology 44:11, 2002. 15. Zaremba J, Stepien M, Jelowick M, et al.: Hereditary neurocutaneous angioma: a new genetic entity? J Med Genet 16:443, 1979. 16. Avasthey P, Ray SB: Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema feet in a family. Br Heart J 30:769, 1968.

Systemic Vasculature 17. Begbie ME, Wallace GMF, Shovlin CL: Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J 79:18, 2003. 18. Putman CM, Chaloupka JC, Fulbright RK, et al.: Exceptional multiplicity of cerebral arteriovenous malformations association with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Am J Neuroradiol 17:1733, 1996. 19. Van den Driesche S, Mummery CL, Westermann CJ: Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovasc Res 58:20, 2003. 20. Eerola I, Boon LM, Mulliken JB, et al.: Capillary malformationarteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73:1240, 2003. 21. Widdess-Walsh P, Friedman NR: Left-sided facial nevus with contralateral leptomeningeal angiomatosis in a child with Sturge-Weber syndrome: case report. J Child Neurol 18:304, 2003. 22. Arzimanoglou AA, Andermann F, Aicardi J, et al.: Sturge-Weber syndrome: indications and results of surgery in 20 patients. Neurology 55:1472, 2000. 23. Ville D, Enjolras O, Chiron C, et al.: Prophylactic antiepileptic treatment in Sturge-Weber disease. Seizure 11:145, 2002. 24. Inan C, Marcus J: Sturge-Weber syndrome: report of an unusual cutaneous distribution. Brain Dev 21:68, 1999. 25. Comi AM: Pathophysiology of Sturge-Weber syndrome. J Child Neurol 18:509, 2003.

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26. Leaute-Labreze C, Boralevi F, et al.: Pulsed dye laser for Sturge-Weber syndrome. Arch Dis Child 87:434, 2002. 27. Frima-Verhoeven PAW, Op de Coul AAW, Tijssen CC, et al.: Intracranial cavernous angiomas: diagnosis and therapy. Eur Neurol 29:56, 1989. 28. Fortuna A, Ferrante L, Mastronardi L, et al.: Cerebral angioma in children. Child Nerv Syst 5:201, 1989. 29. Verlaan DJ, Davenport WJ, Stefan H, et al.: Cerebral cavernous malformations: mutations in Krit1. Neurology 58:853, 2002. 30. Dobyns WB, Michaels VV, Groover RV, et al.: Familial cavernous malformations of the central nervous system and retina. Ann Neurol 21:578, 1987. 31. Laurans MS, Deluna ML, Shin D, et al.: Mutational analysis of 206 families with cavernous malformations. J Neurosurg 99:38, 2003. 32. Liquori CL, Berg MJ, Siegel AM, et al.: Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73:1459, 2003. 33. Bergametti F, Denier C, Labauge P, et al.: Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76:42, 2005. 34. Folkersma H, Mooij JJ: Follow-up of 13 patients with surgical treatment of cerebral cavernous malformations: effect on epilepsy and patient disability. Clin Neurol Neurosurg 103:67, 2001.

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4 Lymphatic System Judith E. Allanson

T

he lymphatic system plays a fundamental part in regulating the physiologic environment by returning protein, cells, macromolecules, and fluid to the bloodstream, as well as by removing metabolic byproducts, dying or mutant cells, microbes, and inorganic matter.1 It also acts as a conduit for trafficking immune cell populations. Lymphatics were first observed by Herophilos about 300 BC and by Erasistratus about 310–250 BC, but it was not until 1622 that Asellius described lacteals and their content in the mesentery of dogs and human beings. Pecquet described the cisterna chyli and thoracic duct shortly thereafter. Independently, in 1653, Rudbeck and Bartholen introduced the term lymphatics. Although Harvey gave an account of the closed circulation of the blood in this era, interest in the function of the lymphatic system lagged until the twentieth century.2 Over the past decade, the era of molecular lymphology has dawned, with the discovery and characterization of lymphaticdirected vascular growth-modulating factors (VEGF-C and -D and angiopoietin-2) and their corresponding tyrosine kinase endothelial receptors (VEGFR-3 and Tie-2). Subsequently, specific gene mutations and candidate loci have been identified in several forms of hereditary lymphedema, and new mouse models of lymphatic disease have been developed.3–5 VEGF-C and VEGF-D interact with VEGFR-3 in lymphatic endothelial cells. VEGF-C and VEGFR-3 are usually co-expressed at sites where lymphatic vessels sprout. VEGF-C induces growth, migration, and survival of primary lymphatic cells, and, when overexpressed in a mouse model, induces lymphatic vessel hyperplasia. Regulation of lymphangiogenesis is likely to be as complex as angiogenesis. Some insights into the role of additional lymphangiogenic signals have been recently derived from gene targeting studies. Loss of angiopoietin-2, another vascular-specific growth factor that binds the Tie-2 receptor tyrosine kinase, results in abnormal lymphatic patterning and function. Mice with deficient DNA binding of Net, a member of the Ets-domain transcription factor that is co-expressed with VEGFR-3 in lymphatic vessels, succumb neonatally of insufficient lymph drainage. Ang2 knockout mice exhibit arrest of lymphatic development with absent or atretic peripheral lymphatics and chylous effusions, suggesting Ang2 is required for either initial lymphatic network development or subsequent sprouting or remodeling crucial for the linkage of peripheral

lymphatics to the primitive lymph sacs and the central venous system. In humans, VEGFR-3 mutations cause Milroy disease (congenital lymphedema), by reducing tyrosine kinase activity with subsequent failure in transducing VEGF-C/VEGF-D signals, and lymphatic vessel hypoplasia. FOXC2 mutations cause lymphedema–distichiasis syndrome, and mutations in this gene have been described in families with several other lymphedema phenotypes, including lymphedema-ptosis, Meige, and yellow nail syndromes (see Table 4-1 for details). Derailed growth of VEGFR-3/podoplanin-postive lymphatic vessels results in lymphangioma formation, with secondary lymphedema due to impaired lymph drainage. The theories regarding embryologic origin of the lymphatic system development remain controversial. According to the centrifugal theory, the lymphatics develop as saclike outgrowths of the endothelium of the anterior cardinal vein and mesonephric vein into paired sacs, the jugular and iliac lymph sacs.6,7 In addition to these paired sacs, two single sacs form; one is the anlage of the cisterna chyli and lower thoracic duct, and the other develops into the lymphatics of the abdominal viscera. The primary lymph nodes develop from the lymphatic primordia-superficial sacs, the deep cervical nodes from the jugular sacs, and the deep inguinal, internal iliac, and lumbar nodes from the iliac sacs. By continuous elongation, centrifugal outgrowth, and branching, these saclike growths invade most of the tissues of the body. The main trunks show gradual differentiation in their walls and become interrupted by valves and secondary and tertiary lymph nodes. According to the alternative centripetal theory, mesenchymal slits appear in the reticulum of venous plexuses at an early stage of embryonic development (9–12 mm).8–11 By coalition of these spaces, larger lymphatic cavities are formed, which open secondarily into the venous system. Now, a century later, genetic studies support the centrifugal model whereby certain venous endothelial cells become responsive to (as yet unknown) lymphatic-inducing signals, differentiate to the lymphatic lineage, and send out lymphatic sprouts. Prox1, a homeobox transcription factor, plays a critical role in the initial transdifferentiation and budding, while VEGFR-3 is initially expressed in embryonic blood vessels but subsequently restricted to lymphatic vessels once they are committed to this lineage and 145

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express additional lymphatic markers podoplanin, LYVE-1, and Nrp-2. Podoplanin, an integral membrane protein, is expressed in the endothelium of lymphatic capillaries. LYVE-1 is a receptor for the extracellular matrix glycosaminoglycan hyaluronan. Nrp-2 null mice display hypo- or aplastic lymphatic vessels. The role of these additional markers remains to be elucidated.3–5 Other elegant work has demonstrated a substantial centripetal contribution from mesenchymal lymphangioblasts, at least in avian species. Thus, both processes may contribute in various degrees to the ultimate links between the lymphatic and blood vasculatures.3 Anatomic studies show that the cisterna chyli begins as the union of the two major lumbar lymph trunks that drain the lower extremities. It receives efferent vessels from the lateral aortic lymph nodes and from the intestines. Usually one thoracic duct arises from the cisterna chyli, but considerable anatomic variation exists. It ascends on the anterior surface of the vertebral bodies to the level of L2, where it dilates and then passes through the aortic hiatus of the diaphragm, between the aorta and the azygos vein into the posterior mediastinum. Between the seventh and fifth thoracic vertebrae, the duct crosses to the left of the vertebral column and ascends behind the aortic arch and the left subclavian artery along the left border of the esophagus toward the base of the neck. It is joined by the left jugular bud. It arches above the clavicle, passing anterior to the subclavian artery, the vertebral artery, the thyrocervical trunk, and the phrenic nerve to terminate in the region of the left jugular and subclavian veins. The thoracic duct serves as the common trunk of all lymph vessels, with the exception of the right lymphatic duct, and empties into the left subclavian vein as it is joined by the left internal jugular vein. The right lymphatic duct drains the right side of the head and neck, the right upper extremity, the thorax, both lungs, the heart, and the diaphragm. Other connections between the lymphatic system and the central venous system occur at the level of the inferior vena cava, renal, portal, azygos, and hemizygous veins.12–15 Communication between the lymphatics and the veins of the thyroid, kidneys, adrenal glands, and liver functions only when the main lymphatics are obstructed.15,16 Superficial and deep peripheral lymphatics are present in all tissues except the central nervous system, the bone marrow, the intralobular portion of the liver, the coats of the eye, the internal ear, and the placenta.17 The superficial lymphatics consist of a valveless, threelayered, dermal network draining into a valved, subdermal arcade.12 Both the dermal and the subdermal networks follow the course of the superficial veins. The deep lymphatics lie intramuscularly, beneath the deep fascia, and follow the course of the main arteries.18 Connections between the superficial and deep lymphatic systems occur in the supratrochlear, popliteal, and inguinal areas.15,18 Histologically, lymph vessels are composed of three layers: a tunica intima, media, and adventia. Unlike other comparable vascular structures, lymph capillaries, although composed of a single layer of endothelium, lack a well-defined basement membrane and exhibit intercellular gaps when examined by the electron microscope.19 These structural differences allow intercellular diffusion of interstitial protein and lipids into the lymphatic circulation. Centrally directed flow of lymph begins in the intercellular spaces, which are continuous with lymph sinusoids, and subsequently drain into lymphatic capillaries and from there into the afferent lymphatics. The lymph is then filtered through the phagocyte and endotheliumlined channels within the regional lymph nodes and then channeled through the efferent vessels into the lymphatic ducts.20 Abnormalities of the lymphatics are characterized by edema, ectasia, tumor formation, and nodal dysfunction. Commonly, two

or more features are observed simultaneously or sequentially, and occasionally all occur together. The terms lymphangioma, lymphangiectasis, and lymphangiectasia imply dilation of lymphatic spaces. The distinction is arbitrary and loose, since histologic features are similar. In this section, the term lymphangiectasia is used when lymphatic vessel dilation is generalized, analogous to a varicose vein, and lymphangioma is used to describe localized spaces that vary in size from capillary dimensions to cysts several centimeters in diameter. References 1. Mayerson HS: On lymph and lymphatics. Circulation 28:839, 1963. 2. Stone EJ, Hugo NE: Lymphedema. Surg Gynecol Obstet 135:625, 1972. 3. Witte MH, Bernas MJ, Martin CP, et al.: Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55:122, 2001. 4. Alitalo K, Carmeliet P: Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1:219, 2002. 5. Kim H, Dumont DJ: Molecular mechanisms in lymphangiogenesis: model systems and implications in human disease. Clin Genet 64:282, 2003. 6. Sabin FR: The development of the lymphatic system. In: Manual of Human Embryology, Vol 2. F Keibel, FP Mall, eds. JB Lippincott, Philadelphia, 1912, p 709. 7. Ranvier L: Morphologie et developement du systeme lymphatique. Arch Anat Microsc Morphol Exp 1:137, 1897. 8. Kampmeier OF: On lymph flow of the human heart, with reference to the development of channels and first appearance, distribution and physiology of their valves. Am Heart J 4:210, 1928. 9. Lewis FT: The development of the lymphatic system in rabbits. Am J Anat 5:95, 1905. 10. Von Recklinghausen FD: Die Lymphgefasse und ihre Beziehung zum Bindegerwebe. A Hirschwald, Berlin, 1862. 11. Huntington GS: The development of the lymphatic system in the reptiles. Anat Rec 5:261, 1911. 12. Crockett DJ: Lymphatic anatomy and lymphedema. Br J Plast Surg 18:12, 1965. 13. Pick JW, Anson BJ, Burnett HW: Communications between lymphatic and venous system at renal level in man. Q Bull Northwestern Univ Med School 18:307, 1944. 14. Threefoot SA, Kossover MF: Lymphaticovenous communications in man. Arch Intern Med 117:213, 1966. 15. Thompson N: The surgical treatment of chronic lymphedema of the extremities. Surg Clin North Am 47:445, 1967. 16. Wallace S, Jackson L, Dodd GO, et al.: Lymphatic dynamics in certain abnormal states. Am J Roentgenol Radium Ther Nucl Med 91:1187, 1964. 17. Bailey F: The circulatory system: the lymph vascular system. In: Textbook of Histology. WM Copenhaver, ed. Williams & Wilkins, Baltimore, 1964, p 277. 18. Malek P, Belan A, Kocandrle VL: The superficial and deep lymphatic system of the lower extremities and their mutual relationship under physiological and pathological conditions. J Cardiovasc Surg 5:686, 1964. 19. Casley-Smith, JR: Endothelial fenestrae: their occurrence and permeabilities, and their probable physiologic roles. VII Int Congr Electron Microsc Grenoble 3:49, 1970. 20. Kobayashi MR, Miller TA: Lymphedema. Clin Plast Surg 14:303, 1987.

4.1 Primary Lymphatic Anomalies Definition

Primary lymphatic anomalies are a primary abnormality of the lymph-conducting elements, involving both the lymph vessels and

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Fig. 4-1. Pathologic-lymphangiographic classification of generalized lymphatic dysplasia. A. Schematic of normal lymphatic drainage from lower limb. B. Distal obliterative disease. C. Distal and pelvic obliterative disease. D. Pelvic obliterative disease. E. Lymphatic hyperplasia. F. Megalymphatics. (Adapted from Wolfe.3)

lymph nodes. Three pathologic/lymphangiographic categories are recognized: aplasia/hypoplasia, bilateral hyperplasia with malformation or absence of the thoracic duct, and megalymphatics (Fig. 4-1). Hypoplasia refers to a reduction in the number and caliber of the subcutaneous lymphatic channels.1,2 Aplasia, or near complete lack of development, is probably very rare and may be an extreme form of hypoplasia.3,4 Hyperplastic lymphatic vessels are moderately dilated, tortuous channels found in association with abnormalities of the major lymph trunks—the thoracic duct or cisterna chyli. Megalymphatics are large, tortuous, dilated lymph vessels, with valvular incompetence, extending from the cisterna chyli through the retroperitoneum into the root of one limb. Synonyms include unilateral hyperplasia, lymphangiectasia, and varicose lymphatic vessels. Anomalous lymph node structure, particularly fibrosis, is increasingly found in association with lymphatic dysplasia as technology improves and may occasionally be the primary pathology.3,5 This classification is problematic. Failure of lymph vessel filling may be related to the site or nature of injection during lymphangiography, radiographic appearances may change with time, and acquired obliteration of lymphatic vessels cannot be ruled out.5 As methods of investigation improve, one may be able to refine the categories in a more physiologic way. Until then, this simple descriptive classification, which does not imply pathogenetic mechanisms, is chosen. Hypoplasia of lymphatic channels is the most common form of primary lymphatic anomaly and has been subdivided into proximal and distal forms.1 Proximal hypoplasia chiefly affects the pelvic and iliac channels (Fig. 4-1). There is a strong association with small fibrotic regional lymph nodes. Some believe the lymph

node pathology to be the primary event, hence the alternative name for this category—obstructive.5,6 Beyond the obstruction, initial lymph vessel distension is followed by atrophy or ‘‘die back’’ of the peripheral lymphatic trunks, secondary to epithelial proliferation or fibrin thrombus.5,7,8 Distal hypoplasia, also known as nonobstructive hypoplasia, is generally confined to the lymph channels of the calf and thigh.1,6 The vessels are reduced in both number and caliber. A solitary lymphatic vessel, without associated lymph node pathology, is frequently found (Fig. 4-1B). Twenty-three percent of hypoplastic lymphatic vessels display a combination of proximal and distal hypoplasia. Small, deformed fibrosclerotic lymph nodes are seen in one-third of these cases.1 Proximal hypoplasia usually presents with rapid onset of severe, unilateral lymphedema within the first months of life. Edema may first be seen in the thigh but quickly involves the entire limb. By contrast, distal hypoplasia is a milder bilateral disease, with spontaneous, painless onset of soft, pitting edema of the foot and ankle, usually in an adolescent girl. It is only slowly progressive. Thoracic duct malformation has been noted in one-third of cases of bilateral hyperplasia, with inadequate or absent filling in the remaining two-thirds.1 Obstruction to lymphatic flow through the mediastinum leads to an increase in the number and caliber of lymphatic vessels in the limbs, groin, abdomen, and, occasionally, in the mediastinum. Bilateral hyperplasia of the lymphatic vessels frequently causes symmetric, below-knee lymphedema, in association with chylous diseases, intestinal lymphangiectasia, and, occasionally, concomitant pleural effusions.1,9 Symptoms may begin at any time of life.1,2

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Megalymphatics may be associated with abnormalities of the thoracic collecting ducts and the central abdominal ducts above the point where the mesenteric lymphatic vessels join the preaortic lymphatic vessels. Occasionally, the megalymphatics are localized in the retroperitoneal region. Megalymphatics usually present as congenital (or early-onset), unilateral or bilateral swelling of the lower limbs.1 The groin and genitalia are frequently involved, with vesicles, leaking chyle or lymphatic fluid, on the overlying skin. Chylous diseases may be associated.4 Lymph nodes are situated at the confluence point of lymphatic streams. Therefore, all lymph from the periphery passes through nodes. Within the node, lymph is recapillarized in sinusoids, with resulting transformation of its protein and cellular composition.10 Normal lymph nodes vary considerably in appearance, and some fibrosis is usually noted in the hilar and pericortical regions. Lymphoid tissue involutes with age, and fibrolipomatosis is a feature in older patients. Taking these changes into account, primary lymphatic dysplasia is often associated with striking, extensive fibrosis emanating from the hilum of the node and initially affecting the medullary sinuses.3,5 This produces obliteration and then recanalization in adjacent lymph vessels. There is no evidence of acute inflammation or association with cellulitis. Fibrosis is seen most commonly in proximal hypoplasia (41%), combined hypoplasia (34%), and bilateral hyperplasia (28%). The amount of fibrosis seen in association with megalymphatics and distal hypoplasia is little different from the normal situation.3 In one study of hypoplastic lymphatic dysplasia, lymph nodes and lymph vessels were found to be diseased in almost 90% of cases.8 Inguinal, iliac, and lumbar nodes were chiefly involved. Beyond the diseased lymph nodes there was a distended network of vessels with ‘‘dermal backflow’’ from dilated deep lymph vessels into the smaller collectors and plexuses of the skin.8 Proliferation of lymph vessel intima, muscle hypertrophy, and subintimal fibrohyalinosis occurs as a consequence of impeded lymphatic drainage.11 Lymph node disease does not appear to be caused by experimental ligation of either the afferent or efferent lymphatics, suggesting that the lymph node pathology is primary.3 Primary lymphatic dysplasia may present in one of five major ways: (1) lymphedema, (2) chylous disease, (3) intestinal lymphangiectasia, (4) cystic renal lymphangiectasia, or (5) generalized (all of the above).

onset and the second on pathologic findings. Congenital lymphedema occurs in 11–25% of cases; lymphedema praecox, with onset before age 35 years, is the most common, found in 60–80% of cases; and lymphedema tarda, with onset after age 35 years, is found in 12–14% of cases.1,6,12 Lymphatic aplasia/hypoplasia accounts for 90% of cases, with hyperplasia in 7% and megalymphatics in 3% of pathologic/lymphangiographic series.1 Nine times out of 10 primary lymphedema affects the lower limbs (Fig. 4-2). Onset is generally spontaneous, although it may be related to a minor event, such as an insect bite, an episode of skin infection, trauma, or surgery, that interrupts underlying collaterals, thus unmasking a primary dysplasia. Lymphedema is generally confined to tissue superficial to the deep fascia. Absence of lymphatic fluid accumulation below this point is attributed to the pumping action of the muscles and blood vessel pulsations. Rare connections exist between the superficial and deep systems of lymphatic vessels in the popliteal and inguinal areas. Lymphaticovenous communications may also be present, although both their presence and function are controversial.1,6,12 In the upper limb, primary lymphedema is less common, congenital in onset, and severe. The arm is more often affected by secondary lymphedema, following mastectomy. The underlying primary lymphedema pathology is hypoplasia/aplasia or hyperplasia of the lymphatics. In contrast to lower limb lymphedema, upper limb involvement is far more likely to be associated with lymphatic abnormalities elsewhere—genital edema, intestinal lymphangiectasia, and thoracic duct abnormalities.1 Lymphedema of the head and neck usually occurs with underlying hypoplasia/aplasia of the lymphatic channels. It is conspicuous and disfiguring. Onset at menarche is common. It may be spontaneous or precipitated by insect bites. Primary genital lymphedema is most frequently associated with proximal or obstructive hypoplasia of lymphatic vessels (Fig. 4-3). Fifty percent of cases present with concomitant lymphedema of the lower limb. Onset is generally in adolescence or early adulthood. Genital lymphedema is most frequently found in males, where anatomic differences allow smaller degrees of obstruction to produce lymphedema.1 Hypoplastic lymphatic vessels of the genital skin and subcutaneous tissue, which drain to the

Lymphedema

Fig. 4-2. Bilateral lymphedema affecting the legs and feet in a 3-week-old infant. His maternal aunt was similarly affected, and the lymphedema was still present at age 30 years. The mother had no evidence of lymphedema but was presumed to have the gene for this condition (OMIM 153100, Nonne-Milroy disease).

Lymphedema is an accumulation of lymph in the interstitial spaces, principally of the subcutaneous fat, caused by a disturbance in equilibrium between the load to be cleared and the transport capacity of the clearing system. Lymphatic stasis results in an interstitial excess of lymph, consisting of 4% protein and increased alpha-globulins, which stretches the reticular fibers attached to the lymphatic vessels, causing dilation. This subsequently leads to valvular incompetence, disoriented flow, backflow, and pooling.12 This situation is initially reversible; however, progressive subcutaneous fibrosis leads to irreversible brawny edema.12 The disturbance probably occurs because of a combination of factors—tissue pressure, inflammation, and hormonal changes at puberty, in pregnancy, and during menopause—in addition to an underlying dysplasia of the lymphatic system.1,5 Diagnosis

Many classifications of lymphedema have been used historically, and the reader is referred to Browse and Stewart5 for details. Two classifications continue in common usage, one based on age of

Lymphatic System

149

Fig. 4-3. Top: lymphangioscintigraphy (LAS) in 13-year-old boy with left leg and penile lymphedema and scrotal lymph fistula demonstrates normal tracer transport on the right. On the left, however, tracer disperses just above the injection site and appears in the scrotum at 48 minutes, with increased scrotal density at 4 hours. Some radioactivity superior to the scrotum at 237 minutes represents tracer accumulation in the urinary bladder. Bottom: direct

lymphography (with ethiodol) in same patient demonstrates hypoplastic lymphatics (insert shows gross genital edema) (left) and reflux of contrast material into scrotum (middle). Fine, dysplastic retroperitoneal lymphatics and near total absence of paravertebral nodes are seen at 24 hours (right). (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

medial superficial inguinal nodes, cause lymphedema. Lymphatic vessel pathology in the testes and adnexa, which drain to the lumbar and iliac nodes, leads to hydrocele. Lymphedema and hydrocele may be seen concurrently if both lumbar and iliac lymph vessels and lymph nodes are diseased. Additional findings include cellulitis or abscess formation, condylomas, vesicles, buboes, and sexual dysfunction. Occasionally, genital lymphatic dysplasia is of the megalymphatic type, with chylous hydrocele and chylous vesicles on the scrotal skin.1

The objectives of diagnosis are first to discover the cause and second to define the type. Conventional oil-contrast lymphangiography has long been the mainstay for lymphatic imaging. However, the emergence of computed tomography and magnetic resonance imaging has curtailed its use. Because of recent improvements and refinements, lymphangioscintigraphy now permits high-resolution imaging of peripheral lymphatic vessels.100 It has value for diagnosis, delineation of pathogenesis, and evaluation of treatment efficacy. It is essentially noninvasive, can easily be

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repeated, and does not adversely affect lymphatic endothelium.100 An intradermal injection into the first interdigital web space is followed by scintigrams in the ilioinguinal region 30 and 60 minutes later (Fig. 4-4). This is a relatively simple technique and may differentiate between primary, secondary, and venous causes of edema. 99Tc radionuclide scanning can locate obstruction, the so-called enhanced pattern of unilateral increased flow, and inguinal lymph node enlargement seen with hyperplasia of the lymphatic vessels.13 Obstruction may be manifested by delayed transit time; extensive extravasation of contrast material through the lymph vessel walls; dilated, tortuous, beaded lymphatic vessels; delayed clearing of contrast or collateral circulation; and dermal backflow (Fig. 4-5).14 Direct lymphangiography can then be used to better define the type of anomaly present. Lymphangiography is performed by localization of a lymphatic vessel in the interdigital web area of the foot using various dyes, such as patent blue violet, with subsequent cannulation of that lymphatic vessel and infusion of lipiodal and ethiodinated oil (Fig. 4-6). Difficulty in cannulating the distal lymphatic channel has often erroneously led to the diagnosis of aplasia.4 The oil may produce allergic reactions and pulmonary oil emboli.1 Watersoluble lymphangiographic agents have been used with minimal side effects; however, the resulting images seem poorer than with the oil-based alternatives. Inguinal lymphangiography is important to differentiate between distal disease, which carries a good prognosis, and proximal obstructive hypoplasia with reduced lymph node opacification and slight coarsening of the internal architecture, which has a poor prognosis.3,14 It is important to remember that interpretation of this radiographic data can be deceiving. There is no absolute correlation between the lymphangiographic findings and clinical severity or between the presence of anatomic abnormality and the likelihood of edema. Physiologic derangement must accompany dysplasia to cause lymphedema.2 The key to the differential diagnosis is to rule out venous disease, whether secondary to chronic venous insufficiency, postphlebitis syndrome, or iliac vein compression. Clinical signs of venous pathology are usually significant enough to make the diagnosis and typically include hyperpigmentation, brawny edema, loss of nails and skin adnexae, and venous stasis ulcers. These changes do not occur with lymphedema, in which capillary perfusion is not impaired. Lymphedema is a genetically determined diffuse enlargement of the subcutaneous tissues of the lower limbs, with loss of their contour. It has a distinct predilection for women and is most frequently symmetric and bilateral. Body habitus is often slim above the waist, with obesity about the pelvis and lower extremities.2 Repeated episodes of infection are uncommon. Primary lymphedema must be distinguished from secondary lymphedema, occurring because of surgical extirpation of lymph nodes or lymph vessels; carcinoma, especially lymphocytic proliferative disorders such as Hodgkin’s disease; filariasis, the leading cause of lymphedema in underdeveloped countries; repeated inflammation; and high dose irradiation. It should also be distinguished from simple edema occurring in the presence of cirrhosis, nephrotic syndrome, congestive cardiac failure, renal failure, or myxedema.1 Congenital absence or malformation of the thoracic duct should be distinguished from traumatic and surgical anomalies of the duct, mediastinitis, tumor, and venous thrombosis.5 Congenital malformations, unrelated to the lymphatics, are seen with primary lymphatic anomalies to a varying extent. Wolfe3 reports a 6% incidence overall, with a 22% incidence in the bilateral hyperplasia group. Kinmonth1 reports a 17.4% frequency. In patients with unilateral megalymphatics, one almost invariably

Fig. 4-4. Normal (early and later phase) lower limb lymphangioscintigraphy (LAS) using 99mTc-HSA (technetium-human serum albumin). Scintigraphic ‘‘bands’’ represent peripheral lymphatic trunks (left) with groin lymph nodes and retroperitoneal lymphatic trunks (right). Once the radiotracer reaches the bloodstream, the heart and liver are rapidly visualized. A small amount of tracer is seen accumulated in the urinary bladder. Circular markers in the midline are xiphoid, symphysis, and knee. (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

finds a circumscribed pink patch or capillary angioma—the socalled vin rose angioma—on the skin of the limb or the trunk near the root of the limb. A number of patients with bilateral hyperplasia of the lymphatic vessels have blotchy red angiomas or erythrocyanosis around the edges of their feet. These are usually symmetric and different from the vin rose angioma. Individuals with bilateral hyperplasia also have an increased incidence of cleft palate and congenital heart defects, especially valvular pulmonary stenosis. In one review, congenital heart defects were seen in five of 31 cases of bilateral hyperplasia with abnormalities of the thoracic duct, in contrast to six cases of congenital heart disease seen in 425 individuals with hypoplastic lymphatics.15 The latter incidence (1.4%) is not statistically different from the incidence of congenital heart defects in the general population. Inherited forms of primary lymphatic dysplasia, with or without other malformations,

Lymphatic System

151

Fig. 4-5. Left two panels: lymphangioscintigraphy (LAS) in a 16-year-old girl with severe hypoplastic lymphedema of the left leg. The right leg is normal, showing peripheral trunks, groin nodes, retroperitoneal nodes and lymphatics in early (30 minute) and delayed (4 hour) films. The left leg shows no migration of tracer from the left foot (cf. Fig. 4-4). Middle two panels: LAS in a 13-year-old girl with right-sided lymphedema demonstrating marked lymphatic

hypoplasia. Left side is normal. Right side shows little or no cephalad migration of the tracer. Right panels: 37-year-old woman with right leg edema since age 3 years. LAS shows dermal diffusion of the tracer with nonvisualization of both the right groin nodes and retroperitoneal trunks (cf. normal left leg). (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

are fairly numerous and are listed in Table 4-1. Perhaps the most well-known of these is Milroy disease (congenital and familial lymphedema), which occurs in 3.4% of patients with lymphedema and affects one in 6000 individuals with a male to female ratio of 1:2.3.1 Meige disease (familial lymphedema praecox) is less common than Milroy disease.

possible mechanisms. In the Butch Landrace pig, autosomal dominant congenital lymphedema (Milroy disease) occurs secondary to nonobstructive distal hypoplasia. The degree of edema is varied. Clinical features are correlated pathologically with the gradation of lymphatic involvement, from total aplasia to minor hypoplasia.51 Cystic and angiomatous configurations are noted, and the prevertebral trunks, lung, and mesenteric vessels are decreased in number, thin-walled, and wide. Lymph nodes are present sporadically in the axillary, gluteal, and inguinal regions. These animals clearly have features in common with cystic hygroma, lymphangioma, and pulmonary and intestinal lymphangiectasia, pointing to a common mechanism in the pathogenesis of these diseases.

Etiology and Distribution

The embryology of the lymphatic system is reviewed in detail in the chapter introduction. The cause of primary lymph vessel and node pathology is unknown. However, three animal models suggest

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Fig. 4-6. Top three illustrations: conventional oil-contrast lymphography in a 13-year-old girl with chylometrorrhea or chylocolporrhea (leakage of visceral lymph through the uterus or vagina) demonstrating massive lymph ‘‘lakes’’ (stasis) in the true pelvis with contrast extravasation into the vaginal vault (arrow). Treatment is usually directed at ligating communicating lymphatics between the retroperitoneum and uterus or vagina. Bottom three illustrations: 15-year-old boy with right leg lymphedema. Conventional oil-contrast lymphography (right two photographs) shows hyperplastic collateral calf lymphatics consistent with primary lymphedema. Lymphangioscintigraphy (left) shows prompt tracer transport in the right leg but with intense and extensive dermal diffusion of tracer into the right calf. (Courtesy of Dr. Charles L. Witte, University of Arizona College of Medicine, Tucson, AZ.)

Embryologically, the lymph vessel primordia are present, but they are underdeveloped and fail to fuse; secondary outgrowth is delayed and progressively inhibited.52 Edema formation, with increasing pressure and structural changes in the tissue surrounding the lymphatics, may cause inhibition of lymphatic outgrowth, which in turn aggravates the lymphedema and fibrosis. Structural abnormalities of the vessels themselves, such as dilation, irregularity, and valvular deficiency, may be due to increased lymph flow through too few vessels.53 The poodle provides a second animal model, this time for autosomal dominant proximal (obstructive) hypoplasia.53 Pathologic studies reveal absence of regional lymph nodes with dilation, increased tortuosity, increased numbers of distal channels, and blind-ending afferent lymph vessels.54 Since central lymphatic vessels and nodes are present, and essentially normal, it appears

that the peripheral and central lymphatic systems fail to make adequate connections, with resultant obstruction to lymphatic drainage from the tissues of the limbs. In Ayrshire cattle, congenital autosomal recessive lymphedema occurs secondary to bilateral hyperplasia of the lymphatics.55 The gene may be present in other breeds.56 Affected cattle can be picked out by the presence of a small accessory earlobe on the dorsal surface of the ear. Internally, the thoracic duct is dilated and tortuous throughout its course, with occasional pulmonary lymphangiectasia; afferent and efferent lymph vessels are tortuous, dilated, and enlarged. There is extensive endothelial proliferation, forming strands of tissue that stretch across the lumen, often dividing it completely, which provides considerable resistance to flow. These pathologic changes, affecting peripheral lymph vessels and secondary and tertiary lymph nodes, suggest a disturbance in organization and growth of the lymphatic endothelium during peripheral lymphatic development, after the primary node and vessel primordia have formed. Estimates of the overall incidence of primary lymphatic dysplasia vary considerably, from one per 67,000 to one per 6000 in the under 20 population.1,57,58 The overall sex ratio is three females to one male. This may reflect the hormonal influence in females at menarche, during pregnancy, or during menopause, plus the fact that subcutaneous tissue pressure is approximately 7 mm Hg greater in males, which may be enough to prevent lymphedema in some cases. Proximal hypoplasia is equally frequent in males and females, with a positive family history in 10% of cases. Distal hypoplasia appears almost exclusively in females, with a positive family history in 22–46% of cases.1,3 Combination proximal-distal hypoplasia is more common in women. Bilateral hyperplasia, with abnormalities of the thoracic duct, occurs twice as often in men as in women. There is a positive family history in one-third of cases. Unilateral megalymphatics are more common in males and are never familial. Prognosis, Prevention, and Treatment

In approximately 50% of patients, an equilibrium point is reached after several years of increased swelling, and, irrespective of treatment measures, swelling remains stable.1,3,57 In other patients, there is a slow, constant, inexorable progression. Once the lymphatic system is unable to drain the interstitium adequately, metabolic byproducts accumulate. Inflammatory changes stimulate migration of macrocytes, whose phagocytic activity is impaired by protein-rich interstitial fluid. The macrocytes are unable to degrade and remove the offending stimuli. Deposition of collagen exceeds macrophage proteolysis, resulting in fibrosis. Chronic injury leads to transformation of smooth muscle cells within the walls of the lymph vessels, which become thickened, fibrosed channels. The combination of subcutaneous and lymphatic vessel fibrosis leads to obstruction and dilation of the lymphatic vessels and valvular incompetence.2 The initial stages are reversible. Long-term, inexorable progression produces fibrokeratotic skin, verrucous growths, and, rarely, malignant angioendothelioma.59 Occasionally, chylous xanthomas, raised yellow nodules approximately 5 mm in diameter, are noted on the skin of children or adolescents. They probably only occur in those individuals with megalymphatics, in whom chylous connections exist between intestinal and lower limb lymphatics.60 An incompetent lymphatic system may lead to deposition of lymph-derived lipoprotein in the skin, which, in association with failure to remove tissue lipid, may lead to accumulation of large amounts of lipid within the skin.61 The xanthomas tend to resolve if lymphatic

Table 4-1. Genetic syndromes with lymphedema/generalized lymphatic dysplasia Causation Gene/Locus

Syndrome

Period of Onset

Prominent Features

Lymph Pathology

Distichiasislymphedema25–27,38,101,102,129

Puberty or later

Distichiasis, recurrent lymphangitis, congenital heart disease, ptosis, varicose veins, cleft palate, spinal extradural cysts

Hypoplasia, bilateral hyperplasia with thoracic duct obstruction

AD (153400) FOXC2, 16q24.3

Familial protein-losing enteropathy48

Childhood

Growth retardation, hepatic vein stenosis, abdominal pain, ascites, diarrhea

Unknown

AR (226300)

Hennekam43,103

Congenital/childhood

Intestinal lymphangiectasia, lymphedema, mental retardation, hypertelorism, ear and tooth anomalies, seizures, cardiac and blood vessel anomalies, glaucoma, hearing loss, renal anomalies

Unknown

AR (235510)

Hypotrichosislymphedematelangiectasia104

Variable

Sparse scalp hair, absent brows and lashes, thin transparent skin, lymphedema, hydrocele, telangiectasia of palms and soles

Unknown

AR and AD SOX18, 20q13

Intestinal lymphangiectasia45,46

Congenital

Intestinal lymphangiectasia, pulmonary lymphangiectasia, double hair whorl, floating ribs

Bilateral hyperplasia with thoracic duct abnormality

AD (152800)

Intestinal lymphangiectasia47

Congenital

Intestinal lymphangiectasia

Unknown

AR

Intestinal lymphangiectasiaaplasia cutis congenita44

Congenital

Intestinal lymphangiectasia, aplasia cutis, optic disc coloboma

Unknown

AR (207731)

Isolated lymphedema18,19

Congenital

Lymphangiectasia-skeletal anomalies34

None

AR

Metaepiphyseal anomalies, unusual face, turricephaly

Unknown

AR/XLR

Lymphedema-atrial septal defect105

Congenital

Lymphedema of the lower limbs, atrial septal defect, hydrocele

Unknown

AR

Lymphedema-hematologic abnormality39

Childhood/puberty

Sensorineural deafmutism, acute myeloblastic anemia, pancytopenia

Dilated lymph vessels

AR/AD

Lymphedemacerebrovascular malformation20

Puberty or later

Cerebral arteriovenous anomaly, primary pulmonary hypertension

Unknown

AD

Lymphedemacholestasis35,106

Congenital/early childhood

Recurrent cholestatic jaundice

Distal hypoplasia

AR (214900) 15q

Lymphedema-chylous ascites49,50

Congenital

Chylous ascites, glaucoma

None

AR

Lymphedema-cleft palate24

Puberty

Cleft palate

Unknown

AD

Lymphedema-Fabry disease42

Praecox

Fabry disease; skin, renal, and neurologic abnormalities

Aplasia

XLR

Lymphedemahypoparathyroidism36

Congenital

Hypoparathyroidism, nephropathy, mitral valve prolapse, brachydactyly, telecanthus, ptosis

Unknown

AR/XLR (247410)

Lymphedemamicrocephaly-chorioretinal dysplasia22,23,107

Congenital

Microcephaly with occipital flattening, variable intelligence with occasional mild mental retardation

Unknown

AD (152950)

(continued)

153

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Table 4-1. Genetic syndromes with lymphedema/generalized lymphatic dysplasia (continued) Prominent Features

Lymph Pathology

Causation Gene/Locus

Congenital/praecox

Unilateral/bilateral pes cavus

Distal hypoplasia

AD

Puberty

Congenital ptosis

Proximal hypoplasia

AD (153000) FOXC2, 16q24.3

Lymphedemarecurrent lymphangitis41

Childhood

Recurrent lymphangitis

Distal hypoplasia

AD

Lymphedema-unusual face28

Congenital

Unusual face, partial ectropion lower lid, heart defect

Distal hypoplasia

AR/XLR

Meige disease17,129

Puberty or later

Lymphedema

Hypoplasia

AD (153200) FOXC2, 16q24.3

Nonne-Milroy disease16,108

Congenital

Lymphedema

Hypoplasia

AD (153100) VEGFR-3, 5q35.3

Noonan29,30,109

Congenital

Short stature, congenital heart defect, webbed neck, pectus, unusual facies

Commonly bilateral hyperplasia with abnormal thoracic duct, but hypoplasia and megalymphatics seen

AD (163950) PTPN11, 12q24

Turner31–33

Congenital

Short stature, congenital heart defect, webbed neck, facial dysmorphism

Mostly hypoplasia, occasional megalymphatics

Chromosomal (45,X)

Urioste syndrome110

Congenital

Persistent mullerian derivatives; lymphangiectasis; hepatic failure; postaxial polydactyly; renal, genital, and craniofacial anomalies

Intestinal lymphangiectasia

AR (235255)

XY female1

Congenital/praecox

Gonadal dysgenesis, androgen insensitivity

Distal hypoplasia

Unknown

Yellow nail37,29

Adulthood

Yellow nails, pleural effusions, thyroid disease, immune deficiency

Hypoplasia

AD (153300) FOXC2, 16q24.3

Syndrome

Period of Onset

Lymphedema-pes cavus40 Lymphedema-ptosis21,129

drainage is improved by either compression or elevation.59 Xanthomas have been noted in unusual sites—the ear concha, preauricular area, vocal cords—in an older woman with type 2A hyperlipidemia.59 One of the primary complications of lymphedema is infection, which occurs in one-third of cases.57 The protein-rich edema fluid promotes bacterial growth, producing cellulitis and lymphangitis with fever, chills, nausea and vomiting, malaise, and headache. Local signs include erythema, induration, tenderness, and lymphadenopathy.17 Staphylococci and streptococci are the most frequent pathogens. Aggressive treatment is necessary to avoid additional injury. Twenty-five percent of cases have recurrent lymphangitis,17 which is particularly common in proximal hypoplastic lymphatic dysplasia.3 Some physicians recommend prophylactic antibiotics for patients with repeated attacks of cellulitis. Penicillin, given orally 1 week per month, has been shown to decrease the infection rate markedly.57 Lymphangiosarcoma was first described in lymphedematous tissue after radical mastectomy and is also known as StewartTreves tumor. It is rare in primary lymphedema and presents as single or multiple, bruiselike, bluish-red, hemorrhagic nodules on the skin, which progress to ulceration and satellite tumor formation. Hematogenous spread is common, with a survival time averaging 19 months.17 Duration of lymphedema prior to tumor

formation is 11 to 40 years, with a mean of 27 years.17 Chronic lymph stasis impairs local immune surveillance and stimulates vicarious angiogenesis, predisposing to chiefly vascular tumors such as Stewart-Treves and Kaposi’s sarcoma.111 Other rare complications include epidermodysplasia verruciformis, an extensive, flat, wartlike lesion with high likelihood of malignant conversion to squamous cell carcinoma, caused by human papillomavirus; and necrotizing fasciitis, a rapidly progressive gangrenous process affecting subcutaneous fascia with an infectious etiology and a mortality of 8–68%.62,63 This rare infection is in contrast to the usual banal infections seen in lymphedema. Recurrent septic arthritis and sterile knee effusions have also been noted rarely.64,65 Full details of the treatment of primary lymphedema are beyond the scope of this chapter. However, interested readers are referred to several other excellent books and articles.1,2,4,17,57,112 The principles of treatment, however, are pertinent to this discussion. The overwhelming majority of patients with lymphedema can be satisfactorily managed nonoperatively. Surgical intervention cannot provide a cure. Medical management is commonly divided into two separate categories, mechanical and pharmacologic, both of which are aimed at controlling the accumulation of protein-rich edema, reducing the incidence of infection, and stopping the development of verrucous growths and hyperkeratotic

Lymphatic System

skin. Mechanical support includes elevation of the involved extremity, graded pressure garments, lymphatic massage, intermittent compression machines, limb hyperthermia, and meticulous skin care.2 During the early stages of lymphedema, limb elevation combined with a custom-fitted graded pressure garment, such as an Ace elastic bandage or Jobst form-fitted pressure stocking, is often successful in minimizing swelling. The edema usually improves slowly over a period of days. New garments must be obtained every few months to ensure adequate compression of the limb. External pneumatic compression promotes flow through existing lymphatics by increasing interstitial pressure and thus increasing transcapillary exchange of extravascular protein and water. Low-pressure, intermittent pumping devices, such as the Jobst pump, Flowtron-aire pump, Wright linear pump, and Lympha-press, work on the principle of sequential, intermittent pneumatic compression of the limb, beginning at the hand and foot and ending with the proximal portion of the limb.57 Each must be used together with a support stocking. Early edema responds quite readily to external pneumatic compression; however, 30–40% of limbs are resistant, primarily in those cases of advanced lymphedema with fibrotic subcutaneous tissue. The compression devices are contraindicated in patients with deep vein thrombosis, severe arterial insufficiency, and acute infection. Limb hyperthermia has been used by the Chinese for centuries.2 Heat controls the recurrence of infection by increasing blood flow, providing nutrition to local cells, hastening the repair of damaged tissue, and reopening lymphatico-venous communications. At this point, the therapeutic indications for this method are uncertain.2 Pharmacologic considerations include antibiotics for treatment of lymphangitis; diuretics, which reduce limb volume by hemoconcentration but are of little value over a long period of time; and benzopyrones, which have been shown experimentally to reduce high-protein edema.2 These agents bind to proteins in the interstitium and stimulate proteolysis by enhancing macrophage phagocytic activity. In addition, they facilitate resorption of protein through the vascular system, decreasing subepithelial fibrosis. Long-term follow-up reveals increasing objective and subjective improvement. Benzopyrone treatment shows promise.113 Indications for surgery include functional impairment related to the progressive enlargement of the extremity, recurrent episodes of infection, and cosmesis. Numerous procedures, both physiologic and excisional, for treating lymphedema have been described since the nineteenth century.2 Physiologic procedures attempt to improve the lymphatic drainage by microvascular techniques, local flaps, or distant pedicles. The excisional procedures remove varying amounts of lymphedematous, subcutaneous tissue.2 Adequate preoperative and postoperative care is of the utmost importance. Prior to operation, the patient should be hospitalized and the extremity elevated for several days to eliminate all residual edema.57 If necessary, a pneumatic pump should be used. Postoperatively, the patient should always wear adequate support and take proper care of the feet to avoid infection. Surgical treatment is not advised for infants less than age 2 years, since, occasionally, edema will diminish once the child begins to walk. It is clear that the results of surgical treatment have been less than satisfying, and, if surgery is considered, the patient should be forewarned that there is only a limited success rate and that complications, especially cosmetic ones, are frequent.57 In one 8-year follow-up study, 70% of patients had at least a 50% reduction in size of the extremity.2 The incidence of cellulitis was significantly

155

decreased. Progressive and continued swelling occurred postoperatively in 6% of patients. Postoperative complications included ischemic necrosis (6%) and loss of sensation on either side of the incision.2 Individuals with proximal (obstructive) hypoplastic lymphatic dysplasia who have demonstrable adequate lymph flow from the foot to the inguinal region, no lymphatic obstruction above the level of the superior mesenteric artery (including the cisterna chyli or thoracic duct), and normal mesenteric lymphatics (no evidence of a protein-losing enteropathy) are good candidates for an enteromesenteric bridge, which bridges the pelvic block by way of the mesenteric lymphatics, successfully establishing lymphatic drainage. Both short- and long-term follow-up indicate good clinical results, with improved lymphangiographic results in three-fourths of the patients. Surgical treatment of genital lymphedema is also successful.57 Recognition that primary congenital lymphedema (Milroy disease) is caused by mutations in VEGFR-3 has led to the development of a mouse model.114 Using virus-mediated VEGF-C gene therapy, researchers have generated functional lymphatic vessels in the lymphedema mice.114 Such growth factor therapy may be applicable to human lymphedema. Intestinal Lymphangiectasia

Intestinal lymphangiectasia is characterized by dilation of the lymphatic channels in the mucosa, serosa, and mesentery of the small bowel. Involvement of lymphatic vessels is variable; the entire small bowel may be affected, or the changes may be confined to a small segment.66 Diagnosis

At the onset, two-thirds of patients have a few gastrointestinal symptoms; however, the majority develop diarrhea, with or without steatorrhea, at some time during the course of the disease.67 Gastrointestinal protein loss may occur as a result of rupture of the dilated lymphatic vessels, with consequent discharge of their contents into the bowel lumen. Alternatively, protein, transuding from the intestinal capillaries, may enter the lumen through an intact epithelium when the mesenteric lymphatics are obstructed and cannot fulfill their normal function in protein transport.67 In the majority of patients, protein loss leads to severe symmetric or asymmetric edema, which may be limited to the lower limbs, may involve the scrotum or anterior abdominal wall, may be generalized without effusions, or may be generalized with pleural or ascitic effusions.68 These effusions are chylous in 30– 50% of cases.67–69 Twenty percent have lymphedema. There is also considerable enteric loss of lymphocytes and immunoglobulins G, A, and M.69,70 This leads to an immune deficiency state, with abnormalities of both the humoral and cellular immune systems. There is increased susceptibility to infection. A more marked deficiency of the cellular immune system, as assessed by intradermal delayed hypersensitivity skin tests or skin allograft survival, is characteristically seen.69 In vitro studies of lymphocyte function, undertaken to assess whether the cellular immune defect is simply the result of a reduced number of peripheral blood lymphocytes, suggest that the residual lymphocyte population may be qualitatively as well as quantitatively defective.69 The diagnosis of intestinal lymphangiectasia often begins with studies to detect and quantitate protein loss. The metabolism of serum albumin can be studied with 51Cr-labeled albumin, 131I-labeled polyvinyl pyrrolidone, and 131I-labeled serum

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proteins.66–68 Fecal fat estimation and xylose tolerance may be used as adjuncts. Barium meal appearance is characteristic, with mucosal edema and ‘‘puddling’’ of the radiocontrast material around the enlarged lymphatics of the small bowel.71 Peroral jejunal biopsy and lymphography provide definitive diagnosis.66,67 Affected portions of the small intestine are edematous with a dusky, congested serosal surface that shows areas of fibrinous exudate. Serosal lymphatic vessels are often dilated and may contain yellow nodules, less than 5 mm in diameter, along their course.67 The intestinal villi have enlarged, bleblike tips, imparting a white, pebbly, almost papillary appearance to the mucosal surface. Microscopic examination of the small bowel reveals a variable degree of dilation of the lymph vessels of the mucosa and submucosa. In some areas the dilated lymphatic vessels do not disturb villous architecture, whereas in other areas plexiform enlargement of many channels results in widening and distortion of the villi. There may be an increase in elastic fibers of the mucosal lymphatics. Mesenteric lymphatics may have a thickened and fragmented elastica interna with hypertrophy of the muscular layers of the media. Mesenteric lymph nodes are similarly affected, with hypertrophy of the capsular elastic fibers and fibrous thickening of the trabeculae. The sinuses of the majority of nodes are dilated and relatively acellular, but there may be reticulum cell hyperplasia.67 Lymphography demonstrates that the intestinal lymphatics are both numerous and abnormally dilated.66 There are frequent reports of associated lymphatic dilation in the lower limbs, pelvis, and retroperitoneal space, abnormalities of the cisterna chyli or thoracic duct, and occasional limb lymphatic hypoplasia and hypoplasia of the inguinal, pelvic, and retroperitoneal lymph nodes.66–68 Most patients with intestinal lymphangiectasia are young. In one study, one-third of patients had onset of symptoms before age 10 years, while the oldest patient was 28 years old.67 Males and females appear to be equally affected. Differential diagnosis of hypoproteinemia due to proteinlosing enteropathy includes adenocarcinoma of the stomach, giant hypertrophic gastritis (Menetrier disease), acute gastroenteritis, ulcerative colitis, regional ileitis (Crohn disease), Whipple disease, nontropical sprue, and renal or hepatic disease.67,72 Differential diagnosis of radiologic findings also includes secondary lymphedema due to retroperitoneal fibrosis, retroperitoneal tumors, intestinal scleroderma, pancreatitis, constrictive pericarditis, congestive cardiac failure, radiation enteritis, mesenteric and diffuse lymphomas, and abdominal tuberculosis.73 Intestinal lymphangiectasia has been reported in association with nephrotic syndrome, Graves disease, Behcet disease, ataxia telangiectasia, aplasia cutis congenita, and Noonan syndrome.44,74–77,115 Familial cases are rare, but are described with both autosomal recessive and autosomal dominant patterns of inheritance.45–47 Familial protein-losing enteropathy has also been reported.48 Prenatal ultrasound has demonstrated multiple small cysts in the abdomen that later proved to be lymphangiectasia in the mesentery of the small bowel. The fetal abdomen was filled with small cystic spaces containing fine, low-level echoes.78 Etiology and Distribution

The high incidence of concomitant chylous effusions and lymphedema, together with evidence of abnormal peripheral and retroperitoneal lymphatics, cisterna chyli, and thoracic duct, indicates that intestinal lymphangiectasia is often part of a generalized dysplasia of the lymphatic system.68 The enteric component

occurs because of an anatomic block to flow through the central lymph vessels.66,67 The severity of the systemic lymphatic disorder correlates with the significance of clinical symptoms.68 Intestinal lymphangiectasia has been described in the small intestine of several types of dogs.116 The disease resembles proteinlosing enteropathy of man, characterized by dilation of the intestinal lymphatics, panhypoproteinemia, edema, hydrothorax, hydropericardium, and hypocalcemia. In addition to the typical intestinal findings, pathologic examination may reveal atrophy of the mesenteric lymph nodes or lymphadenopathy, and dilated lacteals. Prognosis, Prevention, and Treatment

Treatment of intestinal lymphangiectasia is difficult and often unsatisfactory. The goal is to maintain plasma protein level, and thus circulating blood volume, and to inhibit excessive extravascular retention by reducing enteric loss of protein. Symptomatic relief may be obtained by intravenous albumin, diuretics, and a low-fat diet.67 Medium-chain triglycerides, which are absorbed into the portal vein rather than through the lymphatics of the bowel, may be of value, since reduced fat absorption causes a reduction in intestinal lymph flow.70,79 In refractory cases, treatment with a long-acting somatostatin analog has shown promise, although the mechanism of action is unclear.117 Somatostatin may decrease protein loss, reduce intestinal blood flow, inhibit triglyceride resorption, and reduce lymph flow. It may directly affect lymphatic vessels or have an effect outside the gut.117 There may be a subset of patients who have increased tissue or plasma fibrinolytic activity, which may cause gastrointestinal bleeding from diffuse areas of hyperfibrinolysis, and who may respond to antiplasmin therapy.118 Surgical resection of a localized segment of intestine may be successful, and lymphaticovenous anastomosis is occasionally used.70,79 Cystic Renal Lymphangiectasia

Cystic renal lymphangiectasia is characterized by dilated endothelial-lined spaces, primarily in the cortex with sparing of the medulla. Glomeruli and tubules are generally normal in appearance.119,120 Diagnosis

Only 11 reports of cystic renal lymphangiectasia are found in the literature, eight males and three females.120 The majority of affected individuals were diagnosed early in life during evaluation of a renal mass. Age at diagnosis has ranged from 1 day to 10 years. Symptoms prompting evaluation have included abdominal mass or distension, hypertension, ascites, hematuria, proteinuria, nephromegaly, pyelonephritis, and renal insufficiency.120 The disease may be unilateral or bilateral, but extrarenal involvement is rare. Sonography may demonstrate a discrete mass with or without septations, multiple renal cortical cysts, or diffusely echogenic kidneys with decreased corticomedullary differentiation.120 Renal biopsy reveals dilated endothelial-lined spaces, primarily in the cortex with sparing of the medulla. Mild dilation of accompanying interlobar arteries and veins may be present. Glomeruli and tubules are generally normal in appearance.119,120 Unfortunately, biopsy may be complicated by persistent lymphatic leak. The differential diagnosis includes cystic renal dysplasia with or without urinary tract anomalies, cystic neoplasia, localized cystic disease, hereditary (autosomal dominant or recessive) polycystic disease, and familial renal lymphangiomatosis.120 Renal cystic

Lymphatic System

lymphangiectasia is distinct from lymphangiomatosis, which is characterized by osseous or multiorgan involvement, often with poor prognosis. Etiology and Distribution

This disorder is localized to the renal cortex and rarely demonstrates extrarenal involvement. Etiology is not known. Prognosis, Prevention, and Treatment

The prognosis for children is promising without specific therapy. In some individuals, conservative treatment with antihypertensives has resulted in stabilization or even amelioration of symptoms. In others, a surgical approach with unilateral nephrectomy has been chosen, with good outcomes. There are no reports of progressive renal insufficiency. Adult cases are often discovered coincidentally at autopsy. Chylous Diseases

Dietary fats, in the form of long-chain triglycerides, are transformed into chylomicra and very low density lipoproteins. These are secreted into the intestinal lacteals and lymphatics and transported to the cisterna chyli and then to the thoracic duct as chyle. Chyle is alkaline and bacteriostatic, a characteristic probably due to its high fatty acid content, with a specific gravity invariably greater than 1.012. It has a total fat content greater than 1000 mg/dL, with elevated concentrations of chylomicra and triglycerides, plus fat-soluble vitamins. Protein content varies from 2.2 to 6 g/dL, and electrolyte composition is similar to that of serum. Of the cellular elements, lymphocytes (the T-cell type) predominate.80,81 Between 1.5 and 2.5 liters of chyle empty into the venous system daily. Both volume and flow rate vary considerably, depending on the type of meal and its fat content in particular. Ingestion of fat increases lymph flow in the thoracic duct to two to 10 times the resting level, for several hours. Ingestion of water also increases chyle flow, whereas ingestion of proteins or carbohydrates has little effect.81 Starvation reduces flow to the merest trickle of clear lymph. The flow of chyle also depends on contraction of the thoracic duct wall, adjacent arterial pulsations, and intrathoracic and intra-abdominal pressure changes.81 Diagnosis

Chylous complications of general lymphatic dysplasia affect many areas of the body, particularly the lower limbs where chylous vesicles complicate early onset of lymphedema. The underlying lymphatic anomaly is usually bilateral hyperplasia with abnormalities of the thoracic duct or megalymphatics.1 There may be associated involvement of the perineum and genitalia, including chylocele. Chyle may enter the urinary tract at various levels, generally by fistulous communication with the urethra, bladder, or renal pelvis. Megalymphatics are frequently the underlying pathology. Chylopericardium is rare and generally leads to cardiac tamponade.1 The remainder of this discussion concentrates on chylothorax and chylous ascites. The symptoms and signs of chylothorax are those encountered with a comparable pleural effusion of any etiology. The presence of chyle is suspected only after thoracocentesis. Respiratory insufficiency is the chief complaint.80 Fifty percent of infants with neonatal chylothorax have symptoms within the first 24 hours; 75% have symptoms by the end of the first week.80,81 The effusion is initially serous and assumes its typical chylous

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appearance only after milk feedings have commenced. Pleuritic chest pain and high fever are rare, because chyle is not irritating to the pleural surface.81 Cyanosis, absence of fever, increased respiratory rate, and dullness to percussion of the lungs are characteristic findings. The metabolic effects of chylothorax are a serious threat to life and are proportional to the duration and volume of lymph drainage. Substantial loss of proteins, fats, electrolytes, bicarbonate, fat-soluble vitamins, and lymphocytes leads to malnutrition, metabolic acidosis, and compromised immunologic status.80,81 The diagnosis of chylothorax depends on accurate assessment of clinical features, presence of a pleural effusion on chest radiographs, and demonstration of chyle in pleural fluid obtained by thoracocentesis.80 Milky or creamy pleural fluid is considered to be diagnostic; however, confirmation can be obtained by analysis of the fluid’s composition. Computed tomography scans may demonstrate pleural thickening.81 An alternative diagnostic method involves ingestion of radiolabeled triglyceride (131I-triolein). Samples of pleural fluid collected within 46 hours of administration that demonstrate a high level of radioactivity confirm the presence of chylothorax.81 Lymphoscintigraphy, using 99Tc human serum albumin or dextran by intradermal injection into the web space between the toes, or lymphangiography may demonstrate obstruction to the cisterna chyli and chylous reflux in both chylothorax and chylous ascites.80 Tumors, particularly lymphomas, are responsible for over 50% of chylothoraces and are the most common cause in adults.81 Hence, a nontraumatic chylothorax in an adult demands a careful search for malignancy. Chylothorax may develop when a tumor compresses or directly invades the thoracic duct or when the lymphatics are obliterated following radiotherapy.81 The second leading cause of chylothorax is trauma, which accounts for approximately 25% of cases. Surgical trauma is more common than nonsurgical trauma. The thoracic duct can be injured during cardiovascular surgery, corrective surgery for congenital heart disease or tracheoesophageal fistula, coronary bypass grafting, Bochdalek herniorrhaphy, esophageal resection, esophagoscopy, stellate ganglion blockade, thoracic sympathectomy, radical neck dissection, and high translumbar aortography, and following use of the superior vena cava and subclavian vein for central hyperalimentation or hemodynamic monitoring.81 Nonsurgical trauma includes penetrating injuries to the thoracic duct due to gunshot or stab wounds and nonpenetrating injuries following sudden hyperextension of the spine, fracture of vertebrae or ribs, and blast and crush injuries. Less impressive trauma includes weight-lifting, straining, severe bouts of coughing or vomiting, and vigorous stretching while yawning.81 Rare causes, accounting for less than 10% of cases, include filariasis, lymph node enlargement, tuberculosis, amyloidosis, sarcoidosis, cirrhosis, congestive cardiac failure, aneurysm of the thoracic aorta, tuberous sclerosis, and pulmonary lymphangioleiomyomatosis. Occasionally, the thoracic duct is involved in a lymphangiomatous malformation, either alone or as part of generalized lymphangiomatosis.83,84 The reader is referred to the section on lymphangiomatosis for further details. So-called idiopathic chylothorax accounts for about 15% of cases, usually of neonatal onset. Causal hypotheses include increased fetal venous pressure during delivery, leading to rupture of a weak thoracic duct. Chylothorax has been seen in association with tracheoesophageal fistula, hemangiomas, and cutis marmorata telangiectatica congenita.80,85,86 This latter condition is comprised of dilated capillaries, veins, and lymphatics in both the dermis and the

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subcutaneous tissues. Concomitant malformations of venous and lymphatic systems are also seen in Klippel-Trenauney-Weber syndrome. Chylothorax has been described in infants with Down syndrome, although malformations of the major lymphatic vessels have not been substantiated.87–89 Abnormalities of the thoracic duct, accompanied by chylothorax, have been noted in Noonan syndrome.30,87 Chylothorax has also been described in cardio-faciocutaneous syndrome121 and Adams-Oliver syndrome.122 Lee and Young49 described two siblings with chylous ascites and lymphedema secondary to abnormalities of the thoracic duct, while Williams and Josephson123 reported an Amish brother and sister with congenital chylothorax. Further details of associated syndromes are given in Table 4-1. Successful ultrasonographic prenatal diagnosis of chylothorax has been reported on several occasions.90 Antenatal thoracocentesis allows expansion of the lungs, but this is not sustained, and fluid reaccumulates within hours. Placement of a pleuroamniotic shunt may improve morbidity and mortality.91 Successful intrapleural sclerotherapy has been reported in utero.124 Chylous ascites results from effusion or leakage of lymphatic fluid from the mesentery, cisterna chyli, or lower thoracic duct into the peritoneum and generally presents with abdominal distension.82 Intestinal lymphangiectasia is considered a variant in which proteins, lymphocytes, and immunoglobulins are lost into the gastrointestinal tract, and fat is malabsorbed. Clinical features are discussed in an earlier section. Chylous ascites may form because of compression of the retroperitoneal lymphatics by glandular enlargement, tumor formation, or abdominal adhesions. In the developed world, the most common causes are malignancy and cirrhosis, which account for two-thirds of all cases. In contrast, infectious etiologies such as tuberculosis and filariasis account for the majority of cases in developing countries.125 In children, 50% of cases are caused by congenital abnormalities of the lymphatic system.80 Etiology and Distribution

The embryology of the lymphatic system is reviewed in the chapter introduction. Various malformations of the lymphatic system lead to chylothorax, including absence or atresia of the thoracic duct, multiple dilated lymphatic channels with failure of the peripheral channels to communicate with the central lymphatics, and multiple fistulas between the thoracic duct and the pleural space due to failure of communication of multiple segmental components of the embryonic duct.92,93 Following obstruction of the thoracic duct, chyle refluxes by two routes, either through the left posterior intercostal lymphatics to the parietal pleura or through the bronchomediastinal vessels to the pulmonary parenchyma and visceral pleura. Subsequently, it leaks from the parietal or visceral pleural lymphatics into the pleural cavities.94 Interestingly, ligation of the thoracic duct in both humans or experimental animals fails to produce chylothorax because of extensive collateral vessels and lymphaticovenous anastomoses.81 Chylous ascites occurs with fistulous communication between the peritoneum and hypoplastic lymphatics or megalymphatics, or obstruction of the cisterna chyli, with retrograde chylous reflux into the peritoneal space and the lumen of the small intestine.1,80 When atresia of the cisterna chyli is associated with aplasia/ hypoplasia of lymph nodes and lymphatic vessels of the small bowel and mesentery, intestinal lymphangiectasia and proteinlosing enteropathy are not seen.82 Thoracic duct obstruction, with resultant dilation of mediastinal and pleural lymphatics, has been incriminated as a cause of

chylothorax in the dog, notably the Afghan hound.95 Congenital obstruction of the thoracic duct has been postulated, yet the affected dogs are middle-aged or older.95 Both chylothorax and chylous ascites are rare conditions. Between 1955 and 1982, only 16 primary cases were reported by the Mayo Clinic. The male to female ratio is 2:1.80,96 Sixty percent of cases of chylothorax are right-sided, probably because the thoracic duct travels on the right side of the vertebral bodies during most of its thoracic course. Nix et al.,97 reviewing 123 cases of chylothorax, noted that only 10% of cases were due to intrinsic lymphatic abnormalities. They also reviewed 146 cases of chylous ascites and found lymphatic malformations in 22% of the total.97 Prognosis, Prevention, and Treatment

In up to 75% of cases of chylothorax or chylous ascites, the symptoms resolve or stabilize with conservative treatment.80 In the group with neonatal onset, irrespective of the etiology, mortality is up to 50%, with death related to malnutrition and secondary infection. Poor prognosis is associated with delivery prior to 35 weeks gestation, abnormal karyotype, presence of other congenital anomalies, or hydrops.81,126 The first principle of management of chylothorax is to maintain adequate nutrition and minimize chyle formation. Modern hyperalimentation techniques, combined with meticulous replacement of water and electrolytes, can, to a large extent, prevent the serious metabolic consequences of prolonged loss of chyle due to repeated thoracocentesis or chest tube drainage. The substitution of dietary fat with medium-chain triglycerides, which are absorbed directly into the portal venous system, causes a dramatic reduction in chyle flow. Fat-soluble vitamin supplementation is necessary. Adequate drainage of the pleural space prevents cardiorespiratory embarrassment, and a fully expanded lung may promote pleural symphysis. If the chylothorax persists after one or two thoracocenteses, a chest tube with slight negative pressure is inserted, and total parenteral nutrition should replace oral diet. In an attempt to maintain nutrition, chyle removed by thoracocentesis can be returned orally, per rectum, or by intravenous infusion.80,98 Use of a somatostatin analog to reduce thoracic duct flow has been successful in one patient.127 If none of these procedures controls the effusion, surgical exploration of the major lymphatic vessels, pleurodesis, or both should be performed.128 It is not clear whether pleurodesis, by decortication, counters the chylous effusion by obliterating the pleural space or by removing the primary cause— an abnormal pleura.71 Conservative management in the treatment of chylous ascites should be given a fair trial before surgery is considered. Treatment should begin with several therapeutic paracenteses, a high-protein, low-fat diet with medium-chain triglycerides, and added fatsoluble and water-soluble vitamins.49,80 After 2 weeks, a drain should be inserted and maintained with slight negative pressure. The next step should include total parenteral nutrition. Surgery may benefit patients with postoperative, neoplastic, and congenital causes.125 Peritoneovenous anastomosis has been performed with mixed results.49,80 The only treatment for chylopericardium is partial pericardiectomy, with or without ligation of the thoracic duct. Generalized Lymphatic Dysplasia

Although generalized lymphatic dysplasia is, by definition, a combination of lymphedema, intestinal lymphangiectasia, and chylous disorders, which have been reviewed individually, there

Lymphatic System

are some points concerning this entity that should be discussed in their own right. There are few reports of documented generalized lymphatic dysplasia in the literature.80 Lymphedema is usually present at birth but may develop later. The presenting symptom is often shortness of breath secondary to chylothorax, with onset in childhood. In one 19-year-old, the onset was heralded by episodes of scrotal swelling and groin pain, associated with shaking, chills, and fever. The overlap with generalized lymphangiomatosis is significant. Chang et al.99 described one case with lymphangiomatous tissue in the posterior mediastinum and peritoneum, in addition to generalized lymphatic dilation in the internal organs. Smeltzer et al.80 reported a patient suspected of having lymphangiomas of the femur and clavicle, leading to pathologic fracture, who, at autopsy, was found to have probable lymphangiomas in the spleen. Chang et al.99 have tried to distinguish between the terms lymphangioma and lymphangiectasis. They define lymphangioma as a primary truly dysplastic process, whereas lymphangiectasis is a secondary dilation of preexisting, normally developed lymphatic vessels, that is, a deformation or disruption. The distinction is difficult to make clinically. After reviewing the literature, Smeltzer et al.80 believe the pathogenic mechanism begins with a congenital malformation of the thoracic duct, the cisterna chyli, or the connection between normally developing peripheral lymphatic vessels and central vessels. This initial malformation reduces the normal flow of lymph from the limbs. The peripheral lymphatics, having an increasing load, dilate, form collaterals, and often rupture, leaking chyle into the pleural and peritoneal cavities or into the limbs. Once the effusion begins, the pressure gradient rarely allows it to stop spontaneously, and it often persists until the patient dies from respiratory insufficiency. Autopsies of six children with generalized lymphatic abnormality revealed dilation of lymphatics throughout the body. The thoracic duct was normal in two patients, obstructed in two, atrophied in one, and not seen in one. Only two of the eight patients were female. However, in view of the small number of cases, little significance can be attached to this ratio. Most individuals have died, and the condition of the survivors has worsened after the initial diagnosis. The consistency of findings, both during the patient’s life and at autopsy, has led Smeltzer et al.80 to suggest the following treatment plan. First, the diagnosis should be made on the basis of history and physical examination, with thoracocentesis or paracentesis to document the chylous nature of the effusion. Conservative treatment, consisting of a high-protein, medium-chain triglyceride diet with vitamin supplements, should be started, with several repeat taps during the first 2 weeks. If no improvement is seen, total parenteral nutrition should be instituted with no oral feedings, accompanied by repeated aspirations of the effusions. Surgery, with blind ligation of the thoracic duct and pleural decortication, must be considered a last resort. References (Primary Lymphatic Anomalies) 1. Kinmonth JB: The Lymphatics. Surgery, Lymphography and Diseases of the Chyle and Lymph Systems. Edward Arnold, London, 1982. 2. Kobayashi MR, Miller TA: Lymphedema. Clin Plast Surg 14:303, 1987. 3. Wolfe JHN: The prognosis and possible cause of primary lymphedema. Ann R Coll Surg Engl 66:251, 1984. 4. Browse NL: The diagnosis and management of primary lymphedema. J Vasc Surg 3:181, 1986. 5. Browse NL, Stewart G: Lymphedema: pathophysiology and classification. J Cardiovasc Surg 26:91, 1985.

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6. Gough MH: Primary lymphedema: clinical and lymphographic studies. Br J Surg 53:917, 1966. 7. Fyfe NCM, Wolfe JHN, Kinmonth JB: ‘‘Die-back’’ in primary lymphedema—lymphographic and clinical correlations. Lymphology 15:66, 1982. 8. Kinmonth JB, Eustace PW: Lymph nodes and vessels in primary lymphedema. Their relative importance in aetiology. Ann R Coll Surg Engl 58:278, 1976. 9. Lewis M, Kallenbach J, Zaltzman M, et al.: Pleurectomy in the management of massive pleural effusion associated with primary lymphedema: demonstration of abnormal pleural lymphatics. Thorax 38:637, 1983. 10. Rada IO, Tudose N, Bibescu Roxin R: Lympho-nodal fibrosclerosis in primary lymphedema. Part two: consequences of lympho-nodal fibrosclerosis on lymph stasis in primary lymphedema. Lymphology 16:223, 1983. 11. Tudose N, Rada IO: Structural and ultrastructural changes of lymph nodes in primary lymphoedema. Morphol Embryol (Bucur) 30:29, 1984. 12. Stone EJ, Hugo NE: Lymphedema. Surg Gynecol Obstet 135:625, 1972. 13. Intenzo CM, Desai AG, Kim SS, et al.: Lymphedema of the lower extremities: evaluation by microcolloidal imaging. Clin Nucl Med 14: 107, 1989. 14. Dan SJ, Efremidis SC, Tey PH, et al.: Primary lymphedema: four cases with vessel and node findings. Mt Sinai J Med 50:69, 1983. 15. Corbett CRR, Dale RF, Coltart DJ, et al.: Congenital heart disease in patients with primary lymphedemas. Lymphology 15:85, 1982. 16. Lewis JM, Wald ER: Lymphedema praecox. J Pediatr 104:641, 1984. 17. Kostler E: Das trophodem (Nonne-Milroy-Meige). Dermatol Monatsschr 162:465, 1976. 18. Kajii T, Tsukahara M: Congenital lymphedema in two siblings. Jpn J Hum Genet 30:31, 1985. 19. Esterly JR: Congenital hereditary lymphedema. J Med Genet 2:93, 1965. 20. Avasthey P, Roy SB: Primary pulmonary hypertension, cerebrovascular malformation, and lymphedema feet in a family. Br Heart J 30:769, 1968. 21. Bloom D: Hereditary lymphedema (Nonne-Milroy-Meige). Report of a family with hereditary lymphedema associated with ptosis of the eyelids in several generations. N Y J Med 41:856, 1941. 22. Leung AKC: Dominantly inherited syndrome of microcephaly and congenital lymphedema. Clin Genet 27:611, 1985. 23. Crowe CA, Dickerman LH: Brief clinical report: a genetic association between microcephaly and lymphedema. Am J Med Genet 24:131, 1986. 24. Figueroa AA, Pruzanski S, Rollnick BR: Meige disease (familial lymphedema praecox) and cleft palate: report of a family and review of the literature. Cleft Palate J 20:151, 1983. 25. Falls HF, Kertesz ED: A new syndrome combining pterygium colli with developmental anomalies of the eyelids and lymphatics of the lower extremities. Trans Am Ophthalmol Soc 62:248, 1964. 26. Robinow M, Johnson GF, Verhagen AD: Distichiasis-Lymphedema. A hereditary syndrome of multiple congenital defects. Am J Dis Child 119:343, 1970. 27. Schwartz JF, O’Brien MS, Hoffman JC: Hereditary spinal arachnoid cysts, distichiasis and lymphedema. Ann Neurol 7:340, 1980. 28. Mucke J, Hoepffner W, Scheerschmidt G, et al.: Early onset lymphoedema, recessive form: a new form of genetic lymphoedema syndrome. Eur J Pediatr 145:195, 1986. 29. Herzog DB, Logan R, Kooistra JB: The Noonan syndrome with intestinal lymphangiectasia. J Pediatr 88:270, 1976. 30. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841, 1987. 31. Benson PF, Gough MH, Polani PE: Lymphangiography and chromosome studies in females with lymphoedema and possible ovarian dysgenesis. Arch Dis Child 40:27, 1965.

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32. Van der Putte SCJ: Lymphatic malformation in human fetuses. A study of fetuses with Turner’s syndrome or Status Bonnevie-Ullrich. Virchows Arch 376:233, 1977. 33. Vittay P, Bosze P, Gaal M, et al.: Lymph vessel defects in patients with ovarian dysgenesis. Clin Genet 18:387, 1980. 34. Wasser ST, Beyreiss K, Himmel D, et al.: Exsudative Enteropathie bei kongenitaler intestinaler Lymphangiektasie mit multiplen Skelettveranderungen. Acta Paediatr Acad Sci Hung 15:17, 1974. 35. Aagenaes O: Hereditary recurrent cholestasis with lymphoedema: two new families. Acta Paediatr Scand 63:465, 1974. 36. Dahlberg PJ, Borer WZ, Newcomer KL, et al.: Autosomal or X-linked recessive syndrome of congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve and brachytelephalangy. Am J Med Genet 16:99, 1983. 37. Nordkild P, Kromann-Andersen H, Struve-Christensen E: Yellow nail syndrome—the triad of yellow nails, lymphedema and pleural effusions. A review of the literature and a case report. Acta Med Scand 219:221, 1986. 38. Kaariainen H: Hereditary lymphedema: a new combination of lymphatic symptoms not fitting into present classifications. Clin Genet 26:254, 1984. 39. Emberger JM, Navarro M, Dejean M, et al.: Surdi-mutite, lymphoedeme des membres inferieurs et anomalies hematologiques (Leucose aigue, cytopenies) a transmission autosomique dominante. J Genet Hum 27:237, 1979. 40. Jackson BT, Kinmonth JB: Pes cavus and lymphedema. An unusual familial syndrome. J Bone Joint Surg Br 52-B:518, 1970. 41. Holmes LB, Fields JP, Zabriskie JB: Hereditary late-onset lymphedema. Pediatrics 61:575, 1978. 42. Gemignani F, Pietrini V, Tagliavini F, et al.: Fabry’s disease with familial lymphedema of the lower limbs. Case report and family study. Eur Neurol 18:84, 1979. 43. Hennekam RCM, Geerdink RA, Hamel BCJ, et al.: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34:593, 1989. 44. Bronspiegel N, Zelnick N, Rabinowitz H, et al.: Aplasia cutis congenita and intestinal lymphangiectasia. Am J Dis Child 139:509, 1985. 45. Murphy EA: Familial lymphatic dysplasia with intestinal lymphangiectasia. Birth Defects Orig Artic Ser VIII(2):180, 1972. 46. Vardy PA, Lebenthal E, Shwachman H: Intestinal lymphangiectasia: a reappraisal. Pediatrics 55:842, 1975. 47. Parfitt AM: Familial neonatal hypoproteinemia with exudative enteropathy and intestinal lymphangiectasis. Arch Dis Child 41:54, 1966. 48. Shani M, Theodor E, Frand M, et al.: A family with protein-losing enteropathy. Gastroenterology 66:433, 1974. 49. Lee CH, Young JR: Chylous ascites in siblings. J Pediatr 42:83, 1953. 50. Flores S, Leungas J, Arredondo-Vega F, et al.: Chylous ascites in sibs from a consanguineous marriage. Am J Med Genet 3:145, 1979. 51. Van der Putte SCJ: Congenital hereditary lymphedema in the pig. Lymphology 11:1, 1978. 52. Van der Putte SCJ: Pathogenesis of congenital hereditary lymphedema in the pig. Lymphology 11:10, 1978. 53. Patterson DF, Medway W, Luginbuhl H, et al.: Congenital hereditary lymphedema in the dog. J Med Genet 4:145, 1967. 54. Luginbuhl H, Chacko SK, Patterson DF, et al.: Congenital hereditary lymphedema in the dog. J Med Genet 4:153, 1967. 55. Morris B, Blood DC, Sidman WR, et al.: Congenital lymphatic oedema in Ayrshire cattle. Aust J Exp Biol 32:265, 1954. 56. Mulei CM, Atwell RB: Congenital lymphedema in an Ayrshire-Friesian crossbred female calf. Aust Vet J 66:227, 1989. 57. Smeltzer DM, Stickler GB, Schirger A: Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206, 1985. 58. Dale RF: The inheritance of primary lymphedema. J Med Genet 22: 274, 1985. 59. Tatnall FM, Sarkany I: Primary facial lymphedema with xanthomas. J R Soc Med 81:113, 1988. 60. Mishkel MA: Xanthomatosis and chylous lymphedema. Arch Dermatol 106:601, 1972.

61. Wells GC: Primary unilateral megalymphatic lymphedema. J R Soc Med 72:63, 1979. 62. Ostrow RS, Manias D, Mitchell AJ, et al.: Epidermodysplasia verruciformis. A case associated with primary lymphatic dysplasia, depressed cell-mediated immunity and Bowen’s disease containing human papillomavirus 16 DNA. Arch Dermatol 123:1511, 1987. 63. Kiaer T, Larsen J: Necrotizing fasciitis in congenital lymphedema. Acta Chir Scand 154:665, 1988. 64. Albornoz MA, Myers AR: Recurrent septic arthritis and Milroy’s disease. J Rheumatol 15:1726, 1988. 65. Frayha RA, Tabbara KR, Mooradian A: Transudative knee effusions in Milroy’s disease. J Rheumatol 8:670, 1981. 66. Mistilis SP, Skyring AP, Stephen DD: Intestinal lymphangiectasia. Mechanism of enteric loss of plasma-protein and fat. Lancet 1:77, 1965. 67. Waldmann TA, Steinfeld JL, Dutcher TF, et al.: The role of the gastrointestinal system in ‘‘idiopathic hypoproteinemia.’’ Gastroenterology 41:197, 1961. 68. Pomerantz M, Waldmann TA: Systemic lymphatic abnormalities associated with gastrointestinal protein loss secondary to intestinal lymphangiectasia. Gastroenterology 45:703, 1963. 69. Weiden PL, Blaese RM, Strober W, et al.: Impaired lymphocyte transformation in intestinal lymphangiectasia: evidence for at least two functionally distinct lymphocyte populations in man. J Clin Invest 51:1319, 1972. 70. McGuigan JE, Purkerson ML, Trudeau WL, et al.: Studies of the immunological defects associated with intestinal lymphangiectasia. Ann Intern Med 68:398, 1968. 71. Barrett DS, Large SR, Rees GM: Pleurectomy for chylothorax associated with intestinal lymphangiectasia. Thorax 42:557, 1987. 72. McDonagh TJ, Gueft B, Pyun K, et al.: Hypoproteinemia, chylous ascites, steatorrhea, and protein-losing enteropathy due to chronic inflammatory obstruction of major intestinal lymph vessels. Gastroenterology 48:642, 1965. 73. Fairlie NC, Nakielny R, Polacarz SV: Case report: the computed tomographic appearances of lymphangiectasia in the pelvis. Clin Radiol 39:560, 1988. 74. De Sousa JS, Guerreiro O, Cunha A, et al.: Association of nephrotic syndrome with intestinal lymphangiectasia. Arch Dis Child 43:245, 1968. 75. Madhaven T, Rupe CE: Intestinal lymphangiectasia with normal immunological function. Henry Ford Hosp Med J 18:65, 1970. 76. Asakura H, Morita A, Morishita T, et al.: Histopathological and electron microscopic studies of lymphangiectasia of the small intestine in Behcet’s disease. Gut 14:196, 1973. 77. Scott RE: Ataxia-telangiectasia. Arch Pathol 88:78, 1969. 78. Dewbury KC, Rao KS, Poll V: Prenatal ultrasound demonstration of lymphangiectasia in the mesentery of the small bowel. Br J Radiol 54:687, 1981. 79. Campbell RSF, Brobst D, Bisgard G: Intestinal lymphangiectasia in a dog. JAMA 153:1050, 1968. 80. Smeltzer DM, Stickler GB, Fleming RE: Primary lymphatic dysplasia in children: chylothorax, chylous ascites, and generalised lymphatic dysplasia. Eur J Pediatr 145:286, 1986. 81. Sassoon CS, Light RW: Chylothorax and pseudochylothorax. Clin Chest Med 6:163, 1985. 82. Warwick WJ, Holman RT, Quie PG, et al.: Chylous ascites and lymphedema. Am J Dis Child 98:317, 1959. 83. Bell KA, Simon BK: Chylothorax and lymphangiomas of bone: unusual manifestations of lymphatic disease. South Med J 71:459, 1978. 84. Morphis LG, Arcinue EL, Krause JR: Generalized lymphangioma in infancy with chylothorax. Pediatrics 46:566, 1970. 85. Harvey JG, Houlsby W, Sherman K, et al.: Congenital chylothorax: report of unique case associated with ‘‘H’’-type tracheo-oesophageal fistula. Br J Surg 66:485, 1979. 86. Pearl KN, Wilson RG: Management problem in a child with congenital marble skin and chylothorax requiring repeated drainage. Lancet 2:90, 1981.

Lymphatic System 87. Van Aerde J, Campbell AN, Smyth JA, et al.: Spontaneous chylothorax in newborns. Am J Dis Child 138:961, 1984. 88. Yoss BS, Lipsitz PJ: Chylothorax in two mongoloid infants. Clin Genet 12:357, 1977. 89. Ho NK, Leong NKY, Lim SB: Chylothorax in Down’s syndrome associated with hydrops fetalis. J Sing Paediatr Soc 31:90, 1989. 90. Meizner I, Carmi R, Bar-ziv J: Congenital chylothorax—prenatal ultrasonic diagnosis and successful postpartum management. Prenat Diagn 6:217, 1986. 91. Booth P, Nicolaides KH, Greenough A, et al.: Pleuro-amniotic shunting for fetal chylothorax. Early Hum Dev 15:365, 1987. 92. Bessone LN, Ferguson TB, Burford TH: Chylothorax. Ann Thor Surg 12:527, 1971. 93. Said DM, Rosalinas AA, Reichelderfer TE: Chylothorax in the newborn. Report of a case associated with polyhydramnios. Med Ann DC 37:536, 1968. 94. Gullane PJ, Marsh AS: Bilateral spontaneous chylothorax presenting as a neck mass. J Otolaryngol 13:255, 1984. 95. Birchard SJ, Fossum TW: Chylothorax in the dog and cat. Vet Clin North Am 17:271, 1987. 96. Yancy WS, Spock A: Spontaneous neonatal pleural effusion. J Pediatr Surg 2:313, 1967. 97. Nix JT, Albert M, Dugas JE, et al.: Chylothorax and chylous ascites. A study of 302 selected cases. Am J Gastroenterol 28:40, 1957. 98. Hesseling PB, Hoffman H: Chylothorax. A review of the literature and report of 3 cases. S Afr Med J 60:675, 1981. 99. Chang CK, Viseskul C, Opitz JM, et al.: Generalised lymphangiectasis associated with chylothorax: a possible dysplasia of the lymphatic system. Z Kinderheilkd 118:9, 1974. 100. Witte CL, Witte MH, Unger EC, et al.: Advances in imaging of lymph flow disorders. Radiographics 20:1697, 2000. 101. Fang JM, Dagenais SL, Erickson RP, et al.: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382, 2000. 102. Brice G, Mansour S, Bell R, et al.: Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet 39:478, 2002. 103. Van Balkom IDC, Alders M, Allanson J, et al.: Lymphedemalymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet 112:412, 2002. 104. Irrthum A, Devriendt K, Chitayat D, et al.: Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72:1470, 2003. 105. Irons M, Bianchi DW, Geggel RL, et al.: Possible new autosomal recessive syndrome of lymphedema, hydroceles, atrial septal defect, and characteristic facial changes. Am J Med Genet 66:69, 1996. 106. Bull LN, Roche E, Song EJ, et al.: Mapping of the locus for cholestasislymphedema syndrome (Aagenaes syndrome) to a 6.6cM interval on chromosome 15q. Am J Hum Genet 67:994, 2000. 107. Limwongse C, Wyszynski RE, Dickerman LH, et al.: Microcephalylymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance. Am J Med Genet 86:215, 1999. 108. Evans AL, Bell R, Brice G, et al.: Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet 40:697, 2003. 109. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465, 2001. 110. Urioste M, Rodriguez JI, Barcia JM, et al.: Persistence of mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet 47:494, 1993. 111. Ruocco V, Schwartz RA, Ruocco E: Lymphedema: An immunologically vulnerable site for development of neoplasms. J Am Acad Dermatol 47:124, 2002.

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112. Cohen SR, Payne DK, Tunkel RS: Lymphedema. Strategies for management. Cancer 92:980, 2001. 113. Casley-Smith JR, Morgan RG, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-(a)-pyrone. N Engl J Med 329:1158, 1993. 114. Karkkainen MJ, Saaristo A, Jussila L, et al.: A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98:12677, 2001. 115. Keberle M, Mork H, Jenett M, et al.: Computed tomography after lymphangiography in the diagnosis of intestinal lymphangiectasia with protein-losing enteropathy in Noonan’s syndrome. Eur Radiol 10: 1591, 2000. 116. Kull PA, Hess R, Craig LE, et al.: Clinical, clinicopathologic, radiographic, and ultrasonographic characteristics of intestinal lymphangiectasia in dogs: 17 cases (1996-1998). J Am Vet Med Assoc 219:197, 2001. 117. Takahashi H, Imai K: What are the objectives of treatment for intestinal lymphangiectasia? J Gastroenterol 36:137, 2001. 118. MacLean JE, Cohen E, Weinstein W: Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy. Pediatrics 109: 1177, 2002. 119. Simonton SC, Saltzman DA, Brennom W, et al.: Cystic renal lymphangiectasia: a distinctive clinicopathological entity in the pediatric age group. Ped Pathol Lab Med 17:293, 1997. 120. Cadnapaphornchai MA, Ford DM, Tyson RW, et al.: Cystic renal lymphangiectasia presenting as renal insufficiency in childhood. Pediatr Nephrol 15:129, 2000. 121. Chan PC, Chiu HC, Hwu WH: Spontaneous chylothorax in a case of cardio-facio-cutaneous syndrome. Clin Dysmorphol 11:297, 2002. 122. Farrell SA, Warda LJ, LaFlair P, et al.: Adams-Oliver syndrome: a case with juvenile chronic myelogenous leukemia and chylothorax. Am J Med Genet 47:1175, 1993. 123. Williams MS, Josephson KD: Unusual autosomal recessive lymphatic anomalies in two unrelated Amish families. Am J Med Genet 73:286, 1997. 124. Tanemura M, Nishikawa N, Kojima K, et al.: A case of successful fetal therapy for congenital chylothorax by intrapleural injection of OK432. Ultrasound Obstet Gynecol 18:371, 2001. 125. Cardenas A, Chopra S: Chylous ascites. Am J Gastroenterol 97:1897, 2002. 126. Dubin PJ, King IN, Gallagher PG: Congenital chylothorax. Curr Opin Pediatr 12:505, 2000. 127. Demos NJ, Kozel J, Scerbo JE: Somatostatin in the treatment of chylothorax. Chest 119:964, 2001. 128. Noel AA, Gloviczki P, Bender CE, et al.: Treatment of symptomatic primary chylous disorders. J Vasc Surg 34:785, 2001. 129. Finegold DN, Kimak MA, Lawrence EC, et al.: Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet 15:1185, 2001.

4.2 Pulmonary Lymphangiectasia Definition

Pulmonary lymphangiectasia is the congenital dilation of the superficial lymphatics of the pleura and septa and of the intrapulmonary lymphatics in the peribronchial and perivascular adventitia. These lymphatics normally drain to the paratracheal, peribronchial, and pleuropulmonary lymph nodes. Diagnosis

Pulmonary lymphangiectasia is characterized by intercommunicating, thin-walled, endothelium-lined, fluid-filled cysts of greatly varying diameter, situated in abundant subpleural, peribronchial,

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and interlobular connective tissue.1 The pleural surface is smooth and intact but shows multiple localized areas of swelling, which are fluctuant on palpation. Minute cysts may be seen to a lesser extent in the lung substance. The lungs are bulky and firm, with clearly defined lobulation. They have the consistency of sponge rubber, are resistant to compression, and deflate slowly.2 Although the entire lung is generally affected, lobar involvement has been reported.3,25 The majority of affected individuals are stillborn or die within the first 24 hours of life.2 Liveborn individuals typically develop acute respiratory distress with tachypnea, cyanosis, subcostal retraction, and prolonged expiration very soon after birth.7 High concentrations of oxygen do not provide relief. Those who survive the newborn period often suffer attacks of chronic respiratory distress precipitated by respiratory infections, with wheezing and coughing. The signs and symptoms mimic chronic asthma. Recurrent pneumonia may be described.26 Delayed onset may be accompanied by sweating, poor feeding, hepatomegaly, peripheral edema, and other signs of congestive cardiac failure.4 Rare presentations include acute dyspnea and chest pain, resulting from pneumothorax, and pleural effusions associated with disordered lymphatic drainage, which may be ascertained by prenatal ultrasonography.5,6 In the past, pulmonary lymphangiectasia has been the domain of the pathologist, which is not surprising for a disease seen almost exclusively in stillborn infants and neonates dying in the first hours of life. Over the past few years a number of clinical reports have stressed the rather characteristic radiographic findings.2,7 In severe pulmonary lymphangiectasia, the chest radiograph generally shows large, punctate, military-like lesions distributed throughout the lungs, reticular areas of increased density that represent dilated lymphatics, Kerley B lines at the costophrenic angles, and overaeration of the lung fields, with a flattened diaphragm and a normal-sized heart. The diffuse reticular pattern, interspersed with small cystic areas, is one example of so-called honeycomb lung. In less extreme cases the radiograph shows only a diffuse congestive pattern that precludes confident diagnosis. Infants who survive may demonstrate decreased interstitial markings over time and increased hyperinflation associated with persistent patchy areas of ground-glass opacity.27 Lung biopsy is the only definitive diagnostic method. Microscopic examination reveals the presence of multiple cystic spaces and dilated channels, lined by flattened endothelial cells and supported by various amounts of fibrous connective tissue. They occur predominantly subpleurally, between the connective tissue septa of the lung, and peribronchially, in close approximation to the pulmonary vasculature, but without connection to either arteries or veins.1,8 The lung parenchyma is often diffusely atelectatic, with the exception of a few respiratory bronchioles and alveolar ducts.9 The distribution of cysts and dilated channels corresponds to the site of normal lymph vessels. The endotheliumlike lining distinguishes them from bronchiogenic cysts, which are lined by cylindrical bronchial or respiratory epithelium. Pulmonary lymphangiectasia shares some characteristics with lymphangiomatosis. However, in lymphangiectasia, the cysts are thin-walled and separated by normal connective tissue, whereas lymphangioma cysts are separated by thick, fibrous-tissue septa, in which lymph follicles and lymphocytes, islets of fat cells, and smooth muscle fibers may be found.9 Histologically, congenital lymphangiectasia must be differentiated from the dilated but normal lymphatics seen in hyaline membrane disease and hydrops

fetalis, from cystic disease of bronchial origin, and from interstitial emphysema. Peripheral pulmonary cystic disease is rarely fatal in the newborn period, the distribution of the cysts is somewhat different, and they are air-filled rather than fluid-filled, with a cuboidal epithelial rather than an endothelial lining. Radiographically, this disease process can generally be differentiated from the more common causes of respiratory distress in newborns, such as hyaline membrane disease, by lack of ground-glass appearance, and by the presence of overaeration of the lung fields. Transient tachypnea of the newborn may be distinguished by the presence of cardiomegaly and engorged pulmonary vasculature rather than a reticulonodular pulmonary interstitial pattern.10 Pulmonary lymphangiectasia does closely resemble ‘‘aspiration syndrome’’ and infectious pneumonitis in the newborn; however, Kerley B lines are not seen in the latter two conditions.10 Certain features are common to both pulmonary lymphangiectasia and Wilson-Mikity syndrome, although the latter is more likely to be found in premature infants, with onset after the 1st week of life, in association with maternal hemorrhage. Chest radiographs are quite similar, particularly in the early stages of Wilson-Mikity syndrome.11 The differential diagnosis also includes pneumocystis carinii pneumonia, Hamman-Rich syndrome, and adenomatous dysplasia. Between one-third and one-half of all cases are associated with congenital heart defects, particularly total anomalous pulmonary venous drainage, hypoplastic left heart syndrome, and premature closure of the foramen ovale.1,4,12–14 Intrauterine obstruction to pulmonary venous flow caused by these cardiac anomalies, or blind-ending common pulmonary vein, may increase pulmonary venous pressure, leading to lymphatic dilation.15 It is unclear whether hemodynamic factors are solely responsible for dilated lymphatic channels or whether there is a coexistent congenital lymphatic malformation. Factors in favor of a coexistent lymphatic malformation include absence of arterialization of the pulmonary veins, normally found when increased pulmonary venous pressure occurs secondary to acquired cardiac disease, such as mitral stenosis, and lack of pulmonary lymphangiectasia in many cases of obstructed pulmonary venous return.13 Pulmonary lymphangiectasia and complex congenital heart disease have been found in combination with asplenia and Noonan syndrome.4,16,17 Single cases have been reported with omphalocele, malrotation of the intestine, cretinism, arachnodactyly, trisomy 13, ureterovesical obstruction, Ehlers-Danlos syndrome, ichthyosis, cystic fibrosis, cystic hyperplasia of the bile ducts, and diaphragmatic hernia through the foramen of Bochdalek.4,14,18 Four cases have been associated with polycystic kidney disease.14 One infant born to a woman with phenylketonuria had pulmonary lymphangiectasia, hypoplastic left heart, and microcephaly.19 Etiology and Distribution

The lymphatics first grow into the lung bud in week 9 of intrauterine life. They rapidly and extensively invade the whole developing organ so that, by the end of week 14, the subpleural lymphatic plexus is well-developed.8 At the 12–16 week stage, large lymphatics, situated in the connective tissue, divide the pulmonary parenchyma into fairly distinct lobules. The lymphatics are so large in comparison to the size of the whole organ that there is a reversal of the normal tissue proportions. Normally, by weeks 18–20, the lobulations become less prominent, the connective tissue diminishes in amount, and the lymphatics become much narrower.8 Congenital pulmonary lymphangiectasia probably represents continued growth of the lung, with the tissue elements maintaining

Lymphatic System

their 12–16 week proportions. This accounts for normally developed parenchyma and grossly dilated lymphatic vessels with only slightly hypertrophied walls.8 Giammalvo, a proponent of the centripetal theory of lymphatic embryology, thought that cystic dilation of the lymphatics resulted from failure of or delay in linkage of isolated lymphatic spaces.20 Laurence infers that, if this were the explanation, cysts would probably be confined to the peripheral portions of the lungs where fusion occurs last, whereas, in fact, the distribution is diffuse and more in keeping with Laurence’s developmental arrest theory.8 Noonan and colleagues have classified pulmonary lymphangiectasia into three groups.1 In group 1, the dilated pulmonary lymphatics are part of a generalized form of lymphangiectasia, with coexisting intestinal lymphangiectasia, peripheral lymphedema, and dilated lymphatics of the lung, heart, pancreas, mesentery, and mediastinum.9,21–23 Pulmonary involvement in this group is less severe and is often associated with a much better prognosis. Group 2 includes those cases with congenital heart disease and obstruction to pulmonary venous flow mentioned previously. Group 3 comprises patients with a primary developmental defect of the lung lymphatics. This group clearly forms the majority and is associated with the worst prognosis. Since the first case of pulmonary lymphangiectasia was reported in 1856 by Virchow, over 100 cases have been described.13 No particular racial or ethnic predilection is apparent, but there is a fairly striking sex discrepancy, with a male to female ratio of 2:1.4,11,14 Two sibs with isolated pulmonary lymphangiectasia have been reported, and two other sib pairs, in whom pulmonary lymphangiectasia is associated with total anomalous pulmonary venous drainage, are described.4,24 Several families have been reported in which multiple siblings have nonimmune hydrops fetalis, chylothorax, pulmonary lymphangiectasia, distal lymphedema, and swelling of the face, a phenotype similar to Hennekam syndrome (see Table 4-1).28,29 Autosomal recessive inheritance seems likely. Prognosis, Prevention, and Treatment

The majority of affected individuals are stillborn or die within the first 24 hours of life. In series analyzed by France and Brown and by Fronstin et al., less than one-quarter of patients survived the 1st week.4,11 However, long-term survival is reported in a few individuals.1 Lobar pulmonary lymphangiectasia is cured by resection of the affected lobe(s).3,25 In the majority, treatment is merely palliative, with digoxin and diuretics given for congestive cardiac failure. Improvement occasionally follows atrial balloon septostomy in total anomalous pulmonary venous drainage. References (Pulmonary Lymphangiectasia) 1. Noonan JA, Walters LR, Reeves JT: Congenital pulmonary lymphangiectasis. Am J Dis Child 120:314, 1970. 2. Javett SN, Webster I, Braudo JL: Congenital dilatation of the pulmonary lymphatics. Pediatrics 31:416, 1963. 3. Wagenaar SS, Swierenga J, Wagenvoort CA: Late presentation of primary pulmonary lymphangiectasis. Thorax 33:791, 1978. 4. France NE, Brown RJK: Congenital pulmonary lymphangiectasis: report of 11 examples with special reference to cardiovascular findings. Arch Dis Child 46:528, 1971. 5. Siegal A, Katsenstein M, Wolach B: Neonatal pneumothorax, a rare complication of pulmonary cystic lymphangiectasis. Eur J Respir Dis 66:153, 1985. 6. Wilson RH, Duncan A, Hume R, et al.: Prenatal pleural effusion associated with congenital pulmonary lymphangiectasia. Prenat Diagn 5:73, 1985.

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7. Arkoff RS: Congenital pulmonary lymphangiectasis. Calif Med 109:464, 1968. 8. Laurence KM: Congenital pulmonary cystic lymphangiectasis. J Pathol Bacteriol 70:325, 1955. 9. Frank JF, Piper PG: Congenital pulmonary cystic lymphangiectasis. JAMA 171:1094, 1959. 10. Smith PL: Radiologic seminar CXCV: pulmonary lymphangiectasia. An uncommon cause of respiratory distress in the newborn. J Miss State Med Assoc 20:225, 1979. 11. Fronstin MH, Hooper GS, Besse BE, et al.: Congenital pulmonary cystic lymphangiectasis. Am J Dis Child 114:330, 1967. 12. Shortland-Webb WR, Tozer RA, Cameron AH: Intra-uterine closure of the atrial septum. J Clin Pathol 19:549, 1966. 13. Moerman PL, Van Dijck H, Lauweryns JM, et al.: Premature closure of the foramen ovale and congenital pulmonary cystic lymphangiectasis in aortic valve atresia or in severe aortic valve stenosis. Am J Cardiol 57:703, 1986. 14. Felman AH, Rhatigan RM, Pierson KK: Pulmonary lymphangiectasia: observation in 17 patients and proposed classification. Am J Radiol 116: 548, 1972. 15. Rywlin AM, Fojaco RM: Congenital pulmonary lymphangiectasis associated with a blind common pulmonary vein. Pediatrics 41:931, 1968. 16. Esterly JR, Oppenheimer EH: Lymphangiectasis and other pulmonary lesions in the asplenia syndrome. Arch Pathol 90:553, 1970. 17. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841, 1987. 18. Liew SH: A case of congenital pulmonary lymphangiectasis. Med J Malaysia 28:293, 1974. 19. Huntley CC, Stevenson RE: Maternal phenylketonuria. Course of two pregnancies. Obstet Gynecol 34:694, 1969. 20. Giammalvo JT: Congenital lymphangiomatosis of the lung: a form of cystic disease. Lab Invest 4:450, 1955. 21. Mann TP: Hemihypertrophy left side of body. Congenital lymphatic oedema of left arm. Radiological enlargement of heart shadow. Proc R Soc Med 48:12, 1955. 22. McKendry JBJ, Lindsay WK, Gerstein MC: Congenital defects of the lymphatics in infancy. Pediatrics 19:21, 1957. 23. Ekelund H, Palmstierna S, Ostberg G: Congenital pulmonary lymphangiectasis. Acta Paediatr Scand 55:121, 1966. 24. Scott-Emuakpor AB, Warren ST, Kapur S, et al.: Familial occurrence of congenital pulmonary lymphangiectasis. Am J Dis Child 135:532, 1981. 25. Rettwitz-Volk W, Schlosser R, Ahrens P, et al.: Congenital unilobar lymphangiectasis. Pediatr Pulmonol 27:290, 1999. 26. Bouchard S, Di Lorenzo M, Youssef S, et al.: Pulmonary lymphangiectasia revisited. J Pediatr Surg 35:796, 2000. 27. Chung CJ, Fordham LA, Barker P, et al.: Children with congenital pulmonary lymphangiectasia: after infancy. Am J Roentgenol 173:1583, 1999. 28. Njolstad PR, Reigstad H, Westby J, et al.: Familial non-immune hydrops fetalis and congenital pulmonary lymphangiectasia. Eur J Pediatr 157:498, 1998. 29. Jacquemont S, Barbarot S, Boceno M, et al.: Familial congenital pulmonary lymphangiectasia, non-immune hydrops fetalis, facial and lower limb lymphedema: confirmation of Njolstad’s report. Am J Med Genet 93:264, 2000.

4.3 Fetal Cystic Hygroma Definition

Fetal cystic hygroma is a single or multiloculated fluid-filled cavity, most often in the posterior nuchal region, caused by failure

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Fig. 4-7. Large fetal cystic hygroma in a fetus (18 weeks gestation with Turner syndrome [45,X]). (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

of or delay in jugular lymphaticovenous communication (Fig. 4-7). The term fetal cystic hygroma is used here to distinguish jugular lymphatic obstruction from cystic lymphangioma, which is also designated by some as cystic hygroma or giant cystic hygroma (see Section 4.4). Diagnosis

Fetal cystic hygromas (FCH) are generally bilateral, thin-walled, unilocular or multilocular, fluid-filled cavities in the posterior aspect of the neck.1 They may be asymmetric or symmetric.1–3 In most cases, the cavities are subdivided into a variable number of compartments by incomplete septa. They are lined by smooth endothelium and contain turbid light-brown fluid. The cavities may extend posteriorly from the upper part of the occipital bone to the level of the seventh cervical vertebra or scapular area, medially to beneath the sternocleidomastoid muscle, and rarely into the axilla or anterior chest wall.4 They are found superficial to the musculature of the neck, with a deep connection to the proximal part of the internal jugular vein.2 Dilated lymphatic vessels are often found in the walls of the cavity.5,6 There may be associated serpiginous, or multilocular, intradermal fluid collections in the skin and subcutaneous tissues of the thorax and abdomen.7 Some cavities are continuous, with intricate systems of irregular lymph channels, extending into the edematous connective tissue around adjacent anatomic structures, while others are well-demarcated.2 Absence of the lymphaticovenous communication near the jugulosubclavian junction, with blind-ending thoracic duct, paratracheal, and internal mammary lymph trunks, is described.2 Fetal cystic hygromas are frequently reported in association with abnormalities of the major lymph trunks. Aplasia, hypoplasia, or dilation of the lymphatic channels leads to peripheral edema and pleural, pericardial, and peritoneal effusions.1,2,6 Generalized hydrops accompanies 60–90% of FCH cases.1,4,8,9 Fetal cystic hygromas can be diagnosed reliably by ultrasound.8 The posterolateral position and cystic appearance are

characteristic (Fig. 4-8). Larger FCH are frequently divided by random, incomplete septa. They often have a dense midline septum, which represents the nuchal ligament and provides a useful landmark to differentiate FCH from other craniocervical masses. Maternal serum or amniotic fluid alpha-fetoprotein estimation has been used to aid diagnosis. However, the concentration of alphafetoprotein is inconsistent and adds little to the sonographic findings.8,10 Alpha-fetoprotein concentration in hygroma fluid is often markedly elevated.8 Transvaginal ultrasonography enables very early detection of FCH. Certain sonographic features help to differentiate FCH from other craniocervical masses, for example, encephalocele or other neural tube defects, cystic teratoma, twin sac of a blighted ovum, or nuchal edema. These features include an intact skull and spinal column, the lack of a solid component to the mass, a constant position of the mass relative to the fetal head, and cysts and septa.8 Microscopic appearance of FCH is characterized by dilated endothelium-lined spaces filled with serous fluid and focal and interstitial lymphoid aggregates.2 The tissues lining the cysts may be edematous, and distinct lymphatic channels are often observed.6,11 Blood vessels and nerves course within the thin septa separating the cysts. These features contrast with those observed in lymphangiomas removed from infants and children, in which lymphoid follicles and bundles of smooth muscle are regularly found in the cyst walls. Fetal cystic hygroma is a nonspecific malformation found in a number of unrelated conditions, the most common of which is Turner syndrome (45,X). Between 50% and 75% of all cases are cytogenetically abnormal.9,12,13 Of these, 40–80% are 45,X, while the majority of the remainder are autosomal trisomies.3,8,10,11,15 Within the group that is chromosomally normal are a number of single-gene disorders and patterns of malformations resulting from in utero exposure to known teratogens.29,33,35–46 A complete list is given in Table 4-2 on pp. 166–167. Congenital heart defects are found in association with FCH. In Turner syndrome, a spectrum of cardiac defects occurs that is

Lymphatic System

Fig. 4-8. Transverse sonogram showing a fetal cystic hygroma with characteristic midline septum. The cystic hygroma is slightly larger than the fetal head. P, placenta; CH, cystic hygroma; S, septum; FH, fetal head. (Reprinted with permission from Chervenak FA, et al.: N Engl J Med 309:822, 1983.8)

limited, almost exclusively, to those associated with decreased left heart blood flow, including coarctation of the aorta, hypoplastic left heart, aortic atresia, aortic valve stenosis, and bicuspid aortic valve.15,16 Different cardiac defects have been described when FCH is associated with trisomy 13 (double outlet right ventricle and agenesis of the semilunar valves) and trisomy 21 (abnormality of the atrioventricular orifice or valves).19 Septal defects, pulmonary valvular stenosis, and hypoplastic left heart have been reported with FCH in Noonan syndrome.36 Other malformations observed in rare instances include hydronephrosis, double ureter, horseshoe kidney, bilateral renal agenesis, two vessel cord, intrauterine growth retardation, and polysplenia syndrome.1,4,11 Etiology and Distribution

The jugular lymphatic sacs develop lateral to the internal jugular vein, beneath the sternocleidomastoid muscle, and extend to the posterior triangle of the neck. The right jugular lymphatic sac will become the right lymphatic duct, providing lymphatic drainage for the right side of the head and neck, the right upper extremity, both lungs, the heart, and the diaphragm. The left jugular lymphatic sac, after connecting with other lymphatic primordia, will become the thoracic duct, which serves as the common lymph trunk draining all other parts of the body. Normally, the two jugular lymphatic sacs drain into their respective internal jugular veins by way of two or three small foramina.2 In FCH, the lymphatic sacs do not connect normally with the venous system (Fig. 4-9). Failure of development of this communication results in stasis of lymph fluid, which causes a host of consequences secondary to jugular lymphatic obstruction. This is apparently a lethal anomaly unless the communication between the jugular lymph sac and the jugular vein develops by middle to late fetal life.

165

Once the link does occur, the distended jugular lymph sac collapses, leaving redundant skin in the neck region, with alteration in the posterior hairline and hair directional patterning plus elevation and sometimes protrusion or posterior angulation of the auricle. As the neck lengthens, the redundant skin forms folds known as pterygium colli. Peripheral accumulation of lymphedema fluid causes full subcutaneous tissues with relative overgrowth of the overlying skin, prominent fingertip pads, and narrow hyperconvex nails, which are often deeply set at the base. Peripheral lymphedema may not completely disappear by birth, leaving puffy hands and feet. Distension of lymph channels in the thoracic wall may distort the placement of the nipples and symmetry of the chest. Dilated vessels in the lower abdominal wall may impede descent of the testes into the scrotum, leading to cryptorchidism. Further support for the jugular lymphatic obstruction pathogenesis of fetal cystic hygroma comes from the description of a fetus with a unilateral left cystic hygroma and edema of the entire body except the right arm, apparently caused by interrupted communication between the thoracic duct and left jugular vein, with normal connection between the right lymphatic duct and venous system.17 Clark suggests that dilated lymphatic vessels at the base of the heart encroach on the ascending aorta, increasing resistance to left-sided blood flow.15 This can alter the proportion of aortic and pulmonary flow, creating a branch point at the juxtaductal aorta, which forms the aortic flange and manifests as coarctation. Severe reduction in left heart blood flow may lead to hypoplastic left heart or aortic atresia. Less severe flow reduction may result in partial opening of the aortic valve leaflets, which then fuse, causing bicuspid aortic valve. This pathogenetic link between FCH and congenital heart defects is supported by findings in Turner syndrome in which the incidence of congenital heart disease differs significantly between those patients with neck webbing and those without neck webbing.16,18 The difference is most striking when one looks at coarctation of the aorta, of which the incidence is 25% in those with neck webbing and 3% in those without neck webbing.15 Two animal models also confirm the pathogenetic link between FCH, hydrops, and congenital heart defects. The embryology of the heart’s lymphatic system has been studied in the chick embryo.15 Lymphatic vessels coalesce at the base of the heart, and

Fig. 4-9. Lymphatic system in a normal fetus (left) with a patent connection between the jugular lymphatic sac and the internal jugular vein; cystic hygroma and hydrops (right) from failed lymphaticovenous connection. (Reprinted with permission from Chervenak FA, et al.: N Engl J Med 309:822, 1983.8)

Table 4-2. Syndromes with fetal cystic hygroma Syndrome

Prominent Features

Causation Gene/Locus

Achondrogenesis type II

Short-limbed dwarfism, decreased vertebral ossification, large head with normal ossification of the calvarium, subcutaneous edema

AR (200610) 12q13.11-q13.2

Alcohol, prenatal33

Growth and mental impairment, microcephaly, small palpebral fissures, ptosis, smooth philtrum, heart defects

Teratogen exposure

Aminopterin, prenatal33

Defective cranial ossification, hypertelorism, micrognathia, growth impairment

Teratogen exposure

Campomelic dysplasia48

Anterior bowing of femora and tibiae, dimples over location of maximum curvature, sex reversal, flat face, prenatal growth deficiency

AD (114290) SOX9, 17q24.3-q25.1

Chromosome aberrations: Dup(11p)31

Hydrops, cleft lip and palate, preductal coarctation, left diaphragmatic hernia, intestinal malrotation, cryptorchidism

Chromosomal

11q;22q Translocation34

Low birth weight, delayed psychomotor development, hypotonia, microcephaly, craniofacial asymmetry, malformed ears with pits and tags, cleft palate, congenital heart disease, cryptorchidism

Chromosomal

Trisomy 1328

Microcephaly, microphthalmia, cleft lip/palate, polydactyly, cardiac and renal defects, mental retardation

Chromosomal

Del(13q)33

Microcephaly, prominent nasal bridge, radial hypoplasia, mental retardation

Chromosomal

Trisomy 1827

Growth and mental impairment, micrognathia, cardiac defects, overlapping digits

Chromosomal

Del(18p)32

Retinal coloboma, absent labia minora, external ear abnormalities, midface hypoplasia, epicanthal folds, high-arched palate

Chromosomal

Down27

Growth and mental impairment, microbrachycephaly, upslanted palpebral fissures, Brushfield spots, small mouth, flat facies, hypotonia, cardiac defects

Chromosomal

Trisomy 22/mosaicism32

Facial asymmetry, telecanthus, ptosis, down-slanting palpebrae, preauricular pits, short neck, low posterior hairline, clitoromegaly

Chromosomal

Turner3,11

Hydrops, preductal coarctation, short stature, ovarian dysgenesis, facial dysmorphism, excess nuchal skin, low posterior hairline, low-set and posteriorly angulated ears, widely spaced nipples, deep-set nails

Chromosomal

45,X/46,XY46

Hydrops, hypoplastic left heart, ambiguous genitalia

Chromosomal

Klinefelter29

Tall stature, mild learning disabilities, eunuchoid habitus if untreated in adolescence

Chromosomal

49,XXXXY47

Facial dysmorphism, tall stature, mental retardation, congenital heart defects

Tetraploidy30

Hydrops, preductal coarctation, intestinal malrotation, horseshoe kidney

Chromosomal

Cowchock38

Cleft palate, asplenia

AR

Cumming39

Campomelia; short gut; polysplenia; polycystic kidneys, pancreas, and liver

AR (211890)

37

(continued)

166

Lymphatic System

167

Table 4-2. Syndromes with fetal cystic hygroma (continued) Syndrome

Prominent Features

Causation Gene/Locus

Distichiasis-lymphedema

Distichiasis, lymphedema, spinal extradural cysts, congenital heart disease

AD (153400) FOXC2, 16.24.3

Holoprosencephaly13

Cyclopia, cebocephaly, ethmocephaly, single central incisor, absent sense of smell, proboscis, midline brain anomalies

Chromosomal anomalies; AR (236100) AD (142945) SHH, 7q36 (603073) ZIC2, 13q32 AD (157170) SIX3, 2p21 AD (142946) TGIF, 18p11

Lethal multiple pterygium42

Hydrops, cleft palate, joint contractures, multiple pterygia, muscular atrophy, gracile bones, pulmonary and cardiac hypoplasia

AR (253290)

Lethal multiple pterygium, X-linked43

Cleft palate, multiple pterygia, radioulnar hypoplasia, dislocated hips

XL (312150)

Noonan35,36,49

Short stature, congenital heart defect, mental retardation, downward-slanting palpebrae, widely spaced eyes, ptosis, pectus deformity, webbed neck, cryptorchidism, other lymphatic abnormalities including hydrops, peripheral lymphedema, chylous effusions

AD (163950) PTPN11, 12q24

Nuchal blebs40,41

Hydrops, short neck

AR (257350)

Oculodentodigital13

Close-spaced eyes, microphthalmos, dental enamel hypoplasia, camptodactyly of fifth fingers, thin hypoplastic alae nasi, fine sparse hair

AD (164200) Connexin 43, 6q21q23.2

Thrombocytopenia-absent radius13

Radial agenesis with normal thumbs, thrombocytopenia in early infancy, variable lower limb anomalies

AD (274000)

Trimethadione, prenatal33

Growth and mental impairment, V-shaped eyebrows, epicanthus, microcephaly, retroverted pinnae

Teratogen exposure

44

the lymphatic ducts course to the jugular lymphatic sac, parallel to the aorta. Clark speculates that the increase in hydrostatic pressure within the jugular lymphatic sac would also distend the cardiac lymphatics, leading to reduced cardiac blood flow and anomalous development.15 Mouse trisomy 16 is the animal model of human trisomy 21 because of cardiovascular malformations common to both and homologous gene loci on the concerned chromosomes.19 Cystic accumulation of fluid at the back of the fetus has been observed in mouse trisomy 16, and cardiovascular malformations such as persistent truncus arteriosus, double outlet right ventricle, and aortic arch anomalies have been recognized.19 In a histologic study of normal mouse fetuses, the communication between the jugular lymphatic sac and the jugular vein was recognized from day 14. In trisomy 16 fetuses, the communication was not formed until days 15–16, and nuchal edema always appeared on day 14. The edema was largely caused by cystic dilation of lymph vessels in the nuchal region and was followed by generalized subcutaneous accumulation of fluid. Miyabara et al. speculate that the malformations observed in mouse trisomy 16, including abnormal lymph vessels, cardiovascular malformations, and hypoplastic thymus, may be related to the abnormal migration of neural crest cells and abnormal distribution of extracellular matrix.19 This alternative mechanism may

explain the variation between the pattern of cardiac defects seen in trisomy 21 and that found in Turner syndrome. The role of fetal proteins in the etiology of edema and FCH is unclear. In studies of Turner syndrome fetuses, Shepard et al. have found significantly reduced concentrations of plasma protein and albumin compared with gestational age-appropriate controls.20 Hypoalbuminemia may result from decreased production, altered distribution, or decreased half-life. Lymphatic abnormalities could increase the extravascular component, allowing redistribution with consequent dilution of albumin. The effect of lower oncotic pressure on the development of the lymphatic system in the embryo and early fetus is unknown. FCH is found in one per 700 to 1000 prenatal diagnostic ultrasound scans, but the incidence is higher, around 1%, when transvaginal ultrasonography is used from the end of the first trimester to the early second trimester.5,21 FCH accounts for between 1% and 5% of malformations diagnosed before 26 weeks gestation.5,10 A study of spontaneously aborted fetuses has documented FCH in one of 875. The incidence increased to one of 200 in fetuses with an over 3 cm crown to rump length.11 More than 150 cases are now described in the literature. There does not appear to be any ethnic or racial predisposition. More females than males are

168

Cardiorespiratory Organs

ascertained because of the frequent association with Turner syndrome. Prognosis, Prevention, and Treatment

The natural history of FCH is variable and depends to a large extent on the presence or absence of hydrops. Concomitant hydrops is described in 60–90% of cases, and in these cases the outlook is generally grave, although resolution is reported.1,4,8,9,13 Data from several large series suggest that less than 10% of continuing pregnancies result in liveborn infants.9,l0,13 The majority of cases are terminated at the parents’ request.10 Over 90% of the remainder result in spontaneous abortion, intrauterine fetal demise, or early neonatal death.9,10,13,14 There are many reports of FCH without hydrops in which resolution of the FCH occurred. Excess nuchal skin, minor degrees of pedal edema, and, in one case, bicuspid aortic valve were noted.13,22–26 In these cases, fetal cystic hygromas were diagnosed by ultrasound at 11–16 weeks gestation and had resolved by 16–29 weeks gestation. Within this group are cases with a chromosome abnormality and cases that are cytogenetically normal. Prognosis may also depend on the gestational timing of ascertainment. In the past the diagnosis of FCH has been made at gestational ages greater than 9–15 weeks. Most cases are septated and multiloculated, with a poor prognosis. The septated lesions may be associated with complete obstruction of the cervical lymphatic sacs. The accumulating lymphatic fluid infiltrates between the cervical tissues, creating multilocular cysts and ultimately generalized fetal hydrops. In contrast, nonseptated FCH may represent temporary accumulation of lymph with enlargement of the lymphatic sacs. Increasing pressure within the sacs overcomes an incomplete obstruction with subsequent gradual decompression. This may be a normal variant in the development of lymphaticovenous communication, which has gone unnoticed until the advent of early, transvaginal ultrasound. Early reports speculated that one might be able to distinguish between the septated lesions (with bad outcome) and the early-onset, nonseptated lesions (with good outcome). It now seems clear that this distinction is too simplistic and resolving FCH cases may or may not be septated.13,14,23,25,26 A high incidence of chromosome abnormality is found in FCH, whether diagnosis is made in the first or early second trimester. However the etiology appears to differ depending on gestational age at ascertainment. In the first trimester, there is a high incidence of trisomies 21, 18, and 13, while Turner syndrome is less common. This latter diagnosis is much more frequently found when ascertainment occurs in the second trimester.14 The prenatal diagnosis of cystic hygroma poses a serious dilemma for pregnancy management and family counseling. The diagnosis of FCH should be sonographically confirmed and distinguished from other craniocervical masses. A detailed search for other malformations, intrauterine growth retardation, and generalized hydrops should be combined with an estimate of the extent of the FCH. Amniocentesis and fetal karyotyping are essential. Alpha-fetoprotein estimation provides little additional information. In those cases in which a chromosome abnormality can be detected or in which additional malformations are identified by ultrasonography, an informed decision may be reached more easily. When the diagnosis and/or prognosis is uncertain, however, parental adjustment to an already difficult situation is further complicated by the inability to obtain precise information. Optimal care requires a multidisciplinary approach, including obstetrician, radiologist, geneticist, neonatologist, and surgeon. When termination of pregnancy or fetal demise occurs, autopsy

is essential. The FCH must be confirmed histologically and differentiated from nuchal edema. A cytogenetic study should be performed if it was not completed antemortem, and a detailed search should be made for the features of the various syndromes detailed in Table 4-2. References (Fetal Cystic Hygroma) 1. Garden AS, Benzie RJ, Miskin M, et al.: Fetal cystic hygroma colli: antenatal diagnosis, significance and management. Am J Obstet Gynecol 154:224, 1986. 2. Van der Putte SCJ: Lymphatic malformation in human fetuses. A study of fetuses with Turner’s syndrome or Status Bonnevie-Ullrich. Virchows Arch Pathol Anat 376:233, 1977. 3. Singh RP, Carr DH: The anatomy and histology of XO human embryos and fetuses. Anat Rec 155:369, 1966. 4. Gembruch U, Hansmann M, Bald R, et al.: Prenatal diagnosis and management in fetuses with cystic hygroma colli. Eur J Obstet Gynecol Reprod Biol 29:241, 1988. 5. Bronshtein M, Rottem S, Yotte N, et al.: First-trimester and early second trimester diagnosis of nuchal cystic hygroma by transvaginal sonography: diverse prognosis of the septated from the nonseptated lesion. Am J Obstet Gynecol 161:78, 1989. 6. Chitayat D, Kalousek DK, Bamforth JS: Lymphatic abnormalities in fetuses with posterior cervical cystic hygroma. Am J Med Genet 33:352, 1989. 7. Philips HE, McGahan JP: Intrauterine fetal cystic hygroma: sonographic detection. Am J Radiol 136:799, 1981. 8. Chervenak FA, Isaacson G, Blakemore KJ, et al.: Fetal cystic hygroma: cause and natural history. New Eng J Med 309:822, 1983. 9. Abramowicz JS, Warsof SL, Doyle DL, et al.: Congenital cystic hygroma of the neck diagnosed prenatally: outcome with normal and abnormal karyotype. Prenat Diagn 9:321, 1989. 10. Cohen MM, Schwartz S, Schwartz MF, et al.: Antenatal detection of cystic hygroma. Obstet Gynecol Surg 44:481, 1989. 11. Byrne J, Blanc WA, Warburton D, et al.: The significance of cystic hygroma in fetuses. Hum Pathol 15:61, 1984. 12. Kalousek DK, Seller MJ: Differential diagnosis of posterior cervical hygroma in previable fetuses. Am J Med Genet 28:83, 1987. 13. Bernstein HS, Filly RA, Goldberg JD, et al.: Prognosis of fetuses with a cystic hygroma. Prenat Diagn 11:349, 1991. 14. Johnson MP, Johnson A, Holzgreve W, et al.: First-trimester simple hygroma: cause and outcome. Am J Obstet Gynecol 168:156, 1993. 15. Clark EB: Neck web and congenital heart defects: a pathogenic association in 45 X-O Turner syndrome? Teratology 29:355, 1984. 16. Lacro RV, Jones KL, Benirschke K: Coarctation of the aorta in Turner syndrome: a pathologic study of fetuses with nuchal cystic hygromas, hydrops fetalis, and female genitalia. Pediatrics 81:445, 1988. 17. Shaub M, Wilson R, Collea J: Fetal cystic lymphangioma (cystic hygroma): prepartum ultrasonic findings. Radiology 121:449, 1976. 18. Lin AE, Garver KL: Monozygotic Turner syndrome twins—correlation of phenotype severity and heart defect. Am J Med Genet 29:529, 1988. 19. Miyabara S, Sugihara H, Maehara N, et al.: Significance of cardiovascular malformations in cystic hygroma: a new interpretation of the pathogenesis. Am J Med Genet 34:489, 1989. 20. Shepard TH, Wener MH, Myhre SA, et al.: Lowered plasma albumin concentration in fetal Turner syndrome. J Pediatr 108:114, 1986. 21. Marchese C, Savin E, Dragone E, et al.: Cystic hygroma: prenatal diagnosis and genetic counseling. Prenat Diagn 5:221, 1985. 22. Chodirker BN, Harman CR, Greenberg CR: Spontaneous resolution of a cystic hygroma in a fetus with Turner syndrome. Prenat Diagn 8:291, 1988. 23. Macken MB, Grantmyre EB, Vincer MJ: Regression of nuchal cystic hygroma in utero. J Ultrasound Med 8:101, 1989. 24. Darby BG: Resolution of cystic hygroma. Prenat Diagn 9:447, 1989. 25. Distell BM, Hertzberg BS, Bowie JD: Spontaneous resolution of a cystic neck mass in a fetus with normal karyotype. Am J Radiol 153:380, 1989. 26. Rodis JF, Vintzileos AM, Campbell WA, et al.: Spontaneous resolution of fetal cystic hygroma in Down’s syndrome. Obstet Gynecol 71:976, 1988.

Lymphatic System 27. Pearce JM, Griffin D, Campbell S: Cystic hygroma in trisomy 18 and 21. Prenat Diagn 4:371, 1984. 28. Greenberg F, Carpenter RJ, Ledbetter DH: Cystic hygroma and hydrops fetalis in a fetus with trisomy 13. Clin Genet 24:389, 1983. 29. Hoyme HE, Byrne-Essif KE: Prenatal edema and the ‘‘Noonan phenotype’’ in Klinefelter syndrome. Clin Res 38:187A, 1990. 30. Fryns JP, Vanderberghe K, Moerman F, et al.: Tetraploidy with hydrops fetalis, cystic nuchal hygroma and 90,XX karyotype. Clin Genet 31:158, 1987. 31. Fryns JP, Kleczkowska A, Vandenberghe K, et al.: Cystic hygroma and hydrops fetalis in dup (1lp) syndrome. Am J Med Genet 22:287, 1985. 32. Pagon RA, Hall JG, Davenport SLH, et al.: Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Med Genet 31:54, 1979. 33. Graham JM Jr, Stephens TD, Shepard TH: Nuchal cystic hygroma in a fetus with presumed Roberts syndrome. Am J Med Genet 15:163, 1983. 34. Fraccaro M, Lindstell J, Ford CE, et al.: The 1lq; 22q translocation: a European collaborative analysis of 43 cases. Hum Genet 56:21, 1980. 35. Allanson JE: Noonan syndrome. J Med Genet 24:9, 1987. 36. Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 27:841, 1987. 37. Wenstrom KD, Williamson RA, Hoover WW, et al.: Achondrogenesis type II (Langer-Saldino) in association with jugular lymphatic obstruction sequence. Prenat Diagn 9:527, 1989. 38. Cowchock FS, Wapner RJ, Kurtz A, et al.: Brief clinical report: not all cystic hygromas occur in the Ullrich Turner syndrome. Am J Med Genet 12:327, 1982. 39. Cumming WA, Ohlsson A, Ali A: Brief clinical report: campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:785, 1986. 40. Bieber FR, Petres RE, Bieber JM, et al.: Prenatal detection of a familial nuchal bleb simulating encephalocele. Birth Defects Orig Artic Ser XV(5A):51, 1979. 41. Dallapiccola B, Zelante L, Perla G, et al.: Prenatal diagnosis of recurrence of cystic hygroma with normal chromosomes. Prenat Diagn 4:383, 1984. 42. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809, 1984. 43. Tolmie JL, Patrick A, Yates JRW: A lethal multiple pterygium syndrome with apparent X-linked recessive inheritance. Am J Med Genet 27:913, 1987. 44. Robinow M, Johnson GF, Verhage AD: Distichiasis-lymphedema: a hereditary syndrome of multiple congenital defects. Am J Dis Child 119: 343, 1970. 45. Watson WJ, Thorp JM, Seeds JW: Familial cystic hygroma with normal karyotype. Prenat Diagn 10:37, 1990. 46. Verp MS, Sheikh Z, Anarose AP, et al.: Cystic hygroma and 45,X/46,XY mosaicism. Am J Med Genet 33:402, 1989. 47. Cullen MT, Gabrielli S, Green JJ, et al.: Diagnosis and significance of cystic hygroma in the first trimester. Prenat Diagn 11:643–651, 1991. 48. Tricoire J, Sarramon MF, Rolland M, et al.: Familial cystic hygroma. Report of 8 cases in 3 families. Genet Couns 4:265, 1993. 49. Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465, 2001.

4.4 Lymphangioma Definition

Lymphangioma is lymph-containing, endothelial-lined spaces, which vary in size from channels of capillary dimensions to cysts several centimeters in diameter.

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Diagnosis

Lymphangiomas are abnormal structures consisting of endotheliallined spaces of various sizes, supported by connective tissue stroma of varying thicknesses, often containing lymph nodes, round cells, and, occasionally, vestiges of smooth muscle and other neighboring tissues (Figs. 4-10 to 4-13). They may be small and circumscribed or so large and diffuse that adequate therapy is difficult. The cysts and capillaries are filled with thin, watery, clear to straw-colored fluid.

Fig. 4-10. High-power microscopic view of a cystic lymphangioma, showing numerous small and large spaces lined by flat endothelium. Many spaces are filled with eosinophilic fluid (hematoxylin-eosin, X128). (Reprinted with permission from Karmody CS, et al.: Otolaryng Head Neck Surg 90:283, 1982.89)

Fig. 4-11. Newborn infant with a giant beardlike cyst lymphangioma causing respiratory distress. (Reprinted with permission from Seashore JH, et al.: Am J Surg 149:459, 1985.46)

170

Cardiorespiratory Organs

Fig. 4-12. Cystic lymphangioma of the axilla in a 2-week-old male infant. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Institute, Wilmington, DE.)

This fluid may contain lymphocytes, monocytes, and occasional polymorphonuclear cells. The contents of the cyst may be bloody following trauma.1 Landing and Farber2 have classified lymphangiomas into three groups: 1. Capillary: thin-walled, endothelial-lined capillary-sized channels, confined to the dermis and epidermis, that clinically present as slightly elevated papules or wartlike excrescences on skin or mucous membranes. They are generally white or purple in hue, the latter being due to a blood coagulum within the lesion.3,4 They may be single or multiple and may involve the oral region, particularly the tongue, and the genital region. They are often referred to as lymphangioma simplex. Lymphangioma cutis circumscriptum is another capillary type, characterized by multiple bleblike nodules with hyperkeratosis, located on the face, chest, and extremities.3,5 Histologically, these often extend deeper into the dermis than lymphangioma simplex, and there are increased numbers of

confluent lesions in the papillary layer of the dermis.6 Capillary lymphangioma has been alternatively classified into ‘‘classic’’ and ‘‘localized’’ groups based on differing presentation and prognosis.4 Classic lesions are usually present at birth or soon thereafter, but may appear in adulthood. The affected area may be quite extensive and most frequently involves the proximal extremities, notably the upper arm, axilla, and adjacent chest wall. Although usually asymptomatic, minor bleeding and infection can occur. In contrast, a localized lesion may become apparent at any age, without a particular anatomic predilection. Mucous membranes may be involved, and symptoms are uncommon.4 2. Cavernous: lesions composed of dilated, endothelial-lined lymphatic sinuses within a delicate reticular network of areolar tissue.3,4 Contained within the malformation are irregular masses of lymphocytes, lymph nodes, lymph follicles, and many interconnecting channels. The cavernous element may extend deep into the underlying muscles and surrounding tissues.5 The skin overlying a cavernous lymphangioma is typically unaffected, and the lesion frequently feels much like a lipoma or cyst but is occasionally fibrotic, depending on the number of previous episodes of lymphangitis.6 Gross pathologic appearance is that of a multilocular cyst, lined with a glistening white membrane, adherent to surrounding structures.3 Cavernous lesions may be single or multiple and can be found in any area of the body, although they typically occur in the tongue, mouth, parotid gland, and larynx. Patients most commonly present with a painless mass that has gradually enlarged. Symptoms result from mass effects as well as from local tissue invasion. The tongue may be the single most common anatomic site affected.4 3. Cystic (cystic hygroma): the most common of the lymphangiomas,4 composed of cysts from a few millimeters to several centimeters in diameter.1 From 75% to 90% are found in the neck, and about 20% are located in the axilla.4 The posterior cervical triangle is most frequently involved. Presentation in the anterior triangle of the neck is associated with extensive infiltration of local structures and can involve the floor of the mouth, tongue, or upper respiratory tract.3 About 2–3% of cervical cystic lymphangiomas extend to the mediastinum and even to the diaphragm.4 Less than 1% are located exclusively in the mediastinum.4 Curiously, while cervicomediastinal cystic lymphangiomas are typically found

Fig. 4-13. Cystic lymphangiomas of the neck. Left: large lymphangioma of the left side of the neck in a 3-day-old infant. Middle: smaller lymphangioma of left supraclavicular area in a 3-year-old girl. Right: lymphangioma of anterior neck in a 6-year-old male. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Institute, Wilmington, DE.)

Lymphatic System Table 4-3. Anatomic location of lymphangiomas Site

No.

Percent

Head

219

20

Neck

438

41

Axilla

130

13

Trunk

122

11

Extremities

122

11

13

1

Mediastinum Abdomen/genitalia Total

39

3

1075

100

Data are compiled from several sources.1,7,9–12

in infants, pure mediastinal lesions predominate in adults.4 Other less common sites include the groin, pelvis, retroperitoneal space, viscera, and bones.4 Several large reviews document the anatomic variability.1,7–12 Details of location, based on the above series, are provided in Table 4-3. Subsections, based on anatomic location, detailing demographic, clinical, and diagnostic features are provided at the end of this entry. Cystic lymphangiomas usually present as a painless mass, often associated with marked distortion of the tissues.5 Other clinical features depend on the size and location of the lymphangioma. They tend to be soft, compressible, and rounded or lobulated. Cystic lymphangiomas are also known as cystic hygromas. The term lymphangioma is used here to differentiate these malformations from fetal cystic hygroma (jugular lymphatic obstruction sequence) that has totally separate embryologic, pathologic, and clinical features. Although cystic and cavernous lymphangiomas may appear quite different clinically, there is no sharp dividing line between the two. Moreover, all three types of lymphangioma are not infrequently found together. There is some evidence that cystic lymphangiomas might first have been cavernous lesions. The physical structure of the tumor may be determined by the nature of the surrounding tissues.1 In the lips, cheek, tongue, and, to a lesser extent, the floor of the mouth, there are muscle fibers interlocking with the superficial tissues, leading to the development of smaller capillary or cavernous lymphangiomas. In the neck, axilla, and chest wall, where there are clearly defined tissue planes with loose fatty tissue surrounding large compact muscles and neurovascular structures, there is ample space for expansion of single cysts and for tongues of cystic structures to insinuate themselves among the large vessel and nerve trunks forming cystic lesions. Combinations of capillary, cavernous, and cystic lymphangiomas are frequently seen, with the cystic portions and the cavernous/capillary portions occupying separate but neighboring regions, dictated by the nature of the surrounding tissues.1 While a number of these malformations have been described in adults, between 50% and 65% are present at birth and 80–90% are detected before the end of the 2nd year of life.1,7,10,12–14 Both ultrasonography and computed tomography (CT) scanning have been used in diagnosis. Ultrasound delineates cystic masses with indistinct borders.15,16 The masses are often multilocular, with linear septations of variable thicknesses. Most lymphangiomas have solid components related to the cyst walls or to the septa. This sonographic appearance is reminiscent of benign multilocular cysts of the kidney or mucinous cystadenoma of the ovary. Sonographic-pathologic correlation demonstrates that the echo-

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genic component often corresponds to a cluster of abnormal lymphatic channels, too small to be individually resolved by ultrasound. The thickness and echogenicity of the septa vary with the amount of connective tissue, muscle tissue, and adipose tissue present in between the cysts.15 Large lesions have ill-defined boundaries, with some cysts dissecting between normal planes. CT scanning is considered by some to be the best method for examining neck masses.16 The differential diagnosis of a predominantly cystic, extrathyroidal neck mass includes branchial cleft cyst and thyroglossal duct cyst.15 These embryologic remains occur in characteristic locations: the former is found anterolateral to the carotid sheath, and the latter is found in the midline. Both tend to be unilocular, unlike most cystic lymphangiomas. Abscesses and resolving hematomas can also be cystic but are often more localized with an appropriate clinical presentation.15 Teratoma is a rare lesion but has a complex echo pattern that may be difficult to distinguish from cystic lymphangioma. Enlarged lymph nodes are usually solid and hypoechoic but can occasionally mimic cystic masses. Most other neck masses are solid and are therefore more circumscribed and less fluctuant than lymphangioma.3 Such solid masses include neuroblastoma, lipoma, salivary gland tumor, and neurofibroma.15 Hemangioma may be especially difficult to differentiate clinically from lymphangioma because both are soft on palpation. The distinction is difficult even with electron microscopy and is simply made on the basis of presence or absence of red cells and lymph. Sonography can be helpful, since hemangiomas are primarily echogenic, some containing small serpiginous anechoic spaces.15 Diagnostic difficulties can arise, however, if the cystic lymphangioma contains a large solid component. Meningoencephaloceles are alternative causes of masses in the occipital region.10 Fetal cystic hygroma is an etiologically distinct condition that results from jugular lymphatic obstruction in utero. It is histologically distinct from cystic lymphangioma (see Section 4.3) and is rarely present at birth. It is marked by other phenotypic features, including redundant neck skin, seen after jugular-venous communication occurs and the cystic hygroma decompresses. Details of the differential diagnosis of lymphangioma in other locations are given in the anatomic subsections at the end of this entry. Anomalies, including congenital heart defects, cleft lip, and spina bifida, are rarely described in association with lymphangiomas.17 Prenatal ultrasonographic diagnosis of cystic lymphangioma in various sites usually occurs as an incidental finding in the third trimester. The masses contain multiple cysts and solid portions within and between the cysts and thus have an appearance different from a fetal cystic hygroma caused by jugular lymphatic obstruction.18 Etiology and Distribution

Goetsch19 believed that a cystic lymphangioma represented a true infiltrating neoplasm, while Willis20 regarded lymphangioma as a hamartoma, that is, an embryologic tumor formed by excessive growth of tissues in their normal location. He compared them with hemangiomas.20 The most likely explanation is built on the centrifugal embryologic theory of Sabin,21 which has been validated by Van der Putte.22 In the process of centrifugal growth and outpouching of the lymphatic primordia, various areas of the lymphatic anlage grow abnormally, become sequestered, and never achieve efficient anastomoses with the larger lymph channels.1 Functionally they exist as a localized area of lymphatic stasis due to congenital blockage of regional lymphatic drainage. There is no evidence to support active infiltration of surrounding tissues, as described by Goetsch.19

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Lymphangioma is a rare tumor and accounts for only 6% of benign tumors in childhood and for 5% of vascular growths. In a series of 152 benign neck tumors, only four lymphangiomas were detected.12 In another series of 768 benign tumors, seen over a 15-year period, only 48 were lymphangiomas.14 The sexes are affected equally. Prognosis, Prevention, and Treatment

Lymphangiomas may spontaneously involute either completely or partially. Broomhead was the first to report a 16% complete spontaneous involution of cavernous lymphangiomas of the neck.23 With no treatment, most of the masses were gone by the time the patients reached age 2 years. More recently, Grabb et al. presented evidence of complete spontaneous involution in 40% and partial involution in 29% of patients.24 Involution was complete by age 2 to 3 years in many patients and by age 5 years in all the untreated patients. The exact percentage of lymphangiomas that involute is not yet known because many of these benign lesions are operated on early in life. Grabb et al. estimated that the true rate for partial or complete involution of all lymphangiomas of the head and neck is between 15% and 70% during the first 20 years of life.24 Noninvoluting lymphangiomas may grow slowly, at the same rate or at a greater rate than the child’s growth. Lymphangiomas of the head and neck region can enlarge over a period of a few hours in conjunction with an upper respiratory tract infection and then will recede over a period of months to approximately their original size. The goals of treatment are eradication of the lesion with complete healing, absence of morbidity and mortality, and good aesthetic result. Surgical excision seems to be the most reliable form of therapy, and generally clinicians agree with the recommendation of Grabbe et al. to wait until approximately the 3rd year of life before considering excision.24 This remains a controversial topic, with some surgeons promoting early radical excision during infancy, with cure rates ranging from 80–100%.25,26 It was stressed that the infant must be free of infection. Medical treatment during episodes of infection is essential, and corticosteroids are recommended, in addition to antibiotics, to reduce edema in inflamed lymphangioma tissue.4 Localized capillary lymphangiomas are readily treated, if indicated, by surgical excision, with full cure. Occasional recurrence may be related to deeper subcutaneous cisterns as described by Whimster.27 Therefore, excision to or including the fascia is recommended. Capillary lymphangiomas are also amenable to electrodesiccation and cryotherapy, although the results of these alternative treatment modes may not compare well with those of surgery.3,4 Definitive treatment of cavernous lymphangiomas requires complete excision. This may not always be feasible, particularly when lesions involve the tongue and floor of the mouth.4 In the anterior triangle, respiration and swallowing may be compromised, making prompt surgical intervention imperative. Staged resection is indicated when function and cosmesis would otherwise be compromised.4 Although isolated reports of successful excision of cystic lymphangiomas were scattered throughout the nineteenth-century literature, the associated morbidity and mortality encouraged examination of other modalities of treatment.4 Mortality rates approaching 50% were the norm in the preantibiotic era. As a consequence, radiotherapy was frequently used; however, the associated risks of malignancy and growth retardation are not justified by its sporadic success.4 Incision and drainage or aspiration may serve as temporizing measures. In life-threatening situations, such as airway compromise, they do not provide more than a

transient regression of the lymphangioma. If conservative measures fail, tracheostomy may be required. A variety of sclerosants, including sodium morrhuate, hypertonic saline, glucose, tetracycline, and boiling water, have been injected into cystic lymphangiomas with variable success. Nevertheless, scarring of the cyst walls, resulting from the use of these agents, may make subsequent excision extremely difficult.4 More recently, bleomycin has been introduced as a sclerosant and has met with some favorable response.28 The use of picibanil, a potent immunostimulant, as a sclerosant for head and neck lymphangiomas has been studied in a prospective randomized trial.90 Eightysix percent of 22 patients had a successful outcome, defined as complete or more than 60% reduction in size. It is clear that surgical excision remains the treatment of choice. Debulking or partial excision may be dictated by certain instances in which a more extended procedure might cause additional facial deformity, but the recurrence rate will be significantly higher. Rupture of the cyst increases the difficulty of surgically defining its margins.4 Death following surgery is now rare, in marked contrast to half a century ago.4 The most frequent postoperative complication is edema of the neighboring tissues, often with associated lymph accumulation and lymphatic drainage, which may occur in up to 50% of patients.1 When large tumors are resected, or when abnormal lymphatic channels have been left, a drain should be inserted to prevent loculation of the accumulating fluid. A mildpressure dressing will eliminate potential spaces.1 The anatomic location and the extent of surgery are related to the success of treatment, and recurrence may certainly occur. The recurrence rate of excised cavernous lesions of the tongue and floor of the mouth is probably the highest of all lymphangiomas. In one series, a recurrence rate of 50% was reported, with a new lesion appearing within 4 years. This has been attributed to the greater difficulty of complete removal of this more invasive lesion.4 Surgical sites with the lowest recurrence rate are the axilla and trunk.17 Overall, recurrence is said to occur in 6% with ‘‘complete’’ excision and in 35% with ‘‘incomplete’’ excision.17 In general, tumors that extend over several adjacent anatomic regions are more prone to recurrence or persistence than are more localized lesions.1 As a rule, a tumor with a large cavernous or capillary component may be twice as hard to eradicate as one consisting primarily of cystic elements. As this is not a malignant lesion, vital structures should not be sacrificed, and cysts that cannot be removed completely should be unroofed to promote atrophy and scarring.17 Eye

Ocular involvement is infrequent but may include the lids, conjunctiva, or orbit. Lymphangioma accounts for 3% of all ocular masses. Rootman et al. classified these lesions into superficial, deep, and combined types.29 The clinical manifestations, prognosis, and management directly correlate with the pathophysiology and location of the lesions. Superficial lesions are isolated multicystic abnormalities of cosmetic significance only. Typically there is a small eyelid or conjunctival mass that neither affects vision nor displaces the globe. If cosmetically unacceptable, it can be removed with relative ease due to limited location and small size.29 The differential diagnosis in this site includes epidermal inclusion cyst, hydrocystoma of either eccrine or apocrine origin, and, occasionally, cystic basal cell carcinoma, none of which would normally be associated with hemorrhage. A deep lesion usually presents with sudden proptosis due to spontaneous hemorrhage into a previously unrecognized lesion.

Lymphatic System

Hemorrhage is often disproportionate to the apparent minor degree of injury. Bleeding may be mild, producing subconjunctival hemorrhage, or severe, causing rapid increase in proptosis, even to the point of severe corneal exposure, potential optic nerve stretching or compression, or globe compression requiring emergency decompression. The majority of cases occur in childhood, although late onset up to age 59 years has been reported.30 Occasionally, an extensive congenital lesion of the orbit may occur, which may be ulcerative, rapidly growing, and repeatedly bleeding, producing destruction of the surrounding face. Differential diagnosis of this latter variety includes hemangioma, encephalocele, or rapidly growing malignant mesenchymal tumor. The differential diagnosis of orbital masses in children includes cellulitis, pseudotumor, dermoid and epidermoid cyst, capillary hemangioma, rhabdomyosarcoma, optic nerve glioma, neurofibroma, leukemia, and metastatic tumor (frequently neuroblastoma).31 In adults, the differential diagnosis includes Graves disease, pseudotumor, secondary tumor (frequently from the sinuses), lacrimal gland tumor, lymphoma, sinus mucocele, and dermoid and epidermoid cysts. The combined lesions are usually recognized within the 1st year of life and grow slowly over years. There may be spontaneous hemorrhage into the deep portion, producing some of the symptoms noted with the deep lesions. Combined lesions are frequently massive, involving the intraconal, extraconal, preseptal, and postseptal spaces. Very large lesions produce significant cosmetic disfigurement and frequently cause decreased vision from optic atrophy or amblyopia. Astigmatism, proptosis, strabismus, and decreased visual acuity may be presenting features. Diagnosis of these lesions is frequently based on venography, computerized axial tomography, conventional radiographs, and nuclear magnetic resonance imaging. It is generally believed that there are no lymphatics in the orbit. Embryonal rests may occur in this area, but it is more likely that the site of origin of the tumor is in the anterior lid or conjunctiva, where lymphatics are numerous.30 The objectives of treatment include drainage of acute hemorrhage, obliteration of large cystic spaces, and excision of as much tumor mass as possible, without jeopardizing normal orbital structures. Sclerosing agents and radiotherapy have been attempted, but are no longer recommended. Laser treatment has been introduced, but it has frequent complications. Surgical excision remains the treatment of choice. Recurrence may be observed even after long periods of observation and probably occurs in 10–15% of cases.26 In some cases, complete excision is not possible due to the diffuse, nonencapsulated growth pattern that allows these lesions to interdigitate with normal orbital structures. In this situation, multiple subtotal excisions may result in less than satisfactory results. Wilson et al. have had some success with conservative management consisting of activity limitation or bed rest as an outpatient or inpatient, cold compresses, and monitoring visual acuity, pupillary light reaction, and appetite.32 The differential diagnosis includes conjunctival hemorrhagic lymphangiectasis. This unusual condition occurs because of an abnormal communication between a conjunctival blood vessel and conjunctival lymphatic channel, resulting in either permanent or intermittent filling of the lymphatic with blood. The site and etiology of these abnormal communications remain obscure, although, in some cases, they may be congenital.33 Salivary Gland

Lymphangioma of the salivary gland is rare. Two parotid lesions were noted out of a total of 300 tumors of the major salivary

173

glands treated over a 9-year period.34 In a review of the pathology of 2500 salivary gland tumors, three lymphangiomas were found by Noone and Brown.35 Two arose primarily in the parotid and one in the submaxillary gland. These lesions usually present as subcutaneous cystic masses evident at birth or appearing within the first 2 years of life, although they have been noted in the 3rd decade or later. They may be associated with facial nerve paralysis, which probably occurs secondary to infection or hemorrhage. The differential diagnosis includes parotid abscess, tuberculosis, hemangioma, lymphoma, branchial cleft cyst, lipoma, mucocele, sialocele, unilateral mumps, and cyst associated with obstruction. Operative excision remains the treatment of choice, whenever feasible without sacrifice of neurovascular structures. Recurrence has been reported and can be treated with further excisional surgery. Aspiration, excision and drainage, radiotherapy, and injection of sclerosing agents have all been attempted in the past but have proved unsatisfactory. Larynx/Pharynx

Lesions of the larynx/pharynx are rare. Bill and Sumner reported only one laryngeal lymphangioma in a series of 61 patients.1 Only six cases were found in a review of 866 laryngeal anomalies performed over a 30-year period.36 Onset is uncommon in the older child and rare in the adult.37 In general, patients present with symptoms referable to airway compromise—progressive dyspnea, sudden airway obstruction, stridor, sleep apnea, or voice change. Dysphagia, drooling, and oral bleeding may occur when the tongue and floor of the mouth are involved.37 A mass involving the larynx or parapharyngeal tissue can be diagnosed by radiography of the neck, ultrasonography, barium esophagography, or CT scan. Differential diagnosis includes dermoid or foregut cyst and carcinoma. Complete excision should always be the goal of therapy. Transitory Horner syndrome, recurrent laryngeal palsy, and damage to the spinal accessory nerve may accompany surgery.38 Follow-up over an 18-year period is reported in one case.36 Subtotal excision had been originally performed, and several subsequent endoscopic procedures were required for removal of residual tumor along the posterior pharyngeal wall. Oral Cavity

Lymphangioma involves the tongue more frequently than any other intraoral site but may also be seen in the lips (macrocheilia), buccal mucosa, gingiva, and palate.39 These lesions are a common cause of macroglossia in children. They usually present within the first few years of life, and growth is usually slow, with quiescence for many years. Embryologically, lymphangiomas are derived from lymphatic tissue that originates in the lateral swellings of the tongue and the tuberculum impar of the mandibular arches. They are said to occur only in the anterior two-thirds; however, in one review of 46 cases there was no such predilection, and involvement at the base of the tongue occurred in five cases, with extension to the epiglottis in two of them.40,41 Lymphangiomas arising in the superficial submucosa of the tongue generally present as a sessile, papillary nodule that is bluish in color. If located in deeper tissues of the submucosa, the bluish color will be masked, and a pink, smooth or nodular, dome-shaped lesion is found. The irregularity of the surface of the tongue, with grey and pink projections affecting both dorsal and ventral surfaces, is the most common sign of this lesion (Fig. 4-14). Small, single, pale white or pink, soft, fluctuant lesions of the tongue are generally cavernous lymphangiomas and are by far the most common.39 When diffuse, causing macroglossia, the lymphangioma can lead to impairment

174

Cardiorespiratory Organs

due to lymphangioma may be seen in the 1st year of life or at a later age.42 It generally causes enlargement of the vermilion and is treated by excision. Lymphangioma of the buccal mucosa may be circumscribed and superficial or a deep diffuse mass or nodule. Long-standing lesions are knotty and nodular in consistency, as a result of recurrent trauma, periodic attacks of inflammation, periodic swelling, and subsequent fibrosis. Surgical excision is the treatment of choice, although total resection is often impossible. The lesion has a great tendency to recur.43 Lymphangiomas of the alveolar ridges appear to have a striking predilection for blacks, with a male to female distribution of approximately 2:1.44 One white female has been described.45 Blue-domed, fluid-filled lesions on the alveolar ridges of neonates were noted in 3.7% of black newborns examined in one large study.44 They varied from 1 to 9 mm in size, the majority being 3 to 4 mm. Multiple lesions were more common than single lesions. Lesions were most often found on the posterior crest of the maxillary alveolar ridges and on the posterior lingual surface of the mandibular ridges. The majority of these lesions resolve spontaneously.44,45 The differential diagnosis includes Epstein pearl, Bohn nodule, eruption cyst, dental laminar cyst, mucus retention phenomenon, and congenital epulis of the newborn. Anterior Neck

Fig. 4-14. Diffuse lymphangioma involving the dorsal and ventral surfaces of the tongue. (Reprinted with permission from Postlethwaite KR: Br J Oral Maxillofac Surg 24:63, 1986.41)

of speech, drooling, difficulties in mastication, dysphagia, and dentoalveolar problems, such as an increased maxillomandibular angle with an anterior open bite, mandibular prognathism, and spacing of the teeth.41 There have been reports of periodic enlargement of the tongue during menstruation.41 Rapid enlargement may also accompany inflammatory edema, occurring secondary to upper respiratory tract and pharyngeal infections or to accidental trauma.40 During bouts of acute swelling due to trauma or infection, corticosteroids, together with antibiotics and effective analgesia, are required. In young children, sedation may occasionally be necessary. With episodes of acute enlargement of the tongue, the airway is rarely jeopardized, but feeding may become a problem, requiring intravenous infusion or nasogastric feeding.40 A variety of techniques, including radiotherapy, insulated needle diathermy, electrodesiccation, and cryotherapy, have been described for the removal of lymphangiomas, although surgical excision is the treatment of choice.40,41 Diffuse lesions require horizontal partial wedge resection. Total excision of small, circumscribed lesions is generally possible. Adjunctive therapy may include reduction of sharp incisal edges, early orthodontic treatment for open bite, and orthognathic surgery. A variety of lesions can cause macrocheilia: lymphangiomas, hemangiomas, neurofibromas, lipomas, hamartomas, minor salivary gland hypertrophy, and trauma. These lesions are typically asymmetric. Symmetric macrocheilia as a manifestation of angioneurotic edema is rarely seen without other signs. Macrocheilia

The so-called giant beardlike cystic lymphangioma of the anterior nuchal area is distinctly uncommon (Fig. 4-11). The largest series reported nine cases out of 763 lymphangiomas at a major children’s hospital.46 Giant cystic lymphangiomas are defined less by size than by their tendencies to infiltrate throughout both sides of the neck, to involve multiple structures, and to extend into the mediastinum, pharynx, mouth, and tongue. There are dozens or even hundreds of cysts of various sizes. These lesions invariably present at birth or in the first weeks of life. They completely encircle vessels, nerves, and glands and insinuate between and around muscle fibers. They do not actually invade and destroy other tissues, and cell structure is normal, with no evidence of neoplasia. The diagnosis is usually straightforward. These lesions are quite different from fetal cystic hygroma, which occurs secondary to jugular lymphatic obstruction and is not found postnatally, except as redundant neck skin and aberrant posterior hair patterning. The cysts are characteristically soft and ballotable and the overlying skin is normal, but there may be a faint bluish discoloration over the larger cysts. Inspection and palpation of the tongue and floor of the mouth is necessary. Lateral radiography of the neck is helpful to define the size at the base of the tongue and epiglottis and to demonstrate narrowing of the esophagus and upper airway. Frontal and lateral chest radiographs are important to look for mediastinal extension. Ultrasonography and CT have been of limited value in defining the extent of these lesions. Laryngoscopy is useful to determine whether there is involvement of the mucosal surface of the base of the tongue, epiglottis, posterior pharynx, and larynx. Bronchoscopy may help to show the degree of tracheal compression, but intrinsic involvement of the trachea is rare. Management of giant lymphangiomas is difficult and challenging. Recommendations in the literature range from doing nothing to early radical extirpative surgery. It seems that early conservative surgery, combined with temporary tracheostomy, is appropriate initial treatment.46 Recurrence and extension into adjacent areas is common, and multiple operations over several years are almost always necessary to achieve an optimal result.

Lymphatic System

Injection of sclerosing agents and radiotherapy are ineffective, and spontaneous resolution is rare. As in other areas, dramatic tumor enlargement can occur in the presence of infection or trauma, leading to acute airway obstruction. Despite the extensive nature of these lesions, the impossibility of complete excision because of damage to normal structures, and the need for multiple operations, the long-term results may be satisfactory.46 Dental malocclusion and mandibular abnormalities may be striking accompaniments of anterior nuchal cystic lymphangiomas. They require complex maxillofacial evaluation and surgical treatment.47 Thorax

Intrathoracic lesions make up less than 10% of the total number of lymphangiomas. Fewer than 1% are totally within the thorax, and most of these develop in adults (75%), with less than 8% in children under age 1 year.48 Lymphangiomas account for 0.7–4.5% of mediastinal tumors. The most common intrathoracic lesion is a mediastinal extension of a preexisting cervical cystic lymphangioma, which occurs in approximately 10% of the latter lesions. Masses in the superior mediastinum constitute about one-half of all intrathoracic lymphangiomas and are generally described in young patients.49 There is a tendency for them to recur because of the infiltrative growth pattern, incomplete resection, and subsequent cystic dilation of remnants. Approximately one-third of intrathoracic lymphangiomas involve the anterior mediastinum and are found in middle-age. They are often asymptomatic. Presenting features include a mass seen on routine radiograph examination, chest discomfort, chylothorax, obstruction of the superior vena cava, cough, wheezing, and pain. In young children, respiratory symptoms may be dramatic. When intrathoracic lesions are part of generalized lymphangiomatosis, there are additional problems. Cystic lymphangiomas have a predilection for local infiltration of tissue planes and occasional widespread extension. The axilla and chest wall may be particularly prone to this behavior due to local prevalence of major muscular and neurovascular bundles loosely embedded in fat. Muscle atrophy, neural impairment, and tracheal or esophageal obstruction may result from local compression. Conventional radiograph findings are nonspecific. The round contour, sharp border, and uniform density may differentiate the lesion from a malignant neoplasm; however, CT contributes to diagnosis by clear delineation of the anatomic location, demonstration of its molding by and compression of the surrounding structures, confirmation of its cystic nature with a homogeneous content of low density, and assurance of lack of calcium deposition.50 Arteriogram may reveal displacement of the adjacent arterial branches, without neovascularization. Real-time ultrasound can facilitate diagnosis and has also allowed prenatal diagnosis of axillary cystic lymphangioma with mediastinal extension.51,52 Differential diagnosis includes substernal goiter, teratoma, thymoma, lymphoma, bronchial-esophageal cyst, aneurysm, pericardial cyst, neurenteric and thoracic duct cysts, retropharyngeal and mediastinal abscess, and granulomatous disease.53 Treatment is early surgical excision, although rare cases, after multiple recurrences, have responded to radiotherapy. Lymphangiomas of the lung may cause hemoptysis and distortion and circumferential compression of airways.54 These lesions may be similar to those found in lobar pulmonary lymphangiectasia (Section 4.2). Esophageal lymphangiomas are whitishyellow lesions, often in the middle to lower part of the esophagus, and cavernous in nature. They cause achalasia, with dysphagia and

175

vomiting after meals. The differential diagnosis includes esophageal varices, hemangioma, and leiomyoma.55 Intrathoracic lymphangiomas lying outside the mediastinum have been described in the pericardium and just above the diaphragm.48 Abdomen

Intraabdominal lymphangiomas make up only 1% of the total number of lymphangiomas and are usually found incidentally through lymphangiography, during elective abdominal surgery, in an acute surgical abdomen, or at postmortem examination. The incidence ranges from one per 27,000 to 100,000 hospital admissions.56 Seventy percent are found in the mesentery (usually juxtaintestinal, ileal, or ileocecal), where they are the most common cystic masses. Five percent are retroperitoneal.57 They occur in the spleen, liver, uterus, rectum, pancreas, esophagus, and bowel. Approximately 25% come to attention in the 1st decade of life, with up to 20% in each subsequent 4 decades. Fewer than 13% have been reported in patients over age 50 years. There is a significant male predilection. There are few clinical features that help to differentiate retroperitoneal lymphangioma from other retroperitoneal masses. The most common clinical manifestation is that of a soft, palpable, cystic mass that usually enlarges slowly. It may cause a ‘‘dragging sensation’’ or may be asymptomatic. It may remain occult until pressure occurs or until the mass has become visible or palpable. Pressure symptoms depend largely on location and may produce partial intestinal obstruction, displacement of the kidneys and ureters, ureteric obstruction, and displacement of the middle colic artery.56 The cysts seldom cause acute clinical symptoms, and diagnosis is often entirely accidental. Acute symptoms, due to hemorrhage, inflammation, infection, perforation, torsion, volvulus, or rupture, include abdominal pain, tenderness, guarding, and fever, mimicking appendicitis. There are several imaging techniques that afford a preoperative diagnosis. Radiographs, intravenous urography, and barium enema may demonstrate organ displacement. The typical sonographic picture is a cystic mass with multiple thin septa containing anechoic fluid. Thicker septa occur with inflammation and/or accumulations of fatty tissue. Chylous or creamy fluid displays fine diffuse echoes, whereas hemorrhage results in coarse echoes and/or solid masses. Magnetic resonance imaging signal intensities can be used to distinguish between the composition of cystic fluids. Lymphangiography is only useful in rare cases where the lymphangioma communicates with major lymphatic trunks. Of all the above methods, ultrasound and CT appear to be the most efficacious. The differential diagnosis includes mesenteric cyst, ovarian teratoma, mucinous cystadenoma, pancreatic pseudocyst, multilocular cystic nephroma, lymphoma, hematoma, foregut cyst, enteric duplication cyst, polycystic kidney disease, cystic dysplasia of the kidney, epidermoid cyst of the spleen, mesenchymal hamartoma of the liver, cystic hepatoblastoma, hemangioendothelioma of the liver, choledochal cyst, and embryonal sarcoma. The clinical setting may indicate which condition is more likely.58 Ultrasonography has also been used prenatally to demonstrate a fetal abdominal cystic lymphangioma with associated soft tissue enlargement of the lower extremities. Diagnosis was made by 19 weeks gestation.59 Complete excision is the treatment of choice; it is usually carried out with relative ease and rarely followed by recurrence. Occasionally, retroperitoneal cystic lymphangiomas will be found incidentally and can be managed conservatively. Aspiration of larger cysts lessens the difficulty with exposure. If the cyst has

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invaded an abdominal organ, such as the small bowel, spleen, or tail of the pancreas, total excision with resection of the involved organ is indicated.56 Juxtaintestinal cysts may require intestinal resection with removal of adjacent mesentery, because simple excision is impossible without damaging the bowel. If complete excision is technically impossible, since there is no need to sacrifice normal structures, excision of most of the mass, with internal marsupialization, results in apparent cure with minimal morbidity. Most lesions are unicentric and benign, but 10% of cases show an associated diffuse mesenteric or extraabdominal lymphatic dysplasia.60 The latter has a tendency to recur locally or to exhibit extradigestive manifestations, such as chylothorax and intraosseous lymphangiectasia. Lymphangiomas have been described in both small and large bowel, but they are an uncommon lesion at either site. Raiford reported 88 benign gastrointestinal tumors, including only one jejunal lymphangioma, in a retrospective analysis of 11,500 autopsies and 4500 surgical specimens.61 Another series of 292 tumors of the colon and rectum included only four lymphangiomas. Perzin and Bridge reported 21 cases of small bowel lymphangioma, accounting for 10% of the tumors and pseudotumors of the small bowel.62 Average age of onset is 51 years, with a range of 22 to 77 years. Over 30% of patients present in the 7th decade. Some authors report a predominant occurrence in females.63 The lesion originates in the lymphatic plexus within the submucosa, into which the lacteals of the villi empty. Some lesions extend to the mucosa and present as a pedunculated, sessile, or polypoidal lesion.63 Lymphangiomas have been reported more frequently since the development of widespread use of fiberoptic instruments. It is possible to diagnose lymphangiomas endoscopically, because they are lustrous and smooth on the surface and pliable on compression, and half of them have a stalk or waist at the base. They are pinkish and translucent and change shape with peristalsis, compression, and the patient’s position. The most common presentations are abdominal pain and intestinal bleeding. Abdominal mass and diarrhea are rare. Protein-losing enteropathy is uncommon. Lymphangiomas range from 5 to 100 mm in diameter; they are generally single and unilocular or bilocular. Differential diagnosis includes lymphatic cysts, which are common, occurring in up to 20% of autopsies.64 Lymphatic cysts may be associated with aging; they usually appear as yellowish nodules on the proximal small intestinal wall, often protruding on the serosal and mucosal surfaces. Other rare benign colonic and rectal neoplasms include lipoma, leiomyoma, hemangioma, mesothelioma, fibroma, ganglioneuroma, and teratoma. In the past, treatment has focused on segmental resection, but snare-polypectomy and electrocautery, since their development, have become the preferred treatment of smaller lymphangiomas.65 The spleen is the least common intraabdominal site. Fowler reviewed the world literature from 1940 to 1952 and found 27 cases among 265 splenic cysts.66 The spleen is also one of the sites involved in cystic (multifocal) lymphangiomatosis. If this latter condition is suspected, evaluation should also be directed toward the lungs, skeleton, and liver. Sixty percent of splenic cysts occur in women, and 75% present between ages 10 and 50 years. The differential diagnosis of splenic cysts has been reviewed by Pearl and Nassar67 and includes parasitic cysts (taenia echinococcus), endothelial-lined cysts (hemangioma, lymphangioma), epithelial-lined cysts (dermoid, epidermoid), transitional celllined cysts, and secondary or traumatic cysts, which do not have a true cellular lining and account for 80% of the total. When

symptoms are present, splenic cysts most commonly produce pain or discomfort in the left upper quadrant and are in some cases accompanied by weight loss, nausea and vomiting, portal hypertension, and varices. Of the various radiographic studies available for the evaluation of splenic masses, angiography and ultrasound are probably the most useful. However, straight radiographs and radionuclide scanning may occasionally be used. The treatment of choice—splenectomy—is indicated when there is significant enlargement or discomfort, portal hypertension, and varices. Hepatic lymphangioma usually occurs as part of multiorgan lymphangiomatosis. It is occasionally observed alone, usually in children and adolescents. It presents as an abdominal mass, with occasional pain, diarrhea, and weight loss. Diagnosis is made with ultrasound. Gross pathology demonstrates multiple whitish nodules that are soft and release chylous milky fluid on puncture biopsy.68 The differential diagnosis includes mesenchymal hamartoma, hemangiomatosis, and necrotic metastases. Twenty-one cases of renal lymphangioma have been described, with a male to female ratio of 1:2. Presenting features include dull local discomfort, mass, and hematuria. Age range at presentation has been 6 months to 76 years. Differential diagnosis includes hydronephrosis, polycystic kidney disease (both adult and infantile types), neoplasia, and infiltrative disorders such as leukemia and glycogen storage disease.69 Renal malignancy, such as Wilms tumor, should also be considered. Pericalyceal, peripelvic, and hilus lymphatic cysts are more common than lymphangioma. The majority develop in the 5th decade, often following a history of inflammation, obstruction, or calculus. These may be secondary cysts occurring after acquired blockage of the lymphatics.70 Two sisters were described with multiple lymphatic cysts in the renal cortex and medulla, renal sinus, and paranephric tissues.71 Both sisters, during pregnancy, developed collections of perinephric fluid and ascites, with mild impairment of renal function and hypertension. This is the only familial case of lymphangiomatosis involving the kidneys. It may be part of widespread lymphatic dysplasia, although this alternative was not specifically explored. Two or three lymphangiomas of the pancreas have been described, presenting as a mass in the upper abdomen or picked up by a gastrointestinal series or alternative imaging technique. The differential diagnosis includes carcinoma and cystadenoma.72 Adrenal cysts are relatively infrequent lesions that usually are asymptomatic. Most cases are diagnosed at surgery or autopsy. Forty-two percent of adrenal cysts are lymphangiomatous.73 The vast majority are of minute size and may be noted on CT scans performed for other reasons. Bladder lymphangioma has only been reported in one 13- year-old child who presented with microscopic, painless hematuria.74 The lesion was diagnosed by intravenous pyelography and cystoscopy and treated by partial cystectomy. Lymphangioma of the vulva or labia minora is rare.75 In one case, genital ambiguity was the mode of presentation. The lymphangioma was capillary in type and similar to those seen on the lips and tongue. Optimal treatment is complete surgical excision, without damage to surrounding vital structures, with care to include all affected tissue, since involved margins have been shown to increase the recurrence rate. Injection of sclerosing agents, irradiation, and laser therapy are rarely beneficial. Less than 30 cases of scrotal lymphangiomas have been reported. They arise in the skin of the scrotum and cannot be separated from it, although they are distinctly separate from the testis and spermatic cord.76 Definitive treatment requires surgical excision.

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One unusual case of cystic lymphangioma of the scrotum has been reported.77 A right scrotal mass had been present since early childhood, in association with several large lymph nodes in the groin, nonpitting edema of the right lower extremity, and multiple vesicles of the skin of the right lower extremity and scrotum. The lymph nodes and scrotal masses were found to be cystic lymphangioma. There was no evidence of cysts in the pelvis. It seems likely that the lymphangiomatous involvement of the lymph nodes in the inguinal region and scrotum caused lymphatic obstruction with secondary lymphedema of the lower limb. Lymphangioma of the tunica vaginalis has been reported 11 times. It is difficult to distinguish clinically from either an encysted hydrocele of the cord or a communicating hydrocele. The mass is in the anterosuperior portion of the scrotum, is separate from both testicle and scrotal skin, and transilluminates. Lymphangiomas involving the female internal genitalia are noted usually as incidental findings, but occasionally may attain a size sufficient to cause symptoms by displacement, compression, or involvement of adjacent structures.78 Most are isolated ovarian masses, although they can be seen as part of peritoneal lymphangiomatosis. Treatment of choice is total surgical excision. If neighboring vital structures are involved, precluding total resection, marsupialization may be performed. Radiotherapy is infrequently necessary as an adjunct to prevent recurrence. Bone

Solitary intraosseous lymphangioma is a very rare lesion. It has been located in the medullary cavity of long bones (Fig. 4-15), tibia, mandible, calvaria, and the small bones of the hand.79,80 Solitary lymphangioma of bone shares histologic features with systemic lymphangiomatosis and massive osteolysis.79 Metastatic disease, histiocytosis X, Gaucher disease, fibrous dysplasia, congenital fibromatosis, and neurofibromatosis are also part of the differential diagnosis.80 The lesion is frequently indolent, although it may encroach on the bone, producing pressure atrophy, destruction, and pathologic fracture. Curettage is an effective cure. Systemic Lymphangiomatosis

Systemic lymphangiomatosis is an uncommon disease characterized by multicentric angiomatous malformations of the skeletal system, with concomitant skin, soft tissue, and visceral involvement in over 50% of cases (Fig. 4-16).81 It is believed to be due to a generalized maldevelopment of the lymphatic system and has been reported with cystic outpouching of the thoracic duct.82 Synonyms include cystic angiomatosis, skeletal hemangiomatosis, multiple lymphangiectasis of bone, cystic lymphangiomatosis of bone, and cystic angiomatosis of bone. Radiographically, the long bone lesions are described as lucent areas, with or without reactive borders, with a multiloculated soap bubble appearance. In vertebrae, an area of rarefaction may be traversed by thick bony trabeculae. The under 30-year age group is most often affected, and there is no apparent sex predilection.81,82 The course of the disease appears to be benign and often self-limited in those patients without extraskeletal involvement. However, if extraskeletal involvement, especially chylous effusions, is present, the prognosis is poor.83 Management of generalized lymphangiomatosis can be challenging.84 Recurrent chylothorax and multiple pleural aspirations often result in marked protein loss, lymphocytopenia, and critically low levels of humoral and cell-mediated immunity with inherent complications. Chylopericardium with tamponade and cardiac failure can also occur. Limited success has been achieved

Fig. 4-15. A multicystic solitary intraosseous lymphangioma involving the left humerus of a 3-year-old girl. (Reprinted with permission from Jumbelic M, et al.: J Bone Joint Surg 66-A:1479, 1984.79)

with a diet of medium-chain triglycerides. Radiation of skeletal lesions may induce temporary remission. Chemotherapy has failed to control massive accumulation of chylothorax, although pleurectomy, excision of lymphatic lakes, and ligation of the thoracic duct above the diaphragm have been more successful. Systemic lymphangiomatosis is closely related to Gorham massive osteolysis, also known as acute spontaneous absorption of bone, phantom bone disease, and disappearing bone disease.81 In Gorham disease, patients typically have involvement of contiguous bones and soft tissue in the general vicinity of the bony changes. By contrast, in systemic lymphangiomatosis, the bone and visceral involvement is of a noncontiguous type. However, large soft tissue lymphangiomas can occur in Gorham disease, blurring the distinction between the two entities. The cause of Gorham disease is unknown, the clinical progression and prognosis are unpredictable, and treatment is uncertain.85 Although the angiomas themselves are benign, absorption of bone can be relentlessly progressive, and widespread involvement of the ribs and vertebrae can ultimately lead to death.81 The factors that transform a benign, localized lesion into one that causes massive bone destruction are poorly understood. Some authors speculate that the bony lesions might be embryonic rests, responsive to a stimulating growth factor or hormone, as in endometriosis or trophoblast embolism.82 Edwards et al. have reviewed this overlapping group of conditions.86

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Fig. 4-16. Giant lymphangioma involving the legs, perineum, left pelvis, and left abdomen of a fetus (27 weeks gestation). The left leg and perineum are overgrown by nodular, subcutaneous, cystic, blood-filled, tumor masses. Histologic studies confirmed the mixed lymphatic and angiomatous nature of the neoplasm. (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

Skin

Lymphangiomas are mainly found in the neck and axilla, breasts and chest, and buttocks and thighs, but may occur on almost any area of skin. The highest frequency occurs during infancy, and the majority are present by age 5 years, but they may appear spontaneously in adolescence or adult life.87 No family recurrences are known. Cutaneous lymphangiomas can be capillary or cavernous. Treatment modalities include surgery, liquid nitrogen, carbon dioxide snow, local cautery, irradiation, incision and drainage, and sclerotherapy.88–90 In one review, single surgical excision cured 75% of cases and re-excision cured an additional 12%. Recently, carbon dioxide and argon lasers have been used effectively.88 References (Lymphangioma) 1. Bill AH, Sumner OS: A unified concept of lymphangioma and cystic hygroma. Surg Gynecol Obstet 120:70, 1965. 2. Landing BH, Farber S: Tumors of the Cardiovascular System. Atlas of Tumor Pathology. Armed Forces Institute of Pathology, Washington, DC, 1956. 3. Stal S, Hamilton S, Spira M: Hemangiomas, lymphangiomas, and vascular malformations of the head and neck. Otolaryngol Clin North Am 19:769, 1986. 4. Wisnicki JL: Hemangiomas and vascular malformations. Ann Plast Surg 12:41, 1984. 5. Williams HB: Hemangiomas and lymphangiomas. Adv Surg 15:317, 1981. 6. Thomson H: Cutaneous hemangiomas and lymphangiomas. Clin Plast Surg 14:341, 1987. 7. Ninh TN, Ninh TX: Cystic hygroma in children: a report of 126 cases. J Pediatr Surg 9:191, 1974.

8. Singh S, Baboo ML, Pathak IC: Cystic lymphangioma in children: report of 32 cases including lesions at rare sites. Surgery 64:947, 1971. 9. Siegel MJ, McAlister WH, Askin FN: Lymphangiomas in children: report of 121 cases. J Can Assoc Radiol 30:99, 1979. 10. Saijo M, Munro IR, Mancer K: Lymphangioma: a long term follow-up study. Plast Reconstr Surg 56:642, 1975. 11. Bhattacharyya NC, Yadav K, Mitra SK, et al.: Lymphangiomas in children. Aust N Z J Surg 51:296, 1981. 12. Van Cauwelaert P, Oruwez JA: Experience with lymphangioma. Lymphology 11:43, 1978. 13. Tatu WF, Pope TL Jr, Daniel TM, et al.: Computed tomography of mediastinal cystic hygroma in an adult: case report and review of the literature. J Comput Assist Tomogr 9:233, 1985. 14. Anderson DH: Tumours of infancy and childhood. Cancer 4:890, 1951. 15. Sheth S, Nussbaum AR, Hutchins OM, et al.: Cystic hygromas in children: sonographic-pathologic correlation. Radiology 162:821, 1987. 16. Woods D, Young JEM, Filice R, et al.: Late onset cystic hygromas: the role of CT. J Can Assoc Radiol 40:159, 1984. 17. Brock ME, Smith RJH, Parey SE, et al.: Lymphangioma. An otolaryngologic perspective. Int J Pediatr Otorhinolaryngol 14: 133, 1987. 18. Benacerraf BR, Frigoletto FD: Prenatal sonographic diagnosis of isolated congenital cystic hygroma, unassociated with lymphedema or other morphologic abnormality. J Ultrasound Med 6:63, 1987. 19. Goetsch E: Hygroma colli cysticum and hygroma axillare: pathologic and clinical study and report of 12 cases. Arch Surg 36:394, 1938. 20. Willis RA: Pathology of Tumors, ed 4. Butterworths, London, 1967, p 728. 21. Sabin FR: The origin and development of the lymphatic system. Johns Hopkins Hosp Rep 17:347, 1916. 22. Van der Putte SCJ: The early development of the lymphatic system in mouse embryos. Acta Morphol Neerl Scand 13:245, 1975. 23. Broomhead IW: Cystic hygroma of the neck. Br J Plast Surg 17:225, 1964.

Lymphatic System 24. Grabb WC, Dingman RO, Oneal RM, et al.: Facial hamartomas in children: neurofibroma, lymphangioma, and hemangioma. Plast Reconstr Surg 66:509, 1980. 25. Vistnes LM: Treatment of lymphangiomas and cystic hygromas. In: Symposium on Vascular Malformations and Melanotic Lesions. Williams HB, ed. CV Mosby, St. Louis, 1983, p 186. 26. Ravitch MM, Rush BF Jr: Cystic hygroma. In: Pediatric Surgery, ed 3. MM Ravitch, KJ Welch, CD Benson, et al., eds. Year Book Medical Publishers, Chicago, 1979, p 368. 27. Whimster IW: The pathology of lymphangioma circumscriptum. Br J Dermatol 94:473, 1976. 28. Ogita S, Tsuto T, Tokiwa K, et al.: Treatment of cystic hygroma in children with special reference to OK-432 therapy. Z Kinderchir 42:279, 1987. 29. Rootman J, Hay E, Graeb D, et al.: Orbital-adnexal lymphangiomas. A spectrum of hemodynamically isolated vascular hamartomas. Ophthalmology 93:1558, 1986. 30. Iliff WJ, Green WR: Orbital lymphangiomas. Ophthalmology 86:914, 1979. 31. Hemmer KM, Marsh JL, Milder B: Orbital lymphangioma. Plast Reconstr Surg 82:340, 1988. 32. Wilson ME, Parker PL, Chavis RM: Conservative management of childhood orbital lymphangioma. Ophthalmology 95:484, 1989. 33. Chelsky MP, Magnus DE: Conjunctival hemorrhagic lymphangiectasis. J Am Optometr Assoc 59:676, 1988. 34. Crawford AP: Lymphangioma of the parotid gland. Med J Aust 2:141, 1981. 35. Noone RB, Brown HJ: Cystic hygroma of the parotid gland. Am J Surg 120:404, 1979. 36. Myer CM, Bratcher GO: Laryngeal cystic hygroma. Head Neck Surg 6:706, 1983. 37. Cohen SR, Thompson JW: Lymphangiomas of the larynx in infants and children. A study of pediatric lymphangioma. Ann Otol Rhinol Laryngol 127(suppl):1, 1986. 38. Kahn A, Blum D, Hoffman A, et al.: Obstructive sleep apnea induced by a parapharyngeal cystic hygroma in an infant. Sleep 8:363, 1985. 39. White MA: Lymphangioma of the tongue: report of case. J Dent Child 54:280, 1987. 40. Goldberg MH, Nemarich AN, Danielson P: Lymphangioma of the tongue: medical and surgical therapy. J Oral Surg 35:841, 1977. 41. Postlethwaite KR: Lymphangiomas of the tongue. Br J Oral Maxillofac Surg 24:63, 1986. 42. Welsh F, Fahmy A, Shadid EA: Macrocheilia due to lymphangiectasia. South Med J 69:485, 1976. 43. Zachariades N, Koundouris I: Lymphangioma of the oral cavity: report of a case. J Oral Med 39:33, 1984. 44. Levin LS, Jorgenson RJ, Jarvey BA: Lymphangiomas of the alveolar ridges in neonates. Pediatrics 58:881, 1976. 45. Josephson P, Van Wyk CW: Bilateral symmetrical lymphangiomas of the gingiva. A case report. J Periodontol 55:47, 1984. 46. Seashore JH, Gardiner U, Ariyan S: Management of giant cystic hygromas in infants. Am J Surg 149:459, 1985. 47. Osborne TE, Levin LS, Tilghman DM, et al.: Surgical correction of mandibulofacial deformities secondary to large cervical cystic hygromas. J Oral Maxillofac Surg 45:1015, 1987. 48. Pike MG, Wood AJ, Corrin B, et al.: Intrathoracic extramediastinal cystic hygroma. Arch Dis Child 59:75, 1984. 49. Brown LR, Reiman HM, Rosenow EC III, et al.: Intrathoracic lymphangioma. Mayo Clin Proc 61:882, 1986. 50. Shin MS, Berland LL, Ho KJ: Mediastinal cystic hygromas: CT characteristics and pathogenetic consideration. J Comput Assist Tomogr 9:297, 1985. 51. de Orbe Rueda A, Prieto Arellano C, Diaz de Rojas F, et al.: Ultrasound diagnosis of mediastinal cystic hygroma. J Clin Ultrasound 12:180, 1984. 52. Hoffman Tretin J, Koenigsberg M, Ziprkowski M: Antenatal detection of axillary cystic hygroma. J Ultrasound Med 7:233, 1988. 53. Feutz EP, Yune HY, Mandelbaum I, et al.: Intrathoracic cystic hygroma. Radiology 108:61, 1973.

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54. Holden WE, Morris JF, Antonovic R, et al.: Adult intrapulmonary and mediastinal lymphangioma causing hemoptysis. Thorax 42:635, 1987. 55. Tamada R, Sugimachi K, Yaita A, et al.: Lymphangioma of the esophagus presenting symptoms of achalasia—a case report. Jpn J Surg 10:59, 1980. 56. Roisman I, Manny J, Fields S, et al.: Intra-abdominal lymphangioma. Br J Surg 76:485, 1989. 57. Galifer RB, Pous JG, Juskiewenski S, et al.: Intra-abdominal cystic lymphangiomas in childhood. Prog Pediatr Surg 11:173, 1978. 58. Blumhagen JD, Wood BJ, Rosenbaum DM: Sonographic evaluation of abdominal lymphangiomas in children. J Ultrasound Med 6:487, 1987. 59. Kozlowski KJ, Frazier CN, Quirk JG: Prenatal diagnosis of abdominal cystic hygroma. Prenat Diagn 8:405, 1988. 60. Axiotis CA, Zeman RK, Chuong JJH, et al.: Intra-abdominal lymphangiectatic cysts: an uncommon abdominal lesion in children and young adults. J Clin Gastroenterol 5:541, 1983. 61. Raiford TS: Tumors of the small intestine. Arch Surg 25:122, 1932. 62. Perzin KH, Bridge MF: Adenomas of the small intestine: a clinicopathologic review of 51 cases and a study of their relationship to carcinoma. Cancer 48:799, 1981. 63. Lawson JP, Myerson PJ, Myerson DA: Colonic lymphangioma. Gastrointest Radiol 1:85, 1976. 64. Davis M, Fenoglio-Preiser C, Haque AK: Cavernous lymphangioma of the duodenum: case report and review of the literature. Gastrointest Radiol 12:10, 1987. 65. Kuramoto S, Sakai S, Tsuda K, et al.: Lymphangioma of the large intestine: report of a case. Dis Colon Rectum 31:900, 1988. 66. Fowler RH: Non-parasitic benign cystic tumors of the spleen. Int Abstr Surg 96:209, 1953. 67. Pearl GS, Nassar VH: Cystic lymphangioma of the spleen. South Med J 72:667, 1979. 68. Van Steenbergen W, Joosten E, Marchal G, et al.: Hepatic lymphangiomatosis. Report of a case and review of the literature. Gastroenterology 88:1968, 1985. 69. Singer DRJ, Miller JDB, Smith G: Lymphangioma of kidney. Scott Med J 28:293, 1983. 70. Kutcher R, Rosenblatt R, Mahadevia P, et al.: Renal peripelvic multicystic lymphangiectasia. Urology 30:177, 1987. 71. Meredith WT, Levine E, Ahlstrom NG, et al.: Exacerbation of familial renal lymphangiomatosis during pregnancy. Am J Radiol 151:965, 1988. 72. Gregory IL: Lymphangioma of pancreas. N Y State J Med 76:289, 1976. 73. Foster DG: Adrenal cysts. Review of literature and report of case. Arch Surg 92:131, 1966. 74. Bolkier M, Ginesin Y, Lichtig C, et al.: Lymphangioma of bladder. J Urol 129:1049, 1983. 75. Abu-Hamad A, Provencher D, Ganjei P, et al.: Lymphangioma circumscriptum of the vulva: case report and review of the literature. Obstet Gynecol 73:496, 1989. 76. MacMillan RW, MacDonald BR, Alpern HD: Scrotal lymphangioma. Urology 23:79, 1984. 77. Merka ST, Bhatt KS, Wood FW: Cystic lymphangioma of the scrotum: a case report. J Urol 131:1179, 1984. 78. Aristizabal SA, Galindo JH, Davis JR, et al.: Lymphangiomas involving the ovary. Report of a case and review of the literature. Lymphology 10:219, 1977. 79. Jumbelic M, Feuerstein IM, Dorfman HD: Solitary intraosseous lymphangioma. J Bone Jt Surg Am 66:1479, 1984. 80. Kopperman M, Antoine JE: Primary lymphangioma of the calvarium. Am J Radiol 121:118, 1974. 81. Griffin GK, Tatu WF, Fisher LM, et al.: Systemic lymphangiomatosis: a combined diagnostic approach of lymphangiography and computed tomography. J Comput Tomogr 10:335, 1986. 82. Bowman CA, Witte MH, Witte CL, et al.: Cystic hygroma reconsidered: hamartoma or neoplasm? Primary culture of an endothelial cell line from a massive cervicomediastinal hygroma with bony lymphangiomatosis. Lymphology 17:15, 1984.

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83. Ellis GL, Brannon RB: Intraosseous lymphangiomas of the mandible. Skeletal Radiol 5:253, 1980. 84. Bhatti MAK, Ferrante JW, Gielchinsky I, et al.: Pleuropulmonary and skeletal lymphangiomatosis with chylothorax and chylopericardium. Ann Thorac Surg 40:398, 1985. 85. Canady AI, Chou SN: Cervical lymphangiomatosis with progressive craniospinal deformity. Neurosurgery 6:422, 1980. 86. Edwards WH Jr, Thompson RC, Yarsa EW: Lymphangiomatosis and massive osteolysis of the cervical spine. Clin Orthop 177:222, 1983. 87. Flanagan BP, Helwig EB: Cutaneous lymphangioma. Arch Dermatol 113:24, 1977. 88. Eliezra Y, Sklar JA: Lymphangioma circumscriptum: review and evaluation of carbon dioxide laser vaporization. J Dermatol Surg Oncol 14:357, 1988. 89. Karmody CS, Fortson JK, Calcaterra YE: Lymphangiomas of the head and neck in adults. Otolaryngol Head Neck Surg 90:283, 1982. 90. Giguere CM, Bauman NM, Sato Y, et al.: Treatment of lymphangiomas with OK-432 (picibanil) sclerotherapy. Arch Otolaryngol Head Neck Surg 128:1137, 2002.

4.5 Lymphangioleiomyomatosis Definition

Lymphangioleiomyomatosis is a benign, often multicentric, tumorlike malformation or hamartoma involving the major lymphatic trunks of the mediastinum and retroperitoneum, the lymph nodes, and pulmonary lymphatics. The terminology for the disease has evolved from lymphangiomyoma to lymphangiomyomatosis to lymphangioleiomyomatosis. To date, more than 300 cases have been described, and it is estimated that the worldwide occurrence is more than 100 new cases per year.1,2 Diagnosis

First described by Enterline and Roberts,3 lymphangioleiomyomatosis is characterized by one or more nodules of tumorlike proliferation of smooth muscle fascicles, separated from each other by lymphatic channels. Lymphangioleiomyomatosis involves the walls of preexisting lymphatic channels of all calibers, from the major lymphatic trunks in the mediastinum and retroperitoneum to small sinusoids. Occasionally, mediastinal and retroperitoneal lymph nodes are involved. In two-thirds of cases the lymphatics of the lungs are affected, causing the principal features of progressively worsening dyspnea and cyanosis, often followed by chylothorax. Proliferation of smooth muscle tissue occurs to a lesser extent in bronchioles and blood.4 Pulmonary venule obstruction causes intrapulmonary hemorrhage, pulmonary siderosis, and hemoptysis. Bronchiolar obstruction results in hyperinflation, air trapping, and frequent formation of cysts and bullae, leading to spontaneous pneumothorax in 40% of cases. Respiratory distress can thus be caused by chylous effusions, pulmonary involvement of lymphangioleiomyomatosis, and/or pneumothorax. Abdominal signs and symptoms include retroperitoneal mass, abdominal pain, swelling, and associated weight loss. There may also be chylous ascites, chylopericardium, chyluria, or lymphedema of the extremities, depending on the site(s) of lymphatic vessel involvement.5 In many cases the chest radiograph shows a diffuse, coarse, reticulonodular pattern similar to that seen in fibrosing alveolitis or pulmonary fibrosis, with or without a pleural effusion. Pulmonary function testing demonstrates a combined obstructive and restrictive ventilatory defect, with reduction in vital capacity

and gas transfer. Lymphangiography may show blockage to the flow of dye at various levels, fistulas between the thoracic duct and the pleural cavity, replacement of the thoracic duct by multiple irregular mediastinal lymphatic vessels, attenuation of retroperitoneal lymph trunks with mesenteric backflow, or lymphaticovenous communication in the pelvis.4,6 Computed tomography, magnetic resonance imaging, and radioisotope studies may be employed to define the lesion further. Occasionally, surgery or needle biopsy of the lung has been required to make the diagnosis. Lymphangioleiomyomatosis appears to present almost exclusively in women of reproductive age. In the largest reported series, the age at presentation ranged from 17 to 41 years, with rare onset of symptoms after menopause.7 Wolff found the average age to be 40.8 years, with a range of 18 to 69 years.4 Microscopic examination reveals plump clusters of spindleshaped cells coursing in various directions, forming interanastomosing trabeculae with spaces between the clusters that are lined by flattened cells. The spindle-shaped cells have regular bland nuclei without mitoses. Fine reticulin fibers surround the separate cells of the cluster and also support the endothelial cells lining the vascular spaces. The cystic spaces, with varying amounts of smooth muscle in the walls, are lymphatic channels. Electron microscopy reveals immature elongated smooth muscle cells with nuclei containing prominent small nucleoli, sparse chromatin, numerous mitochondria and small vesicles, and abundant cytoplasm. The cells are separated into groups by vascular channels lined by endothelial cells. Pulmonary lymphangioleiomyomatosis must be distinguished from other conditions in which abnormal quantities of smooth muscle are present in the lungs, including chronic bronchiectasis, emphysema, and secondary pulmonary hypertension. Smooth muscle proliferation is also a feature of benign metastasizing leiomyoma, which can present with pulmonary involvement in women of reproductive age and can be difficult to distinguish from lymphangioleiomyomatosis; of intravenous leiomyomatosis, which is characterized by direct extension of leiomyoma into the pelvic veins; and of leiomyomatosis peritonealis disseminata, a rare peritoneal seeding of benign smooth muscle nodules, often seen in association with pregnancy or gonadotropin therapy. Diffuse lung disease, histologically resembling lymphangioleiomyomatosis, has also been described in tuberous sclerosis.8 However, in tuberous sclerosis, chylothorax is conspicuously absent. The lymph nodes may be involved in both conditions. Renal angiomyolipomas occur in about half of the individuals with lymphangioleiomyomatosis and 70% of individuals with tuberous sclerosis.9 This overlap in features is particularly intriguing since tuberous sclerosis is also a hamartomatous condition, and pulmonary disease in tuberous sclerosis almost always affects women.8 Recent evidence suggests that the proliferative and invasive nature of lymphangioleiomyomatosis cells may be due, in part, to somatic mutations in TSC2, the second tuberous sclerosis gene to be identified.10 Etiology and Distribution

Although more than 100 cases of lymphangioleiomyomatosis have been described, the etiology is obscure. Hamartoma formation seems most likely, while alternative theories include reactive muscular proliferation; trauma to the thoracic duct, causing chylomediastinum and chylothorax with subsequent inflammation and secondary muscular proliferation; and neoplasia.3 The role of hormones in this condition remains unclear. This is exclusively a disease of women of reproductive age, and the onset or exacerbation of symptoms may be coincident with pregnancy.11 A

Lymphatic System

menstrual periodicity of symptoms, including dyspnea, chest pain, and even pneumothorax, has also been described. Onset of symptoms has followed chorionic gonadotropin therapy. While normal lung tissue contains no demonstrable estrogen or progesterone receptors, tissue from patients with pulmonary lymphangioleiomyomatosis has been shown on occasion to have significant receptor levels.11 Prognosis, Treatment, and Prevention

Cases with predominantly respiratory symptoms usually have a poor prognosis. Abdominal symptoms herald a more favorable course. The best outcome appears to occur with caudal involvement of the lumbar trunks and isolated peripheral lymphedema.12 Several large cohorts have been reported with survival up to 27 years, with an average survival of 9 years.4,13,14 Patients usually succumb to metabolic disturbance secondary to continuing loss of fluid, lipids, and protein in the chylous fluid leading to cachexia, hypotension, and renal failure, or to severe progressive dyspnea with recurrent chylous effusions leading to respiratory insufficiency. Surgery, with excision of the lesion in combination with ligation of the thoracic duct or lymphatic chain, and postoperative radiotherapy have been successful modes of treatment.4 Pleurectomy and pleurodesis by installation of sclerosing agents such as nitrogen mustard into the pleural cavity have been used when thoracentesis and/or diuretics have failed to limit the formation of chylous effusions.15 Peritoneal-jugular shunt has been performed, and low-fat diet has been used.5,16 Because of the presence of progesterone and, to a lesser extent, estrogen receptors, hormonal manipulation has been used with mixed results. Oophorectomy, progestational agents, and antiestrogenic compounds have been successful in some cases. Lung transplantation can be valuable therapy for end-stage lymphangiomyomatosis.17 References (Lymphangioleiomyomatosis) 1. Kelly J, Moss J: Lymphangioleiomyomatosis. Am J Med Sci 321:17, 2001.

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2. Hancock E, Osborne J: Lymphangioleiomyomatosis: a review of the literature. Respir Med 96:1, 2002. 3. Enterline HT, Roberts B: Lymphangiopericytoma. Cancer 8:582, 1955. 4. Wolff M: Lymphangiomyoma: clinicopathologic study and ultrastructural confirmation of its histogenesis. Cancer 31:988, 1973. 5. Frack MD, Simon L, Dawson BH: The lymphangiomyomatosis syndrome. Cancer 22:428, 1968. 6. Collard M, Fievez M, Godart S, et al.: The contribution of lymphography in the study of diffuse lymphangiomyomatosis. Am J Roentgenol 102:466, 1968. 7. Cornog GL, Enterline HT: Lymphangiomyoma-benign lesions of chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer 19:1909, 1966. 8. Jao J, Gilbert S, Messer R: Lymphangiomyoma and tuberous sclerosis. Cancer 29:1188, 1972. 9. Smolarek TA, Wessner LL, McCormack FX, et al.: Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Hum Genet 62:810, 1998. 10. Pacheco-Rodriguez G, Kristof AS, Stevens LA, et al.: Genetics and gene expression in lymphangioleiomyomatosis. Chest 121:56S, 2002. 11. Hughes E, Hodder RV: Pulmonary lymphangiomyomatosis complicating pregnancy: a case report. J Reprod Med 32:553, 1987. 12. Abe R, Kimura M, Hirosaki A, et al.: Retroperitoneal lymphangiomyomatosis with lymphedema of the legs. Lymph 13:62, 1980. 13. Taylor JR, Ryu J, Colby TV, et al.: Lymphangioleiomyomatosis. N Engl J Med 323:1254, 1990. 14. Seyama K, Kira S, Takahashi H, et al.: Longitudinal follow up study of 11 patients with pulmonary lymphangioleiomyomatosis: diverse clinical courses of LAM allow some patients to be treated without antihormone therapy. Respirology 6:331, 2001. 15. Bush JL, McLean RL, Sicker HO: Diffuse lung disease due to lymphangiomyoma. Am J Med 46:645, 1969. 16. Joliat G, Stalder H, Kapanci Y: Lymphangiomyomatosis: a clinicoanatomical entity. Cancer 31:455, 1973. 17. Boehler A, Speich R, Russi EW, et al.: Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 335:1275, 1996.

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5 Spleen Arthur S. Aylsworth

he spleen forms during the 5th week (when the embryo is 8– 10 mm) as a local mesodermal condensation in an area of tissue on the left side of the dorsal mesogastrium. It is the only organ that is left-sided at its inception.1 The splanchnopleuric epithelium thickens to form a ridge of mesoderm that extends along the dorsolateral border of the developing stomach. The ridge lies between areas of tissue that eventually will form the gastrosplenic and pancreaticosplenic portions of the dorsal mesentery and extends to the region of the developing mesonephros (Fig. 5-1).2 Several genes involved in spleen development have been identified in the mouse. These include Hox11, Wt1, Bapx1, and capsulin. The orphan homeobox gene Hox11 is expressed in the splenic anlage arising from the splanchnic mesoderm. The human homologue, HOX11, is the T-cell acute leukemia gene that maps to 10q24. Homozygous Hox11-deficient mice have asplenia but are otherwise normal with no defects in the development of other splanchnic derivatives.3 Spleen formation begins normally in these homozygous embryos, but the splenic anlage subsequently undergoes rapid and complete resorption.4 Rudimentary spleen cells fail to organize, proliferate, or differentiate, and hematopoietic cells do not populate the tissue.5 The Wilms tumor supressor gene, Wt1, is also necessary for spleen development, as demonstrated in a homozygous Wt1-deficient mouse model.6 In these mice, the normal expression of Hox11 was not affected by the inactivation of Wt1. On the other hand, Wt1 mRNA is significantly reduced in the splenic anlage of Hox11-null mice, suggesting that Wt1 functions downstream from Hox11 in the pathway of normal spleen development.7 The human homologue, WT1, maps to 11p13. Bapx1 expression in the mouse is detected in the splanchnic mesoderm adjacent to the prospective gut endoderm and in the sclerotomal portion of the somites. The human homologue maps to 4p16.1. Targeted disruption of Bapx1 produced homozygous mice with no identifiable splenic tissue, in addition to a lethal skeletal dysplasia with defects in the axial skeleton and base of the skull.8 In addition, Hox11 expression was absent in the splanchnic mesoderm where it is normally found during spleen development. An increase in apoptosis was found in all affected tissues.9 The drosophila homologue bap also plays an important role in gut mesoderm development.

T

Human capsulin, or transcription factor 21 (TCF21), maps to 6q23-q24. In the mouse, it is expressed at sites of epithelialmesenchymal interactions in mesenchyme that encapsulates the epithelial primordia of the kidney, lung, intestine, and pancreas.10 It is also expressed in the epicardium and in the mesoderm that gives rise to the spleen. Mice homozygous for a capsulin (also called Pod1) null mutation have asplenia along with a lethal combination of lung and kidney hypoplasia.11,12 As in the Hox11and Bapx1-deficient animals, early spleen development was initiated, but there was no subsequent proliferation or differentiation of precursor cells. The spleen is intraperitoneal and freely movable. Position and fixation are related to the phrenicocolic ligament, which runs between the left flexure of the colon and the left hemidiaphragm and limits downward displacement of the spleen. The splenic artery develops from a branch of the celiac artery that passes through the dorsal mesogastrium, supplying the greater curvature of the stomach. Vascularization of the spleen occurs early in the 3rd month of development, although red pulp cords may be present as early as the 6th week. B cells and T cells appear during the 4th month and a distinction between the red and white pulp is possible by the 6th month, but germinal centers are not usually seen until the perinatal or postnatal period. Based on research in nonhuman mammals, it is assumed that the spleen plays a role in hematopoiesis during the 4th and 5th months of gestation, with decreasing importance as intramedullary hematopoiesis develops. Studies using sensitive immunohistologic techniques, however, fail to demonstrate a significant collection of true precursors of myelopoiesis in the human fetal spleen, and it has been suggested that the few precursor cells found can be accounted for by trapping from the peripheral blood.13 As in the liver, hematopoietic activity is found only occasionally at birth. References 1. Van Mierop LHS, Gessner IH, Schiebler GL: Asplenia and polysplenia syndromes. Birth Defects Orig Artic Ser VIII(5):36, 1972. 2. Sulik KK: Development of the gut with special reference to the liver, gallbladder, pancreas, and spleen: a review. Proc Greenwood Genet Center 8:91, 1989. 3. Roberts CW, Shutter JR, Korsmeyer SJ: Hox11 controls the genesis of the spleen. Nature 368:747, 1994. 183

184

Cardiorespiratory Organs

Fig. 5-1. A,B. Scanning electron micrographs illustrating a cut at the level of the stomach in gestational day 11 (49 somite pair) mouse embryos, corresponding to 6-week human embryos. Note the dorsal mesentery (mesogastrium, arrowheads) extending from the dorsal midline to the lateral (left) border of the stomach (S). H, hindlimb bud; G, gonadal ridge; N, neural tube; M, midgut. C. The dorsal mesentery, visualized from its dorsal side following removal of the posterior (dorsal) body wall. Note the thickened ridge of mesoderm, which represents the initial formation of the spleen (arrows). As

development proceeds, the spleen becomes suspended between the stomach and pancreas by the gastrosplenic (asterisk) and pancreaticosplenic ligaments (star), respectively. P, pancreas. D. Human, day 67. A horizontal cut was made through the stomach, spleen, and pancreas. By the time the human conceptus reaches 9 weeks, the gross morphology of this region is similar to that in the adult. P, pancreas; Sp, spleen. (From Proceedings of the Greenwood Genetic Center, vol. 8, 1989, Greenwood Genetic Center. Used by permission.)

4. Dear TN, Colledge WH, Carlton MB, et al.: The Hox11 gene is essential for cell survival during spleen development. Development 121:2909, 1995. 5. Kanzler B, Dear TN: Hox11 acts cell autonomously in spleen development and its absence results in altered cell fate of mesenchymal spleen precursors. Dev Biol 234:231, 2001. 6. Herzer U, Crocoll A, Barton D, et al.: The Wilms tumor suppressor gene Wt1 is required for development of the spleen. Curr Biol 9:837, 1999. 7. Koehler K, Franz T, Dear TN: Hox11 is required to maintain normal Wt1 mRNA levels in the developing spleen. Dev Dyn 218:201, 2000. 8. Lettice LA, Purdie LA, Carlson GJ, et al.: The mouse bagpipe gene controls development of axial skeleton, skull, and spleen. Proc Natl Acad Sci U S A 96:9695, 1999.

9. Tribioli C, Lufkin T: The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development 126:5699, 1999. 10. Quaggin SE, Vanden Heuvel GB, Igarashi P: Pod-1, a mesoderm-specific basic-helix-loop-helix protein expressed in mesenchymal and glomerular epithelial cells in the developing kidney. Mech Dev 71:37-48, 1998. 11. Lu J, Chang P, Richardson JA, et al.: The basic helix-loop-helix transcription factor capsulin controls spleen organogenesis. Proc Natl Acad Sci U S A 97:9525, 2000. 12. Patterson M: A mean spleen gene. Nat Rev Genet 1:8, 2000. 13. Wolf BC, Luevano E, Neiman RS: Evidence to suggest that the human fetal spleen is not a hematopoietic organ. Am J Clin Pathol 80:140, 1983.

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Most parts of the human body are structurally symmetric about the sagittal plane. Asymmetric organs include the heart and great vessels, the lungs, the liver, the gallbladder and biliary tract, the gastrointestinal tract, and the spleen. The usual or ‘‘normal’’ positioning of the asymmetric organs is called situs solitus, and a mirror-image reversal of this arrangement is called situs inversus.

Figure 5-2A shows the ‘‘normal’’ or usual configuration of thoracic and abdominal organs. The right lung usually has three lobes, and the right mainstem bronchus is shorter and deviates from the midline by a smaller angle than the left. The right superior lobe bronchus arises and passes above the pulmonary artery and is called an eparterial bronchus, in contrast to the right middle and lower lobe bronchi, which are called hyparterial. The left mainstem bronchus is approximately twice as long as the right and narrower in diameter. It extends above the pulmonary artery but then passes below the aorta and pulmonary artery before branching into hyparterial bronchi to the superior and inferior lobes. Figure 5-2B shows situs inversus, the mirror-image reversal of the normal configuration. Total situs inversus is usually asymptomatic. Approximately 20–25% will have an immotile cilia syndrome (primary ciliary dyskinesia) and less than 10% have associated structural malformations. A normal, right-sided spleen is present. Some patients have what appears to be a combination of situs solitus and situs inversus—some organs are in their usual position and some are reversed. These individuals usually have major birth defects involving one or more of the asymmetric organs, especially malformations of the heart and great vessels, anomalies of the liver and biliary tract, and malrotation of the bowel. These patients usually have either congenital asplenia or polysplenia. Isomerism refers to the duplication of structures typical of one side of the body on the other side, a situation also described by the terms bilateral right-sidedness and bilateral left-sidedness. Asplenia has been called bilateral right-sidedness (dextroisomerism) because of the apparent bilateral duplication of right-sided

Fig. 5-2. A. Situs solitus. A schematic representation of situs solitus showing the eparterial bronchus on the right with the trilobed right lung (RL). On the left, there is a hyparterial bronchus because the pulmonary artery crosses over the bronchus. The left lung (LL) has two lobes. The left bronchus is longer than the right by about a 1.7 to 2.1 ratio. The right atrium (RA) is on the patient’s right side and the left atrium (LA) is on the left side. The abdominal viscera are normal, with the liver on the right and the spleen and stomach on the left. The inferior vena cava is to the right of the spine, and

the aorta descends to the left of the spine in the normal or situs solitus situation. B. Situs inversus. In the schematic representation of situs inversus, there is a mirror image, with the trilobed lung and eparterial bronchus on the left, a bilobed lung and hyparterial bronchus on the right, dextrocardia, and reversal of the abdominal organs and vessels. (Illustration and legend from Tonkin ILD: The definition of cardiac malpositions with echocardiography and computed tomography, in Pediatric Cardiac Imaging, WF Friedman, CB Higgins, eds, WB Saunders Company, Philadelphia, 1984. Used by permission.)

5.1 Polyasplenia Definition

A composite term that includes asplenia (absence of the spleen) and polysplenia (multiple spleens). Historically, asplenia and polysplenia (and their accompanying anomalies) have been treated as separate entities and the terms asplenia syndrome and polysplenia syndrome widely used to refer to the complex of malformations and heterotaxy that is associated with each splenic anomaly. However, because they are both associated with similar malformations in other organ systems and occasional families include cases of both, polysplenia and asplenia can be thought of as different manifestations of a common set of morphogenetic errors.1–6 Opitz coined the term polyasplenia to indicate the likelihood that asplenia and polysplenia are part of a single spectrum of malformation.7 This spectrum does not constitute a specific malformation syndrome but represents a collection of nonrandom associations with more than one causally specific syndrome. The polyasplenia spectrum includes phenotype labels such as Ivemark asplenia syndrome, polysplenia syndrome, situs ambiguus, heterotaxia, partial or complete situs inversus, isomerism, and laterality defect.8 Diagnosis

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Cardiorespiratory Organs

structures, such as bilateral trilobed lungs in association with absent spleen. Polysplenia has been called bilateral left-sidedness because of the apparent bilateral duplication of left-sided structures, such as bilateral bilobed lungs in association with multiple spleens.9 In polyasplenia there is an unusual spatial arrangement of the thoracic and/or abdominal organs in relationship to each other called visceral heterotaxia or heterotaxy, as well as malformations in one or more organ systems. Note that polyasplenia with associated anomalies is sometimes incorrectly referred to as ‘‘situs inversus.’’ This term should be reserved for situations where there is a mirror-image reversal of organ relationships, that is, so-called ‘‘complete’’ situs inversus. The terms ‘‘partial’’ or ‘‘incomplete’’ situs inversus have also been used for polyasplenia, but situs ambiguus is less confusing and preferred. Figure 5-3 shows the situs ambiguus configurations associated with polyasplenia. Asplenia is found in association with right isomerism (Fig. 5-3A), and polysplenia occurs with left isomerism (Fig. 5-3B). Patients with situs ambiguus usually have lifethreatening structural malformations that can involve any organ system. Evidence that situs ambiguus and complete, mirror-image situs inversus (thoracic and/or abdominal, with or without ciliary abnormality) may be parts of the same spectrum of malformationassociation is suggested by families where both occur.4,10 Although patients with situs inversus usually have a low incidence of other structural malformations, occasional families have a high frequency of other anomalies.11 Some families have had recurrence of the malformations that are typically associated with situs

ambiguus, such as congenital heart disease with only variable occurrence of complete situs inversus or polyasplenia.11–15 One should suspect situs ambiguus in any child who has cyanotic congenital heart disease and an apparently symmetric liver, with the edge palpable across the entire upper abdomen, or an inverted liver with the left lobe larger than the right. Most visceroatrial situs abnormalities can be diagnosed with a combination of chest radiography, abdominal ultrasonography, echocardiography, and either computed tomography (CT) or magnetic resonance imaging (MRI).16 Radiography of the chest and upright abdomen will allow determination of heart malposition and mainstem bronchial anatomy, an indicator of atrial situs.17–19 Asplenia is suggested by the observation of Heinz bodies or Howell-Jolly bodies in a peripheral blood smear. Hepatobiliary radionuclide imaging may identify liver symmetry and shape.20 Radionuclide spleen scanning may also be used to identify spleen position but not spleen number, because in polysplenia the splenules may be so closely situated that they form a multilobulated mass that appears, on scan, to be a single spleen (Fig. 5-4).21,22 In polysplenia, the multiple spleens are typically, but not invariably, found along the greater curvature of the stomach.9 The electrocardiogram and echocardiogram are helpful in cases with cardiac malposition, inversion, or other malformation. Abdominal CT and MRI can be very useful when combined with ultrasonographic studies.16,23 Patients with asplenia or polysplenia usually have other, severe malformations that are life-threatening. The list of associated malformations is extensive and involves virtually every thoracic and abdominal organ system24 (Table 5-1). Most commonly,

Fig. 5-3. A. With situs ambiguus, there may be bilateral right isomerism with bilateral trilobed lungs and eparterial bronchi of the same short length. In the instance of right atrial isomerism, the atrial appendages are usually symmetric and resemble a broad-based right atrial appendage. The liver is frequently in the midline, as may be the stomach with absence of the spleen. The abdominal aorta and inferior vena cava cross to the same side of the spine in the abdomen with inferior vena cava–right atrial continuity. B. In left isomerism or polysplenia syndrome, there are bilateral hyparterial bronchi, bilobed lungs, and bilateral left atria or a

common atrium. By definition, at least two spleens are along the greater curvature of the stomach. Left isomerism frequently involves interruption of the inferior vena cava with azygos or hemiazygos continuation to a superior vena cava. Heart disease is less severe in this syndrome, with a 5–10% incidence of no congenital heart disease. (Illustration and legend from Tonkin ILD: The definition of cardiac malpositions with echocardiography and computed tomography, in Pediatric Cardiac Imaging, WF Friedman, CB Higgins, eds, WB Saunders Company, Philadelphia, 1984. Used by permission.)

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Fig. 5-4. Anatomic specimen from 2-month-old girl with polysplenia, dextrocardia, double-outlet right ventricle, ventricular septal defect, partial anomalous venous return, absent inferior vena cava with azygous continuation, patent ductus, inverted liver with left lobe larger than right, midline gallbladder, left-sided stomach, and bilateral bilobed lungs with symmetric bronchial anatomy. A. Location of spleens on

greater curvature of the left-sided stomach (arrows indicate extent of splenic mass; liver has been reflected upward). B. Multiple small spleens form a multilobulated splenic mass, the total size of which is appropriate for the age of the infant. (Illustrations courtesy of F. Dalldorf and K. Willits, Department of Pathology, University of North Carolina.)

cardiovascular anomalies predominate. As many as 90% of patients with polysplenia and 99% of patients with asplenia have congenital heart disease.16 Numerous reports of patients with situs ambiguus who have central nervous system anomalies or defects of the axial skeleton suggest that such malformations are also nonrandomly associated with the polyasplenia spectrum (Table 5-1). It should be noted that since many patients and reported series are ascertained by malformations in single organ systems (for example, congenital heart disease), prevalence data for associated anomalies may be biased.

lungs, both with eparterial bronchi). Abdominal heterotaxy also occurs, often with bowel malrotation and a symmetric liver. The stomach is frequently located on the right side. Extracardiac malformations are common and frequently involve the gastrointestinal, genitourinary, bronchopulmonary, skeletal, and central nervous systems (Table 5-1). Cardiovascular malformations are usually conotruncal anomalies and tend to be more severe than those associated with polysplenia. They include malposition, common atrium, bilateral superior vena cavae, total anomalous pulmonary venous return, transposition of the great vessels, and pulmonary stenosis or atresia (Table 5-1). The inferior vena cava and the abdominal aorta have an anomalous relationship, both lying on the same side of the spine, regardless of the side occupied by the vena cava. This relationship seemed pathognomonic for the asplenia complex until Freedom34 observed it in a patient with malformations typical of polysplenia, another example supporting the concept of a polyasplenia spectrum of malformation.

Asplenia Phenotype

Adult presentations of asplenia have been described.25 Asplenia occurs rarely in individuals with situs solitus without other severe malformations.21,26–30 Many of these have been familial cases consistent with an autosomal dominant mode of inheritance.30 Two patients with isolated agenesis of the spleen presented with secondary thrombocytosis mimicking essential thrombocythemia.29 Isolated asplenia is also a rare cause of sudden unexpected death in childhood.31 Asplenia with heterotaxy but without cardiac malformation seems to be very rare.32 A significant relationship between asplenia, cardiac malformations, and other visceral anomalies was noted by Polhemus and Schafer1 in 1952 and by Ivemark in 1955.33 Asplenia became known as bilateral right-sidedness (dextroisomerism) because of the apparent bilateral duplication of right-sided structures (for example, asplenia is commonly associated with bilateral trilobed

Polysplenia Phenotype

One or more small, accessory spleens are found commonly in individuals with situs solitus. This normal variant should not be confused with true polysplenia. Accessory spleens are usually asymptomatic but may be associated with other malformations such as splenogonadal fusion and limb reduction (see Section 5.3).

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Cardiorespiratory Organs

Table 5-1. Malformations associated with asplenia and polysplenia Pulmonary42,118–120

Pulmonary isomerism (bilateral trilobed lungs with eparterial bronchi in asplenia, bilateral bilobed lungs with hyparterial bronchi in polysplenia), four-lobed lungs, anomalous (absent or extra) major fissures, pulmonary situs inversus, tracheoesophageal fistula, tracheal agenesis with bronchoesophageal fistula, total tracheopulmonary agenesis

Cardiovascular1,9,16,22,23,26,33–37,42,79,119,121–124

Malposition, single atrium, bilateral superior vena cavae, anomalous pulmonary venous return (including a rare variant with intrapulmonary drainage of one lung by the other), transposition of the great vessels, pulmonic stenosis or atresia, atrial septal defect, ventricular septal defect, atrioventricular canal, intrahepatic interruption of the inferior vena cava with azygous continuation of the superior vena cava, persistent left superior vena cava to coronary sinus, double outlet right ventricle, subaortic stenosis, hypoplastic left heart with malformed aortic and mitral valves, endocardial cushion defect, right-sided aortic arch

Skeletal125,126

Vertebral malformation (hypoplasia, dysplasia, hemivertebrae, spina bifida), scoliosis, hypoplastic sternum, radial and/or ulnar hypoplasia

Nervous2,26,36,40,42,44,95,118,119,125,127–129

Neural tube defects (anencephaly, spina bifida and encephalocele, especially craniocervical), iniencephaly, holoprosencephaly, microphthalmia, hydrocephalus, third ventricle hypoplasia, septum pellucidum abnormality, cerebellar dysplasia or hypoplasia, Dandy-Walker malformation, arteriovenous malformation, porencephaly, hydranencephaly

Craniofacial36,125,126

Cleft lip with or without cleft palate, cleft palate without cleft lip, microphthalmia

Gastrointestinal

36,40,42,44,125,126,130–133

Esophageal atresia with tracheoesophageal fistula, esophageal varices, liver midline, symmetrical or inverted (left lobe larger than right), extrahepatic biliary atresia, hypoplastic or absent gallbladder with or without biliary atresia, annular or semiannular pancreas, hypoplastic pancreas, duplication of the stomach, microgastria, tubular stomach, duodenal or jejunal atresia, malrotation of the bowel, short bowel, intestinal web, duplication of the hindgut, aganglionosis, imperforate anus, rectal stenosis

Urinary26,125,126

Renal agenesis, renal hypoplasia, horseshoe kidney, double ureters, hydronephrosis, renal cysts, posterior urethral valves

Endocrine125,126,134

Fused adrenal glands, absence of one adrenal, adrenal hyperplasia

125,126

Genital

Undescended testicles, testicular hypoplasia, bicornuate uterus and other unspecified uterine anomalies, ovarian cysts

Other26,125

Diaphragmatic hernia or agenesis, single umbilical artery, inguinal hernia, premature birth, fetal hydrops

In 1967, Moller and colleagues9 described similarities between patients with asplenia and polysplenia, giving the latter the term bilateral left-sidedness (levoisomerism). Two or more spleens are usually present along the greater curvature of the stomach. Patients with polysplenia typically have bilateral bilobed lungs with hyparterial bronchi, abdominal heterotaxy with bowel malrotation, and a liver that is symmetric or inverted with the larger lobe on the left. The stomach is usually right-sided. Extracardiac malformations are common as in asplenia and also involve the gastrointestinal, genitourinary, bronchopulmonary, skeletal, and central nervous systems (Table 5-1). Cardiovascular malformations most commonly include malposition, atrial septal defects, ventricular septal defects, bilateral superior vena cavae, partial anomalous pulmonary venous return, and intrahepatic interruption of the inferior vena cava with connection to the azygous or hemiazygous vein (Table 5-1). One patient with a complex of anomalies otherwise typical of the polysplenia spectrum had a single, hypoplastic, ectopic spleen.35 Adult presentations of polysplenia have been delineated.25 Unlike the situation with asplenia, a number of cases of polysplenia with heterotaxia but without severe or complex heart malformation have been observed, and rarely the diagnosis is first made in adult life.25,32,36–39 Extrahepatic biliary atresia (EHBA) occurs in a subgroup of patients who have polysplenia with other typical extracardiac anomalies but a relatively low frequency of congenital heart disease.40 It is estimated that between 6% and 23% of EHBA patients

have polysplenia and 31–50% of patients with polysplenia present with EHBA.41 Etiology and Distribution

The minimal incidence of polysplenia and asplenia was estimated by Rose and colleagues to be 1 of 40,000 live births.42 Gatrad and colleagues found 1 of 24,000 affected in an English population and 1 of 2700 affected in a highly inbred Asian population.5 Lin and colleagues found a heterotaxy prevalence of approximately 1 per 10,000 total births in Boston.43 Asplenia is more commonly reported than is polysplenia. There seems to be a male predominance in asplenia and an equal sex distribution among cases with polysplenia.16,22,26,42,44 The polyasplenia-situs ambiguus spectrum of malformation appears to be associated with errors in the early embryonic determination of body asymmetry. The genetic controls and embryologic events involved in determining situs solitus are becoming better understood as the result of elegant research in model organisms. The pathogenetic mechanisms leading to situs inversus and the polyasplenia spectrum are still largely unknown, although some causative factors and genes in the pathways of normal laterality determination have been elucidated (see Chapter 33, Introduction and Section 33.1).45–51 In asplenia, there appears to be incomplete or aberrant development of left-sided structures, and in polysplenia, bilateral development of left-sided structures. Visceral heterotaxies seem to be related to interruption of normal early embryonic morphogenetic processes, which results in

Spleen

retention of some symmetrical embryonic organization and structure.34 For example, the presence of bilateral superior vena cavae represents persistence of the normally paired anterior cardinal veins, and atrial isomerism is the result of incomplete incorporation of the left horn of sinus venosus into the coronary sinus. In asplenia, one often finds no coronary sinus and the connection of the left anterior cardinal vein (persistent left superior vena cava) to the left horn of sinus venosus (into the left atrium). Numerous abnormalities in the ciliary apparatus have been associated with the immotile cilia syndrome or primary ciliary dyskinesia.52–54 These appear to be caused by autosomal mutations that are recessively expressed. Among affected homozygotes, one-half have situs solitus and one-half have situs inversus.55 These mutant genes, therefore, seem to release the early embryo from its normal program of situs determination, allowing laterality to be established randomly with regard to situs solitus and situs inversus.55,56 Complete situs inversus usually is not associated with polyasplenia. Therefore, that group of disorders will not be covered in this entry. Immotile cilia have been found in a few individuals with situs ambiguus, however, and polysplenia and Kartagener syndrome have been observed in sibs.10,57,58 Such observations suggested that normal ciliary activity might be a part of the mechanism by which situs solitus is established, and subsequent studies have identified the importance of nodal ciliary activity at the time of gastrulation in determining normal leftright asymmetry. 51,59,60 Prenatal exposure to retinoic acid produces malformations in many organ systems in hamsters, depending on the time of treatment.61 What was reported as situs inversus was produced by treatment at the earliest times that caused anomalies, stages that are also those of peak embryo sensitivity. Both a deficit and an excess of retinoic acid can produce cardiac defects, which depend on dose and timing. The mechanism proposed was that retinoic acid causes these cardiac defects by disrupting production of the extracellular matrix.62 Subsequent studies have confirmed an important role for retinoic acid in left-right patterning.63–66 Retinoic acid acts in a synergistic manner with the type IIB activin receptor.64 Acvr2b knockout mice die shortly after birth with asplenia, complicated cardiac malformations, renal anomalies, and thoracic hypersegmentation. The human gene, ACVR2B, has been characterized, and two missense mutations have been identified in three patients with situs ambiguus. These were found by screening samples from 112 sporadic and 14 familial cases of laterality defects.67 Maternal diabetes causes fetal anomalies of the neural tube, cardiovascular system, and many other structures. In Kucera’s study of the incidence of birth defects, an anomaly referred to as ‘‘situs inversus’’ was second only to defects of the spine in the offspring of diabetic women compared to controls.68 Because these observations involved congenital anomalies diagnosed in newborns, it seems likely that all probably had some form of situs ambiguus. Subsequent reports continue to support a causative association between maternal diabetes and polyasplenia.69–71 Maternal diabetes is clearly the cause of laterality defects in the offspring of NOD mice, a model of insulin-dependent diabetes mellitus.72 The induction of polyasplenia with heterotaxy and malformation in fetuses of NOD mothers by maternal diabetes is influenced by the fetal genotype.73 The fetal genotype appears to set a level of predisposition to malformation, while the abnormal glucose homeostasis in the environment disrupts normal development in susceptible embryos. Sequence variations in HNF3beta, Lefty1, and Nodal genes have been identified that appear to

189

influence the susceptibility to situs abnormalities in this mouse model.74 Most cases of polyasplenia occur sporadically, but numerous familial cases suggest that there are major monogenic factors involved. Observations of affected cousins in families initially suggested an inherited predisposition to polyasplenia.2,13 Parental consanguinity and/or familial recurrences of polyasplenia have been cited as evidence consistent with the hypothesis that some cases are caused by recessively expressed mutations in autosomal genes.1–3,5,6,13–15,33,36,42,75–88 Recessive causation of complete situs inversus without symptoms of ciliary dysfunction is also suggested by an instance of probable pseudodominant inheritance where an affected man married his cousin and had two affected sons.89 Before recognition of the ciliary disorders, Cockayne concluded that complete situs inversus was of autosomal recessive causation.90 He also suggested that different types of ‘‘partial situs inversus’’ (situs ambiguus) were of monogenic origin and that these conditions formed a continuous spectrum of malformation with ‘‘an almost perfect gradation leading up to complete transposition.’’ A significant paternal age effect for ‘‘situs inversus’’ was found among malformed babies in the Metropolitan Atlanta Congenital Defects Program, leading to the conclusion that a proportion is due to new, dominantly expressed mutations.91 Because the study ascertained babies with malformations, this group probably had situs ambiguus rather than total situs inversus. A father with complete situs inversus has had two children with different manifestations of the situs ambiguus spectrum.4 One had asplenia and the other polysplenia, both manifesting typical associated lethal anomalies. An apparent autosomal dominant predisposition to laterality defects has been described over three generations of a family.92 Two individuals had asplenia with heterotaxy (situs ambiguus), while two others had apparent complete mirror-image situs inversus without other malposition or malformation. Several other reports also suggest the existence of either straightforward autosomal dominant inheritance of situs inversus and situs ambiguus, or at least a monogenic predisposition to laterality defects running through families.4,58,93 It is unclear whether father-to-son transmission of nonsyndromic asplenia is caused by genes involved in laterality determination.94 Mathias and colleagues described a family with X-linked situs ambiguus affecting 11 males.95 Both asplenia and polysplenia occurred, with cardiac, CNS, and vertebral malformations, including sacral dysplasia with anorectal anomalies. Another X-linked family also featured caudal anomalies in the affected males and genitourinary anomalies in carrier females (bicornuate uterus, uterine septum, septate vagina and uterus), one of which also had anal stenosis.96 The causes of this phenotype of X-linked situs ambiguus with caudal dysplasia are various mutations in the X-linked gene, ZIC3.97,98 Zic3 is also the gene deleted in the X-linked mouse mutation Bent Tail. Kinked tails in these mice are due to aberrant tail bone development. Some have exencephaly. Both the hemizygous males and heterozygous females may have situs ambiguus.99,100 The Zic3 knockout mouse has a phenotype similar to the human ZIC3 mutations, including situs ambiguus, CNS malformations (exencephaly), and axial skeletal anomalies (vertebral dysplasia, fusion, and duplication).101,102 One X-linked family with a ZIC3 mutation has the unique finding of situs inversus in carrier females and situs ambiguus in males.97 The affected males had lethal malformation syndromes associated with situs ambiguus, while carrier females have mirror-image situs inversus or situs solitus. Anal anomalies occur in both affected

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males and carrier females. Most reported familial recurrences of situs inversus or situs ambiguus with caudal dysplasia are compatible with X-linked inheritance. Therefore, caudal dysplasia appears to be a clinical finding highly associated with heterotaxies caused by mutations in ZIC3. Several other nonfamilial cases of situs ambiguus with caudal dysgenesis have been described; it is not clear whether they also have ZIC3 mutations.36,103,104 Situs abnormalities are occasionally found in patients with chromosome abnormalities. Since these patients may have overexpression of duplicated genes, deficiency of deleted gene products,

or disruption of single genes, they may be useful in identifying genes involved in left-right axis determination. It should be remembered that associations reported in only a single subject may be coincidental or nonspecific. On the other hand, involvement of the same chromosomal region in more than one patient with heterotaxy may suggest a true association and support a search for candidate genes in the region. Reports of situs inversus or situs ambiguus with chromosome abnormalities are summarized in Table 5-2. Other non-chromosomal syndromes syndromes reported with asplenia or polysplenia are summarized in Table 5-3.

Table 5-2. Chromosome abnormalities associated with laterality defects Phenotype

Chromosome Abnormality 135

Situs inversus abdominus, complex congenital heart disease

dup(2)(pter-p24) and del(2)(q34-qter)

Situs ambiguus and familial split hand/foot malformation136,137

Familial, apparently balanced, reciprocal t(2;7)(q21.1;q22.1) (baby with situs ambiguus not karyotyped)

Situs inversus, malrotation, duodenal and jejunal atresia, short stature, mental retardation, seizures138

Microdeletion of 2q37.3

Adult with mild mental retardation, heterotaxy, malrotation and malposition of large and small bowel, with most of the bowel above the liver and spleen, malrotation and malposition of the right kidney, hypoplastic male genitalia138

Microdeletion of 2q37.3

Situs ambiguous139

Partial trisomy 3p(mat); [maternal translocation t(3:4)(p23;q35)]

Absent left arm, short bowel, malrotation, pseudo-obstruction, dextrocardia with situs solitus, patent ductus arteriosus, and a tiny atrophic spleen140

Mosaic ring 4 with partial trisomy of 4pter to q22.3 and partial monosomy 4q22.3 to qter

Agnathia, holoprosencephaly, situs solitus141

dup(6)(pter-p24) and del(18)(pter-p11.21)

[Similarly affected sister had apparent situs solitus but also cardiac malformations, renal hypoplasia, and malrotation] Inversely located heart, stomach, duodenum, and cecum; cerebral atrophy, hypertelorism, severe mental retardation142

46,XX,t(6;18)(q21;q21.3)

Atrioventricular septal defect, left atrial isomerism, large atrial septal defect, right-sided aorta, left inferior vena cava, persistent left superior vena cava, abdominal situs inversus with right stomach and spleen, left liver, malrotation143

46,XX,t(6;20)(q21.1;p13)

Holoprosencephaly (HPE), sacral anomalies, abdominal situs ambiguus144

46,XY,der(7)t(2;7)(p23.2;q36.1)—hemizygosity for SHH and HLXB9 probably caused the HPE and sacral anomalies, respectively

Complete situs inversus, cystic fibrosis, normal cilia by electron microscopy145

Paternal isodisomy of chromosome 7 (see iv mouse)

Situs ambiguus, polysplenia, bilateral split hand malformation146

46,XY,ins(7;8)(q22;q12q24); insertion of 8q12q24 into 7q22

Situs inversus, volvulus with duodenal obstruction, patent ductus arteriosus, abnormal origin of the carotid artery, absent lung lobation, annular pancreas147

46,XX,t(7;16)(p22;q24)

Situs ambiguus, omphalocele, cleft lip and palate148

46,XX,del(10)(q21q23)

Asplenia, pulmonic stenosis, Hirschsprung disease, minor anomalies, mental retardation149

46,XX,t(11;20)(q13.1;q13.13)(pat)

Situs ambiguus, polysplenia [Father phenotypically normal]150

inv(11)(q13.5;q25)(pat)

Situs ambiguus, asplenia [Mother phenotypically normal]151

46,XX,t(12;13)(q13.1;p13)(mat)

Situs ambiguus [Mother phenotypically normal]46

46,XX,inv(12)(q12;q24.3)(mat)

Situs ambiguus, microcephaly, absent thumbs148

46,XX,del(13)(q31qter)

Polysplenia, hydrocephalus, intrauterine growth retardation, single umbilical artery, agenesis of the corpus callosum152

Confined placental mosaicism 47,XXX,þ16

Situs ambiguus and other features of del 18p phenotype153

del(18)(p11.21)

24

Dextrocardia

22q11 deletion

Left isomerism sequence24

22q11 deletion

Primary ciliary dyskinesia, situs inversus154,155

45,X/46,X þ mar (80%/20%)

Mirror-image dextrocardia, complete situs inversus, 19 week fetus155

45,X/46,XY

Spleen

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Table 5-3. Syndromes with asplenia or polysplenia Causation Gene/Locus

Syndrome

Major Findings

X-linked laterality syndrome95–97,99,156,157

A variable spectrum of asplenia and polysplenia, situs inversus and situs ambiguus, congenital heart disease, arrhinencephaly, meningomyelocele, sacral dysgenesis, cerebellar hypoplasia, and extrahepatic biliary atresia. In at least one family, carriers had complete, mirror-image situs inversus without other heterotaxy, but with variable degrees of caudal dysplasia such as anal atresia or stenosis

XLR (304750) ZIC3

Maternal diabetes, prenatal68,69

Situs inversus or ambiguus, sacral dysgenesis, neural tube defects, congenital heart malformation, arthrogryposis, and an extremely wide and variable spectrum of malformations involving the genitourinary tracts, gastrointestinal tract, nervous system, craniofacies, and skeleton

Multifactorial

Agnathia and/or holoprosencephaly158–168

Agnathia, holoprosencephaly, situs inversus, situs ambiguus, genitourinary anomalies

Unknown

Absence/hypoplasia of the tongue165,169–173

Microglossia or aglossia, situs inversus, situs ambiguus (possibly related to agnathia association above)

Unknown

Cumming campomelia syndrome174,175,181,182

Polysplenia, campomelia, cervical lymphocele, short bowel, multicystic/polycystic dysplasia of kidneys, liver, and/or pancreas, abnormal lung lobation (bilateral left bronchial morphology), dextrocardia, total anomalous pulmonary venous return, left superior vena cava, right aortic arch, short pancreas with absence of the body and tail

AR probable

Rare patients/families are described with polyasplenia and features of the Carpenter syndrome,176,177 Johanson-Blizzard syndrome,178 Meckel syndrome,179,180 and the autosomal recessive ciliary dyskinesia syndromes with immotile cilia.10,57,58

Prognosis, Prevention, and Treatment

Children with polyasplenia usually have other severe malformations that cause death in the newborn period or during the 1st year. Malformations associated with asplenia are more commonly lethal than those occurring with polysplenia, but rare cases have been reported of prolonged survival in patients who have asplenia and situs ambiguus with cardiac malformation.32,39,105–107 Patients with asplenia have a risk of dying from sepsis, because they lack the normal splenic functions that protect against bacterial infection, and arrhythmias.27,108 Pneumococcal and other bacterial vaccines should be considered, in conjunction with antibiotic prophylaxis, for treatment of patients with congenital asplenia.13,109 Some patients with polysplenia have cardiovascular malformations for which surgery is feasible. A suggestion has been made that heart transplantation is a viable therapy for high-risk patients with polyasplenia, and that it may offer better survival than standard surgical management for some patients with complex heart malformations.110 Orthotopic liver transplantation procedures tend to be much more complex in individuals with abdominal heterotaxy than in patients with situs solitus, initially resulting in excessive postoperative complications and poor survival rates. This is because the associated complex vascular anomalies such as interrupted inferior vena cava, preduodenal portal vein, and anomalous origin of the hepatic artery increase the technical difficulties of the operation. In spite of the need for significant technical modifications, however, polysplenia with abdominal heterotaxy is not a contraindication to liver transplantation, and good results have been obtained.111 Living-related donor grafts are now being used successfully to treat end-stage liver disease due to biliary atresia in children with polysplenia.112–114 A French national study concluded that early performance of a Kasai operation appears to

provide children with biliary atresia the best chance of survival without the need for liver transplantation.115 Prenatal diagnosis by ultrasonography is feasible and appears to be accurate.116 In pregnancies with no family history to suggest heterotaxy, affected babies can be identified by the presence of cardiac malformation, malposition, or dysrhythmia associated with other organ malposition and malformations of the skeleton, urinary tract, or central nervous system. In those with a previous history, a single anomaly in any organ system suggests recurrence. The spleen can usually be detected by 20 weeks gestation, and nonvisualization has led to the prenatal diagnosis of asplenia in fetuses with cardiac malformation and dysrhythmia.117 Berg et al. concluded that left isomerism is suggested by two or more of the following: (1) complete atrioventricular septal defect or other structural heart disease; (2) interruption of inferior vena cava with azygos continuation; (3) early fetal heart block; or (4) viscerocardiac heterotaxy. Right isomerism should be suspected when finding at least two of the following: (1) structural heart disease, namely complete atrioventricular septal defect; (2) juxtaposition of inferior vena cava and descending aorta; or (3) viscerocardiac heterotaxy.116 References (Polyasplenia) 1. Polhemus DW, Schafer WB: Congenital absence of the spleen; syndrome with atrioventricularis and situs inversus. Pediatrics 9:696, 1952. 2. Chen SC, Monteleone PL: Familial splenic anomaly syndrome. J Pediatr 91:160, 1977. 3. Zlotogora J, Elian E: Asplenia and polysplenia syndromes with abnormalities of lateralisation in a sibship. J Med Genet 18:301, 1981. 4. Niikawa N, Kohsaka S, Mizumoto M, et al.: Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. Am J Med Genet 16:43, 1983. 5. Gatrad AR, Read AP, Watson GH: Consanguinity and complex cardiac anomalies with situs ambiguus. Arch Dis Child 59:242, 1984.

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6. De la Monte SM, Hutchins GM: Sisters with polysplenia. Am J Med Genet 21:171, 1985. 7. Opitz JM: Editorial comment on the paper by de la Monte and Hutchins on familial polyasplenia. Am J Med Genet 21:175, 1985. 8. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001. 9. Moller JH, Nakib A, Anderson RC, et al.: Congenital cardiac disease associated with polysplenia. A developmental complex of bilateral ‘‘left-sidedness.’’ Circulation 36:789, 1967. 10. Schidlow DV, Katz SM, Turtz MG, et al.: Polysplenia and Kartagener syndromes in a sibship: association with abnormal respiratory cilia. J Pediatr 100:401, 1982. 11. Zlotogora J, Schimmel MS, Glaser Y: Familial situs inversus and congenital heart defects. Am J Med Genet 26:181, 1987. 12. Silver W, Steier M, Chandra N: Asplenia syndrome with congenital heart disease and tetralogy of Fallot in siblings. Am J Cardiol 30:91, 1972. 13. Katcher AL: Familial asplenia, other malformations, and sudden death. Pediatrics 65:633, 1980. 14. Arnold GL, Bixler D, Girod D: Probable autosomal recessive inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am J Med Genet 16:35, 1983. 15. Distefano G, Romeo MG, Grasso S, et al.: Dextrocardia with and without situs viscerum inversus in two sibs. Am J Med Genet 27:929, 1987. 16. Tonkin ILD: The definition of cardiac malpositions with echocardiography and computed tomography. In: Pediatric Cardiac Imaging. Friedman WF, Higgins CB, eds. WB Saunders Co, Philadelphia, 1984, p 157. 17. Van Mierop LH, Eisen S, Schiebler GL: The radiographic appearance of the tracheobronchial tree as an indicator of visceral situs. Am J Cardiol 26:432, 1970. 18. Soto B, Pacifico AD, Souza AS Jr, et al.: Identification of thoracic isomerism from the plain chest radiograph. AJR Am J Roentgenol 131:995, 1978. 19. Furlonger BJ: High kV filtered beam technique for demonstrating bronchial situs. Radiography 48:197, 1982. 20. Polga JP, Spencer RP: Hepatobiliary imaging as an aid in determining situs in a case of polysplenia. Clin Nucl Med 9:159, 1984. 21. Muir CS: Splenic agenesis and multilobulate spleen. Arch Dis Child 34:431, 1969. 22. Van Mierop LHS, Gessner IH, Schiebler GL: Asplenia and polysplenia syndromes. Birth Defects Orig Artic Ser VIII:36, 1972. 23. Winer-Muram HT, Tonkin IL: The spectrum of heterotaxic syndromes. Radiol Clin North Am 27:1147, 1989. 24. Splitt MP, Burn J, Goodship J: Defects in the determination of leftright asymmetry. J Med Genet 33:498, 1996. 25. Winer-Muram HT: Adult presentation of heterotaxic syndromes and related complexes. J Thorac Imaging 10:43, 1995. 26. Putschar WGJ, Manion WC: Congenital absence of the spleen and associated anomalies. Am J Clin Pathol 26:429, 1956. 27. Waldman JD, Rosenthal A, Smith AL, et al.: Sepsis and congenital asplenia. J Pediatr 90:555, 1977. 28. Hauser GJ, Silberman C: Incidental discovery of asplenia syndrome, with situs inversus and a normal heart by radionuclide biliary imaging. A case report. Clin Nucl Med 7:543, 1982. 29. Chanet V, Tournilhac O, Dieu-Bellamy V, et al.: Isolated spleen agenesis: a rare cause of thrombocytosis mimicking essential thrombocythemia. Haematologica 85:1211, 2000. 30. Gilbert B, Menetrey C, Belin V, et al.: Familial isolated congenital asplenia: a rare, frequently hereditary dominant condition, often detected too late as a cause of overwhelming pneumococcal sepsis. Report of a new case and review of 31 others. Eur J Pediatr 161:368, 2002. 31. Kanthan R, Moyana T, Nyssen J: Asplenia as a cause of sudden unexpected death in childhood. Am J Forensic Med Pathol 20:57, 1999. 32. Fulcher AS, Turner MA: Abdominal manifestations of situs anomalies in adults. Radiographics 22:1439, 2002. 33. Ivemark BI: Implications of agenesis of the spleen on the pathogenesis of cono-truncus anomalies in childhood: analysis of the heart malformations in the splenic agenesis syndrome, with fourteen new cases. Acta Pediatr 44(suppl 104):1, 1955.

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Spleen 60. McGrath J, Somlo S, Makova S, et al.: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61, 2003. 61. Shenefelt RE: Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment. Teratology 5:103, 1972. 62. Sinning AR: Role of vitamin A in the formation of congenital heart defects. Anat Rec 253:147, 1998. 63. Kim SH, Son CS, Lee JW, et al.: Visceral heterotaxy syndrome induced by retinoids in mouse embryo. J Korean Med Sci 10:250, 1995. 64. Oh SP, Li E: The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11:1812, 1997. 65. Schneider A, Mijalski T, Schlange T, et al.: The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Curr Biol 9:911, 1999. 66. Wasiak S, Lohnes D: Retinoic acid affects left-right patterning. Dev Biol (Orlando) 215:332, 1999. 67. Kosaki R, Gebbia M, Kosaki K, et al.: Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 82:70, 1999. 68. Kucera J: Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7:61, 1971. 69. Gonzalez A, Krassikoff N, Gilbert-Barness EF: Polyasplenia complex with mesocardia and renal agenesis in an infant of a diabetic mother. Am J Med Genet 32:457, 1989. 70. Slavotinek A, Hellen E, Gould S, et al.: Three infants of diabetic mothers with malformations of left-right asymmetry—further evidence for the aetiological role of diabetes in this malformation spectrum. Clin Dysmorphol 5:241, 1996. 71. Martinez-Frias ML: Heterotaxia as an outcome of maternal diabetes: an epidemiological study. Am J Med Genet 99:142, 2001. 72. Morishima M, Ando M, Takao A: Visceroatrial heterotaxy syndrome in the NOD mouse with special reference to atrial situs. Teratology 44:91, 1991. 73. Morishima M, Yasui H, Ando M, et al.: Influence of genetic and maternal diabetes in the pathogenesis of visceroatrial heterotaxy in mice. Teratology 54:183, 1996. 74. Maeyama K, Kosaki R, Yoshihashi H, et al.: Mutation analysis of leftright axis determining genes in NOD and ICR, strains susceptible to maternal diabetes. Teratology 63:119, 2001. 75. Schonfeld EA, Frischman B: Syndrome of spleen agenesis, defects of the heart and vessels and situs inversus. Report of a case suggesting heredity as an aetiological factor. Helv Paediatr Acta 13:636, 1958. 76. Badr-El-Din M: Syndrome of levocardia, multiple cardiac defects, situs inversus, and absent spleen. Am Heart J 63:115, 1962. 77. Neimann N, Pernot C, Gentin G, et al.: Le syndrome d’Ivemark: cardiopathie congenitale cyanogene severe, heterotaxie thoracoabdominale complexe et asplenie ou polysplenie. Pediatrie 21:511, 1966. 78. Simpson J, Zellweger H: Familial occurrence of Ivemark syndrome with splenic hypoplasia and asplenia in sibs. J Med Genet 10:303, 1973. 79. Hallett JJ, Gang DL, Holmes LB: Familial polysplenia and cardiovascular defects. Pediatr Res 13:344, 1979. 80. Kawagoe K, Hara K, Jimbo T, et al.: Occurrence of Ivemark syndrome with polysplenia in sibs of a family. Proc Jpn Acad 56:633, 1980. 81. Hurwitz RC, Caskey CT: Ivemark syndrome in siblings. Clin Genet 22:7, 1982. 82. Neill CA: Congenital cardiac malformations and syndromes. In: Genetics of Cardiovascular Disease. Pierpont ME, Moller JH, eds. Martinus Nijhoff, Boston, 1986, p 95. 83. Toriello HV, Kokx N, Higgins JV, et al.: Sibs with the polyasplenia developmental field defect. Am J Med Genet (suppl)2:31, 1986. 84. Czeizel A: Familial situs inversus and congenital heart defects [letter]. Am J Med Genet 28:227, 1987. 85. McChane RH, Hersh JH, Russell LJ, et al.: Ivemark’s ‘‘asplenia’’ syndrome: a single gene disorder. South Med J 82:1312, 1989. 86. Cesko I, Hajdu J, Toth T, et al.: Ivemark syndrome with asplenia in siblings. J Pediatr 130:822, 1997.

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87. Cesko I, Hajdu J, Marton T, et al.: Polysplenia and situs inversus in siblings. Case reports. Fetal Diagn Ther 16:1, 2001. 88. Eronen M, Kajantie E, Boldt T, et al.: Right atrial isomerism in four siblings. Pediatr Cardiol 2003. 89. Chib P, Grover DN, Shahi BN: Unusual occurrence of dextrocardia with situs inversus in succeeding generations of a family. J Med Genet 14:30, 1977. 90. Cockayne EA: The genetics of transposition of the viscera. Quart J Med 7:479, 1938. 91. Lian ZH, Zack MM, Erickson JD: Paternal age and the occurrence of birth defects. Am J Hum Genet 39:648, 1986. 92. Casey B, Cuneo BF, Vitali C, et al.: Autosomal dominant transmission of familial laterality defects. Am J Med Genet 61:325, 1996. 93. Alonso S, Pierpont ME, Radtke W, et al.: Heterotaxia syndrome and autosomal dominant inheritance. Am J Med Genet 56:12, 1995. 94. Lindor NM, Smithson WA, Ahumada CA, et al.: Asplenia in two father-son pairs. Am J Med Genet 56:10, 1995. 95. Mathias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. 96. Mikkila SP, Janas M, Karikoski R, et al.: X-linked laterality sequence in a family with carrier manifestations. Am J Med Genet 49:435, 1994. 97. Gebbia M, Ferrero GB, Pilia G, et al.: X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305, 1997. 98. Ferrero GB, Gebbia M, Pilia G, et al.: A submicroscopic deletion in Xq26 associated with familial situs ambiguus. Am J Hum Genet 61:395, 1997. 99. Klootwijk R, Franke B, van der Zee CEEM, et al.: A deletion encompassing Zic3 in bent tail, a mouse model for X-linked neural tube defects. Hum Mol Genet 9:1615, 2000. 100. Carrel TL, Purandare SM, Harrison W, et al.: The X-linked mouse mutation bent tail is associated with a deletion of the Zic3 locus [abstract & notes]. Am J Hum Genet 67(suppl 2):66, 2000. 101. Purandare SM, Gebbia M, Bassi MT, et al.: Zic3-deficient mice manifest defects in left-right axis development. Am J Hum Genet 67(suppl 2): 173, 2000. 102. Purandare SM, Ware SM, Kwan KM, et al.: A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129:2293, 2002. 103. Fullana A, Garcia-Frias E, Martinez-Frias ML, et al.: Caudal deficiency and asplenia anomalies in sibs. Am J Med Genet (suppl)2:23, 1986. 104. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet 38:99, 1991. 105. Wolfe MW, Vacek JL, Kinard RE, et al.: Prolonged and functional survival with the asplenia syndrome. Am J Med 81:1089, 1986. 106. Vanhoenacker FM, De Ruysscher D, De Backer AI, et al.: Heterotaxy syndrome in an adult, with polysplenia, visceral and cardiovascular malposition. JBR-BTR 84:1, 2001. 107. Brandenburg VM, Krueger S, Haage P, et al.: Heterotaxy syndrome with severe pulmonary hypertension in an adult. South Med J 95:536, 2002. 108. Wu MH, Wang JK, Lue HC: Sudden death in patients with right isomerism (asplenism) after palliation. J Pediatr 140:93, 2002. 109. Biggar WD, Ramirez RA, Rose V: Congenital asplenia: immunologic assessment and a clinical review of eight surviving patients. Pediatrics 67:548, 1981. 110. Larsen RL, Eguchi JH, Mulla NF, et al.: Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and single right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy. Am J Cardiol 89:1275, 2002. 111. Farmer DG, Shaked A, Olthoff KM, et al.: Evaluation, operative management, and outcome after liver transplantation in children with biliary atresia and situs inversus. Ann Surg 222:47, 1995. 112. Maggard MA, Goss JA, Swenson KL, et al.: Liver transplantation in polysplenia syndrome: use of a living-related donor. Transplantation 68:1206, 1999. 113. Srinivasan P, Heaton ND, Rela M: Liver transplantation in polysplenia syndrome. Transplantation 71:818, 2001.

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114. Hasegawa T, Kimura T, Sasaki T, et al.: Living-related liver transplantation for biliary atresia associated with polysplenia syndrome. Pediatr Transplant 6:78, 2002. 115. Chardot C, Carton M, Spire-Bendelac N, et al.: Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology 30:606, 1999. 116. Berg C, Geipel A, Smrcek J, et al.: Prenatal diagnosis of cardiosplenic syndromes: a 10-year experience. Ultrasound Obstet Gynecol 22:451, 2003. 117. Chitayat D, Lao A, Wilson RD, et al.: Prenatal diagnosis of asplenia/ polysplenia syndrome. Am J Obstet Gynecol 158:1085, 1988. 118. Devi B, More JRS: Total tracheopulmonary agenesis associated with asplenia, agenesis of umbilical artery and other anomalies. Acta Paediatr Scand 55:107, 1966. 119. Majeski JA, Upshur JK: Asplenia syndrome. A study of congenital anomalies in 16 cases. JAMA 240:1508, 1978. 120. Bates AW: Variation in major pulmonary fissures: incidence in fetal postmortem examinations and a review of significant extrapulmonary structural abnormalities in sixty cases. Pediatr Dev Pathol 1:289, 1998. 121. Phoon CK, Neill CA: Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 73:581, 1994. 122. Chung JH, Suh YL, Lee HJ, et al.: Rare variant of total anomalous pulmonary venous connection: intrapulmonary drainage of one lung by the other—a case report and review of the literature. Pediatr Pathol Lab Med 17:133, 1997. 123. Campbell M, Deuchar DC: Absent inferior vena cava, symmetrical liver, splenic agenesis, and situs inversus, and their embryology. Br Heart J 29:268, 1967. 124. Ruttenberg HD, Neufeld HN, Lucas RV Jr, et al.: Syndrome of congenital cardiac disease with asplenia. Distinction from other forms of congenital cyanotic cardiac disease. Am J Cardiol 13:387, 1964. 125. Freedom RM: The asplenia syndrome: a review of significant extracardiac structural abnormalities in 29 necropsied patients. J Pediatr 81:1130, 1972. 126. Ticho BS, Goldstein AM, Van Praagh R: Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. Am J Cardiol 85:729, 2000. 127. Pantke OA, Gorlin RJ, Burke BA: Polysplenia syndrome with skeletal and central nervous system anomalies. Birth Defects Orig Artic Ser XI(2):252, 1975. 128. Jones MC, Jones KL, Chernoff GF: Possible mesodermal origin for axial dysraphic disorders. J Pediatr 101:845, 1982. 129. Aylsworth AS, Laco JM: The association of central nervous system malformations with defects in determination of laterality. Proc Greenwood Genet Center 8:154, 1989. 130. Paddock RJ, Arensman RM: Polysplenia syndrome: spectrum of gastrointestinal congenital anomalies. J Pediatr Surg 17:563, 1982. 131. Sullivan RF, Madell SJ, Oates E, et al.: A case of biliary atresia and polysplenia. Evaluation by hepatobiliary scintigraphy. Clin Nucl Med 12:55, 1987. 132. Hernaiz D, Gohlich-Ratmann G, Konig R, et al.: Congenital microgastria, growth hormone deficiency and diabetes insipidus. Eur J Pediatr 156:37, 1997. 133. Kobayashi H, Kawamoto S, Tamaki T, et al.: Polysplenia associated with semiannular pancreas. Eur Radiol 11:1639, 2001. 134. Coen RW, Aase JM: Fusion of the adrenal glands in association with asplenia. J Pediatr 88:152, 1976. 135. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, Inc., Hawthorne, NY, 2001. 136. Genuardi M, Pomponi MG, Sammito V, et al.: Split hand/split foot anomaly in a family segregating a balanced translocation with breakpoint on 7q22.1. Am J Med Genet 47:823, 1993. 137. Genuardi M, Gurrieri F, Neri G: Genes for split hand/split foot and laterality defects on 7q22.1 and Xq24-q27.1. Am J Med Genet 50:101, 1994. 138. Reddy KS, Flannery D, Farrer RJ: Microdeletion of chromosome subband 2q37.3 in two patients with abnormal situs viscerum. Am J Med Genet 84:460, 1999.

139. Schinzel A, Hanson JW, Pagon RA, et al.: Trisomy 3 (p23-pter) resulting from maternal translocation, t(3;4)(p23;q35). Ann Genet 21:168, 1978. 140. Hou JW, Wang TR: Amelia, dextrocardia, asplenia, and congenital short bowel in deleted ring chromosome 4. J Med Genet 33:879, 1996. 141. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 142. Kato R, Yamada Y, Niikawa N: De novo balanced translocation (6;18) (q21;q21.3 or q22) [corrected] in a patient with heterotaxia [published erratum appears in Am J Med Genet 70(1):104]. Am J Med Genet 66: 184, 1996. 143. Peeters H, Debeer P, Groenen P, et al.: Recurrent involvement of chromosomal region 6q21 in heterotaxy. Am J Med Genet 103:44, 2001. 144. Nowaczyk MJ, Huggins MJ, Tomkins DJ, et al.: Holoprosencephaly, sacral anomalies, and situs ambiguus in an infant with partial monosomy 7q/trisomy 2p and SHH and HLXB9 haploinsufficiency. Clin Genet 57:388, 2000. 145. Pan Y, McCaskill CD, Thompson KH, et al.: Paternal isodisomy of chromosome 7 associated with complete situs inversus and immotile cilia [letter]. Am J Hum Genet 62:1551, 1998. 146. Koiffmann CP, Wajntal A, de Souza DH, et al.: Human situs determination and chromosome constitution 46,XY,ins(7;8)(q22;q12q24). Am J Med Genet 47:568, 1993. 147. Warburton D: De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995, 1991. 148. Carmi R, Boughman JA, Rosenbaum KR: Human situs determination is probably controlled by several different genes. Am J Med Genet 44:246, 1992. 149. Freeman SB, Muralidharan K, Pettay D, et al.: Asplenia syndrome in a child with a balanced reciprocal translocation of chromosomes 11 and 20 [46,XX,t(11;20)(q13.1;q13.13)]. Am J Med Genet 61:340, 1996. 150. Iida A, Emi M, Matsuoka R, et al.: Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left-right axis malformation. Hum Genet 106:277, 2000. 151. Wilson GN, Stout JP, Schneider NR, et al.: Balanced translocation 12/ 13 and situs abnormalities: homology of early pattern formation in man and lower organisms? Am J Med Genet 38:601, 1991. 152. Sanchez JM, Lopez D, Panal MJ, et al.: Severe fetal malformations associated with trisomy 16 confined to the placenta. Prenat Diagn 17:777, 1997. 153. Digilio MC, Marino B, Giannotti A, et al.: Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am J Med Genet 94:198, 2000. 154. Oggiano N, Kantar A, Fabbrizi E, et al.: Respiratory distress in a newborn with primary ciliary dyskinesia, situs inversus and Turner syndrome. Minerva Pediatr 46:153, 1994. 155. Ortiga DJ, Chiba Y, Kanai H, et al.: Antenatal diagnosis of mirrorimage dextrocardia in association with situs inversus and Turner’s mosaicism. J Matern Fetal Med 10:357, 2001. 156. Carrel T, Purandare SM, Harrison W, et al.: The X-linked mouse mutation bent tail is associated with a deletion of the Zic3 locus. Hum Mol Genet 9:1937, 2000. 157. Ware SM, Peng J, Zhu L, et al.: Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 74:93, 2004. 158. Pauli RM, Graham JM Jr, Barr M Jr: Agnathia, situs inversus, and associated malformations. Teratology 23:85, 1981. 159. Leech RW, Bowlby LS, Brumback RA, et al.: Agnathia, holoprosencephaly, and situs inversus: report of a case. Am J Med Genet 29:483, 1988. 160. Hersh JH, McChane RH, Rosenberg EM, et al.: Otocephaly-midline malformation association. Am J Med Genet 34:246, 1989. 161. Robinson HB Jr, Lenke R: Agnathia, holoprosencephaly, and situs inversus. Am J Med Genet 34:266, 1989. 162. Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inversus: a third report. Am J Med Genet 37:286, 1990.

Spleen 163. Persutte WH, Yeasting RA, Kurczynski TW, et al.: Agnathia malformation complex associated with a cystic distention of the oral cavity and hydranencepahly. J Craniofac Genet Dev Biol 10:391, 1990. 164. Stoler JM, Holmes LB: A case of agnathia, situs inversus, and a normal central nervous system. Teratology 46:213, 1992. 165. Chabrolle JP, Labenne M, Cailliez D, et al.: [Hypoglossia, situs inversus and absence of the pituitary in a neonate: teratogenic effect of maternal hyperthermia?]. [French]. Archives de Pediatrie 5:163, 1998. 166. Ozden S, Ficicioglu C, Kara M, et al.: Agnathia-holoprosencephalysitus inversus. Am J Med Genet 91:235, 2000. 167. Tohma T, Asato Y, Chinen Y, et al.: An infant of agnathia, situs inversus, and no brain malformation. Am J Hum Genet 67(suppl 2):129, 2000. 168. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn 22:840, 2002. 169. Hussels IE: Microglossia, hypodontia, micrognathia, situs inversus. Birth Defects Orig Artic Ser VII(7):282, 1971. 170. Oulis CJ, Thornton JB: Severe congenital hypoglossia and micrognathia with other multiple birth defects. J Oral Pathol 11:276, 1982. 171. Dunham ME, Austin TL: Congenital aglossia and situs inversus. Int J Pediatr Otorhinolaryngol 19:163, 1990. 172. Jang GY, Lee KC, Choung JT, et al.: Congenital aglossia with situs inversus totalis—a case report. J Korean Med Sci 12:55, 1997. 173. Amor DJ, Craig JE: Situs inversus totalis and congenital hypoglossia. Clin Dysmorphol 10:47, 2001. 174. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 175. Ming JE, McDonald-McGinn DM, Markowitz RI, et al.: Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia, and multicystic dysplastic kidneys: expanding the phenotype of Cumming syndrome. Am J Med Genet 73:419, 1997. 176. McLoughlin TG, Krovetz LJ, Schiebler GL: Heart disease in the Laurence-Moon-Biedl-Bardet syndrome. J Pediatr 65:388, 1964. 177. Temtamy SA: Carpenter’s syndrome: acrocephalopolysyndactyly. An autosomal recessive syndrome. J Pediatr 69:111, 1966. 178. Helin I, Jodal U: A syndrome of congenital hypoplasia of the alae nasi, situs inversus, and severe hypoproteinemia in two siblings. J Pediatr 99:932, 1981. 179. Moerman P, Verbeken E, Fryns JP, et al.: Association of Meckel syndrome with M-anisosplenia in one patient. Clin Genet 22:143, 1982. 180. Shen-Schwarz S, Dave H: Meckel syndrome with polysplenia: case report and review of the literature. Am J Med Genet 31:349, 1988. 181. Urioste M, Arroyo A, Martinez-Frias ML: Campomelia, polycystic dysplasia, and cervical lymphocele in two sibs. Am J Med Genet 41:475, 1991. 182. Perez del Rio MJ, Fernandez-Toral J, Madrigal B, et al.: Two new cases of Cumming syndrome confirming autosomal recessive inheritance. Am J Med Genet 82:340, 1999.

5.2 Positional Alterations of the Spleen Definition

Positional alterations of the spleen is the positioning of the spleen outside of the left upper quadrant of the abdomen. It includes wandering spleen, floating spleen, excessive mobility of the spleen, ectopic spleen, and splenic ptosis. Diagnosis

Ectopic or ‘‘wandering’’ spleens are found in both children and adults, and symptoms may or may not be present at the time of diagnosis.1–5 An enlarged spleen with an elongated pedicle may present as an asymptomatic abdominal or pelvic mass. It often occurs in women who have no complaints other than mild, episodic abdominal pain. Torsion of the elongated pedicle causes

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acute, severe abdominal pain due to splenic congestion and/or infarction. When symptomatic, an ectopic spleen may be misdiagnosed as appendicitis, ovarian cyst, diverticulitis, cholecystitis, bowel obstruction, peritonitis, or lymphoma.3,6 In his review, Robinson7 points out that although the first postmortem description of wandering spleen was by Van Horne in 1667, it was a condition that had been recognized by Hippocrates, Pliny, Herophilus, and Galen. Abdominal palpation reveals a mass with a notched border. The mass is usually mobile, with painless movement toward the left upper quadrant and painful, limited movement in other directions. A number of imaging techniques are potentially helpful.3,4,8–11 Abdominal plain-film radiography may show a notched abdominal or pelvic mass and left upper quadrant bowel loops. Ultrasonography can detect an enlarged, ectopic, disoriented, coarsely hyperechoic spleen with characteristic vascular pulsations. This technique has the advantages of noninvasiveness, relative convenience, and lack of radiation exposure. Angiography will identify the location of the spleen, can aid in diagnosing pancreatic involvement, and is useful in demonstrating vascular compromise associated with torsion. 99mTc-sulfur colloid liver-spleen scanning can be useful in identifying and locating a splenic ectopia; significant torsion of the pedicle can interfere with uptake, resulting in a negative scan. Computed tomography (CT) may reveal an enlarged, ectopic, disoriented, radiolucent spleen and has the advantage of also allowing noninvasive assessment of the pancreatic tail. Torsion of the pedicle can also interfere with CT enhancement. A combination of two or more of these techniques may be required for accurate delineation of the anomaly. Etiology and Distribution

The spleen is normally fixed in the left upper quadrant by a combination of neighboring structures and peritoneal reflections called supporting ligaments. A combination of congenital and acquired factors is probably necessary to cause or allow location of the spleen outside of the left upper quadrant in an individual who otherwise has normal situs solitus abdominal organ positioning. Evidence for underlying, predisposing, or causative genetic factors includes observations that splenic ligamentous supports (gastrosplenic, splenorenal, splenophrenic, splenocolic, splenopancreatic, presplenic fold, pancreaticocolic, and phrenocolic) may be lax, hypoplastic, or absent. Some patients have had hypermobility or congenital anomalies of other abdominal structures, including prune belly (hypoplasia or absence of abdominal musculature, usually associated with dilation of the urinary tract and undescended testicles),12,13 renal agenesis,14,15 gastric volvulus,16–18 diaphragmatic eventration,19,20 and congenital diaphragmatic hernia.18 The lack of reported familial recurrences, however, suggests that genetic factors play a relatively minor role in causation. Acquired factors appear to include splenomegaly and abdominal laxity. Wandering spleen has been associated with splenomegaly due to chronic disease21 and multiparity.22 Early reports emphasized the association of splenic ectopia with splenomegaly (most notably hypertrophy due to malaria) and suggested that an enlarged spleen allows increased mobility by stretching and elongating the supporting structures.7,23,24 Prevalence data for wandering spleen are variable.7 In a review of 708 patients undergoing splenectomy prior to 1908, Johnston found that 139 of them (20%) had ectopic spleens.23 Of these, 52 were associated with malarial disease and 87 had idiopathic splenomegaly. On the other hand, Whipple25 does not mention

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splenic ectopia in his series of 1457 patients evaluated in a combined medical-surgical spleen clinic. Subsequent reviews suggest that the condition is probably rare.7,26 In a series of 1413 children having splenectomy between 1956 and 1965, wandering spleen is not mentioned, but four patients had torsion of the spleen.27 Estimates of the male to female ratio vary widely. There appears to be a male predominance of patients presenting in the 1st year of life but a female predominance after the age of 1.4,7,24,28 Prognosis, Prevention, and Treatment

Torsion of an elongated splenic pedicle can cause acute congestion or infarction. Mortality rates are greatest in patients who present with acute abdominal findings, especially when this occurs during pregnancy. An enlarged, congested spleen is also at increased risk of being ruptured by trauma. Early diagnosis and treatment are essential for the prevention of morbidity and mortality. Surgical options include splenectomy or splenopexy to shorten the pedicle and prevent future torsion by fixation. Originally, these were done as open procedures, but now both can be performed using laparoscopic techniques with less postoperative recovery time and fewer complications.29–36 Splenectomy, when necessary, should be accompanied by the use of pneumococcal vaccine. References (Positional Alterations of the Spleen) 1. Rodkey ML, Macknin ML: Pediatric wandering spleen: case report and review of literature. Clin Pediatr (Phila) 31:289, 1992. 2. Dawson JH, Roberts NG: Management of the wandering spleen. Aust N Z J Surg 64:441, 1994. 3. Desai DC, Hebra A, Davidoff AM, et al.: Wandering spleen: a challenging diagnosis. South Med J 90:439, 1997. 4. Brown CV, Virgilio GR, Vazquez WD: Wandering spleen and its complications in children: a case series and review of the literature. J Pediatr Surg 38:1676, 2003. 5. Dalpe C, Cunningham M: Wandering spleen as an asymptomatic pelvic mass. Obstet Gynecol 101:1102, 2003. 6. Moll S, Igelhart JD, Ortel TL: Thrombocytopenia in association with a wandering spleen. Am J Hematol 53:250, 1996. 7. Robinson AP: Wandering spleen: case report and review. Mt Sinai J Med 55:428, 1988. 8. Freeman JL, Jafri SZ, Roberts JL, et al.: CT of congenital and acquired abnormalities of the spleen. Radiographics 13:597, 1993. 9. Murray KF, Ryan SP, Hough MC: Radiological case of the month. Pancreatitis associated with a wandering spleen. Arch Pediatr Adolesc Med 149:460, 1995. 10. Paterson A, Frush DP, Donnelly LF, et al.: A pattern-oriented approach to splenic imaging in infants and children. Radiographics 19:1465, 1999. 11. Gayer G, Zissin R, Apter S, et al.: CT findings in congenital anomalies of the spleen. Br J Radiol 74:767, 2001. 12. Heydenrych JJ, du Toit DF: Torsion of the spleen and associated ‘‘prune belly syndrome.’’ A case report and review of the literature. S Afr Med J 53:637, 1978. 13. Teramoto R, Opas LM, Andrassy R: Splenic torsion with prune belly syndrome. J Pediatr 98:91, 1981. 14. Pearson JB: Torsion of the spleen associated with congenital absence of the left kidney. Br J Surg 51:393, 1964. 15. Boschert MT, Helikson MA: Splenic torsion in the presence of renal agenesis. Pediatr Surg Int 13:426, 1998. 16. Uc A, Kao SC, Sanders KD, et al.: Gastric volvulus and wandering spleen. Am J Gastroenterol 93:1146, 1998. 17. Spector JM, Chappell J: Gastric volvulus associated with wandering spleen in a child. J Pediatr Surg 35:641, 2000. 18. Pelizzo G, Lembo MA, Franchella A, et al.: Gastric volvulus associated with congenital diaphragmatic hernia, wandering spleen, and intrathoracic left kidney: CT findings. Abdom Imaging 26:306, 2001.

19. Melikoglu M, Colak T, Kavasoglu T: Two unusual cases of wandering spleen requiring splenectomy. Eur J Pediatr Surg 5:48, 1995. 20. Ratan SK, Grover SB, Kulsreshtha R, et al.: Left diaphragmatic eventration with a suprapubic spleen: report of a case. Surg Today 31:184, 2001. 21. Carswell JW: Wandering spleen: 11 cases from Uganda. Br J Surg 61:495, 1974. 22. Miller EI: Wandering spleen and pregnancy: case report. J Clin Ultrasound 3:281, 1975. 23. Johnston GB: Splenectomy. Ann Surg 48:50, 1908. 24. Abell I: Wandering spleen with torsion of the pedicle. Ann Surg 98:722, 1933. 25. Whipple AO: The medical-surgical splenopathies. Bull N Y Acad Med 15:174, 1939. 26. Pugh HL: Splenectomy, with special reference to its historical background. Int Abstr Surg 83:209, 1946. 27. Eraklis AJ, Filler RM: Splenectomy in childhood: a review of 1413 cases. J Pediatr Surg 7:382, 1972. 28. Allen KB, Andrews G: Pediatric wandering spleen—the case for splenopexy: review of 35 reported cases in the literature. J Pediatr Surg 24:432, 1989. 29. Cohen MS, Soper NJ, Underwood RA, et al.: Laparoscopic splenopexy for wandering (pelvic) spleen. Surg Laparosc Endosc 8:286, 1998. 30. Gurski RR, Schirmer CC, Fischer CA, et al.: Laparoscopic approach to wandering spleen: a case report and an update to the question. Surg Laparosc Endosc Percutan Tech 8:363, 1998. 31. Hirose R, Kitano S, Bando T, et al.: Laparoscopic splenopexy for pediatric wandering spleen. J Pediatr Surg 33:1571, 1998. 32. Haj M, Bickel A, Weiss M, et al.: Laparoscopic splenopexy of a wandering spleen. J Laparoendosc Adv Surg Tech A 9:357, 1999. 33. Nomura H, Haji S, Kuroda D, et al.: Laparoscopic splenopexy for adult wandering spleen: sandwich method with two sheets of absorbable knitted mesh. Surg Laparosc Endosc Percutan Tech 10:332, 2000. 34. Peitgen K, Majetschak M, Walz MK: Laparoscopic splenopexy by peritoneal and omental pouch construction for intermittent splenic torsion (‘‘wandering spleen’’). Surg Endosc 15:413, 2001. 35. Benevento A, Boni L, Dionigi G, et al.: Emergency laparoscopic splenectomy for ‘‘wandering’’ (pelvic) spleen: case report and review of the literature on laparoscopic approach to splenic diseases. Surg Endosc 16:1364, 2002. 36. Rosin D, Bank I, Gayer G, et al.: Laparoscopic splenectomy for torsion of wandering spleen associated with celiac axis occlusion. Surg Endosc 16:1110, 2002.

5.3 Accessory Spleens, Structural Variation, and Fusion to Other Organs Definition

Accessory spleens are small nodules of splenic tissue that are present in addition to a main spleen that is usually of normal size. Structural variations include splenic notches, clefts, and lobulation. The main spleen or accessory spleen may fuse with gonads or other organs. Polysplenia with situs ambiguus is discussed in Section 5.1. Diagnosis Accessory Spleens

One or more asymptomatic accessory spleens are found in at least 10% of the human population and usually diagnosed at surgery or incidentally at autopsy. The location of accessory splenic tissue is variable. The most common sites are the hilum of the spleen and the tail of the pancreas. Other frequent sites include the gastrosplenic ligament near the tail of the pancreas, the splenocolic

Spleen

ligament, the splenorenal ligament, the pancreaticosplenic ligament, the greater omentum, along the splenic artery, and in the connective tissue under the left diaphragm.1,2,3 They may also be found scattered on the peritoneal surface, on the transverse colon, imbedded in the liver, in the body or tail of the pancreas, in the inguinal canal, and in the scrotum. Although usually associated with a normal size spleen, a number of accessory spleens have been observed in a patient with only a very small ‘‘walnut-sized’’ main spleen.1 Approximately 15% of accessory spleens found at autopsy are located at sites sufficiently far enough from the hilum of the spleen that they would be difficult to find at routine splenectomy without a specific search being made.3 Abdominal computed tomography, ultrasound, magnetic resonance imaging, angiography, and splenic scintigraphy have been used successfully to detect accessory spleens preoperatively.4–12 A symptomatic accessory spleen usually presents as an abdominal mass with or without pain. The abdominal mass may be caused by epidermoid cyst formation.10,13–16 Accessory spleens may have long attachments causing torsion, giving rise to the term wandering accessory spleen.7,9,17–22 Since accessory spleens are found commonly as ‘‘normal’’ variant structures in individuals without other malformations, their presence in patients with other malformation associations and syndromes usually can be thought of as coincidental. The principal malformation associations that specifically involve accessory or ectopic splenic tissue are those in which fusion occurs between splenic and gonadal tissue. Structural Variation

Structural variations include splenic notches, clefts, thinning, and lobulation. These appear to be nonspecific normal variants. Splenic Fusion to Other Organs

Fusion can involve a single main spleen or accessory spleens. Splenorenal fusion occurs rarely.23,24 Accessory spleens are commonly found in the pancreas.5,25–27 Presentation as a cystic abdominal mass seems to be associated with those accessory spleens that are associated with the pancreas.10,13–15 The gonad may be attached to the spleen by a fibrous cord containing splenic tissue (continuous fusion), or ectopic rests of splenic tissue may be attached to the gonad without an intervening attachment to the spleen (discontinuous fusion).28 Pain is caused by torsion of accessory splenic tissue or obstruction of the bowel by the fibrous cord present in continuous splenogonadal fusion. When an accessory spleen is fused to a testicle in the scrotal sac, it may be mistaken for a hernia or third testicle. Patients may be aware of a testicular or scrotal mass for years prior to diagnosis.29 If a diagnosis can be made prior to or during surgery, it may be possible to avoid orchiectomy. Diagnostic techniques include radiocolloid spleen scintigraphy, angiography, ultrasound, and laparascopy.30–36 Splenogonadal fusion may be associated with other anomalies such as inguinal hernia, hydrocele, congenital heart disease, transverse limb reduction anomalies, cryptorchism, micrognathia, cleft palate, and anal anomalies. Microgastria, a rare anomaly that is sometimes seen in association with asplenia, has been noted.37 Limb anomalies, cryptorchism, and micrognathia are much more commonly associated with continuous fusion than with discontinuous fusion.29,38 The presence of any of these associated anomalies should suggest the possibility that a scrotal mass is actually benign splenic tissue rather than testicular cancer.

197

Most patients with associated limb anomalies are severely affected but not invariably so. Pauli and Greenlaw reviewed 14 cases and pointed out that the legs are usually more severely affected than the arms and, while both sides can be involved, there may be a slight predilection for the right side to be more frequently and more severely affected (Fig. 5-5).39 Most reported patients have had terminal transverse reduction anomalies. Two exceptions to this were patients with apparent absence of the femur and fibula, maintenance of a bone or bones that appeared to be tibia, severe arm reduction anomalies, and the additional atypical finding of significant central nervous system involvement.39 The combination of splenogonadal fusion with transverse limb reduction anomalies constitutes a memorable phenotype and, as such, is sometimes considered to be a separate, distinct entity (MIM No. 183300). There is obvious similarity to and overlap with phenotypes in the spectrum known as the oromandibularlimb hypogenesis syndromes.40–42 Micrognathia occurs commonly in both groups, and splenogonadal fusion has been observed in patients with normal limbs and paucity of facial expression diagnosed as ‘‘Moebius syndrome,’’ part of the oromandibular limb hypogenesis phenotypic spectrum.41,43 Etiology and Distribution Accessory Spleens

The spleen forms by a merging of the hillocks that have formed in the left side of the dorsal mesogastrium during the 5th week of development. Accessory spleens probably represent hillocks or centers of mesenchymal cell proliferation that fail to fuse with the main mass and usually remain in the gastrosplenic ligament, which eventually becomes a narrow band of mesentery attaching at the hilus of the spleen. Occasionally, peritoneal accessory spleens are found in patients after abdominal trauma or spleen surgery, suggesting that in these cases small splenic particles released by trauma or surgery find implantation sites and grow (‘‘peritoneal splenosis’’).1,33 Because accessory spleens may be difficult to detect and because they are usually studied in patients with symptoms who go on to have surgery, the true incidences of both accessory spleens and splenosis are unknown.44 One or more accessory spleens is a common variant in humans, occurring in 10–19% of patients at surgery or autopsy.2,3,25 In other animals, estimates of incidence include 23.8% in Chinese hamsters, 27% in golden hamsters, 8.9% in rabbits, and 51% in New Hampshire pigs.45 As expected for a variant that is common in the general population, accessory spleens are commonly found in patients with chromosomal abnormalities. Although not a characteristic feature of either syndrome, accessory spleens have been observed in as high as 30–50% of patients with trisomy 13 and trisomy 18 who have had thorough anatomic studies.46–48 Structural Variation

The spleen forms by a merging of the mesenchymal cell clusters that have formed in the left side of the dorsal mesogastrium during the 5th week of development. It seems likely that some spleens appear to be cleft or lobulated because of incomplete fusion of these embryonic hillocks. Splenic Fusion to Other Organs

Proximity between the developing spleen and other organs appears to predispose to abnormal connections being formed. Accessory spleens are commonly found fused to the pancreas.3,25

198

Cardiorespiratory Organs

Fig. 5-5. Drawings summarizing the limb and long bone abnormalities in 14 cases of splenogonadal fusion with limb reduction. Question mark (?) indicates cases with vaguely described limb anomalies. The cases in the box at lower right, m and n, are the two with nonterminal defects. (From Pauli RM, Greenlaw A, Am J Med Genet 13:81, 1982. John Wiley and Sons, Inc. Used by permission.)

At the time the splenic centers are growing and fusing in the dorsal mesogastrium, the mesonephros or Wolffian body is separated from them by two layers of peritoneum. During the next 5 weeks, the gonad ‘‘migrates’’ caudally, the gut tube rotates, and the splenic anlage is in close proximity to the left urogenital fold. Fusion presumably can take place at any time during this period. This anatomic relationship explains why splenogonadal fusion usually involves the left-sided gonad. Splenogonadal fusion occurs sporadically, without evidence of genetic or environmental (teratogenic) causation. The syndrome of splenogonadal fusion with limb defects also occurs sporadically. Splenogonadal fusion occurs rarely. A literature review in 1988 summarized 93 cases.29 The male to female ratio was approximately 12:1, but ascertainment was probably biased by the relative likelihood of male genital complications coming to medical attention. Fifty-one cases (45 males and six females) had the continuous type and 42 had discontinuous fusion (41 males and one female). Only two cases (2.2%) involved the right side, and both were male. Limb reduction occurred in 16 with the continuous type, but in only one of those with the discontinuous type. The cause of splenogonadal fusion with limb defects (SGFLD) is unknown, but recent reviews have pointed out similarities with syndromes in the oromandibular-limb hypogenesis spectrum, for which vascular causes have been proposed.42,49 SGFLD occurs sporadically. Associated anomalies include man-

dibular hypoplasia, cleft palate, microglossia, anal atresia, diaphragmatic hernia, and complex congenital heart malformations. Prognosis, Treatment, and Prevention Accessory Spleens

Accessory spleens are usually found coincidentally at autopsy and, therefore, are probably asymptomatic and of no clinical importance most of the time. The fibrous cord present in continuous splenogonadal fusion may cause obstruction of the bowel. When accessory spleens occur in the scrotal sac, they may be mistaken for a hernia, a third testicle, or testicular cancer. Torsion may occur, causing acute abdominal symptoms requiring surgical intervention. Undetected accessory spleens may be the underlying cause of patients with hypersplenism failing to respond to splenectomy, in which case a second surgical exploration may be necessary.50,51 For example, recurrence of idiopathic thrombocytopenic purpura years after splenectomy has been reported numerous times as the result of one or more accessory spleens not identified at the time of initial surgery. Since accessory spleens may be missed, a specific search should be made prior to or during surgery. Preoperative and intraoperative imaging techniques such as computed tomography and scintigraphy may be useful, especially in the case where a patient has failed to respond to initial splenectomy and reoperation is being considered.

Spleen

Splenogonadal Fusion

Often it is difficult to avoid orchiectomy when the patient has splenogonadal fusion and testicular cancer is in the original differential diagnosis. When a testicle is intraabdominal, the presence of splenogonadal fusion does not necessarily eliminate the possibility of cancer.52 The association of splenogonadal fusion with transverse limb reduction anomalies is usually, but not universally, a lethal combination of severe malformations. Most patients have other associated anomalies and die during early infancy. One boy, however, with severe deficiency of all limbs, splenogonadal fusion, mild developmental delay, and micrognathia had otherwise good health at age 10 years.39 Ultrasonography and spleen scintigraphy are recommended for all patients with the Hanhart phenotype and the femoral-facial syndrome, because of their associated anomalies and similarities to patients with the SGFLD phenotype.34,39,42,49 References (Accessory Spleens, Structural Variation, and Fusion to Other Organs) 1. Robertson RF: The clinical importance of accessory spleens. Can Med Assoc J 39:222, 1938. 2. Eraklis AJ, Filler RM: Splenectomy in childhood: a review of 1413 cases. J Pediatr Surg 7:382, 1972. 3. Wadham BM, Adams PB, Johnson MA: Incidence and location of accessory spleens. N Engl J Med 304:111, 1981. 4. Koyanagi N, Kanematsu T, Sugimachi K: Preoperative computed tomography and scintigraphy to facilitate the detection of accessory spleen in patients with hematologic disorders. Jpn J Surg 18:101, 1988. 5. Harris GN, Kase DJ, Bradnock H, et al.: Accessory spleen causing a mass in the tail of the pancreas: MR imaging findings. AJR Am J Roentgenol 163:1120, 1994. 6. Marchant LK, Levine MS, Furth EE: Splenic implant in the jejunum: radiographic and pathologic findings. Abdom Imaging 20:518, 1995. 7. Jans R, Vanslembrouck R, Van Hoe L, et al.: Torsion of accessory spleen in an adult patient: imaging findings at CT, MRI and angiography. J Belge Radiol 80:229, 1997. 8. Barawi M, Bekal P, Gress F: Accessory spleen: a potential cause of misdiagnosis at EUS. Gastrointest Endosc Clin N Am 52:769, 2000. 9. Perez Fontan FJ, Soler R, Santos M, et al.: Accessory spleen torsion: US, CT and MR findings. Eur Radiol 11:509, 2001. 10. Yokomizo H, Hifumi M, Yamane T, et al.: Epidermoid cyst of an accessory spleen at the pancreatic tail: diagnostic value of MRI. Abdom Imaging 27:557, 2002. 11. Miyayama S, Matsui O, Yamamoto T, et al.: Intrapancreatic accessory spleen: evaluation by CT arteriography. Abdom Imaging 28:862, 2003. 12. Ota T, Ono S: Intrapancreatic accessory spleen: diagnosis using contrast enhanced ultrasound. Br J Radiol 77:148, 2004. 13. Tsutsumi S, Kojima T, Fukai Y, et al.: Epidermoid cyst of an intrapancreatic accessory spleen—a case report. Hepatogastroenterology 47:1462, 2000. 14. Horibe Y, Murakami M, Yamao K, et al.: Epithelial inclusion cyst (epidermoid cyst) formation with epithelioid cell granuloma in an intrapancreatic accessory spleen. Pathol Int 51:50, 2001. 15. Sonomura T, Kataoka S, Chikugo T, et al.: Epidermoid cyst originating from an intrapancreatic accessory spleen. Abdom Imaging 27:560, 2002. 16. Mori M, Ishii T, Iida T, et al.: Giant epithelial cyst of the accessory spleen. J Hepatobiliary Pancreat Surg 10:118, 2003. 17. Grunspan M, Wechsler U, Weintraub S: Torsion of an accessory spleen simulating acute appendicitis. Isr J Med Sci 17:458, 1981. 18. Seo T, Ito T, Watanabe Y, et al.: Torsion of an accessory spleen presenting as an acute abdomen with an inflammatory mass. US, CT, and MRI findings. Pediatr Radiol 24:532, 1994.

199 19. Dahlin LB, Anagnostaki L, Delshammar M, et al.: Torsion of an accessory spleen in an adult. Case report. Eur J Surg 161:607, 1995. 20. Erden A, Karaalp G, Ozcan H, et al.: Wandering accessory spleen. Surg Radiol Anat 17:89, 1995. 21. Valls C, Mones L, Guma A, et al.: Torsion of a wandering accessory spleen: CT findings. Abdom Imaging 23:194, 1998. 22. Kaniklides C, Wester T, Olsen L: Accessory wandering spleen associated with short pancreas. A pediatric case report. Acta Radiol 40:104, 1999. 23. Rosenthal JT, Bedetti CD, Labayen RF, et al.: Right splenorenal fusion with associated hypersplenism. J Urol 126:812, 1981. 24. Obley DL, Slasky BS, Bron KM: Right-sided splenorenal fusion with arteriographic, ultrasonic, and computerized tomographic correlation. Urol Radiol 4:221, 1982. 25. Halpert B, Gyorkey F: Accessory spleen in the tail of the pancreas. Arch Pathol 64:266, 1957. 26. Lauffer JM, Baer HU, Maurer CA, et al.: A rare cause of a pancreatic mass. Int J Pancreatol 25:65, 1999. 27. Weiand G, Mangold G: Accessory spleen in the pancreatic tail—a neglected entity? A contribution to embryology, topography and pathology of ectopic splenic tissue. Chirurg 74:1170, 2003. 28. Putschar WGJ, Manion WC: Splenic-gonadal fusion. Am J Pathol 32:15, 1956. 29. Walther MM, Trulock TS, Finnerty DP, et al.: Splenic gonadal fusion. Urology 32:521, 1988. 30. Guarin U, Dimitrieva Z, Ashley SJ: Splenogonadal fusion—a rare congenital anomaly demonstrated by 99mTc-sulfur colloid imaging: case report. J Nucl Med 16:922, 1975. 31. Heloury Y, Valayer J, Leborgne J, et al.: Spleno-gonadal fusion: anatomic and angiographic study of a case. Surg Radiol Anat 8:147, 1986. 32. McLean GK, Alavi A, Ziegler MM, et al.: Splenic-gonadal fusion: identification by radionuclide scanning. J Pediatr Surg 16:649, 1981. 33. Sty JR, Conway JJ: The spleen: development and functional evaluation. Sem Nucl Med 15:276, 1985. 34. Steinmetz AP, Rappaport A, Nikolov G, et al.: Splenogonadal fusion diagnosed by spleen scintigraphy. J Nucl Med 38:1153, 1997. 35. Braga LH, Braga MM, Dias MA: Laparoscopic diagnosis and treatment of splenogonadal fusion associated with intra-abdominal cryptorchidism in a child. Pediatr Surg Int 15:465, 1999. 36. Rubenstein RA, Dogra VS, Seftel AD, et al.: Benign intrascrotal lesions. J Urol 171:1765, 2004. 37. Mandell GA, Heyman S, Alavi A, et al.: A case of microgastria in association with splenic-gonadal fusion. Pediatr Radiol 13:95, 1983. 38. Le Roux PJ, Heddle RM: Splenogonadal fusion: is the accepted classification system accurate? BJU Int 85:114, 2000. 39. Pauli RM, Greenlaw A: Limb deficiency and splenogonadal fusion. Am J Med Genet 13:81, 1982. 40. Barr M: Amelia-splenogonadal fusion and Hanhart syndrome: the same or different conditions? Proc Greenwood Genet Center 6:180, 1987. 41. Lammens M, Moerman P, Fryns JP, et al.: Neuropathological findings in Moebius syndrome. Clin Genet 54:136, 1998. 42. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb defect syndrome: report of five new cases and review. Am J Med Genet 86:347, 1999. 43. Sieber WK: Splenotesticular cord (splenogonadal fusion) associated with inguinal hernia. J Pediatr Surg 4:208, 1969. 44. Targarona EM, Espert JJ, Lomena F, et al.: Inadequate detection of accessory spleens and splenosis with laparoscopic splenectomy: a shortcoming of the laparoscopic approach in hematological diseases. Surg Endosc 13:196, 1999. 45. Yoon YS, Shin JW, Park CB, et al.: Morphological structure of accessory spleen in Chinese hamsters. J Vet Sci 1:73, 2000. 46. Mottet NK, Jensen H: The anomalous embryonic development associated with trisomy 13-15. Am J Clin Pathol 43:334, 1965. 47. Warkany J, Passarge E, Smith LB: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502, 1966. 48. Hashida Y, Jaffe R, Yunis EJ: Pancreatic pathology in trisomy 13. Pediatr Pathol 1:169, 1983.

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49. McPherson F, Frias JL, Spicer D, et al.: Splenogonadal fusion-limb defect ‘‘syndrome’’ and associated malformations. Am J Med Genet 120A:518, 2003. 50. Walters DN, Roberts JL, Votaw M: Accessory splenectomy in the management of recurrent immune thrombocytopenic purpura. Am Surg 64:1077, 1998.

51. MacDonald JK, Wilke RA, Jacobs WE: Accessory spleens in the thoracic and abdominal cavities after a relapse of idiopathic thrombocytopenic purpura: a case report. J Nucl Med Technol 28:49, 2000. 52. Imperial SL, Sidhu JS: Nonseminomatous germ cell tumor arising in splenogonadal fusion. Arch Pathol Lab Med 126:1222, 2002.

6 The Lower Respiratory Organs Laurie H. Seaver

T

he lower respiratory organs consist of the larynx (including the epiglottis), trachea, bronchi, and lungs. The diaphragm, although not a respiratory tract organ per se, is included here because malformations of this organ impact the developing respiratory tract. The frequency of congenital lung and airway anomalies is reported to comprise approximately 7–19% of all congenital malformations, although this may be an underestimate since some malformations are asymptomatic or delayed in presentation.1 The malformations discussed in this chapter are presented because they frequently come to the attention of those interested in the field of birth defects, because they impact prenatal, perinatal, or neonatal management, or because they are frequently associated with other respiratory tract and nonrespiratory tract malformations. The pertinent embryology is discussed within each section. Little is known about molecular developmental pathways of the respiratory tract. Hepatocyte nuclear factor-3ß (HNF-3ß) is a transcription factor important in early embryonic development, including the endoderm of the foregut from which the respiratory tract is derived.2 Another transcription factor, thyroid transcription factor-1 (TTF-1) is also critical in early lung embryogenesis, specifically regulating genes involved in the development of the respiratory epithelium.2 Successive stages of lung growth and differentiation include branching and the development of pulmonary parenchyma, cartilage and pulmonary vessels. A variety of growth factors, including fibroblast growth factors, plateletderived growth factors, and vascular endothelial growth factors are required. There are now animal models, and a few human examples, of developmental lung defects associated with disruption of specific genes and pathways.2

6.1 Bifid Epiglottis Definition

Bifid epiglottis is an epiglottis with two distinct cartilaginous halves and a midline cleft extending at least two-thirds of its length.1 Excluded are minor defects, including notching, indentation, or a submucosal bifid appearance, which are much more frequent. Diagnosis

Symptoms of a bifid epiglottis are often present in the neonatal period or infancy and include stridor, aspiration, and/or failure to thrive. Some cases, however, are asymptomatic.2,3 The diagnosis is made by direct laryngoscopy (Fig. 6-1). Etiology and Distribution

Bifid epiglottis is a rare defect, with less than 50 cases reported in the literature.1,3 In a review of 21 cases, Stroh et al. reported 13 males and 8 females of various racial backgrounds, primarily Caucasian (90%).1 It may be an isolated finding but more commonly is associated with other anomalies. Polydactyly, facial clefts, hypopituitarism, hypothalamic hamartoma, genitourinary defects, Fig. 6-1. Bifid epiglottis in a patient with Bardet-Biedl syndrome. Courtesy of Drs. Cathy Stevens and Joel C. Ledbetter, T.C. Thompson Children’s Hospital, Chattanooga, TN.

References 1. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby Inc., St. Louis, 1999, p 1106. 2. Whitsett JA, Wert SE: Molecular determinants of lung development. In: Kendig’s Disorders of the Respiratory Tract in Children, ed 6. Chernick V, Boat TF, Kendig EL Jr, eds. WB Saunders Company, Philadelphia, 1998, p 3. The author acknowledges the important contributions of Gary M. Albers and Robert E. Wood to the first edition of this text, which provided the basis for this chapter.

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202

Cardiorespiratory Organs Table 6-1. Syndromes with bifid epiglottis Syndrome

Significant Features

Causation Gene/Locus

Pallister-Hall

Hypothalamic hamartoma, postaxial polydactyly, imperforate anus, genital and cardiac defects

AD (146510) GLI3, 7p13

Bardet-Biedl

Mental retardation, pigmentary retinopathy, polydactyly, obesity, hypogenitalism

AR (209900) BBS1, 11q13 BBS2, 16q21 BBS4, 15q22.3-q23 BBS6, 20p12 BBS7, 4q27 Also 3p13-p12, 2q31

McKusick-Kaufman

Hydrometrocolpos, polydactyly, hypospadias, obesity, retinal dystrophy

AR (236700) BBS6, 20p12

Hirschsprung disease, heart defects, laryngeal anomalies, preaxial polydactyly5

Cleft lip/palate, hallux duplication, postaxial polydactyly, cardiac defect, Hirschsprung disease

AR (604211)

Hypothyroidism, spiky hair, cleft palate6

Athyroidal hypothyroidism, choanal atresia, cleft palate, abnormal hair

AR (241850) FKHL15/TTF2, 9q22

Joubert7

Episodic hyperpnea, abnormal eye movements, retinal coloboma, macrocephaly, prominent forehead, cerebellar vermis hypoplasia, ‘‘molar tooth’’ sign on cranial imaging

AR (213300) 9q34.3

Weyers acrofacial dysostosis8

Postaxial polydactyly, mandibular hypoplasia, short limbs, teeth and nail defects

AD (193530) EVC, 4p16

gastrointestinal defects, and cardiac defects are common.1,3 Fifty percent of patients with bifid epiglottis have a potentially lethal central nervous system lesion, and therefore cranial magnetic resonance imaging and endocrine evaluation are important.1 Bifid epiglottis should strongly be considered in a patient with polydactyly who presents with stridor and/or aspiration.1 Syndromes associated with bifid epiglottis are reported in Table 6-1. The embryology of the epiglottis is not well-understood. The epiglottis arises from the hypobranchial eminence (third and fourth branchial arches), but it is less clear whether this is a midline structure or a bilateral structure. Based on an example of a tricleft epiglottis, Sturgis and Howell proposed that the hypobranchial eminence arises from two midline swellings that fuse separately from the fourth branchial arch.4 The lateral portions of the epiglottis are derived from the fourth branchial arch, which fuses to the hypobranchial eminence. This hypothesis would explain midline, off-midline, and both narrow and wide clefts of the epiglottis.1,4 Prognosis and Treatment

Treatment of bifid epiglottis is dependent on the degree of symptomatology. There are few reports of surgical correction. Microlaryngoscopy with carbon dioxide laser and epiglottectomy with tracheostomy have been attempted in cases with severe symptoms of aspiration or airway compromise.9,10 References (Bifid Epiglottis) 1. Stroh B, Rimmell FL, Mendelson N: Case report: bifid epiglottis. Int J Pediatr Otorhinolaryngol 47:81, 1999. 2. Ondrey F, Griffth A, Van Waes C, et al.: Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome. Am J Med Genet 94:64, 2000.

3. Stevens CA, Ledbetter JC: The significance of bifid epiglottis. Presented at the 24th Annual David W. Smith Workshop on Malformations and Morphogenesis, Vancouver, British Columbia, 2003. 4. Sturgis EM, Howell LL: Bifid epiglottis syndrome. Int J Pediatr Otorhinolaryngol 33:149, 1995. 5. Huang T, Elias ER, Mulliken JB, et al.: A new syndrome: heart defects, laryngeal anomalies, preaxial polydactyly and colonic aganglionosis in sibs. Genet Med 1:104, 1999. 6. Bamforth JS, Hughes IA, Lazarus JH, et al.: Congenital hypothyroidism, spiky hair, and cleft palate. J Med Genet 26:49, 1989. 7. Sung MW, Kim JW, Kim KH: Bifid epiglottis associated with Joubert’s syndrome. Ann Otol Rhinol Laryngol 110:194, 2001. 8. Wittig FJ, Hickey SA, Kumar M: Double epiglottis in Weyer’s acrofacial dysostosis. J Laryngol Otol 112:976, 1998. 9. Montreuil F: Bifid epiglottis—report of a case. Laryngoscope 59:194, 1949. 10. Prescott CA: Bifid epiglottis: a case report. Int J Pediatr Otorhinolaryngol 30:167, 1994.

6.2 Laryngeal Atresia, Webs, and Stenosis Definition

Laryngeal atresia, webs, and stenosis are a spectrum of anomalies of arrested development of the larynx resulting in various combinations of supraglottic, glottic, and subglottic obstruction or hypoplasia. This excludes acquired forms of subglottic stenosis. Diagnosis

The clinical presentation of this category of laryngeal anomalies depends on the severity of the obstruction. Complete laryngeal atresia presents immediately upon delivery of the infant with severe respiratory distress and cyanosis, no audible cry, and inability

The Lower Respiratory Organs

to pass an endotracheal tube. If the infant can be successfully resuscitated by emergency tracheotomy, diagnosis can be confirmed by laryngoscopy augmented by computerized tomography. Some infants can be ventilated by mask or esophageal intubation if a tracheoesophageal fistula is present. The diagnosis of laryngeal atresia has been made prenatally by ultrasonography and is characterized by increased echogenicity of large lungs, inverted diaphragms, dilated trachea, ascites, or other signs of fetal hydrops1–3 (Fig. 6-2). Marked immature amniotic fluid lung maturity studies have also been reported near term.4 Laryngeal webs, typically at the level of the glottis, may also present with variable symptom severity, depending on the degree of obstruction, including severe respiratory distress, inspiratory stridor, weak or hoarse voice or cry, and recurrent crouplike illness.5,6 Diagnosis can be suggested by well-penetrated lateral radiograph of the neck, but flexible laryngoscopy and/or rigid endoscopy of the airway are typically required. Barium swallow is used to differentiate from other laryngeal defects, including laryngeal clefts, tracheoesophageal fistula, or vascular rings.5 Congenital subglottic stenosis accounts for approximately 19% of congenital laryngeal abnormalities and is the most common congenital indication for tracheostomy in infants. Acquired subglottic stenosis is more common than congenital, and it is typically more severe than the congenital form.5 Symptoms vary with the degree of obstruction, which can range from mild to severe. Individuals may be asymptomatic, only noted to accept a smaller than expected endotracheal tube placed for an unrelated procedure, or may have recurrent crouplike illnesses. Inspiratory and expiratory stridor and a weak cry may also suggest the diagnosis. The diagnosis may be suspected on a standard anterior-

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posterior view of the neck, although flexible or rigid laryngoscopy is required to fully evaluate the airway.5 Etiology and Distribution

The embryology of the larynx, and the classification of laryngeal obstructive abnormalities based on embryologic principles, has been the subject of numerous reviews.6–8 The larynx begins to develop during the fourth week of development on day 25 with thickening of the epithelium, the respiratory primordium, along the ventral foregut. The respiratory diverticulum, the outpouching of the foregut on the floor of the primitive pharynx, extends into the respiratory primordium and delineates the level of the glottis. The respiratory diverticulum extends caudally as the trachea and separates from the esophagus. Abnormal septation between the primitive respiratory and gastrointestinal tracts gives rise to laryngotracheoesophageal clefting and fistula. The muscular and cartilaginous structures of the larynx derive from the fourth and sixth pharyngeal arches. Rapid proliferation of the surrounding mesenchyme forms the arytenoid swellings, changing the primitive sagittal orifice to a T-shaped opening. The epithelial lining of the posterior pharynx also proliferates rapidly, resulting in near occlusion of the lumen, leaving only a minor dorsal opening, the pharyngoglottic duct. Recanalization progresses cephalocaudally, with the last remnant at the glottis at week 10, and should be complete by week 12.6,8 Laryngeal atresia has been classified into three types depending on the level and degree of obstruction.7,8 Likewise, anterior laryngeal webs have been classified into four types of increasing severity.9 Laryngeal webs and atresias account for approximately 5% of laryngeal defects. The true incidence is not known.

Fig. 6-2. Laryngeal atresia. A. Profile of 20 week gestation hydropic fetus with laryngeal atresia. B. Lung overgrowth associated with laryngeal atresia (top) compared to gestational age matched control. Note the scalloped edges from rib compression.

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Associated malformations of the upper and lower airways, esophagus, and other organ systems are common, especially in the more severe laryngeal lesions.7,10 Familial cases have been reported, typically in an autosomal dominant pattern.11,12 Discordant monozygotic twins have also been reported.13 McElhinney et al. reported a series of 25 patients with laryngeal web and found

deletions by fluorescence in situ hybridization (FISH) of chromosome 22q11.2 (DiGeorge critical region) in 7 of the 12 patients that had cytogenetic analysis. They also reported associated cardiovascular anomalies in 9 of 25 patients, most commonly involving the aortic arch.14 Syndromes associated with laryngeal defects are presented in Table 6-2.

Table 6-2. Patterns of malformation associated with laryngeal abnormalities Syndrome

Significant Features

Causation Gene/Locus

Fraser

LA, LS, cryptophthalmos, frontolateral hair growth, syndactyly, genital abnormality, nasal coloboma, ear abnormality

AR (219000) FRAS1, 4q21

Opitz

LC, LH, hypertelorism, telecanthus, anteverted nares, cleft lip/palate, hypospadias, cryptorchidism, cardiac defect, developmental delay

XLR (300000) Xp22

Pallister-Hall

LC, SGS, hypothalamic hamartoma, postaxial polydactyly, imperforate anus, genital and cardiac defects

AD (146510) GLI3, 7p13

Short rib polydactyly, type II (Majewski)

LH, short ribs, median cleft upper lip, pre- and/or postaxial polydactyly, short ovoid tibiae, fetal hydrops

AR (263520)

Oral-facial-digial, type IV (Baraitser-Burn)

LH, cleft lip, broad nasal root and tip, hypertelorism, micrognathia, brachydactyly, pre- and/or postaxial polydactyly, short tibiae, talipes equinovarus

AR (258860)

Oral-facial-digital, type II (Mohr)

LH, midline cleft of upper lip, cleft tongue, postaxial polydactyly of hands, hallux duplication, mental retardation, other central nervous system defects

AR (252100)

Trisomy 21

LW, LC, SGS, flat facies, upslanted palpebral fissures, small ears, cardiac defect, brachydactyly, clinodactyly, hypotonia

Chromosomal

Velocardiofacial 22q11.2 deletion

LW, long face, malar flattening, tubular nose, micrognathia, cleft palate, conotruncal heart defect

Chromosomal AD (192430) del 22q11.2

Ulnar-mammary

LW, LS, breast and/or nipple hypoplasia, anal defect, genital defect, hypoplasia of ulna/radius/humerus, postaxial polydactyly

AD (181450) TBX3, 12q24.1

Frontometaphyseal dysplasia

SGS, coarse facies, prominent supraorbital ridge, micrognathia, hypertelorism, hearing loss, dental defects, skeletal defects, urinary tract anomalies, mental retardation

XLD (305620) FLNA, Xq28

Larsen18

SGS, LM, short stature, flat facies, prominent forehead, hypertelorsim, low nasal bridge, cardiac defect, multiple joint dislocations, spatulate thumbs

AD (150250) 3p21.1-p14.1

Marshall-Smith19

LH, accelerated skeletal maturation, prominent forehead, prominent eyes, micrognathia, failure to thrive, developmental delay

Sporadic (602535)

Acrofacial dysostosis (Nager)

LH, hypoplasia of zygoma, maxilla, and mandible, radial ray defect, ear anomalies, cleft palate, hearing loss

AD (154400) 9q32

Robin sequence with cleft mandible and limb anomalies20

LH, short stature, Robin sequence, cleft mandible, hypoplastic thumbs, talipes equinovarus

AR (268305)

Laryngeal atresia, encephalocele and limb deformities21

LA, anterior encephalocele, radial defects, tibial defects, oligodactyly, syndactyly, camptodactyly, fetal hydrops

Unknown (607132)

Chondrodysplasia punctata, rhizomelic type22

LA, frontal bossing, flat nasal bridge, microcephaly, cleft palate, cataracts, ichthyosis, rhizomelia

AR (215100) PEX7, 6q22-q34 AR (222765) Chrom 1 AR (600121) AGPS, 2q31

Hirschsprung disease, heart defects, laryngeal anomalies, preaxial polydactyly23

LH, cleft lip/palate, hallux duplication, postaxial polydactyly, cardiac defect, Hirschsprung disease

AR (604211)

Mosaic chromosome 13q deletion24

LC, growth retardation, microcephaly, hypertelorism, ear anomalies, agenesis of corpus callosum, laryngeal cleft, cardiac defect, renal hypoplasia, skeletal anomalies, digital anomalies

Chromosomal

Fraser-like25

SGS, fused eyelids, digital anomalies

AR (229230)

LA: laryngeal atresia, LS: laryngeal stenosis, LC: laryngeal cleft, LH: laryngeal hypoplasia, SGS: subglottic stenosis, LW: laryngeal web, LM: laryngomalacia

The Lower Respiratory Organs

Prognosis and Treatment

Congenital high airway obstruction (CHAOS) due to laryngeal atresia is commonly lethal due to inability to establish an airway and associated defects. A small patent pharyngoglottic duct or tracheoesophageal fistula may allow ventilation until definitive measures to establish an airway can be taken.15 A novel surgical approach, EXIT (ex utero intrapartum treatment), has been successfully utilized in cases where the airway obstruction is diagnosed prenatally.16,17 Laryngeal webs are managed according to the extent and thickness of the web. Small, thin webs are treated endoscopically, while more extensive webs with subglottic extension or associated cricoid abnormality require an open surgical approach.5,6 Temporary tracheostomy is sometimes required for extensive or staged repairs. Congenital subglottic stenosis can often be managed conservatively, as most children improve over several years. Severe cases may require tracheostomy and reconstruction.5 References (Laryngeal Atresia, Webs, and Stenosis) 1. Morrison PJ, Macphail S, Williams D, et al.: Laryngeal atresia or stenosis presenting as second-trimester fetal ascites—diagnosis and pathology in three independent cases. Prenat Diagn 18:963, 1998. 2. Meizner I, Sherizly I, Mashiach R, et al.: Prenatal sonographic diagnosis of laryngeal atresia in association with single umbilical artery. J Clin Ultrasound 28:435, 2000. 3. Onderoglu L, Saygan-Karamursel B, Bulun A, et al.: Prenatal diagnosis of laryngeal atresia. Prenat Diagn 23:277, 2003. 4. Watson MJ, Munson DP: Amniotic fluid analysis in a fetus with laryngeal atresia. Prenat Diagn 15:571, 1995. 5. Wiatrak BJ: Congenital anomalies of the larynx and trachea. Otolaryngol Clin North Am 33:91, 2000. 6. Hartnick CJ, Cotton RT: Congenital laryngeal anomalies. Otolaryngol Clin North Am 33:1293, 2000. 7. Smith II, Bain AD: Congenital atresia of the larynx: a report on nine cases. Ann Otol Rhinol Laryngol 74:338, 1965. 8. Zaw-Tun HI: Development of congenital laryngeal atresias and clefts. Ann Otol Rhinol Laryngol 97:353, 1988. 9. Cohen SR: Congenital glottic webs in children: a retrospective review of 51 patients. Ann Otol Rhinol Laryngol 121(suppl):2, 1985. 10. Smith RJH, Catlin FI: Congenital anomalies of the larynx. Am J Dis Child 138:35, 1984. 11. Howie TO, Ladefoged P, Stark RE: Congenital subglottic bars found in 3 generations of one family. Folia Phoniatr Logop 13:56, 1961. 12. Strakowski SM, Butler MG, Cheek JW, et al.: Familial laryngeal web in three generations with probable autosomal dominant transmission. Dysmorphol Clin Genet 2:9, 1988. 13. Tang PT, Meagher SE, Khan AA, et al.: Laryngeal atresia: antenatal diagnosis in a twin pregnancy. Ultrasound Obstet Gynecol 7:371, 1996. 14. McElhinney DB, Jacobs I, McDonald-McGinn DM, et al.: Chromosomal and cardiovascular anomalies associated with congenital laryngeal web. Int J Pediatr Otorhinolaryngol 66:23, 2002. 15. Hicks BA, Contador MP, Perlman JM: Laryngeal atresia in the newborn: surgical implications. Am J Perinatol 13:409, 1996. 16. Bui TH, Grunewald C, Frenckner B, et al.: Successful EXIT (ex utero intrapartum treatment) procedure in a fetus diagnosis prenatally with congenital high-airway obstruction syndrome due to laryngeal atresia. Eur J Pediatr Surg 10:328, 2000. 17. Lim FY, Crombleholme TM, Hedrick HL, et al.: Congenital high airway obstruction: natural history and management. J Pediatr Surg 38:940, 2003. 18. Hoeve HJ, Joosten KF, Bogers AJ, et al.: Malformation and stenosis of the cricoid cartilage in association with Larsen’s syndrome. Laryngoscope 107:792, 1997. 19. Cullen A, Clarke TA, O’Dwyer TP: The Marshall-Smith syndrome: a review of the laryngeal complications. Eur J Pediatr 156:463, 1997.

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20. Tabith Jr A, Bento-Goncalves CG: Laryngeal malformations in the Richieri-Costa and Pereira form of acrofacial dysostosis. Am J Med Genet 66:399, 1996. 21. Kalache KD, Masturzo B, Scott RJ: Laryngeal atresia, encephalocele, and limb deformities (LEL): a possible new syndrome. J Med Genet 38:420, 2001. 22. Storm W, Fasse M: [Laryngeal atresia in an infant with chondrodysplasia punctata, rhizomelic type]. Monatsschr Kinderheilkd 139:629, 1991. 23. Huang T, Elias ER, Mulliken JB, et al.: A new syndrome: heart defects, laryngeal anomalies, preaxial polydactyly and colonic aganglionosis in sibs. Genet Med 1:104, 1999. 24. Lorentz CP, Jalal SM, Thompson DM, et al.: Mosaic r(13) resulting in large deletion of chromosome 13q in a newborn female with multiple congenital anomalies. Am J Med Genet 111:61, 2002. 25. Mena W, Krassikoff N, Philips JB III: Fused eyelids, airway anomalies, ovarian cysts and digital abnormalities in siblings: a new autosomal recessive syndrome or a variant of Fraser syndrome? Am J Med Genet 40:377, 1991.

6.3 Laryngotracheoesophageal Cleft Definition

Laryngotracheoesophageal cleft is a partial or complete communication between the larynx, subglottis, and trachea with the hypopharynx and/or esophagus due to deficiency of the interarytenoid musculature and cricoid lamina rostrally and/or the membranous trachea caudally. Ventral laryngeal clefts are extremely rare, with less than five reports in the literature, and are excluded from this discussion. Diagnosis

The extent of the cleft determines the severity of presenting symptomatology. Posterior laryngeal clefts are commonly classified according to the scheme set forth by Benjamin and Inglis:1 Type I: Supraglottic interarytenoid cleft Type II: Partial cricoid cleft extending below the vocal cords Type III: Complete cricoid cleft extending into the cervical trachea Type IV: Complete cleft extending into thoracic trachea Patients with type I clefts may present with nonspecific symptoms, including wheezing or asthmalike symptoms, chronic cough, and failure to thrive. More specific symptoms include inspiratory stridor, weak cry, cyanotic spells with feeding, and increased secretions. Affected children often present with recurrent pneumonia.2 The more severe clefts always present with more severe signs and symptoms of aspiration and other evidence of incompetent larynx, including cough and choking with feeding and absent or very weak cry.3 Differential diagnosis includes laryngomalacia for the type I clefts and other laryngeal defects. Accurate and timely diagnosis requires a high index of suspicion. Chest radiograph may show evidence of aspiration pneumonia. Contrast swallow study may also demonstrate laryngeal incompetence and aspiration. The diagnosis is not always obvious during flexible laryngoscopy; definitive diagnosis is made with rigid endoscopy and may require specific instrumentation and techniques to identify the defect.2,4 Etiology and Distribution

Posterior laryngeal clefts occur in approximately 1 in 10,000 to 20,000 live births, accounting for less than 1% of all laryngeal anomalies.5 A recent report, however, found type I clefts in 6.2% of 660 children evaluated by microlaryngoscopy when each case was specifically

206

Cardiorespiratory Organs

evaluated for the possibility of a posterior laryngeal cleft.2 Associated anomalies are common, present in 60–70% of cases.2,3 The more severe clefts are nearly always associated with multiple anomalies.3 Other defects of the upper and lower airway and esophagus are most common and include tracheoesophageal fistula, esophageal atresia, laryngomalacia, bronchomalacia, subglottic stenosis, subglottic cysts, laryngeal hamartomata, tracheal stenosis, and gastroesophageal reflux. Nonrespiratory defects include cleft lip with or without cleft palate, heart defects, and gastrointestinal and genitourinary system anomalies.2–4 Syndromes associated with laryngeal clefts and other laryngeal anomalies are also set forth in Table 6-2. Opitz syndrome and Trisomy 21 are the most commonly recognized conditions associated with posterior laryngeal clefts.2,3 Males are more commonly affected than females, with a 63–66% predominance,2,6 some of which is undoubtedly accounted for by the frequency of laryngeal clefts in Opitz syndrome. Familial cases, without an underlying diagnosis, have been reported.7,8 An interesting kindred of two sibships of double first cousins, each with three affected, was reported by Phelan et al. in 1973.9 Follow-up of the family revealed several affected children of the original patients, suggesting autosomal dominant inheritance.10 Prognosis and Treatment

Type I laryngeal clefts may not require surgical intervention. Speech and feeding therapy are required to control aspiration and gastroesophageal reflux.2–4 Type I clefts that are not responsive to conservative therapy, and all of the more severe clefts, require surgical treatment. Minor repairs may be accomplished endoscopically, but revisions are frequently required; open repair is necessary for the more severe clefts. Repair is accomplished either from an anterior approach, lateral pharyngotomy, or thoracotomy, depending on the extent of the cleft and associated defects.3 Gastroesophageal reflux commonly complicates the management of posterior laryngeal clefts, occurring in up to 44%.2,3 The mortality rate associated with posterior laryngeal clefts was reported by Roth et al. in 1983 as being as high as 40% for type I, 50% for type II, and greater than 90% for type III.11 However, recent advances in diagnosis, anesthesia, and surgical techniques have lowered the mortality rate to as low as 14% in a recent series that included 44 patients with type I to IV clefts. Of note is that many patients died from a cause not attributable to the airway cleft.3 References (Laryngotracheoesophageal Clefts) 1. Benjamin B, Inglis A: Minor congenital laryngeal clefts: diagnosis and classification. Ann Otol Rhinol Laryngol 98:417, 1989. 2. Parsons DS, Stivers E, Giovanetto DR, et al.: Type I posterior laryngeal clefts. Laryngoscope 108:403, 1998. 3. Evans KL, Courteney-Harris R, Bailey CM, et al.: Management of posterior laryngeal and laryngotracheoesophageal clefts. Arch Otolaryngol Head Neck Surg 121:1380, 1995. 4. Hartnick CJ, Cotton RT: Congenital laryngeal anomalies. Otolaryngol Clin North Am 33:1293, 2000. 5. Dubois JJ, Pokorny WJ, Harberg FJ, et al.: Current management of laryngeal and laryngotracheoesophageal clefts. J Pediatr Surg 25:855, 1990. 6. Tyler DC: Laryngeal cleft: report of eight patients and a review of the literature. Am J Med Genet 21:61, 1985. 7. Finlay HVL: Familial congenital stridor. Arch Dis Child 24:219, 1949. 8. Crooks J: Non-inflammatory laryngeal stridor in infants. Arch Dis Child 29:12, 1954. 9. Phelan PD, Stocks JG, Williams HE, et al.: Familial ocurrence of congenital laryngeal clefts. Arch Dis Child 48:275, 1973. 10. Phelan PD, Williams H, Danks D: Familial occurrence of congenital laryngeal clefts (Letter). Arch Dis Child 72:98, 1995. 11. Roth B, Rose KG, Benz-Bohm G, et al.: Laryngotracheoesophageal cleft: clinical features, diagnosis, and therapy. Eur J Pediatr 140:41, 1983.

6.4 Tracheal Agenesis Definition

The terms tracheal agenesis (agenesis meaning absence of an organ) and tracheal aplasia (aplasia meaning lack or failure of development of an organ) may be used interchangeably, although tracheal agenesis appears to be the preferred term in the literature. Tracheal atresia (atresia meaning congenital absence or closure of an opening) is also used to describe discontinuity of the tracheal lumen. All of these terms are used in the literature to describe absence of all or most of the trachea between the larynx and mainstem bronchi. Tracheal agenesis is classified into three anatomic types according to Floyd et al.:1 Type I: Agenesis of the proximal trachea with a normal short segment of distal tracheal and a tracheoesophageal fistula Type II: Agenesis of the entire trachea with normal main stem bronchi fused in the midline at the carina. There is often a fistula between the carina and the esophagus. Type III: Agenesis of the trachea and carina with the mainstem bronchi arising separately from the esophagus1,2 The relative frequencies for types I to III are 13%, 65%, and 22%, respectively.3 Diagnosis

Polyhydramnios, often leading to premature delivery, complicates approximately 50% of cases of tracheal agenesis.2 At birth, there is immediate respiratory distress, lack of air movement, and no audible cry. Endotracheal intubation is impossible, although esophageal intubation may provide some respiratory support via a distal tracheoesophageal fistula. Contrast radiographic studies and computerized tomography may be helpful in the diagnosis if the infant’s respiratory status is stabilized. Etiology and Distribution

Tracheal agenesis is rare, with an incidence of less than 1:50,000.4 Over 100 cases have been reported in the literature and are the subject of recent reviews.2,5 Epidemiologic characteristics of tracheal agenesis are presented in Table 6-3. The embryologic development of embryonic foregut leading to separate respiratory and gastrointestinal tracts is controversial. Recent understanding has been aided by the development of an animal model of aberrant tracheoesophageal development, the adriamycin-exposed rat.6–8 Previously, it was believed that bilateral esophagotracheal ridges divided the ventral (respiratory) from the

Table 6-3. Selected epidemiologic characteristics of tracheal agenesis Characteristic

Summary Information

Incidence

<1:50,0004

Geographic variation

None reported

Race/ethnic differences

None reported

Gender difference

M/F 2:12

Gestation

Prematurity commonly associated with polyhydramnios

Familial patterns

No recurrence reported

The Lower Respiratory Organs

dorsal (gastrointestinal) foregut.9 More recent data have suggested that the respiratory diverticulum, a ventral outgrowth of the foregut during the 4th week of development, elongates, forming a stalk that will develop into the trachea. The surrounding mesenchyme between the primitive trachea and esophagus actually constitutes the septum or tissue dividing the two structures.10 In abnormal foregut development in adriamycin-exposed rats, normal lung buds develop, but the elongation of the trachea does not occur. If ventral development predominates, the foregut develops into a trachea, and the upper esophageal segment is only a pouch from the dorsal foregut (esophageal atresia). If dorsal development predominates, the foregut develops into the esophagus, and the ventral foregut derivative is a blind pouch (tracheal agenesis).8 The mechanism in the adriamycin model is hypothesized to be arrest or delay of normal development due to cytotoxicity and impaired DNA synthesis.8 Greater growth potential of dorsal upper foregut cells compared to ventral cells may explain the relative rarity of tracheal agenesis compared to esophageal atresia.8 In 90–95% of cases, tracheal agenesis is associated with other malformations.2,5 Cardiovascular, gastrointestinal, and genitourinary malformations are the most commonly associated. Although there is some overlap with malformations included in the VATER/ VACTERL association, Evans et al. have noted a distinct difference in the nature and frequency of the associated malformations and concluded that tracheal agenesis is a separate entity.5,11 Analysis of 86 cases of tracheal agenesis with associated malformations suggested four consistent subgroups: (1) anomalies primarily confined to the thorax, including cardiovascular and laryngeal defects and rare unilateral limb and renal defects; (2) complex congenital heart defects and abnormal lung lobation; (3) cardiac and caudal anomalies, including imperforate anus, rectal fistula, renal, bladder, and genital defects; (4) similar to group 3 but with more frequent cardiac and foregut defects. A male excess was noted in groups 1 to 3, while an equal sex ratio characterized group 4.5 No chromosomal, teratogenic, or single gene has been identified as contributing to the development of tracheal agenesis in humans. No familial cases are recorded, although a woman with tetralogy of Fallot and absent pulmonary valve gave birth to a female infant with a similar heart defect associated with tracheal agenesis.12 The pathogenesis is unknown, but Evans et al. have suggested a disturbance of epithelial-mesenchymal interaction, or disruption of a primary developmental field, as potential explanations for tracheal agenesis and the common associated defects.5 Prognosis and Treatment

Complete tracheal agenesis remains a lethal condition.2,5 One child with Floyd’s type I tracheal agenesis, with a distal tracheal segment, survived over 6 years ventilated through a distal tracheostomy.13 No suitable autologous, homologous, or artificial tissue replacement has been successful for long-segment tracheal agenesis.14 References (Tracheal Agenesis) 1. Floyd J, Campbell DC, Dominy DE: Agenesis of the trachea. Am Rev Respir Dis 86:557, 1962. 2. Van Veenendaal MB, Liem KD, Marres HAM: Congenital absence of the trachea. Eur J Pediatr 159:8, 2000. 3. Koltai PJ, Quiney R: Tracheal agenesis. Ann Otol Rhinol Laryngol 101:560, 1992. 4. Manschot HJ, van den Anker JN, Tibboel D: Tracheal agenesis. Anaesthesia 49:788, 1994. 5. Evans JA, Greenberg CR, Erdile L: Tracheal agenesis revisited: analysis of associated anomalies. Am J Med Genet 82:415, 1999.

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6. Thompson DJ, Molello JM, Strebing RJ, et al.: Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Teratology 17:151, 1978. 7. Diez-Pardo JA, Qi B, Navarro C, et al.: A new rodent experimental model of esophageal atresia and tracheoesophageal fistula: preliminary report. J Pediatr Surg 31:498, 1996. 8. Merei JM, Hutson JM: Embryogenesis of tracheoesophageal anomalies: a review. Pediatr Surg Int 18:319, 2002. 9. Sadler TW: Langman’s Medical Embryology, ed 8. Lippincott Williams and Wilkins, Baltimore, 2000, p 260. 10. O’Rahilly R, Mu¨ller F: Respiratory and alimentary relations in staged human embryos, new embryological data and congenital anomalies. Ann Otol Laryngol 93:421, 1984. 11. Evans JA, Reggin J, Greenberg C: Tracheal agenesis and associated malformations: a comparison with tracheoesophageal fistula and the VACTERL association. Am J Med Genet 21:21, 1985. 12. Hirt-Armon K, Pober BR, Holmes LB: Type III tracheal agenesis with familial tetralogy of Fallot and absent pulmonary valve syndrome. Am J Med Genet 65:266, 1996. 13. Soh H, Kawahawa H, Imura K, et al.: Tracheal agenesis in a child who survived for 6 years. J Pediatr Surg 34:1541, 1999. 14. Haben CM, Rappaport JM, Clarke KD: Tracheal agenesis. J Am Coll Surg 194:217, 2002.

6.5 Tracheal Stenosis Definition

Tracheal stenosis is a fixed intrinsic narrowing of the trachea. The narrowing can be localized to a short or long tracheal segment, often due to complete tracheal rings. Alternatively, the tracheal lumen may become progressively narrow caudally. Excluded from this discussion is narrowing caused by extrinsic compression of the trachea, which occurs most commonly due to an aberrant left pulmonary artery ‘‘sling.’’ Congenital tracheal cartilaginous sleeve, with vertical fusion of tracheal rings, occasionally presents with tracheal stenosis and is considered separately. Diagnosis

Tracheal stenosis typically presents in infancy, but may not present until adolescence or adulthood.1,2 Severe forms present at birth with respiratory distress, inspiratory and expiratory stridor, and difficult tracheal intubation.1 Inspiratory stridor characterizes extrathoracic tracheal stenosis, whereas wheezing, with or without stridor, may be present in cases of intrathoracic tracheal stenosis.3 Highly penetrated radiographs may demonstrate the narrowed airway, but bronchoscopy is often required. Computerized tomography is also useful to demonstrate the length and extent of the stenotic lesion and is useful in planning surgical repair. Etiology and Distribution

The etiology of tracheal stenosis is unknown. The C-shaped cartilage, muscle, and connective tissue of the trachea are derived from the surrounding splanchnic mesenchyme and are well-developed by 11 to 12 weeks gestation.4 There is no period during normal development in which the cartilaginous rings completely encircle the trachea. Tracheal stenosis is rare. Albers and Wood reported complete tracheal rings in 5 of 1147 (0.4%) children who underwent bronchoscopy. Associated anomalies were reported in 19 of 21 infants with congenital tracheal stenosis, most commonly involving the respiratory tract and esophagus.1 The specific defects included bronchial stenosis (18 of 21), tracheal bronchus (4 of 21), pulmonary hypoplasia or agenesis (6 of 21), and tracheoesophageal

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Table 6-4. Patterns of malformations associated with tracheal stenosis Causation Gene/Locus

Syndrome

Significant Features

Anterior chamber cleavage disorder, cerebellar hypoplasia, hypothyroidism, tracheal stenosis8

Growth retardation, iris coloboma, congenital hypothyroidism, narrow external auditory canal, cerebellar hypoplasia, short neck, hip dysplasia, dense scalp hair, genital hypoplasia, growth hormone deficiency.

Unknown (601427)

Conradi-Hu¨nermann

Growth retardation, flat facies, prominent forehead, macrocephaly, eye anomalies, ear anomalies, short neck, punctate calcifications, scoliosis, skeletal asymmetry, hydronephrosis, congenital ichthyosiform erythroderma, sparse hair

XLD (302960) EBP, Xp11.23-p11.22

Mosaic chromosome 13q deletion9

Growth retardation, microcephaly, hypertelorism, ear anomalies, agenesis of corpus callosum, laryngeal cleft, cardiac defect, renal hypoplasia, skeletal anomalies, digital anomalies

Chromosomal

Frontometaphyseal dysplasia10

Coarse facies, prominent supraorbital ridge, micrognathia, hypertelorism, hearing loss, dental defects, skeletal defects, urinary tract anomalies, mental retardation

XLD (305620) FLNA, Xq28

Goldenhar11

Facial asymmetry, macrostomia, microtia, preauricular skin tags, hearing loss, epibulbar dermoid, vertebral anomalies, cardiac defects

Sporadic, AD (164210) 14q32

Geleophysic dysplasia

Short stature, round face, thickened helices, short nose, wide mouth, high-pitched voice, cardiac defects, skeletal anomalies including contractures, abnormal skin and nails, developmental delay

AR (231050)

Hydrolethalus

Growth retardation; cleft lip/palate; micrognathia; polydactyly; central nervous system, genitourinary, gastrointestinal, and diaphragmatic defects

AR (236680) 11q23-q25

Keutel12

Midface hypoplasia, low nasal bridge, small alae nasi, hearing loss, peripheral pulmonary stenosis, brachyphalangy, stippled cartilage calcification

AR (245150) 12p13.1-p12.3

Laryngotracheal stenosis, short stature, arthropathy13

Progressive/acquired laryngotracheal stenosis, short stature, joint limitation, minor facial anomalies

Unknown (603391)

Larsen

Short stature, flat facies, prominent forehead, hypertelorism, low nasal bridge, cardiac defect, multiple joint dislocations, spatulate thumbs

AD (150250) 3p21.1-p14.1

Opitz14

Hypertelorism, telecanthus, anteverted nares, cleft lip/palate, hypospadias, cryptorchidism, cardiac defect, developmental delay

XLR (300000) MID1, Xp22

Oral-facial-digital, type II15

Midline cleft of upper lip, cleft tongue, postaxial polydactyly of hands, hallux duplication, mental retardation, other central nervous system defects

AR (252100)

Thoracolaryngopelvic dysplasia16

Thoracic dystrophy, short ribs, wide costochondral junctions, small pelvis

AD (187760)

Trisomy 21

Flat facies, upslanted palpebral fissures, small ears, cardiac defect, brachydactyly, clinodactyly, hypotonia

Chromosomal

VATER/VACTERL17

Vertebral defects, anal atresia, cardiac defect, tracheoesophageal fistula, radial ray defect, renal defect, other limb defects

Sporadic (192350)

fistula (3 of 21). Other defects included congenital lobar emphysema, tracheomalacia, tracheal web, congenital subglottic stenosis, and laryngeal hypoplasia. Cardiac defects were also reported, including common atrioventricular canal, aortic coarctation, and dextrocardia with ventriculoseptal defect. Skeletal defects reported in that series included hemivertebrae, radial ray defects, radioulnar synostosis, and micrognathia. Tracheal stenosis is usually a sporadic defect. Wong et al. reported congenital tracheobronchial stenosis in a pair of monozygotic twin females.5 Lethal tracheal stenosis was reported in two infants of diabetic mothers.7 Syndromes associated with tracheal stenosis are set forth in Table 6-4.

References (Tracheal Stenosis) 1. Benjamin B, Pitkin J, Cohen D: Congenital tracheal stenosis. Ann Otol Rhinol Laryngol 90:364, 1981. 2. Donnelly J: Congenital tracheal stenosis in an adult, complicated by asphyxial pulmonary oedema. Anaesth Intens Care 16:212, 1988. 3. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 4. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, ed 7. WB Saunders Company, Philadelphia, 2003, p 245. 5. Albers GM, Wood RE: The lower respiratory organs. In: Human Malformations and Related Anomalies, ed 1, vol II. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 347.

The Lower Respiratory Organs 6. Wong KS, Lien R, Lin TY: Congenital tracheobronchial stenosis in monozygotic twins. Eur J Pediatr 157:1023, 1998. 7. Tack E, Perlman J: Tracheal stenosis: lethal malformation in two infants of diabetic mothers. Am J Dis Child 141:77, 1987. 8. Jung C, Wolff G, Back E, et al.: Two unrelated children with developmental delay, short statures and anterior chamber cleavage disorder, cerebellar hypoplasia, endocrine disturbances and tracheostenosis: a new entity? Clin Dysmorphol 4:44, 1995. 9. Lorentz CP, Jalal SM, Thompson DM, et al.: Mosaic r(13) resulting in large deletion of chromosome 13q in a newborn female with multiple congenital anomalies. Am J Med Genet 111:61, 2002. 10. Leggett JM: Laryngo-tracheal stenosis in frontometaphyseal dysplasia. J Laryngol Otol 102:74, 1988. 11. Downing GJ, Kilbride H: An interesting case presentation: pulmonary malformations associated with oculoauriculovertebral dysplasia (Goldenhar anomalad). J Perinatol 11:190, 1991. 12. Meier M, Weng LP, Alexandrakis E, et al.: Tracheobronchial stenosis in Keutel syndrome. Eur Respir J 17:566, 2001. 13. Hopkin RJ, Cotton R, Langer LO, et al.: Laryngotracheal stenosis, progressive with short stature and arthropathy. Am J Med Genet 80:241, 1998. 14. Buckley JG, Hinton AE, Penter G, et al.: Total laryngotracheal hypoplasia in a case of G syndrome. J Laryngol Otol 102:1056, 1988. 15. Steichen-Gersdorf E, Gassner I, Cofi B, et al.: Oral-facial-digital syndrome II. Transitional type between Mohr and Majewski syndrome: report of a new case with congenital stenosis of the trachea. Clin Dysmorphol 3:245, 1994. 16. Wood E, Kearns D: Laryngotracheal stenosis in thoracolaryngopelvic dysplasia: Barnes syndrome. Otolaryngol Head Neck Surg 113:807, 1995. 17. Kairamkonda V, Thorburn K, Sarginson R: Tracheal bronchus associated with VACTERL. Eur J Pediatr 162:165, 2003.

6.6 Congenital Tracheal Cartilaginous Sleeve Definition

Congenital tracheal cartilaginous sleeves are discrete tracheal rings replaced by an uninterrupted cartilaginous cylinder secondary to vertical fusion of the tracheal cartilages. Other terms used to describe this lesion include ‘‘pipe-stem’’ or ‘‘stovepipe trachea’’.1

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Prognosis and Treatment

Most of the patients have respiratory symptoms, for the most part attributable to the upper respiratory tract. The functional significance of tracheal cartilaginous sleeve is unclear. Tracheostomy may be required due to the upper airway obstruction or due to associated tracheal stenosis. Aggressive treatment of respiratory infections and secretions is required in these patients. Tracheal cartilaginous sleeve is compatible with long-term survival.1,2 References (Tracheal Cartilaginous Sleeve) 1. Lin SY, Chen JC, Hotaling AJ, et al.: Congenital tracheal cartilaginous sleeve. Laryngoscope 105:1213, 1995. 2. Davis S, Bove KE, Wells TR, et al.: Tracheal cartilaginous sleeve. Pediatr Pathol 12:349, 1992. 3. Inglis AF Jr, Kokesh J, Seibert J, et al.: Vertically fused tracheal cartilage. An underrecognized anomaly. Arch Otolaryngol Head Neck Surg 118: 436, 1992. 4. Noorily MR, Farmer DL, Belenky WM, et al.: Congenital tracheal anomalies in the craniosynostosis syndromes. J Pediatr Surg 34:1036, 1999. 5. Scheid SC, Spector AR, Luft JD: Tracheal cartilaginous sleeve in Crouzon syndrome. Int J Pediatr Otorhinolaryngol 65:147, 2002. 6. Okajima K, Aoki I, Sagehashi N, et al.: Three craniosynostotic patients with tracheal sleeve. Clin Dysmorphol 12:75, 2003.

6.7 Tracheoesophageal Fistula Definition

Tracheoesophageal fistula is an abnormal communication between the trachea and the esophagus. Tracheoesophageal fistula is almost always accompanied by esophageal atresia and discussed in detail in Chapter 24. Fistulous connection between the trachea and esophagus is also associated with tracheal agenesis, discussed in section 6.4. 6.8 Pulmonary Agenesis/Aplasia

Diagnosis

The diagnosis of tracheal cartilaginous sleeve is often not suspected. Affected individuals typically have additional malformations, most notably craniosynostosis syndromes, with associated symptomatic upper airway anomalies. The lesion does not usually lead to tracheal stenosis. Symptoms may include increased mucous production, cough, crouplike episodes, or increased respiratory infections. The diagnosis can be suspected at bronchoscopy with the finding of a smooth tracheal surface, or at the time of tracheostomy. The diagnosis has often been made at autopsy.1,2 Etiology and Distribution

Tracheal cartilaginous sleeve is a rare lesion, with 23 cases reported. Out of the 23 cases, 21 have craniosynostosis syndromes, with clinical diagnoses of Crouzon, Pfeiffer, and Apert syndromes.1–5 Two cases are reported with Goldenhar syndrome.1,3 No mutation in the FGFR2 gene (exons IIIa and IIIc) was found in three craniosynostosis patients studied by Okajima.6 Two had the clinical diagnosis of Crouzon syndrome and one had Pfeiffer syndrome; all had some atypical features. Although the pathogenesis is unknown, there is an obvious analogy between fusion of tracheal cartilage and fusion of cranial sutures and other joints in the craniosynostosis syndromes.2

Definition

Pulmonary agenesis refers to unilateral or bilateral absence of the bronchus, pulmonary parenchyma, and pulmonary vasculature. Pulmonary aplasia is considered in the same spectrum and differs only in the presence of a tracheal or bronchial stump. Pulmonary segmentation defects due to the absence of one or more lobes are included in this definition and are sometimes termed pulmonary hypoplasia. Excluded from this definition are primary pulmonary hypoplasia and pulmonary hypoplasia secondary to extrinsic factors including oligohydramnios, thoracic space-occupying lesions, etc. Diagnosis

Significant pulmonary aplasia or agenesis presents in the neonatal period with respiratory distress and cyanosis. Examination findings may be subtle, with decreased breath sounds and cardiac impulse shifted ipsilateral to the affected side. In unilateral agenesis, the affected hemithorax may be opacified or may show partial aeration due to shift of the normal lung and mediastinal contents. Further evaluation could include computerized tomography, echocardiography or angiography demonstrating absence of ipsilateral pulmonary artery, and bronchoscopy.

Fig. 6-3. Pulmonary agenesis. A. 31 week gestation female infant with Matthew Wood syndrome. Note bilateral microphthalmia and thoracic hypoplasia. B. Note extremely small thoracic cavity, elevated diaphragms, absent lungs, and large, globular heart with a single midline great artery (aorta). C. Note tracheal agenesis (long arrow) and empty pleural cavity (short arrow).

Table 6-5. Recognizable patterns associated with pulmonary agenesis and aplasia (including lobar aplasia) Causation Gene/Locus

Syndrome

Significant Features

Fryns

Large for gestational age, coarse facies, malformed ears, wide mouth, cleft lip/palate, microretrognathia, agenesis of corpus callosum, heart defect, renal defect, digital and nail hypoplasia

AR (229850)

Hydrolethalus

Growth retardation; cleft lip/palate; micrognathia; polydactyly; central nervous system, genitourinary, gastrointestinal, and diaphragmatic defects

AR (236680) 11q23-q25

Matthew Wood16

Microphthalmia, anophthalmia, pulmonary hypoplasia/agenesis

Uncertain (601186)

Microcephaly, congenital heart disease, unilateral renal agenesis, hyposegmented lungs17

Congenital microcephaly; growth retardation; cleft palate; ear, heart, genitourinary, and central nervous system defects

Uncertain (601355)

Pallister-Hall

Growth retardation; polydactyly; syndactyly; central nervous system defect including hypothalamic hamartoma; genitourinary, heart, and endocrine defects

Sporadic AD (146510) GLI3, 7p13

Pulmonary and diaphragmatic agenesis18

Unilateral or bilateral agenesis of the diaphragm, heart defect, skin tags (nose), hypoplastic uterus

Uncertain

Smith-Lemli-Opitz

Growth retardation; cleft palate; postaxial polydactyly; syndactyly; ambiguous genitalia; heart, urinary, and central nervous system defects

AR (268670) DHCR7, 11q12-q13

Tetra-amelia with pulmonary hypoplasia19

Amelia, micrognathia, cleft lip/palate, hydrocephalus

AR (273395)

VACTERL20

Vertebral, anal, cardiac, renal, and radial defects; tracheoesophageal fistula

Sporadic

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The Lower Respiratory Organs

Etiology and Distribution

The trachea develops as an outgrowth of the foregut during the 4th week of development. The respiratory diverticulum extends from the ventral wall of the foregut and becomes separated from the foregut. Right and left mainstem bronchi develop from the primitive trachea at 5 weeks gestation. The right side develops three secondary bronchi and the left side, two, which is the earliest evidence of asymmetric lung lobation. Growth of the lungs continues within the pleural cavities. Subsequent branching of the secondary bronchi continues throughout gestation, and even postnatally, and is regulated by epithelial-mesenchymal interactions between the endoderm of the lung buds and the surrounding splanchnic mesoderm. Fibroblast growth factors are important mediators of these epithelial-mesenchymal interactions; Fgf-10 knockout mice demonstrate complete pulmonary agenesis.1 Pulmonary agenesis and aplasia are uncommon defects; bilateral cases are especially rare. Mardini and Nyhan report a prevalence of 0.5 to 1 per 10,000 patients.2 Seventy percent of unilateral pulmonary agenesis involves the left side.3 Males and females are equally affected.4,5 Associated anomalies are common including the heart, diaphragm, vertebrae, ribs, thumbs, spleen, gastrointestinal and genitourinary tracts, and craniofacial defects (Fig. 6-3). Most cases in which chromosomes have been studied report normal karyotypes, although there are two reports of infants with chromosome anomalies including 2p21p246,7 and a rare association with trisomy 18.8 Several instances of sibling recurrence have been reported,9,10 including several consanguineous families,2 suggesting autosomal recessive inheritance in some cases. Monozygotic twins, both concordant and discordant for pulmonary agenesis/aplasia, have also been reported.11,12 Vitamin A deficiency in rats is associated with pulmonary agenesis and other anomalies.13 Recognizable patterns of malformation associated with pulmonary agenesis and aplasia are set forth in Table 6-5. Prognosis and Treatment

Bilateral pulmonary agenesis or significant aplasia is lethal. For unilateral or less severe cases, the mortality rate is 50% in the first year and may be associated with the presence of additional anomalies.14 Late presentations and deaths in adults from related and unrelated causes are reported.10,15 Management and treatment of the pulmonary complications, including pulmonary hypertension, is supportive.15 References (Pulmonary Agenesis/Aplasia) 1. Min H, Danilenko DM, Scully SA, et al.: Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12:3156, 1998. 2. Mardini MK, Nyhan WL: Agenesis of the lung: report of four patients with unusual anomalies. Chest 87:522, 1985. 3. Gilbert EF, Opitz JM: The pathology of some malformations and hereditary diseases of the respiratory tract. Birth Defects Orig Artic Ser XII(6):239, 1976. 4. Oyamada A, Gasul BM, Holinger PH: Agenesis of the lung: report of a case, with a review of all previously reported cases. Am J Dis Child 85:182, 1953. 5. Maltz DL, Nadas AS: Agenesis of the lung: presentation of eight new cases and review of the literature. Pediatrics 42:175, 1968. 6. Say B, Carpenter NJ, Giacoai G, et al.: Agenesis of the lung associated with a chromosome abnormality (46,XX,2pþ). J Med Genet 17:477, 1980. 7. Schober PH, Mu¨ller WD, Behmel A, et al.: [Pulmonary agenesis in partial trisomy 2p and 21q]. Klin Padiatr 195:291–293, 1983.

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8. Voorhess ML, Vahard T, Gardner LI: Trisomy 16-18 syndrome. Lancet 2:992, 1962. 9. Podlech J, Richter J, Czygan P, et al.: Bilateral agenesis/aplasia of the lungs: report of a second case in the offspring of one woman. Pediatr Pathol Lab Med 15:781, 1995. 10. Fokstuen S, Schinzel A: Unilateral lobar pulmonary agenesis in sibs. J Med Genet 37:557, 2000. 11. Yount F: Agenesis of the right lung in each of identical twins. Arizona Med 5:48, 1948. 12. Booth JB, Berry CL: Unilateral pulmonary agenesis. Arch Dis Child 42:361, 1967. 13. Warkany J, Roth CB, Wilson JG: Multiple congenital malformations: a consideration of etiologic factors. Pediatrics 1:462, 1948. 14. Krummel TM: Congenital malformations of the lower respiratory tract. In: Kendig’s Disorders of the Respiratory Tract in Children, ed 6. Chernick V, Boat T, eds. WB Saunders Company, Philadelphia, 1998, p 307. 15. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 16. Seller MJ, Davis TB, Fear CN, et al.: Two sibs with anophthalmia and pulmonary hypoplasia (Matthew Wood syndrome). Am J Med Genet 62:227, 1996. 17. Ellis IH, Yale C, Thomas R, et al.: Three sibs with microcephaly, congenital heart disease, lung segmentation defects and unilateral absent kidney: a new recessive multiple congenital anomaly (MCA) syndrome? Clin Dysmorphol 5:129, 1996. 18. Toriello HV, Higgins JV, Jones AS, et al.: Pulmonary and diaphragmatic agenesis: report of affected sibs. Am J Med Genet 21:87, 1985. 19. Rosenak D, Ariel I, Arnon J, et al.: Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs. Am J Med Genet 38:25, 1991. 20. Knowles S, Thomas RM, Lindenbaum RH, et al.: Pulmonary agenesis as part of the VACTERL sequence. Arch Dis Child 63:723, 1988.

6.9 Congenital Cystic Adenomatoid Malformation Definition

Congenital cystic adenomatoid malformation is a pulmonary hamartomatous lesion composed of noncartilage-containing terminal respiratory structures resembling terminal bronchioles. There are three morphologic subtypes recognized: Type I, Macrocystic: One or more large cysts (2–10 cm) predominate. The cysts are lined by ciliated pseudostratified columnar epithelium, which occasionally produce mucin. Bronchiolar and alveolar elements are present between the cysts. Type II, Microcystic: Contains mostly small uniform cysts (0.5–2 cm) lined by cuboidal or columnar epithelium. Type III, Solid: An airless mass consisting almost entirely of bronchiolar and alveolar elements. Gross cysts are not obvious, but microscopic alveolar cysts are present.1,2 Diagnosis

The diagnosis of cystic adenomatoid malformation is often made by prenatal ultrasound. Other frequently associated findings include maternal polyhydramnios and hydrops fetalis.3 The differential diagnosis of fetal chest masses includes pulmonary sequestration, congenital diaphragmatic hernia, pulmonary lymphangiectasia, and congenital lobar emphysema. Fetal magnetic resonance imaging techniques can be utilized to aid in diagnosis and to guide pregnancy and neonatal management.4,5

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Cardiorespiratory Organs

Fig. 6-4. Congenital cystadenomatoid malformation. A. Radiograph of type 1 malformation shows the entire left lung to be involved with multiple cystic lesions, with the mediastinum shifted toward the right. B. A CT scan of a type 2 malformation shows a large cystic lesion in the right lung with crowding of adjacent parenchyma. At least one septum (arrow) is visible within the cyst.

Respiratory symptoms may be present at birth. Large lesions may cause mediastinal shift, and cyst rupture may cause pneumothorax.1 Chest radiograph will show a solid or cystic mass involving a portion of, or an entire, hemithorax. The radiographic findings may overlap with other pulmonary or extrapulmonary chest masses, including simple pulmonary cysts, congenital lobar emphysema, diaphragmatic hernia, and pulmonary sequestration. Computerized axial tomography or magnetic resonance imaging can be used to aid in diagnosis (Fig. 6-4). Etiology and Distribution

The incidence of cystic adenomatoid malformation has been estimated at 1 in 25,000 to 35,000 pregnancies,6 accounting for approximately 25% of congenital pulmonary parenchymal lesions.7 Type II lesions account for 73%, and types I and III account for approximately 13% each.8 Males and females are equally affected.2 The etiology and pathogenesis are unknown, although increased cell proliferation and decreased apoptosis of affected tissue has been demonstrated.9 Cystic adenomatoid malformations can be associated with other pulmonary lesions and nonrespiratory system defects. Large lesions may be complicated by the development of fetal hydrops. Congenital cystic renal disease or renal agenesis, congenital heart defects, and bony lesions were present in 25 of 142 cases reviewed by Stocker et al.7 Laberge reported a case of trisomy 18.6 Prognosis and Treatment

Type II lesions tend to be extensive and may have the greatest number of associated defects;7 thus, they carry a worse prognosis. In prenatally diagnosed cases, microcystic lesions, bilateral lesions, and fetal hydrops were each associated with poor prognosis, whereas polyhydramnios and mediastinal shift were not necessarily associated with poor outcome.10 Partial or apparently complete in utero regression of cystic adenomatoid lesions is well-documented,11,12 up to 56% in one series.6 Some infants are asymptomatic at birth, and chest radiograph may be normal or only demonstrate subtle abnormality.11–13 Normal chest radiograph does not indicate complete resolution of a cystic adenomatoid lesion, and computed tomography scan detects abnormalities not shown on chest radiograph.12,13 Timing of excision in an asymptomatic patient is controversial. Chronic or

recurrent pulmonary infection may result from unresected or unidentified lesions.14 References (Cystic Adenomatoid Malformation) 1. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 2. Mandell G: Congenital cystic adenomatoid malformation. www. emedicine.com/radio/topic186.htm. 3. Adzick HS, Harrison MR, Glick PL, et al.: Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. J Pediatr Surg 20:483, 1985. 4. Hubbard AM, Adzick NS, Crombleholme TM, et al.: Congenital chest lesions: diagnosis and characterization with prenatal MR imaging. Radiology 212:43, 1999. 5. Hubbard AM, States LJ: Fetal magnetic resonance imaging. Top Magn Reson Imaging 12:93, 2001. 6. Laberge JM, Flageole H, Pugash D, et al.: Outcome of the prenatally diagnosed congenital cystic adenomatoid lung malformation: a Canadian experience. Fetal Diagn Ther 16:178, 2001. 7. Stocker JT, Drake RM, Madewell JE: Cystic and congenital lung disease in the newborn. Perspect Pediatr Pathol 4:93, 1978. 8. Madewell JE, Stocker JT, Korsower JM: Cystic adenomatoid malformations of the lung: morphologic analysis. Am J Roentgenol Radium Ther Nucl Med 124:436, 1975. 9. Cass DL, Quinn TM, Yang EY, et al.: Increased cell proliferation and decreased apoptosis characterizes congenital cystic adenomatoid malformation of the lung. J Pediatr Surg 33:1043, 1998. 10. Bunduki V, Ruano R, Da Silva MM, et al.: Prognostic factors associated with congenital cystic adenomatoid malformation of the lung. Prenat Diagn 20:459, 2000. 11. Cacciari A, Ceccarelli PL, Pilu GL, et al.: A series of 17 cases of congenital cystic adenomatoid malformation of the lung: management and outcome. Eur J Pediatr Surg 7:84, 1997. 12. Van Leeuwen K, Teitelbaum DH, Hirschl RB, et al.: Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal presentation, surgical indication and natural history. J Pediatr Surg 34:794, 1999. 13. Winters WD, Effmann EL, Nghiem HG, et al.: Disappearing fetal lung masses: importance of postnatal imaging studies. Pediatr Radiol 27:535, 1997. 14. Haller JA Jr, Golladay ES, Pickard LR, et al.: Surgical management of lung bud anomalies: lobar emphysema, bronchogenic cyst, cystic adenomatoid malformation, and intralobar sequestration. Ann Thorac Surg 28:33, 1978.

The Lower Respiratory Organs

6.10 Congenital Lobar Emphysema Definition

Congenital lobar emphysema is the postnatal hyperinflation of one or more lobes of the lung due to an intrinsic defect of the bronchopulmonary tree. Extrinsic compression causing segmental hyperinflation is excluded. Diagnosis

Most infants present in the newborn period with respiratory distress with or without cyanosis. Chest asymmetry, decreased breath sounds, hyperresonance on the affected side, and mediastinal shift may be apparent on physical examination. Chest radiograph performed shortly after birth may initially show an opaque, fluid-filled lobe, but follow-up radiograph will characteristically reveal overdistention and air trapping in the affected lobe, herniation across the mediastinum, and compression of surrounding normal lung tissue. Computerized tomography, ventilation/perfusion scan, and bronchoscopy can be used to aid in diagnosis.1 The diagnosis of congenital lobar emphysema can be made by fetal ultrasonography and fetal magnetic resonance imaging.2,3 The differential diagnosis includes other congenital chest masses (diaphragmatic hernia, cystic adenomatoid malformation, bronchopulmonary sequestration), and postnatal atelectasis with compensatory emphysema may also be considered. Other acquired lesions including bronchiolitis, asthma, and foreign body should be considered in cases that present beyond the neonatal period.1,4 Etiology and Distribution

Congenital lobar emphysema is the most common congenital lesion involving the lung parenchyma, accounting for approximately 50%.5 Typically, only one lobe is affected, with the left upper lobe being the most common, followed by the right middle and right upper lobes.1 In most cases, there is a deficiency or dysplasia of bronchial cartilage in the affected lobe5,6 leading to bronchial collapse and air trapping with expiration. Bronchial stenosis or atresia is also reported, as are a variety of other pathologic lesions.1,7 One series reported a male excess (1.8:1).5 Associated anomalies are uncommon. Congenital heart disease is reported in 10–15% of cases.4,8 Most cases are sporadic, although recurrence in twins,9 siblings,10,11 and mother-daughter12 and father-son13 pairs is reported. Prognosis and Treatment

Surgical treatment in the form of lobectomy or partial lobectomy is required for neonates with significant respiratory distress. Several cases diagnosed by fetal ultrasonography have appeared to regress in utero, but neonatal symptoms or radiographic progression led to surgical treatment.2,3 Nonoperative management is possible in mildly symptomatic or asymptomatic cases.8,14 References (Congenital Lobar Emphysema) 1. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 2. Olutoye OO, Coleman BG, Hubbard AM, et al.: Prenatal diagnosis and management of congenital lobar emphysema. J Pediatr Surg 35:792, 2000.

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3. Babu R, Kyle P, Spicer RD: Prenatal sonographic features of congenital lobar emphysema. Fetal Diagn Ther 16:200, 2001. 4. Krummel TM: Congenital malformations of the lower respiratory tract. In: Kendig’s Disorders of the Respiratory Tract in Children, ed 6. Chernick V, Boat T, eds. WB Saunders Company, Philadelphia, 1998, p 310. 5. Stocker JT, Drake RM, Madewell JE: Cystic and congenital lung disease in the newborn. Perspect Pediatr Pathol 4:93, 1978. 6. Dogan R, Demircin M, Sarigul A, et al.: Surgical management of congenital lobar emphysema. Turk J Pediatr 39:35, 1997. 7. Leape LL, Longino LA: Infantile lobar emphysema. Pediatric 34:246, 1964. 8. Karnak I, Senocak ME, Ciftci AO, et al.: Congenital lobar emphysema: diagnostic and therapeutic considerations. J Pediatr Surg 34:1347, 1999. 9. Thompson AJ, Reid AJ, Reid M: Congenital lobar emphysema occurring in twins. J Perinat Med 28:155, 2000. 10. Sloan H: Lobar obstructive emphysema in infancy treated by lobectomy. J Thorac Cardiovasc Surg 26:1, 1953. 11. Hendren WH, McKee DM: Lobar emphysema of infancy. J Pediatr Surg 1:24, 1966. 12. Wall MA, Eisenberg JD, Campbell JR: Congenital lobar emphysema in a mother and daughter. Pediatrics 70:131, 1982. 13. Roberts PA, Holland AJ, Halliday RJ, et al.: Congenital lobar emphysema: like father, like son. J Pediatr Surg 37:799, 2002. 14. Ozcelik U, Gocmen A, Kiper N, et al.: Congenital lobar emphysema: evaluation and long-term follow-up of thirty cases at a single center. Pediatr Pulmonol 35:384, 2003.

6.11 Primary Pulmonary Hypoplasia Definition

Primary pulmonary hypoplasia is the underdevelopment of the pulmonary parenchyma of one or both lungs. Excluded from this definition is pulmonary agenesis/aplasia in which there is unilateral or bilateral absence of the bronchus, pulmonary parenchyma, and vasculature. Also excluded is secondary pulmonary hypoplasia due to oligohydramnios, thoracic dysplasia, or thoracic space-occupying lesions. Diagnosis

Significant pulmonary hypoplasia presents in the immediate newborn period with respiratory distress and cyanosis. Physical examination is typically otherwise normal, without evidence of other malformations. Chest radiograph reveals small but clear lungs, normal heart size, elevated diaphragms, and bell-shaped thorax.1,2 Pneumothorax, either spontaneous or after mechanical ventilation, may complicate the picture. Severe pulmonary hypertension or persistent fetal circulation is also common, which makes accurate diagnosis of the primary pulmonary lesion difficult. Diagnosis can be suggested based on radiographic criteria2 but is often not made until autopsy. Lung weight to body weight ratio of less than 0.013 is diagnostic.3 The differential diagnosis includes pulmonary agenesis/aplasia and secondary pulmonary hypoplasia, the latter of which typically will have associated anomalies that lead to a specific diagnosis. Etiology and Distribution

Primary pulmonary hypoplasia is rare. In a series of 756 newborn autopsies, only 10 out of 77 cases of pulmonary hypoplasia were felt to be primary.4 A different series reported 3 cases in 1377 infants admitted to a newborn intensive care nursery over a 4-year period.1 Primary pulmonary hypoplasia is not associated with

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other congenital defects and is sporadic. The etiology and pathogenesis are unknown. The defect is hypothesized to occur after 16 weeks gestation with failure of development of terminal bronchioles and alveoli.5 Familial cases have been reported, including concordant identical twins and siblings of consanguineous parents,2,6,7 suggesting that there may be a genetic component. Prognosis and Treatment

The prognosis is dependent on the degree of pulmonary hypoplasia. Mortality is high with only 3 of 28 reported infants surviving to discharge.8 Mechanical ventilation with high inspired oxygen content and high ventilatory pressures is typical. A term infant was unsuccessfully treated with inhaled nitric oxide and high frequency oscillatory ventilation.8 Extracorporeal membrane oxygenation may only be helpful if there is sufficient pulmonary parenchymal tissue to sustain life.7

including bowel infarction, lead to diagnosis, which is made by lateral chest radiograph or bowel contrast study.6 Retroesophageal hernias also typically present after infancy with vomiting, gastroesophageal reflux, aspiration, or chronic respiratory symptoms. Diagnosis is confirmed by barium swallow.4 Eventration of the diaphragm may be asymptomatic or present with cardiorespiratory symptoms depending on the severity of the muscular hypoplasia. Respiratory symptoms tend to improve with age due to increased rigidity of the thoracic cage. Chest radiograph reveals elevation of the hemidiaphragm and fluoroscopy demonstrates limited or paradoxical movement of the diaphragm with respiration.4 The differential diagnosis of prenatally diagnosed diaphragmatic hernia includes other space-occupying lesions, including cystic adenomatoid malformations and bronchopulmonary sequestration. Etiology and Distribution

References (Primary Pulmonary Hypoplasia) 1. Swischuk LE, Richardson CJ, Nichols MM, et al.: Primary pulmonary hypoplasia in the neonate. J Pediatr 95:573, 1979. 2. Langer R, Kaufmann HJ: Primary (isolated) bilateral pulmonary hypoplasia: a comparative study of radiologic findings and autopsy results. Pediatr Radiol 16:175, 1986. 3. Askenazi SS, Perlman M: Pulmonary hypoplasia: lung weight and radial alveolar count as criteria of diagnosis. Arch Dis Child 54:614, 1979. 4. Page DV, Stocker JT: Anomalies associated with pulmonary hypoplasia. Am Rev Respir Dis 125:216, 1982. 5. Mendelsohn G, Hutchins GM: Primary pulmonary hypoplasia: report of a case with polyhydramnios. Am J Dis Child 131:1220, 1977. 6. Boylan P, Howe A, Gearty J, et al.: Familial pulmonary hypoplasia. Ir J Med Sci 146:179, 1977. 7. Cregg N, Casey W: Primary congenital pulmonary hypoplasia—genetic component to aetiology. Paediatr Anaesth 7:329, 1997. 8. Odd DE, Battin MR, Hallam L, et al.: Primary pulmonary hypoplasia: a case report and review of the literature. J Paediatr Child Health 39:467, 2003.

Formation of the body cavities begins during the 4th week of development after fertilization with transverse and ventral folding of the embryo. The mesoderm-derived septum transversum, which will form the central tendon of the diaphragm, originates cranial to the heart but is carried caudally with ventral folding of the head region. The septum transversum partially separates the pericardial and abdominal cavities, which are continuous dorsally through the pleuroperitoneal canals. Bilateral pleuroperitoneal membranes fuse with the dorsal mesentery, in which the openings for the aorta, inferior vena cava, and esophagus are located, and with the septum transversum to complete separation between the thoracic and

Fig. 6-5. Schematic showing location of diaphragmatic hernias.

6.12 Congenital Diaphragmatic Hernia Definition

Congenital diaphragmatic hernia is the absence or hypoplasia of the tendinous or muscular parts of the diaphragm, which allows herniation of abdominal viscera into the thoracic cavity. Posterolateral (Bochdalek), anterior (Morgagni), paraesophageal defects, defects of the central tendon, hemiagenesis, and eventration of the diaphragm are included. Diagnosis

Diagnosis of Bochdalek hernia is often made on fetal ultrasonogram. Associated sonographic features include polyhydramnios, deviation of the heart, absent or displaced stomach bubble, and dilated bowel loops within the thorax.1 Fetal magnetic resonance imaging is also used for diagnosis of fetal chest masses.2 Hydrops fetalis can also be a complicating feature.3 Postnatally, cardiorespiratory symptoms are frequent, including dyspnea, tachypnea, and cyanosis. Physical examination may reveal a scaphoid abdomen. Chest radiograph is usually diagnostic, showing mediastinal shift and abdominal viscera within the chest.4 Small defects may present later with cough, dyspnea, vomiting, or cyanosis.5 Morgagni hernias are typically small and do not commonly present in the neonatal period. Cardiorespiratory or gastrointestinal symptoms,

Table 6-6. Epidemiologic considerations of congenital diaphragmatic Hernia Characteristic

Summary Information

Prevalence

1–4 of 10,000 live births and stillbirths

Geographic variation

Low in Hungary (0.3 of 10,0000) and high in Japan (6.4 of 10,000)8

Gender difference

2 male to 1 female4

Temporal trends

Relatively stable

Twinning

Increased among conjoined twins9

Familial patterns

Isolated cases considered multifactorial, recurrence risk 2%10

The Lower Respiratory Organs

215

Table 6-7. Recognizable patterns associated with posterolateral diaphragmatic hernia Causation Gene/Locus

Syndrome

Significant Features

Trisomy 13

Holoprosencephaly, microcephaly, aplasia cutis congenita, microphthalmia, cleft lip/palate, malformed ears, heart defect polydactyly

Chromosomal

Trisomy 18

Growth retardation, microcephaly, cleft lip/plate, clenched hands or overlapping fingers, radial defect, short sternum, heart defect, vertebral defect, neural tube defect

Chromosomal

Wolf-Hirschhorn, del 4p16.3

Growth retardation, microcephaly, high forehead, prominent glabella, hypertelorism, ocular coloboma, cleft lip/palate, preauricular pits, heart defect, digital anomalies, mental retardation

Chromosomal

Pallister-Killian, Mosaic tetrasomy 12p

Coarse facies, frontotemporal sparse hair, tall forehead, hypertelorism, short anteverted nose, prominent philtrum, wide mouth, hypopigmented macules, mental retardation

Chromosomal

Trisomy 2227

Growth retardation, microcephaly, hypertelorism, epicanthal folds, ocular coloboma, cleft lip/palate, preauricular pits/tags, micrognathia, webbed neck, heart defect, distal phalangeal hypoplasia, anal atresia

Chromosomal

Other chromosomal: del 1q, 3q, 4p, 8p, 8q, 15q dup 1q, 2p, 4q, 22q28,29

Various defects depending on specific segmental aneuploidy

Chromosomal

Amniotic bands, limb-body wall complex30,31

Neural tube defect, facial cleft, limb defect, ventral wall defect, scoliosis, some with very short umbilical cord

Unknown

Cornelia de Lange

Growth retardation, microcephaly, brachycephaly, synophrys, long eyelashes, thin upper lip, downturned mouth, heart defect, asymmetric limb defect, hirsutism, mental retardation

Sporadic AD (122470) NIPBL, 5p13.1

Denys-Drash, Wilms tumor, pseudohermaphroditism32

Ambiguous genitalia, gonadal dysgenesis, renal disease, Wilms tumor, gonadoblastoma

Sporadic AD (194080) WT1, 11p13

Donnai-Barrow33

Hypertelorism, myopia, iris coloboma, deafness, agenesis of corpus callosum, omphalocele

AR (222448)

Fryns

Large for gestational age, coarse facies, malformed ears, wide mouth, cleft lip/palate, microretrognathia, agenesis of corpus callosum, heart defect, renal defect, digital and nail hypoplasia

AR (229850)

Goltz, focal dermal hypoplasia34,35

Focal areas of absent or hypoplastic skin with or without fat herniation, eye defects, dental defects, nail defects, heart defect, limb defects, laryngeal or esophageal papilloma

XLD (305600) Male lethal

Kabuki36

Growth retardation, microcephaly, long palpebral fissures with lateral lower lid eversion, trapezoidal philtrum, cleft palate, preauricular pit, heart defect, vertebral defect, renal defect, premature thelarche, hypotonia, mental retardation

Sporadic, AD

Lethal multiple pterygium37

Nuchal cystic hygroma, hydrops fetalis, hypertelorism, cleft palate, micrognathia, amyoplasia, pterygia, bony fusions, thin ribs, pulmonary hypoplasia

AR (253290) XL (312150)

Matthew Wood38

Microphthalmia, anophthalmia, pulmonary hypoplasia/agenesis

Uncertain (601186)

Meacham39

Male sex reversal, ambiguous genitalia, gonadal dysgenesis, double/septate vagina, lung defect, heart defect

Unknown

Microphthalmia with linear skin defects, MIDAS40

Asymmetric and linear erythematous skin, hypoplasia of head and neck, microphthalmia, corneal opacity, agenesis of corpus callosum, seizures, gonadal dysgenesis

XLD del Xp22.3

Pentalogy of Cantrell, thoracoabdominal

Midline supraumbilical ventral wall defect, omphalocele, sternal defect, ectopia cordis, heart defect

Unknown XLD (313850) Xq25-26.1

Simpson-Golabi-Behmel

Large for gestational age, tall stature, microcephaly, coarse facies, supernumerary nipples, postaxial polydactyly, hypotonia, mental retardation, embryonal tumor

(312870) GPC3, Xq26

abdominal cavities. Muscle cells originating from the lateral body wall form the crura and muscular portions of the diaphragm (Fig. 6-5). Bochdalek hernias result from defective development or failure of fusion of the pleuroperitoneal membranes, which occurs more commonly on the left side. Anterior herniation through the foramen of Morgagni, through which the epigastric vessels pass, is

rare. Herniation may also occur through the esophageal opening. Eventration of the diaphragm is abnormal elevation of the diaphragm due to deficient muscular development. Bochdalek hernias represent 90% of all congenital diaphragmatic hernias,4 with 85–90% being left-sided.7 Epidemiologic considerations of diaphragmatic hernia are shown in Table 6-6.

216

Cardiorespiratory Organs

Congenital diaphragmatic hernia may be an isolated defect or associated with multiple malformations. When congenital diaphragmatic hernia is diagnosed prenatally, associated abnormalities are detected in 26–72%.11–14 Associated defects include primarily cardiovascular, skeletal, genitourinary, and nervous systems. Associated anomalies are reported in 36–48% of liveborn infants.11,12 Cardiac defects are reported in 18–23% of infants with congenital diaphragmatic hernia.15,16 Identifiable syndromes, including chromosome anomalies, were diagnosed in 12–44% of cases with multiple malformations.11–13,16 Syndromes associated with Bochdalek type of congenital diaphragmatic hernia are shown in Table 6-7. Morgagni hernias account for 2–11% of all diaphragmatic hernias.17,18 One series of 15 cases showed a male excess of 4:1.18 Associated anomalies in that series included malrotation (27%) and congenital heart defects (27%). Several authors report an association with Down syndrome.17–19 Prognosis and Treatment

Congenital diaphragmatic hernia, especially when associated with multiple anomalies, is associated with dismal outcome.11–14 In isolated cases, mortality rates have improved over time due to advances in diagnosis, perinatal, neonatal, and surgical care, including extracorporeal membrane oxygenation.20 Survival rates for liveborn infants are reported as 56–86%.13,20–22 Survival rates are highest for infants with isolated and left-sided defects.22 Open fetal repair of fetal diaphragmatic hernia, once hoped to decrease complications such as pulmonary hypoplasia, is no longer utilized. However, fetoscopic tracheal occlusion to improve lung growth is being used, but randomized controlled trials have not yet been performed.23 Recently, ex utero intrapartum therapy (EXIT), maintaining uteroplacental blood flow and gas exchange during intrapartum fetal procedures, has been used to reduce tracheal occlusion and for prenatal treatment of congenital diaphragmatic hernia and other fetal airway malformations.24 Chronic pulmonary disease,25,26 gastroesophageal reflux, and developmental delay are common complications in surviving children.26 References (Congenital Diaphragmatic Hernia) 1. Benacerraf BR, Adzick NS: Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 19 cases. Am J Obstet Gynecol 156: 573, 1987. 2. Hubbard AM, Adzick NS, Crombleholme TM, et al.: Congenital chest lesions: diagnosis and characterization with prenatal MR imaging. Radiology 212:43, 1999. 3. Sydorak RM, Goldstein R, Hirose S, et al.: Congenital diaphragmatic hernia and hydrops: a lethal association? J Pediatr Surg 37:1678, 2002. 4. Clements BS: Congenital malformations of the lungs and airways. In: Pediatric Respiratory Medicine. Taussig LM, Landau LI, eds. Mosby, St. Louis, 1999, p 1106. 5. Ozturk H, Karnak I, Sakarya MT, et al.: Late presentation of Bochdalek hernia: clinical and radiological aspects. Pediatr Pulmonol 31:306, 2001. 6. Salzberg AM, Krummel TM: Congenital malformations of the lower respiratory tract. In: Kendig’s Disorders of the Respiratory Tract in Children. Chernick V, Kendig E, eds. WB Saunders Company, Philadelphia, 1990, p 227. 7. McNamara JJ, Eraklis AJ, Gross RE: Congenital posterolateral diaphragmatic hernia in the newborn. J Thorac Cardiovasc Surg 55:55, 1968. 8. International Clearinghouse for Birth Defects Monitoring Systems 2002 Annual Report. www.icbd.org.publications.htm.

9. Edmonds L, Layde P: Conjoined twins in the United States, 1970– 1977. Teratology 25:301, 1982. 10. Norio R, Kaarianen H, Rapola J, et al.: Familial congenital diaphragmatic defects: aspects of etiology, prenatal diagnosis and treatment. Am J Med Genet 17:471, 1984. 11. Bollmann R, Kalache K, Mau H, et al.: Associated malformations and chromosomal defects in congenital diaphragmatic hernia. Fetal Diagn Ther 10:52, 1995. 12. Enns GM, Cox VA, Goldstein RB, et al.: Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review. Am J Med Genet 79:215, 1998. 13. Dillon E, Renwick M, Wright C: Congenital diaphragmatic herniation: antenatal detection and outcome. Br J Radiol 73:360, 2000. 14. Witters I, Legius E, Moerman P, et al.: Associated malformations and chromosomal anomalies in 42 cases of prenatally diagnosed diaphragmatic hernia. Am J Med Genet 103:278, 2001. 15. Greenwood RD, Rosenthal A, Nadas AS: Cardiovascular abnormalities associated with congenital diaphragmatic hernia. Pediatrics 57:92, 1976. 16. Cunniff C, Jones KL, Jones MC: Patterns of malformations in children with congenital diaphragmatic defects. J Pediatr 116:258, 1990. 17. Parmar RC, Tullu MS, Bavdekar SB, et al.: Morgagni hernia with Down syndrome: a rare association-case report and review of literature. J Postgrad Med 47:188, 2001. 18. Al-Salem AH, Nawaz Am, Matta H, et al.: Herniation through the foramen of Morgagni: early diagnosis and treatment. Pediatr Surg Int 18:93, 2002. 19. Honore LH, Torfs CP, Curry CJ: Possible association between the hernia of Morgagni and trisomy 21. Am J Med Genet 47:255, 1993. 20. Weber TR, Kountzman B, Dillon PA, et al.: Improved survival in congenital diaphragmatic hernia with evolving therapeutic strategies. Arch Surg 133:498, 1998. 21. Beresford MW, Shaw NJ: Outcome of congenital diaphragmatic hernia. Pediatr Pulmonol 30:249, 2000. 22. Geary MP, Chitty LS, Morrison JJ, et al.: Perinatal outcome and prognostic factors in prenatally diagnosed congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 12:107, 1998. 23. Sydorak RM, Harrison MR: Congenital diaphragmatic hernia: advances in prenatal therapy. Clin Perinatol 30:465, 2003. 24. Hedrick HL: Ex utero intrapartum therapy. Semin Pediatr Surg 12:190, 2003. 25. Muratore CS, Kharasch V, Lund DP, et al.: Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg 36:133, 2001. 26. Lally KP: Congenital diaphragmatic hernia. Curr Opin Pediatr 14:486, 2002. 27. Kim EH, Cohen RS, Ramachandran P, et al.: Trisomy 22 with congenital diaphragmatic hernia and absence of corpus callosum in a liveborn premature infant. Am J Med Genet 44:427, 1992. 28. Howe DT, Kilby MD, Sirry H, et al.: Structural chromosome anomalies in congenital diaphragmatic hernia. Prenat Diagn 16:1003, 1996. 29. Lurie IW: Where to look for the genes related to diaphragmatic hernia? Genet Couns 14:75, 2003. 30. VanAllen MI, Curry C, Gallagher L: Limb-body wall complex: I. Pathogenesis. Am J Med Genet 28:529, 1987. 31. Russo R, D’Armiento M, Pasquale A, et al.: Limb body wall complex: A critical review and a nosological proposal. Am J Med Genet 47:893, 1993. 32. Devriendt K, Deloof E, Moerman P, et al.: Diaphragmatic hernia in Denys-Drash syndrome. Am J Med Genet 57:97, 1995. 33. Donnai D, Barrow M: Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder? Am J Med Genet 47:679, 1993. 34. Patel JS, Maher ER, Charles AK: Focal dermal hypoplasia (Goltz syndrome) presenting as a severe fetal malformation syndrome. Clin Dysmorphol 6:267, 1997.

The Lower Respiratory Organs 35. Han XY, Wu SS, Conway DH, et al.: Truncus arteriosus and other lethal internal anomalies in Goltz syndrome. Am J Med Genet 90:45, 2000. 36. Donadio A, Garavelli L, Banchini G, et al.: Kabuki syndrome and diaphragmatic defects: a frequent association in non-Asian patients? Am J Med Genet 91:164, 2000. 37. Entezami M, Runkel S, Kunze J, et al.: Prenatal diagnosis of a lethal multiple pterygium syndrome type II. Case report. Fetal Diagn Ther 13:35, 1998.

217

38. Seller MJ, Davis TB, Fear CN, et al.: Two sibs with anophthalmia and pulmonary hypoplasia (Matthew Wood syndrome). Am J Med Genet 62:227, 1996. 39. Killeen OG, Kelehan P, Reardon W: Double vagina with sex reversal, congenital diaphragmatic hernia, pulmonary and cardiac malformationsanother case of Meacham syndrome. Clin Dysmorphol 11:25, 2002. 40. Allanson J, Richter S: Linear skin defects and congenital microphthalmia: a new syndrome at Xp22.2. J Med Genet 28:143, 1991.

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Part III Craniofacial Structures

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7 Skull John M. Graham, Jr.

N

eural crest cells in the head region differentiate into mesenchymal cells that form the bones of the face (viscerocranium), while the cranial base and other portions of the cranium are formed by the mesodermally derived occipital somites and somitomeres. The portion of the skull surrounding the brain is termed the neurocranium. The neurocranium is divided into the membranous part, which forms the flat bones of the cranial vault, and the chondrocranium, which forms the cartilaginous bones of the base of the skull. The chondrocranium develops by fusion of a number of cartilaginous structures, which ossify by endochondral ossification to form the base of the skull. Posteriorly, the base of the occipital bone is formed from parachordal cartilage and three occipital sclerotomes. Anteriorly, the sphenoid and ethmoid bones are formed from the hypophyseal cartilages and trabeculae cranii. On either side of the medial plate, the ala orbicularis and ala temporalis form the sphenoid bones, and the periotic capsule forms the temporal bones. The membranous neurocranium (dura mater) ossifies to form the cranial vault through bone spicules, which progressively radiate from primary ossification centers near the center of each bony plate toward the periphery, where the sutures develop. The membranous cranial bones are separated by connective tissue seams, which are termed sutures. Membranous bones enlarge during fetal and postnatal life by the apposition of new layers to the outer surface of the skull (ectocranial bone deposition), while endocranial osteoclastic bone resorption occurs on the inner surface. Growth of cranial bones is directly related to brain growth, and fusion of cranial sutures is related to the cessation of brain growth. There are six fibrous areas where two or more cranial bones meet (fontanels). The five major sutures are the metopic, sagittal, coronal, squamosal, and lambdoid sutures; the six fontanels are the anterior (1), sphenoidal (2), posterolateral (2), and posterior (1) (Fig. 7-1). The presence of the sutures and fontanels allow the bones of the skull to overlap each other (termed molding) during the birth process. At birth, the cranium is disproportionately large compared with the facial skeleton, and it continues to grow rapidly until the 5th to 7th years (Fig. 7-2). Different sutures become ossified at different times, with the metopic suture being the first to ossify at 4 to 7 months, while the remaining sutures do not become completely ossified until adulthood. Sutural synostosis involves secretion of various isoforms of transforming growth factor beta. Fibroblast growth factor

Fig. 7-1. Schematic showing location of cranial sutures and fontanels.

receptors (FGFR-1 and FGFR-2) are expressed in the precartilaginous craniofacial structures, while FGFR-3 is expressed in the growth plates of long bones. In general, FGFR-1 promotes osteogenic differentiation, FGFR-2 increases proliferation, and FGFR-3 increases long bone growth, with increased expression also noted in the occipital region. TWIST is a DNA-binding protein that regulates cell proliferation, and MSX2 and ALX4 regulate parietal cell growth. Mutations in these genes can affect the morphogenesis of the skull. Reference Sadler TW: Langman’s Medical Embryology, ed 9. Williams and Wilkins, Baltimore, 2004, p 173.

7.1 Craniosynostosis Definition

The term craniostenosis (literally ‘‘cranial narrowing’’) is used to describe an abnormal head shape that results from premature fusion of one or more sutures, while craniosynostosis is the process of premature sutural fusion that results in craniostenosis. In clinical usage, the term craniosynostosis is used more widely, 221

222

Craniofacial Structures

physical therapy and repositioning, or cranial orthotic therapy if those measures are unsuccessful.1–4 Diagnosis

Fig. 7-2. Skulls from a newborn (left), 7-year-old child (center), and adult (right) showing the proportional relationships between the neurocranium and viscerocranium, with the chondrocranial relationships displayed in the bottom frames. (Courtesy of Dr. Bernard Sarnat, Cedars-Sinai Medical Center, Los Angeles, CA.)

perhaps in an effort to distinguish deformational nonsynostotic head shapes from those caused by underlying sutural synostosis; however, the two terms are often used interchangeably. Plagiocephaly is a nonspecific term used to describe an asymmetric head shape, which can result from either craniosynostosis or cranial deformation, and differentiation between these two causes is critical to determining the proper mode of treatment (that is, surgery versus physical techniques). Synostotic plagiocephaly is usually treated with a neurosurgical procedure involving partial calvariectomy, while deformational plagiocephaly responds to early

In an otherwise normal fetus, prenatal relaxation of normal growth-stretch tensile forces in the underlying dura across a suture during late fetal life can result in craniosynostosis.5–10 This may also occur when the lack of growth stretch is caused by a deficit in brain growth, as in severe primary microcephaly. Experimental prolongation of gestation, resulting in fetal crowding after installation of a cervical clip in pregnant mice, has been shown to result in craniosynostosis.10 The degree of craniosynostosis was greatest among those fetuses located proximally in the uterine horns, where the crowding was most severe. The most common cause of craniostenosis in otherwise normal infants is constraint of the fetal head in utero.5–10 When external fetal head constraint limits growth stretch parallel to a cranial suture, it may lead to craniosynostosis of an intervening suture between the constraining points. Sagittal craniosynostosis (the most common type of craniosynostosis) usually occurs in an otherwise normal child. The constrained suture tends to develop a bony ridge, especially at the point of maximal constraint between the biparietal eminences. Such ridging can easily be palpated or visualized on skull radiographs, and threedimensional cranial computed tomography (3-D CT) allows the ridge to be seen even more clearly (Fig. 7-3). Craniosynostosis is usually recognized shortly after birth from the shape of the head. Early closure of a fontanel, head asymmetry, and/or palpable ridging along a closed suture can be presenting features. With synostosis, cranial radiographs may reveal sclerosis of the suture with no apparent intervening sutural ligament, but it may be difficult to distinguish an overlapping suture from synostosis. On cross-sectional images, dense ridging over the suture may be evident, particularly with sagittal and metopic synostosis. If there is uncertainty as to whether sutures are truly synostotic, 3-D CT can provide a more accurate appraisal (Fig. 7-3). In general, craniosynostosis begins at one point and then spreads along a suture.10,11 At the fused suture, there is complete sutural obliteration, with nonlamellar bone extending completely across the sutural space, while further away from the initial site of fusion, the sutural margins are closely approximated with ossifying connective tissue. As the age when the suture is surgically removed increases, there is a tendency for more of the suture to become synostotic, with synostosis usually beginning at only one location in most cases.10 Synostosis prevents future expansion at that site, and the rapidly growing brain then distorts the calvaria into an aberrant shape, depending on which sutures have become synostotic. The earlier the synostosis takes place, the greater the effect on skull shape. Craniosynostosis may be caused by many different mechanisms, such as mutant genes, chromosome disorders, storage disorders, hyperthyroidism, or failure of normal brain growth (Tables 7-1, 7-2, 7-3, 7-4). The entire topic of craniosynostosis has been comprehensively reviewed by Cohen and MacLean.11 Different terms have been used to describe the different head shape alterations caused by craniosynostosis, with the resultant head shape dependent on the suture involved. A long, keel-shaped skull with prominent forehead and occiput is termed dolichocephaly or scaphocephaly. This head shape is usually associated with premature sagittal suture closure and a palpable ridge toward the posterior end of the suture (Fig. 7-3). Syndromes featuring sagittal synostosis are listed in Table 7-1. Sagittal synostosis must be distinguished from lateral deformation of the infant cranium due to persistently sleeping on the side of the head (more common

Skull

223

Fig. 7-3. A. Schematic drawing showing sagittal synostosis with dolichocephaly. B, C. Radiographs showing dolichocephaly secondary to partial synostosis in a 6-month-old male. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.) D, E. 3-D CT scan in 6-week-old male showing sagittal synostosis.

in hypotonic, prone-sleeping, and prematurely born infants). Individuals with scaphocephaly have a decreased cephalic index (CI) of less than 76% (CI = head width/head length  100%). With the current emphasis on positioning infants for sleep in the supine position to reduce the incidence of sudden infant death syndrome

(SIDS), the average CI in infancy has increased from 76–81% to 86–88% in cultures with supine-sleeping infants.3 Premature fusion of both coronal sutures produces a high, wide forehead with a short skull, resulting in brachycephaly (Fig. 7-4), while fusion of one coronal suture produces an asymmetric

Table 7-1. Syndromes with craniosynostosis Syndrome

Major Features

Suture

Causation Gene/Locus

Acrocraniofacial dysostosis

Acrocephaly, short stature, ear anomalies, deafness, ptosis, choanal atresia, cleft palate, cardiac defects, polydactyly

Coronal

AR (201050)

Antley-Bixler

Brachycephaly, kleeblattschadel, choanal atresia, flat midface, cardiac defect, ambiguous genitalia, joint synostosis, multiple fractures

Coronal, lambdoid

AR (207410) POR, 7q11.2

Apert

Brachycephaly, acrocephaly, delayed closure of fontanel, kleeblattschadel, prominent eyes, flat facial profile, cleft or narrow palate, syndactyly

Coronal

AD (101200) FGFR2, 10q26

Armendares11

Retinitis pigmentosa, short fifth fingers with clinodactyly, growth deficiency

Coronal, sagittal

Unknown

Auralcephalosyndactyly

Brachycephaly, ridged or wide cranial sutures, ear anomalies, deafness, cardiac defect

Coronal

AD (109050)

Baller-Gerold

Turribrachycephaly, absent thumbs, radial aplasia, growth deficiency

Multiple

AR (218600)

Baraitser

Mental retardation, seizures, choroidal colobomas, beaked nose, cleft lip/palate, cystic dysplastic kidneys

Coronal

AR (218650)

Beare-Stevenson cutis gyrata

Brachycephaly, acrocephaly, kleeblattschadel, ear anomalies, midface hypoplasia, hepatomegaly

Multiple

AD (123790) FGFR2, 10q26

Berant11

Dolichocephaly, acrocephaly, radioulnar synostosis

Sagittal

AD

Boston type

Fronto-orbital recession, turribrachycephaly

Multiple

AD (604757) MSX2, 5q34-q35

Calabro11

Unilateral ulnar aplasia, micrognathia, oligodactyly, cryptorchidism, pulmonic stenosis, micropenis

Coronal, metopic

Unknown

Carpenter

Brachycephaly, acrocephaly, kleeblattschadel, ear anomalies, cardiac and genital defects, polydactyly, mental retardation

Multiple

AR (201000)

Chitayat hypophosphatemia

Dolichocephaly, renal hypophosphatemia, minor facial dysmorphism, intracerebral calcifications, nonrachitic bone changes

Sagittal

AR (241519)

COH11

Kleeblattschadel, polymicrogyria, absent olfactory tracts and bulbs, thumb duplication, bifid scrotum, agenesis of cervical thymic lobes, bilobed lungs

Multiple

Sporadic

Cole-Carpenter

Osteogenesis imperfecta, hydrocephalus, ocular proptosis, frontal bossing

Multiple

AD (112240)

Cranioectodermal dysplasia

Dolichocephaly, short stature, sparse hair, dental anomalies, brachydactyly, hypoplastic fibula

Sagittal

AR (218330)

Craniofacial dyssynostosis

Craniofacial dysostosis, mental retardation, short stature

Lambdoid, posterior sagittal

AR (218350)

Cranio-fronto-nasal dysplasia

Brachycephaly, widow’s peak, ear anomalies, cardiac and genital defects, polydactyly, mental retardation

Coronal (females only)

AD (304110) EFNB1, Xq28

Craniomicromelic dysplasia

Macroturricephaly, short palpebral fissures, pinched nose, micrognathia, microstomia, short limbs, hypoplastic lungs, absent/hypoplastic gallbladder, short intestine, hypoplastic uterus

Coronal

AR (602558)

Craniorhiny

Oxycephaly, recessed forehead, lack of frontonasal angle, nasal changes, absent nasolacrimal ducts

Coronal

AD (123050)

Craniosynostosis with ectopia lentis

Ectopia lentis, hirsutism on back, hyperlaxity of elbows and knees, hypoplastic toe nails

Sagittal, metopic

Unknown (603595)

Craniotelencephalic dysplasia

Protuberance of frontal bone, retarded neurologic development

Multiple

AR (218670) (continued)

224

Table 7-1. Syndromes with craniosynostosis (continued) Syndrome

Major Features

Suture

Causation Gene/Locus

Crouzon

Brachycephaly, kleeblattschadel, ridged sutures, deafness, convex beaked nose, tooth anomalies, malocclusion

Multiple

AD (123500) FGFR2, 10q26

Crouzon with acanthosis nigricans (Crouzonodermoskeletal)

Crouzon syndrome, choanal atresia, hydrocephalus, acanthosis nigricans

Multiple

AD (134934) FGFR3, 4p16.3

Curry-Jones11

Plagiocephaly, unilateral microphthalmia, iris coloboma, syndactyly, preaxial polydactyly, skin lesions, abnormal gut development

Unilateral Coronal

Unknown AR

Elejalde: acrocephalopolydactylous dysplasia

Acrocephaly, high birth weight, obesity, omphalocele, visceral anomalies, thick skin

Multiple

AR (200995)

Fontaine-Farriaux11

Phalangeal hypoplasia with anonychia, patches of lipodystrophy, aplasia of abdominal muscles, genital hypoplasia, hypospadias, cryptorchidism

Multiple

Unknown

Frydman trigonocephaly

Trigonocephaly, S-curved lower lids, preauricular tags, hypotelorism, omphalocele

Metopic

AD (190440)

Fryns type11

Asymmetric long face, high narrow forehead, short upper lip, highly arched palate, sensorineural hearing loss

Coronal, metopic

Unknown

Gomez-Lopez-Hernandez

Ataxia, trigeminal anesthesia, corneal opacity, ear deformities, pons-vermis fusion, parietal alopecia, midface hypoplasia

Multiple

Unknown AR (601853)

Gorlin-Chaudhry-Moss

Brachycephaly, hirsutism, deafness, microphthalmia, high/narrow palate, short stature, mental retardation

Coronal

AR (233500)

Hersh11

Sensorineural deafness, micrognathia, sparse curly hair

Coronal

AR

Holoprosencephaly with craniosynostosis

Semilobar holoprosencephaly, small vertebral bodies, coxa valga

Multiple

Unknown AR (601370)

Hunter-McAlpine

Microcephaly, mental retardation, short stature, minor acral anomalies

Coronal, lambdoid

AD (601379) Subtelomere rearrangement (5q, 13p)

Hypomandibular faciocranial dysostosis

Prominent eyes, deficient midface and zygomatic arches, short nose with anteverted nares, minute oral aperture, severe mandibular hypoplasia

Coronal

AR (241310)

Ives-Houston

Perinatal death, intrauterine growth retardation, marked microcephaly, severe malformations of limbs

Multiple

AR (251230)

Jackson-Weiss

Midface hypoplasia, feet abnormalities

Multiple

AD (123150) FGFR2, 10q26

Jones: craniosynostosisDandy-Walker malformation

Dolichocephaly, plagiocephaly, Dandy-Walker cyst

Sagittal

AD (123155)

Lin-Gettig

Dolichocephaly, trigonocephaly, agenesis of corpus callosum, facial anomalies, camptodactyly, hypogonadism

Sagittal, metopic

AR or XLR (218649)

Lowry

Fibular aplasia

Coronal, sagittal

AR (218550)

Lowry-MacLean

Mental retardation, cleft palate, proptosis, beaked nose, eventration of diaphragm, microcephaly, growth failure, mental deficiency

Multiple

Unknown AD (600252)

Michels

Anterior chamber eye abnormalities, craniofacial anomalies, skeletal defects

Lambdoid, coronal

AR (257920)

Muenke

Midface hypoplasia, downslanting palpebral fissures, highly arched palate, coned epiphyses

Coronal

AD (602849) FGFR3, 4p16.3

Opitz C trigonocephaly

Trigonocephaly, craniofacial dysmorphism, central nervous system abnormalities, mental deficiency, redundant skin

Metopic

AR (211750)

(continued)

225

226

Craniofacial Structures

Table 7-1. Syndromes with craniosynostosis (continued) Syndrome

Major Features

Suture

Causation Gene/Locus

Osteoglophonic dysplasia

Acrocephaly, kleeblattschadel, hypertelorism, prominent eyes, rhizomelia, osteoporosis

Multiple

AD (166250)

Pfeiffer

Brachycephaly, kleeblattschadel, hypertelorism, cutaneous syndactyly, broad thumbs/hallux

Coronal; sagittal variable

AD (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Pfeiffer cardiocranial

Dolichocephaly, anomalous ears, cleft palate, cardiac defect, genital defect, joint contractures, mental retardation

Sagittal

AR (218450)

Philadelphia type

Dolichocephaly, cutaneous syndactyly

Sagittal

AD (601222)

Richieri-Costa overgrowth11

Dolichocephaly, mental retardation, overgrowth, distal arthrogryposis, sacral dimple, joint laxity

Sagittal

AR

Saethre-Chotzen

Brachycephaly, ear anomalies, prominent eyes with ptosis, asymmetric face, cleft/high palate

Coronal; lambdoid/ metopic variable

AD (101400) TWIST, 7p21

Sakati

Acrocephalopolysyndactyly, short limbs, congenital heart defect, ear anomalies, skin defects

Multiple

AD (101120)

San Francisco type11

Midface hypoplasia, ptosis of eyelids, bulbous nose, small ears

Multiple

AD

Say-Barber

Microcephaly, short stature, flexion contractures, chemotactic defect, increased infections, hypogonadism

Multiple

AR (251240)

Say-Meyer

Trigonocephaly, short stature, developmental delay

Metopic

XLR (314320)

Say-Poznanski11

Kleeblatschadel, polydactyly, abnormal metacarpals and metatarsals, angular ulnas, short and wide clavicles, unusually shaped ribs

Multiple

Unknown

SCARF

Skeletal abnormalities, cutis laxa, ambiguous genitalia, psychomotor retardation, facial abnormalities

Multiple

XLR (312830)

Seckel

Microcephaly, growth deficiency, beaked nose, micrognathia, mental deficiency

Multiple

AR (210600) ATR, 3q22-q24

Shprintzen-Goldberg

Dolichocephaly, hypertelorism, proptosis, maxillary hypoplasia, micrognathia, arachnodactyly

Sagittal

Sporadic (182212) FBN1, 15q21.1 (some cases)

Spondyloepiphyseal dysplasia with craniosynostosis

Spondyloepiphyseal dysplasia, cataracts, micrognathia, cleft palate, mental deficiency

Coronal

AR (602611)

Thanatophoric dysplasia

Kleeblattschadel, short stature, platybasia, macrocephaly, short limbs, narrow thorax

Multiple

AD (187600) FGFR3, 4p16.3

Tricho-dento-osseous type I

Dolichocephaly, kinky or curly hair, enamel hypoplasia, radiodense bones, normal calvarial thickness

Sagittal

AD (190320) DLX3, 17q21.3-q22

Ventruto

Symphalangism, carpal and tarsal fusion, brachydactyly, strabismus, hip osteochondritis

Coronal

AD (113100) GDF5, 20q11.2

head shape termed plagiocephaly (Fig. 7-5). When coronal craniosynostosis occurs, it is important to examine the patient carefully for associated anomalies that might suggest a recognizable syndrome. Evaluation of the limbs, ears, and cardiovascular system are quite helpful in diagnosing syndromes associated with coronal craniosynostosis (Table 7-1). Limb defects, such as syndactyly, brachydactyly, carpal coalition, or broad, deviated thumbs and/or halluces, can suggest an associated syndrome and indicate what types of molecular analysis to pursue. It is also important to examine both parents for similar anomalies, carpal coalition, and/or facial asymmetry, since these findings may represent variable expression of an altered gene in a parent.

Premature fusion of both the coronal and sagittal sutures generally leads to a tall, towerlike skull (turricephaly), with more severe synostosis of multiple sutures producing a tall, pointed skull (acrocephaly or oxycephaly). In this condition, the limitations of calvarial expansion are so extreme that there may be limited room for brain growth (Fig. 7-6). Synostosis of multiple cranial sutures is more likely to result in elevated intracranial pressure and to require shunting for hydrocephalus. In extreme cases, a cloverleaf head shape can result from multiple suture synostosis, usually with signs of increased intracranial pressure and a ‘‘beaten copper’’ radiographic appearance of the inner table of the skull (Fig. 7-6A). There may also be optic atrophy, proptosis, and

Skull

227

Table 7-2. Chromosomal anomalies associated with craniosynostosis

Table 7-3. Conditions with secondary craniosynostosis

del(1)(q24-q31)

Metabolic disorders

del(2)(q14-q21)

Hyperthyroidism

del(2)(q24.3-q32.1) dup(3)(pter-p21) del(3)(q27-qter) dup(3)(q21qter)

Rickets Hypophosphatemia Hypercalcemia, idiopathic Mucopolysaccharidoses and related disorders

del(4)(q21.1-q22.1)

Mucopolysaccharidosis I-H (Hurler)

dup(5)(pter-p11)

Mucopolysaccharidosis IV (Morquio)

dup(6)(pter-p21)

Mucopolysaccharidosis VI (Maroteaux-Lamy)

del(6)(q22.2-q23.1)

Beta glucuronidase deficiency

dup(6)(q25-qter) del(7)(pter-p15) del(8)(q21-q22)

Mucolipodosis III (psuedo-Hurler) Alpha-D-mannosidase deficiency Hematologic disorders

dup(8)(q22-qter)

Sickle cell

del(9)(pter-p22)

Thalassemia

del(11)(p12-p15.3)

Polycythemia vera

del(11)(q23-qter) del(12)(pter-p13.1)

Congenital hemolytic icterus Teratogens

del(13)(q32-qter)

Hydantoin

dup(13)(q14-qter)

Retinoids

dup(13)(q14.1-14.3)/tetrasomy(13) (q14.3-q22)

Valproate

Tetrasomy 14q

Methotrexate

dup(15)(q22-qter)

Fluconazole

Trisomy 16 mosaicism

Trimethadione

del(17)(p11.2) del(18p)/dup(20p)

Aminopterin

Cyclophosphamide Malformations

del(22)(q11)

Microcephaly

45,X

Holoprosencephaly

45,X/46,X,þ frag

Encephalocele

46, fragX(q27.3)Y

Iatrogenic disorders

47,XX,þcen frag/46,XX Partial trisomy X

Hydrocephalus with shunt Adapted from Cohen and MacLean11

Triploidy Induced chromosomal aberrations Y chromosome aberrations in vivo with mitotic instability in vitro Adapted from Cohen and MacLean11

loss of vision. Combinations of sutural synostosis, such as sagittal plus coronal, are also referred to as compound craniosynostosis, and multiple suture synostosis usually has a genetic basis (Table 7-1). A triangle-shaped skull (trigonocephaly) is caused by premature fusion of the metopic suture (Fig. 7-7). The similarity in epidemiologic features between sagittal and metopic craniosynostosis suggests that prenatal lateral constraint of the frontal part of the head may be a frequent cause of metopic craniosynostosis. Examples of constraint-induced metopic synostosis have included a monozygotic triplet whose forehead was wedged between the buttocks of her two co-triplets, and an infant whose head was compressed within one horn of his mother’s bicornuate uterus.8 Syndromic metopic synostosis can also occur, and trigonocephaly

is seen in a variety of syndromes (Table 7-4), some of which are associated with mental retardation or chromosome anomalies. Unilateral lambdoid synostosis results in trapezoidal plagiocephaly (Fig. 7-8), which differs from deformational posterior plagiocephaly due to supine positioning and torticollis (Fig. 7-9), and from synostotic anterior plagiocephaly due to unicoronal synostosis (Fig. 7-5). Unlike coronal synostosis, facial structures and orbits are usually less affected by lambdoid synostosis. Radiographic signs include trapezoidal cranial asymmetry, small posterior fossa, and sutural sclerosis with ridging; however, sole reliance on skull radiographs and clinical signs can lead to misdiagnosis, so it is best to confirm the diagnosis of suspected lambdoid synostosis with a 3-D CT scan, which clearly images the involved suture(s) and permits secure diagnosis (Fig. 7-8). Among 102 patients with deformational posterior plagiocephaly and 130 patients with craniosynostosis requiring surgery, only four patients (3.1%) manifested clinical, imaging, and operative features of true unilambdoidal craniosynostosis.15 These features included a thick bony ridge over the fused suture, with contralateral parietal and

228

Craniofacial Structures

Table 7-4. Syndromes with trigonocephaly Syndrome

Major Features

Causation Gene/Locus

Atelencephaly

Brain anomalies, cutis gyrata of scalp, hypertelorism, cleft palate, genital anomalies, seizures, mental retardation

Unknown

Blepharophimosis with facial and genital anomalies

Ptosis, midface hypoplasia, low-set ears, dental anomalies, sensorineural hearing loss, mental retardation

AR (604314)

Craniosynostosis, early and asymmetric closures of fontanels, cranial asymmetry

Del 7pter-p15

-9p monosomy

Synophrys, short broad neck, long philtrum, mental retardation

AD (158170) Del 9pter-p22

-11q monosomy (Jacobsen)

Intrauterine growth restriction, failure to thrive, ventricular septal defect, pyloric stenosis, micro-macrocephaly

Isolated (147791) Del 11q23-qter

C-trigonocephaly (Opitz)

Dysplastic and low-set ears, small nose with anteverted nares, cardiac defect, polydactyly, syndactyly

AR (211750)

Fronto-ocular

Proptosis, ptosis, elevated nasal bridge, developmental disabilities, congenital heart defects

AD, XLD (605321)

Frydman-trigonocephaly

Auricular tags, synophrys, hemivertebrae, omphalocele

AD (190440)

Goldblatt: hypospadius, mental retardation

Ear anomalies, synophrys, beaked nose, joint laxity, mental retardation

AR (241760)

Holoprosencephaly

Arhinencephaly-cebocephaly-cyclopia, primary defect in prechordal mesoderm

AR (236100) Multiple loci

Lin-Gettig

Agenesis of corpus callosum, dolichocephaly, facial anomalies, camptodactyly, hypogonadism

AR (218649)

Say-Meyer

Short stature, early closure of fontanels, highly arched palate, mental retardation

XLR (314320)

Trigonocephaly

Agenesis of olfactory bulbs

AR (275600)

Valproic acid embryopathy

Low nasal bridge, midface hypoplasia, long philtrum, meningomyelocele, cleft lip

Prenatal exposure

11

Chromosomal abnormalities -7p deletion

frontal bulging, and an ipsilateral occipitomastoid bulge, leading to tilting of the ipsilateral skull base and a downward/posterior displacement of the ear on the synostotic side. In contrast, infants with deformational, nonsynostotic posterior plagiocephaly had a parallelogram-shaped head, with forward displacement of the ear and frontal bossing on the side ipsilateral to the occipitoparietal flattening, accompanied by contralateral occipital bossing (Fig. 7-9).2 Of the 102 patients with deformational posterior head deformation, only three had severe, progressive deformation requiring surgery; the other cases of deformational plagiocephaly were successfully managed with changes in sleeping position or helmet therapy.15 When craniosynostosis occurs secondary to decreased brain growth associated with severe microcephaly, the head shape tends to be normal, but quite small. Brachycephaly, turricephaly, and acrocephaly associated with exophthalmos, shallow orbits; low-set ears; broad nasal bridge; a narrow, highly arched palate; and malocclusion may suggest a syndromic form of craniosynostosis, especially when there are associated distal limb anomalies (broad deviated halluces or thumbs, syndactyly of the third and fourth fingers, and/or clinodactyly). Syndromic craniosynostosis can be associated with mental retardation, hydrocephalus, and/or optic atrophy secondary to increased intracranial pressure. Craniosynostosis has also occurred with numerous chromosomal abnormalities, and may arise secondarily when there is reduced brain growth or metabolic/hematologic alterations of cranial bones (Tables 7-1 to 7-4). Plagiocephaly, which literally translates from the Greek term plagio kephale, or ‘‘oblique head,’’ is a term used to describe

asymmetry of the head shape when viewed from the top.1,2 It is a nonspecific term that has been used to describe head asymmetry caused by either premature sutural fusion or postnatal head deformation resulting from a positional preference; hence, modifying terms such as ‘‘nonsynostotic,’’ ‘‘deformational,’’ or ‘‘positional’’ have been used to distinguish plagiocephaly without synostosis. The term deformational plagiocephaly should suffice to distinguish this type of defect and its proper type of management. The side of the plagiocephaly is usually indicated by the bone that has been most flattened by the deforming forces (usually the occiput for infants who sleep on their backs). Late during fetal life, the head may become compressed unevenly in utero, but most plagiocephalic head deformation occurs postnatally due to a positional preference.2 Such inequality of positional gravitational forces results in asymmetric molding of the head and/or face. Torticollis is a condition in which the sternocleidomastoid muscle is shorter or tighter on one side of the neck, usually causing the head to tilt toward the affected muscle and the head to turn away. This is the most frequent cause of deformational plagiocephaly, which results in progressive occipital flattening when an infant with torticollis is placed in a supine sleeping position and preferentially turns his or her head to one side.2 Since the torticollis is usually on the side opposite the head turn, the forehead on the side of the torticollis may appear normal or recessed, while the forehead and ear ipsilateral to the flattened occiput appears to have become displaced anteriorly (Fig. 7-9).2 If the infant sleeps on his or her stomach with a preferential head turn, then the frontal region on the side of the torticollis becomes flattened as the infant turns his or her head away from the short or tight sternocleidomastoid

Skull

Fig. 7-4. A. Schematic showing bilateral premature coronal synostosis. B and C. Front and top views of bilateral coronal synostosis by 3-D CT in a 3-month-old female. Fig. 7-5. 3-D CT of unilateral nonsyndromal right-sided coronal synostosis in a 3-month-old female.

229

230

Craniofacial Structures

Fig. 7-6. A. Radiograph showing acrocephaly or oxycephaly in a 14-year-old female with Apert syndrome; note the complete absence of normal sutures and presence of a ‘‘beaten copper’’ radiographic appearance of the inner table of the skull. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.) B and C. 3-D CT of compound synostosis (left frontal and lateral views) involving both coronal sutures and the sagittal suture with associated hydrocephalus in a 6-week-old male, showing irregular cranial configuration with multiple areas of skull thinning (lu¨ckenscha¨del).

muscle. Deformational plagiocephaly is usually not associated with premature closure of a cranial suture; however, since craniosynostosis can also be caused by fetal head constraint when both deformational plagiocephaly and craniosynostosis occur together, the diagnosis can be difficult, requiring complex management (Fig. 7-10).

Late fetal compression may affect the sternocleidomastoid muscle, resulting in ischemic changes within the muscle, with or without consequent fibrosis and persistent torticollis. Such compression is most likely to occur in first-born babies and in large babies, and deformational plagiocephaly is also much more frequent among multiple gestation infants.1,2 In the

Skull

Fig. 7-7. Metopic synostosis. A. Photographs show trigonocephaly in a 1-year-old male secondary to metopic synostosis with associated microcephaly (occipitofrontal circumference less than third centile) but normal development. His brother, father, and paternal grandfather were similarly affected. (Reprinted with permission from Hennekam RCM and van den Boogaard MJ. Clin Genet 38:374, 1990.) B. Radiographs show trigonocephaly associated with metopic synostosis. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.) C. 3-D CT scans of metopic synostosis in an otherwise normal 2-month-old male.

231

232

Craniofacial Structures

Fig. 7-8. 3-D CT scan in a 2-month-old female with left lambdoid craniosynostosis. A. Rear view shows a thick bony ridge over the fused lambdoid suture on the left, with contralateral parietal and frontal bulging, and an ipsilateral occipitomastoid bulge, leading to tilting of the ipsilateral skull base and a downward/posterior displacement of the left ear on the synostotic side. B. Top view shows a trapezoidal skull shape.

infants with limited mobility due to hypotonia, hydrocephalus, macrocephaly, or limb anomalies are also more likely to develop deformational plagiocephaly, so this anomaly can complicate syndromes with these features. Predisposing factors resulting in excessive or asymmetric head deformation include restrictive intrauterine environments, poor muscle tone, torticollis, clavicular fracture, cervical-vertebral abnormalities, sleeping position, multiple gestation, and incomplete bone mineralization. It is essential to place infants on their backs for sleep, except in cases of prematurity, gastroesophageal reflux, or obstructive sleep apnea. Infants should be placed on their stomachs whenever they are awake and under direct adult supervision to develop their motor skills and encourage full range of neck motion.3 The development of excessive positional brachycephaly, with or without plagiocephaly, can be an early indication that parents are not providing their infants with adequate ‘‘tummy time.’’ It is important to distinguish deformational plagiocephaly from that which results from craniosynostosis, because therapy and management differ. Fig. 7-9. Right occipital deformational posterior plagiocephaly in a supine-sleeping 6-month-old female infant with left-sided congenital muscular torticollis. Note that all sutures remain open, with a parallelogram-shaped head when viewed from the top.

torticollis-plagiocephaly deformation sequence, the infant characteristically has a head tilt toward the side of shortened sternocleidomastoid muscle. By definition, this anomaly involves deformation or reshaping of normal structures, and thus the growth and development of the brain is usually normal. However,

Etiology and Distribution

The frequency of craniosynostosis is 3.4 per 10,000 births, and it is usually an isolated, sporadic anomaly in an otherwise normal child. About 8% of all craniosynostosis cases are familial. Familial types of craniosynostosis are most frequent in coronal synostosis, accounting for 14.4% of coronal synostosis, 6% of sagittal synostosis, and 5.6% of metopic synostosis,12–14 while lambdoidal synostosis is almost never familial. The frequency of associated twinning is increased, and most twin pairs are discordant, especially with sagittal and metopic

Skull

233

Fig. 7-10. This 3-D CT scan depicts an otherwise normal 9-year-old female, who has untreated left lambdoid craniosynostosis with persistent left torticollis resulting in striking craniofacial asymmetry and facial scoliosis.

synostosis. This would tend to support fetal crowding as a cause of these types of synostosis, while concordance for coronal synostosis is much higher for monozygotic twins than dizygotic twins, suggesting that many cases of coronal synostosis have a genetic basis.13 Sagittal synostosis is the most common type of craniosynostosis, accounting for 50–60% of cases and occurring in 1.9 per 10,000 births, with a 3.5:1 male to female ratio.12 Only 6% of cases are familial, with 72% of cases sporadic and no paternal or maternal age effects noted. Twinning occurred in 4.8% of 366 cases, with only one monozygotic twin pair being concordant, and intrauterine constraint is the cause for most cases.12 Coronal craniosynostosis is the second most frequent type of craniosynostosis (accounting for 20–30% of cases). Unilateral coronal craniosynostosis can be either genetic or due to fetal head constraint from an aberrant fetal lie, multiple gestation, or small uterine cavity.6,7 Approximately 71% of unilateral coronal craniosynostosis is right-sided, and 67% of vertex presentations are in the left occiput transverse position, possibly explaining the prevalence of right-sided, unilateral, coronal craniostenosis.6 Nonsyndromic coronal craniosynostosis occurs in 0.94 per 10,000 births, with 61% of cases sporadic, and 14.4% of 180 pedigrees familial. Bilateral cases occur much more frequently than unilateral cases, and coronal synostosis is more frequent in females (with a male to female ratio of 1:2). The paternal age is significantly older than average (32.7 years), and these data have been interpreted as being consistent with autosomal dominant inheritance with 60% penetrance, when the synostosis has a genetic basis.13 Metopic synostosis occurs in about 0.67 per 10,000 births, making it the third most frequent type of craniosynostosis (accounting for 10–20% of patients). Like sagittal synostosis, metopic synostosis is more frequent in males (3.3:1 male to female ratio) and seldom familial (5.6% of cases).14 There is no maternal or paternal age effect, and the frequency of associated twinning was 7.8% of 179 pedigrees studied, with only two twin monozygotic pairs concordant.14

Familial craniosynostosis is usually transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. A wide variety of chromosomal anomalies have also been associated with craniosynostosis (Table 7-2). This emphasizes the importance of chromosomal analysis for patients with syndromic craniosynostosis in whom a recognizable monogenic syndrome is not apparent, particularly when there is associated developmental delay and growth deficiency. As comparative genomic hybridization becomes more clinically available, this will be even more useful than standard cytogenetics for many such cases. In addition, craniosynostosis can occur as a component of numerous syndromes, many of which manifest phenotypic overlap and genetic heterogeneity (Table 7-1).11 Craniosynostosis syndromes with a demonstrated mutational basis include Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Jackson-Weiss syndrome, Boston craniosynostosis, Beare-Stevenson cutis gyrata syndrome, and Muenke syndrome. However, the efficiency of actually detecting a mutation for a given syndrome varies from about 60% for Crouzon syndrome to 98% for Apert syndrome.11 Secondary craniosynostosis (Table 7-3) can occur with certain primary metabolic disorders (hyperthyroidism, rickets), storage disorders (mucopolysaccharidosis), hematologic disorders (thalassemia, sickle cell anemia, polycythemia vera, congenital hemolytic icterus), brain malformations (holoprosencephaly, microcephaly, encephalocele, or overshunted hydrocephalus), and selected teratogenic exposures (diphenylhydantoin, retinoic acid, valproic acid, aminopterin, fluconazole, cyclophosphamide).11 Inability to demonstrate a mutation does not rule out a genetic basis for the craniosynostosis, and not every person with a pathogenic mutation manifests craniosynostosis. Bilateral coronal synostosis often lacks sutural ridging and usually has a genetic pathogenesis, suggesting that all such patients should be screened for mutations. Among 57 patients with bilateral coronal synostosis, mutations in fibroblast growth factor receptor (FRGR) genes were found for all 38 patients with a syndromic form of craniosynostosis. Among 19 patients with nonsyndromic bilateral craniosynostosis, mutations were found in or near exon 9 of FGFR2 in four

234

Craniofacial Structures

patients, as well as finding the common Pro250Arg mutation in exon 7 of FGFR3 in 10 patients (Muenke syndrome); only five patients (9%) lacked a detectable mutation in FGFR1, -2, or 3.16 This study suggests that mutation analysis should be considered in most patients with bilateral coronal synostosis. Prognosis, Prevention, and Treatment

Mild degrees of craniostenosis may not always require surgery; however, in moderately severe cases, early surgery is usually warranted. The usual indication for surgery is to restore normal craniofacial shape and growth. When both the coronal and sagittal sutures are synostotic, impairing brain growth early in infancy, surgery is indicated to help prevent neurologic and ophthalmologic complications associated with increased intracranial pressure and inadequate orbital volume. A variety of neurosurgical techniques have been developed for the treatment of craniosynostosis.11 Most of these techniques involve removing the aberrant portion of the bony calvaria from its underlying dura, including the area surrounding the synostotic suture(s). If this is done within the first few months after birth, a new bony calvaria will usually develop within the remaining dura mater under the same principles that guide normal prenatal calvarial morphogenesis. As long as there is continued growth stretch from the expanding brain, the sites over the dural reflections remain unossified, thereby maintaining the sutures in a fibrous, open state. Thus the calvaria and its sutures usually re-form normally after a partial calvarectomy for craniosynostosis. The new bony calvaria begins to develop within 2 to 3 weeks after surgery and is usually firm by 5 to 8 weeks after surgery. If the procedure is done after 3 to 4 months of age, the approach is similar with the exception that pieces of the calvaria are usually replaced in a mosaic pattern over the dura mater to act as nidi for the mineralization of new calvaria. Newer endoscopic repair techniques have been developed, followed by postoperative orthotic molding. Such procedures are most effective if done relatively early in infancy. These techniques are most effective in normal infants without a syndromic type of craniosynostosis. Following early surgery for isolated craniosynostosis (primary fronto-orbital advancement and/or calvarial vault remodeling at a mean age of 8 months), only 13% of 104 patients (10 bilateral coronal, 57 unilateral coronal, 29 metopic, and eight sagittal) required a second cranial vault operation for residual defects at a mean age of 23 months. Perioperative complications were minimal (5%), with 87.5% of patients considered to have satisfactory craniofacial form and low rates of hydrocephalus (3.8%), shunt placement (1%), and seizures (2.9%). Among such cases of isolated craniosynostosis, unilateral coronal synostosis was the most problematic type due to vertical orbital dystopia, nasal tip deviation, and altered craniofacial growth problems with residual craniofacial asymmetry.17 In a second study of 167 children with both nonsyndromal (isolated) and syndromal craniosynostosis (12 bilateral coronal, 18 unilateral coronal, 39 metopic, and 46 sagittal), repeat operations were necessary in only 7%. Repeat operations were more common in syndromic cases (27.3%) than in nonsyndromic craniosynostosis (5.6%).18 Even though intracranial pressure can be elevated in patients with nonsyndromic craniosynostosis, they may not have decreased cranial volumes either before or after surgical repair and as a group show slightly larger intracranial volumes when compared with normal controls. This could reflect the impact of fetal head constraint on fetuses with larger heads, or it might relate to the known association of macrocephaly with nonsyndromic coronal craniosynostosis due to the common Pro250Arg mutation in FGFR3

(which was not analyzed in these studies).19 Hydrocephalus occurs in 4 –10% of patients with craniosynostosis and is more frequent with syndromic and multiple sutural craniosynostosis. In nonsyndromic patients, the rate of cerebral ventricular dilation is the same as that observed in the general population, and it appears to be related to venous hypertension induced by jugular foramen stenosis. Such dilation usually stabilizes spontaneously and rarely requires shunting. Some cases of progressive hydrocephalus in syndromic craniosynostosis cases were related to multiple sutural involvement, thereby constricting cranial volume, constricting the skull base, crowding the posterior fossa, and causing jugular foraminal stenosis.20 These findings were most frequent among patients with Crouzon, Pfeiffer, and Apert syndromes, especially in association with cloverleaf skull abnormalities. A diffuse beaten copper pattern on skull radiographs, along with obliteration of anterior sulci or narrowing of basal cisterns in children under the age of 18 months, is predictive of increased intracranial pressure in over 95% of cases.21 References (Craniosynostosis) 1. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005. 2. Graham JM Jr, Gomez M, Halberg A, et al.: Management of deformational plagiocephaly: repositioning versus orthotic therapy. J Pediatr 146:258, 2005. 3. Graham JM Jr, Kreutzman J, Earl D, et al.: Deformational brachycephaly in supine-sleeping infants. J Pediatr 146:253, 2005. 4. Graham JM Jr: Craniofacial deformation. Ballieres Clin Pediatr 6:293, 1998. 5. Graham JM Jr, deSaxe M, Smith DW: Sagittal craniostenosis: fetal head constraint as one possible cause. J Pediatr 95:747, 1979. 6. Graham JM Jr, Badura R, Smith DW: Coronal craniostenosis: fetal head constraint as one possible cause. Pediatrics 65:995, 1980. 7. Higgenbottom MC, Jones KL, James HE: Intrauterine constraint and craniosynostosis. Neurosurgery 6:39, 1980. 8. Graham JM Jr, Smith DW: Metopic craniostenosis and fetal head constraint: two interesting experiments of nature. Pediatrics 65:1000, 1980. 9. Koskinen-Moffet LK, Moffet BC, Graham JM Jr: Cranial synostosis and intra-uterine compression: a developmental study of human sutures. In: Factors and Mechanisms Influencing Bone Growth. AD Dixon, BG Sarnat, eds. Alan R. Liss Inc., New York, 1982, p 365. 10. Koskinen-Moffett L, Moffet BC: Sutures and intrauterine deformation. In: Scientific Foundations and Surgical Treatment of Craniosynostosis. JA Pershing, MT Edgerton, JA Jane, eds. Williams and Wilkins, Baltimore, 1989, p 96. 11. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 12. Lajeunie E, Le Merrer M, Bonati-Pellie C, et al.: Genetic study of scaphocephaly. Am J Med Genet 62:282, 1996. 13. Lajeunie E, Le Merrer M, Bonati-Pellie C, et al.: Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 55:500, 1995. 14. Lajeunie E, Arnaud E, Le Merrer M, et al.: Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. Am J Med Genet 55:500, 1998. 15. Huang MHS, Gruss JS, Clarren SK, et al.: The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding. Plast Reconstr Surg 98:765, 1996. 16. Mulliken JB, Steinberger D, Kunze S, et al.: Molecular diagnosis of bilateral coronal synostosis. Plast Reconstr Surg 104:1603, 1999. 17. McCarthy JG, Glasberg SB, Cutting CB, et al.: Twenty-year experience with early surgery for craniosynostosis: I. Isolated craniofacial synostosis— results and unsolved problems. Plast Reconstr Surg 96:273, 1995. 18. Williams JK, Cohen SR, Burstein FD, et al.: A longitudinal, statistical study of reoperation rates in craniosynostosis. Plast Reconstr Surg 100:305, 1997. 19. Polley JW, Charbel FT, Kim D, et al.: Nonsyndromal craniosynostosis: longitudinal outcome following cranio-orbital reconstruction in infancy. Plast Reconstr Surg 102:619, 1998.

Skull 20. Cinalli G, Sainte-Rose C, Kollar EM, et al.: Hydrocephalus and craniosynostosis. J Neurosurg 88:209, 1998. 21. Tuite GF, Evanston J, Chong WK, et al.: The beaten copper cranium: a correlation between intracranial pressure, cranial radiographs, and computed tomographic scans in children with craniosynostosis. Neurosurgery 39:691, 1996.

7.2 Kleeblattscha¨del Kleeblattsch€ adel is a term used to describe a cloverleaf skull configuration consisting of protrusion of each of the cranial bones, with broadening of the temporal region and face. These cranial protrusions are separated into focal bulges by furrows along the suture lines (Fig. 7-11). The eyes often protrude, leading to corneal ulceration, scarring, and subsequent blindness if the corneal surface remains unprotected.1 Occipital encephaloceles can occur, and associated hydrocephalus is common. The palate is usually highly arched, but clefting is rare. The presence of kleeblattscha¨del indicates that multiple sutural fusions occurred during early prenatal life. Often the sagittal, coronal, and lambdoid sutures are involved, although other combinations are also possible, including coronal, lambdoid, and metopic closure, or sagittal and squamosal closure. In addition, increased thickening of the base of the occipital bone prevents lengthening of the skull, thus yielding the typical shape.2 One child has also been described who had a cloverleaf skull without craniosynostosis (in which the primary defect was thought

235

to be a cranial bone dysplasia that allowed for eventration of the brain and resultant cloverleaf configuration).3 Multiple sutural synostosis is much more likely to result from genetic mutations in fibroblast growth factor receptor genes, TWIST, or MSX2, all of which result in syndromes that can present with cloverleaf skull or kleeblattscha¨del (Table 7-5).4 This skull anomaly can result from synostosis involving the coronal, lambdoid, and metopic sutures with bulging of the cerebrum through the open sagittal suture or through open squamosal sutures. There can also be synostosis of the sagittal and squamosal sutures with eventration through a widely patent anterior fontanel. The most common syndrome associated with cloverleaf skull is thanatophoric dysplasia type 2, which is due to mutations in FGFR3. Type 2 Pfeiffer syndrome due to mutations in FGFR2 can result in cloverleaf skull, as can Crouzon syndrome and Apert syndrome, which are also due to mutations in FGFR2. Other syndromes, such as FGFR3-associated coronal synostosis, rarely result in cloverleaf skull, but some rare syndromes like Boston craniosynostosis and Crouzon syndrome with acanthosis nigricans can sometimes manifest cloverleaf skull. In Boston craniosynostosis, the mutant MSX2 product has enhanced affinity for binding to its DNA target sequence, resulting in activated osteoblastic activity and aggressive cranial ossification.5–7 In Crouzon syndrome with acanthosis nigricans, a specific FGFR3 mutation (Ala391Glu) leads to early onset of acanthosis nigricans during childhood, often with associated choanal atresia and hydrocephalus.8 The association of choanal atresia with hydrocephalus in an individual with Crouzon facial features should suggest molecular analysis for this mutation, and

Fig. 7-11. A. Radiographic view of kleeblattscha¨del or cloverleaf skull configuration in a newborn infant. B. This child with cloverleaf skull configuration due to Crouzon syndrome with acanthosis nigricans caused by an Ala391Glu mutation in FGFR3 had associated hydrocephalus and choanal atresia and underwent early posterior skull release at 9 weeks with subsequent craniofacial reconstruction at 2 years, along with early shunting for hydrocephalus and postoperative orthotic therapy. At age 5 years his facial features and cognitive skills were relatively normal.

236

Craniofacial Structures

Table 7-5. Syndromes with cloverleaf skull (kleeblattschadel) Syndrome

Major Features

Amniotic bands

Unusual facial clefts, cephalocele, congenital amputation

Unknown (217100)

Antley-Bixler

Brachycephaly, choanal atresia, flat midface, cardiac defect, ambiguous genitalia, joint synostosis

AD (207410) POR, 7q11.2

Apert

Brachycephaly, acrocephaly, delayed closure of fontanels, prominent eyes, flat midface, cleft or high palate, syndactyly

AD (1901200) FGFR2, 10q26

Campomelia: Cumming type

Cervical lymphocele, multicystic dysplastic kidneys, polysplenia, lung hypoplasia

AR (211890)

Campomelic dysplasia

Flat facial profile, tracheal/laryngeal anomalies, bowed long legs, deficient adipose tissue

AD (114290) SOX9, 17q24.3-q25.1

Carpenter

Brachycephaly, acrocephaly, ear anomalies, cardiac and genital defects, polydactyly

AD (201000)

Crouzon

Brachycephaly, ridged sutures, deafness, convex/beaked nose, tooth anomalies, malocclusion

AD (123500) FGFR2, 10q26

Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal)

Crouzon syndrome, multiple synostosis, choanal atresia, hydrocephalus, acanthosis nigricans

AD (134934) FGFR3, 4p16.3

Cutis gyrata-acanthosis nigricans (Beare-Stevenson)

Brachycephaly, acrocephaly, ear anomalies, midface hypoplasia, hepatomegaly

AD (123790) FGFR2, 10q26

Kleetblattschadel

Craniosynostosis, hydrocephalus, exophthalmos, corneal ulcerations

AR (148800) Heterogeneous

Micromelic bone dysplasia with cloverleaf skull

Micromelia less severe than thanatophoric dysplasia, similar radiologic picture

AD or AR (156830)

Multiple congenital anomalies with cloverleaf skull

Short limbs and hands, frontal bossing, cataract, narrow chest, ambiguous genitalia, agenesis of corpus callosum, ventricular septal defect

AR (607161)

Osteoglophonic dysplasia

Acrocephaly, hypertelorism, prominent eyes, rhizomelia, osteoporosis

AD (166250)

Pfeiffer

Brachycephaly, hypertelorism, skin syndactyly, broad thumbs/hallux

AR (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Say-Poznanski

Polydactyly of hands and feet, short clavicles, winged scapulas, unusually shaped ribs

Unknown (217100)

Thanatophoric dysplasia

Short stature, platybasia, macrocephaly, wide sutures, short limbs, narrow thorax

AD (187600) FGFR3, 4p16.3

Thanatophoric-cloverleaf skull

Short stature, platybasia, craniosynostosis, narrow thorax, short limbs

AD (187601) FGFR3, 4p16.3

Craniosynostosis (Boston type)

Forehead retrusion, frontal bossing, turribrachycephaly, visual problems

Unknown (604757, 216340) MSX2, 5q34-q35

the combination of hydrocephalus with craniosynostosis may predispose toward a cloverleaf skull.8 Eighty-five percent of children with kleeblattscha¨del will have other anomalies, and the pattern is often consistent with a syndrome diagnosis (Table 7-5). No ethnic or sex predilection has been noted. The prognosis is usually syndrome-dependent and can be quite poor, with early death due to respiratory difficulties or progressive brain damage from hydrocephalus, which is common.9 However, subtotal craniectomy within the first 3 weeks of life in individuals with mild kleeblattscha¨del may result in normal or near-normal development.9–11 Early extensive calvarectomy is merited to preserve brain function and development as well as to allow reformation of the craniofacial skeletal features. Many craniofacial surgeons prefer to begin with a posterior skull release in the early months of life (mean age 4 months), followed by fronto-orbital advancement around the end of the 1st year (mean age 14 months), with insertion of a ventriculoperitoneal shunt at the time of the first procedure if there is associated hydrocephalus.12 The use of postoperative orthotic molding can help to channel brain growth into a more normal form,

Causation Gene/Locus

leading to improved postoperative results over those obtained via surgery alone.8 When lambdoid synostosis occurs as part of a syndrome with multiple suture involvement, there is often bilateral involvement, and early posterior release may alleviate some associated increased intracranial pressure. Patients with kleeblattscha¨del need to be followed carefully for hydrocephalus, which may be part of the syndrome rather than due to the multiple suture synostosis. Restricted growth of the posterior fossa is particularly common in severe craniofacial dysostosis syndromes. The purpose of surgery should be to decompress the brain, expand the bony orbits to accommodate the globes, and open airway passages.11 Prenatal diagnosis may be possible by ultrasonography.1

References (Kleeblattscha¨del) 1. Stevenson RE, Saul RA: The significance of the kleeblattscha¨del malformation. Proc Greenwood Genet Center 5:76, 1986. 2. Dambrain R, Freund M, Verellen G, et al.: Considerations about the cloverleaf skull. J Craniofac Genet Dev Biol 7:387, 1987.

Skull 3. Witt DR: Rare kleeblattscha¨del anomaly without craniosynostosis. Proc Greenwood Genet Center 7:161, 1988. 4. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 5. Warman ML, Mulliken JB, Hayward PG, et al.: Newly recognized autosomal dominant disorder with craniosynostosis. Am J Med Genet 46:444, 1993. 6. Jabs EW, Muller U, Li X, et al.: A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75:443, 1993. 7. Ma L, Golden S, Maxson R: The molecular basis of Boston-type craniosynostosis: the pro148-to-his mutation in the N-terminal arm of the MSX2 homeodomain stabilized DNA binding without altering nucleotide sequence preferences. Hum Mol Genet 5:1915, 1996. 8. Schweitzer DN, Graham JM Jr, Lachman RS, et al.: Jabs Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3. Am J Med Genet 98:75, 2001. 9. Frank LM, Mason MA, Magee WP Jr, et al.: The kleeblattscha¨del deformity: neurologic outcome with early treatment. Pediatr Neurol 1:379, 1985. 10. Turner PT, Reynolds AF: Generous craniectomy for kleeblattscha¨del anomaly. Neurosurgery 6:555, 1980. 11. Kroczek RA, Muhlbauer W, Zimmermann I: Cloverleaf skull associated with Pfeiffer syndrome: pathology and management. Eur J Pediatr 145:442, 1986.

237 12. Sgouros S, Goldin JH, Hockley AD, et al.: Posterior skull surgery in craniosynostosis. Child Nerv Syst 12:727, 1996.

7.3 Wide Cranial Sutures Cranial sutures are considered to be widened when they are separated by more than two standard deviations above the mean suture width for age. Diagnosis is confirmed radiographically, although it may also be appreciated on palpation of the skull. Criteria for determining suture width in infants up to 45 days old have been published by Erasmie and Ringertz.1 Wide cranial sutures themselves cause no impairment, but they may be an indication of increased intracranial pressure or caused by craniosynostosis in another part of the skull. Wide cranial sutures are a feature of numerous syndromes (Table 7-6). There are several possible causes of wide cranial sutures, including increased intracranial pressure, delayed maturation of bone, or resorption of bone. The younger the child, the earlier sutural diastasis will appear after acutely increased intracranial pressure. The prognosis depends on the underlying cause.

Table 7-6. Syndromes with wide cranial sutures Syndrome

Major Features

Causation Gene/Locus

Acromelic frontonasal dysostosis

Frontonasal dysplasia, central nervous system malformations, limb defects

AR (603671)

Cleidocranial dysostosis

Brachycephaly, wormian bones, delayed fontanel closure, joint contractures, acro-osteolysis

AD (119600) CBFA1, 6p21

Craniolenticulosutural dysplasia

Large fontanels, frontal bossing, hyperpigmentation, forehead hemangioma, hypertelorism, broad prominent nose

AR (607812) 14q13-q21

Cree mental retardation

Brachycephaly, triangular facies, hypertelorism, ocular colobomas, bifid scrotum, psychomotor retardation, webbed neck and fingers

AR (606851)

Cutis laxa, recessive, type II

Delayed fontanel closure, low birth weight, hydrocephalus, kyphoscoliosis, joint laxity, mental retardation

AR (219200)

Fibrochondrogenesis

Brachycephaly, wide sutures, ear anomalies, flat and round face, rhizomelia

AR (228520)

Hajdu-Cheney

Platybasia, wormian bones, delayed fontanel closure, short stature, oligodontia, vertebral anomalies

AD (102500)

Hypothyroidism

Slow growth, coarse facies, umbilical hernia, delayed development

Variable

Mandibuloacral dysplasia

Wormian bones, large fontanel, beaked nose, micrognathia, dental anomalies, skin atrophy

AR (248370) LMNA, 1q21.2

Oto-palato-digital II

Sclerosis, wormian bones, hypertelorism, micrognathia, skeletal anomalies, syndactyly, polydactyly

XLR (304120) FLNA, Xq28

Prader: psuedodeficiency rickets

Delayed fontanel closure, short stature, enamel anomalies, aminoaciduria, hypotonia, seizures, multiple fractures

AR (264700) CYP27B1, 12q14

Pycnodysostosis

Delayed fontanel closure, wormian bones, beaked nose, micrognathia, hepatosplenomegaly, multiple fractures

AR (265800) Cathepsin K, 1q21

Restrictive dermopathy

Thick, cracked, or peeling skin; ectropion of eyelids; joint contractures; open mouth

AR (275210)

Rickets

Short stature, widened metaphyses

Variable

Schinzel-Gideon: hypertrichosis-midface retraction

Sclerosis of skull, wormian bones, midface retraction, hypertrichosis, hydronephrosis, mental retardation

AR (269150)

Wiedemann-Rautenstrauch

Delayed fontanel closure, neonatal teeth, large penis, deficient adipose, short stature

AR (264090)

Yunis-Varon

Delayed fontanel closure, dysplastic ears, sparse hair, facial anomalies, absent or hypoplastic clavicles and thumbs

AR (216340)

Zellweger

High forehead, ocular anomalies, hepatosplenomegaly, hypotonia, seizures; peroxisomal disorder that displays genetic heterogeneity

AR (214100) PEX 1, 2, 3, 5, 6, 12 Multiple loci

238

Craniofacial Structures

Reference (Wide Cranial Sutures) 1. Erasmie V, Ringertz H: Normal width of cranial sutures in neonates and infants. Acta Radiol 17:572, 1976.

7.4 Anomalies of Fontanels Definitions Size

A fontanel whose size is either 2 standard deviations (SD) below or 2 SD above the mean for age is termed small or large, respectively. Time of Closure

Closure of the anterior fontanel before 6 months is considered early, whereas closure after 18 months is late. The other fontanels are normally closed at birth. Extra Fontanels

Extra fontanels are inconsistently occurring bony defects situated along the suture lines or at the junction of major bone plates of the skull. One such extra fontanel occurs along the sagittal suture about 2 cm anterior to the posterior fontanel. This fontanel is called the obeliac, interparietal, or sagittal fontanel, as well as the fontanel of Gerdy. Being midline, it is distinct from the parietal foramina, but parietal foramina may evolve in the lateral extremes of a large sagittal fontanel. Glabellar, metopic, or cerebellar fontanels also exist (Fig. 7-12).1 Diagnosis

The anterior fontanel is the largest of the fontanels and is diamondshaped (Figs. 7-1, 7-12). It normally closes by 18 months. The posterior fontanel is triangular in shape and is usually closed at birth. Fontanel size may be measured in several different ways (Fig. 7-13). Measurement of the anterior fontanel may be expressed as width (measurement along the coronal suture), length (measurement along the sagittal suture), area (width  length), or diagonal diameter. Standard curves are available for measurements taken by each method.2 The posterior fontanel is usually measured only in length

Fig. 7-12. Schematic showing glabella, metopic, sagittal, and cerebellar fontanels (stippled) in relation to constant fontanels (solid). See also the newborn skull pictured in Fig. 7-2.

(measurement along the sagittal suture) but may also be measured along the lambdoid suture (width) and the area calculated (length  width). Depending on the cause, a small or absent anterior fontanel may be noted at birth by palpation and confirmed by measurement and comparison with normal values for length and width.2 A small or absent anterior fontanel usually indicates some type of underlying pathology, with the most common etiologies including any cause of congenital microcephaly, craniosynostosis (particularly involving the metopic suture), or accelerated bone maturation such as occurs in hyperthyroidism.3 Large fontanels may be noted at birth by palpation and confirmed by measurement (Fig. 7-13). Causes of both large fontanels and delayed closure include increased intracranial pressure or delayed ossification of the cranium.3 Several syndromes in which a large or late-closing fontanel is part of the phenotype are listed in Table 7-7. Cleidocranial dysplasia is a common genetic syndrome that results in delayed closure of the anterior fontanel (Fig. 7-14).

Fig. 7-13. Left: mean anterior fontanel measurement (length plus width divided by two) during the 1st year. The posterior fontanel was fingertip size or smaller in 95% of neonates, based on 201 full-term Caucasian infants from Seattle, WA, and adapted from Popovitch and Smith.3 Right: percentiles for anterior fontanel size from term to age 24 months for both sexes by measurement of oblique diameter, based on data from Duc and Largo.7

Table 7-7. Syndromes with delayed closure or large fontanel Syndrome

Major Features

Causation Gene/Locus

Aase

Short stature, cleft lip/palate, cardiac defects, triphalangeal thumb, anemia, hepatosplenomegaly

AR (205600)

Acrocallosal

Macrocephaly, malformed ears, mental/growth retardation, hypertelorism, cleft lip/palate, cardiac septal defects

AR (200990) 12p13.3-p11.2

Acrogeria

Wormian bones, short stature, alopecia, premature aging, deficient adipose, prominent vessels, distal limb skin atrophy

AR (201200)

Al-Gazali: Hirschsprung-hypoplastic nails

Facial anomalies, hydronephrosis, anal atresia, cutis laxa, mental retardation

AR (601356)

Antley-Bixler

Brachycephaly, choanal atresia, flat midface, cardiac defect, ambiguous genitalia, joint synostosis

AD (207410) POR, 7q11.2

Apert

Acrocephaly, brachycephaly, cloverleaf skull, prominent eyes, flat facial profile, cleft or narrow palate, syndactyly

AD (101200) FGFR2, 10q26

Beckwith-Wiedeman

Macroglossia, omphalocele, macrosomia, ear creases

AD (130650) UPD 11p15.5

‘‘Baby Rattle’’ pelvis dysplasia

Bifid distal ends of long bones, absent vertebral body ossification, midface hypoplasia, protuberant abdomen

Unknown (605838)

Bartsocas-Papas (popliteal pterygium, lethal)

Digital hypoplasia, facial cleft, absent eyebrows/eyelashes, absent nails

AR (263650)

Chondrodysplasia punctata

Short stature, flat facial profile, limb asymmetry, sparse hair

XLD (302960) EBP, Xp11.23-p11.22

Chromosomal anomalies

Prominent feature in numerous chromosomal aberrations del(1p), del(11p), del(16q), dup(1q), dup(7p), dup(7q), dup(9p), dup(10p)

Chromosomal

Cleidocranial dysostosis

Brachycephaly, wormian bones, wide sutures, flat midface, hypoplastic clavicles, short ribs

AD (119600) CBFA1, 6p21

Coffin-Lowry

Short stature, prominent ears, coarse facial features, kyphosis/scoliosis, large hands, joint laxity

XL (303600) RSK2, Xp22.2-p22.1

Crane-Heise

Cleft lip/palate, agenesis of clavicles and cervical vertebrae, talipes equinovarus

AR (218090)

Craniometadiaphyseal dysplasia

Sclerosis of skull, deafness, prominent eyes, facial weakness, osteosclerosis

AD (123000) ANKH, 5p15.2-p14.1

Cutis laxa, type II, autosomal recessive

Wide cranial sutures, low birth weight, hydrocephalus, kyphoscoliosis, joint laxity, mental retardation

AR (219200)

De Barsy

Cutis laxa, corneal clouding, mental retardation, dwarfism

AR (219150)

Dysosteosclerosis

Short stature, fractures, cranial nerve compression, cranial hyperostosis

AR (224300)

Ehlers Danlos type VII

Short stature, blue sclerae, pneumothorax, hernias, joint laxity, delayed motor milestones

AR (225410) ADAMTS2, 5q23

ACE inhibitors

Oligohydramnios, pulmonary hypoplasia, renal tubular dysgenesis

Prenatal exposure

Aminopterin/methotrexate

Microcephaly, cranial dysplasia, cleft palate, mesomelia, hypodactyly

Prenatal exposure

Fluconozole

Brachycephaly, depressed nasal bridge, midfacial hypoplasia, proptosis, craniosynostosis

Prenatal exposure

Hydantoin

Metopic ridging, hypertelorism, short nose, cleft lip/palate, hypoplasia of distal phalanges, short neck, widely spaced nipples

Prenatal exposure

Primidone

Microcephaly, hirsutism, cardiac defects, metopic ridging, anteverted nares, micrognathia

Prenatal exposure

Rubella

Microcephaly, deafness, cataracts, glaucoma, congenital heart defects, hepatosplenomegaly

Prenatal exposure

Exposures

Fibrochondrogenesis

Brachycephaly, wide cranial sutures, ear anomalies, rhizomelia

AR (228520)

GAPO

Growth retardation, alopecia, pseudoanodontia, optic atrophy, macrocephaly, cerebral atrophy, facial anomalies, hepatomegaly, mental retardation

AR (230740)

Glutaric aciduria II

Undermineralization of skull, dolichocephaly, brain abnormalities, organic aciduria

XLR (231680) Multiple loci: ETFA, 19q13.3 ETFB, 15q23-q25 ETFDH, 4q32-qter (continued)

239

Table 7-7. Syndromes with delayed closure or large fontanel (continued) Syndrome

Major Features

Causation Gene/Locus

Hallerman-Streiff (progerioid syndrome)

Sparse hair, corneal clouding, thin nose, dental anomalies

AR (234100)

Hypophosphatasia

Undermineralization of skull, dental anomalies, bowed long bones, fractures

AR (241510) ALPL, 1p36.1-p34

Hypothyroidism

Coarse facies, slow growth, umbilical hernia, slow development

Variable

Infantile multisystem inflammatory disease

Chronic meningitis, migratory skin rash, joint inflammation, progressive visual defect, perceptive deafness

Unknown (607115)

Kenny-Caffey

Thick calvaria, wide cranial sutures, macular abnormalities, sparse eyebrows/lashes, hypercalcemia or hypocalcemia

AD (127000) TBCE, 1q42-q43

Lenz-Majewski

Thick or thin calvaria, sclerosis of skull, choanal atresia, joint laxity and/or contractures, cutis laxa

AD (151050)

Melnick-Needles

Sclerosis of skull, proptosis, full cheeks, cleft or high palate, vertebral anomalies, skeletal defects

XLD (309350) FLNA, Xq28

Mevalonic aciduria

Dolichocephaly, microcephaly, ear anomalies, cataract, hepatosplenomegaly, hypotonia, mental retardation

AR (251170) MVK, 12q24

Opsismodysplasia

Small nose; rib, vertebral, and skeletal defects; rhizomelia; hypotonia

AR (258480)

Opitz BBBG

Hypertelorism, esophageal abnormalities, hypospadias, mental retardation

AD (145410) 22q11.2 XL (300000) MID1, Xp22

Osteogenesis imperfecta

Blue sclerae, numerous fractures, deafness

AD (166200, 259400) Multiple loci: COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Osteosclerotic chrondrodysplasia, lethal

Midface hypoplasia; micrognathia; increased density of base of skull, clavicles, vertebrae, ribs

Unknown (603393)

Oto-palato-digital

Hypertelorism, cleft palate, abnormal ears, deafness, broad thumbs, curved toes

XLD (311300) FLNA, Xq28

Parietal foramina (cranium bifidum)

Seizures, cleft lip/palate, spina bifida occulta, defects in parietal bone and medial frontal bone

AD (168500) MSX2, 11p11.2 ALX4, 5q34-q35

Progeria

Low birth weight, premature aging, short stature, alopecia

AD (176670) LMNA, 1q21.2

Pycnodysostosis

Wormian bones, wide cranial sutures, beaked nose, micrognathia, hepatosplenomegaly

AR (265800) Cathepsin K, 1q21

Ritscher-Schinzel (3C syndrome)

Macrocephaly, undermineralization of skull, parietal foramen, hydrocephalus, facial anomalies, hypotonia, mental retardation

AR (220210)

Robinow

Macrocephaly, hypertelorism, small nose, hemivertebrae, genital defect, short limbs

AR (268310) ROR2, 9q22

Rubinstein-Taybi

Microcephaly, downward-slanting palpebral fissures, ptosis, beaked nose, broad thumbs and great toes

AD (180849) CREBBP, 16p13.3

Russell-Silver

Short stature, triangular face, asymmetry, clinodactyly, hypoglycemia

Isolated (180860) UPD 7p11.2

Schinzel-Giedion

Sclerosis of skull, wide sutures, limb anomalies, mental retardation

AR (269150)

Urbach: skeletal dysplasia (rhizomelic syndrome)

Short stature, sparse hair, large tongue, pulmonary stenosis

AR(268250)

Wiedemann-Rautenstrauch

Wide cranial sutures, neonatal teeth, large penis, deficient adipose, short stature

AR (264090)

Winchester

Short stature, severe joint contractures, corneal opacities, coarse facies, osteoporosis

AR (247950)

Yunis-Varon

Wide cranial sutures, dysplastic ears, sparse hair, facial anomalies, absent or hypoplastic clavicles and thumbs

AR (216340)

Zellweger

High forehead, ocular anomalies, hepatosplenomegaly, hypotonia, seizures

AR (214100) Heterogeneous

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Skull

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Fig. 7-14. Cleidocranial dysplasia in an 8-year-old male. Skull radiograph shows a large anterior fontanel and chest radiograph shows absent clavicles. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute and Children’s Hospital, Wilmington, DE.)

Occasionally, the anterior fontanel will ossify into a bony plate, which may be slightly elevated in relation to the rest of the cranium. This may relate to decreased growth-stretch tensile forces across the anterior fontanel and is sometimes seen with multiple sutural synostosis; however, it can also occur in otherwise normal infants, in which case it is considered a normal variant.4 Instead of the usual flat, uncalcified, diamond-shaped anterior fontanel, there is a slightly raised diamond-shaped plate of bone in its place. Etiology and Distribution

A small or absent anterior fontanel may be secondary to microcephaly (because of decreased brain growth), craniosynostosis af-

fecting the metopic, sagittal, and/or coronal suture, or accelerated osseous maturation. There have also been reports of normal infants with absent anterior fontanels at birth. The shape of the anterior fontanel bone often remains visible on skull radiographs throughout childhood and into adulthood, with a characteristic appearance on Towne projection. The appearance of the fusing anterior fontanel bone can be confused with a depressed skull fracture in the lateral projection.5 Occasionally, children thought to have a small or absent anterior fontanel will have an anterior intrafontanel bone, which is of no significance. Causes of large or late-closing fontanels include increased intracranial pressure or delayed ossification of the skull (Table 7-7).3

242

Craniofacial Structures 5. Girdany, BR, Blank E: Anterior fontanel bones. AJR Am J Roentgenol 95:148, 1965. 6. Chemke J, Robinson A: The third fontanelle. J Pediatr 75:617, 1968. 7. Duc G, Larago RH: Anterior fontanelle: size and closure in term and preterm infants. Pediatrics 78:904, 1986.

7.5 Cranial Dermal Sinus

Fig. 7-15. Age at closure of anterior fontanel (cumulative percentage). Based on data from Zurich, Switzerland (111 term neonates and 131 preterm neonates collected from 1974 to 1978).7

The sagittal fontanel is caused by a lack of union at the medial edge of junction of the two parietal ossification centers. This union normally occurs by the 7th month of gestation but may occur 2 to 3 months after birth.6 Anterior fontanel closure occurs in 1% of normal infants by age 3 months, in 38% by 12 months, in 70% by 18 months, and in 97% by 24 months (Fig. 7-15).7 Therefore, early or late closure is reasonably common, but care must be taken to rule out underlying pathology. In normal infants there is no sex difference in the size and age of closure of the anterior fontanel, nor is there any correlation with gestational age at delivery, head circumference, or bone age. The size of the fontanel at birth does not predict time of closure.7 A sagittal fontanel is found in 6.3% of all newborns. In one study of those with a diameter of greater than 13 mm, 5% had major anomalies and 35% had minor anomalies. In those with a diameter less than 13 mm, two of 45 infants studied had Down syndrome, and one had a major anomaly. The latter group accounted for two-thirds of all children with this third fontanel.4 Although it is unknown whether there is ethnic variability in the prevalence of sagittal fontanels, the majority of individuals with this feature are male.6 Individuals with Down syndrome commonly have large fontanels that close late, along with a sagittal fontanel and persistence of the metopic suture.6 Diagnosis of an extra fontanel is made by palpation or radiography. It is often an isolated malformation but may be sometimes be associated with rare syndromes. Prognosis

In all cases, prognosis is dependent on the underlying cause. If the anomaly is isolated, there is no ill effect. References (Anomalies of Fontanels) 1. Currarino G: Normal variants and congenital anomalies in the region of the obelion. AJR Am J RoentgenoI 127:487, 1976. 2. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, New York, 1989, p 121. 3. Popich GA, Smith DW: Fontanelles: range of normal size. J Pediatr 80:749, 1972. 4. Keats TE: Atlas of Normal Roentgen Variants That May Simulate Disease. Mosby Year Book, St Louis, 1992, p 13.

A cranial dermal sinus is a midline depression or tract lined by stratified squamous epithelium that extends from the skin toward the central nervous system or its coverings. Cranial dermal sinuses are associated with bony defects in 80% of cases.1 Diagnosis is best achieved radiographically via computed tomography (CT) scan, which reveals a low-density lesion that may be surrounded by an enhancing ring.2 Cranial dermal sinuses are most common in the occipital region but can be found anywhere. Size can vary from a very small defect to a large, expanding mass. Clinical presentation is often as a cutaneous localized swelling that presents as infection or cystic expansion of the sinus tract beneath the skin surface, occasionally with drainage. There is often an abnormal distribution of hair along the defect. Occasionally cystic expansion occurs within the cranial cavity, which obstructs cerebrospinal fluid flow, compresses the adjacent neural structures, and/or ruptures to cause sterile meningitis, which can be recurrent.1,2 Cranial dermal sinuses are thought to be the result of faulty separation of neurectoderm from cutaneous ectoderm during early gestation.1 The recommended treatment is surgery; prognosis is good if treatment is done prior to the development of complications. In the facial region, the most frequent congenital midline mass is a nasal dermoid sinus cyst, which can have intracranial extension and be associated with other anomalies.3,4 Nasal dermoid sinus cysts constitute 11–12% of dermoids found in the head and neck4 and usually arise sporadically, although reports of familial occurrence have been documented.3,4 At 50 to 60 days, the nasal and frontal bones develop through intramembranous ossification, remaining separated by a space termed the fonticulus nasofrontalis. During growth, the nasal process of the frontal bone separates the skin from the dura. The dura connects to the frontal aspect of the skull via a projection that ends at an opening in the frontal bones termed the foramen cecum. The foramen cecum eventually fuses with the fonticulus nasofrontalis in the area of the future cribriform plate, thereby obliterating the previous neuroectodermal connection. If this process remains incomplete, dermal connections (termed nasal dermoid sinus cysts) may occur anywhere from the nasal tip to the intracranial space through the foramen cecum.3 Such dermoid sinus cysts contain both ectodermal and mesodermal derivatives, and they are composed of a stratified squamous epithelial lining and specialized adnexal structures such as hair follicles, pilosebaceous glands, and smooth muscle.3 Nasal pits are present in 50% of patients with nasal dermoids,5 often with hairs protruding from the pit, and they can appear anywhere along the nose, with intracranial extension noted in 36–45% of cases.3,4 Associated anomalies were present in 41% of one series examined by a multidisciplinary team, and they were associated with syndromes such as hemifacial microsomia, orofaciodigital syndrome (Type1), frontonasal dysplasia, chromosome problems, VATER association, and/or central nervous system malformations.4 Complications can result from enlargement of the cyst, skeletal distortion, and recurrent infection, so surgical excision

Skull

243

is recommended after CT scanning to identify intracranial extension and to plan the surgical approach. References (Cranial Dermal Sinus) 1. Shackelford GD, Shackelford PG, Sehwetschenau PR, et al.: Congenital occipital dermal sinus. Radiology 111:161, 1974. 2. Starinsky R, Wald U, Michowitz SD, et al.: Dermoids of the posterior fossa: case reports and review. Clin Pediatr 27:579, 1988. 3. Posnick JC, Bortoluzzi P, Armstrong DC, et al.: Intracranial nasal dermoid sinus cysts: computed tomographic scan findings and surgical results. Plast Reconstr Surg 93:745, 1994. 4. Wardinsky TD, Pagon RA, Kropp RJ, et al.: Nasal dermoid sinus cysts: association with intracranial extension and multiple malformations. Cleft Palate Craniofac J 28:87, 1991. 5. McCaffey TV, McDonald TJ, Gorenstein A: Dermoid cyst of the nose: review of 21 cases. Otolaryngol Head Neck Surg 95:303, 1979.

7.6 Parietal Foramina (Includes Cranium Bifidum) Parietal foramina are small defects in the superoposterior angles of the parietal bones through which emissary veins may pass through the calvaria. Usually, parietal foramina present as symmetrical oval defects situated on each side of the sagittal suture, which are separated from each other by a narrow bridge of bone, and their size diminishes with age. They are covered with scalp tissue and hair and are detected through palpation and radiography. Occasionally, brain covered by dura and intact scalp can bulge through extensive lesions, suggesting the possibility of an encephalocele, but the location of these lesions off the midline differentiates them from neural tube closure defects. Sometimes the entire sagittal suture remains widely patent from the frontal to the parietal bones, and this is termed cranium bifidum, with this defect subsequently ossifying to resemble parietal foramina during mid-childhood or adulthood. (Fig. 7-16).1 Parietal foramina usually are small, with 60% less than 1 mm; such small defects can only be detected radiographically. However, 10% are 5 mm or more and can be as large as 50 mm in diameter. Reported individuals have had defects as large as 57 mm in diameter, with seizures apparently secondary to venous obstruction and meningocerebral adhesions at the margins of the defect.2 Although parietal foramina themselves cause no impairment, they can occur as part of the phenotype in a few syndromes (Table 7-8). The diagnosis of large parietal foramina may be suspected by palpation but is best confirmed radiographically.3

Fig. 7-16. Parietal foramina (arrows) in an adult woman. Two of her four children also had large parietal foramina.

Parietal foramina represent defects of calvarial ossification, and they usually manifest autosomal dominant inheritance with variable expression. As ossification of the parietal bones normally progresses, sagittal fontanels form within the posterior parietal bones. These fontanels normally close by the 7th fetal month; however, closure may be delayed and not occur until later in life. Parietal foramina may result if midsagittal bridging occurs, and ossification lateral to the bony bridging remains incomplete. Thus, parietal foramina evolve from the sagittal fontanel but are distinct lesions in that the sagittal fontanel is a single midline defect, whereas parietal foramina are usually paired defects just off the midline.4 Small parietal foramina are found in 60–70% of all adults, whereas large parietal foramina are present in less than 1% of adults.1,3,6 Small unilateral defects are more common than bilateral defects. When the defect is unilateral, it more often involves the right side, and males are more commonly affected than females, with a ratio of 5:3.6 Goldsmith initially called this condition Catlin marks after observing the condition in 16 members of a five-generation family named Catlin.5 This genetic condition can present as cranium bifidum in early life, developing into parietal foramina by later childhood. Cranium bifidum means literally ‘‘cleft skull,’’ and it presents as a wide opening between the frontal and parietal bones, which normally begin their process of intramembranous ossification in the center of each bone and then spread towards the

Table 7-8. Syndromes with parietal foramina Syndrome

Major Features

Causation Gene/Locus

Parietal foramina with cleidocranial dysplasia

Dolichocephaly, macrocephaly, dysplastic ears

AD (168550)

Potocki-Shaffer

Mental retardation, brachy-/turricephaly, craniofacial dysostosis

Unknown (601224) Del 11p11.2

Ritscher-Schinzel: Dandy-Walker anomaly-atrioventricular septal defect

Delayed closure of fontanels, macrocephaly, undermineralization of skull, hydrocephalus, facial anomalies, hypotonia, mental retardation

AR (220210)

Rubinstein-Taybi

Broad thumbs and toes, downslanted palpebral fissures, hypoplastic maxilla, large anterior fontanel

AD (180849) CBP, 16p13.3

Saethre-Chotzen

Short stature, maxillary hypoplasia, deafness, hypertelorism, cleft palate, congenital heart defects

AD (101400) TWIST, 7p21 FGFR2, 10q26

244

Craniofacial Structures

sutures. During mid-childhood, these areas ossify, leaving only symmetric openings in the frontal and parietal bones. One reported family included individuals with both cranium bifidum and parietal foramina, confirming that cranium bifidum in infancy and early childhood can evolve into large parietal foramina in later childhood and adulthood.3 Wilkie et al. described heterozygous MSX2 mutations in three unrelated families with enlarged parietal foramina, suggesting that loss of MSX2 activity results in calvarial defects.7 A second gene has been implicated in those families who do not link to 5q34-q35, where MSX2 is located, and mutations or deletions of ALX4 on 11p11.2 can also result in parietal foramina.8 Parietal foramina can occur as an isolated trait due to mutations in or haploinsufficiency of MSX2 or ALX4, or as a component of a multiple congenital anomaly syndrome, such as Saethre-Chotzen syndrome, Cleidocranial dysplasia, or Rubinstein-Taybi syndrome. The combination of parietal foramina with multiple exostoses is now known to be a contiguous gene deletion of ALX4 and EXT2 on chromosome 11p11-p12 (also termed DEFECT11 syndrome). Surgery is usually unnecessary, since the lesions tend to ossify on their own, but occasionally a protective helmet is used for extensive defects. Care must be exercised during delivery to avoid trauma to the brain underlying such extensive parietal foraminal defects. Location and intact scalp tissue help to differentiate parietal foramina from encephaloceles. This lesion must also be differentiated from scalp vertex aplasia (Section 7.8), which is also inherited in an autosomal dominant fashion, when it is an isolated trait. There is usually denuded scalp over such lesions, which can include both scalp and calvaria, but their location in the midline near the hair whorl sets these lesions apart from parietal foramina. They usually heal with some degree of scarring and absence of scalp

hair, so these bald spots should be searched for on the scalps of both parents. Occasionally, areas of scalp vertex aplasia can be part of a syndrome such as trisomy 13, or they can result from in utero vascular disruption. When scalp vertex aplasia occurs with absence of digits, the possibility of Adams-Oliver syndrome needs to be considered. Finally, vertex craniotabes can present as an extensive area of incomplete calvarial ossification over the vertex in the midline, but the edges are not sharp and demarcated like parietal foramina, and vertex craniotabes ossifies quite rapidly within the first few months after birth.

References (Parietal Foramina) 1. Currarino G: Normal variants and congenital anomalies in the region of the obelion. AJR Am J RoentgenoI 127:487, 1976. 2. Epstein JA, Epstein BS: Deformities of the skull surface in infancy and childhood. J Pediatr 70:636, 1967. 3. Little BB, Knoll KA, Klein VR, et al.: Hereditary cranium bifidum and symmetric parietal foramina are the same entity. Am J Med Genet 35:353, 1990. 4. Murphy J, Gooding CA: Evolution of persistently enlarged foramina. Radiology 97:391, 1970. 5. Goldsmith WM: The ‘‘Catlin mark’’: the inheritance of an unusual opening in the parietal bones. J Hered 13:69, 1922. 6. O’Rahilly R, Twohy MJ: Foramina parietalia permagna. Am J Roentgenol Radiol Ther 67:551, 1952. 7. Wilkie AOM, Tang Z, Elanko N, et al.: Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nat Genet 24:387, 2000. 8. Wu YQ, Badano JL, McCaskill C, et al.: Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous genedeletion syndrome. Am J Hum Genet 67:1327, 2000.

Fig. 7-17. Wormian bones. Deficient cranial ossification with multiple bone islands (wormian bones) in a 6-year-old male with cleidocranial dysplasia. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.)

Skull

7.7 Wormian Bones Wormian bones are accessory bones that occur within cranial suture lines or fontanels.1,2 Wormian bones are named for Dr. Worm, not because they are ‘‘wormlike.’’ They can occur singly, or in large numbers, and are diagnosed radiographically. Although they can occur within any suture, they are rare in coronal or sagittal sutures (Fig. 7-17). They do not cause any impairment themselves, but their significance is variable. In one study, the majority of children with an ‘‘excessive’’ number of wormian bones had some abnormality of the central nervous system.1 These abnormalities ranged from gross malformations to minimal brain dysfunction, though this study may have been biased as coming from a hospital-based population. Thus, some individuals with many Wormian bones may have other anomalies and/or central nervous system dysfunction (Table 7-9). More than 10 Wormian bones is unusual. The pathogenesis of wormian bones is thought to be related to intracranial strain along with open sutures causing ossification

245

defects. Such sutural bones persist and are not incorporated into the adjacent bone during mineralization and maturation.2 Although the prevalence of wormian bones in the general population is 17%, the prevalence varies with age. Males are more often affected than females, and differences between ethnic groups have been noted. Blacks have more wormian bones than whites or Native Americans, and 80% of Chinese individuals have wormian bones, which represents the highest incidence. A positive correlation has been noted between the frequency of wormian bones and the degree of deformation in Kakiutl Indians, who practiced head binding, but it is unclear how this anomaly might be related to unusual postnatal deformational practices.3 Wormian bones are commonly seen in osteogenesis imperfecta and other disorders that result in defective cranial bone mineralization. Such infants also become quite brachycephalic as a consequence of postnatal supine positioning with soft cranial bones.4 The increased frequency of wormian bones in Chinese infants might relate to traditional supine sleep position practices in this population and their resultant brachycephalization. If so, an increased frequency of wormian bones may soon be noted in other cultures that

Table 7-9. Syndromes with Wormian bones Syndrome

Major features

Causation Gene/Locus

Acrogeria

Delayed fontanel closure, short stature, alopecia, premature aging, deficient adipose tissue, prominent vessels, acro-osteolysis

AR (201200)

Aminopterin, prenatal

Microcephaly, cranial dysplasia, cleft palate, mesomelia, hypodactyly

Prenatal drug exposure

Cleidocranial dysostosis

Brachycephaly, late fontanel closure, wide sutures, flat midface, hypoplastic clavicles, short ribs

AD (119600) CBFA1, 6p21

Grant

Brachycephaly, delayed fontanel closure, micrognathia, blue sclerae, joint laxity

AD (138930)

Hajdu-Cheney

Platybasia, delayed fontanel closure, wide sutures, short stature, oligodontia, vertebral anomalies

AD (102500)

Hallermann-Streiff (progeroid syndrome)

Microphthalmia, small pinched noses, hypotrichosis

AR (264090)

Hypophosphatasia

Poorly mineralized cranium, short ribs, hypoplastic fragile bones

AR (241500) ALPL, 1p36.1-34

Hypothyroidism

Coarse facies, slow growth, umbilical hernia, slow development

Variable

Infantile multisystem inflammatory disease (CINCA)

Chronic meningitis, migratory skin rash, joint inflammation, progressive visual defect, perceptive deafness

(607115) CIAS1, 1q44

Mandibular dysplasia

Large fontanel, wide cranial sutures, beaked nose, micrognathia, dental anomalies, skin atrophy

AR (248370) LMNA, 1q21.2

Menkes

Brain malformation, brittle and kinky hair, dry skin, seizures, mental retardation

XLR (309400) ATP7A, Xq12-q13

Oto-palato-digital II

Sclerosis of skull, wide sutures, hypertelorism, micrognathia, skeletal anomalies, syndactyly, polydactyly

XLR (304120) FLNA, Xq28

Osteogenesis imperfecta

Blue sclerae, numerous fractures, deafness

AD (166200, 259400) Heterogeneous COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Progeria

Alopecia, atrophy of subcutaneous fat, skeletal hypoplasia and dysplasia, premature aging

AD (176670) LMNA, 1q21.2

Pycnodysostosis

Large fontanel, wide sutures, beaked nose, micrognathia, hepatosplenomegaly, multiple fractures

AR (265800) Cathepsin K, 1q21

Roberts-SC phocomelia

Hypomelia, midfacial defect, severe growth deficiency

AR (269000)

Schnizel-Giedon hypertrichosis-midface retraction

Sclerosis of skull, wide sutures, limb anomalies, mental retardation

AR (269150)

Stratton-Parker

Growth hormone deficiency, dextrocardia, brachycamptodactyly

Unknown (185120)

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Craniofacial Structures

have recommended supine sleep positioning to prevent sudden infant death syndrome. References (Wormian Bones) 1. Pryles C, Khan AJ: Wormian bones. Am J Dis Child 133:380,1979. 2. Gooding CA: Cranial sutures and fontanelles. In: Radiology of the Skull and Brain. TH Newton, DO Potts, eds. Medibooks, Great Neck, NY, 1971. 3. Bennett KA: The etiology and genetics of wormian bones. Am J Phys Anthropol 23:255, 1965. 4. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Co, Philadelphia, 2005.

7.8 Scalp Vertex Aplasia Scalp vertex aplasia, or aplasia cutis congenita (ACC), is a relatively common congenital defect resulting in localized absence of skin, usually occurring on the scalp as an isolated finding not associated with other abnormalities. Scalp vertex aplasia begins as multiple or solitary sharply marginated raw areas with absence of skin that mature into atrophic scars devoid of adnexal structures, usually in the scalp vertex area or midline superior occipital region (Fig. 7-18).1 The cause of these lesions is heterogeneous and includes vascular disruption, trauma, teratogens, and genetic factors.2 Because vas-

cular disruption and placental infarcts are seen in antiphospholipid antibody syndrome, some cases of extensive scalp vertex aplasia may be related to the effects of this maternal disease state or some other type of thrombophilia during pregnancy.2,3 The frequency is one per 3000 live births, and a classification system of subtypes for ACC has been suggested by Frieden.4 Lesions may be ulcerated, bullous, cicatricial, or covered with a tough, translucent membrane, and they occasionally extend to the bone or dura.1 They may be circular, elongated, stellate, or triangular in shape and of variable depth,5 with 86% of the solitary lesions occurring on the scalp, most often near the parietal hair whorl.6,7 Type 1 ACC manifests scalp involvement without other abnormalities, and when familial, it manifests autosomal dominant inheritance.8,9 Less frequently, other parts of the body may be involved, with or without associated defects. When the lesions are midline and overlying the spine or midcranium, they can be associated with occult spinal dysraphism or tiny encephaloceles (ACC type 4). When there are multiple areas of ACC involving primarily the lower extremities, particularly the flank, thighs, and knees, a careful examination of the placenta may reveal a fetus papyraceus, which occurs in one in 12,000 live births and affects one in 200 twin pregnancies.10–12 Larger defects can be complicated by hemorrhage, venous thrombosis, and rarely meningitis. With extensive ACC and other vasculodisruptive defects, survival during the neonatal period can be severely compromised.13 ACC can be associated with teratogenic or genetic disorders, and it is important to search for

Fig. 7-18. Examples of scalp vertex cutis aplasia in an otherwise normal infant (A) and in an infant with trisomy 13 (B).

Skull

associated malformations in order to counsel parents concerning prognosis and recurrence risks in relation to the underlying disorder. ACC associated with epidermal nevus or nevus sebaceous syndrome (or ACC type 3) is the association of a sebaceous nevus (a linear yellow verrucous nevus) on the head and neck with variable ocular, cerebral, neurologic, skeletal, cardiac, and other abnormalities, usually on a sporadic basis.14,15 Epidermolysis bullosa (EB) is a term applied to a group of hereditary skin disorders that result in the formation of blisters after minor skin trauma. There are three subtypes, based on the histopathologic location of the

247

bullae: dystrophic EB with subepidermal bullae below the periodic acid-schiff (PAS) staining basement membrane, junctional EB with subepidermal bullae above the PAS-staining membrane, and simplex EB with intraepidermal bullae in the suprabasal area.16,17 Dystrophic and simplex EB can be either autosomal recessive or dominant, but junctional EB is always autosomal recessive. EB can be associated with pyloric atresia and/or ACC and manifest autosomal recessive inheritance, and histopathology is usually of the junctional type.16 These findings suggest that when ACC occurs with EB, it is most likely to be autosomal recessive, and some cases

Fig. 7-19. Thin cranial bones in infants with kleeblattscha¨del due to multiple suture synostosis (A and B) and early amnion rupture (C and D). Cranial bones in B. are uniformly thin, while the cranium in D. has irregular areas of localized thinning.

248

Craniofacial Structures

of junctional EB with pyloric atresia have demonstrated mutations in integrin beta 4.16 Finally, ACC has been associated with numerous cytogenetic and genetic malformation syndromes as ACC type 9.2,9,18,19 Wound treatment in cases of superficial ulceration is conservative with antibacterial dressings, but extensive or deep lesions may require reconstruction of the scalp. Small hairless areas can be excised and covered with a neighboring flap from the scalp.20 This approach works for the most common scalp ACC lesions, which are frequently round, punched-out lesions in the vertex region or less frequently triangular lesions in the temporal region (termed temporal triangular alopecia).20,21 With extensive scalp lesions (over 6 cm in diameter), it is especially important to avoid eschar formation immediately after birth by covering exposed dura with split thickness skin grafts from adjacent healthy scalp and moist dressings. Prompt closure is important because of the high risk of fatal hemorrhage from the sagittal sinus when the eschar becomes dry and separated, causing the underlying dura to become damaged and tear.21 Once the superficial defect is completely healed, the subsequent scar alopecia may be treated by tissue-expanded local flaps, pericranial flaps, or free vascularized flaps when the child is older. With prompt closure and a healthy underlying dura, cranial bone growth will occur after prompt early wound closure, and the risk of fatal hemorrhage or meningitis is greatly lessened.22 References (Scalp Vertex Aplasia) 1. Tann HH, Tay YK: Familial aplasia cutis congenita of the scalp: a case report and review. Ann Acad Med Singapore 26:500, 1997. 2. Evers MEJW, Steijlen PM, Hamel BCJ: Aplasia cutis congenita and associated disorders: an update. Clin Genet 47:295, 1995. 3. Roll C, Hanssler L, Voit T, et al.: Aplasia cutis congenita—etiological relationship to antiphospholipid syndrome? Clin Dysmorphol 8:215, 1999. 4. Frieden IJ: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646, 1986. 5. Rudolph RJ, Schwartz W, Leyden JJ: Bitemporal aplasia cutis congenita. Arch Dermatol 110:615, 1974. 6. Demmel U: Clinical aspects of congenital skin defects: I. Congenital skin defects of the head of the newborn; II. Congenital defects of the trunk and extremities of the newborn; III. Causal and formal genesis of congenital skin defects of the newborn. Eur J Pediatr 121:21, 1975. 7. Stephan MJ, Smith DW, Ponzi JW: Origin of scalp vertex aplasia cutis. J Pediatr 101:850, 1982. 8. Itin P, Pletscher M: Familial aplasia cutis congenita of the scalp without other defects in 6 members of three successive generations. Dermatologica 177:123, 1988. 9. Fimiani M, Seri M, Rubegni P, et al.: Autosomal dominant aplasia cutis congenita: report of a large Italian family and no hint for candidate chromosomal regions. Arch Dermatol Res 291:637, 1999. 10. Mannino FL, Jones KL, Benirschke K: Congenital skin defects and fetus papyraceus. J. Pediatr 91:559, 1977. 11. Daw E: Fetus papyraceus—11 cases. Postgrad Med J 59:598, 1983. 12. Leaute-Labreze C, Depaire-Duclos F, Sarlangue J, et al.: Congenital cutaneous defects as complications in surviving co-twins: aplasia cutis congenita and neonatal Volkmann ischemic contracture of the forearm. Arch Dermatol 143:1121, 1998. 13. Lane W, Zanol K: Duodenal atresia, biliary atresia, and intestinal infarct in truncal aplasia cutis congenita. Ped Dermatol 17:290, 2000. 14. Hogler W, Sidoroff A, Weber F, et al.: Aplasia cutis congenita, uvula bifida and bilateral retinal dystrophy in a girl with naevus sebaceous syndrome. Brit J Dermatol 140:542, 1999. 15. Shields JA, Shields CL, Eagle RC, et al.: Ocular manifestation of the organoid nevus syndrome. Ophthalmology 104:549, 1997. 16. Maman E, Maor E, Kachko L, et al.: Epidermolysis bullosa, pyloric atresia, aplasia cutis congenita: histopathological definition of an autosomal recessive disease. Am J Med Genet 78:127, 1998.

17. Gilbert-Barness E, Barness LA: Disorders of collagen metabolism. In: Metabolic Diseases: Foundations of Clinical Management, Genetics and Pathology. Eaton Publishing, Natick, MA, 2000. 18. Zvulunov A, Kachko L, Manor E, et al.: Reticulolinear aplasia cutis congenita of the face and neck: a distinctive cutaneous manifestation in several syndromes linked to Xp22. Br J Dermatol 138:1046, 1998. 19. Edwards MJ, McDonald D, Moore P, et al.: Scalp-ear-nipple syndrome: additional manifestations. Am J Med Genet 50:247, 1994. 20. Kruk-Jeromin J, Janik J, Rykala J: Aplasia cutis congenita of the scalp: report of 16 cases. Dermatol Surg 24:549, 1998. 21. Trakimas C, Sperling LC, Skelton HG, et al.: Clinical and histologic findings in temporal triangular alopecia. J Am Acad Dermatol 31:205, 1994. 22. Yang JY, Yang WG: Large scalp and skull defect in aplasia cutis congenita. Br J Plast Surg 53:619, 2000.

7.9 Thin Cranial Bones Thin cranial bones are those that appear thinner than average and have little or no diploe. The diagnosis of thin cranial bones is made radiographically and is usually subjective.1 Radiolucency is often noted (Fig. 7-19). Thin calvarial bones can be secondary to craniosynostosis (particularly adjacent to the ridging in sagittal synostosis) and hydrocephalus, or it can occur as part of several syndromes in which undermineralization is a feature (Table 7-10).2 Areas of radiolucency are called craniolacunae (luckensch€ € adel) and are often secondary to spinal dysraphism (Fig. 7-20). These generally disappear by age 1 year.3 Regionally thinned areas can also occur in association with porencephaly, subdural hygroma, arachnoid cyst, and some tumors.2 Generalized thinning of cranial bones also results from increased dural distension, when expansion of the brain outpaces the growth of the skull. In other instances, undermineralization is the cause. As with thickened cranial bones, it is unknown whether thin cranial bones can occur as an isolated trait. Craniolacunae probably represent defective membranous bone formation, particularly along the inner periosteum of the vault.3 Craniolacunae probably do not occur as isolated traits. Prognosis is dependent on the underlying cause of this condition, and lacunar skull defects themselves have no direct effects on the infant. References (Thin Cranial Bones) 1. Ethier R: Thickness and texture. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 154. 2. Hodges FJ III: Pathology of the skull. In: Neuroradiology of the Head and Neck, vol 3. JM Taveras, ed. JB Lippincott Co, Philadelphia, 1989. 3. McRae DL: Lacunar skull, lu¨ckenscha¨del. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 648.

7.10 Undermineralization of the Skull Undermineralization of the skull results in increased radiolucency of the cranial bones and is attributable to decreased calcium deposition. Although this is distinct from thin cranial bones, the two traits are often found together, and for this reason, both entities are covered in Table 7-10. Congenital undermineralization occurs in a number of syndromes, particularly osteogenesis imperfecta and hypophosphatasia (Fig. 7-21). Hypophosphatasia occurs in at least three forms, including infantile, childhood, and adult forms. Undermineralization is most pronounced in the infantile form and least evident in the adult form. The infantile form can usually be diagnosed

Skull

249

Table 7-10. Syndromes with thin cranial bones and/or defective ossification Syndrome

Major Features

Causation Gene/Locus

Achondrogenesis

Macrocephaly, severe micromelia, early death

AR (200600, 200710) COL2A1, 12q13.11-q13.2

Aminopterin, prenatal

Microcephaly, cranial dysplasia, cleft palate, mesomelia, hypodactyly

Drug exposure

Anderson (familial osteodysplasia)

Large earlobes, midface hypoplasia, kyphosis, scoliosis

AR (607689) FARA2, 5q31.1

Cleidocranial dysplasia

Brachycephaly, late fontanel closure, wide sutures, flat midface, hypoplastic clavicles, short ribs

AD (119600) CBFA1, 6p21

Crane-Heise

Cleft lip/palate, agenesis of clavicles and cervical vertebrae, talipes equinovarus

AR (218090)

Ehlers-Danlos

Short stature, blue sclerae, ectopia lentis, mitral valve prolapse, joint hypermobility/dislocation

AD (130000, 225400) Heterogeneous COL5A1, 9q34.2-q34.3 COL5A2, 2q31 COL1A1, 17q21.31-q22

Hallermann-Streiff

Sparse hair, corneal clouding, thin nose, dental anomalies

AR (264090)

Hypophosphatasia

Premature shedding of teeth, rachitic skeletal changes, bowed long bones, fractures, low serum phosphatase

AR (241510) ALPL, 1p36.1-p34

Hydrops-ectopic calcification moth-eaten skull dysplasia

Macrocephaly, micrognathia, narrow thorax, rhizomelia, polydactyly, laryngeal/tracheal calcifications

AR (215140) LBR, 1q42.1

Lethal (osteosclerotic) skeletal dysplasia (Ashey-Kendall)

Short trunk, micromelia, small chest, abnormal lung lobation, situs inversus, polyhydramnios

AR (259775)

Metaphyseal chondrodysplasia-Jansen type

Thick cranium, deafness, micrognathia, limb anomalies, multiple fractures, short stature

AD (156400) PTHR, 3p22-p21.1

Osteogenesis imperfecta

Blue sclerae, fractures, osteopenia, wormian bones, dentinogenesis imperfecta, deafness

AD (166200, 259400) COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Oto-palato-digital type II

Microcephaly, small mouth, cleft palate, syndactyly

XLR (304120) FLNA, Xq28

Restrictive dermopathy

Hypertelorism, micrognathia, severe intrauterine growth restriction, polyhydramnios, cleft palate

AR (275210)

Ritscher-Schinzel

Macrocephaly, large fontanel, parietal foramina, hydrocephalus, facial anomalies, hypotonia, mental retardation

AR (220210)

Stanescu dysostosis

Brachycephaly, midface hypoplasia, tooth anomalies

AD (122900)

Fig. 7-20. Lu¨ckenscha¨del in an infant with congenital hydrocephalus treated with ventriculoperitoneal shunting due to a meningomyelocele. Note lacunar skull patterning due to rapid brain expansion. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.) See also Fig. 7-6.

by fetal ultrasound, whereas the other forms are often diagnosed after birth by radiographs and measurement of serum alkaline phosphatase levels.1–3 The other conditions listed in Table 7-10 are less frequent, and also diagnosed through radiographic and clinical features. Fluorosis and vitamin D-dependent rickets can also produce postnatal undermineralization of the skull, but areas of sclerosis are also present in fluorosis.4 The incidence of undermineralization is low, and prognosis is dependent on cause, varying widely from stillbirth or death during infancy, to little effect. References (Undermineralization of the Skull) 1. Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983. 2. Wynne-Davies R, Hale CM, Apley AG: Atlas of Skeletal Dysplasias. Churchill Livingstone, New York, 1987. 3. Edeiken J: Roentgen Diagnosis of Diseases of Bone, vol 2, ed 3. Williams & Wilkins, Baltimore, 1981, p 858. 4. Christie DP: The spectrum of radiographic bone changes in children with fluorosis. Radiology 36:85, 1980.

7.11 Craniotabes Prolonged forceful pressure on the fetal vertex may result in diminished cranial mineralization, affecting the superior portions of the parietal bones. Such craniotabes is more likely to occur in

250

Craniofacial Structures

Fig. 7-21. A and B. Undermineralization of calvarium in newborn infant with lethal osteogenesis imperfecta (Type II). C. Extensive brachycephalization in an infant with severe osteogenesis (Type III) due to severe undermineralization.

first-born infants, especially with early fetal head descent into a vertex presentation for a prolonged period of time. Mild degrees of craniotabes occur in about 2% of newborn babies, and more extensive degrees of craniotabes are less common.1,2 Craniotabes was first described in congenital syphilis, and it can also be seen with subclinical rickets due to vitamin D deficiency.3–8 Rickets should be considered in any infant with a nonvertex presentation, whose mother might be at risk for nutritional deficiency, and such infants usually manifest generalized craniotabes with osteomalacia. With compression-related craniotabes, the superior parietooccipital region tends to be soft to palpation and often indents upon finger compression. In extreme cases, the entire top of the head can be involved (Fig. 7-22). The presence of a normally firm bony calvaria along the sides of the calvaria and in the mastoid regions readily differentiates this benign form of craniotabes from more generalized problems of decreased mineralization, such as hypophosphatasia, osteogenesis imperfecta, or infantile rickets. Within the affected region of the calvaria, the sutures and fontanels may also feel wider than usual. Accentuated vertex molding can be an associated feature in a fetus with prolonged vertex engagement. Benign vertex craniotabes has not been reported in babies in breech presentation, and radiolucency of the parietal bones in the vertex of the skull is considered to be a normal anatomic variant on neonatal head computed tomography scans.9

With compression-related craniotabes, the prognosis is excellent, and the calvaria usually mineralizes in a normal fashion within 1 to 2 months after birth.10 If the mother has vitamin D-deficient rickets and there is more generalized craniotabes and osteomalacia, this condition usually manifests a prompt response to vitamin D therapy over the next few months. Vitamin D-deficient rickets generally is accompanied by metaphyseal changes at the wrist and low 25-hydroxyvitamin D concentrations (less than 12 ng/mL), with a variably elevated alkaline phosphatase level. As in other defects of skeletal mineralization, such as osteogenesis imperfecta and hypophosphatasia, initial care must be taken to avoid fractures. Infants with osteogenesis imperfecta or hypophosphatasia usually show generalized osteomalacia, brittle bones, and wormian bones. References (Craniotabes) 1. Graham JM, Smith DW: Parietal craniotabes in the neonate: its origin and relevance. J Pediatr 95:114, 1979. 2. Fox GN, Maier MK: Neonatal craniotabes. Am Fam Physician 30:149, 1984. 3. Pettifor JM, Isdale JM, Sahakian J, et al.: Diagnosis of subclinical rickets. Arch Dis Child 55:155, 1980. 4. Pettifor JM, Pentopoulos M, Moodley GP, et al.: Is craniotabes a pathognomonic sign of rickets in 3-month-old infants? S Afr Med J 65:549, 1984.

Skull

251

Fig. 7-23. Mild thickening of the calvarium in a 3-year-old male with Sanfilippo syndrome (mucopolysaccharidosis III).

Fig. 7-22. Newborn infant with early head descent and engagement, resulting in extensive vertex molding with craniotabes over the conical deformation.

5. Kokkonen J, Koivisto M, Lautala, et al.: Serum calcium and 25-OH-D in mothers of newborns with craniotabes. J Perinat Med 11:127, 1983. 6. Congdon P, Horsman A, Kirby PA, et al.: Mineral content of the forearms of babies born to Asian and white mothers. Br Med J [Clin Res] 286:1233, 1983. 7. Park W, Paust H, Kaufmann HJ, et al.: Osteomalacia of the mother— rickets of the newborn. Eur J Pediatr 146:292, 1987. 8. Reif S, Katzir Y, Eisenberg Z, et al.: Serum 25-hydroxyvitamin D levels in congenital craniotabes. Acta Paediatr Scand 77:167, 1988. 9. Pastakia B, Herdt JR: Radiolucent ‘‘zones’’ in parietal bones seen on computed tomography: a normal variant. J Comput Assist Tomogr 8:108, 1984. 10. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005.

7.12 Thick Cranial Bones Increased thickness of cranial bones is detected on radiographic examination, and there may be normal or increased cranial density. The calvaria has three tables: the inner and outer tables are composed of compact bone, while the middle table (diploe) consists of cancellous bone. In general, the thickness of the normal skull is proportionate to the width of the middle table. The diagnosis of a thickened cranium is made radiographically, although no formal criteria have been established for determining whether cranial bones are thick (Fig. 7-23). Although there is wide variability among different individuals, in general the thickest part of a normal cranium is no greater than 1 cm. The density of the skull may be increased, normal, or decreased.1 Thickening of the middle table is usually a manifestation of overproliferation of bone marrow in hemolytic disease or bone

Fig. 7-24. Thickening of the calvarium with ‘‘hair on end’’ pattern in a 4-year-old male with thalassemia. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.)

diseases (Fig. 7-24). In hemolytic diseases, such as thalassemia, vertical striations (‘‘hair on end’’ appearance) occur, whereas in bone diseases, such as osteopetrosis, sclerosis occurs.1–4 Overgrowth of the middle table can also occur in microcephaly. In situations in which a shunt has been placed to relieve hydrocephalus, thickening of both inner and middle tables can occur. Thickening of only the outer table is extremely rare.1 Numerous syndromes with thick calvarial bones have been described (Table 7-11). There are both ethnic and sex-related variations in skull thickness. Women have thicker skulls than men, and blacks have thicker skulls than whites. It is unknown whether thick cranial bones can occur as an isolated trait, and the prognosis depends on the underlying condition. References (Thick Cranial Bones) 1. Ethier R: Thickness and texture. In: Radiology of the Skull and Brain. TH Newton, DO Potts, eds. Medibooks, Great Neck, NY, 1971, p 154. 2. Becker MH, Genieser NB, Piomelli S, et al.: Roentgenographic manifestations of pyruvate kinase deficiency hemolytic anemia. AJR Am J Roentgenol 113:491, 1971.

Table 7-11. Syndromes with thick cranial bones Syndrome

Prominent Features

Causation Gene/Locus

Acrodysostosis

Brachycephaly, hearing loss, minor facial anomalies, mesomelia of upper limbs, mental retardation

AD (101800)

Acromegaly

Functional pituitary adenoma, acanthosis nigricans, galactorrhea

AD (102200) GNAS1, 11q13

Aspartylglycosaminuria

Brachycephaly, cataract, coarse facial features, hepatosplenomegaly, telangiectasia

AR (208400) AGA, 4q32-q33

Camurati-Engelmann (diaphyseal dysplasia)

Diaphyseal dysplasia, weakness, leg pain

AD (131300) TGFB-1, 19q13.1

Clouston (ectodermal dysplasia)

Nail dystrophy, dyskeratotic palms and soles, hair hypoplasia

AD (129500) GJB6, 13q12

Cockayne

Asthenia, short stature, cataracts, prominent nose, premature aging, joint contractures, mental retardation

AR (216400) ERCC8, Chr. 5

Coffin-Lowry

Short stature, prominent ears, coarse facial features, kyphosis/scoliosis, large hands, joint laxity

XLR (303600, 102500) RSK2, Xp22/2-p22.1

Craniodiaphyseal dysplasia

Facial distortion

AD (218300)

Craniometaphyseal dysplasia

Sclerosis of skull, deafness, prominent eyes, facial weakness, osteosclerosis

AD (123000) ANKH, 5p15.2-p14.1

Dyke-Davidoff-Masson

Sclerosis of skull, cerebral atrophy, hemiplegia, seizures

Dysosteosclerosis

Sclerosis of skull, short stature, dental anomalies, mental retardation, multiple fractures

AR (224300)

Van Buchem

Optic atrophy, deafness, diffuse osteosclerosis

AR (239100) 17q11.2

Worth

Sclerosis of skull, prominent mandible, dental cysts, osteosclerosis

AD (144750) LRPS, 11q13.4

Fanconi anemia

Small stature, radial aplasia, thumb deformity, pancytopenia, microcephaly, congenital heart defect, kidney malformations, mental retardation

AR (227650) FANCA-G, 16q24.3 Multiple loci

Fluorosis

Joint deformity, spine rigidity, myelopathy, dental mottling

Toxicity

Fountain

Sclerosis of skull, coarse facial features, small broad hands, cutis laxa, skin granuloma, mental retardation

AR (229120)

Fucosidosis

Short stature, coarse facial features, cardiomegaly, hepatosplenomegaly

AR (230000) FUCA, 1p34

Homocystinuria

Subluxation of lens, malar flush, osteoporosis

AR (236200) CBS, 21q22.3

Hyperphosphatasia

Plagiocephaly, macrocephaly, deafness, retinal anomalies, kyphosis/ scoliosis, heart defects, bowed long bones, patchy pigmentation

AR (239300)

Hypoparathyroidism

Cataracts, seizures, chronic tetany, hypocalcemia, hyperphosphatemia

Variable

Hypothyroidism

Coarse facies, slow growth, umbilical hernia, slow development

Variable

Infantile multisystem inflammatory disease

Chronic meningitis, migratory skin rash, joint inflammation, progressive visual defect, perceptive deafness

(607115) CIAS1, 1q44

Jansen-metaphyseal dysplasia

Sclerosis of skull, deafness, micrognathia, limb anomalies, multiple fractures, short stature

AD (156400) PTHR, 3p11-p21.1

Kenny-Caffey

Delayed fontanel closure, wide cranial sutures, macular abnormalities, sparse eyebrows/lashes, hypercalcemia or hypocalcemia

AD (127000) TBCE, 1q42-q43

Lenz-Majewski

Delayed fontanel closure, sclerosis of skull, choanal atresia, joint laxity, and/or contractures, cutis laxa

AD (151500)

Lipodystrophy-cystic angiomatosis

Hirsutism, hepatosplenomegaly, muscle hypertrophy, acanthosis nigricans

AR (272500)

Mannosidosis (alpha)

Large ears, coarse facial features, vertebral anomalies, mental retardation

AR (248500) MAN2B1, 19cen-q12

Marfan

Arachnodactyly with hyperextensibility, lens subluxation, aortic dilation

AD (154700) FBN1, 15q21.1

Marshall

Short stature, cataracts, sensorineural deafness, short depressed nose, large eyes

AD (154780) COL11A1, 1p21

Morgagni-Stewart-Morel

Hyperostosis frontalis interna, obesity, hypertrichosis, hyperprolactinemia, diabetes

AD (144800)

Endosteal hyperostosis

(continued)

252

Table 7-11. Syndromes with thick cranial bones (continued) Syndrome

Prominent Features

Causation Gene/Locus

II

Early alveolar ridge hypertrophy, joint limitation, tight thick skin in early infancy

AR (252500) GNPTA, 4q21-q23

IIIA

Coarse facies, stiff joints by 2–4 years, no mucopolysacchariduria

AR (252600) GNPTA, 4q21-q23

I-H (Hurler)

Coarse facies, stiff joints, mental deficiency, cloudy corneas by 1–2 years

AR (252800) IDUA, 4p16.3

II (Hunter)

Coarse facies, growth deficiency, stiff joints by 2–4 years, clear corneas

XLR (309900) IDS, Xq28

IIIA (Sanfilippo)

Mild coarse facies, mild joint stiffness, mental deficiency

AR (252900) SGSH, 17q25.3

IV (Morquio)

Onset at 1–3 years of age, mild coarse facies, severe kyphosis and knock-knees, cloudy corneas

AR (253000) GALNS, 16q24.3

Myhre: growth deficiencyclefting-mental retardation

Minor facial anomalies, vertebral defects, genital anomalies

AD (139210)

Myotonic dystrophy

Myotonia with muscle atrophy, cataract, hypogonadism

AD (160900) DMPK, 19q13.2-q13.3

Neu-Laxova

Microcephaly/lissencephaly, canine facies with exophthalmos, syndactyly with subcutaneous edema

AR (256520)

Osteogenesis imperfecta

Blue sclerae, numerous fractures, deafness

AD (166200, 259400) Multiple loci COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Osteopathia striata

Hearing loss, scoliosis, cleft palate

AD (166500)

Osteopetrosis

Dense, thick, fragile bone; secondary pancytopenia; cranial nerve compression

AR (259700) Multiple loci: CLCN7, 16p13 LRP5, 11q13.4-q13.5 GL, 6q21 TCIRG1, 11q13.4-q13.5

Osteosclerosis-distal

Cortical hyperostosis

AD (126250)

Oto-palato-digital

Short stature, hypertelorism, facial anomalies, abnormal toes, mental retardation

XLD (311300) FLNA, Xq28

Pagoni: calvarial hyperostosis

Sclerosis of skull, wide forehead, flat nasal bridge

XLR (302030)

Proteus

Segmental overgrowth, hemihypertrophy, nevi

Unknown (176920)

Polyostotic fibrous dysplasia (McCune-Albright)

Deafness, blindness, irregular skin pigmentation, sexual precocity, hyperthyroidism, hyperparathyroidism, Cushing syndrome, acromegaly

Mosaic (174800) GNAS1, 20q13.2

Pycnodysostosis

Osteosclerosis, short distal phalanges, delayed closure of fontanels

AR (265800) Cathepsin K, 1q21

Pyle metaphyseal dysplasia

Prominent supraorbital ridges, broad clavicles, thick ribs, muscle weakness, osteoporosis

AR (265900)

Pyruvate kinase deficiency

Severe hemolytic anemia

AR (266200) Cathepsin K, 1q21

Salla (Sialuria)

Growth retardation, mental retardation, ataxia, athetosis, impaired speech

AR (604369) SLCI7A5, 6q14-q15

Sclerosteosis

Syndactyly, square-jawed appearance

AR (269500) SOST, 17q12-q21

Sickle cell anemia

Anemia, joint pain, aplastic crises, splenic sequestration, priapism, dactylitis

AR (603903)

Spherocytosis

Splenomegaly, gallstones, jaundice

AD (182900) ANK1, 8p11.2

Thalassemia

Anemia, splenomegaly

AR (141900) HBB, 11p15.5

Tricho-dento-osseous syndrome II

Sparse curly hair, dental hypoplasia, premature dental eruption

AD (190320) DLX3, 17q21.3-q22

Vitamin D intoxication

Hypotonia, anorexia, irritability, constipation, polydipsia, polyuria, pallor, aortic valve stenosis, vomiting, hypertension, retinopathy, cloudy cornea

Excess ingestion

Weill-Marchesani

Brachydactyly, small spherical lens, short stature

AR (277600) ADAMTS10, 19p13.3-13.2

Mucolipidosis

Mucopolysaccharidosis

253

254

Craniofacial Structures

3. Leeds N, Seaman WB: Fibrous dysplasia of the skull and its differential diagnosis. Radiology 78:570, 1962. 4. Hodges FJ III: Pathology of the skull. In: Radiology: Diagnosis, Imaging, Intervention, vol 3, chapt 3. JM Taveras, ed. JB Lippincott, Philadelphia, 1989, p 1.

7.13 Sclerosis and Hyperostosis of the Skull Increased density or overmineralization of the cranial bones can be generalized or localized, and this is termed sclerosis or hyperostosis of the skull. Sclerosis generally refers to an increase in bone density without an alteration in width, while hyperostosis is caused by bone overgrowth that leads to an increase in density and width; however, not all cases fit cleanly into one category or the other.1 Hyperostosis is distinct from thick cranial bones, although hyperostosis and occasionally sclerosis can also cause thick cranial bones.2 Most of the sclerosing bone dysplasias manifest generalized changes that are classified on the basis of the distribution and configuration of these abnormalities. One subclassification divides these disorders into osteosclerosis, craniotubular dysplasias, and craniotubular hyperostoses. In such conditions, basal sclerosis may be present without significant calvarial involvement, but the converse rarely occurs.1 The presence of sclerosis or hyperostosis can be diagnosed radiographically or by computed tomography, and scintigraphy may provide information on disease progression (Fig. 7-25).3 Radiologic changes are age-related, and definitive diagnosis may be difficult in early childhood.1 All conditions that cause generalized osteosclerosis affect the skull.1 Localized sclerosis of the base of the skull can occur in fibrous dysplasia, Jansen-type metaphyseal dysplasia, severe anemia, hypercalcuria, and Paget disease. It may also be seen with a meningioma or inflammation.1 Symptoms include narrowing of cranial nerve foramina, which in turn can cause nerve palsy, deafness, or vision defects.4 Increased intracranial pressure is not uncommon, and papilledema can occur as a

complication. Craniosynostosis also occurs in some cases, perhaps related to overstimulation of bone growth along suture edges. Several syndromes have sclerosis as a feature (Table 7-12). Two primary pathologic processes can lead to sclerosis: overproduction of bone and/or failure of osteoclastic absorption of bone.2 The prognosis depends on the underlying cause and varies from individuals being asymptomatic to sudden death from medullary compression. In addition, facial palsy as well as hearing and vision loss may occur due to cranial nerve compression within stenotic formena.3,4 This may require decompression. Craniotomy to relieve increased intracranial pressure may also be indicated. References (Sclerosis and Hyperostosis of the Skull) 1. Kozlowski K, Beighton P: Gamut Index of Skeletal Dysplasias, ed 2. Springer, New York, 1995, p 33. 2. Ethier R: Thickness and texture. In: Radiology of the Skull and Brain. TH Newton, DG0 Potts, eds. Medibooks, Great Neck, NY, 1971. 3. Kumar B, Murphy WA, Whyte MP: Progressive diaphyseal dysplasia (Engelmann disease): scintigraphic-radiographic correlations. Radiology 140:87, 1981. 4. Beighton P, Durr L, Hamersma H: The clinical features of sclerosteosis: a review of the manifestations in twenty five affected individuals. Ann Intern Med 84:393, 1976.

7.14 Vertex Birth Molding Vertex birth molding refers to the mechanical changes in fetal head shape that result from cranial compression and bony adjustments within the cranial vault as the neonate in vertex presentation passes through the birth canal.1 Additional soft tissue swelling can significantly alter the shape of the neonatal head, and prolonged pressure against the fetal cranium can delay normal ossification in the vertex region (benign vertex craniotabes). The birth canal is a long, curved tube through which a mature fetal

Fig. 7-25. Progressive cranial hyperostosis at 4 months (left), 15 months (center), and 5 years (right) in a patient with craniodiaphysial dysplasia. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston, SC.)

Skull

255

Table 7-12. Syndromes with hyperostosis/sclerosis of skull Syndrome

Major Features

Causation Gene/Locus

Camurati-Engelmann

Diaphyseal dysplasia, muscle weakness, deafness

AD (131300) TGFB-1, 19q13.1

Craniodiaphyseal dysplasia

Facial distortion, mental retardation

AR (218300)

Craniometaphyseal dysplasia

Thick cranium, deafness, prominent eyes, facial weakness, osteosclerosis

AD (123000) ANKH, 5p15.2-p14.1

Dysosteosclerosis

Short stature, dental anomalies, mental retardation, multiple fractures

AR (224300)

Van Buchem type

Optic atrophy, deafness, diffuse osteosclerosis

AR (239100) 17q11.2

Worth type

Thick cranium, prominent mandible, dental cysts, osteosclerosis

AD (144750) LRP5, 11q13.4

Familial hyperostosis cranialis interna (Manni)

Recurrent facial palsy; variable impaired smell, taste, vision, and cochleovestibular function

AD (144755)

Fluorosis

Joint deformity, spine rigidity, myelopathy, dental mottling

Toxicity: none

Frontometaphyseal dysplasia

Coarse facial features, flexion contractures, arachnodactyly, deafness

XLR (305620) FLNA, Xq28

Jansen-metaphyseal dysplasia

Thick cranium, deafness, micrognathia, limb anomalies, multiple fractures, short stature

AD (156400) PTHR, 3p22-p21.1

Lenz-Majewski

Delayed closure fontanel, thick cranium, choanal atresia, joint laxity and/or contractures, cutis laxa

AD (151050)

McCune-Albright

Proptosis, diabetes, hypercalcemia, bowed long bones, genital anomalies, skin hyperpigmentation

Somatic mosaicism (174800) GNAS1, 20q13.2

Melnick-Needles

Large fontanel, proptosis, full cheeks, cleft or high palate, vertebral anomalies, skeletal defects

XLD (309350) FLNA, Xq28

Morgagni Stewart Morel

Hyperostosis frontalis interna, obesity, hypertrichosis, hyperprolactinemia, diabetes

AD (144800)

Oculodentodigital dysplasia

Microcephaly, hearing loss, cleft lip and palate, mental retardation

AD (164200) GJA1, 6q21-23.2

Osteopathia striata

Hearing loss, scoliosis, cleft palate

AD (166500)

Osteosclerosis, distal

Cortical hyperostosis

AD (126250)

Oto-palato-digital

Conductive deafness, cleft palate, facial anomalies, widely spaced toes

XLD (311300) FLNA, Xq28

Oto-palato-digital II

Microcephaly, small mouth, cleft palate, syndactyly

XLR (304120) FLNA, Xq28

Paget

Short stature, wide forehead, flat nasal bridge

AR (239000) TMFRSF11B, 8q24

Pagon-calvarial hyperostosis

Thick cranium, wide forehead, flat nasal bridge

XLR (302030)

Proteus

Hemihypertrophy, macrodactyly, subcutaneous tumors

Unknown (176920)

Pychodysostosis

Osteosclerosis, short distal phalanges, delayed closure of fontanels

AR (265800) Cathepsin K, 1q21

Sclerosteosis

Syndactyly, thickening and overgrowth of bone

AR (269500) SOST, 17q12-q21

Endosteal hyperostosis

head can only pass by rotating as it descends. There are a number of factors that influence the fetal cranial response to the normal forces of labor around the time of delivery, such as fetal head position and size, gestational age, maternal pelvic shape and dimensions, and the quality of uterine contractions.2,3 During normal vertex molding, moderate anteroposterior compression causes the frontal and occipital bones to slide under the parietal bones along the entire length of the coronal and lambdoid sutures. This elongates the occipitofrontal diameter to its greatest

possible extent to diminish the vertical diameter of the fetal head to its smallest dimensions. The cranial base is capable of bending slightly to allow elevation of the occipital plates, with biparietal pressure decreasing the transverse diameter enough to prevent the frontal and occipital bones from overriding the parietal bones when longitudinal pressure is applied.4 Vertex molding is characterized by an elevation of the vertex, an increase in the biparietal diameter, and an inward displacement of the occipital and frontal

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Craniofacial Structures

bones, which cause a reduction in the occipitofrontal diameter. The amount of molding is directly related to the length of labor, and normal vertex molding results from pressures from the maternal soft tissues, not the bony pelvis.5,6 A contracted pelvis is associated with more fetal head molding than that seen in normal deliveries, and excessive muscular contraction in the lower uterine segment results in more vertex molding, with an increased elevation of the fetal vertex. In a photographic and anthropometric study of vertex molding in 319 term infants delivered vaginally, several factors influenced the degree of molding.7 Infants born to primiparous women showed significantly more molding, as did those born after oxytocin-stimulated labors and via vacuum extraction. The duration of the first stage of labor did not influence the degree of molding, but a prolonged second stage in primiparous mothers was associated with more extensive molding. Fetuses born in occiput posterior and breech presentations showed significantly less molding than those born in occiput anterior presentation. Some degree of molding does occur within the uterus prior to labor, and repetitive Braxton-Hicks contractions throughout pregnancy were also a factor influencing the head shape of infants before the onset of labor.7 Extreme fetal head elongation due to vertex molding, from fetal cephalic fixation with persistent uterine contractions, has been noted via prenatal ultrasonography as early as 30 weeks gestation.8 During initial cervical dilation, pressure is greatest on the upper portion of the parietal bones, leading to a decrease in biparietal diameter, with a slight increase in the height and curvature of the vertex. At complete dilation, the biparietal diameter decreases to its smallest dimension, with continued elevation and curvature of the vertex and inward bending of both the frontal and occipital bones. As the fetus descends, pressure shifts to the lower portions of the parietal bones, causing them to rotate inward and move upward, thereby increasing the biparietal diameter, along with progressively widening the temporosquamosal and sagittal sutures. Recovery from this molded state takes place in two phases: first, an acute elastic recovery before the head is actually delivered, and second, a slower viscoelastic recovery during the postpartum period, which is usually completed within 3 to 7 days after delivery.9 With any normal fetus presenting in the vertex position, there may be appreciable molding of the head at birth. This is especially likely if the infant is the first born with the fetal head located deep in the uterine outlet for a prolonged time or if the mother has a prolonged second stage of labor and/or an incompletely dilated rigid cervix. The typical vertex molded newborn head is elongated and cylindrical and resumes a rounded shape within the 1st week of life (Fig. 7-26).1 The forehead tends to slope and the parieto-occipital region is prominently elevated into a conical shape. Head circumference measurements may be spuriously low because of the degree of molding. Persistent vertex molding usually reflects prolongation of the initial stages of normal fetal molding due to entrapment of the fetal head. The prognosis for spontaneous resolution of normal vertex birth molding, as well as the traumatic components that may accompany it, is generally excellent. With extensive vertex molding, management of the infant’s resting position will usually facilitate a complete return to normal form.1 If the baby is allowed to rest exclusively on the sides of the head, this conical deformation may become stabilized, and an elongated head shape will persist. Thus, it is important to bring pressure against the vertex to help collapse the conical head shape that may persist with extensive vertex molding.1 Along the leading part of the parieto-occipital region there may be edema of the skin and subcutaneous tissues, the so-called caput

Fig. 7-26. Vertex birth molding in a term newborn male whose head shape, with postnatal supine positioning and a blanket roll under the shoulders so as to put pressure against the top of the elongated fetal vertex cone, returned to normal appearance.

succedaneum. Associated craniotabes may also be extensive in the vertex region (Fig. 7-22C). Hemorrhages may occasionally be evident in the sclera and in the retina, and occasionally there may be a traumatic subperiosteal hemorrhage, most commonly in the outer table of the parietal bone. This will give rise to a soft, fluctuant mass. With time, its borders will become elevated and craterlike as the raised periosteum begins to deposit bone at its borders. The subperiosteal hemorrhage with a subsequent crater-rim of bone at its outer borders may give the impression of a skull fracture, sometimes raising the question of a depressed skull fracture, but such subperiosteal hemorrhage usually is a benign lesion. Rarely, posterior fossa hemorrhage in the term neonate can lead to severe molding with elongation of the head. These infants are readily distinguished from benign vertex molding by their neurologic deficits. References (Vertex Birth Molding) 1. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005. 2. Passingham RE: Changes in the size and organization of the brain in man and his ancestors. Brain, Behavior and Evolution 11:73, 1975. 3. Compton AA: Soft tissue and pelvic dystocia. Clin Obstet Gynecol 30:69, 1987. 4. Moloy HC: Studies of head molding during labor. Am J Obstet Gynecol 44:762, 1942. 5. Borell U, Fernstrom I: X-ray diagnosis of muscular spasm in the lower part of the uterus from the degree of molding of the fetal head. Acta Obstet Gynecol Scand 38:188, 1959. 6. Borell U, Fernstrom I: The mechanisms of labor in face and brow presentation. Acta Obstet Gynecol Scand 39:626, 1960. 7. Sorbe B, Dahlgren SS: Some important factors in the molding of the fetal head during vaginal delivery—a photographic study. Int J Gynaecol Obstet 21:205, 1983. 8. Carla SJ, Wyble L, Lense J, et al.: Fetal head molding: diagnosis by ultrasound and a review of the literature. J Perinatol 11:105, 1991. 9. McPherson GK, Kriewall TJ: The elastic modulus of fetal cranial bone: a first step towards an understanding of the biomechanics of fetal head molding. J Biomech 13:9, 1980.

Skull

7.15 Breech Head (Bathrocephaly) The frequency of singleton breech presentation at term is 3.1%, rising to 6.2% if multiple births are included.1–4 Among a large series of infants with deformations, 32% were in breech presentation, and 23% of malformed infants were also in breech presentation.3 Among 142 infants with spina bifida, 38% were in breech presentation and 68% had lower extremity weakness or paralysis, but among those with paralyzed legs, 93% manifested breech presentation.4 Thus, there are numerous fetal and maternal factors that can lead to breech presentation and thereby increase the risk for adverse outcomes. Though there is controversy concerning the best mode of delivery for infants in breech presentation, most studies suggest that the risk for neonatal morbidity and mortality is increased when term, singleton infants in breech presentation are delivered vaginally, as opposed to by cesarean section.3,5–8 Traumatic injuries following vaginal delivery of breech infants can include fractures and dislocations, brachial plexus injuries, facial nerve injuries, cerebral hemorrhages, bruising with hyperbilirubinemia, cervical cord injuries, cord prolapse, birth asphyxia, and testicular trauma.2–5 Breech presentation is more common in the primigravida, especially the older primigravida, presumably because of the shape of the uterus and the reduced space for fetal and uterine growth. The spatial restrictions associated with twinning also increase the likelihood of breech presentation, especially for the second in birth order. The prematurely born baby is also less likely to have shifted into the vertex birth position, and prematurity is more common with multiple births. Unless there is oligohydramnios or twinning, the premature fetus in breech presentation generally does not have deformations. This is because there has not been sufficient constraint to cause fetal deformation. Furthermore, breech presentation can be considered normal with prematurity, since at 32 weeks of gestation, 25% of all fetuses are in breech presentation, and after this time, the majority of fetuses shift into vertex presentation.3 Any situation that causes oligohydramnios, whether it be chronic leakage of amniotic fluid or lack of urine flow into the amniotic space, will restrict movement and greatly increase the chance of the fetus being in breech presentation. Alterations in the size and shape of the uterine cavity may also increase the frequency of breech presentation. This may be secondary to uterine structural anomalies or to myomas. The implantation and placement of the placenta may also be a factor, since 66% of placentas in breech deliveries implant in the cornualfundal region (versus 4% of vertex presentations), while 76% of vertex presentations implant on the midwall of the uterus (versus 4% of breech presentations).3 About 70% of fetuses in breech presentation have their legs extended in front of the abdomen.4 Breech presentation with the hips flexed and knees extended is termed frank breech. With the hips and knees flexed, it is called complete breech, and with the hips and knees extended, it is called footling breech. Prolonged breech position in late fetal life will give rise to increased uterine fundal pressure and molding of the fetal head, which may become retroflexed. This type of constraint results in anterior-posterior elongation of the head (dolichocephaly) with a prominent occipital shelf (bathrocephaly), and it is commonly termed breech head (Fig. 7-27).9,10 The shoulders are often thrust under the auricle, and there may also be distortion of the mandible. The legs may be caught in front of the fetus, tending to dislocate the hips and occasionally causing genu recurvatum of the knee and often cal-

257

caneovalgus position of the feet. In the complete breech position, with the legs flexed across the abdomen, the feet are liable to be compressed into an equinovarus position. The head is elongated into a dolichocephalic form, often with a prominent occipital shelf, termed bathrocephaly. There may be redundant folds of skin in the posterior neck as a result of compression due to retroflexion of the head. The lambdoid sutures may appear to be overlapping and/or ridged because of the fetal head constraint. The lower auricle may be forced upward into the location where the shoulder has been, and there may be a ‘‘hollow’’ appearance at the manubrial region of the mandible. The shoulder compression is often asymmetric, and hence there may be asymmetry of the mandible with an ‘‘upward tilt’’ on the more compressed side. Torticollis may occur secondary to asymmetric stretching or frank tearing of the sternocleidomastoid muscle or due to clavicular fracture during a traumatic breech vaginal delivery; 20% of torticollis occurs in babies who were in breech presentation.2,3 Of gravest concern is the vaginal delivery of a breech fetus with a hyperextended head (measured angle of less than 908 by ultrasound between the cervical vertebrae and the tangent plane of the occipital bone), which occurs in 11–15% of breech fetuses and is associated with cervical cord damage when delivered vaginally. In management of breech presentation, three factors must be considered.10 First is prevention of the deformities and complications of vaginal delivery by moving the fetus into the vertex position before the time of delivery by external cephalic version. Second is avoidance of the complications that relate to vaginal delivery of the breech fetus by utilizing cesarean section delivery, particularly when the fetal head is hyperextended. Third is the Fig. 7-27. Newborn male in prolonged breech presentation with bathrocephaly and equinovarus foot deformation. Breech positioning results in prominent occipital shelf with shoulders thrust up and head slightly retroflexed, resulting in bathrocephaly.

258

Craniofacial Structures

management of any deformations and complications after delivery of the breech fetus. After birth, the head shape and the mandibular retrusion tend to gradually return to normal, with no specific management being indicated.10 The most important question is whether an otherwise normal infant became caught in the breech position. If so, the prognosis, without birth complications, is usually excellent. If the infant was in the breech presentation because of a fetal problem, the prognosis relates predominantly to the basic diagnosis.10 An elongated, scaphocephalic head may also result from sagittal craniosynostosis. Usually palpation of the normally mobile sagittal suture is all that is required to clarify this diagnosis. Any doubt that might exist can usually be resolved by radiographs and follow-up examination, which shows progressive improvement toward normal form for the molded breech head.

Management of a transverse lie at term consists of expectant management, external cephalic version, or elective cesarean section.2,3 With expectant management, the spontaneous conversion rate to a longitudinal lie before labor is as high as 83%.2 This must be weighed against the increased risks of cord prolapse and birth trauma/asphyxia with persistent transverse lie versus the risks of cesarean section. The proven value of external cephalic version in term breech deliveries and in multiparous women with a transverse lie should not be extended to primiparous women with a transverse lie (who may have some kind of underlying pathology inhibiting the normal process of version). The compressive effects of a prolonged transverse lie or prolonged face and brow presentation can cause extensive facial compression (Fig. 7-28).4

References (Breech Head, Bathrocephaly)

In face and brow presentations, the face is the compressed presenting part, usually with extension of the head. Face presentation occurs in 1 to 2 per 1250 deliveries,5–7 and brow presentation occurs in one per 1444 deliveries.7 Face presentation is more common in multiparas (81%) and is variably associated with large infants weighing over 4000 grams (42%), small infants weighing less than 2300 grams (16%), and cephalopelvic disproportion.5–7 High parity, low birth weight, and cephalopelvic disproportion have also been proposed as etiologic factors in brow presentation, with relative cephalopelvic disproportion attributed to the presenting diameters of the fetal head being greater in brow presentation than in face or vertex presentations.7 In face presentation, the fetal head is hyperextended so that the occiput touches the back, and the presenting part is the fetal face between the orbital ridges and the chin.7 The growth of the fetal mandible and nose may be restrained. The position of comfort for the baby after birth is often with the neck retroflexed. As a consequence of compression of the chin and neck region with retroflexion, there tends to be redundant folds of skin in the

1. Lee KS, Khoshnood B, Sriram S, et al.: Relationship of cesarean delivery to lower birth-weight-specific neonatal mortality in singleton breech infants in the United States. Obstet Gynecol 92:769, 1998. 2. Dunn PM: Congenital postural deformities. Br Med Bull 32:71, 1976. 3. Dunn PM: Breech delivery: perinatal morbidity and mortality. 5th European Congress of Perinatal Medicine, Uppsala Sweden, 1976, p 57. 4. Dunn PM: Breech delivery: maternal and fetal aetiological factors. 5th European Congress of Perinatal Medicine, Uppsala Sweden, 1976, p 76. 5. Cheng M, Hannah M: Breech delivery at term: a critical review of the literature. Obstet Gynecol 82:605, 1993. 6. Thorpe-Beeston JG, Banfeld PJ, Saunders NJ: Outcome of breech delivery at term. Br Med J 305:746, 1992. 7. Roman J, Bakos O, Cnattingius S: Pregnancy outcomes by mode of delivery among term breech births: Swedish experience 1987–1993. Obstet Gynecol 92:945, 1998. 8. Albrechtsen S, Rasmussen S, Dalaker K, et al.: Perinatal mortality in breech presentation sibships. Obstet Gynecol 92:775, 1998 9. Haberkern C, Smith DW, Jones KL: The ‘‘breech head’’ and its relevance. Am J Dis Child 133:154, 1979. 10. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005.

7.16 Other Cranial Deformations Due to Abnormal Fetal Presentation Transverse Lie

Transverse lie occurs in 2.5 per 1000 deliveries and is associated with multiparity (90%), prematurity (13%), placenta previa (11%), polyhydramnios (8%), uterine anomalies (8%), and uterine myomas (3%), especially when the myomas are located in the lower uterine segment. Predisposing factors, such as uterine structural anomalies, prematurity, and placenta previa, are found in 66% of primiparas, but in only 33% of multiparas.1 In association with multiparity, women delivering transverse-lying infants tend to be older than those delivering vertex-presenting infants, with the other factors such as low-lying placenta, uterine anomalies, myomas, or prematurity occurring more frequently in primigravidas. Laxity of abdominal musculature in multiparous women is believed to be the predominant factor accounting for the liability toward transverse lie in these women. The occurrence of polyhydramnios may relate to being unable to swallow amniotic fluid because the wall of the uterus obstructs the mouth. Full frontal constraint may flatten the face, limit mandibular growth, and result in a retroflexed head with a prominent occipital shelf. There may be associated torticollis and/or scoliosis, as well as other deformations.

Face and Brow Presentation

Fig. 7-28. Face presentation with severe limitation of mandibular growth, which recovered after birth.

Skull

anterior upper neck, with retrognathia and an extremely prominent occipital shelf (Fig. 7-28). In some instances, the prolonged facial compression may lead to feeding difficulties, with difficulty swallowing. There may also be jaw subluxation and a palpable/ audible click as the jaw moves in and out of the socket (similar to that detected with a subluxable hip). Prolonged compression of the neck against the pubic ramus during delivery can cause trauma to the trachea or the larynx.8 In brow presentation, the fetal head is midway between flexion and hyperextension, and the presenting part is the brow between the orbital ridges and the anterior fontanelle.7 Most cases of brow presentation are diagnosed during labor and delivery, with cephalopelvic disproportion being the suspected cause for many persistent brow presentations, resulting in prolonged dysfunctional labors. The brow is unusually prominent, whereas the midface is less prominent than usual. There may be increased molding with persistent brow presentations in the frontoposterior position, making conversion more difficult and leading to excessively prolonged labors in 40–50% of cases.7,9 Face and brow presentation carry an increased risk of difficult labor. Cesarean section merits consideration, especially if the fetus is large, the mother has a relatively small pelvis, or there is a persistent mentum posterior presentation with arrested descent. If progress is being made in dilation and descent, the optimal management of face and brow presentations is expectant, but if progress ceases, delivery should be by cesarean section.7 Only anterior face positions can be delivered vaginally because of the inability of the fetal neck to further extend in the posterior position. After delivery of the fetus in face or brow presentation, there tends to be catch-up of the restrained facial growth toward normal.4 Though there is hyperextension of the fetal head in vaginal face presentation, vaginal delivery does not appear to pose the same risks for spinal and cerebellar injuries, as is seen with

259

breech presentation. The head gradually resumes a more normal posture, and the redundant skin that may be present on the anterior neck with face presentation usually resolves with postnatal growth. Usually no treatment other than gentle massage is indicated for congenital jaw subluxation.4 References (Other Cranial Deformations Due to Abnormal Fetal Presentation) 1. Gemer O, Segal S: Incidence and contribution of predisposing factors to transverse lie presentation. Int J Gynecol Obstet 44:219, 1994. 2. Phelan JP, Boucher M, Mueller E, et al.: The nonlaboring transverse lie: a management dilemma. J Reprod Med 31:184, 1986. 3. Lau WC, Fung HYM, Lau TK, et al.: A benign polypoid adenomyoma: an unusual cause of persistent fetal transverse lie. Eur J Obstet Gynecol Reprod Biol 74:23, 1997. 4. Graham JM Jr: Smith’s Recognizable Patterns of Human Deformation, ed 3. WB Saunders Company, Philadelphia, 2005. 5. Fougerousse CE: Management of face presentation. J Ark Med Soc 63:462, 1967. 6. Benedetti TJ, Lowensohn RI, Turscott AM: Face presentation at term. Obstet Gynecol 55:199, 1980. 7. Cruikshank DP, Cruikshank JE: Face and brow presentation: a review. Clin Obstet Gynecol 24:333, 1981. 8. Lansford A, Arias D, Smith BE: Respiratory obstruction associated with face presentation. Am J Dis Child 116:318, 1968. 9. Jennings PN: Brow presentation and vaginal delivery. Aust N Z J Obstet Gynecol 8:219, 1968.

7.17 Anomalies of the Sella Turcica Anomalies include abnormal size and/or shape of the sella turcica, which is the central depression within the sphenoid bone that

Fig. 7-29. A. Enlarged and J-shaped sella turcica in a 13-year-old male with mucopolysaccharidosis I–H. B. Enlarged, rounded sella turcica in a 10-year-old male with mucopolysaccharidosis I–H/I–S.

260

Craniofacial Structures

contains the pituitary gland. Assessment of the sella turcica can best be done radiographically or by computed tomography.1 Measurements of normal sella turcica size have been published, with considerable overlap between normal and abnormal ranges.2,3 Small sellas have been described in patients with hypopituitarism and myotonic dystrophy, whereas large sellas occur in patients with storage disorders, pituitary tumors, empty sella syndrome, craniopharyngioma, intrasellar aneurysm, untreated hypogonadism, and hypothyroidism (Fig. 7-29). A J-shaped sella describes the lateral profile of the sella turcica in which the sella resembles a ‘‘J’’ lying on its side. A J-shaped sella can occur as a normal variant but may also occur in individuals with calvarial enlargement or optic nerve gliomas.4 Bridged sella is caused by bony bridging between anterior and posterior clinoids and can be a normal variant. It can also be seen in nevoid basal cell carcinoma syndrome (Gorlin syndrome). The sphenoid bone consists of two main cartilaginous parts (hypophyseal cartilage) until the 7th or 8th month of gestation. The presphenoid will contribute to the anterior part of the sella turcica, while the postsphenoid forms the remainder. At birth, the sella is only a small depression; it begins to ossify soon after birth. Since 80% of the sella is occupied by the pituitary gland, it is not unusual for pituitary anomalies to cause abnormalities in the sella. In individuals with optic nerve gliomas the chiasmatic groove will appear scalloped, whereas in cases of calvarial enlargement it will appear elongated.4 Sellar abnormalities do not themselves require treatment. However, they are usually indicative of an underlying pathologic process that may require treatment. Prognosis therefore is dependent on the underlying cause. References (Anomalies of the Sella Turcica) 1. Pribam HW, duBoulay GH: Sella turcica. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 357. 2. DiChiro G, Nelson KB: The volume of the sella turcica. AJR Am J Roentgenol 87:989, 1962. 3. Oon CL: The size of the pituitary fossa in adults. Br J Radiol 36:294, 1963. 4. Swischuk LE: The normal pediatric skull: variations and artifacts. Radiol Clin North Am 10(2):277, 1972.

7.18 Anomalies of Foramen Magnum Definition

The foramen magnum is normally an oval-shaped opening in the occipital bone bound anteriorly by the basiocciput, laterally by the occipital condyles, and posteriorly by the supraocciput.1 Anomalies include either small or large size or a keyhole shape. Diagnosis

Magnetic resonance imaging best achieves diagnostic assessment of foramen magnum size or shape, although radiography or computed tomography may also be used (Fig. 7-30).2–4 Tables have been published indicating normal foramen magnum size.5 Effects of a small foramen magnum vary from producing no symptoms to being associated with weakness, apneic spells, hyperreflexia, hydrocephalus, and abnormal somatosensory potentials and/or polysomnograms.5 Achondroplasia is the most common syndrome in which a small foramen magnum occurs, but other skeletal dysplasias and disorders associated with scle-

Fig. 7-30. Foramen magnum size. Top: mean þ/1 standard deviation (SD) for transverse diameter. Bottom: mean þ/1 SD for sagittal diameter. (From Heckt et al.5)

rosis of the skull can also lead to a small foramen magnum. Patients with achondroplasia usually do not experience neurologic complications until the foramen magnum is 4 standard deviations (SD) or more below the mean,5 and 96% of achondroplastic patients with neurologic manifestations have foramen magnum sizes more than 3 SD below the mean.6 A small foramen magnum can be accompanied by a short cranial base, and anterior herniation of the brain through an open metopic suture has been known to occur in such cases.1 A large foramen magnum usually results from chronic increased intracranial pressure or from direct effects of an expanding process within the foramen magnum (syringomyelia, Arnold-Chiari malformation).3–9 Large foramen magnum has also been described in children with either Rubinstein-Taybi or Angelman syndrome.10,11 Asymmetry of the foramen magnum occurs with craniovertebral anomalies or premature synostosis of one or more of the occipital synchondroses.8 Children with the latter may tend to hold their heads

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obliquely. A keyhole-shaped foramen magnum has been described in the hydrolethalus syndrome.9,12

Table 7-13. Foramina and canals of the base of the cranium Foramen or Canal

Primary Structure Within

Etiology and Distribution

Foramen rotundum

Maxillary nerve, occasionally emissary veins

Foramen ovale

Mandibular nerve

Foramen spinosum

Middle meningeal artery and vein, meningeal branch of mandibular nerve

Foramen of vesalius

Vein connecting cavernous sinus and pterygoid plexus

Canal of Arnold

Lesser superficial petrosal nerve

Foramen lacerum

Meningeal branch of ascending pharyngeal artery and nerve of pterygoid canal

Prognosis, Prevention, and Treatment

Pterygoid canal

Nerve and artery of pterygoid canal

Prognosis for small foramen magnum is variable, but the most serious outcome of brain stem compression may be sudden death. Recommended treatment is suboccipital craniectomy.5 The prognosis for a large or abnormally shaped foramen magnum is dependent on the underlying cause.

Carotid canal

Internal carotid artery and nerve, small veins

Jugular foramen

Inferior petrosal sinus, glossopharyngeal nerve, internal jugular vein, vagus nerve, accessory nerve, meningeal branches of ascending pharyngeal and occipital arteries

Greater palatine foramen

Greater palatine artery and branch of sphenopalatine nerve

Lesser palatine foramen

Lesser palatine nerve and branches from greater palatine artery

The foramen magnum is an oval-shaped orifice bound by the exoccipital, supraoccipital, and baso-occipital bones, which develop and grow by enchondral ossification. These bones are separated by two anterior and two posterior synchondroses that begin to fuse at 12 months and completely fuse by 3 to 4 years and 7 years, respectively.5 If enchondral ossification is abnormal, suture fusion premature, or both, a small foramen magnum is the result. Premature synostosis of one or two sutures may cause asymmetry.8

References (Anomalies of Foramen Magnum) 1. McRae DL: Craniovertebral junction. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 260. 2. Deck MDF: Computed tomography and magnetic resonance imaging of the skull and brain. Clin Imaging 13:95, 1989. 3. Bliesener JA, Schmidt LR: Normal and pathologic growth of the foramen occipitale magnum shown in the plain radiograph. Pediatr Radiol 10:65, 1980. 4. Hone H, Watanabe K, Kusumoto S, et al.: Optimal positioning for CT examinations of the skull base. Eur J Radiol 7:225, 1987. 5. Hecht JT, Nelson FW, Butler IJ, et al.: Computerized tomography of the foramen magnum: achondroplastic values compared to normal standards. Am J Med Genet 20:355, 1985. 6. Wang H, Rosenbaum AE, Reid CS, et al.: Pediatric patients with achondroplasia: CT evaluation of the craniocervical junction. Radiology 164:515, 1987. 7. Cohen MM Jr, Kreiborg S: The central nervous system in the Apert syndrome. Am J Med Genet 35:36, 1990. 8. Coin CG, Malkasian DR: Foramen magnum. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 275. 9. Salonen R, Herva R, Reijo N: The hydrolethalus syndrome: delineation of a ‘‘new’’ malformation syndrome based on 28 patients. Clin Genet 19:321, 1981. 10. Hennekam RCM, VanDenBoogaard MJ, Sibbles BJ, et al.: RubinsteinTaybi syndrome in the Netherlands. Am J Med Genet (suppl)6:17, 1990. 11. William CA, Hendrickson JE, Cantu ES, et al.: Angelman syndrome in a daughter with del(15)(qllqI3) associated with brachycephaly, hearing loss, enlarged foramen magnum and ataxia in the mother. Am J Med Genet 32:333, 1989. 12. Krassikoff N, Konick L, Gilbert EF: The hydrolethalis syndrome. Birth Defects Orig Artic Ser XXIII(1):411, 1987.

7.19 Anomalies of the Other Basal Foramina and Canals Definition

Anomalies of other basal foramina can include abnormal configuration or size of openings in the basal part of the skull that transmit nerves, blood vessels, or both.

Diagnosis

There are at least 11 foramina and canals in the base of the cranium through which blood vessels and nerves enter or leave the intracranial space (Table 7-13).1 Increased intracranial pressure aneurysms, tumors, and arteriovenous malformations can all cause pathologic enlargement of these foramina. Congenital anomalies include asymmetry of paired foramina, communication with other foramina, and absence if the transmitted structure is absent. Diagnosis of these anomalies is achieved radiographically or by using basal tomography, although they usually produce incidental findings. Reference (Anomalies of the Other Basal Foramina and Canals) 1. Sondheimer FK: Basal foramina and canals. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 287.

7.20 Basilar Impression Definition

Basilar impression is a malformation or deformation of the cranial base consisting of indentation of the base of the skull at the craniospinal junction. Primary basilar impression is a malformation in which the base of the skull and the upper two cervical vertebrae fail to segment and exist as a bony mass within which the posterior fossa, brain stem, and upper cervical spinal cord may become compressed. Some degree of basilar impression may occur with platybasia, defined as a craniocervical angle of greater than 1408. Diagnosis

Basilar impression may be suspected when there is limited movement and shortening of the neck, but definitive diagnosis

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Craniofacial Structures

Fig. 7-31. Basilar impression. Platybasia with basilar impression at ages 10 months and 8 years in a male with Hajdu-Cheny syndrome. Note also the dolichocephaly, absence of frontal sinuses, and wormian bones. (Courtesy of Drs. Rodney I. Macpherson and G. Shashidhar Pai, Medical University of South Carolina, Charleston, SC.)

requires radiography, computed tomography scan, or magnetic resonance imaging scan (Fig. 7-31).1 In basilar impression, the odontoid moves cephalad and can protrude into the foramen magnum, thus compromising function of the spinal cord, brain stem, and cerebellum as well as impeding the flow of cerebrospinal fluid. Symptoms include pain, limitation of movement, increased intracranial pressure, hydrocephalus, and cranial nerve symptoms.2–4 Symptoms may appear suddenly or develop over several months. Etiology and Distribution

Primary basilar impression is caused by a congenital defect of osseous structures in the cervico-occipital region and can occur as an autosomal dominant trait.4 Secondary basilar impression is related to disease of the skull. It has been reported in association with Paget disease, histiocytosis X, rheumatoid arthritis, rickets, and hypoparathyroidism. It also occurs in several skeletal dysplasias and malformation syndromes (Table 7-14). The incidence in the general population is one per 3300, although it may be more common in Eskimos and in cultures where carrying heavy loads on the top of the head is practiced.5 Prognosis, Prevention, and Treatment

The prognosis is quite variable. Affected individuals may be asymptomatic, develop sudden or progressive symptoms, or die suddenly. Most patients present with symptoms in late childhood or early adulthood, which corresponds to the time of closure of the anterior synchondroses (6 years) and spheno-occipital synchondrosis (25 years) of the occipital bone.3 Treatment consists of immobilization or, in severe cases, decompression of the foramen

magnum, laminectomy of the first and second cervical vertebrae, and cervico-occipital fusion.1 Shunting for hydrocephalus may also be indicated. References (Basilar Impression) 1. Rush PJ, Berbrayer D, Reilly DJ: Basilar impression and osteogenesis imperfecta in a three year old girl: CT and MRI. Radiology 19:142, 1989. 2. McRae DL: Craniovertebral junction. In: Radiology of the Skull and Brain. TH Newton, DG Potts, eds. Medibooks, Great Neck, NY, 1971, p 260. 3. Adam AM: Skull radiograph measurements of normals and patients with basilar impression: use of Landzert’s angle. Surg Radiol Anat 9:225, 1987. 4. Bull JWD, Nixon WLB, Pratt RTC: The radiologic criteria and familial occurrence of primary basilar impression. Brain 78:229, 1955. 5. Teodori JB, Painter MJ: Basilar impression in children. Pediatrics 74:1097, 1984.

7.21 Cephalhematoma and Caput Succedaneum Cephalhematoma is a subperiosteal hemorrhage, which may enlarge after delivery and sometimes takes weeks to resolve, while the scalp edema of caput succedaneum is maximal in size at birth and usually resolves within a few days. Both lesions are believed to result from an injury to the cranial periosteum during labor in a traumatic delivery, but cephalhematomas are sometimes detected as echogenic bulges on the cranium during prenatal ultrasound evaluations, suggesting that they may also arise in utero. Traumatic subperiosteal hemorrhages occur most commonly in the outer

Skull

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Table 7-14. Syndromes with basilar impression Syndrome

Major Features

Causation Gene/Locus

Achondroplasia

Frontal bossing, large head, short stature, lordosis

AD (100800) FGFR3, 4p16.3

Ankylosing spondylitis

Iridocyclitis, sacroiliitis, bamboo spine, atrio-ventricular block

AD (106300) 6p21.3

Cleidocranial dysplasia

Large head, wide fontanels, delayed dentition, hypoplastic clavicles

AD (119600) CBFA1, 6p21

Crouzon

Brachycephaly, kleeblattschadel, ridged sutures, deafness, convex beaked nose, tooth anomalies, malocclusion

AD (123500) FGFR2, 10q26

Down

Hypotonia, mental retardation, single palm creases, distinctive face, atlanto-occipital spinal instability

Chromosomal Trisomy 21

Empty sella turcica with generalized dysplasia

Thick calvarium, sclerosis of skull, wormian bones, ear anomalies, prominent eyes, meningocele, abnormal gait

AD (130720)

Familial primary basilar impression

Syringomelia, Horner syndrome, limb muscle weakness, kyphoscoliosis

AD (109500)

Hajdu-Cheney (acroosteolysis)

Delayed fontanel closure, wormian bones, wide cranial sutures, short stature, oligodontia, vertebral anomalies

AD (102500)

Hyperparathyroidism (primary)

Hypercalcemia, primary chief cell hyperplasia

AD (145000) HRPT2, 1q25-q31, 11q13

Hypophosphatasia

Globular skull, short limbs, blue sclerae

AR (241510) AD (146300) ALPL, 1p36.1-p34

Klippel-Feil

Cervical vertebral fusions, malformed laryngeal cartilages, deafness

AD (148900) 8q22.2

Larsen

Multiple congenital joint dislocations, flat nasal bridge, prominent forehead, accessory carpal bones, broad thumbs, cylindrical fingers with short terminal phalanges, cleft palate

AD (150250) FLNB, 3p14.3

Mucopolysaccharidosis

Coarse facies, dysostosis multiplex congenita, corneal clouding, hernias, hepatosplenomegaly

AR, XLR Multiple loci

Osteogenesis imperfecta

Blue sclerae, fractures, deafness

AD (166200, 259400) Multiple loci: COL1A1, 17q21.31-q22 COL1A2, 7q22.1

Pycnodysostosis

Osteosclerosis, short distal phalanges, delayed closure of fontanels

AR (166200) (259400) (259420) Cathepsin K, 1q21

Syringomelia

Bilateral Babinski sign, scoliosis, Arnold-Chiari malformation

AD (186700)

Thanatophoric dysplasia

Wide sutures, short limbs, narrow thorax, platyspondyly

AD (187600) FGFR3, 4p16.3

table of the parietal bone, giving rise to a soft, fluctuant mass. With time, its borders will become elevated and craterlike, as the raised periosteum begins to deposit bone at its borders. Calcified cephalhematomas resolve slowly over the course of the 1st year during the normal process of cranial remodeling with normal calvarial growth. Cephalhematoma is a hemorrhage, which occurs beneath the periosteum with no extension over a sutural margin, and definite palpable edges are usually evident. Among 16,292 fetuses undergoing comprehensive ultrasound examinations between 1993 and 1996, seven cephalhematomas were detected on exams done between 23 and 38 weeks (five occipital and two temporal). The diagnosis was confirmed at birth to be cephalhematoma in two cases, and caput succedaneum in the

remaining five cases, but it was not possible to make this distinction prenatally. The seven affected infants were not delivered by vacuum extraction or forceps, none had any signs of intracranial hemorrhage or skull fracture by ultrasound, and none required any treatment, including blood transfusion. Five of the seven cases had associated premature rupture of membranes, with oligohydramnios in four cases, suggesting this might have played a role.1 Cephalhematoma, subdural hematoma, and caput succedaneum have all been found more frequently in infants delivered by vacuum extraction than in infants delivered spontaneously.2,3 In a prospective randomized trial of 322 cases delivered via vacuum extraction, cephalhematomas were strongly associated with the

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Craniofacial Structures

station of the presenting part, asynclitism, and increasing application to delivery time, but none of these infants experienced any long-term complications or needed blood transfusions.4 There have also been reports of fetal death and stillbirth after prenatal diagnosis of fetal subdural hematomas following suspected or confirmed trauma.5–8 Thus, cephalhematomas can occur prenatally before the onset of labor, especially when there is premature rupture of membranes with prolonged oligohydramnios. Maternal abdominal trauma can result in serious subdural hematomas, which can be seen by ultrasound prenatally, and this type of intracranial hemorrhage may threaten fetal survival. Since vacuum extraction has been associated with cephalhematomas, there are concerns about whether this mode of delivery may result in more serious intracranial vascular injuries (subdural, cerebral, intraventricular, or subarachnoid hemorrhages). Among 583,340 liveborn singleton California infants weighing 2500 to 4000 grams, who were born to nulliparous women between 1992 and 1994, the rate of intracranial hemorrhage was significantly higher among infants delivered by vacuum extraction, forceps, or cesarean section during labor than among infants delivered spontaneously.9 There was an incremental increase in the rate of hemorrhage if more than one method of delivery was used. Since the rate of hemorrhage was not significantly higher among infants delivered by cesarean section before labor, much of the morbidity associated with operative vaginal delivery is thought to be due to an underlying abnormality of labor rather than the specific operative procedure. The rate of intracranial hemorrhage has decreased by three times (to less than 1%) since the substitution of plastic cups for metal cups in vacuum extractors during the 1980s.9 Cephalhematomas are benign lesions, which begin as soft fluctuant masses within the periosteum of the parietal bones and then slowly calcify over the 1st year of life. At the cranial vertex, there may be edema of the skin and subcutaneous tissues, the socalled caput succedaneum. Caput succedaneum can cross suture lines and is maximal at birth, resolving in just a few days. The subperiosteal hemorrhage associated with a cephalhematoma may manifest a subsequent crater-rim of bone at its outer borders, sometimes giving the impression of a depressed skull fracture, but cephalhematoma is a benign lesion.

7.22 Miscellaneous Anomalies of the Skull Paracondylar Process

A paracondylar process is an asymptomatic anatomic variant that is visible only on computed tomography and consists of a process of bone that arises from the lateral aspect of the condyloid process and extends toward the transverse process of the atlas. It is generally of no significance but has been reported in children with hemifacial microsomia. It is present in 7–8% of all human skulls.1 Bathrocephaly

Bathrocephaly is a skull deformation that appears as a steplike deformity at the back of the skull, and it is also termed an occipital shelf. It is not associated with craniosynostosis but can occur secondary to breech position in utero (Figs. 7-27 and Fig. 7-32). When associated with breech presentation (Section 7.15), the head is usually also dolichocephalic in shape. When associated with other Fig. 7-32. Schematic showing bathrocephaly, a steplike deformation of the skull (arrow) at the lambdoid suture.

References (Cephalhematoma and Caput Succedaneum) 1. Petrikovsky BM, Schneider E, Smith-Levitin M, et al.: Cephalhematoma and caput succedaneum: do they always occur in labor? Am J Obstet Gynecol 179:906, 1998. 2. Fall O, Ryden G, Finnstrom K, et al.: Forceps or vacuum extraction? A comparison of effects on the newborn infants. Acta Obstet Gynecol Scand 65:75, 1986. 3. Teng FY, Sayre JW: Vacuum extraction: does duration predict scalp injury? Obstet Gynecol 89:281, 1997. 4. Bofill JA, Rust OA, Devidas M, et al.: Neonatal cephalhematoma from vacuum extraction. J Reprod Med 42:565, 1997. 5. Demir RH, Ggleisher N, Myers S: A traumatic antepartum subdural hematoma causing fetal death. Am J Obstet Gynecol 160:619, 1989. 6. Gunn TR, Becroft DMO: Unexplained intracranial haemorrhage in utero: the battered fetus? Aust N Z J Obstet Gynaecol 24:17, 1984. 7. Winter TC, Mack LA, Cyr DR: Prenatal sonographic diagnosis of scalp edema/cephalhematoma mimicking an encephalhematoma mimicking an encephalocele. AJR Am J Roentgenol 161:1247, 1993. 8. Grylack L: Prenatal sonographic diagnosis of cephalhematoma due to pre-labor trauma. Pediatr Radiol 12:145, 1982. 9. Towner D, Castro MA, Eby-Wilkens E, et al.: Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 341:1709, 1999.

Fig. 7-33. Schematic of the bony exostoses of the inferior occiput (arrow) seen in the occipital horn syndrome (Ehlers-Danlos type IX).

Skull

abnormal fetal positions, such as transverse lie, face presentation, or brow presentation (Section 7.16), the forehead may be compressed. Hence, any constraining fetal position that retroflexes the head against the posterior neck and shoulders can result in bathrocephaly. Other anomalies related to breech presentation are often present, and these include dislocated hips, clubfoot, or uplifted ear lobes. In general, this anomaly is of no significance, and spontaneous improvement usually occurs. Prognosis is poor only if breech position is secondary to malformation or neurologic dysfunction.2 Occipital Horns

Occipital horns are bony protuberances situated on both sides of the foramen magnum and pointing caudad (Fig. 7-33). They have

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only been described in individuals with an X-linked syndrome that also includes obstructive uropathy, joint laxity, and other features of Ehlers-Danlos type IX.3 References (Miscellaneous Anomalies of the Skull) 1. Silverman FN: Caffey’s Pediatric X-Ray Diagnosis, ed. 8. Year Book Medical Publishers, Chicago, 1985, p 25. 2. Haberkorn CM, Smith DW, Jones KL: The ‘‘breech head’’ and its relevance. Am J Dis Child 133:154, 1979. 3. Lazoff SG, Rybak JJ, Parker BR, et al.: Skeletal dysplasia, occipital horns, intestinal malabsorption, and obstructive uropathy—a new hereditary syndrome. Birth Defects Orig Artic Ser XI(5):71, 1975.

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8 Facial Bones Karen Gripp and Luis Fernando Escobar

H

umans are very adept at recognizing one another. This ability is largely based on the identification of faces. The uniqueness of each human face, with the possible exception of monozygotic twins, allows for identification and recognition of an individual with deeper implications in human interaction and, more important, in social functioning. The recognition of an individual face, whose combination of features is remembered as belonging to a certain person, may be compared to the recognition of a syndrome diagnosis based on certain characteristics of the facial structures. The shape of individual facial structures can be recognized, but the combination of findings may lead to the identification of a facial ‘‘gestalt’’ that may be associated with a genetic syndrome. On a more formal level, anthropometric measurements of facial structures may be taken, and profiles of these measurements can be constructed. Facial indexes such as those developed by Blumenbach and Camper in the eighteenth century demonstrate the fascination that the facial bones provoked in early ‘‘dysmorphologists.’’ Attempts to objectively recognize the abnormal from the normal facial appearance have led to the development of dysmorphic indexes.1 Today, computer-driven facial recognition uses the correlation of the measurements to identify individual faces or to identify a pattern known to be characteristic for a specific syndrome. Based on consistent patterns of age-dependent growth and maturation of facial structures, facial photographs may be manipulated to predict the changes with age. The human facial form results from the interaction between the skeletal and soft tissue elements. The skeletal framework provides the structural support of the face and is largely responsible for size, shape, and proportions of each facial structure.2,3 Anomalies such as cyclopia or proboscis are clearly associated with structural abnormalities of the facial skeleton; however, more subtle facial anomalies may lack evident skeletal findings that would be identifiable only on facial radiographs or other imaging studies. Consistent differences in the facial bony structures may underlie the characteristic facial findings that would allow syndrome recognition. The face may be conveniently divided into thirds—the upper, middle, and lower—delimited by horizontal planes passing through the pupils of the eyes and the rima oris. The three parts correspond generally to the embryonic frontonasal, maxillary, and mandibular processes, respectively. The upper third of the face is predominantly of neurocranial composition. The middle third is

skeletally complex, composed in part of the cranial base, and involves both the nasal extension from the upper third of the face (frontonasal process) and the maxillary processes from the first branchial arch. The lower third is composed skeletally of the mandible. Although these three segments develop through similar embryologic processes, their individual origins differ. The form of the facial bones is not as dependent on brain development as are the calvarial bones. Anencephaly, for example, presents with no calvarial bones but relatively good formation of the cranial base and skeletal facial structures. The various facial bones are derived as portions of the neurocranium, chondrocranium, or viscerocranium. These skeletal elements have neural crest or paraxial mesodermal origins. The chondrocranium is the cartilaginous precursor of the cranial base and the capsules surrounding the nasal and auditory organs. The base of the skull becomes part of the neurocranium, the bony tissue that surrounds the brain. The cranial base ossifies endochondrally, while the vault undergoes intermembranous ossification. The viscerocranium is comprised of neural crest-derived bones of the jaws (maxilla and mandible) as well as the zygoma (part of the temporal bone), nasal, and lacrimal bones. The teeth, with the exception of their enamel, which is ectodermally derived, are also comprised of neural crest cells. Craniofacial development is an extremely complex process that requires a perfectly organized interaction and integration between multiple specialized tissues, such as ectoderm, neural crest, mesoderm, and pharyngeal endoderm. The complex mechanisms and molecular cascades continue to be an enigmatic process. It has not been until recent years that molecular biologists have been able to focus on specific mechanisms involved in craniofacial development.4–6 We are beginning to understand some of these mechanisms, such as those that involve fibroblast growth factor or nodal signaling and the role of homeobox genes. The complex interplay of numerous signaling cascades controls the proliferation and differentiation of specific cell populations. A thorough understanding of these developmental events is essential to defining the basis for the patterning of individual facial bones and their relative positioning. This chapter includes information regarding the most common defects that affect the facial skeleton. We review their 267

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frequency and their involvement in specific syndromic disorders. We limit our discussion to the frontal bones, orbits, zygomas, the nasal skeletal area, the maxillary structures, and the mandible.

into a triangular shape, leading to trigonocephaly. The orbits assume an excessively mesial position, which may be apparent as ocular hypotelorism.

References

Diagnosis

1. Escobar LF, Bixler D, Padilla LM: Quantitation of craniofacial anomalies in utero: fetal alcohol, Crouzon syndromes and Thanatophoric dysplasia. Am J Med Genet 45:25, 1993. 2. Friede H: Normal development and growth of the human neurocranium and cranial base. Scand J Plast Reconstr Surg 15:163, 1981. 3. Lavelle CL: An analysis of foetal craniofacial growth. Ann Hum Biol 1:269, 1974. 4. Trainor PA: Making headway: the roles of hox genes and neural crest cells in craniofacial development. Scientific WorldJournal 3:240, 2003. 5. David NB, Saint-Etienne L, Tsang M, et al.: Requirement for endoderm and FGF3 in ventral head skeleton formation. Development 129:4457, 2002. 6. Couly G, Creuzet S, Bennaceur S, et al.: Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 129:1061, 2002.

8.1 Premature Metopic Sutural Synostosis Definition

Premature metopic sutural synostosis is the premature fusion of the metopic suture in utero. It deforms the anterior cranial fossa

Premature metopic sutural synostosis is characterized by the presence of a keel-like ridge at the site of the metopic suture. The head, viewed from above, appears triangular (Fig. 8-1). Physical examination of the affected individual may show a vertical bony ridge of the forehead that coincides with the anatomic midline. Due to bony hypotelorism, the superolateral aspect of the orbits is positioned more mesially and posteriorly than normal. The occiput bulges with compensatory expansion to accommodate brain growth.1 In patients in whom metopic synostosis is suspected, radiologic confirmation is obligatory. Hypotelorism characterizes the anteroposterior skull films, in addition to low-set lateroinferior orbital angles. The roof of the orbits seems to be highly placed in relation to the horizontal plate of the ethmoid bone. Computerized tomography (CT) may show compression of the anterior cranial fossa and the cribriform plate in the midline.1 When 3-D CT study is used to identify metopic synostosis, it is important to note that physiologic metopic closure occurs between 3 and 9 months of age; closure earlier than 3 months should be suspected abnormal.2 The spectrum of facial morphology associated with metopic synostosis is broad, from minor prominence of the forehead to severe aesthetic deformity.

Fig. 8-1. A. Preoperative right lateral, frontal, and top views of the craniofacies in a patient with isolated premature metopic synostosis. B. Right lateral, frontal, and top views of patient 3 months after surgical correction. Note the reduction of hypotelorism. (From Marsh and Vannier.1)

Facial Bones

Two types of premature metopic sutural synostosis can be recognized. Isolated metopic synostosis occurs at a rate of approximately 0.3 per 1000 live births and is usually sporadic. In the second type, metopic synostosis is associated with multiple congenital anomalies.3 These anomalies include aortic stenosis, tetralogy of Fallot, omphalocele, cleft palate, hypospadias, multiple hemivertebrae, congenital abducens nerve palsies, absence of the corpus callosum, and agenesis of the septum pellucidum.1 It is not clear at present whether the different phenotypical combinations seen in these patients represent different conditions or belong together in a wide spectrum of abnormalities with a single etiology. Mental retardation is rarely seen as part of isolated early metopic sutural synostosis. There is no evidence that a disturbance in brain growth as a result of the cranial deformity contributes to the retardation occasionally seen. Syndromes that include metopic synostosis are listed in Table 8-1. Etiology and Distribution

As with any other type of early synostosis, early metopic fusion may lead to a sequence of developmental abnormalities. In this case, striking changes in the facial skeleton may result. Unfortunately, the mechanism that prematurely initiates this normal process of development is unknown. During fetal life the two frontal bones are separated by a sutural space, which consists of fibrous tissue and mesenchymal cells responsible for the growth of the frontal bones. This mesenchymal tissue has the potential to differentiate either into bone or into secondary cartilage.12 For the metopic suture, it is suggested that closure of the sutural space is due to the differentiation of the mesenchyme into chondroid tissue instead of bone. The chondroid tissue, then, is responsible for the growth of each frontal bone toward the other and constitutes the first bridge of union between the two bones.13 Active bone resorption prevents

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this primary union from closing prematurely. Any interruption either during mesenchymal differentiation or in the maintenance of an open sutural space can lead to premature metopic synostosis. It has been suggested that absence of interosseous movement might lead to sutural fusion. Experimental evidence seems to support this; immobilization of adjacent bone by cyanoacrylate glue, bone grafting, or periosteal grafting induces synostosis.14 This also would be consistent with the occurrence of metopic synostosis in infants with intrauterine constraint of the cranium due to uterine malformation or twinning.15 Teratogens causing trigonocephaly include valproic acid and hydantoin (Table 8-1).7,16 Metopic synostosis constitutes 4–10% of all cases of craniosynostosis,1,17,18 and male to female ratios of 3:4 and 2:3 have been reported.17 Prognosis, Treatment, and Prevention

Early surgical intervention strikingly improves the growth of the facial skeleton in isolated metopic synostosis.19–21 Bicoronal craniectomies can be helpful to free the frontal bones, with excision of the keel down to the frontonasal suture. Orbital advancement may be necessary to restore a normal brow contour. Straightening of the supraorbital bar and reshaping of the forehead using variations according to the deformity are very satisfactory. Following this procedure, hypotelorism tends to disappear clinically and diminishes radiologically.21 Recent forensic findings in Salzburg, Austria, suggest that the great musician Wolfgang Amadeus Mozart had premature synostosis of the metopic suture.22 This was characterized, in his case, by mild hypotelorism, reduction of the orbital volume, and a supraglabellar sulcus divided in the midline by a small protuberance that formed a ridge near the nasion. The prognosis of affected individuals is very encouraging, and, unless seen in multiple anomaly syndromes, metopic synostosis should

Table 8-1. Syndromes associated with premature metopic suture synostosis Causation Gene/Locus

Syndrome

Prominent Features

Baller-Gerold4

Growth deficiency, craniosynostosis, radial aplasia/hypoplasia, short curved ulna, missing small bones of the hands, imperforate anus, anteriorly placed anus, mental deficiency (50%)

AR (218600)

Chromosome abnormalities5

Multiple congenital anomalies, learning differences

Abnormal karyotype

Deletion 9p

Craniosynostosis, trigonocephaly, midfacial hypoplasia, short nose, anteverted nares, long philtrum, poorly formed ears, extra digital flexion creases, excess in whorl patterns, heart defect

(158170) Abnormal karyotype

Hydantoin, prenatal7

Growth deficiency, ocular hypertelorism, broad nasal bridge, short nose, clefting, hypoplasia of distal phalanges, low arch dermal ridges, digitalized thumb, short neck, rib anomalies, variable mental function

(132810) Hydantoin teratogenesis

Jacobsen8

Low-set ears, ptosis, congenital heart disease, hypospadias, labial and clitoral hypoplasia, joint contractures, hypotonia, mental retardation, thrombocytopenia

(147791) Monosomy 11q23-qter

Opitz-C9

Craniosynostosis, narrow bifrontal diameter, microcornea, short broad nose, long philtrum, thin lips, high arched palate, micrognathia, rhizomelic shortening and postaxial hexadactyly of all limbs, thin ribs, humeral and femoral shortening

(211750) Unknown

Saethre-Chotzen10

Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, hallux valgus

AD (101400) TWIST, 7p21

Trigonocephaly-short staturedevelopmental delay11

Marked frontal vertical ridge, narrow forehead, hypertelorism, growth retardation, variable mental development

XL (314320)

Trigonocephaly, isolated5

Craniosynostosis limited to the metopic region, giving a prow appearance to the forehead, normal brain development

AD (190440, 275600)

6

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Craniofacial Structures

be considered a relatively benign form of craniofacial synostosis. No reports of prenatal diagnosis of metopic synostosis can be found in the literature, but ultrasonography may be helpful in detecting this abnormality via fetal cephalometry and detection of unusual craniofacial shape. Prevention methodology is limited to prenatal counseling. References (Premature Metopic Sutural Synostosis) 1. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. JL Marsh, MW Vonnier, WG Stevens, eds. CV Mosby, St. Louis, 1985, p 154. 2. Vu HL, Panchal J, Parker EE, et al.: The timing of physiologic closure of the metopic suture: a review of 159 patients using reconstructed 3D CT scans of the craniofacial region. J Craniofac Surg 12: 527, 2001. 3. Lajeunie E, Le Merrer M, Marchac D, et al.: Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. Am J Med Genet 75:211, 1998. 4. Cohen MM Jr, Toriello HV: Is there a Baller-Gerold syndrome? Am J Med Genet. 61:63, 1996. 5. Azimi C, Kennedy SJ, Chitayat D, et al.: Clinical and genetic aspects of trigonocephaly: a study of 25 cases. Am J Med Genet 117A:127, 2003. 6. Deroover J, Fryns JP, Parloir C, et al.: Partial monosomy of the short arm of chromosome 9: a distinct clinical entity. Hum Genet 44:195, 1978. 7. Hanson JW, Myrianthopoulos NC, Sedgwick MHA, et al.: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976. 8. Penny LA, Dell’Aquila M, Jones MC, et al.: Clinical and molecular characterization of patients with distal 11q deletions. Am J Hum Genet 56:676, 1995. 9. Lalatta F, Clerici Bagozzi D, Salmoiraghi MG, et al.: ‘C’ trigonocephaly syndrome: clinical variability and possibility of surgical treatment. Am J Med Genet 37:451, 1990. 10. Paznekas WA, Cunningham ML, Howard TD, et al.: Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet 62:1370, 1998. 11. Say B, Mayer J: Familial trigonocephaly associated with short stature and developmental delay. Am J Dis Child 135:711, 1981. 12. Hall BK: Tissue interactions and chondrogenesis. In: Cartilage: Development, Differentiation and Growth, vol. 2. BK Hall, ed. Academic Press, New York, 1983, p 188. 13. Manzanares MC, Goret-Nicaise M, Dhem A: Metopic sutural closure in the human skull. J Anat 161:203, 1988. 14. Engstrom C, Kiliaridis S, Thilander B: Facial suture synostosis related to altered craniofacial bone remodelling induced by biochemical forces and metabolic factors. In: Normal and Abnormal Bone Growth: Basic and Clinical Research. AD Dixon, BG Sarnat, eds. Alan R. Liss, Inc., New York, 1985, p 379. 15. Graham JM Jr, Smith DW: Metopic craniosynostosis as a consequence of fetal head constraint: two interesting experiments of nature. Pediatrics 65:1000, 1980. 16. Lajeunie E, Barcik U, Thorne JA, et al.: Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 95:778, 2001. 17. Cohen MM Jr: Craniosynostosis and syndromes with craniosynostosis: incidence, genetics, penetrance, variability and new syndrome updating. Birth Defects Orig Artic Ser XV(5B):13, 1979. 18. Shuper A, Merlob P, Grunebaum M, et al.: The incidence of isolated craniosynostosis in the newborn infant. Am J Dis Child 139: 85, 1985. 19. Dhellemmes P, Pellerin PH, Lejune JP, et al.: Surgical treatment of trigonocephaly. Childs Nerv System 2:228, 1986. 20. Anderson FM, Gwinn JL, Todt JC: Trigonocephaly: identity and surgical treatment. J Neurosurg 19:723, 1962. 21. Marchac D: Early surgery in craniofacial synostosis. In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Co., Boston, 1985, p 246. 22. Puech B, Puech PF, Tichy G, et al.: Craniofacial dysmorphism in Mozart’s skull. J Forensic Sci 34:487, 1989.

8.2 Orbital Hypotelorism Definition

Orbital hypotelorism is the decreased measurement between the bony orbits, determined by decreased bony interorbital measurement and decreased interpupillary measurement. Cyclopia represents the most severe form of orbital hypotelorism. Diagnosis

Orbital hypotelorism encompasses a wide spectrum of abnormalities ranging from mild reduction of the interorbital measurement to complete fusion of the orbits. Even though simple clinical inspection can detect orbital hypotelorism in the majority of cases, inner canthal measurements are very useful in the recognition of mild forms (Fig. 8-2).1 In contrast to orbital hypertelorism, inner canthal measurements are very helpful as an indicator of reduced space between interorbital walls. More accurate measurements can be made from the posteroanterior radiographs of the skull when direct evaluation is possible. Orbital hypotelorism can result from abnormalities in several developmental events. Although it may be seen as an isolated feature reflecting one end of the spectrum of continuous variation in facial structure, the clinician should methodically search for associated anomalies. Since orbital hypotelorism is consistently found in association with holoprosencephaly, this possibility should always be considered.2,3 Additional facial findings associated with holoprosencephaly include absence of the upper frenulum and a single upper medial incisor. These subtle findings can be present in otherwise healthy carriers of mutations predisposing to holoprosencephaly, for example, in sonic hedgehog (SHH), and may allow the identification of affected family members, suggesting an autosomal dominant inheritance pattern. The most severe form of orbital hypotelorism is seen in cyclopia, ethmocephaly, and cebocephaly, which are among the arrhinencephalic defects.4 Cyclopia is the fusion of the orbits into a single ring, which may encircle a wide range of intraorbital anomalies (Fig. 8-3). Several chromosomal abnormalities have been associated with cyclopia, including del 18p,5 del 2p,6 partial trisomy 3p, and partial trisomy 7q.7 In ethmocephaly, severe ocular hypotelorism occurs together with a blind-ended proboscis located between the eyes; this differs from cebocephaly, which presents with a blind-ended single nostril nose. In addition to the association with holoprosencephaly, orbital hypotelorism can be seen in maternal phenylketonuria, CoffinSiris, Langer-Giedion, Meckel-Gruber, and Williams syndromes (Table 8-2). Chromosomal abnormalities such as trisomy 13 and trisomy 20p have also been associated with reduction of the interorbital measurement.16 In some cases, clefting disorders (cleft lip and palate) are associated with some degree of orbital hypotelorism.17 An autosomal dominant form of ocular hypotelorism with submucosal cleft palate and hypospadias was recognized by Shilbach and Rott18 in a five-generation family with 10 affected individuals. Pashayan and Lewis19 described a patient with hypotelorism, nasomaxillary hypoplasia, and cleft lip and palate. The patient had normal neurologic structures and development. Another case was reported by Joss et al. in 2002.20 This rare entity was confirmed by Stark,21 who reported a similar case.

Facial Bones

271

Fig. 8-2. Standard curves for outer canthal, inner canthal, and interpupillary measurements. Data from a study population of 2403 newborns to children 14 years of age (56% male, 44% female; 2006 white, 206 black, 43 Asian). (From Feingold and Bossert.12)

Other developmental abnormalities that involve mechanical influences on the final position of the orbits include craniosynostotic processes such as premature closure of the metopic suture.

Etiology and Distribution

Hypotelorism results from excessive medial migration of the orbits due to inadequate development of the frontal-cribriform area, as a result of either metopic craniosynostosis or neural hypoplasia

272

Craniofacial Structures

Fig. 8-3. Hypotelorism associated with holoprosencephaly, absent nasal structures, and median cleft in trisomy 13 (left). At right is an infant with cyclopia and proboscis. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.) Table 8-2. Syndromes with orbital hypotelorism Causation Gene/Locus

Syndrome

Prominent Features

Coffin-Siris8

Growth deficiency, variable mental development, mild microcephaly, coarse facies with full lips, hypoplastic to absent fifth finger, radial dislocation at elbow, coxa valga, general hirsutism

(135900)

Holoprosencephaly9

Deficit of midline facial development, incomplete morphogenesis of the forebrain, cyclopia, olfactory placodes consolidated into single tubelike proboscis above the eye

Heterogeneous, including maternal diabetes (600725) SHH, 7q36 (603073) ZIC2, 13q32 (603714) SIX3, 2p21 (602630) TGIF, 18p11.3

Langer-Giedion10

Growth deficiency, mild to severe mental deficiency, microcephaly, heavy eyebrows, deep-set eyes, sparse scalp hair, redundancy of the skin, cone-shaped epiphyses, brittle nails, multiple exostoses, syndactyly, tendency to fractures

AD (150230) microdeletion 8q24.11-q24.13

Phenylketonuria, maternal11

Mental deficiency, growth deficiency, round facies, strabismus, smooth philtrum, small upturned nose, mandibular hypoplasia, congenital heart disease

Maternal metabolic disturbance

Kallmann12

Anosmia, hypogonadotropic hypogonadism, short stature, sensorineural hearing loss, mental retardation

Heterogeneous (147950, 308700, 244200) FGFR1, 8p11

Meckel-Gruber13

Growth deficiency, posterior encephalocele, microcephaly, cerebellar hypoplasia, microphthalmia, cleft palate, ear anomalies, polydactyly, bile duct proliferation, fibrosis and cysts of the kidneys and liver, cryptorchidism, incomplete development of external and/or internal genitalia

(AR 249000) 17q22-q23 and other loci

Smith-Lemli-Opitz14

Elevated 7-dehydrocholesterol, microcephaly, epicanthus, ptosis, cardiac defects, postaxial polydactyly, increase of whorls on dermatoglyphic pattern, hypospadias, syndactyly of toes 2 and 3, failure to thrive, mental retardation

AR (270400) DHCR7, 11q12-q13

Trisomy 1315

Holoprosencephaly, microcephaly, iris colobomata, microphthalmia, retinal dysplasia, cleft lip and palate, distal proximal triradii, camptodactyly, congenital heart disease, cryptorchidism, bicornuate uterus

Abnormal karyotype

Facial Bones

(the holoprosencephaly series). Since orbital hypotelorism is often part of a multiple congenital anomalies disorder, the incidence, sex ratio, and recurrence risk are variable, depending on the underlying cause. When hypotelorism occurs as part of the holoprosencephaly spectrum, the underlying cause for the holoprosencephaly may be identifiable. A chromosome anomaly or gene mutation may be identified, allowing for testing of at-risk family members and appropriate counseling. Human teratogens causing holoprosencephaly include maternal diabetes, alcohol, retinoic acid, and possibly drugs interfering with cholesterol metabolism.22,23 The autosomal recessive Smith-Lemli-Opitz syndrome,14 due to an enzymatic block of the last step of cholesterol biosynthesis, represents a rare cause of holoprosencephaly (Table 8-2). Prognosis, Treatment, and Prevention

Patients affected with cyclocephalic disorders have severe malformations of the brain that result in developmental delay. Depending on the extent of the defect, these individuals may not survive the neonatal period or infancy. The mild forms of orbital hypotelorism do not cause visual impairment and have few clinical implications. They usually do not require surgical correction, except for aesthetic reasons. Prenatal diagnosis is possible by ultrasonography, by interorbital measurement.6 The presence of orbital hypotelorism should alert the ultrasonographer to search for other fetal anomalies. Reproductive genetic counseling is the only means of prevention and should be individualized to each case. Recurrence figures can be estimated according to the inheritance pattern of the primary defect. References (Orbital Hypotelorism) 1. Feingold M, Bossert WH: Normal values for selected physical parameters. Birth Defects Orig Artic Ser X(13):1, 1974. 2. Sedano HO, Gorlin RJ: The oral manifestations of cyclopia. Oral Surg Oral Med Oral Pathol 16:823, 1963. 3. Roulatt V, Pruzansky S: Premaxillary agenesis, ocular hypotelorism, holoprosencephaly and extracranial anomalies in an infant with a normal karyogram. Cleft Palate J 17:197, 1980. 4. Cohen MM Jr: An update of holoprosencephalic disorders. J Pediatr 101:865, 1982. 5. Klein VR, Harrod MJE, Brown CEL, et al.: Prenatal diagnosis of cyclopia. Proc Greenwood Genet Center 6:138, 1987. 6. Grundy HO, Niemeyer P, Rupani MK, et al.: Prenatal detection of cyclopia associated with interstitial deletion 2p. Am J Med Genet 34:268, 1989. 7. Burrig KF, Gebaner J, Terinde R, et al.: Case of cyclopia with an unbalanced karyotype attributable to a balanced 3/7 translocation. Clin Gen 35:262, 1989. 8. Carey JC, Hall BD: The Coffin-Siris syndrome: five cases including two siblings. Am J Dis Child 132:667, 1978. 9. Cohen MM Jr: Malformations of the craniofacial region: evolutionary, embryonic, genetic, and clinical perspectives. Am J Med Genet 115: 245, 2002. 10. Ludecke HJ, Wagner MJ, Nardmann J: Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Hum Molec Genet 4:31, 1995. 11. Sweeney E, Fryer A: Nasomaxillary hypoplasia and severe orofacial clefting in a child of a mother with phenylketonuria. J Inherit Metab Dis 25:77, 2002. 12. Dode C, Levilliers J, Dupont JM, et al.: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463, 2003. 13. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 14. Cunniff C, Kratz LE, Moser A, et al.: Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet 68:263, 1997.

273

15. Delatycki M, Gardner RJ: Three cases of trisomy 13 mosaicism and a review of the literature. Clin Genet 51:403, 1997. 16. Taybi H: Radiology of Syndromes and Metabolic Disorders, ed 2. Year Book Medical Publishers, Chicago, 1983, p 444. 17. Ben-Hur N, Ashur H, Mieurreri M: An unusual case of median cleft lip with orbital hypotelorism—a missing link in the classification. Cleft Palate J 15:365, 1978. 18. Shilbach U, Rott HD: Ocular hypotelorism, submucosal cleft palate and hypospadias: a new autosomal dominant syndrome. Am J Med Genet 31:863, 1980. 19. Pashayan HM, Lewis MB: Hypotelorism, nasomaxillary hypoplasia and cleft lip and palate in a patient with normocephaly and normal intelligence—a case report. Cleft Palate J 17:62, 1980. 20. Joss SK, Paterson W, Donaldson MD, et al.: Cleft palate, hypotelorism, and hypospadias: Schilbach-Rott syndrome. Am J Med Genet 113:105, 2002. 21. Stark DB: Hypotelorism, nasomaxillary hypoplasia and cleft lip and palate in a patient with normocephaly and normal intelligence, a case report (letter). Cleft Palate J 17:262, 1980. 22. Cohen MM, Shiota K: Teratogenesis of holoprosencephaly. Am J Med Genet 109:1, 2002. 23. Edison RJ, Muenke M: Central nervous syndrome and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 350: 1579, 2004.

8.3 Orbital Hypertelorism Definitions

Orbital hypertelorism is the excessive separation of the medial walls of the bony orbits. As with other growth parameters, the interorbital measurement is age-related, with an increase from approximately 16 mm at birth to approximately 27 mm in adult life. Orbital hypertelorism is present when the interorbital measurement exceeds 2 standard deviations (SD) above the mean. In the adult, the upper limit of normal is approximately 30 mm. Ocular Hypertelorism

Ocular hypertelorism is the increased space between the eyes as determined by interpupillary measurement. Determination of ocular hypertelorism using interpupillary measurement requires that the eyes be properly aligned. Alternatively, ocular hypertelorism can be assumed if the interorbital measurement is greater than 2 SD above the mean and the eyes are of normal size. Telecanthus

Telecanthus is the increased measurement between the inner canthi but with normally spaced eyes. Telecanthus results from lateral displacement of the inner canthus and lacrimal punctae. The iris is shifted medially from its normally central position in the palpebral aperture. Graphs with the normal range of intraorbital, interpupillary, and inner canthal measurements have been prepared by several groups of investigators (Fig. 8-2).1–6 Diagnosis

The term hypertelorism was probably introduced in 1924 by Greig7 to describe a discrete condition with excessive separation of the eyes. It is often used indiscriminately to convey the impression that the eyes are widely spaced. The experienced observer can usually detect true orbital hypertelorism and ocular hypertelorism by simple inspection (Fig. 8-4). This, however, is not always the case. The clinician can be confused by the impression of hypertelorism produced by

274

Craniofacial Structures

(Fig. 8-5). It often represents the mildest form of midline facial clefting. Over 200 malformation syndromes include orbital hypertelorism; Table 8-3 lists the most common of these syndromes. Orbital and ocular hypertelorism usually coexist. It is possible, however, for the eyes to be displaced laterally by encroachment into the orbital space by tumor, neural tissue, or ethmoid air cells, with normal interorbital measurement.35 Etiology and Distribution

Fig. 8-4. Isolated ocular hypertelorism in a 9-year-old male without associated defects (Greig hypertelorism).

telecanthus in the presence of normal interorbital and interpupillary measurements. Diagnosis of orbital hypertelorism requires radiologic studies to confirm the presence of a wide separation of the orbits. Because of involvement of soft tissue, the determination of the measurement between the bony orbital walls is difficult. Several quantitative methods such as inner canthal measurement, interpupillary measurement, canthal index, and circumference interorbital index have been used in an attempt to establish the position of the orbits in relation to each other.1 Of the various methods for determining orbital hypertelorism, the preferable one probably is the interorbital measurement as determined directly from posteroanterior skull radiographs.4 Values 2 SD or greater above the mean compared with Tessier data are diagnostic of orbital hypertelorism. The use of computed tomography (CT) to measure interorbital space has been investigated.8 However, the high cost may limit its use for assessment of orbital hypertelorism. On the other hand, CT scanning allows study of the orbital contents with respect to the bony orbit. It allows independent measurement for each globe, which is necessary to uncover asymmetric displacement that could lead to binocular stereoscopic vision and other visual complications. Orbital hypertelorism may be an isolated craniofacial characteristic, but this is uncommon.9,10 Usually it is a component of one of numerous multiple congenital anomaly syndromes

During early stages of embryonic life, the eyes extend laterally as evaginations of the forebrain. Differential growth, occurring prior to ossification of the bones of the skull, results in convergence toward the facial midline from this primitive lateral position. Aberrations in this differential growth affect the position of the orbits. Since orbital hypertelorism is a characteristic finding in several craniofacial malformation syndromes that involve different pathogenicities, there is no identifiable single mechanism that leads to the disorder. Three main mechanisms have been postulated to produce orbital hypertelorism.4,36 The first possible mechanism is a time-specific deficiency in differential growth, with a primary effect on the forebrain and optic primordia or their supporting tissues. The second possible mechanism is migration being interrupted due to the presence of a midline lesion, such as a nasoencephalocele, which inhibits the progressive medial approximation of the orbits. A third proposed mechanism is the occurrence of a parallel pathologic process on the cranial base (secondary to craniosynostosis, for example) that could separate the orbits during intrauterine life and persist through early postnatal growth. Isolated hypertelorism is rare and usually occurs in a sporadic form. Apparently dominant and recessive cases have been reported; however, the sexes appear to be equally affected. Syndromic hypertelorism has many causes (Table 8-3), and the recurrence risks depend on the cause. As the genes causally involved in these syndromes are identified, it becomes clear that many of them encode transcription factors active in early embryologic development. The gene product encoded by the cleidocranial dysplasia gene is a transcription factor essential for cell proliferation and differentiation,37 whereas the transcription factor encoded by the Greig syndrome gene (GLI3) acts as a repressor of signaling through FGF838 and sonic hedgehog (see Section 8.2). Of note, the protein product encoded by the gene involved in Gorlin syndrome (Table 8-3) is a cell membrane bound receptor for sonic hedgehog. In contrast to these molecules involved in transcription and the sonic hedgehog signaling pathway, mutations affecting proteins involved in the cytoskeletal organization, such as filamin A (OPD spectrum disorders, Table 8-3), are more likely to result in structural malformations by abnormal cell migration.29 In a review of patients with a primary presenting diagnosis of hypertelorism, excluding patients with syndromic craniosynostosis or cleft lip, the most common cause was frontonasal dysplasia, followed by craniofrontonasal dysplasia.39 Numerous chromosome aberrations cause orbital hypertelorism. These include XXXXY syndrome, trisomy 22, trisomy 13, deletion 4p, deletion 5p, and deletion 17p. Teratogenic exposures associated with hypertelorism include hydantoin, warfarin, and aminopterin. Prognosis, Treatment, and Prevention

The prognosis of the patient with bony orbital hypertelorism depends on the primary defect. Multiple congenital anomaly

Facial Bones

275

Fig. 8-5. Ocular hypertelorism in a 26-month-old male with Aarskog syndrome showing triangular face, broad forehead, and widow’s peak (A); in an infant girl with bifid nose (B); in an infant girl with median cleft face (C); and in an adult with frontonasal dysplasia showing broad nose and widow’s peak (D). (B and C courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

syndromes that severely affect the orbital area may represent major surgical challenges requiring multiple interventions. Orbital hypertelorism is classified into three different categories according to the interorbital measurement. Each category is treated surgically in a different manner. First-degree orbital hypertelorism (interorbital distance [IOD] between 30 and 34 mm) can be corrected by rhinoplasty, correction of the epicanthal folds, or both. Second-degree orbital hypertelorism (IOD between 34 and 40 mm) can be corrected by extracranial osteotomy. Thirddegree orbital hypertelorism (IOD greater than 44 mm) requires an intracranial approach.40 Surgical correction rests on transposition of the portion of the orbit that must be moved to effect a movement of the globe. This procedure can be done with excellent

results during early infancy. Early intervention results in a normal appearance, which minimizes the psychological problems for the patient. Prognosis should be individualized according to the primary defect involved. Prenatal diagnosis of orbital hypertelorism is possible with real-time ultrasonography. Normal standards have been established by different investigators, with similar results.41–43 Figure 8-6 shows a coronal section of the fetal craniofacies at 18 weeks gestation from our normal sample. Landmarks for determining the interorbital measurement have been identified. In the presence of fetal orbital hypertelorism, along with an accurate last menstrual period date, the clinician should investigate the possibility of associated birth defects.

Table 8-3. Syndromes associated with orbital hypertelorism Causation Gene/Locus

Syndrome

Prominent Features

Aarskog11

Moderate short stature, rounded facies, ptosis, slight downward-slanting palpebral fissures, small nose, anteverted nostrils, hypodontia, brachydactyly, mild interdigital webbing, mild pectus, shawl scrotum

XL (305400) FGD1, Xp11.21

Acrocallosal12

Growth and mental deficiency, agenesis of the corpus callosum, preaxial polydactyly, syndactyly, prominent forehead and occiput, hypoplastic midface

AR (200990)

Acrodysostosis13

Growth deficiency and mental deficiency, brachydactyly, low nasal bridge, upturned small nose, short and broad hands

(101800)

Cat eye14

Mental deficiency, inferior coloboma of the iris, micrognathia, cardiac defects, anal atresia, rectovesicular fistula, renal agenesis

(115470) Partial tetrasomy 22 due to inv dup (22)(q11)

Cleidocranial dysplasia15

Wide, late-closing fontanel; depressed nasal bridge; supernumerary teeth; hypoplastic clavicles; minor skeletal abnormalities; mild short stature

AD (119600) CBFA1(RUNX2), 6p21

Craniofrontonasal16

Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and splits in nails

XL (304110) EFNB1, Xq12

Coffin-Lowry17

Downslanting palpebrae, open mouth with thick lips, growth and mental deficiency, pectus anomalies, wide hands with tapering digits, hyperextensible joints, drop attacks

XL (303600) RSK2, Xp22.2-p22.1

Donnai-Barrow18

Diaphragmatic hernia, exomphalos, absent corpus callosum, iris coloboma, myopia, sensorineural deafness

AR (222448)

Escobar19

Small stature, inner canthal folds, micrognathia, cleft palate, expressionless face, multiple large joint pterygia, camptodactyly, syndactyly, cryptorchidism

AR (265000)

Frontonasal dysplasia20

Lateral displacement of inner canthi, widow’s peak, broad nasal bridge, hypoplasia to absence of the prolabium, premaxilla

(136760)

Gorlin21

Macrocephaly, odontogenic keratocysts, basal cell nevi, palmar pits, mental retardation, medulloblastoma

AD (109400) PTCH, 9q22.3

Greig cephalopolysyndactyly22

High forehead, frontal bossing, macrocephaly, broad nasal root, postaxial polydactyly, broad thumbs, syndactyly, preaxial polydactyly of toes

AD (175700) GLI3, 7p13

Killian/Teschler-Nicola23

Obesity, short stature, seizures, hypotonia, deafness, sparse anterior scalp hair, delayed dental eruption, large ears, flat broad nasal root, coarse face, long philtrum, thin upper lip, short neck, broad hands with short digits, diaphragmatic hernia

Tetrasomy 12p

Larsen24

Flat facies; depressed nasal ridge; prominent forehead; dislocations of elbow, wrist, and knee; dysplastic epiphyseal centers; spatulate thumbs; short nails; short metacarpals; talipes equinovarus; cervical vertebrae hypoplasia

Heterogeneous (150250, 245600, 245650) 3p21.1-p14.1 for AD form

Lenz-Majewski25

Short stature, variable mental development, prominent forehead, late closure of fontanels, proptosis, choanal stenosis, cutis laxa, cutaneous syndactyly, sparse hair, dysplastic enamel, proximal symphalangism, absent middle phalanges, long and flared metaphyses

(151050)

Multiple lentigines (LEOPARD)26

Lentigines, prominent ears, ptosis, short neck, pulmonic stenosis, ECG abnormalities, short stature

AD, allelic to Noonan (151900) PTPN11, 12q24.1

Neu-Laxova27

Microcephaly, lissencephaly, absence of corpus callosum, absence of olfactory bulbs, absence of lids, flattened nose, gaping mouth, micrognathia, short neck, transparent scaling skin, ichthyosis, short limbs, syndactyly of fingers and toes, poorly mineralized bones, cataracts, microphthalmia, absence of eyelashes and scalp hair

AR (256520)

Noonan28

Short stature, variable mental impairment, epicanthal folds, ptosis, downslanting palpebrae, low-set and abnormally shaped ears, webbed neck, shield chest, pectus carinatum and/or excavatum, cubitus valgus, pulmonary valve stenosis, cryptorchidism, bleeding tendency, multiple giant cell lesions

AD (163950) Heterogeneous PTPN11, 12q24.1

Oto-palato-digital (OPD) spectrum29

OPD type 2: growth deficiency, large anterior fontanel, wide sutures, prominent forehead, flat nasal bridge, small mouth, cleft palate, small mandible, flexed overlapping fingers, short thumbs, syndactyly, bowed long bones, subluxed joints, narrow chest

XL (311300, 304120, 309350, 305620) Allelic to Melnick-Needles, frontometaphyseal dysplasia, and periventricular heterotopia FLNA, Xq28

Hypertelorism-hypospadias (Opitz)30

Variable mental development, widow’s peak, laryngeal abnormalities, hypospadias, cryptorchidism, bifid scrotum, hernias

AD (145410) 22q11.2 XL (300000) MID1, Xp22.3 (continued )

276

Facial Bones

277

Table 8-3. Syndromes associated with orbital hypertelorism (continued) Causation Gene/Locus

Syndrome

Prominent Features

Robinow31

Moderate short stature, macrocephaly, frontal bossing, proptosis, small triangular mouth, micrognathia, hyperplastic alveolar ridges, short forearms, hemivertebrae, small penis or clitoris, cryptorchidism

AD (180700) AR (268310) Allelic to brachydactyly type B ROR2, 9q22

Sotos32

Overgrowth, macrocephaly, prominent forehead, prognathism variable mental development, large hands and feet, accelerated phalangeal centers, premature eruption of teeth

AD (117550) NSD1, 5q35

Teebi33

Heavy eyebrows, downslanting palpebrae, depressed nasal bridge, short nose, mild syndactyly, shawl scrotum

AD (145420)

Weaver34

Accelerated growth and maturation, long philtrum, large ears, mild hypertonia, spasticity, camptodactyly, broad thumbs, thin deep-set nails, limited elbow and knee extension, relatively loose skin, thin hair, umbilical hernia

AD (277590) Unknown in most; NSD1, 5q35 point mutation in some cases

Fig. 8-6. Coronal ultrasonographic view of the fetal facial skeleton at 18 weeks of gestation. Note localization of landmarks for evaluation of interorbital measurement.

References (Orbital Hypertelorism) 1. Feingold M, Bossert WH: Normal values for selected physical parameters. Birth Defects Orig Artic Ser X(13):1, 1974. 2. Merlob P, Sivan Y, Reisner SH: Anthropometric measurements of the newborn infant (27 to 41 gestational weeks). Birth Defects Orig Artic Ser XX(7):1, 1984. 3. Laestadius ND, Aase JM, Smith DW: Normal inner canthal and outer orbital dimensions. J Pediatr 74:465, 1969. 4. Tessier P: Orbital hypertelorism. 1. Successive surgical attempts, materials and methods. Causes and mechanisms. Scand J Plast Reconstr Surg 6:135, 1972. 5. Hall JG, Froster-lskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 6. Saul RA, Stevenson RE, Rogers RC, et al.: Growth references from conception to adulthood. Proc Greenwood Genet Center, Suppl 1, 1988.

7. Greig DM: Hypertelorism: a hitherto undifferentiated congenital craniofacial deformity. Edinburgh Med J 31:350, 1924. 8. Costaras M, Pruzansky S, Broadbent BH Jr.: Bony interorbital distance (BIOD), head size, and level of the cribriform plate relative to orbital height: I. Possible pathogenesis of orbital hypertelorism. J Craniofac Genet Dev Biol 2:5, 1982. 9. Myrianthopoulos NC: Epidemiology of craniofacial malformations: foundations of craniofacial genetics. In: Clinical Dysmorphology of Oral-Facial Structures. M Melnick, ED Shields, NJ Burzynski, eds. John Wright, PSG, Boston, 1982, p 12. 10. Morin JD, Hill JC, Anderson MC, et al.: A study of growth in the interorbital region. Am J Ophthalmol 56:895, 1963. 11. Fryns JP: Aarskog syndrome: the changing phenotype with age. Am J Med Genet 43:420, 1992. 12. Koenig R, Bach A, Woelki U, et al.: Spectrum of the acrocallosal syndrome. Am J Med Genet 108:7, 2002. 13. Robinow M, Pfeiffer RA, Gorlin RJ, et al.: Acrodysostosis: a syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am J Dis Child 121:195, 1971. 14. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: decentric small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57:148, 1981. 15. Cooper SC, Flaitz CM, Johnston DA, et al.: A natural history of cleidocranial dysplasia. Am J Med Genet 104:1, 2001. 16. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996. 17. Hunter AGW: Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet 111:345, 2002. 18. Gripp KW, Donnai D, Clericuzio CL, et al.: Diaphragmatic herniaexomphalos-hypertelorism syndrome: a new case and further evidence of autosomal recessive inheritance. Am J Med Genet 68:441, 1997. 19. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: a review and report of eleven patients. Am J Med Genet 12:377, 1982. 20. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 76:906, 1970. 21. Evans DGR, Ladusans EJ, Rimmer S, et al.: Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet 30:460, 1993. 22. Debeer P, Peeters H, Driess S, et al.: Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet 120A:49, 2003. 23. Schaefer GB, Jochar A, Muneer R, et al.: Clinical variability of tetrasomy 12p. Clin Genet 51:102, 1997. 24. Larsen LJ, Schottstaedt ER, Bost FC: Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 37:574, 1950.

278

Craniofacial Structures

25. Robinow M, Johanson AJ, Smith TH: The Lenz-Majewski hyperostotic dwarfism: a syndrome of multiple congenital anomalies, mental retardation, and progressive skeletal sclerosis. J Pediatr 91:417, 1977. 26. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiplelentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389, 2002. 27. Neu RL, Kajii T, Gardner LI, et al.: A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics 47: 610, 1971. 28. Allanson JE, Hall JG, Hughes HE, et al.: Noonan syndrome: the changing phenotype. Am J Med Genet 21:507, 1985. 29. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 30. Opitz JM: G syndrome (hypertelorism with esophageal abnormality and hypospadias, or hypospadias-dysphagia, or ‘Opitz-Frias’ or ‘Opitz-G’ syndrome)—perspective in 1987 and bibliography. Am J Med Genet 28:275, 1987. 31. Robinow M, Silverman FN, Smith HD: A newly recognized dwarfing syndrome. Am J Dis Child 117:645, 1969. 32. Allanson JE, Cole TRP: Sotos syndrome: evolution of facial phenotype subjective and objective assessment. Am J Med Genet 65:13, 1996. 33. Teebi AS: New autosomal dominant syndrome resembling craniofrontonasal dysplasia. Am J Med Genet 28:581, 1987. 34. Weaver DD, Graham CB, Thomas IT: A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly. J Pediatr 84:547, 1974. 35. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. CV Mosby, St. Louis, 1985, p 184. 36. DeMyer W: The median cleft face syndrome. Differential diagnosis of cranium bifidum occultum and hypertelorism in median cleft nose, lip and palate. Neurology 17:961, 1967. 37. Coffman JA: Runx transcription factors and the developmental balance between cell proliferation and differentiation. Cell Biol Int 27:315, 2003. 38. Aoto K, Nishimura T, Eto K, et al.: Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 251:320, 2002. 39. Tan ST, Mulliken JB: Hypertelorism: nosologic analysis of 90 patients. Plast Reconstr Surg 99:317, 1997. 40. Psillakis JM: Surgical treatment of hypertelorbitism. In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Company, Boston, 1985, p 190. 41. Mayden KL, Tortora M, Berkowitz RL: Orbital diameters: a new parameter for prenatal diagnosis and dating. Am J Obstet Gynecol 144:289, 1982. 42. Jeanty P, Cantraine F, Cousaert E, et al.: The binocular distance: a new way to estimate fetal age. J Ultrasound Med 3:241, 1984. 43. Escobar LF, Bixler D, Padilla M, et al.: Fetal craniofacial morphometrics in utero. Evaluation at 16 weeks of gestation. Obstet Gynecol 72:677, 1988.

8.4 Midline Facial Skeletal Clefting Definition

Midline facial skeletal clefting is a sagittally oriented fissure dividing the craniofacial structures at the midline. Midline facial clefts result from failure of the facial processes to fuse during the embryonic stage. Diagnosis

Midline facial clefting (MFC) is classified according to the morphologic characteristics. Table 8-4 lists the different types of facial bone involvement as shown by computed tomography

Table 8-4. Facial bone abnormalities in midline facial clefts Tessier1 type

0

Keel-shaped maxillary alveolus, reduction of median and paramedian midfacial height, thickening of the nasal septum, broad and flat maxilla, orbital hypertelorism, widening of anterior cranial fossa

1

Clefting of the maxilla with or without cleft palate, maxillary hypoplasia, flattening of the nasal dorsum, asymmetry of the ptyrigoid plates, keel-shaped alveolus

2

Alveolar cleft that extends to soft and hard palate, deviation of the nasal septum

3

Deviation of the nasal septum, no septation between nasal cavity and the cleft side of the maxilla, cleft extending to the medial portion of the orbital floor and into the inferior orbital rim, orbit and anterior cranial fossa inferiorly displaced

4

Palatal cleft from the maxilla to the infraorbital foramen, medial septation separating the nasal cavity from the orbit, maxillary sinus and mouth present

5

From narrow to broad cleft of the maxilla to the infraorbital foramen and maxillary sinus, cleft entering the inferolateral orbital rim

12

Flattening of the frontal process of the maxilla, orbital hypertelorism, flattening of the frontal bone, obtuse nasofrontal angle

13

Bony cleft beginning in the region of the nasal bone and extending superiorly through the full height of the frontal bone; posteriorly, cleft extends through the cribiform plate and ethmoid sinus as far as the lesser wing and body of the sphenoid

14

Median frontal cleft defect sometimes with herniation of a frontal encephalocele, flattened glabella, shortening of the anterior dimension of the middle cranial fossa

Tessier types 6–11 involve regions other than the craniofacial midline. Therefore, they are not included here. Further information is given by David et al.2

(CT) scanning. Initially recognized by soft tissue abnormalities, midline facial clefts vary from mild broadening of the philtrum, or a true medial cleft lip (MFC 0), to severe orbital hypertelorism, with anterior cranium bifidum occultum. Recognition of the degree of skeletal involvement requires radiologic techniques such as CT. CT and tridimensional reconstruction are essential in evaluating accurately the severity of the defect and in planning reconstructive procedures (Fig. 8-7). In addition, cephalometric analysis of the skeletal craniofacies is helpful in delineating skeletal morphology. Midline facial clefts are characterized by the combination of two or more of the following: (1) true ocular hypertelorism, (2) broadening of the nasal root, (3) median facial cleft affecting the nose or both nose and upper lip and at times the palate, (4) unilateral or bilateral clefting of the alae nasi, (5) lack of formation of the nasal tip, (6) anterior cranium bifidum occultum, and (7) V-shaped hair prolongation onto the forehead, generally over the area of the cranium bifidum.3 Distinction has to be made between median and paramedian craniofacial clefts and also between median clefts and the group of frontoethmoidal meningoencephaloceles, which are associated with a normal craniofacial skeleton that is displaced in position (Fig. 8-8).4,5 However, encephaloceles are sometimes associated with true craniofacial clefts with markedly abnormal skulls. Since frontoethmoidal meningoencephaloceles lack the frontal

Facial Bones

279

Fig. 8-8. Ten-month-old female with frontoethmoidal meningoencephalocele. She was exposed prenatally to hydantoin and had a unilateral constriction ring of the arm and nail hypoplasia.

Fig. 8-7. Three-year-old patient with facial cleft. Note the facial skeletal defect as seen via 3-D CT reformat sequence. (From David et al.2)

hairline indicator, this sign may be helpful in distinguishing the two entities. Other entities that include ocular hypertelorism must be carefully differentiated from mild forms of midline facial clefts. Syndromes including ocular hypertelorism usually affect other areas of the body in addition to the midline of the face. Etiology and Distribution

Severe midline facial clefting is associated with gross malformations of the head and rarely presents in an isolated form. As suggested by Sedano and Gorlin3 in 1988, frontonasal malformation may represent the reaction of part, or parts, of an embryo as a unit to both normal and abnormal stimuli. The spectrum of frontonasal malformations involves individual entities that may include midfacial clefts as a major characteristic (Table 8-5). Examples are craniofrontonasal dysplasia, ophthalmofrontonasal dysplasia, and Greig cephalopolysyndactyly. Midline craniofacial clefting has been reported to occur in hemifacial microsomia (sporadic), Treacher

Collins syndrome (autosomal dominant), and acrofrontofacionasal dysostosis (autosomal recessive). In addition, it can be seen as part of some multiple congenital anomaly syndromes or can represent a single developmental event in a malformation sequence, as was suggested by Toriello and collaborators.11 Midline facial clefting appears to result from insult during the embryonic period.3 The developmental basis for these defects was investigated by Darab and coworkers.12 They were able to produce a spectrum of defects ranging from narrow midline nasal-groove defects to frank midfacial clefting in mouse embryos exposed to methotrexate during day 9 of pregnancy (corresponding to week 4 of human gestation). Affected embryos showed dilation and congestion of blood vessels in the frontonasal process, suggesting that vascular damage may be responsible for initiating the sequence of events leading to midline facial clefting. Caution is suggested, since mice may be highly sensitive to teratogenic clefting and this may not be the case in humans. The majority of midline facial clefts are sporadic, with a somewhat low recurrence risk. The recurrence risk, however, can be substantial if the clefts are associated with other anomalies in a recognized malformation syndrome. A particularly interesting example is the craniofrontonasal syndrome, due to mutations in the EFNB1 gene located in the pericentromeric region of the X chromosome.13 In contrast to other X-linked disorders, craniofrontonasal syndrome affects females more severely, and males show milder manifestations, such as hypertelorism only. Prognosis, Treatment, and Prevention

The child with midfacial cleft should be approached by a multidisciplinary team of professionals. The evaluation and treatment of these children should include audiology, genetics, maxillofacial prosthetics, neurology, neurosurgery, ophthalmology, oral and maxillofacial surgery, orthodontics, pediatrics, psychiatry, psychology, radiology, social work, and speech pathology. Some centers have the advantage of including physical anthropology. This ‘‘team’’ approach has greatly improved the prognosis for the child with midfacial clefts. Surgical reconstruction in childhood has become routine at a few centers. Initially, surgeons were reluctant to do major reconstructive surgery on young children, preferring to wait until most of the facial growth had occurred. The current change to earlier surgery has probably been motivated by concern for the patient’s psychological adjustments. However, depending

280

Craniofacial Structures

Table 8-5. Syndromes associated with midline facial skeletal clefting Syndrome

Prominent Features

Causation Gene/Locus

Craniofrontonasal6

Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and splits in nails

XL (304110) EFNB1, Xq28

Facio-auriculo-vertebral spectrum7

Macrostomia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, hypoplasia of one side of face

Unknown, sporadic (164210, 257700)

Frontonasal dysplasia8

Ocular hypertelorism, lateral displacement of inner canthi, widow’s peak, deficit in midline frontal bone, notched broad nasal tip, medial cleft lip, broad nasal root, nasal tags, mental deficiency

Unknown, sporadic (136760)

Oto-palato-digital (OPD) spectrum9

Frontometaphyseal dysplasia: coarse facies; prominent supraorbital ridges; partial anodontia; high palate; small mandible; wide foramen magnum; flared pelvis; mixed conductive and sensorineural hearing loss; flexion defects of fingers, wrists, elbows, knees, and ankles

XL (305620, 311300, 304120, 309350) FLNA, Xq28 Allelic to Melnick-Needles, OPD types 1 and 2, and periventricular heterotopia

Greig cephalopolysyndactyly10

High forehead, frontal bossing, macrocephaly, hypertelorism, broad nasal root, postaxial polydactyly of hands, broad thumbs, preaxial polydactyly of feet, broad halluces, syndactyly

AD (175700) GLI3, 7p13

on the severity of the defects, multiple procedures may be required. This process may take from a few months to years. Between 15% and 20% of patients with midfacial clefts have some degree of developmental delay. This can, in most cases, be reasonably attributed to other causes, such as extreme prematurity, perinatal difficulties, or multiple other congenital anomalies.14 Prevention of midline facial clefting is limited to reproductive genetic counseling and prenatal testing for pregnancies at risk. Prenatal diagnosis by ultrasonography has been accomplished in the past, and ultrasonography is a relatively good indicator of the severity of the defect.15,16 Since no chromosomal abnormality has been identified, amniocentesis has limited diagnostic value. In specialized centers, fetoscopy remains as an important backup procedure for confirmation of midline facial clefts. References (Midline Facial Skeletal Clefting) 1. Tessier P: Anatomical classification facial, cranio-facial and laterofacial clefts. J Maxillofac Surg 4:69, 1976. 2. David DJ, Moore MH, Cooler RD: Tessier clefts revisited with a third dimension. Cleft Palate J 26:163, 1989. 3. Sedano HO, Gorlin RJ: Frontonasal malformation as a field defect and in syndromic associations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 65:804, 1988. 4. David DJ, Sheffield L, Simpson D, et al.: Frontoethmoidal meningoencephaloceles, morphology and treatment. Br J Plast Surg 37:271, 1984. 5. Moore MH, David DJ, Cooler RD: Hairline indicators of craniofacial clefts. Plast Reconstr Surg 82:589, 1988. 6. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996. 7. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 8. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 76:906, 1970. 9. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 10. Debeer P, Peeters H, Driess S, et al.: Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet 120A:49, 2003.

11. Toriello HV, Radecky LL, Sharda J, et al.: Frontonasal ‘‘dysplasia,’’ cerebral anomalies, and polydactyly. Report of a new syndrome and discussion from a developmental field perspective. Am J Med Genet (suppl)2:89, 1986. 12. Darab DJ, Minkoff R, Sciote J, et al.: Pathogenesis of median clefts in mice treated with methotrexate. Teratology 36:77, 1987. 13. Wieland I, Jakubiczka S, Muschke P, et al.: Mutations of the Ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 74:1209, 2004. 14. Stewart RE: The value of establishing the genetic component in etiology of craniofacial anomalies. Birth Defects Orig Artic Ser XVI(5): 27, 1980. 15. Chevernak FA, Tortora M, Mayden K, et al.: Antenatal diagnosis of median cleft syndrome: sonographic demonstration of cleft lip and hypertelorism. Am J Obstet Gynecol 149:94, 1984. 16. Gianluigi P, Reece EA, Romero R, et al.: Prenatal diagnosis of craniofacial malformations with ultrasonography. Am J Obstet Gynecol 155: 45, 1986.

8.5 Absence and Hypoplasia of the Zygoma Definition

Absence and hypoplasia of the zygoma is the impaired development of the zygomatic bone leading to deficiency of the midface and orbital floor. Hypoplasia/aplasia of the zygoma represents an anomaly of the first branchial arch and has wide phenotypic variability. Diagnosis

Hypoplasia of the malar bones and zygomatic arches is usually recognizable on simple clinical inspection of the affected individual (Fig. 8-9). Striking deficiency of the midface in the zygomatic area is characteristic. The deficient facial skeleton is reflected in soft tissue abnormalities such as tongues of hair protruding onto the cheeks, lateral canthal colobomas, downward obliquity of the palpebral fissures, lower lid colobomas, lower lid ciliary agenesis, and a small face with prominent nose. Facial anomalies of this type are usually seen in well-defined entities such as Treacher Collins syndrome and ablepharon-macrostomia.1,2

Facial Bones

281

a defect of the inferior rim and floor of the orbit, with inferolateral herniation.3,4 Total absence of the zygomatic bones and zygomatic arches is rare, and, in many cases, a remnant of zygomatic bone can be found appended to the sphenoid tubercle, without connection to the maxilla or the frontal or temporal bone. Zygomatic absence is responsible for the absence of the lateral orbital rim, with formation of the lateral orbital wall by the hypoplastic greater wing of the sphenoid.5 In the ablepharon-macrostomia syndrome, radiologic studies may show profound hypoplasia of the malars, infraorbital rims, and lateral walls and absent zygomatic arches. Other entities that include zygomatic hypoplasia or absence are Goldenhar (hemifacial microsomia), Nager (preaxial acrofacial dysostosis), and Miller (postaxial acrofacial dysostosis) syndromes (Table 8-6). Clinical caution is suggested since the occurrence of incomplete and or asymmetric forms may lead to diagnostic difficulties. Etiology and Distribution

Fig. 8-9. Top: Frontal (A) and lateral (B) view of patient with hypoplasia of zygomatic bone. Bottom: Frontal view of 13-month-old female with Treacher Collins syndrome showing downslanting palpebral fissures, sagging (cleft) lower lids, and hypoplasia of the zygoma. (A and B from Jackson et al.2)

Due to the wide spectrum of abnormalities associated with absence or hypoplasia of the zygoma, radiologic studies are essential in establishing the areas involved and in evaluating the extent of the defect. This is best accomplished by the Waters radiologic view and frontal tomograms that demonstrate deficiency of the malar bones and partial or complete absence of the zygomatic arches. In addition, modification of the orbital shape with an inferolateral elongation can be observed. The hypoplasia can be described in relation to the three articulations of the zygoma: zygomaticotemporal, zygomaticofrontal, and zygomaticomaxillary. Impairment in the development of the temporal process of the zygoma, in conjunction with impairment of the zygomatic process of the temporal bone, results in partial to complete absence of the zygomatic arch. Impairment of the frontal process causes absence of the anterior portion of the lateral orbital wall. Impairment along the maxillary articulation results in

It is important to emphasize that absence or hypoplasia of the zygoma does not occur as an isolated malformation. It is the result of a deficient growth and aberrant tissue interaction between several embryologic craniofacial structures. Opitz21 suggested that these abnormalities constitute part of the mandible, zygoma, ear ossicles developmental field (MZEDF), which may imply that whenever one of the three structures becomes anomalous, abnormal growth will occur in the other two. Positive statistical correlations exist between the frequency of aberrant development of these three structures, supporting a developmental field concept.22 This idea is particularly attractive when one observes the close clinical linkage between syndromes that affect the structures derived from the first branchial arches. These include mandibulofacial dysostosis; ablepharon-macrostomia; otocephaly; and Goldenhar, Miller, and Nager syndromes. Etiologically, the primary developmental defect that leads to abnormalities of the zygoma is unknown; however, damage to the stapedial artery has been suggested to cause failure of migration of the neural crest cells, leading to deficient growth of the zygomatic structures.23 This appears to be a plausible explanation, but it fails to account for the occurrence of bilateral defects. Nevertheless, the possibility that some cases of first branchial arch deficiency are due to this mechanism or to similar mechanisms of vascular origin cannot be dismissed. If the vascular theory holds true, this may lead to excessive and/or premature deficiencies in the amounts of cell death in the first and second arch. Among the cell populations that may be particularly affected are the first arch epithelial placode cells.24 The appearance of single ossification centers for each of the zygomatic bones at approximately the 8th week of gestation has led to the suggestion that any arrest in chondrogenesis could result in absence or hypoplasia of the zygoma.2 This suggested mechanism would support the idea of failure of cell differentiation due to the absence of an appropriate extracellular matrix during the early developmental stages.25 The gene causally involved in mandibulofacial dysostosis has been identified as TCOF1. It encodes a nucleolar phosphoprotein named treacle, whose biologic function remains poorly defined. Investigation of a mouse model showed that heterozygous Tcof1 deletion leads to perinatal death from severe craniofacial anomalies caused by a massive increase of apoptosis in the prefusion neural folds. These studies, in combination with the mutations identified in patients with Treacher

Table 8-6. Syndromes associated with absence or hypoplasia of the zygoma Syndrome

Prominent Features

Causation Gene/Locus

Bloom6

Growth deficiency, microcephaly, dolichocephaly, small nose, butterfly telangiectatic erythema involving the midface region exacerbated by sunlight

AR (210900) RECQL3, 15q26.1

Chondrodysplasia punctata7

Growth deficiency, short limbs, epiphyseal stippling, low nasal bridge, downward-slanting palpebral fissures, variable joint contractures, scoliosis, follicular atrophoderma, ichthyosis

Multiple loci XL (302960) EBP, Xp11.23 XL (302950) ARSE, Xp22.3 AD (118650) AR (215100) PEX7, 6q22-q24

Deletion 22q11.28

Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, prominent nasal tip, hypoplastic alae nasi, learning difficulties

(192430) Microdeletion, 22q11.2

Diamond-Blackfan anemiamicrotia-cleft palate9

Macrocytic anemia, short stature, downslanting palpebral fissures, microtia, cleft palate, micrognathia

AD (606164)

Facio-auriculo-vertebral spectrum10

Macrostomia, unilateral hypoplasia of malar and mandibular region, microtia, periauricular tags, epibulbar dermoid, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, cardiac and renal malformation

Unknown, sporadic (164210, 257700)

Hallermann-Streiff11

Small stature, brachycephaly, frontal bossing, thin calvarium, delayed ossification of sutures, micrognathia, anterior displacement of the temporomandibular joint, microphthalmia, cataracts, small nose with hypoplasia of the cartilage, microstomia, hypoplasia of the teeth, partial anodontia

Unknown, sporadic (234100)

Marshall12

Short stature, depressed nose with flat nasal bridge, anteverted nares, flat midface, myopia, cataracts, calvarial thickening, irregular distal femoral and proximal tibial epiphyses, bowing of the radius and ulna

AD (154780) Allelic to Stickler type 2 COL1A11, 1p21

Miller13

Downslanting palpebral fissures, eyelid coloboma, ectropion, micrognathia, cleft lip and/or palate, postaxial limb deficiencies, syndactyly, accessory nipple

AR (263750) Most sporadic, AD rarely reported

Mohr14

Short stature, conductive deafness, low nasal bridge, broad nasal tip, slightly bifid, midline cleft of tongue, hypoplasia of the maxilla and body of the mandible, duplication of hallux and first metatarsals, duplication of tarsal bones, polydactyly, metaphyseal flaring

AR (252100)

Nager15

Normal intelligence, short stature, conductive deafness and articulation problems, downslanting palpebral fissures, micrognathia, absence of the lower eyelashes, periauricular tags, atresia of external ear canal, hypoplasia to aplasia of the thumb, proximal radioulnar synostosis, short forearms

AD, AR (154400)

Oto-palato-digital (OPD) spectrum16

OPD type 1: variable mental deficiency, short stature, moderate conductive deafness, thick base of skull, facial bone hypoplasia, absence of frontal and sphenoid sinuses, partial anodontia, impacted teeth, small trunk, pectus excavatum, small iliac crests, joint contractures, broad distal phalanges, accessory ossification center at the base of the second metatarsal

XL (311300, 304120, 309350, 305620) FLNA, Xq28 Allelic to Melnick-Needles, frontometaphyseal dysplasia and periventricular heterotopia

Pycnodysostosis 17

Small stature, osteosclerosis with tendency toward transverse fracture, delayed closure of sutures, persistence of anterior fontanel, lack of frontal sinus, facial hypoplasia, irregular permanent teeth, dysplasia to loss of acromion of the clavicle, acro-osteolysis of distal phalanges, wrinkled skin over dorsa of distal fingers

AR (265800) CTSK, 1q21

Seckel18

Growth deficiency, mental deficiency, microcephaly, receding forehead, prominent nose, downward-slanting palpebral fissures, clinodactyly of fifth finger, proximal radial hypoplasia with dislocation of radial head, hypoplasia of proximal fibula

AR (210600) ATR, 3q22-q24 heterogeneous

Townes-Brocks19

Hemifacial microsomia with preauricular tags, abnormal ear shape, sensorineural hearing loss, thumb anomalies, imperforate anus, renal malformations

AD (107480) SALL1, 16q21.1

Treacher Collins20

Downslanting palpebral fissures, cleft in zygomatic bone, lower lid coloboma, partial to total absence of lower eyelashes, malformed auricles, external ear malformation, conductive deafness, cleft palate, extension of scalp hair onto lateral cheek

AD (154500) TCOF1, 5q32-q33

282

Facial Bones

Collins syndrome, suggest that the protein is crucial for the survival of cephalic neural crest cells, and that haploinsufficiency is disease causing.26 Prognosis, Treatment, and Prevention

The prognosis for patients with zygomatic anomalies and related disorders is very good. In a small number of cases, neonatal complications cause insults to the central nervous system, but the majority of patients have normal intelligence. Treatment of these anomalies is primarily surgical and is designed to build the zygomatic bones and zygomatic arches. If other anomalies are involved, the correction can be made at the same time these are corrected depending on the degree of involvement. These procedures are usually performed during childhood with excellent results. Jackson and collaborators1 have used bilateral full-thickness vascularized skull grafts raised on the anterior one-third of the temporalis muscle to correct the skeletal anomalies in the ablepharon-macrostomia syndrome. The grafts are contoured to form the zygomatic arch and to augment the lateral orbital wall. Only cranial bone grafts may be used on the anterior aspect of the orbital rim. Considering that, in most severe forms, two malar bones and two zygomatic arches have to be reconstructed and that partial resorption may occur, the donor sites for bone grafts may be insufficient. In such cases, cranial vault and tibia are used to preserve ribs and iliac crest for additional procedures that may be required. Distraction osteotomy may be used as a primary procedure or after bone grafting.27 As was mentioned previously, zygomatic deficiency is not an isolated birth defect, and careful consideration of syndromic associations must be made. Recurrence figures must be calculated for the primary diagnosis. In mandibulofacial dysostosis, for example, the recurrence risk for the offspring of an affected individual will be 50%, with high penetrance and equal distribution between sexes. Prenatal diagnosis of zygomatic hypoplasia in association with mandibulofacial dysostosis has been accomplished via fetoscopy and ultrasonography.28,29 Fetal cephalometry with ultrasound should be attempted to establish the degree of deficient growth. Prenatal counseling is at present the only means of prevention. References (Absence and Hypoplasia of the Zygoma) 1. Jackson IT, Shaw KE, Pinal-Matorras F: A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence. Br J Plast Surg 41:410, 1988. 2. Kay ED, Kay CN: Dysmorphogenesis of the mandible, zygoma and mandible, ear ossicles in hemifacial microsomia and mandibulofacial dysostosis. Am J Med Genet 32:27, 1989. 3. Tessier P: Anatomical classification of facial, craniofacial and laterofacial clefts. J Maxillofac Surg 4:69, 1976. 4. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. JL Marsh, MW Vannier, WG Stevens, eds. CV Mosby, St. Louis, 1985, p 256. 5. Raulo Y: Treacher Collins syndrome: analysis and principles of surgery. In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Co, Boston, 1985, p 372. 6. Ellis NA, German J: Molecular genetics of Bloom’s syndrome. Hum Molec Genet 5:1457, 1996. 7. Spranger JW, Opitz JM, Bibber U: Heterogeneity of chondrodysplasia punctata. Hum Genet 11:190, 1971. 8. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261, 1992.

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9. Gripp KW, McDonald-McGinn DM, La Rossa D, et al.: Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. Am J Med Genet 101:268, 2001. 10. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 11. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488, 1991. 12. Griffith AJ, Sprunger LK, Sirko-Osadsa DA, et al.: Marshall syndrome associated with a splicing defect at the COL11A1 locus. Am J Hum Genet 62:816, 1998. 13. Miller M, Fineman R, Smith DW: Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970, 1979. 14. Toriello HV: Heterogeneity and variability in the oral-facial-digital syndromes. Am J Med Genet (suppl)4:149, 1988. 15. Aylsworth AS, Lin AE, Friedman PA: Nager acrofacial dysostosis: maleto-male transmission in 2 families. Am J Med Genet 41:83, 1991. 16. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 17. Gelb BD, Shi GP, Chapman HA, et al.: Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236, 1996. 18. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497, 2003. 19. Kohlhase J, Wischermann A, Reichenbach H, et al.: Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18:81, 1998. 20. Splendore A, Silva EO, Alonso LG, et al.: High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat 16:315, 2000. 21. Opitz JM: The developmental field concept in clinical genetics. J Pediatr 101:805, 1982. 22. Kumakawa K, Funasaka S: Middle ear malformation with normal external meatus; correlation of ossicular anomalies with anomalies of auricle, jaw and face. Nippon Jibiinkoka Gakkai Kaiho 88:30, 1985. 23. Poswillo D: The embryological basis of craniofacial dysplasia. Postgrad Med J 53:517, 1977. 24. Sulik KK, Johnson MC, Smiley SJ, et al.: Mandibulofacial dysostosis (Treacher Collins syndrome): a new proposal for its pathogenesis. Am J Med Genet 27:359, 1978. 25. Herring SW, Powlatt UF, Pruzansky S: Anatomical abnormalities in mandibulofacial dysostosis. Am J Med Genet 3:225, 1979. 26. Dixon J, Brakebush C, Fassler R, et al.: Increased levels of apoptosis in the prefusion of neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Hum Mol Genet 9:1473, 2000. 27. McCarthy JG, Hopper RA: Distraction osteogenesis of zygomatic bone grafts in a patient with Treacher Collins syndrome: a case report. J Craniofac Surg 13:279, 2002. 28. Nicolaides KH, Johanston D, Donnai D, et al.: Prenatal diagnosis of mandibulofacial dysostosis. Prenat Diagn 4:201, 1984. 29. Crane JP, Beaver HA: Midtrimester sonographic diagnosis of mandibulofacial dysostosis. Am J Med Genet 25:251, 1986.

8.6 Midface Retrusion and Hypoplasia Definition

Midface retrusion and hypoplasia is the underdevelopment or posterior positioning of the midface. Affecting the inferior portion of the orbits, nasal bones, and maxilla, the human midface growth deficiency gives these individuals a semilunar configuration of the anterior portion of the craniofacial profile.1 Retrusion or hypoplasia of the midface suggests a complex growth deficiency involving neural tissue, cranial base, and branchial arches.

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Diagnosis

For practical purposes, the facial skeleton is divided into three main areas: the upper face, composed of the frontal bones and upper part of the orbits; the midface, composed of the lower portion of the orbits, nasal bones, and maxilla; and the lower face, consisting mainly of the mandible. Abnormalities in any one of these areas distort the normal shape of the craniofacies as a whole. Each is a unique area of growth and development, with relatively independent clinical delineation. Of the three facial areas, the midface may be the most fascinating multistructural complex of facial development. It represents the central point of union of the growing and migrating craniofacial processes (branchial arches), with the final developmental result based on normal growth of the cranial base and brain. In some instances, pathologic processes of the upper and lower skeletal face will modify the shape of the midface (Fig. 8-10). Acrocephalosyndactyly syndromes are good examples of such modification.2 The middle one-third of the skeletal face constitutes the structural support of the nose, which is an important element in facial aesthetics. Alterations of the anteroposterior dimensions of the midface lead to changes in facial convexity and in dental occlusion.1 Evaluation of patients with midface retrusion includes external measurements, lateral radiographs, cephalometry, and study of dental occlusion. A complete dimensional study of the whole face is necessary not only to analyze the relationship between the maxilla and the rest of the facial skeleton but also to determine alterations of the upper or lower one-third of the face.3 Cephalometry is an accurate method of assessing alterations in the anterior projection of the face. It also provides documentation of the preoperative and postoperative findings in affected individuals. Fixed anatomic points, such as the cranial base, the Frankfurt plane, and other facial planes, are used in the regular cephalometric evaluation. Excellent normative data have recently been published for all postnatal ages.4 Dental models have been used to confirm the cephalometric measurements; these may help the clinician to evaluate malocclusion problems and to plan cor-

rective surgical procedures. The cast is cut and different segments are mobilized to determine what type of procedure will produce the most favorable result.1 Midfacial hypoplasia or retrusion may cause obstruction of the nasal airway and inability to feed adequately. This is seen in syndromes such as the Antley-Bixler syndrome, in which patients show choanal atresia and feeding difficulties.5 Since the infant is usually a nose breather, obstruction of the nasal airway in the neonatal period requires rapid recognition and treatment. Orotracheal intubation is usually required. Some patients with midface hypoplasia and/or retrusion have isolated hypoplasia of the maxilla, which provides support to the upper lip. This is usually a hereditary feature (autosomal dominant) and is commonly associated with prognathism. The majority of cases of maxillary hypoplasia result from congenital anomaly syndromes, such as Crouzon, Apert, and Binder syndromes6 (Table 8-7). Etiology and Distribution

Midface hypoplasia or retrusion is seen not as an isolated finding but only as part of a multiple congenital anomaly syndrome. In the absence of a traumatic or infectious cause, a genetic or environmental origin should be investigated.28 The inheritance of midface hypoplasia should be considered in the context of the entity with which it is seen. The growth and development of the midface are not completely understood. It has been suggested that the three areas of the face (upper, middle, and lower one-third) may have relatively independent mechanisms of growth and development, the midface being the most complex of the three.29 Insufficient information is available at present to define a single mechanism that results in midface hypoplasia; perhaps it would be unwise to seek a single cause. This fascinating area of structures may be a developmental field in which growing parts of an embryo are controlled and coordinated in a spatially ordered, temporally synchronized, and epimorphically hierarchical manner. Several authors have attempted to delineate a developmental field by anthropometric analysis. This attempt is based on the

Fig. 8-10. Preoperative (A) and postoperative (B) profile of patient with midface retrusion. (From OrtizMonasterio and Musolas.1)

Table 8-7. Syndromes associated with midface retrusion and hypoplasia Causation Gene/Locus

Syndrome

Prominent Features

Achondroplasia7

Rhizomelia, megalocephaly, small foramen magnum, short cranial base, low nasal bridge, prominent forehead, narrowing of lumbar interpedicular distance, lumbar lordosis, short trident hand

AD (100800) FGFR3, 4p16.3

Angelman8

Growth deficiency, mental retardation, ataxia, seizure disorder, inappropriate laughter, microbrachycephaly, widely spaced teeth

(105830) Mat del 15q11-q13 Pat UPD 15q UBE3A

Antley-Bixler9

Growth deficiency, variable mental development, brachycephaly, choanal stenosis/atresia, craniosynostosis, depressed nasal bridge, radiohumeral synostosis, arachnodactyly, femoral bowing, femoral fractures

AR (207410) Abnormal steroid biogenesis in some cases

Apert10

Craniosynostosis, high forehead, flat facies, irregular supraorbital horizontal groove, shallow orbits, hypertelorism, severe syndactyly hands and feet, broad distal phalanges of thumb, mental retardation

AD (101200) FGFR2, 10q26

Cohen11

Truncal obesity, hypotonia, high nasal bridge, short philtrum, downslanting palpebral fissures, prominent maxillary central incisors, large ears, chorioretinal dystrophy, narrow hands and feet

AR (216550) COH1, 8q22

Deletion 1p3612

Mental retardation, expressive language most severely affected, deep-set eyes, prominent supraorbital ridges, seizure disorder

Subtelomeric deletion

Deletion 18q13

Mental retardation, hypotonia, behavior problems, short stature, narrow external ear canal, microcephaly, hypoplastic labia majora, cryptorchidism

Monosomy for variable 18q region

Deletion 22q11.214

Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, prominent nasal tip, hypoplastic alae nasi, learning difficulties

(192430) 22q11.2 microdeletion

Crouzon15

Bicoronal or pansynostosis, proptosis, beaked nose

AD (123500) FGFR2, 10q26

Facio-auriculo-vertebral spectrum16

Macrostomia, unilateral facial hypoplasia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate

Unknown, sporadic (164210, 257700)

Prenatal alcohol17

Growth deficiency, fine motor dysfunction, poor eye-hand coordination, variable microcephaly, short palpebral fissures, short nose, smooth philtrum, thin smooth upper lip, joint anomalies, small distal phalanges

Teratogen

Prenatal valproate18

Narrow bifrontal diameter, high forehead, epicanthal folds, low nasal bridge, short nose, congenital heart disease, long and thin fingers and toes, meningomyelocele, cleft lip

Teratogen

Prenatal fluconazole19

Phenocopy of Antley-Bixler syndrome

Teratogen, interference with steroid biogenesis

Hallermann-Streiff 20

Small stature, brachycephaly with parietal bossing, thin calvarium, delayed ossification of the sutures, microphthalmia, small nose, microstomia, hypoplasia of the teeth, atrophy of the skin, hypotrichosis

AD (234100)

Pfeiffer21

Brachycephaly, coronal synostosis, hypertelorism, broad distal phalanges of the thumb, medial deviation of thumbs and broad first toes

AD (101600) FGFR1, 8p11 FGFR2, 10q26

Rieger22

Iris dysplasia, short philtrum, thin upper lip, hypodontia, failure of involution of periumbilical skin

AD (180500) PITX2, 4q25-q26

Rubinstein-Taybi23

Short stature, small cranium, palpebral downslant, beaked nose, epicanthal folds, strabismus, malformed auricles, broad thumbs, broad toes, cryptorchidism, mental retardation

(180849) Microdeletion or mutation CREBBP, 16p13.3

Saethre-Chotzen24

Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, hallux valgus

(101400) TWIST, 7p21

Stickler25

Flat facies, depressed nasal bridge, epicanthal folds, clefts of hard and/soft palate, micrognathia, deafness, retinal detachment, cataracts, hypotonia, marfanoid habitus, flat vertebrae

AD (108300, 604841, 184840) COL2A1, 12q31 COL11A1, 1p21 COL11A2, 6p21

Trisomy 2126

Hypotonia, short stature, brachycephaly, upslanting palpebral fissures, small ears, cardiac defects, single palmar crease, clinodactyly

Abnormal karyotype, trisomy 21

Turner27

Small stature, ovarian dysgenesis, transient congenital lymphedema, broad chest, widely spaced nipples, pectus excavatum, abnormal auricles, inner canthal folds, excessive pigmented nevi, renal malformation, congenital heart disease

Abnormal karyotype, 45,X

285

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Craniofacial Structures

concept of spatial relationship between structures belonging to the same growth field, which represents an area of convergence and concentration of several growth forces.30,31 Positive results were obtained by Siebert,29 who suggested a positive delineation of the midface developmental field. However, the representative variables used (inner canthal measurement, outer orbital measurement, nose breadth, and mouth width) are soft tissue measurements that probably do not truly reflect the growth of the skeletal midface. More studies are needed to elucidate the mechanisms involved in the aberrant growth of the middle one-third of the skeletal face. Prognosis, Treatment, and Prevention

The treatment of hypoplasia of the midface is surgical, and the central section of the face must be advanced; a horizontal osteotomy of the maxilla closely following the trace of a LeFort I fracture is indicated. When the facial hypoplasia extends to the floor of the orbit, to the nose, and to the malar eminence, the osteotomy varies according to the amount of advancement required and the particular areas of the face that must be mobilized. Ortiz-Monasterio and Musolas1 have suggested the use of Tessier osteotomies types 2.4 and 5, which follow the course of a LeFort III fracture. These procedures are complemented by cartilage or bone grafts to the pyriform area that will be useful in the restoration of the facial convexity. Distraction osteogenesis has been used in combination with LeFort procedures to increase the amount of midfacial advancement in a single surgical procedure.32,33 Further refinement of this technique allows for distraction in more than one plane.34 Midface advancement is a rewarding technique, with excellent functional correction and improvement of facial aesthetics. The prognosis must be individualized according to the associated congenital malformations, but in general it is considered very good. Prenatal studies of the midface have rarely been reported.29 Recent advances in ultrasonography have raised the possibility of accurately measuring the midface at early gestational ages.35 The presence of midface hypoplasia during a fetal sonogram should alert the ultrasonographer to the possibility of associated fetal anomalies. Midface hypoplasia is not an independent entity. Prevention of this condition is related to the individual situation, with prenatal counseling apparently the only method available at present. References (Midface Retrusion and Hypoplasia) 1. Ortiz-Monasterio F, Musolas A: Midface retrusion. World J Surg 13:410, 1989. 2. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. CV Mosby, St. Louis, 1985, p 209. 3. Ricketts RM: Divine proportion in facial esthetics. Symposium on maxillo-facial surgery. Clin Plast Surg 9:401, 1982. 4. Saksena SS, Bixler D, Yu PL: A Clinical Atlas of Roentgencephalometry in Norma Lateralis. Alan R. Liss, Inc., New York, 1987, p 5. 5. Escobar LF, Bixler D, Sadove M, et al.: Antley-Bixler syndrome from a prognostic perspective: report of a case and review of the literature. Am J Med Genet 29:829, 1988. 6. Gross-Kieselstein E, Har-Even Y, Navon P, et al.: Familial variant of maxillonasal dysplasia? J Craniofac Genet Dev Biol 6:331, 1986. 7. Bellus GA, Hefferon TW, Ortiz de Luna RI, et al.: Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368, 1995. 8. Buntinx IM, Hennekam RCM, Brouwer OF, et al.: Clinical profile of Angelman syndrome at different ages. Am J Med Genet 56:176, 1995. 9. Antley RM, Bixler D: Trapezoidocephaly, midface hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures. Birth Defects Orig Artic Ser XI(2):397, 1975.

10. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. 11. Cohen MM Jr, Hall BD, Smith DW, et al.: A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb anomalies. J Pediatr 83:280, 1973. 12. Heilstedt HA, Ballif BC, Howard LA, et al.: Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am J Hum Genet 72:1200, 2003. 13. Kline AD, White ME, Wapner R, et al.: Molecular analysis of the 18qsyndrome—and correlation with phenotype. Am J Hum Genet 52:895, 1993. 14. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261, 1992. 15. Reardon W, Winter RM, Rutland P, et al.: Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8:98, 1994. 16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 17. Jones KL, Smith DW: The fetal alcohol syndrome. Teratology 12:1, 1975. 18. Kozma C: Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 98:168, 2001. 19. Aleck KA, Bartley DL: Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 72:253, 1997. 20. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488, 1991. 21. Cohen MM Jr: Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am J Med Genet 45:300, 1993. 22. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996. 23. Hennekam RCM, Tilanus M, Hamel BCJ, et al.: Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects. Am J Hum Genet 52:255, 1993. 24. Pantke OA, Cohen MM Jr, Witkop CJ Jr, et al.: The Saethre-Chotzen syndrome. Birth Defects Orig Artic Ser XI(2):190, 1975. 25. Snead MP, Yates JRW: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353, 1999. 26. Korenberg JR, Chen XN, Schipper R, et al.: Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Nat Acad Sci 91:4997, 1994. 27. Saenger P: Turner’s syndrome. N Engl J Med 335:1749, 1996. 28. Hopkin GB: Hypoplasia of the middle third of the face associated with congenital absence of the anterior nasal spine, depression of the nasal bones, and angle class III malocclusion. Br J Plast Surg 16:146, 1963. 29. Siebert JR: Prenatal growth of the median face. Am J Med Genet 25:369, 1986. 30. Lauder GV: Form and function: structural analysis in evolutionary morphology. Paleobiology 7:430, 1981. 31. Cheverud JM: Phenotypic, genetic, and environmental morphology integration in the cranium. Evolution 36:499, 1982. 32. Alonso N, Munhoz AM, Fogaca W, et al.: Midfacial advancement by bone distraction for treatment of craniofacial deformities. J Craniofac Surg 9:114; discussion 119, 1998. 33. Toth BA, Kim JW, Chin M, et al.: Distraction osteogenesis and its application to the midface and bony orbit in craniosynostosis syndromes. J Craniofac Surg 9:100; discussion 119, 1998. 34. Satoh K, Mitsukawa N, Hosaka Y: Dual midfacial distraction osteogenesis: Le Fort III minus I and Le Fort I for syndromic craniosynostosis. Plast Reconstr Surg 111:1019, 2003. 35. Escobar LF, Bixler D, Padilla LM, et al.: A morphometric analysis of the fetal craniofacies by ultrasound: fetal cephalometry. J Craniofac Genet Dev Biol 10:19, 1990.

Facial Bones

8.7 Agnathia Definition

Agnathia is the complete absence of the mandible. This rare condition can be viewed as the most severe form of micrognathia (reduction in mandibular size). However, agnathia and micrognathia probably have different etiologies. Diagnosis

Using simple clinical inspection, the dysmorphologist is frequently able to detect changes in mandibular shape and size. In agnathia, the missing lower one-third of the facial skeleton causes striking morphologic changes (Fig. 8-11). Affected individuals have severe soft tissue anomalies, such as microstomia, cleft lip and/or palate, and ear abnormalities ranging from absence or misplacement of the external auricle to abnormalities of the inner ear. Some patients also have holoprosencephaly and upper respiratory tract anomalies.1 Two groups of patients with agnathia are now recognized: those who have varying degrees of cyclopia, with holoprosencephalic brain, and those without cyclopialike facial malformations.2 The former is a rare lethal condition that has been reported to occur in association with microstomia, aglossia, synotia, and brain Fig. 8-11. Infant with agnathia without holoprosencephaly.

287

malformations. It usually occurs with developmental abnormalities of other systems that lead to early neonatal death.1 The second group is considered less severe and consists of agnathia without holoprosencephaly. Affected patients usually have microstomia, aglossia, blind mouth, middle ear anomalies, cleft lip, cleft palate, and downward-slanting palpebral fissures (Fig. 8-11). Most pregnancies with agnathic fetuses are associated with polyhydramnios, which probably result from fetal inability to swallow because of persistence of the oropharyngeal membrane. As a consequence, premature labor is frequent, with only rare cases reaching 38 weeks of gestation. The neonate shows a blindending mouth, which impedes the passing of an oropharyngeal tube to establish an airway. Early recognition of this situation may prompt the clinician to perform a tracheostomy. Ear positioning is variable, and the use of the term otocephaly does not seem justified. Patients with fusion of the ears in the midline are rare.3 Inner ear anomalies have been reported to occur in about 40% of cases.4 Etiology and Distribution

It seems possible that two different mechanisms are responsible for agnathia holoprosencephaly and agnathia without brain anomalies (otocephaly).1,5,6 Agnathia is considered to be a defect in the ventral portion of the first branchial arch and may be secondary to defective neural crest migration or proliferation or to a mesodermal deficiency in the arch itself.6 Persistence of the oropharyngeal membrane occurs. Bixler and collaborators1 have suggested that a defect in prechordal mesoderm formation and/or its interactions accounts for agnathia-holoprosencephaly. Subsequent effects on neural crest cells may result. A graded series of defects resulting from abnormal formation of the prosencephalon and the mandible occurs. Agnathia without holoprosencephaly is a very rare abnormality, with sporadic occurrence. Autosomal recessive inheritance has been suggested by Pauli et al.2 based on their observation of two affected stillborn siblings. However, an unbalanced chromosome abnormality was later identified in this family.7 Animal models (mouse and guinea pig) have also indicated the existence of an inherited type of agnathia without holoprosencephaly; however, this evidence is not conclusive at the present time.8 Agnathia with holoprosencephaly seems to have a higher incidence than agnathia without holoprosencephaly, with only 24 cases of the latter identified in the 25 years prior to 1985.1 In patients with agnathia with holoprosencephaly, situs inversus may also be present.9 Sex ratios are equal, and excessive incidence has not been described in any racial group. Prognosis, Treatment, and Prevention

As was mentioned previously, agnathia without holoprosencephaly seems to carry a better prognosis than agnathia with holoprosencephaly. In general, the prognosis in both situations is poor; however, there are no adequate data concerning survival rates. In the presence of airway obstruction, the clinician should consider a tracheostomy, since this is the only means of ensuring good ventilatory support. Once the patient is stable, evaluation for surgical correction of associated anomalies is indicated, with the planning of feeding methods to support the child. Reports of prenatal diagnosis of this condition can be found in the literature.10,11 The authors used prenatal radiographs to identify agnathia and polyhydramnios. The use of ultrasonography, which can demonstrate polyhydramnios and agnathia with

288

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holoprosencephaly, has been found to be preferable. Computer tomography has also been used for prenatal diagnosis.12 Since most of the cases are sporadic, no biochemical, DNA, or chromosomal markers have been useful in the diagnosis of agnathia. There appears to be no effective means of prevention at present.

Rarely seen as an isolated characteristic, hypoplasia of the mandible can be familial.2 However, it is more common as part of a multiple congenital anomaly syndrome, with which it follows the corresponding mode of inheritance. More than 130 syndromes and 47 chromosomal anomalies have been reported to include micrognathia as a consistent feature (Table 8-8).

References (Agnathia)

Etiology and Distribution

1. Bixler D, Ward R, Gale DD: Agnathia-holoprosencephaly: a developmental field complex involving face and brain. Report of 3 cases. J Craniofac Genet Dev Biol 1:241, 1985. 2. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly. Am J Med Genet 14:677, 1983. 3. Johnson W, Cook JB: Agnathia associated with pharyngeal isthmus atresia and hydramnios. Arch Pediatr 78:211, 1961. 4. Le Marec B, Bourdiniere J, Le Clech G, et al.: A propos d’un cas d’tocephalie (A case of otocephaly). J Genet Hum 24(suppl):253, 1976. 5. Opitz JM: Letter to the editor. Clin Genet 17:238, 1980. 6. Johnston MC, Sulik KK: Some abnormal patterns of development in the craniofacial region. Birth Defects Orig Artic Ser XV(8): 23, 1979. 7. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 8. Juriloff DM, Sulik KK, Roderick TH, et al.: Morphogenesis of spontaneously occurring otocephaly in a newly developed mouse mutant. Teratology 21:47A, 1980. 9. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn 22:840, 2002. 10. Ursell W: Hydramnios associated with congenital microstomia, agnathia and synotia. J Obstet Gynecol Br Commonwealth 79:185, 1972. 11. Cayea PD, Bieber FR, Ross MJ, et al.: Sonographic findings in otocephaly (synotia). J Ultrasound Med 4:377, 1985. 12. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathiaholoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68, 2001.

8.8 Micrognathia Definition

Micrognathia is the reduction in size of one or all parts of the mandible. Micrognathia should be differentiated from retrognathia, in which the mandible is of normal size but is posteriorly positioned in relation to the skull base. Diagnosis

Malformations of the mandible are among the most common malformations known to humans. Among these, micrognathia may be the most common.1 Severe micrognathia can be detected by the clinician by simple inspection (Fig. 8-12). Mild forms may be difficult to detect, however, and can be easily confused with retrognathia. Roentgenocephalometry is extremely helpful in the differentiation between true micrognathia and retrognathia, and it also provides a substantial amount of information necessary for objective decisions concerning treatment. Mandibular hypoplasia may induce other anomalies, as is the case in the Pierre Robin sequence. Here, acting as a single initiating defect, the small mandible keeps the tongue in a posterior location, impairing the closure of the posterior palatal shelves in the midline. This results in cleft palate.

Micrognathia is believed to result from hypoplasia of the neural crest cell population in the first branchial arch. The bony elements of the lower jaw are neural crest-derived. From two different ossification centers that appear at about the 6th week of gestation, each side of the mandible is formed by posteroanterior ossification spreading over the framework provided by Meckel’s cartilage. At birth, the mandible consists of two halves, with a fibrous union at the symphysis. Complete ossification of the mandible and the fibrous union occurs within the 1st year of life. Evidence for the supportive role of Meckel’s cartilage during growth of the mandible is shown by the effects of the lathyrogen B-aminoproprionitrile (BAPN) on facial growth.39 Administration of BAPN to pregnant rats at about day 15 of gestation reduces the length of the mandible in the fetuses. In some instances, micrognathia may be due to mechanical influences during growth and development. The best example of this situation is the mandibular hypoplasia seen in the oligohydramnios sequence, in which compression impedes normal growth and development of the mandible. Teratogenic factors also have been suggested to play a role in the etiology of micrognathia. Observations in fetuses of mothers who received radiotherapy during pregnancy showed an increased incidence of mandibular hypoplasia.40 Administration of the antiniacin agent 6-aminonicotinamide and the glutamine analogue diazo-oxo norleucine to rats during gestational day 15 produced severe growth retardation of Meckel’s cartilage, thereby producing an inadequate framework for mandibular development.41 Anomalies of the mandible with or without ear abnormalities are considered to occur with a frequency greater than one of every 100 newborn babies.1 Micrognathia does not follow a sex preferential pattern. The mode of inheritance, if any, should be evaluated in the context of the disorder of which micrognathia constitutes a part. Prognosis, Treatment, and Prevention

The prognosis of the patient with mandibular hypoplasia depends on associated birth defects. Cases of isolated micrognathia or even Pierre Robin sequence have an excellent prognosis. The neonate with airway obstruction may require tracheotomy and feeding gastrostomy. Surgical mandibular advancement was previously not recommended for use during infancy.42 This has changed due to the availability of distraction osteogenesis. This technique has been used successfully in children as young as 6 months.43 As the distraction devices become smaller, they can be implanted in even younger infants. This technique may be used to prevent tracheotomy or to allow for decannulation in tracheotomy-dependent patients.44 When there is a stable airway and nutrition can be maintained, orthognathic surgery can be deferred until mid- to late adolescence depending on the sex, since females can undergo such surgery earlier. Micrognathia has been clearly identified in the prenatal period via ultrasonography.45,46 The routine ultrasonographic

Facial Bones

289

Fig. 8-12. Mild micrognathia in a 12-year-old male with MPS 1-H/I-S compound (A), moderate micrognathia in an infant with cerebrocostomandibular syndrome (B and C), and severe micrognathia associated with radial reduction defects in a 5-year-old boy with Nager syndrome (D). (B and C courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

examination between 16 and 18 gestational weeks should allow delineation of the morphology of the mandible. Prenatal recognition of micrognathia is helpful in that it allows the neonatologist, facial surgeon, otolaryngologist, and anesthetist to be prepared for possible complications during and after delivery. References (Micrognathia) 1. Melnick M: Anomalies of branchial-arch-derived otomandibular structures. In: Clinical Dysmorphology of Oral-Facial Structures. M Melnick, ED Shields, NJ Burzmski, eds. John Wright, PSG, Boston, 1982, p 336. 2. Warkany J: Congenital Malformations. Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 622. 3. Hall JG, Reed SD, Driscoll EP: Part 1. Amyoplasia: a common, sporadic condition with congenital contractures. Am J Med Genet 15: 571, 1983. 4. Ellis NA, German J: Molecular genetics of Bloom’s syndrome. Hum Molec Genet 5:1457, 1996.

5. Wagner T, Wirth J, Meyer J, et al.: Autosomal sex reversal and camptomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111, 1994. 6. Dignan PSJ, Martin LW, Zenni EJ Jr: Pierre Robin anomaly with an accessory metacarpal of the index fingers: the Catel-Manzke syndrome. Clin Genet 29:168, 1986. 7. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: Decentric small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57:148, 1981. 8. Plotz FB, van Essen AJ, Bosschaart AN, et al.: Cerebro-costo-mandibular syndrome. Am J Med Genet 62:286, 1996. 9. Pena SDJ, Shokeir MHK: Autosomal recessive cerebro-oculo-facioskeletal (COFS) syndrome. Clin Genet 5:285, 1974. 10. Cohen MM Jr, Hall BD, Smith DW, et al.: A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb anomalies. J Pediatr 83:280, 1973.

Table 8-8. Syndromes associated with micrognathia Causation Gene/Locus

Syndrome

Prominent Features

Amyoplasia congenita3

Round face; small upturned nose; midline capillary hemangioma; severe flexion contractures at metacarpophalangeal joints, with mild contractures at interphalangeal joints, hips usually dislocated, adducted, or abducted

Unknown, sporadic (108110)

Bloom4

Growth deficiency, mild microcephaly with dolichocephaly, small nose, facial telangiectatic erythema that involves the butterfly midface region exacerbated by sunlight

AR (210900) RECQL3, 15q26.1

Campomelic dysplasia5

Growth deficiency, large brain with gross cellular disorganization, small flat-appearing face, cleft palate, short palpebral fissures, anterior bowing of tibiae, short fibula, absence of mineralization of the sternum, hypogenitalism, XY gonadal dysgenesis

AR (211970) SOX9, 17q24-q25

Catel-Manzke6

Hyperphalangy of index finger, postnatal growth deficiency, cleft palate, malformed ears, cardiac defects, clinodactyly

(302380) Majority of cases are sporadic affected males

Cat eye7

Cognitive delay, mild hypertelorism, inferior coloboma of the iris, preauricular pits and tags, cardiac defects (TAPVR), imperforate anus, renal agenesis

(115470) partial tetrasomy 22 (isochromosome 22pter-q11)

Cerebro-costo-mandibular8

Cognitive delay, growth deficiency, glossoptosis, cleft soft palate, bell-shaped small thorax, anomalous rib insertion with ‘‘rib gaps’’

AD (117650)

Cerebro-oculofacio-skeletal (COFS)9

Reduced white matter of brain with gray mottling, microcephaly, large pinnae, blepharophimosis, microphthalmia, cataracts, nystagmus, camptodactyly, flexion contractures of elbows and knees, hirsutism, kyphosis

AR (214150, 126340) ERCC6, 10q11 ERCC2, 19q13

Cohen10

Truncal obesity, hypotonia, high nasal bridge, short philtrum, downslanting palpebral fissures, prominent maxillary central incisors, large ears, chorioretinal dystrophy, narrow hands and feet

AR (216550) COH1, 8q22

Cornelia de Lange11

Short stature, cognitive delay, initial hypertonicity, low-pitched weak cry, long curly eyelashes, small nose, bushy eyebrows, synophrys, hirsutism, micromelia, genital anomalies

AD (122470) Most cases sporadic NIPBL, 5p13.1

Deletion 22q11.212

Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, prominent nasal tip, hypoplastic alae nasi, learning difficulties

(192430) microdeletion 22q11.2

Diamond-Blackfan anemia-microtiacleft palate13

Macrocytic anemia, short stature, downslanting palpebral fissure, microtia, cleft palate, micrognathia

Dominant (606164)

Dubowitz14

Prenatal growth deficiency, variable mental deficiency, short attention span, microcephaly, short palpebral fissures, round nasal tip, prominent dysplastic ears, eczema

AR (223370)

Escobar15

Multiple pterygia, short stature, inner canthal folds, cleft palate, emotionless face, scoliosis, camptodactyly, syndactyly, genital anomalies

AR (265000)

Facio-auriculo-vertebral spectrum16

Macrostomia, unilateral facial hypoplasia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate

Unknown, sporadic (164210, 257700)

Hallermann-Streiff17

Small stature, brachycephaly with parietal bossing, thin calvarium, delayed ossification of the sutures, microphthalmia, small nose, microstomia, hypoplasia of the teeth, atrophy of the skin, hypotrichosis

Unknown, sporadic (234100)

Lethal multiple pterygium18

Generalized amyoplasia, multiple pterygia, contractures, growth deficiency, epicanthal folds, ocular hypertelorism, flat nose, cryptorchidism, mild neck edema and loose skin

AR (253290) Heterogeneous

Marshall-Smith19

Accelerated linear growth and skeletal maturation, long cranium, prominent forehead, bluish sclerae, broad proximal and middle phalanges with narrow distal phalanges, hypertrichosis, respiratory problems

Unknown (602535)

Meckel-Gruber20

Growth deficiency, occipital encephalocele, microcephaly, ear anomalies, cleft palate, microphthalmia, polydactyly, cystic renal dysplasia, cryptorchidism

AR, multiple loci (606361) 8q24 (603194) 11q13 (249000) 17q22-q23 (continued )

290

Table 8-8. Syndromes associated with micrognathia (continued) Causation Gene/Locus

Syndrome

Prominent Features

Melnick-Needles (Oto-palatodigital spectrum)21

Melnick-Needles: prominent eyes, late closure of fontanels, short upper arms and distal phalanges, bowing of radius and tibia, coxa valga, small thoracic cage, pectus excavatum, iliac flaring; often male lethal

XL (309350, 311300, 304120, 305620) FLNA, Xq28 Allelic to OPD1, OPD2, frontometaphyseal dysplasia, periventricular heterotopia

Miller22

Downslanting palpebral fissures, eyelid coloboma, ectropion, cleft lip and/or palate, postaxial limb deficiencies, syndactyly, accessory nipple

AR (263750) Most sporadic, AD rarely reported

Miller-Dieker23

Lissencephaly, heterotopias, absent or hypoplastic corpus callosum, small brain stem, hypotonia, seizures, microcephaly, small nose, late eruption of primary teeth, cryptorchidism

(247200) Microdeletion 17p13.3

Moebius24

Mask-like facies with sixth and seventh nerve palsy, hypoplasia to absence of the central brain nuclei, myopathy

(157900) Majority of cases sporadic, few familial

Nager25

Normal intelligence, short stature, conductive deafness and articulation problems, malar hypoplasia, palpebral downslant, absence of lower eyelashes, periauricular tags, atresia of external ear canal, hypoplasia to aplasia of the thumb, proximal radioulnar synostosis, short forearms

AD, AR (154400)

Nijmegen breakage26

Microcephaly, short stature, palpebral upslant, long nose, immune dysfunction, chromosome breakage, malignancies, neurodegeneration

AR (251260) NBS1, 8q21

Pallister-Hall27

Hypothalamic hamartoblastoma, hypopituitarism, flat midface, anteverted nares, laryngeal cleft, bifid epiglottis, multiple frenuli, abnormal lung lobation, nail dysplasia, postaxial polydactyly, anal defects

AD (146510) GLI3, 7p13 Allelic to Greig

Progeria28

Alopecia, hypoplasia of nails, loss of subcutaneous fat, periarticular fibrosis, skeletal hypoplasia, dysphasia, dental anomalies, atherosclerosis

AD (176670) LMNA, 1q21.2

Prenatal accutane29

Bilateral microtia, anotia, U-shaped palatal cleft, ocular hypertelorism, conotruncal heart defects, hydrocephaly, cerebellar hypoplasia, agenesis of the vermis, thymic abnormalities

Teratogen

Seckel30

Prenatal growth deficiency, microcephaly, receding forehead, prominent nose, mental retardation

AR, heterogeneous (210600) ATR, 3q22 (606744) 18p11-q11

Splenogonadal fusion31

Fused spleen and gonad, limb defects, deep and narrow palate, multiple unerupted teeth

(183300) Sporadic, mostly males, possibly due to vascular event

Stickler32

Flat facies, depressed nasal bridge, epicanthal folds, clefts of hard and/soft palate, deafness, retinal detachment, cataracts, hypotonia, marfanoid habitus, flat vertebrae

AD (108300) COL2A1, 12q31 (604841) COL11A1, 1p21 (184840) COL1A2, 6p21

Treacher Collins33

Downslanting palpebral fissures, cleft in zygomatic bone, lower lid coloboma, partial to total absence of lower eyelashes, external ear malformation, conductive deafness, cleft palate, extension of scalp hair onto lateral cheek

AD (154500) TCOF1, 5q21-q33

Trisomy 834

Variable cognitive deficiency, strabismus, hypertelorism, full lips, cupped ears, camptodactyly, limited supination, long slender trunk, narrow pelvis

Abnormal karyotype

Trisomy 935

Growth deficiency, severe mental deficiency, narrow bifrontal diameter, prominent upper lip, low-set ears, joint anomalies, hypoplastic phalanges, congenital heart disease

Abnormal karyotype

Trisomy 1836

Growth deficiency, hypertonicity, prominent occiput, small mouth, clenched hand, overlapping fingers, cardiac defects, renal malformation, rocker-bottom feet

Abnormal karyotype

Deletion 4p37

Growth deficiency, hypotonia, severe mental deficiency, strabismus, hypertelorism, prominent glabella, posterior midline scalp defects, periaurcular tags, clefting, genital anomalies

Abnormal karyotype

Deletion 13q38

Growth deficiency, mental deficiency, microcephaly, hypertelorism, microphthalmia, retinoblastoma, webbed neck, congenital heart disease, hypospadias, lumbar agenesis

Abnormal karyotype

291

292

Craniofacial Structures

11. Allanson JE, Hennekam RCM, Ireland M: De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes. J Med Genet 34:645, 1997. 12. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261, 1992. 13. Gripp KW, McDonald-McGinn DM, La Rossa D, et al.: Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. Am J Med Genet 101:268, 2001. 14. Tsukahara M, Opitz JM: Dubowitz syndrome: review of 141 cases including 36 previously unreported patients. Am J Med Genet 63:277, 1996. 15. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: a review and report of eleven patients. Am J Med Genet 12:377, 1982. 16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 17. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med Genet 41:488, 1991. 18. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809, 1984. 19. Williams DK, Carlton DR, Green SH, et al.: Marshall-Smith syndrome: the expanding phenotype. J Med Genet 34:842, 1997. 20. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 21. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum Disorders Clinical Collaborative Group: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 22. Miller M, Fineman R, Smith DW: Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970, 1979. 23. Allanson JE, Ledbetter DH, Dobyns WB: Classical lissencephaly syndromes: does the face reflect the brain? J Med Genet 35:920, 1998. 24. Baraitser M: Genetics of Moebius syndrome. J Med Genet 14:415, 1977. 25. Aylsworth AS, Lin AE, Friedman PA: Nager acrofacial dysostosis: maleto-male transmission in 2 families. Am J Med Genet 41:83, 1991. 26. Van der Burgt I, Chrzanowska KH, Smeets D, et al.: Nijmegen breakage syndrome. J Med Genet 33:153, 1996. 27. Kang S, Allen J, Graham JM Jr, et al.: Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 34:441, 1997. 28. Eriksson M, Brown WT, Gordon LB, et al.: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293, 2003. 29. Sulik KK, Cook CS, Webster WS: Teratogens and craniofacial malformations: relationships to cell death. Development 103(suppl):213, 1988. 30. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497, 2003. 31. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb defect syndrome: report of five new cases and review. Am J Med Genet 86:347, 1999. 32. Snead MP, Yates JRW: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353, 1999. 33. Splendore A, Silva EO, Alonso LG, et al.: High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum Mutat 16:315, 2000. 34. Riccardi VM: Trisomy 8: an international study of 70 patients. Birth Defects Orig Artic Ser XIII(3C):171, 1977. 35. Cantu ES, Eicher DJ, Pai GS, et al.: Mosaic vs. nonmosaic trisomy 9: report of a liveborn infant evaluated by fluorescence in situ hybridization and review of the literature. Am J Med Genet 62:330, 1996.

36. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 49:175, 1994. 37. Battaglia A, Carey JC, Cederholm P, et al.: Natural history of WolfHirschhorn syndrome: experience with 15 cases. Pediatrics 103:830, 1999. 38. Tranebjaerg L, Nielsen KB, Tommerup N, et al.: Interstitial deletion 13q: further delineation of the syndrome by clinical and highresolution chromosome analysis of five patients. Am J Med Genet 29:739, 1988. 39. Diewert VM: Correction between alterations in Meckel’s cartilage and induction of cleft palate with B-aminoproprionitrile in the rat. Teratology 24:43, 1981. 40. Fogh-Andersen P: Rare clefts of the face. Acta Chir Scand 129:275, 1965. 41. Diewert VM: Contributions of differential growth of cartilages to changes in craniofacial morphology. In: Factors and Mechanisms Influencing Bone Growth. Alan R. Liss, Inc, New York, 1982, p 229. 42. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care for Craniofacial Deformities. JL Marsh, MW Vannier, WG Stevens, eds. CV Mosby, St Louis, 1985, p 260. 43. Denny AD, Talisman R, Hanson PR, et al.: Mandibular distraction osteogenesis in very young patients to correct airway obstruction. Plast Reconstr Surg 108:302, 2001. 44. Perlyn CA, Schmelzer RE, Sutera SP, et al.: Effect of distraction osteogenesis of the mandible on upper airway volume and resistance in children with micrognathia. Plast Reconstr Surg 109:1809, 2002. 45. Malinger G, Rosen N, Achiron R, et al.: Pierre Robin sequence associated with amniotic band syndrome ultrasonographic diagnosis and pathogenesis. Prenat Diagn 7:455, 1987. 46. Rotten D, Levaillant JM, Martinez H, et al.: The fetal mandible: a 2D and 3D sonographic approach to the diagnosis of retrognathia and micrognathia. Ultrasound Obstet Gynecol 19:122, 2002.

8.9 Congenital Asymmetry of the Facial Skeleton Definition

Congenital asymmetry of the facial skeleton is a quantitative discrepancy in size between the right and left sides of the facial skeleton. The facial midline is determined by the sagittal line drawn from the vertex (highest midpoint of the craniofacies) through the nasion and subnasale points to the gnathion (lowest medial point of the mandible). Diagnosis

Asymmetry of the facial skeleton and of the human skull as a whole to a degree that can be readily appreciated is so common that it has to be recognized as the rule.1 Such normal or anatomic asymmetry must be distinguished from pathologic asymmetry (Fig. 8-13). This difficult task is facilitated by quantitative procedures that can validate clinical observations. Useful techniques include anthropometry, cephalometry, tridimensional computed tomography (CT), and for the prenatal period fetal cephalometry via ultrasound. These techniques not only describe the severity of the asymmetry but provide information necessary to plan adequate corrective treatment. During the neonatal period, one should be particularly careful in distinguishing between facial asymmetry resulting from molding of the cranial bones during the birth process and true malformation of the facial skeleton. Facial asymmetry resulting from excessive molding of the cranium or from displacement of the mandible during breech or face presentations is very common and is usually self-correcting. Morphometric analysis of the face is helpful in establishing the role of skeletal abnormalities in facial

Facial Bones

293

Fig. 8-13. Facial asymmetry in a 31-month-old male with hemifacial microsomia (A), an infant with asymmetric crying face (B), and a teenage girl with Parry-Romberg syndrome (C and D). (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

asymmetry. However, the precise diagnosis requires roentgenographic examination of the craniofacial skeleton, and sometimes more sophisticated technology such as CT, tridimensional imaging (TDI), and magnetic resonance imaging (MRI). With the anteroposterior radiographs of the skull, one can use cephalometric measurements to quantify the extent of the defect and the particular facial areas involved. CT, TDI, and MRI are very useful in distinguishing between congenital (‘‘developmental’’) skeletal facial asymmetry and acquired skeletal facial asymmetry due to pathologic processes and trauma. Radiologic analysis assessing asymmetry of the facial skeleton should include three planes as described by Murray and collaborators.2 The frontal plane view, which is evaluated with an anteroposterior cephalometric radiograph, demonstrates asymmetry of

the mandible, maxilla, pyriform apertures, and orbits. This radiographic view also discloses obliquity and rotation of the plane formed by the two mandibular midlines, dental and skeletal. The dental midline is rotated toward the normal side, while the skeletal midline is rotated toward the abnormal side. The sagittal plane view can demonstrate discrepancies in the ramus height and relationships of the maxilla, mandible, and base of the skull. A panoramic view may reveal anomalies in height and shape of the mandibular rami and the temporomandibular joint (TMJ). The transverse plane is evaluated with a submental vertex radiologic plate to demonstrate the shape and width of the mandibular body, asymmetry in the zygomatic arches, and medial and anterior displacement of the TMJ. The most common cause of congenital facial asymmetry probably is the group of disorders known as the otocraniofacial

294

Craniofacial Structures

syndromes.3 These involve unilateral and bilateral developmental malformations of the skeletal craniofacial structures that may arise from a growth deficiency of the first and second branchial arches. They include conditions such as mandibulofacial dysostosis and hemifacial microsomia. With an incidence of one in 4000, hemifacial microsomia represents a wide spectrum of abnormalities of the facial skeleton.4 Different classifications have been suggested according to the severity of the defects.5 In type I, the malformation of the facial skeleton is slight and mandibular growth is compromised; however, the anatomic development of the TMJ is not impaired. Type II shows a pronounced malformation of the facial skeleton. The body and ramus of the lower jaw, along with the TMJ, are underdeveloped on the affected side. Rudiments of the condylar and coronoid processes are situated below the malar arch and frontally to the site of the natural position of the articular fossa. Underdevelopment of the temporal bone, the mastoid process, and the articular fossa and tubercle also can be observed. Type III is also characterized by pronounced malformation of the facial skeleton. The body of the mandible on the affected side is underdeveloped and ends in a rudiment of the ramus. The TMJ is absent. Radiologic studies usually show pronounced asymmetry and disfigurement of the facial skeleton. The underdeveloped side of the face is flattened, involving the orbit, malar bone, and frontal and occipital bones. The affected malar bone is considerably lower than the analogous bone on the intact side. The body of the lower jaw is hypoplastic and deformed, and the ramus appears as a pointed rudiment.

Etiology and Distribution

Asymmetry of the facial skeleton rarely occurs as an isolated anomaly. In the majority of cases, it represents one component of a multiple anomaly syndrome, usually resulting from an insult in the early development of the branchial arches or brain. One must understand that in the human, various insults to the fetus can produce unilateral facial skeletal defects. Growth of the facial skeleton is influenced by multiple factors, including brain growth.6 Asymmetrical growth of the brain produces rotation of the face on the cranium, which progresses with age and further growth. As the temporal lobes of the cerebrum show a greater asymmetric development, increased displacement of the nasomaxillary segment on the affected side occurs, and this in turn produces a rotation of the face. This seems to apply to a few conditions that include facial asymmetry in their phenotype; however, it cannot be generalized. Vascular theories to explain unilateral birth defects have gained popularity.7–9 Robinson and collaborators7 suggested that a vascular accident interrupting the blood flow to developing facial structures could result in tissue ischemia, necrosis, or both. The severity of the resulting defects would be directly proportional to the magnitude and duration of tissue injury, allowing for a wide phenotypic variability. It has been suggested that a lesion in the stapedial artery, the second aortic arch vessel, can produce unilateral craniofacial defects. Animal models seem to support this theory.9 Vascular theories may also be supported by the increased incidence of hemifacial

Table 8-9. Syndromes associated with congenital asymmetry of the facial skeleton Causation Gene/Locus

Syndrome

Prominent Features

Apert13

Craniosynostosis, high forehead, flat facies, irregular supraorbital horizontal groove, shallow orbits, hypertelorism, severe syndactyly hands and feet, broad distal phalanges of thumb, mental retardation

AD (101200) FGFR2, 10q26

Craniofrontonasal14

Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and splits in nails

XL (304110) EFNB1, Xq12

Cat eye15

Mental deficiency, inferior coloboma of the iris, micrognathia, cardiac defects, anal atresia, rectovesicular fistula, renal agenesis

(115470) Partial tetrasomy 22 due to inv dup (22)(q11)

Facio-auriculo-vertebral spectrum16

Macrostomia, unilateral facial hypoplasia, micrognathia, microtia, periauricular tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, renal and cardiac abnormalities

Unknown, sporadic (164210, 257700)

Hemimaxillofacial dysplasia17

Unilateral enlargement of maxillary alveolar bone and gingival, hypoplastic teeth, hypertrichosis of ipsilateral facial skin

Unknown

Hemifacial hyperplasia with strabismus18

Abnormal growth of the facial skeleton, zygomatic deficiency, convergent strabismus, amblyopia of the affected side, submucous cleft palate

AD (141350)

Hemifacial microsomia with radial defects19

Similar facial findings to those seen in hemifacial microsomia, periauricular pits or skin tags, shortening of the mandibular ramus, radial limb defects, triphalangeal thumbs, duplication of the thumb

AD (141400)

McCune-Albright20

Fibrous dysplasia in bone, irregular patches of pigment of trunk, precocious puberty, hyperthyroidism, hyperparathyroidism, acromegaly, Cushing, hyperprolactinemia, short stature

(174800) GNAS1, 20q13.2

Muenke21

Uni- or bicoronal synostosis, macrocephaly, hearing loss, learning differences

AD (602849) FGFR3, 4p16.3

Saethre-Chotzen22

Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, hallux valgus

AD (101400) TWIST, 7p21

Townes-Brocks23

Hemifacial microsomia with preauricular tags, abnormal ear shape, sensorineural hearing loss, thumb anomalies, imperforate anus, renal malformations

AD (107480) SALL1, 16q21.1

Wildervanck24

Ear anomalies, preauricular tags, pseudopapilledema, Duane anomaly, Klippel-Feil anomaly

(314600) Sporadic, most cases female

Facial Bones

microsomia in offspring of diabetic mothers10,11 and in products of twin or higher-order multiple pregancies.12 Several single-gene defects are known to cause skeletal facial asymmetry as part of the clinical picture (Table 8-9). An autosomal dominant form of isolated facial asymmetry has been described in the past; however, in this case the asymmetry is localized to the maxillomandibular region, without involvement of the upper face and midface.25 Other causes of congenital facial asymmetry include premature unilateral closure of the coronal suture, other craniosynostosis, TMJ anomalies, coronoid process hyperplasia, septic processes of the mandible, and trauma.9 Since skeletal facial asymmetry is not a primary birth defect, its occurrence is usually dependent on another underlying defect in facial embryogenesis. At present, no conclusive studies of sex distribution are available. Prognosis, Treatment, and Prevention

Advancements in surgical methodology have improved the prognosis for patients with facial asymmetry. Mildly affected individuals in whom there is no concern regarding appearance during childhood need no treatment until adolescence. At this time an assessment of the residual asymmetry at the end of growth can be made and appropriate surgery undertaken.4 For many years it was believed that the skeletal problems affecting the jaws and facial skeleton, even in severe cases, should not be surgically corrected until adolescence, mainly to avoid interference with growth. Surgery in the adolescent patient has been directed most often to the centralization of the mandible with bone grafting. Recent years have seen increased interest in earlier restoration of facial symmetry through surgery in the preschool period. Surgical procedures may include the use of costochondral grafts. These grafts with growth potential are placed into the vertical ramus of the mandible to correct any deficiency. Osteotomies, especially in the midface, are sometimes unavoidable. Distraction osteotomy of the mandible has been used successfully in young patients; however, on follow-up it became clear that the affected side grew at a slower rate than the contralateral side, and initial overcorrection was considered.26 A further definitive operation may be required at the end of growth. Prenatal diagnosis of this condition has been accomplished with ultrasonography.27 Fetal craniofacial asymmetry may be the first indication of a multiple congenital anomaly syndrome. At 16 weeks of gestation, an ultrasonographic coronal section may identify differences between both sides of the facial skeleton. Level two ultrasound may indicate the presence of other defects. Prenatal counseling should be available to all couples with a previously affected child. References (Congenital Asymmetry of the Facial Skeleton) 1. Brash JA: The Etiology of Irregularity and Malocclusion of the Teeth. Dental Board of the United Kingdom, London, 1956, p 31. 2. Murray JE, Kaban LB, Mulliken JB, et al.: Analysis and treatment of hemifacial microsomia. In: Craniofacial Surgery. E Caronni, ed. Little, Brown and Co, Boston, 1985, p 377. 3. Pruzansky S: Otocraniofacial syndromes: clinical studies on mandibulofacial dysostosis, hemifacial microsomia, and variants. In: Craniofacial Surgery. E Caronni, ed. Little, Brown and Co, Boston, 1985, p 351. 4. Poole MD: Hemifacial microsomia. World J Surg 13:396, 1989. 5. Bezrukov VM, Plotnikov NA, Gun’ko VI, et al.: Surgical correction of deformation of the facial skeleton in patients with hemifacial microsomia. Acta Chir Plast 30:202, 1988.

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6. Trenouth MJ: Asymmetry of the human skull during fetal growth. Anat Rec 211:205, 1985. 7. Robinson LK, Hoyme HE, Edwards DK, et al.: Vascular pathogenesis of unilateral craniofacial defects. J Pediatr 111:236, 1987. 8. Bavnick JNB, Weaver DD: Subclavian artery supply disruption sequence: Hypothesis of vascular etiology for Poland, Klippel-Feil and Mo¨bius anomalies. Am J Med Genet 23:903, 1986. 9. Poswillo D: The pathogenesis of the first and second branchial arch syndromes. Oral Surg 35:301, 1973. 10. Ewart-Toland A, Yankowitz J, Winder A, et al.: Oculoauriculovertebral abnormalities in children of diabetic mothers. Am J Med Genet 90:303, 2000. 11. Wang R, Martinez-Frias ML, Graham JM Jr: Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: A case-based and case-control approach. J Pediatr 141:611, 2002. 12. Lawson K, Waterhouse N, Gault DT, et al.: Is hemifacial microsomia linked to multiple maternities? Br J Plast Surg 55:474, 2002. 13. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. 14. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996. 15. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: Decentric small marker chromosome probably derived from a 22 (tetrasomy 22pter;q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57: 148, 1981. 16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 17. Miles DA, Lovas JL, Cohen MM Jr: Hemimaxillofacial dysplasia: a newly recognized disorder of facial asymmetry, hypertrichosis of the facial skin, unilateral enlargement of the maxilla, and hypoplastic teeth in two patients. Oral Surg Oral Med Oral Pathol 64:445, 1987. 18. Kurnit D, Hall JG, Shurtleff DB, et al.: An autosomal dominantly inherited syndrome of facial asymmetry, esotropia, amblyopia, and submucous cleft palate (Bencze syndrome). Clin Genet 16:301, 1979. 19. Moeschler J, Clarren SK: Familial occurrence of hemifacial microsomia with radial limb defects. Am J Med Genet 12:371, 1982. 20. Schwindinger WF, Francomano CA, Levine MA: Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G-protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A 89:5152, 1992. 21. Gripp KW, McDonald-McGinn DM, Gaudenz K, et al.: Identification of a genetic cause for isolated unilateral coronal synostosis: a unique mutation in the fibroblast growth factor receptor 3. J Pediatr 132:714, 1998. 22. Paznekas WA, Cunningham ML, Howard TD, et al.: Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet 62:1370, 1998. 23. Kohlhase J, Wischermann A, Reichenbach H, et al.: Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18:81, 1998. 24. Balci S, Oguz KK, Firat MM, et al.: Cervical diastematomyelia in cervicooculo-acoustic (Wildervanck) syndrome: MRI findings. Clin Dysmorphol 11:125, 2002. 25. Burchfield D, Escobar V: Familial facial asymmetry (autosomal dominant hemihypertrophy?). Oral Surg Oral Med Oral Pathol 50: 321, 1980. 26. Hollier LH, Kim JH, Grayson B, et al.: Mandibular growth after distraction in patients under 48 months of age. Plast Reconstr Surg 103:1361, 1999. 27. Tamas DE, Mahony BS, Bowie JD, et al.: Prenatal sonographic diagnosis of hemifacial microsomia (Goldenhar-Gorlin syndrome). J Ultrasound Med 5:461, 1986.

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9 Eye Elias I. Traboulsi

O

cular malformations can occur in isolation or accompany other systemic abnormalities in the context of malformation syndromes. Several ocular malformations can coexist, resulting in complex but well-defined clinical ocular phenotypes such as persistent hyperplastic primary vitreous or aniridia. Other malformations such as Peters anomaly and the morning glory disc anomaly are extremely variable in clinical appearance and have been given a number of descriptive names over the years because of a failure to recognize the spectrum in their morphology. Major ocular malformations are diagnosed at or shortly after birth because of abnormal appearance of the eye or poor vision. Less severe anomalies are usually diagnosed during routine ocular examinations. Infants with multiple congenital anomalies are usually screened for ocular defects, which may be diagnostic. Some ocular anomalies can be classified according to the presumed faulty ocular developmental process that has lead to their formation (Table 9-1); others result from faulty induction, distribution, or resorption of specific embryonic cellular masses such as the neural crest cells in anterior segment dysgenesis (Axenfeld-Rieger spectrum). The number of genes that have been linked to individual ocular malformations is increasing, and a partial list is given in Table 9-2. The management of congenital ocular malformations is challenging but often rewarding. Substantial improvement in visual outcome is possible in many cases in which early recognition of the anomaly results in correction of refractive errors, institution of strabismus and amblyopia therapy as needed, and application of surgical techniques to clear the visual axis where ocular media opacification such as corneal opacities, cataracts, or hyaloid membrane remnants exist. Embryology

The embryonic eye first appears as a depression (optic pit) in the developing forebrain when the neural groove is still open. After complete closure of the neural groove, the optic pits derived from neural ectoderm move away from the brain and toward the surface ectoderm and form the single-layered optic vesicles. The connection between the optic vesicle and the forebrain constricts, forming the optic stalk. Subsequent invagination of the optic vesicle creates the optic cup, whose cells will contribute to the development of the retinal pigment epithelium, neurosensory retina,

ciliary epithelium, iris neuroepithelium, and constrictor and dilator pupillary muscles; the inner layer of the optic cup gives rise to the neurosensory retina, while the outer layer gives rise to the retinal pigment epithelium. There remains a potential space between the two layers that fills with fluid in retinal detachment. At 6 weeks, the inferiorly located embryonic fissure, through which the mesodermal primordium of the hyaloid system of blood vessels has entered, starts to close in the equatorial region and proceeds posteriorly and anteriorly. Failure of closure of the embryonic fissure results in typical inferior uveoretinal colobomas, which can be localized to the posterior segment of the eye or to the iris (a uveal structure and the most anterior part of the fissure to close), or may extend from the optic disc anteriorly to involve the iris. Although all retinal layers, including the rod and cone photoreceptors, are distinguishable by week 12, they are not well-developed until the 8th month of gestation. The macula continues to mature postnatally, and the infant does not attain full visual potential until age 2 to 4 years. Lens development begins as a focal thickening of surface ectoderm overlying the optic cup. When the neuroectodermally derived optic vesicle approximates the surface ectoderm and starts to invaginate, the lens placode is incorporated into this structure, forming the lens vesicle that separates from the surface ectoderm by 35 days. The posterior epithelial cells of the lens primordium elongate and differentiate into primary lens fibers. After filling the lens cavity, the nuclei of these cells disappear and protein synthesis ceases. The anterior lens epithelium continues to form secondary lens fibers that accumulate concentrically around the embryonic nucleus throughout life. The lens capsule is the basement membrane of the anterior lens epithelium. Most of the remaining anterior segment structures are derived from neural crest. Neural crest cells form in the dorsal midline between the brain and surface ectoderm after closure of the neural groove and subsequently move rostrally to form a cellular cluster situated between the optic cup and the overlying surface ectoderm. These cells migrate in three successive waves into the anterior segment of the eye, contributing to the development of the cornea, angle structures, iris, and ciliary region. The sclera, choroidal tissues, and surrounding orbital soft tissue and bone as well as many structures of the head and face are also derived from neural crest cells. 297

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Craniofacial Structures Table 9-1. Malformation syndromes of the eye Failure of optic vesicle to form

Iridohyaloidal vessels

Anophthalmia

Atypical coloboma Persistent pupillary membrane

Failure of optic vesicle to invaginate

Congenital cystic eye Failure of fetal fissure to close

Colobomatous microphthalmia

Congenital falciform fold of the retina Persistent hyperplastic primary vitreous Patent and persistent hyaloid artery Congenital nonattachment of the retina

Uveal coloboma

Failure of ganglion cells to develop

Colobomatous microphthalmia with cyst

Optic nerve hypoplasia

Neuroectodermal abnormality with major effect on development of the iris

Failure of posterior sclera and/or lamina cribrosa to form

Aniridia

Optic pit

Failure of normal separation of lens vesicle from surface ectoderm with ensuing abnormalities of the cornea, iris, and lens

Morning glory disc anomaly

Peters anomaly

Contractile peripapillary coloboma Choristomatous malformations

Sclerocornea

Epibulbar dermoid

Congenital anterior staphyloma1

Medulloepithelioma

Anterior polar cataracts Congenital aphakia Posterior keratoconus Von Hippel internal ulcer

Failure of lid fissure to form

Cryptophthalmia Ankyloblepharon

Congenital cornea guttata with anterior polar cataracts

Failure of lacrimal passages to form

Neural crest abnormalities with anterior segment dysgenesis

Congenital nasolacrimal duct obstruction

Atresia of punctae and canaliculi Congenital dacryocystocele

Axenfeld anomaly Rieger anomaly

Abnormalities of collagen structure

Infantile glaucoma

Nanophthalmos

Congenital hereditary endothelial dystrophy

Megalocornea

Congenital ectropion of the iris

Congenital hereditary stromal dystrophy

Congenital microcornea

Cornea plana

Ectopia lentis et pupillae Iridoschisis Congenital cysts of the iris Failure of regression of fetal vasculature and hyaloidal blood vessels

Mittendorf dot

Failure of extraocular muscles to develop

Aplasia of extraocular muscles Abnormalities of forebrain development with resultant ocular malformations

Cyclopia

Bergmeister papilla

Development of the vitreous begins with the appearance of the hyaloid vasculature, which, along with the mesenchymal cells and fibrillar material, forms the primary vitreous. The hyaloid vessels anastomose anteriorly with the system of blood vessels around the lens and form the tunica vasculosa lentis that completely envelops and provides nutrients to the developing lens, the most metabolically active part of the embryonic eye. The secondary vitreous, an avascular and more compact fibrillar network,

begins to replace the primary vitreous at 8 weeks. It starts from the periphery of the globe and goes toward the center, compressing the primary vitreal structures that regress, leaving in the newborn and adult eye a hollow, hornlike structure: the canal of Cloquet. Occasionally, and in otherwise normal eyes, remnants of the primary vitreous persist as Mittendorf dots on the posterior lens capsule or as a small fibrous veil over the optic disc, forming the so-called Bergmeister papilla.

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Table 9-2. Selected congenital ocular malformations and their responsible genes Gene

Inheritance

Ocular Malformation

SOX2

AR

Anophthalmia

RAX

AD

Microphthalmia

CHX10

AR

Microphthalmia, cataracts, and iris abnormalities

PAX2

AD

Oculorenal syndrome

PAX6

AD

Aniridia, Peters anomaly, anterior segment dysgenesis, foveal hypoplasia, autosomal dominant keratitis, congenital cataract

PITX2

AD

Axenfeld-Rieger syndrome, iridogoniodysgenesis, Peters anomaly

PITX3

AD

Anterior segment mesenchymal dysgenesis and cataracts, congenital cataracts

FOXC1

AD

Anterior segment dysgenesis

FOXC2

AD

Lymphedema-distichiasis, familial distichiasis

FOXL2

AD

Blepharophimosis syndrome

9.1 Anophthalmia Definition

Anophthalmia is the apparent absence of the globe in an orbit that otherwise contains normal adnexal elements. Diagnosis

The lids in anophthalmia are structurally normal except for a decreased horizontal dimension. Normal conjunctiva lines the inside of the lids and orbit, and there is a functioning lacrimal gland. Rudiments of optic vesicle-derived structures and structures derived from the mesoderm and/or neural crest may be found on histopathologic sectioning of the orbit in consecutive or degenerative anophthalmia (clinical anophthalmia) but not in primary or true anophthalmia. The orbit is shallow and orbital volume remains small with increasing age, presumably because of absence of the trophic action of the globe on the orbit (Fig. 9-1). Clinical anophthalmia may be unilateral or bilateral. Etiology and Distribution

When unilateral, there may be contralateral microphthalmia. True or primary anophthalmia is extremely rare and results from failure of the optic vesicle to bud from the cerebral vesicle; the optic nerves and tract are usually absent. In secondary anophthalmia usually there are associated severe forebrain malformations such as holoprosencephaly, and affected fetuses are usually aborted. Consecutive or degenerative anophthalmia results from regression or degeneration of the optic vesicle. Inherited isolated anophthalmia is usually autosomal recessive.1 Driggers et al. reported a child with isolated bilateral anophthalmia and an apparent balanced chromosomal translocation: 46,XX,t(3;11)(q27;p11.2).2 Fantes et al. found that this child had, in fact, a submicroscopic deletion that eliminated the SOX2 gene on chromosome 3 and went on to show nonsense mutations in SOX2 in four of 11 subjects with bilateral anophthalmia.3 SOX2

Fig. 9-1. Clinical anophthalmia. Infant with apparent bilateral anophthalmia with small orbits and normal adnexae (top). Middle and bottom photos show another infant who appears anophthalmic with lids closed. Extreme microphthalmia is evident when lids are separated.

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lies within an intron of a nonexpressed gene, SOX2OT, and is expressed in neuroectoderm early in development. SOX2 protein interacts cooperatively with PAX6 in the induction of lens development and delta-crystallin expression. Traboulsi et al. found a null mutation in SOX2 in a girl with bilateral clinical anophthalmia and absence of the optic nerves, chiasm, and optic tracts (unpublished data). Anophthalmia may be part of multisystem malformation syndromes such as the Waardenburg recessive anophthalmia syndrome or the Lenz microphthalmia syndrome. Waardenburg anophthalmia syndrome is characterized by mental retardation; unilateral or bilateral clinical absence of the globe; distal limb abnormalities in the form of syndactyly, camptodactyly, or hypodactyly; and other inconsistent malformations.4 Lenz syndrome is X-linked and is characterized by microphthalmia or clinical anophthalmia, simple ears, cardiovascular and urogenital anomalies, and distal limb abnormalities such as clinodactyly or duplication of the thumb.5 Anophthalmia also occurs in the Sjo¨gren-Larsson syndrome with mental retardation and other neurologic abnormalities. Prognosis, Prevention, and Treatment

Treatment of anophthalmia consists of maintenance of orbital volume and conjunctival fornical depth by insertion of ocular prostheses of increasing sizes into the orbit. References (Anophthalmia) 1. Kohn G, el Shawwa R, el Rayyes E: Isolated ‘‘clinical anophthalmia’’ in an extensively affected Arab kindred. Clin Genet 33:321, 1988. 2. Driggers RW, Macri CJ, Greenwald J, et al.: Isolated bilateral anophthalmia in a girl with an apparently balanced de novo translocation: 46,XX,t(3;11)(q27;p11.2). Am J Med Genet 87:201, 1999. 3. Fantes J, Ragge NK, Lynch SA, et al.: Mutations in SOX2 cause anophthalmia. Nat Genet 33:461, 2003. 4. Traboulsi EI, Nasr A, Fahd SD, et al.: Waardenburg’s recessive anophthalmia syndrome. Ophthal Paediatr Genet 4:13, 1984. 5. Traboulsi EI, Lenz W, Gonzales-Ramos M, et al.: The Lenz microphthalmia syndrome. Am J Ophthalmol 105:40, 1988.

9.2 Microphthalmia and Typical Uveal Coloboma Definition

In microphthalmia there is a reduction in the volume of the eye. The corneal diameter is usually less than 10 mm, and the anteroposterior globe diameter is less than 20 mm. Diagnosis

There is a wide spectrum of malformations ranging from a mild decrease in the diameter of the eye to extreme microphthalmia or clinical anophthalmia in which remnants of optic vesicle-derived structures can only be found on serial histologic section of the orbit.1 Etiology and Distribution

In a prospective study of 50,000 pregnancies in the United States, the incidence of microphthalmia/clinical anophthalmia was found to be 0.22 per 1000 births; the incidence of coloboma was 0.26 per 1000. About 0.6–1.9% of blind adults have microphthalmia/ coloboma, and 3.2–11.2% of blind children have microphthalmia.2 The diagnosis of microphthalmia can generally be made by inspection of the eye (Fig. 9-2). The cornea is small but may be of normal size in posterior microphthalmos.3 Microcornea can occur in the absence of microphthalmia as a dominant or recessive trait.

Fig. 9-2. Bilateral colobomas of the iris in a patient with the Lenz microphthalmia syndrome. Note smaller palpebral fissure and iris on the left.

There may be a coloboma of the iris, choroid, and/or optic nerve. Cataracts may be present. Microphthalmic eyes usually have high hypermetropic refractive errors but may be myopic. The diagnosis of borderline cases can be confirmed by measuring the diameter of the eye using ultrasonography. The normal adult eye measures between 21.50 and 27.00 mm. Microphthalmia can be unilateral or bilateral and may or may not be associated with uveal coloboma, hence its general classification into colobomatous and noncolobomatous. Asymmetric reduction of the volume of the eyes is common in bilateral cases. Large colobomas may produce a white reflex from the pupil (leukocoria) and have been confused with retinoblastoma. The ocular complications of microphthalmia/coloboma include high refractive errors, angle-closure glaucoma, cataracts, macular or optic nerve involvement, subretinal neovascularization, and, rarely, retinal detachment. Colobomas result from failure of closure of the fetal fissure in the invaginated optic vesicle. This process is usually completed by week 6 of gestation. Since the fetal fissure is located inferiorly, ‘‘typical’’ colobomas are inferonasal and may involve the iris, ciliary body, and/or inferior choroid. The optic nerve head may also be included in the colobomatous defect. Eyes with colobomas may be of normal size but are generally microphthalmic. A posterior or inferior cyst may form in the area of defective closure, producing microphthalmia with cyst. Patients with this condition can present with a bulging of the inferior lid and a superior displacement of the globe by the cyst.4–9 The pathogenetic mechanisms leading to microphthalmia are unclear. The coordinated expression of a large number of developmental genes is necessary for normal ocular and optic nerve development, and the pathways and interactions between these genes are currently being elucidated. Degeneration of the developing optic vesicle results in secondary or consecutive anophthalmia. Microphthalmia can be isolated or familial or can occur in a number of single gene, chromosomal, and embryopathic multisystem malformation syndromes (Tables 9-1 and 9-3).10,11 It is estimated that 15–30% of patients with microphthalmia/coloboma have the CHARGE syndrome.12 In a review of 1313 cases of microphthalmia/ coloboma, Fujiki et al. found that 15% were autosomal recessive, 22% were autosomal dominant, and the rest were isolated.13 Dominant microphthalmia/coloboma may be isolated or may be associated with congenital cataracts or with myopia and ectopic pupils. Variable expressivity is the rule in familial occurrences, with some family

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Table 9-3. A practical classification of microphthalmia/coloboma Isolated microphthalmia (AD)

Microphthalmia with multiple congenital anomaly syndromes

Colobomatous: isolated uveoretinal coloboma; microphthalmia with cyst

CHARGE syndrome (AD)

Noncolobomatous

Duker syndrome

Microphthalmia with ocular anomalies

Oculo-dento-osseous dysplasia (AD, AR)

Lenz microphthalmia syndrome (XR) Microphthalmia with cataract (AD, AR) Microphthalmia with myopia and corectopia (AD) Microphthalmia with ectopia lentis Microphthalmia with congenital retinal detachment (AR) Persistent hyperplastic primary vitreous (sporadic)

Cryptophthalmia syndrome (AD, AR) Cerebro-oculo-facial syndrome (AR) Goltz syndrome or focal dermal hypoplasia (XD) Lowe syndrome (XR) Meckel-Gruber syndrome (AR)

Aicardi syndrome

Basal cell nevus syndrome of GorlinGoltz (AD)

Microphthalmia with mental retardation

Congenital contractural arachznodactyly (AD)

Microphthalmia with mental retardation (AD, AR, XR)

Rubinstein-Taybi syndrome

Microphthalmia with mental retardation and congenital spastic diplegia (Sjogren-Larsson)

Cross syndrome (AR) Fanconi syndrome (AR) Diamond-Blackfan syndrome (AR) Epidermal nevus syndrome

Microphthalmia with craniofacial malformations

Facio-auriculo-vertebral syndrome

Microphthalmia in chromosomal anomalies

Hallermann-Streiff syndrome

T-13 (Patau)

Amniotic band syndrome

4p- (Wolf-Hirschhorn)

Transverse facial cleft

18q-

Microphthalmia with cleft lip/palate

T-18 (Edwards)

Microphthalmia with microcephaly

‘‘Cat eye’’ syndrome (marker 22)

Microphthalmia with microcephaly and retinal folds (XR, AR) Microphthalmia with hydrocephalus and congenital retinal nonattachment (Warburg syndrome) Microphthalmia with malformations of the hands and feet

Other chromosomal aberrations14,18 Microphthalmia and intrauterine insults

Maternal drug intake: thalidomide, alcohol, isotretinoin, others Maternal vitamin A deficiency Maternal phenylketonuria Maternal fever or radiation exposure

Microphthalmia with polydactyly Waardenburg anophthalmia syndrome (AR) Subgroup of CHARGE syndrome (bifid thumbs)

members exhibiting severe microphthalmia and others only small asymptomatic uveal colobomas in normal-sized eyes, hence the importance of ocular examination of all family members. Because of incomplete penetrance, Fujiki et al. estimated that, in families with dominant microphthalmia/coloboma, unaffected individuals have an 8.6% chance of having an affected offspring.13 Warburg and Friedrich14 reviewed the chromosomal abnormalities and Gregory-Evans et al. reviewed the gene mutations associated with microphthalmia/coloboma.11 Percin et al. described mutations in the homeobox gene CHX10 (14q24.3) in two families with autosomal recessive, nonsyndromic microphthalmia, iris abnormalities, and coloboma.15

Intrauterine infections: Cytomegalovirus, Epstein-Barr virus, varicella, herpes simplex, rubella, toxoplasma

Like other homeobox proteins, CHX10 is a transcription factor that binds to specific DNA sequences in the regulatory regions of other genes and affects their transcription during development. Chx10 mutations were previously found in the ocular retardation mouse model, which is characterized by microphthalmia, a thin hypocellular retina and optic nerve aplasia.16 One form of autosomal recessive complex microphthalmia was found by Bessant et al. to map to 14q32.17 Phenotypic features included sclerocornea (eight of eight patients) with secondary corneal vascularization (six of eight patients) and staphyloma formation (three of eight patients), elevated intraocular pressure (five of eight patients), and short axial length (five of five measured).17,18 These

302

Craniofacial Structures

authors ruled out CHX10 and OTX2 as candidate genes in this pedigree. Lehman et al. reported a large Mexican-American pedigree with isolated X-linked recessive colobomatous microphthalmia that maps to either the proximal p or q arm of the X chromosome.19 Microphthalmia can result from intrauterine infection with cytomegalovirus, Epstein-Barr virus, rubella, toxoplasma, herpes simplex, and varicella. Maternal intake of thalidomide, alcohol, isotretinoin, and other medications can lead to microphthalmia in the offspring. Maternal fever or radiation exposure can also result in microphthalmia. Prognosis, Prevention, and Treatment

The treatment of microphthalmia/coloboma depends on the severity of ocular involvement. Errors of refraction should be corrected. Cataract extraction is performed if the retina is attached and the size of the eye is not extremely small. Corneal transplantation can be performed if the cornea is opaque, but with mediocre results.20 Prostheses are fit over very small blind eyes for cosmetic purposes. Genetic counseling should be provided after examination of all available family members to determine the possible mode of inheritance in familial cases. The empiric risk of recurrence in a sibling is 2% if both parents are unaffected and increases to 14% if one parent is affected. The yield of chromosomal studies is poor for isolated microphthalmia/coloboma but increases significantly if there is associated mental retardation and at least one other congenital malformation. Prenatal diagnosis with ultrasonography should be possible if the size of the eye is significantly reduced.21 Hypothalamic dysfunction has been reported in patients with microphthalmia, and the potential for developing hypopituitarism should be included in the counseling of these patients. References (Microphthalmia and Typical Uveal Coloboma) 1. Pagon R: Ocular coloboma. Surv Ophthalmol 25:223, 1981. 2. Bateman J: Microphthalmos. Int Ophthalmol Clin 24:87, 1984. 3. Spitznas M, Gerke E, Bateman JB: Hereditary posterior microphthalmos with papillomacular fold and high hyperopia. Arch Ophthalmol 101:413, 1983. 4. Waring GO 3rd, Roth AM, Rodrigues MM: Clinicopathologic correlation of microphthalmos with cyst. Am J Ophthalmol 82:714, 1976. 5. Porges Y, Gershoni-Baruch R, Leibu R, et al.: Hereditary microphthalmia with colobomatous cyst. Am J Ophthalmol 114:30, 1992. 6. McLean CJ, Ragge NK, Jones RB, et al.: The management of orbital cysts associated with congenital microphthalmos and anophthalmos. Br J Ophthalmol 87:860, 2003. 7. Makley TA Jr, Battles M: Microphthalmos with cyst. Report of two cases in the same family. Surv Ophthalmol 13:200, 1969. 8. Leatherbarrow B, Kwartz J, Noble JL: Microphthalmos with cyst in monozygous twins. J Pediatr Ophthalmol Strabismus 27:294, 1990. 9. Gupta PC, Peralta D, Parker M, et al.: Bilateral microphthalmia with cyst, facial clefts, and limb anomalies: a new syndrome with features of Waardenburg syndrome, cerebro-oculo-nasal syndrome, and craniotelencephalic dysplasia. Am J Med Genet 117A:72, 2003. 10. Warburg M: Update of sporadic microphthalmos and coloboma. Noninherited anomalies. Ophthalmic Paediatr Genet 13:111, 1992. 11. Gregory-Evans CY, Williams MJ, Halford S, et al.: Ocular coloboma: a reassessment in the age of molecular neuroscience. J Med Genet 41:881, 2004. 12. Tellier AL, Cormier-Daire V, Abadie V, et al.: CHARGE syndrome: report of 47 cases and review. Am J Med Genet 76:402, 1998. 13. Fujiki K, Nakajima A, Yasuda N, et al.: Genetic analysis of microphthalmos. Ophthalmic Paediatr Genet 1:139, 1982.

14. Warburg M, Friedrich U: Coloboma and microphthalmos in chromosomal aberrations. Chromosomal aberrations and neural crest cell developmental field. Ophthalmic Paediatr Genet 8:105, 1987. 15. Ferda Percin E, Ploder LA, Yu JJ, et al.: Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nat Genet 25:397, 2000. 16. Burmeister M, Novak J, Liang MY, et al.: Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 12:376, 1996. 17. Bessant DA, Khaliq S, Hameed A, et al.: A locus for autosomal recessive congenital microphthalmia maps to chromosome 14q32. Am J Hum Genet 62:1113, 1998. 18. Bessant DA, Anwar K, Khaliq S, et al.: Phenotype of autosomal recessive congenital microphthalmia mapping to chromosome 14q32. Br J Ophthalmol 83:919, 1999. 19. Lehman DM, Sponsel WE, Stratton RF, et al.: Genetic mapping of a novel X-linked recessive colobomatous microphthalmia. Am J Med Genet 101:114, 2001. 20. Feldman ST, Frucht-Pery J, Brown SI: Corneal transplantation in microphthalmic eyes. Am J Ophthalmol 104:164, 1987. 21. Feldman E, Shalev E, Weiner E, et al.: Microphthalmia-prenatal ultrasonic diagnosis: a case report. Prenat Diagn 5:205, 1985.

9.3 Cyclopia and Synophthalmia Definition

Cyclopia (a single midline eye) and synophthalmia (fusion of the eyes) encompass a spectrum of ocular malformations stemming from an abnormality in the development of the forebrain and frontonasal processes.1 Diagnosis

The eyes, orbits, and most of the midfacial structures may be absent. The eyes and orbits may be normal but closely set and with a single nostril, or the malformation may fit into the spectrum between these extremes. Cyclopia and synophthalmia are two distinct ocular malformations in this spectrum. The anterior part of the brain and the mesodermal midline structures are always abnormal in infants with synophthalmia or cyclopia. The process may involve only one side of the face. Etiology and Distribution

Cyclopia is very rare and seems to occur preferentially in females. It has been reported in female siblings.2 Affected fetuses are usually aborted in the third trimester of gestation. The holoprosencephalic conditions with and without cyclopia are discussed in Section 15.4. The globe in cyclopia may be relatively normal except for retinochoroidal coloboma and retinal dysplasia; however, the globe is usually severely malformed, with a rudimentary dysplastic retina and undifferentiated mesodermal tissue without an optic nerve. Intermediate degrees of abnormalities can occur. Rarely an anophthalmic median orbit is found. In synophthalmia there is a variable degree of fusion of the two developing optic vesicles (Fig. 9-3). All structures may be single except for the presence of a large duplicated lens. Conversely, all structures may be duplicated except for a single optic nerve.3 The optic nerve may also be duplicated. In less severe forms of this spectrum of malformations, there may be two separate eyes in a single median orbit or two separate orbits set very close together in the midface. In such cases, the forebrain is always affected with bilateral or unilateral arrhinencephaly.

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Fig. 9-3. Two infants with cyclopia and alobar holoprosencephaly. A proboscis is located above the synophthalmia. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Hospital for Children, Wilmington, DE, and Dr. Will Blackburn, Fairhope, AL.)

It is believed that the spectrum of holoprosencephaly/cyclopia/ synophthalmus anomalies result from a disturbance in the activity of the prosencephalic organizing center, with gross underdevelopment of the telencephalon and structures derived from the frontonasal processes and overgrowth of the maxillary processes that meet in the midline. A number of developmental genes are involved in this process. Mutations in sonic hedgehog (SHH) cause holoprosencephaly with or without cyclopia, with significant phenotypic variations among family members carrying the same mutation.4 Cyclopia has also been reported with mutations in SIX3,5 in patients with rearrangements of chromosome 3,6 in trisomy 13,7 as well as with other chromosomal abnormalities.8 Prognosis, Prevention, and Treatment

There is no specific treatment for this condition. References (Cyclopia and Synophthalmia) 1. Torczynski E, Jacobiec FA, Johnston MC, et al.: Synophthalmia and cyclopia: a histopathologic, radiographic, and organogenetic analysis. Doc Ophthalmol 44:311, 1977. 2. Balci S, Onol B, Ercal MD, et al.: Autosomal recessive alobar holoprosencephaly with cyclops in three female sibs: prenatal ultrasonographic diagnosis at 18th week. Clin Dysmorphol 2:165, 1993. 3. Liu DP, Burrowes DM, Qureshi MN: Cyclopia: craniofacial appearance on MR and three-dimensional CT. AJNR Am J Neuroradiol 18:543, 1997. 4. Roessler E, Belloni E, Gaudenz K, et al.: Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357, 1996. 5. Pasquier L, Dubourg C, Blayau M, et al.: A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur J Hum Genet 8:797, 2000. 6. Dallapiccola B, Ferranti G: Duplication 3p and cyclopia. Clin Genet 37:490, 1990. 7. Tomoda K, Shea JJ, Shenefelt RE, et al.: Temporal bone findings in trisomy 13 with cyclopia. Arch Otolaryngol 109:553, 1983. 8. Howard RO: Chromosomal abnormalities associated with cyclopia and synophthalmia. Trans Am Ophthalmol Soc 75:505, 1977.

9.4 Cryptophthalmos Definition

Cryptophthalmos is a hidden eye behind skin continuing from the forehead onto the cheek and with no recognizable lid structures. Diagnosis

In typical cryptophthalmos, the eyes are usually malformed, with anomalies ranging from anterior segment dysgenesis to microphthalmia. Francois divided cryptophthalmos into three types.1 In the first typical and complete form, the eyelids are absent and skin extends continuously from the forehead to the cheek, passing in front of the orbit, where it forms a small depression (Fig. 9-4). The eyebrows are poorly developed or nonexistent. The anterior hairline at the temporal area extends forward to fuse with the malformed brow. The eyelashes, Meibomian glands, lacrimal glands, and lacrimal punctae are absent. The eyeball can be palpated through the skin, to which it is usually adherent. There is reaction to light with contraction of the orbicularis, but the eye is usually microphthalmic with major dysplasia, usually more marked in the anterior segment, which is comprised of the conjunctiva, cornea, anterior chamber angle, iris, and lens. There is no conjunctival sac, and incision of the skin often opens directly into the eye. In the second incomplete, atypical, or partial form of cryptophthalmos, there are rudimentary lid structures, and a conjunctival sac may be present temporally. The eyeball is usually microphthalmic and covered with skin. In the third and least severe abortive form, the upper eyelid is adherent to the superior aspect of the globe, does not carry lashes, and continues over the cornea as an epidermal membrane. The free part of the cornea may be vascularized, opaque, or keratinized. The lower eyelid is normal but may lack a lacrimal punctum. The globe is generally of normal size.

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Fig. 9-4. Left: unilateral cryptophthalmia, syndactyly, nasal anomalies, and genital anomalies in a newborn female with cryptophthalmia syndrome. Right: cryptophthalmia syndrome in a 29-year-old mentally retarded female showing partial absence of the eyebrows and eyelashes, rudimentary eyelids, broad nasal root, nasal coloboma, and repaired cleft lip and palate. (Left figure courtesy of Dr. I. T. Thomas, Bowman Gray School of Medicine, Winston-Salem, NC.)

Cases in which there is typical cryptophthalmos on one side and abortive cryptophthalmos on the other side indicate that the two anomalies are equivalent. Cases have been reported with typical cryptophthalmos on one side and a dermoid, microphthalmia, or lid coloboma on the other side. A fourth type of isolated cryptophthalmos also exists, in which the lids are formed with a full complement of adnexal accessories. The lid fissure is displaced inferiorly close to the inferior orbital rim, but the conjunctival sac is rudimentary and the globe is not visible. There is a wide upper lid that adheres to the underlying malformed globe, and there is a short lower lid. The family reported twice by Coover2 (the same family was also reported by Magruder3) and the mother and daughter reported by Saal et al. are examples of this apparently distinct autosomal dominant syndrome in which cryptophthalmos is not accompanied by mental retardation or other congenital anomalies.4 Etiology and Distribution

Cryptophthalmos is most often accompanied by systemic anomalies and inherited in an autosomal recessive fashion, hence the term cryptophthalmos syndrome, cryptophthalmos-syndactyly syndrome, syndromic cryptophthalmos, and Fraser syndrome. The most prominent features of the cryptophthalmos syndrome include mental retardation; dyscephaly with skull malformations mostly in the region of the temples and forehead; anomalies of the auricles, ear canal, or inner ear; anomalies of the nose; laryngeal atresia; total or partial syndactyly of the toes and/or fingers; renal

anomalies; and malformations of the genital organs, especially in females. Other less common malformations include anal atresia and umbilical hernias or a low-set umbilicus. In a review of 86 cases of cryptophthalmos from the world literature, Thomas et al. set forth major and minor criteria for diagnosis of the cryptophthalmos syndrome.5 The major criteria are cryptophthalmos, syndactyly, abnormal genitalia, and a history of a sib with the cryptophthalmos syndrome (Fig. 9-4). Minor criteria include malformations of the nose, ears, and larynx; cleft lip/palate; skeletal defects; umbilical hernias; renal agenesis; and mental retardation. To qualify for a diagnosis of the cryptophthalmos syndrome, patients should satisfy either two major criteria and one minor criterion, or one major criterion and four or more minor criteria. Accompanying congenital anomalies may be severe, especially renal malformations such as renal agenesis or dysplasia, resulting in spontaneous abortions, stillbirths, or neonatal deaths. Indeed, the diagnosis of the cryptophthalmos syndrome should be considered even in the absence of cryptophthalmos if the other constellation of abnormalities is present. Cryptophthalmos is not necessary for the diagnosis of Fraser syndrome.6 There appears to be at least two genetic types of cryptophthalmos: syndromic (with congenital malformations of other systems) and isolated (without other malformations). Syndromic cryptophthalmos is inherited in an autosomal recessive fashion. Sporadic cases of isolated cryptophthalmos may be recessively inherited or may be due to new dominant mutations. Autosomal dominant transmission is most likely in the family reported by Saal and co-workers.4

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The pathogenesis of cryptophthalmos is unclear. The lid fissure forms in the 6th month of gestation after the upper and lower eyelids have developed their complements of tarsus, Meibomian glands, and lashes. Defects in lid differentiation and in lid separation have been postulated to result in cryptophthalmos. McGregor et al. determined that a locus FS1 at chromosome 4q21 is associated with Fraser syndrome and identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix blastocoelar protein found in sea urchin.7 Fraser syndrome appears to be caused by disrupted epithelial integrity in utero. Prognosis, Prevention, and Treatment

Surgical incision in the area of the palpebral fissure may open directly into the anterior segment of the eye. The absence of a conjunctival sac and hence of a normal ocular surface makes the prognosis for a clear corneal graft very poor. Furthermore, the globe in typical cryptophthalmos is often malformed, rendering visual prognosis very guarded even if a good reaction to light is elicited through the skin covering the eyes. In partial or abortive cryptophthalmos, surgical intervention may result in cosmetic and functional improvement. References (Cryptophthalmos) 1. Francois J: Malformative syndrome with cryptophthalmos. Int Ophthalmol Clin 8:817, 1968. 2. Coover DH: Two cases of cryptophthalmia. Ophthalmoscope 8:259, 1910. 3. Magruder AC: Cryptophthalmos. Am J Ophthalmol 4:48, 1921. 4. Saal HM, Traboulsi EI, Gavaris P, et al.: Dominant syndrome with isolated cryptophthalmos and ocular anomalies. Am J Med Genet 43: 785, 1992. 5. Thomas IT, Frias JL, Felix V, et al.: Isolated and syndromic cryptophthalmos. Am J Med Genet 25:85, 1986. 6. Meinecke P: Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clin Genet 30:527, 1986. 7. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003.

9.5 Blepharophimosis Definition

Blepharophimosis is a general diminution of the palpebral aperture in all its dimensions. The lids usually show ptosis, dystopia canthorum, lateral displacement of the lacrimal puncti, or abnormalities of the lashes such as distichiasis or misdirected and stiff lashes (Fig. 9-5). Diagnosis

The criteria for the diagnosis of blepharophimosis include: (1) a palpebral fissure length of 10 to 15 mm and a width of 2 to 4 mm, with measurements remaining almost constant throughout life; (2) a flat nasal bridge; (3) aplasia or hypoplasia of the levator palpebrae and tarsal plates with resultant ptosis, tautness, and transparency of the lid skin, immobility of the lids, and absence of the lid fold; (4) underdevelopment of the eyelashes that grow irregularly from the palpebral margin, a feature especially prominent in the upper lid; (5) lateral displacement of the lacrimal puncti and an elongation of the canthal ligaments and lacrimal canaliculi, resulting in a boat-shaped outline of the palpebral aperture; and (6) lack of contact between the globe and the lids, especially nasally, resulting in epiphora.1

Fig. 9-5. Blepharophimosis syndrome with ptosis, synophrys, and epicanthus inversus.

Patients use the frontalis muscle to elevate their lids; they also assume a chin-up head position to uncover their pupils, allowing them to see. The face appears expressionless, and there may be synophrys of thick eyebrows. The caruncle and semilunar folds are usually hypoplastic. The medial and lateral canthal ligaments are elongated, and there is excessive soft tissue at the bridge of the nose with resultant telecanthus. Eye defects associated with blepharophimosis include strabismus, nystagmus, amblyopia, colobomatous microphthalmia,2 anophthalmia, ptosis, epicanthus, epicanthus inversus, optic nerve hypoplasia,3 and microcornea. The blepharophimosis syndrome, also known as the blepharophimosis-epicanthus inversus-ptosis syndrome or Kohn syndrome, is an autosomal dominant condition characterized by blepharophimosis, ptosis, telecanthus (increased distance between the inner canthi), and epicanthus inversus (a fold of skin running upward from the inner aspect of the lower lid into the medial canthus). Two types have been described associated (type I) or not associated (type II) with premature ovarian failure (POF).4,5 About 50% of cases are due to new mutations. Blepharophimosis is a prominent feature of the SchwartzJampel syndrome.6 This syndrome is characterized by a small muscle mass, peculiar whistling facies, and skeletal abnormalities. Blepharophimosis is also present in the dominantly inherited Freeman-Sheldon syndrome (whistling face syndrome, craniocarpo-tarsal dysplasia).7 Patients with this syndrome have masklike ‘‘whistling’’ facies, hypoplastic alae nasi, and a number of joint and skeletal abnormalities, the most prominent of which is talipes equinovarus. Short palpebral fissures are present in Dubowitz syndrome, which combines growth deficiency, microcephaly, peculiar facies with a broad and flat nasal bridge, infantile eczema, and a number of occasionally present malformations.8 This syndrome is inherited in an autosomal recessive fashion. Blepharophimosis can also occur in Miller-Dieker syndrome and in Ohdo syndrome with mental retardation, congenital heart defect, blepharophimosis, and hypoplastic teeth.9,10 Etiology and Distribution

In a series of 153 cases of ptosis of genetic origin, Edmund found 12 cases with blepharophimosis.1 The blepharophimosis syndrome gene FOXL2 maps to 3q23.11,12 The gene codes for a transcription factor and belongs to the forkhead family of genes.13 The type and location of mutations in FOXL2 correlate partially with the phenotype. In a study of 43 patients, De Baere et al. found that for predicted proteins with a truncation before the poly-Ala tract, the

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risk for development of primary ovarian failure is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation.14,15 It is postulated that dominant negative mutations of FOXL2 could increase expression of follicle differentiation genes in small and medium follicles to accelerate follicle development, resulting in increased initial recruitment of dormant follicles and thus the premature ovarian failure phenotype.16

16. Pisarska MD, Bae J, Klein C, et al.: Forkhead L2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 145:3424, 2004. 17. Beckingsale PS, Sullivan TJ, Wong VA, et al.: Blepharophimosis: a recommendation for early surgery in patients with severe ptosis. Clin Experiment Ophthalmol 31:138, 2003. 18. Callahan A: Surgical correction of the blepharophimosis syndromes. Trans Am Acad Ophthalmol Otolaryngol 77:OP687, 1973. 19. Nowinski TS: Correction of telecanthus in the blepharophimosis syndrome. Int Ophthalmol Clin 32:157, 1992. 20. Karacaoglan N, Sahin U, Ercan U, et al.: One-stage repair of blepharophimosis: a new method. Plast Reconstr Surg 93:1406, 1994. 21. Nakajima T, Yoshimura Y, Onishi K, et al.: One-stage repair of blepharophimosis. Plast Reconstr Surg 87:24, 1991.

Prognosis, Prevention, Treatment

Visual prognosis is good unless there are major associated ocular abnormalities such as colobomatous microphthalmia or there is occlusion or strabismic amblyopia. Surgical repair of the ptosis should be delayed until age 4 to 5 years unless the lids occlude the pupil and the child cannot compensate by assuming a chin-up posture.17,18 Repair of the telecanthus and epicanthus is generally performed before repair of the ptosis,19 but both can be repaired at the same time.20,21 References (Blepharophimosis) 1. Edmund J: Blepharophimosis congenita. Acta Genet 7:279, 1957. 2. Lee LR, Sullivan TJ: Blepharophimosis syndrome: association with colobomatous microphthalmos. Aust N Z J Ophthalmol 23:145, 1995. 3. Chismire KJ, Witkop GS: Optic nerve hypoplasia and angle dysgenesis in a patient with blepharophimosis syndrome. Am J Ophthalmol 117:676, 1994. 4. Jones CA, Collin JR: Blepharophimosis and its association with female infertility. Br J Ophthalmol 68:533, 1984. 5. Zlotogora J, Sagi M, Cohen T: The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am J Hum Genet 35:1020, 1983. 6. Edwards WC, Root AW: Chondrodystrophic myotonia (SchwartzJampel syndrome): report of a new case and follow-up of patients initially reported in 1969. Am J Med Genet 13:51, 1982. 7. Freeman EA, Sheldon JH: Craniocarpotarsal dystrophy. An undescribed congenital malformation. Arch Dis Child Fetal Neonatal Ed 13:277, 1938. 8. Moller KT, Gorlin RJ: The Dubowitz syndrome: a retrospective. J Craniofac Genet Dev Biol Suppl 1:283, 1985. 9. Mhanni AA, Dawson AJ, Chudley AE: Vertical transmission of the Ohdo blepharophimosis syndrome. Am J Med Genet 77:144, 1998. 10. Ohdo S, Madokoro H, Sonoda T, et al.: Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth. J Med Genet 23:242, 1986. 11. Amati P, Chomel JC, Nivelon-Chevalier A, et al.: A gene for blepharophimosis-ptosis-epicanthus inversus syndrome maps to chromosome 3q23. Hum Genet 96:213, 1995. 12. Costa T, Pashby R, Huggins M, et al.: Deletion 3q in two patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). J Pediatr Ophthalmol Strabismus 35:271, 1998. 13. Crisponi L, Deiana M, Loi A, et al.: The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159, 2001. 14. Fokstuen S, Antonarakis SE, Blouin JL: FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. Am J Med Genet 117A:143, 2003. 15. De Baere E, Beysen D, Oley C, et al.: FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotypephenotype correlation. Am J Hum Genet 72:478, 2003.

9.6 Other Anomalies of the Eyelids Eyelid Coloboma

Eyelid coloboma is a full-thickness notch defect of the lid margin. The colobomas may be triangular or quadrilateral in shape. Upper eyelid defects (the majority of colobomatous lid defects) are usually nasal, whereas lower eyelid colobomas are temporal. Colobomas of the eyelids occur in about 10–20% of patients with Goldenhar syndrome, a variant of the oculo-auriculo-vertebral spectrum (Fig. 9-6);1 the coloboma is usually present in conjunction with epibulbar dermoids and preauricular skin tags. Lower eyelid colobomas are seen in Treacher Collins syndrome (Fig. 9-7).2 Upper and lower eyelid defects may also be seen in the amniotic band syndrome.3,4 Distichiasis

Distichiasis refers to the growth of true cilia in ectopic locations, in extra rows along the lid margin, and out of the orifices of Meibomian glands. The accessory row(s) of lashes are usually seen on all four lids and run on the inner part of the intermarginal strip. The cilia may be soft and depigmented or fully developed and pigmented and may rub against the globe, resulting in corneal damage. Several families with autosomal dominant distichiasis have been reported in the world literature.5,6 The distichiasislymphedema syndrome is inherited in an autosomal dominant fashion and combines distichiasis with lymphedema of the limbs, most often affecting the lower limbs below the knees. It results from mutations in the transcription factor FOXC2.7–9 Orbital Hypertelorism

In hypertelorism there is an increased distance between the two orbits. Hypertelorism is present in a large number of malformation syndromes (Table 9-2). Telecanthus

Telecanthus refers to an increased distance between the inner canthi (Fig. 9-8). The ratio between the inner canthal measurement and the outer canthal measurement is approximately 1:3. Telecanthus is a nondiagnostic abnormality in a number of multisystem malformation syndromes. Epibulbar Choristomas

Epibulbar choristomas are tumorous growths on the exterior of the eye derived from tissue not normally present at that location.10 Epibulbar and orbital choristomas are the most common epibulbar

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Fig. 9-7. Temporal colobomas of the lower lids, downslanting palpebral fissures, malar hypoplasia, microtia, and micrognathia in a 10-year-old girl with Treacher Collins syndrome. (Courtesy of Dr. Charles I. Scott Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

Fig. 9-8. Schematic showing normal interpupillary and inner canthal measurement (top), telecanthus with normal interpupillary but increased inner canthal measurement (middle), and hypertelorism with increased interpupillary and inner canthal measurement (bottom).

Fig. 9-6. Dermoids. Top: orbital dermoid in upper outer quadrant, the most common location. Middle: computed tomography demonstrates cystic nature of lesion. (Courtesy of Dr. John F. Gillis.) Bottom: epibulbar dermoid of the left eye associated with a coloboma of the left upper eyelid in the Goldenhar syndrome.

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and orbital tumors in children. Four histopathologic types are recognized: (1) dermoids, which are made of collagenous connective tissue covered with epidermis; (2) lipodermoids, which, in addition, contain adipose tissue; (3) single tissue choristomas that consist either of dermislike tissue or of ectopic mesectodermal tissue of one origin; and (4) complex choristomas that contain tissues of different origins. Clinically, dermoid cysts contain one or more dermal adnexal structures and are lined by keratinizing epithelium; epidermoid cysts have no adnexal structures; teratomas contain tissues derived from all three germinal layers; and teratoid tumors are derived from only two germinal layers. Epibulbar choristomas are solid tumors of the ocular surface that occur in one to three per 10,000 live births. They may be whitish, yellowish, or pinkish in color and vary from small, flat lesions at the limbus to large masses that cover most of the interpalpebral area. Lesions may be unilateral or bilateral, and multiple tumors have also been reported. Of 82 epibulbar choristomas reported by Ash, 52% were in the bulbar conjunctiva, 29% at the limbus, 6% in the cornea, 4% in the caruncle, 4% in the canthal area, 2.5% in the fornix, and 2.5% in the palpebral conjunctiva.11 Associated ocular and facial abnormalities include scleral and corneal staphyloma, aniridia, congenital aphakia, cataract, miliary aneurysms of the retina, microphthalmia, osseous choristoma of the choroid, dermoid cyst of the orbit or eyelid, choristomatous malformations of the face and scalp, and preauricular tags. Epibulbar choristomas that involve the cornea may induce astigmatism, necessitating their surgical excision, the optical correction of the astigmatism, and the prevention of amblyopia.12 Epibulbar choristomas are associated with Goldenhar syndrome in the facio-auriculo-vertebral spectrum of anomalies.13 They can also be associated with the epidermal nevus syndrome, which includes skeletal, neurologic, vascular, and dermatologic abnormalities.14,15 The choristomas in the epidermal nevus syndrome are usually of the complex variety and may involve the whole ocular surface. Epibulbar choristomas may be inherited, usually in an autosomal dominant fashion16 but also in an X-linked recessive or autosomal recessive manner. Episcleral osseous choristomas are rare whitish, pea-sized, raised lesions that occur 5 to 10 mm posterior to the limbus and are composed of compact bone vested by periosteum. These tumors are freely movable but may adhere to sclera or to extraocular muscles. Posterior episcleral choristomas have been described in patients with the organoid nevus syndrome. They are located close or around the optic nerve head and appear as pale irregular lesions. They are highly reflective on ultrasonography and are also visualized on computed tomographic studies.17 Microblepharon

In microblepharon there is a vertical shortening of the lids. An extreme form of microblepharon is seen in the ablepharonmacrostomia syndrome characterized by absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia. Patients with this condition may have visual problems, often related to early corneal exposure. Hearing loss, poor hair growth, finger contractures, and growth retardation are also chronic problems. Mild developmental delay is present in two-thirds of patients.18,19 Ablepharon (no lids) should not be synonymous with cryptophthalmia. Epicanthus

Epicanthus refers to a fold of skin that covers the inner canthus of the palpebral fissure. There are four distinct types: (1) epicanthus supraciliaris, in which epicanthal folds arise from the region of the

eyebrow and run toward the tear sac or the nostril; (2) epicanthus palpebralis, in which the fold arises in the upper lid above the tarsal fold and extends to the lower margin of the orbit; (3) epicanthus tarsalis, in which the fold arises laterally above the tarsal fold and loses itself in the skin next to the inner canthus; and (4) epicanthus inversus, in which a small fold arises in the lower lid and extends upward, partially covering the inner canthus. Epicanthus inversus is usually seen in the blepharophimosis syndrome, along with ptosis and telecanthus. Epicanthus tarsalis is seen in Asians, and epicanthus tarsalis and epicanthus palpebralis are both seen in children of all races. Epiblepharon is probably an exaggerated form of epicanthus tarsalis (Fig. 9-9). Epicanthus supraciliaris is common to a large number of syndromes, for example, Down syndrome, that will not be discussed here. All types of epicanthal folds tend to improve with age, and any cosmetic surgery should be withheld until after full facial growth. Congenital Entropion

Congenital entropion is an infolding of the margins of the eyelids, placing the eyelashes in contact with the optic globe.20 Congenital entropion of the upper eyelid is a very rare abnormality that affects mostly females and has been reported in fewer than 20 patients.21 It is considered an ocular emergency, because corneal ulceration and permanent scarring can result from the associated trichiasis if surgical management is not promptly instituted. Congenital entropion may be due to congenital levator aponeurosis disinsertion or to extreme kinking of the tarsus (congenital tarsal kink). Systemic abnormalities, including agenesis of the corpus callosum, have been reported in patients with entropion of the upper eyelid. Congenital entropion of the upper or lower eyelid should be suspected in infants with atypical or persistent corneal ulceration.22 An examination under sedation or anesthesia would prevent squeezing of the eyelids and would allow correct diagnosis. The presence of distichiasis or other congenital eyelid anomalies are helpful diagnostic clues.23 Autosomal dominant inheritance has been reported.24 Congenital Ectropion

Congenital ectropion is the outfolding of the eyelid margin, exposing the conjunctival surface of the eyelid. Also called congenital eversion of the upper eyelids, this condition is more common in black infants and in patients with Down syndrome.25 It may also be seen in patients with lamellar ichthyosis (Fig. 9-10).26,27 Fig. 9-9. Bilateral epiblepharon in a non-Asian girl.

Eye

Fig. 9-10. Ectropion associated with ichthyosis (harlequin fetus). (Courtesy of Dr. Sami Elhassani, Spartanburg, SC.)

Congenital ectropion is generally a self-limited disease that is best managed with eye lubrication, with or without taping the lids together intermittently or during sleep. Persistent eversion is rare and may require surgical intervention. Congenital upper eyelid eversion is thought to be due to impaired venous return from the upper lids, resulting in eyelid swelling, chemosis, and eversion. Orbicularis spasm may also be a contributory factor. Congenital Eyelid Retraction

Eyelid retraction is an exaggerated elevation of the upper eyelid and lowering of the lower eyelid, exposing the sclera around the cornea. This is a static condition that affects the upper or lower eyelids, or both. It is diagnosed after the exclusion of other causes of lid retraction, such as hyperthyroidism, trauma, proptosis, seventh nerve palsy, and Marcus-Gunn jaw-winking. Patients usually present because of an abnormal staring appearance; corneal exposure is a rare complication. No treatment is required except for lubrication in patients with exposure keratitis. Extensive investigation is not required if the history and clinical course are suggestive of the diagnosis. Some degree of upper eyelid retraction is normal in newborns and young infants. In severe cases, eyelid retractor lengthening procedures may be performed but may be unpredictable, resulting in secondary ptosis. References (Other Anomalies of the Eyelids) 1. Shokeir MH: The Goldenhar syndrome: a natural history. Birth Defects Orig Artic Ser XIII(3C):67, 1977. 2. Fuente del Campo A, Martinez Elizondo M, Arnaud E: Treacher Collins syndrome (mandibulofacial dysostosis). Clin Plast Surg 21:613, 1994. 3. Bagatin M, Der Sarkissian R, Larrabee WF Jr: Craniofacial manifestations of the amniotic band syndrome. Otolaryngol Head Neck Surg 116:525, 1997. 4. Orioli IM, Ribeiro MG, Castilla EE: Clinical and epidemiological studies of amniotic deformity, adhesion, and mutilation (ADAM) sequence in a South American (ECLAMC) population. Am J Med Genet 118A: 135, 2003.

309 5. Robinow M, Johnson GF, Verhagen AD: Distichiasis-lymphedema. A hereditary syndrome of multiple congenital defects. Am J Dis Child 119:343, 1970. 6. Pap Z, Biro T, Szabo L, et al.: Syndrome of lymphoedema and distichiasis. Hum Genet 53:309, 1980. 7. Fang J, Dagenais SL, Erickson RP, et al.: Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382, 2000. 8. Traboulsi EI, Al-Khayer K, Matsumoto M, et al.: Lymphedemadistichiasis syndrome and FOXC2 gene mutation. Am J Ophthalmol 134:592, 2002. 9. Erickson RP, Dagenais SL, Caulder MS, et al.: Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations. J Med Genet 38:761, 2001. 10. Mansour AM, Barber JC, Reinecke RD, et al.: Ocular choristomas. Surv Ophthalmol 33:339, 1989. 11. Ash JE: Epibulbar tumors. Am J Ophthalmol 33:1203, 1950. 12. Gayre GS, Proia AD, Dutton JJ: Epibulbar osseous choristoma: case report and review of the literature. Ophthalmic Surg Lasers Imaging 33:410, 2002. 13. Mansour AM, Wang F, Henkind P, et al.: Ocular findings in the facioauriculovertebral sequence (Goldenhar-Gorlin syndrome). Am J Ophthalmol 100:555, 1985. 14. Mullaney PB, Weatherhead RG: Epidermal nevus syndrome associated with a complex choristoma and a bilateral choroidal osteoma. Arch Ophthalmol 114:1292, 1996. 15. Shields JA, Shields CL, Eagle RC Jr, et al.: Ocular manifestations of the organoid nevus syndrome. Ophthalmology 104:549, 1997. 16. Mattos J, Contreras F, O’Donell FE Jr: Ring dermoid syndrome: a new syndrome of autosomal-dominantly inherited, bilateral, annular limbal dermoids with corneal and conjunctival extension. Arch Ophthalmol 98:1059, 1980. 17. Traboulsi EI, Zin A, Massicotte SJ, et al.: Posterior scleral choristoma in the organoid nevus syndrome (linear nevus sebaceus of Jadassohn). Ophthalmology 106:2126, 1999. 18. Hornblass A, Reifler DM: Ablepharon macrostomia syndrome. Am J Ophthalmol 99:552, 1985. 19. Stevens CA, Sargent LA: Ablepharon-macrostomia syndrome. Am J Med Genet 107:30, 2002. 20. Fox SA: Primary congenital entropion. Ama Arch Opthalmol 56:839, 1956. 21. Barsky D: Congenital entropion of the upper eyelids. J Mich State Med Soc 62:581, 1963. 22. Salour H, Owji N, Razavi ME, et al.: Tarsal kink syndrome associated with congenital corneal ulcer. Ophthal Plast Reconstr Surg 19:81, 2003. 23. Johnson CC: Developmental abnormalities of the eyelids. The 1985 Wendell Hughes lecture. Ophthal Plast Reconstr Surg 2:219, 1986. 24. Amacher AG, 3rd, Mazzoli RA, Gilbert BN, et al.: Dominant familial congenital entropion with tarsal hypoplasia and atrichosis. Ophthal Plast Reconstr Surg 18:381, 2002. 25. Sellar PW, Bryars JH, Archer DB: Late presentation of congenital ectropion of the eyelids in a child with Down syndrome: a case report and review of the literature. J Pediatr Ophthalmol Strabismus 29:64, 1992. 26. Cruz AA, Menezes FA, Chaves R, et al.: Eyelid abnormalities in lamellar ichthyoses. Ophthalmology 107:1895, 2000. 27. Oestreicher JH, Nelson CC: Lamellar ichthyosis and congenital ectropion. Arch Ophthalmol 108:1772, 1990.

9.7 Congenital Corneal Anomalies Cornea Plana

In cornea plana the corneal curvature is flatter than normal. The anterior chamber is shallow, and there is significant hyperopia and astigmatism.1,2 Late development of glaucoma can occur. Autosomal dominant and recessive inheritance have been reported.3

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The more severe recessive form (CNA2) results from mutations in KERA (encoding keratocan) on chromosome 12q.4 Forty-six Finnish patients were found to be homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid.4 Management consists of correction of associated errors of refraction and the detection and treatment of glaucoma. Megalocornea

In megalocornea the cornea measures more than 12 mm in diameter at birth but is otherwise normal in curvature, thickness, and endothelial cell density.5 This contrasts with the enlarged corneal diameter in congenital glaucoma in which the cornea is hazy and thick and has a decreased endothelial cell density.6 Megalocornea is generally inherited in an X-linked recessive fashion. Mackey and coworkers mapped the gene for megalocornea to Xq12-q26.7 Patients may have presenile cataracts and with age develop a corneal arcus and a crocodile shagreen pattern of opacification of their corneas (Fig. 9-11). Carrier females do not show any changes. Megalocornea is occasionally seen in Marfan syndrome, Down syndrome, and Rieger syndrome. Megalocornea is associated with mental and neurologic impairment, minor anomalies in Neuhauser syndrome (megalocornea-mental retardation syndrome), and other related conditions.8 Management of megalocornea consists of the recognition of associated systemic disease when it is present. Older patients may require cataract extraction. Microcornea

In microcornea the corneal diameter is less than 9 to 10 mm at birth. Ocular size as determined by ultrasonography is normal in isolated microcornea and decreased in microphthalmia. Microcornea may be inherited in a dominant or in a recessive fashion. Microcornea with cataracts (Nance-Horan syndrome) is X-linked recessive.9 Nance-Horan syndrome is characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. It was mapped to Xp22.13. Burdon et al. identified the NHS gene and found that the gene plays key functions in the regulation of eye, tooth, brain, and craniofacial development.10 Other associated ocular anomalies with microcornea include aniridia, cataracts, subluxated lenses,11 and glaucoma.

Fig. 9-11. X-linked megalocornea with characteristic posterior crocodile shagreen or mosaic corneal dystrophy. (Courtesy of Dr. David Mackey.)

Fig. 9-12. Sclerocornea with blunting of limbal transition most prominent superiorly.

Management of microcornea includes treatment of the associated glaucoma and cataract if they are present. Sclerocornea

In sclerocornea there is congenital, nonprogressive corneal opacification that may be peripheral, sectorial, or central in location (Fig. 9-12). The cornea has a flat curvature. The great majority of cases are bilateral and may be inherited in an autosomal dominant or recessive fashion.12 Histopathologically, corneal collagen is larger than normal in diameter, and the collagen fibers and lamellae are irregularly arranged, resulting in corneal opacification.13 Descemet membrane and the endothelium may also be absent or abnormal. A number of associated ocular anomalies have been reported, and sclerocornea has occurred in a number of well-defined malformation syndromes14–17 and with mutations in the RAX homeobox gene.18 Corneal transplantation may be required in some patients with sclerocornea and central corneal involvement.19,20 References (Congenital Corneal Anomalies) 1. Sigler-Villanueva A, Tahvanainen E, Lindh S, et al.: Autosomal dominant cornea plana: clinical findings in a Cuban family and a review of the literature. Ophthalmic Genet 18:55, 1997. 2. Eriksson AW, Lehmann W, Forsius J: Congenital cornea plana in Finland. Clin Genet 4:301, 1973. 3. Tahvanainen E, Villanueva AS, Forsius H, et al.: Dominantly and recessively inherited cornea plana congenita map to the same small region of chromosome 12. Genome Res 6:249, 1996. 4. Pellegata NS, Dieguez-Lucena JL, Joensuu T, et al.: Mutations in KERA, encoding keratocan, cause cornea plana. Nat Genet 25:91, 2000. 5. Meire FM: Megalocornea. Clinical and genetic aspects. Doc Ophthalmol 87:1, 1994. 6. Ho CL, Walton DS: Primary megalocornea: clinical features for differentiation from infantile glaucoma. J Pediatr Ophthalmol Strabismus 41:11, 2004, quiz 46-7. 7. Mackey DA, Buttery RG, Wise GM, et al.: Description of X-linked megalocornea with identification of the gene locus. Arch Ophthalmol 109:829, 1991. 8. Verloes A, Journel H, Elmer C, et al.: Heterogeneity versus variability in megalocornea-mental retardation (MMR) syndromes: report of new cases and delineation of 4 probable types. Am J Med Genet 46: 132, 1993. 9. Bixler D, Higgins M, Hartsfield J Jr: The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females. Clin Genet 26:30, 1984.

Eye 10. Burdon KP, McKay JD, Sale MM, et al.: Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet 73:1120, 2003. 11. David R, MacBeath L, Jenkins T: Aniridia associated with microcornea and subluxated lenses. Br J Ophthalmol 62:118, 1978. 12. Elliott JH, Feman SS, O’Day DM, et al.: Hereditary sclerocornea. Arch Ophthalmol 103:676, 1985. 13. Kanai A, Wood TC, Polack FM, et al.: The fine structure of sclerocornea. Invest Ophthalmol Vis Sci 10:687, 1971. 14. Perry LD, Edwards WC, Bramson RT: Melnick-Needles syndrome. J Pediatr Ophthalmol Strabismus 15:226, 1978. 15. Harbin RL, Katz JI, Frias JL, et al.: Sclerocornea associated with the Smith-Lemli-Opitz syndrome. Am J Ophthalmol 84:72, 1977. 16. Happle R, Daniels O, Koopman RJ: MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. Am J Med Genet 47:710, 1993. 17. Schanzlin DJ, Goldberg DB, Brown SI: Hallermann-Streiff syndrome associated with sclerocornea, aniridia, and a chromosomal abnormality. Am J Ophthalmol 90:411, 1980. 18. Voronina VA, Kozhemyakina EA, O’Kernick CM, et al.: Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. Hum Mol Genet 13:315, 2004. 19. Frueh BE, Brown SI: Transplantation of congenitally opaque corneas. Br J Ophthalmol 81:1064, 1997. 20. Waring GO 3rd, Rodrigues MM: Ultrastructure and successful keratoplasty of sclerocornea in Mietens’ syndrome. Am J Ophthalmol 90:469, 1980.

9.8 Anterior Segment Dysgenesis Definition

Anterior segment dysgenesis is a spectrum of ocular malformations characterized by abnormal development of the anterior chamber angle and iris.1,2 Terms that have been used to describe the various configurations of the anterior segment abnormalities in this context are anterior chamber cleavage syndrome, mesodermal dysgenesis of the cornea and iris, primary dysgenesis mesodermalis of the iris, and Axenfeld-Rieger syndrome. Included in anterior segment dysgenesis are (1) Axenfeld anomaly or posterior embryotoxon, in which there is a prominent and anteriorly displaced line of Schwalbe (the most peripheral portion of the Descemet membrane) in the cornea with strands of iris tissue attached to it, and (2) Rieger anomaly, in which, in addition to an Axenfeld anomaly, there exists clinical evidence of iris stromal atrophy with hole or pseudohole formation and corectopia. Rieger syndrome is a distinct autosomal dominant condition in which anterior segment dysgenesis is accompanied by facial, dental, umbilical, and skeletal abnormalities.3 Investigators in the last decade have identified the major genes that cause the Axenfeld-Rieger spectrum of malformations, all of which to date have been homeobox transcription factor genes.4,5 Diagnosis

Anterior segment dysgenesis, or the Axenfeld-Rieger spectrum of malformation, is a bilateral, often symmetric condition that affects males and females equally and that shows a wide spectrum of variability in clinical expression within families in which it is inherited as an autosomal dominant trait. Severe cases are recognized in infancy or childhood because of the abnormal appearance of the anterior segment. Some infants are discovered because of signs and symptoms of associated infantile glaucoma such as tearing,

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photophobia, and corneal clouding. Other patients are discovered in adolescence or early childhood when they present with visual loss and are found to have advanced childhood glaucoma. Glaucoma, the only vision-threatening complication, occurs in about 50% of patients with anterior segment dysgenesis by age 20 years and in 10–15% of patients per decade thereafter. Other cases are discovered during routine examinations within or outside the context of a positive family history of the disease. Nonocular abnormalities suggesting a diagnosis of Rieger syndrome may prompt an ocular examination. The appearance of the iris in the Rieger spectrum of abnormalities is highly variable (Fig. 9-13). The iris stroma is thin, and there may be extensive defects of the iris with polycoria (multiple pupils) or pseudopolycoria. The pupil may be ectopic (corectopia), in which case iris hypoplasia is most severe in the sector of iris away from the direction of corectopia. Megalocornea is a frequent association. Rarely, Rieger anomaly is associated with other ocular abnormalities, including aniridia, blue sclera, cornea plana, dislocated lenses, hypoplasia of the optic nerve head, macular degeneration, medullated nerve fibers, and retinal detachment. Ectropion uveae or proliferation of the neuroectodermally derived pigmented posterior layer of the iris onto the anterior surface of the iris in the region of the pupil may be seen. Congenital Fig. 9-13. Rieger anomaly of the anterior segment with prominent Schwalbe line, corectopia, and extensive iris atrophy with pseudopolycoria (top). Prominent Schwalbe line in a patient with Rieger anomaly (bottom).

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ectropion uveae, or congenital iris ectropion (ME Wilson, personal communication), is classified by some with the goniodysgenesis syndromes and may indeed be a separate well-defined abnormality of neural crest development and differentiation. Other authors have also included primary infantile glaucoma in the goniodysgenetic disorders because of the well-documented defect in anterior chamber angle and trabecular meshwork abnormality. Primary infantile glaucoma is inherited in an autosomal recessive fashion in the majority of cases and may be of multifactorial etiology in others. Infantile glaucoma can be the presenting sign of the Axenfeld-Rieger spectrum of abnormalities. Etiology and Distribution

Prominence of the peripheral edge of Descemet membrane or posterior embryotoxon is present in about 15% of the general adult population and is accompanied by bridging iris strands (Axenfeld anomaly) in 6% of otherwise normal individuals. The incidence of Rieger anomaly is not known. Rieger syndrome is estimated to occur in one per 200,000 of the population. The Axenfeld-Rieger spectrum of anomalies results from an abnormality of neural crest development and/or resorption. Shields et al. have postulated that, late in gestation, a developmental arrest leads to retention of the primordial endothelium over portions of the iris and anterior chamber angle.2 Incomplete posterior recession of the peripheral uvea produces a high insertion of the iris. This arrest also causes the zone of differentiation between the corneal and anterior angle endothelium to be abnormally located and associated with prominence and anterior displacement of the Schwalbe line. The retained endothelial cells may bridge the angle along with a few iris strands and contract, pulling the iris strands toward the center. Contraction of the primordial endothelium also leads to corectopia and ectropion uveae. Endothelial cells will later disappear, leaving the abnormal iris configuration. In Rieger syndrome, associated systemic anomalies are also due to abnormal neural crest differentiation. Neural crest-derived structures such as facial bones and cartilage, dental papillae, and the primitive periumbilical ring are affected, resulting in facial dysmorphism with maxillary hypoplasia and a receding chin, hypodontia, peg-shaped teeth, and redundant periumbilical skin. Rare findings include hypospadias, empty or enlarged sella turcica,6 and growth hormone deficiency.7 The genes for the Axenfeld-Rieger syndrome (ARS) are autosomal dominant, fully penetrant, and variable in expressivity. In 1996, Semina et al. reported mutations in PITX2(RIEG1), a gene on 4q25-q26 that codes for a homeobox transcription factor, in subjects with ARS.8 Additional mutations throughout the PITX2 sequence have been observed in subjects with various forms of anterior segment dysgenesis (ARS, iris hypoplasia, iridogoniodysgenesis, and Peters anomaly).9–15 ARS can also be due to mutations in the FOXC1 gene on 6p25, a member of the forkhead family of transcription factors.11,16–22 As with subjects with PITX2 mutations, subjects with FOXC1 mutations have a great deal of phenotypical variability. At least two other ARS loci on 13q14 and 16q24 await cloning. A few multisystem disorders feature anterior segment dysgenesis, and a careful ophthalmologic evaluation should be part of the routine work-up of patients with Alagille syndrome or arteriohepatic dysplasia,23 the Wolf-Hirschhorn syndrome (4p- syndrome),24,25 and the Abruzzo-Erikson syndrome.26 An association with oculocutaneous albinism has also been reported. Additionally, Rieger syndrome has been associated with a number of chromosomal abnormalities that have been reviewed by Stathacopoulos et al., who reported a patient with Rieger syndrome and an interstitial deletion of chromosome 13(q14q31).27

Prognosis, Treatment, and Prevention

The major complication of the Axenfeld-Rieger spectrum of ocular anomalies is the development of glaucoma and glaucomatous visual loss. When glaucoma occurs in infancy, it is detected early because of the associated signs and symptoms of photophobia, tearing, corneal clouding, and corneal enlargement. Early surgical intervention and postoperative visual rehabilitation result in a fair prognosis for good vision. Patients who develop glaucoma in early adulthood may not come to medical attention until field defects impinge on central vision, indicating an advanced disease process. Such patients are usually given topical antiglaucoma medications but often come to filtering surgery with relatively poor eventual visual outcome. The best scenario involves a sib or offspring of a patient with Axenfeld-Rieger anomaly who is followed closely for the development of glaucoma, which is then treated as soon as it is detected and before the development of visual field loss. Frequent ocular examinations (every 4–6 months) are recommended for patients with this spectrum of ocular disorders and for their affected relatives. All available family members should be examined for anterior segment malformations and should be counseled about the genetic risk in this dominant group of disorders and about the variability of clinical presentation. When anterior segment dysgenesis is associated with a multisystem malformation syndrome, prognosis depends on the severity of the associated congenital abnormalities and on their impact on the patient’s general health. References (Anterior Segment Dysgenesis) 1. Waring GO 3rd, Rodrigues MM, Laibson PR: Anterior chamber cleavage syndrome. A stepladder classification. Surv Ophthalmol 20:3, 1975. 2. Shields MB, Buckley E, Klintworth GK, et al.: Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 29: 387, 1985. 3. Rieger H: Beitrage zur Kenntnis seltener Missbildungen der Iris. Graefes Arch Clin Exp Ophthalmol 133:602, 1935. 4. Alward WL: Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 130:107, 2000. 5. Lines MA, Kozlowski K, Walter MA: Molecular genetics of AxenfeldRieger malformations. Hum Mol Genet 11:1177, 2002. 6. Kleinmann RE, Kazarian EL, Raptopoulos V, et al.: Primary empty sella and Rieger’s anomaly of the anterior chamber of the eye: a familial syndrome. N Engl J Med 304:90, 1981. 7. Sadeghi-Nejad A, Senior B: Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger’s syndrome). J Pediatr 85:644, 1974. 8. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996. 9. Alward WL, Semina EV, Kalenak JW, et al.: Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/ PITX2) gene. Am J Ophthalmol 125:98, 1998. 10. Amendt BA, Sutherland LB, Semina EV, et al.: The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities. J Biol Chem 273:20066, 1998. 11. Borges AS, Susanna R Jr, Carani JC, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 12. Kozlowski K, Walter MA: Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders. Hum Mol Genet 9:2131, 2000. 13. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000.

Eye 14. Phillips JC: Four novel mutations in the PITX2 gene in patients with Axenfeld-Rieger syndrome. Ophthalmic Res 34:324, 2002. 15. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 16. Nishimura DY, Swiderski RE, Alward WL, et al.: The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 19:140, 1998. 17. Honkanen RA, Nishimura DY, Swiderski RE, et al.: A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Am J Ophthalmol 135:368, 2003. 18. Kawase C, Kawase K, Taniguchi T, et al.: Screening for mutations of Axenfeld-Rieger syndrome caused by FOXC1 gene in Japanese patients. J Glaucoma 10:477, 2001. 19. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 20. Panicker SG, Sampath S, Mandal AK, et al.: Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly. Invest Ophthalmol Vis Sci 43:3613, 2002. 21. Saleem RA, Banerjee-Basu S, Berry FB, et al.: Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1. Am J Hum Genet 68:627, 2001. 22. Saleem RA, Murphy TC, Liebmann JM, et al.: Identification and analysis of a novel mutation in the FOXC1 forkhead domain. Invest Ophthalmol Vis Sci 44:4608, 2003. 23. Ozeki H, Shirai S, Ikeda K, et al.: Anomalies associated with AxenfeldRieger syndrome. Graefes Arch Clin Exp Ophthalmol 237:730, 1999. 24. Wilcox LM Jr, Bercovitch L, Howard RO: Ophthalmic features of chromosome deletion 4p- (Wolf-Hirschhorn syndrome). Am J Ophthalmol 86:834, 1978. 25. Mayer UM, Bialasiewicz AA: Ocular findings in a 4 p- deletion syndrome (Wolf-Hirschhorn). Ophthalmic Paediatr Genet 10:69, 1989. 26. Verloes A, Dodinval P: Rieger anomaly and uveal coloboma with associated anomalies. Third observation of a rare oculo-palato-osseous syndrome—the Abruzzo-Erikson syndrome. Ophthalmic Paediatr Genet 11:41, 1990. 27. Stathacopoulos RA, Bateman JB, Sparkes RS, et al.: The Rieger syndrome and a chromosome 13 deletion. J Pediatr Ophthalmol Strabismus 24:198, 1987.

9.9 Peters Anomaly Definition

Peters anomaly is a variable anomaly consisting of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and variable amounts of iris and lenticular attachments to the central aspect of the posterior cornea. Diagnosis

The spectrum of the morphology of Peters anomaly is very wide. The anomaly can take the form of a faint corneal leukoma with a small strand of iris attached to the posterior surface of the cornea and a clear lens to severe corneal opacification, extensive iridocorneal adhesions, and cataract formation (Fig. 9-14). Some cases of sclerocornea are also included in this spectrum because of the absence of the Descemet membrane in many cases of sclerocornea and the co-existence of sclerocornea and Peters anomaly in some patients. Associated ocular defects with Peters anomaly include microcornea, anterior polar cataracts, glaucoma with or

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Fig. 9-14. Peters anomaly with central opacification of the cornea. There were iridocorneal adhesions behind the opacity.

without buphthalmos, spontaneous corneal perforation, aniridia, persistence of the hyaloid system, and total posterior coloboma of the retina and choroid.1 Associated systemic congenital anomalies include short stature, short limbs, abnormal ears, cleft lip/palate abnormalities, malformation of the genitourinary system, cardiovascular anomalies, defects of the limbs, and mental retardation.1–3 Familial cases of Peters anomaly are recessively inherited in some cases4,5; however, pedigrees with autosomal dominant transmission have been published.6 The syndrome of Peters anomaly with short limbs (Kivlin-Krause syndrome) appears to be a distinct recessive condition.7–9 In the Peters-plus syndrome, Peters anomaly occurs in association with clefting, mental retardation, and abnormal ears. Traboulsi and Maumenee have found the spectrum of malformation in Peters-plus syndrome to include midline defects, cardiovascular and urogenital anomalies, and the previously described craniofacial anomalies and mental retardation.1 The most common associated ocular abnormality was coloboma/ microphthalmia in about 25% of cases. Peters anomaly with multiple congenital malformations has been reported in a number of patients with chromosomal abnormalities, such as an interstitial deletion of the long arm of chromosome 11,10 partial deletion of the short arm of chromosome 4,11 ring chromosome 21,12 partial trisomy 5p,13 and a balanced translocation between chromosomes 2 and 15. Mutations in PAX6,14,15 CYP1B1,16 and FOXC1 have also been associated with Peters anomaly.17,18 Etiology and Distribution

Peters anomaly probably results from an abnormality in separation of the lens vesicle from the surface ectoderm with interference in the formation of the central cornea and the formation of oflenticulo-irido-corneal adhesions. Cook and Sulik have developed a mouse model of Peters anomaly by exposing the developing mouse fetuses to high doses of alcohol or isotretinoin.19 Miller et al. reported a number of patients with Peters anomaly and the fetal alcohol syndrome.20 Prognosis, Prevention, and Treatment

The visual prognosis depends on the degree of corneal opacification and on the severity of associated ocular malformations. Combined penetrating keratoplasty and cataract extraction is needed in severe cases, whereas simple separation of iridocorneal

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adhesions suffices in mild cases and results in significant clearing of the corneal opacification.21–24 Unilateral cases are usually associated with deep amblyopia, and the risk to benefit ratio of surgery in such cases is probably very high. Congenital or postsurgical glaucoma is a major cause of visual loss in many cases. More than 50% of eyes with Peters anomaly end up with no light perception because of glaucoma. Chromosomal studies should be obtained in those patients with multiple congenital malformations and Peters anomaly. Families with a child who has isolated Peters anomaly should be counseled as to the probable recessive mode of inheritance of this condition.

21. Yang LL, Lambert SR, Lynn MJ, et al.: Long-term results of corneal graft survival in infants and children with peters anomaly. Ophthalmology 106:833, 1999. 22. Yang LL, Lambert SR: Peters’ anomaly. A synopsis of surgical management and visual outcome. Ophthalmol Clin North Am 14:467, 2001. 23. Dana MR, Schaumberg DA, Moyes AL, et al.: Corneal transplantation in children with Peters anomaly and mesenchymal dysgenesis. Multicenter Pediatric Keratoplasty Study. Ophthalmology 104:1580, 1997. 24. Miller MM, Butrus S, Hidayat A, et al.: Corneoscleral transplantation in congenital corneal staphyloma and Peters’ anomaly. Ophthalmic Genet 24:59, 2003.

References (Peters Anomaly) 1. Traboulsi EI, Maumenee IH: Peters’ anomaly and associated congenital malformations. Arch Ophthalmol 110:1739, 1992. 2. Mayer UM: Peters’ anomaly and combination with other malformations (series of 16 patients). Ophthalmic Paediatr Genet 13:131, 1992. 3. Heon E, Barsoum-Homsy M, Cevrette L, et al.: Peters’ anomaly. The spectrum of associated ocular and systemic malformations. Ophthalmic Paediatr Genet 13:137, 1992. 4. Tabuchi A, Matsuura M, Hirokawa M: Three siblings with Peters’ anomaly. Ophthalmic Paediatr Genet 5:205, 1985. 5. Boel M, Timmermans J, Emmery L, et al.: Primary mesodermal dysgenesis of the cornea (Peters’ anomaly) in two brothers. Hum Genet 51:237, 1979. 6. DeRespinis PA, Wagner RS: Peters’ anomaly in a father and son. Am J Ophthalmol 104:545, 1987. 7. Thompson EM, Winter RM, Baraitser M: Kivlin syndrome and Peters’Plus syndrome: are they the same disorder? Clin Dysmorphol 2:301, 1993. 8. Kivlin JD, Carey JC, Richey MA: Brachymesomelia and Peters anomaly: a new syndrome. Am J Med Genet 45:416, 1993. 9. De Almeida JC, Reis DF, Llerena J Jr, et al.: Short stature, brachydactyly, and Peters’ anomaly (Peters’-plus syndrome): confirmation of autosomal recessive inheritance. J Med Genet 28:277, 1991. 10. Bateman JB, Maumenee IH, Sparkes RS: Peters’ anomaly associated with partial deletion of the long arm of chromosome 11. Am J Ophthalmol 97:11, 1984. 11. Mayer UM, Bialasiewicz AA: Ocular findings in a 4 p- deletion syndrome (Wolf-Hirschhorn). Ophthalmic Paediatr Genet 10:69, 1989. 12. Cibis GW, Waeltermann J, Harris DJ: Peters’ anomaly in association with ring 21 chromosomal abnormality. Am J Ophthalmol 100:733, 1985. 13. Dichtl A, Jonas JB, Naumann GO: Atypical Peters’ anomaly associated with partial trisomy 5p. Am J Ophthalmol 120:541, 1995. 14. Hanson IM, Fletcher JM, Jordan T, et al.: Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet 6:168, 1994. 15. Sonoda S, Isashiki Y, Tabata Y, et al.: A novel PAX6 gene mutation (P118R) in a family with congenital nystagmus associated with a variant form of aniridia. Graefes Arch Clin Exp Ophthalmol 238:552, 2000. 16. Vincent A, Billingsley G, Priston M, et al.: Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters’ anomaly. J Med Genet 38:324, 2001. 17. Doward W, Perveen R, Lloyd IC, et al.: A mutation in the RIEG1 gene associated with Peters’ anomaly. J Med Genet 36:152, 1999. 18. Honkanen RA, Nishimura DY, Swiderski RE, et al.: A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Am J Ophthalmol 135:368, 2003. 19. Cook CS, Sulik KK: Keratolenticular dysgenesis (Peters’ anomaly) as a result of acute embryonic insult during gastrulation. J Pediatr Ophthalmol Strabismus 25:60, 1988. 20. Miller M, Israel J, Cuttone J: Fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 18:6, 1981.

9.10 Hypoplasia of the Iris (Aniridia) Definition

Hypoplasia of the iris (aniridia) is a bilateral malformation of the eye in which the most prominent abnormality is variable to neartotal absence of the iris.1,2 Aniridia is a misnomer since the iris is not totally absent. Diagnosis

In hypoplasia of the iris (aniridia), a stump of tissue is invariably present at the base of the iris, and gonioscopy may be required for its adequate visualization (Fig. 9-15). Aniridia occurs in one per 50,000 live births. Ocular abnormalities associated with aniridia include persistent pupillary membrane, congenital cataracts, ectopia lentis, developmental glaucoma, corneal pannus, keratopathy, persistence of the retina over pars plana, and foveal hypoplasia leading to decreased visual acuity and nystagmus.3 Congenital poor visual function in aniridia is due to macular, foveal, and optic nerve hypoplasia. Acquired causes of visual loss in aniridia include cataract, glaucoma, and anisometropic or strabismic amblyopia.4,5 At least two families have been described in which some members have classical aniridia and other members have atypical iris defects, ranging from radial clefts or atypical colobomas and relatively good vision to more extensive absence of iris tissue.6,7 The keratopathy/corneal pannus of aniridia appears late in the 1st decade of life and is presumably due to insufficient/ absent limbal stem cells that depend on the presence of normal PAX6 complement for their development and maintenance. Nystagmus develops in aniridic patients, presumably due to congenital poor visual acuity. Iris vascular anomalies and leakage have been diagnosed on fluorescein angiography of the anterior segment.7 Etiology and Distribution

Shaw et al. estimated the prevalence of aniridia in the lower peninsula of Michigan in 1960 to be about one in 64,000.1 Approximately two-thirds of patients have at least one other affected family member; the remaining one-third are sporadic. Aniridia is caused in almost all cases by mutations in PAX6, a homeobox transcription factor on 11p13.8,9 In some families, mutations in PAX6 cause a predominant keratopathy phenotype.10 In others, the iris is so well-preserved that the phenotype is predominated by isolated foveal hypoplasia.11 In the well-defined contiguous gene syndrome of Wilms tumor-aniridia-genitourinary abnormalities-retardation, or Miller syndrome, aniridia is of the noninherited variety and is always associated with a deletion of band 13 on the short arm of chromosome 11.12,13 Aniridia with

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Fig. 9-15. Left: aniridia with minimal remnants of the iris. Note circular reflex from edge of the lens. Right: aniridia with significant remnants of the iris (undilated pupil). The patient did not have nystagmus.

cerebellar ataxia and mental retardation is a very rare condition inherited in an autosomal recessive fashion and known as the Gillespie syndrome.14,15 Gillespie syndrome is not due to mutations in PAX6.16 Aniridia can also occur in association with malformations of the globe, such as Peters anomaly or congenital anterior staphyloma, or with microcornea and subluxated lenses. Aniridia can also occur in the context of multisystem malformation syndromes and chromosomal abnormalities such as ring chromosome 6;17 the syndrome of multiple ocular malformations and mental retardation described by Walker and Dyson18 and Hamming et al.;19 and the syndrome of aniridia and absence of the patella.20 When iris hypoplasia is not severe, as in aniridia type II, aniridia may be confused with conditions such as Rieger anomaly, ectopia lentis et pupillae, atypical coloboma of the iris, or essential iris atrophy (Chandler syndrome). Prognosis, Prevention, and Treatment

The management of patients with aniridia includes examination of other family members for the presence of mild degrees of iris hypoplasia. In any patient with aniridia and a negative family history, the risk of developing Wilms tumor is 20%; hence, careful, repeated examination and imaging of the renal system should be performed. Ultrasound examination of the kidneys is done at 6-month intervals supplemented with intravenous pyelography, computed tomography, or magnetic resonance imaging to further evaluate any suspicious finding. About one in 70 patients with Wilms tumor will have aniridia. A karyotype should be obtained in patients in whom mental retardation and genitourinary abnormalities are present to look for an interstitial deletion of the short arm of chromosome 11. There is no consensus as to whether a karyotype should be obtained in all sporadic cases; however, it is our recommendation to obtain one. The management of ocular problems in patients with aniridia can be very challenging. Visual acuity is usually less than 20/200 in most patients but may be as good as 20/20 in patients with

aniridia and preserved ocular function. The main cause of acquired visual loss in aniridia is glaucoma, and patients are screened for its presence at regular intervals. The glaucoma in aniridia typically develops in late childhood or in adulthood; however, it may be present in the 1st year of life. Aniridic glaucoma may be due to trabeculodysgenesis but has been observed to follow occlusion of the filtering angle by an up-pulling of the iris stump. Goniotomy or trabeculotomy may be successful in controlling infantile aniridic glaucoma; however, filtering surgery or cyclocryotherapy may be required. Medical therapy should be tried in older individuals with aniridic glaucoma. Cataracts, which develop in most aniridic patients, are extracted if they produce significant further decrease in visual acuity. Some patients have congenital anterior polar cataracts while others have acquired cataracts that usually develop in early adulthood. Ectopia lentis is occasionally found in aniridic eyes and should be looked for before a lensectomy is performed. Finally, penetrating keratoplasty may be required in some instances if progressive keratopathy leads to corneal opacification and to further loss of vision. References (Hypoplasia of the Iris) 1. Shaw MW, Falls HF, Neel JV: Congenital aniridia. Am J Hum Genet 12:389, 1960. 2. Nelson LB, Spaeth GL, Nowinski TS, et al.: Aniridia. A review. Surv Ophthalmol 28:621, 1984. 3. Layman PR, Anderson DR, Flynn JT: Frequent occurrence of hypoplastic optic disks in patients with aniridia. Am J Ophthalmol 77:513, 1974. 4. Walton DS: Aniridic glaucoma: the results of gonio-surgery to prevent and treat this problem. Trans Am Ophthalmol Soc 84:59, 1986. 5. Grant WM, Walton DS: Progressive changes in the angle in congenital aniridia, with development of glaucoma. Am J Ophthalmol 78:842, 1974. 6. Elsas FJ, Maumenee IH, Kenyon KR, et al.: Familial aniridia with preserved ocular function. Am J Ophthalmol 83:718, 1977. 7. Hittner HM, Riccardi VM, Ferrell RE, et al.: Variable expressivity in autosomal dominant aniridia by clinical, electrophysiologic, and angiographic criteria. Am J Ophthalmol 89:531, 1980.

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8. Ton CC, Hirvonen H, Miwa H, et al.: Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell 67:1059, 1991. 9. Glaser T, Walton DS, Maas RL: Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet 2:232, 1992. 10. Mirzayans F, Pearce WG, MacDonald IM, et al.: Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am J Hum Genet 57:539, 1995. 11. Azuma N, Nishina S, Yanagisawa H, et al.: PAX6 missense mutation in isolated foveal hypoplasia. Nat Genet 13:141, 1996. 12. Miller RW, Fraumeni JF Jr, Manning MD: Association of Wilms’s tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med 270:922, 1964. 13. Turleau C, de Grouchy J, Tournade MF, et al.: Del 11p/aniridia complex. Report of three patients and review of 37 observations from the literature. Clin Genet 26:356, 1984. 14. Gillespie FD: Aniridia, cerebellar ataxia, and oligophrenia in siblings. Arch Ophthalmol 73:338, 1965. 15. Nelson J, Flaherty M, Grattan-Smith P: Gillespie syndrome: a report of two further cases. Am J Med Genet 71:134, 1997. 16. Glaser T, Ton CC, Mueller R, et al.: Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation). Genomics 19:145, 1994. 17. Levin H, Ritch R, Barathur R, et al.: Aniridia, congenital glaucoma, and hydrocephalus in a male infant with ring chromosome 6. Am J Med Genet 25:281, 1986. 18. Walker FA, Dyson C: Dominantly inherited aniridia associated with mental retardation and other eye abnormalities. Birth Defects Orig Artic Ser X(7):147, 1974. 19. Hamming NA, Miller MT, Rabb M: Unusual variant of familial aniridia. J Pediatr Ophthalmol Strabismus 23:195, 1986. 20. Mirkinson AE, Mirkinson NK: A familial syndrome of aniridia and absence of the patella. Birth Defects Orig Artic Ser XI(5):129, 1975.

9.11 Congenital Cataracts Cataracts are opacities of the crystalline lens. They can be congenital or acquired, partial or total, inherited or isolated. Cataracts can occur in otherwise normal eyes or may be seen in microphthalmic or otherwise malformed eyes such as in persistent hyperplastic primary vitreous (PHPV). Congenital cataracts can be classified according to their morphology or to the part or sector of the crystalline lens that they occupy or involve (Table 9-4). A large number of genes have been mapped or cloned that cause inherited congenital or developmental cataracts (Table 9-4). Cataracts are amblyogenic if they occlude the pupillary axis with the pupil in the undilated resting position. In this case surgery is indicated and should be performed as early as the first few weeks of life, and contact lens and amblyopia therapy should be instituted promptly. Infantile and developmental cataracts occur in a number of hereditary patterns and as part of metabolic diseases, malformation syndromes, chromosomal aberrations, or may be secondary to infections or trauma. Table 9-5 gives an etiologic classification of infantile and developmental cataracts. Cataracts may have a number of different morphologic appearances (Table 9-4). The major types are discussed below. Anterior polar cataract is an axial lenticular opacity and varies from 1 to 3.5 mm in size. It may take a pyramidal shape and may be associated with duplicated opacities under the anterior lens capsule. This type of cataract seldom interferes with vision, but

Table 9-4. Inherited cataracts and the responsible genes or gene loci Type of Cataracts

Causation Gene/Locus

Volkmann

(115665) 1p36

Posterior polar or zonular

(116600) 1pter-p36.1

Zonular

(600897) Connexin 50

Nuclear

(607304) 2q12

Nuclear

(123660) CRYG, 2q33-35

Non-nuclear polymorphic

(601286) CRYG1 (123680) CRYGC (123690) CRYGD (603212) BFSP2, 3q21-22

Congenital cataracts

(602669) PITX3, 10q25

Aniridia/cataracts

(607108) PAX6, 11p13

Nuclear

(154050) MIP, 12q13

Zonular

(121015) Connexin 46, 13q11

Anterior polar

(115650) 14q24-qter

Central pouchlike

(605728) 15q21-q22

Zonular

(116800) HSF4, 16q22

Anterior polar

(601202) 17q12-13

Zonular

(600881) CRYBA1, 17q11-12

Cerulean

(115660) 17q24

Hyperferritinemia/cataracts

(600886) FTL, 19q13.3-13.4

Posterior polar

(603307) BFSP1, 20p12-q12

Zonular

(123580) CRYAA, 21q22.3

Cerulean

(123620) CRYBB2, 22q11-12

cases that have progressed to significant opacification have been reported. Anterior polar cataracts may be inherited and are usually found in eyes that are slightly smaller than normal. Nuclear cataract involves the embryonic and fetal nuclear areas of the lens and is usually nonprogressive (Fig. 9-16). Onethird of cases are unilateral and two-thirds are bilateral. Some nuclear cataracts are formed of numerous fine dots between the anterior and posterior ‘‘y’’ sutures, and others are dense enough to be amblyogenic. Some are accompanied by riders in the surrounding

Table 9-5. Etiologic classification of infantile and developmental cataracts INHERITED WITHOUT SYSTEMIC ABNORMALITIES

Craniofacial syndromes

Autosomal dominant

Hallermann-Streiff syndrome (AR-234100)

Autosomal recessive

Crouzon disease (AD-123500)

X-linked

Apert syndrome (AD-101200) Engelmann syndrome (AD-131300)

INHERITED AS PART OF MULTISYSTEM DISORDERS Metabolic disorders

Galactosemia (AR-230400) Galactokinase deficiency (AR-230200) Fabry disease (XLR-301500) Mannosidosis (AR-248500) Refsum disease (AR-266500) Wilson disease (AR-277900)

Lanzieri syndrome Rubinstein-Taybi syndrome (uncertain-268600) Ellis-van Creveld syndrome (AR-225500) Smith-Lemli-Opitz syndrome (AR-214150) Cerebro-oculo-facio-skeletal syndrome (AR-214150) Nance-Horan syndrome (XLR-302350)

Diabetes mellitus Hypocalcemia Hypoglycemia Multiple sulfatase deficiency (AR-272200) Renal diseases

Lowe disease (XLR-309000) Alport syndrome (AD-301050)

ASSOCIATED WITH CHROMOSOMAL ABNORMALITIES

Trisomy 21 Trisomy 13 Trisomy 18 Deletion 5p Deletion 11p

Musculoskeletal disorders

Chondrodysplasia punctata (AD-118650, AR-215100, XLD-302960) Myotonic dystrophy (AD-160900)

Ring 4 10qþ

Marfan syndrome (AD-154700)

ASSOCIATED WITH OCULAR DISEASE

Osteopetrosis (AR-259700)

Leber congenital amaurosis

Weill-Marchesani syndrome (AR-277600)

Aniridia

Stickler syndrome (AD-108300)

Retinitis pigmentosa

Kniest syndrome (AD-156550)

Persistent hyperplastic primary vitreous

Osteogenesis imperfecta (heterogeneous, AR-259410)

Peters anomaly

Albright hereditary osteodystrophy (AD-103580, XLD-300800)

INTRAUTERINE INFECTION

Central nervous system syndrome

Rubella

Zellweger syndrome (AR-214100)

Varicella

Meckel-Gruber syndrome (AR-249000)

Toxoplasmosis

Sjogren-Larsson syndrome (AR-270200)

UVEITIS OR ACQUIRED INFECTION

Marinesco-Sjogren syndrome (AR-248800) Norrie disease (XLR-310600)

Juvenile rheumatoid arthritis Pars planitis

Dermatologic diseases

Toxocara canis

Cockayne syndrome (AR-216400) Goltz syndrome (XL-305600)

DRUG-INDUCED

Rothmund-Thompson syndrome (AR-268400)

Corticosteroids

Atopic dermatitis

Others

Incontinentia pigmenti (XL-308300) Progeria (AD-176670) Werner syndrome (AR-277700)

TRAUMA RADIATION EXPOSURE

Ichthyosis (Heterogeneous) Marshall ectodermal dysplasia

317

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Craniofacial Structures

cortex like rings around the planet Saturn. In unilateral cases, the eye is conspicuously smaller than normal, with a normal-appearing posterior segment. Lamellar or zonular cataracts are formed of opacified shells of cortex around a clear nucleus and are surrounded by normal cortex with or without riders. Most cases are bilateral and inherited in an autosomal dominant fashion, as are most other cataracts. Such cataracts may go unnoticed for years until the pupil is pharmacologically dilated and the opacity appears. They can be misdiagnosed as microspherophakia (small round lens) because one may think that the opacified cortex is the edge of the lens. These cataracts may progress to become total, necessitating surgery in the 1st or 2nd decade of life. Because of the relative clarity of the lens early in life, visual prognosis is excellent following surgery for lamellar cataracts. Posterior lentiglobus is the most common type of unilateral cataract in normal-sized eyes. In these cases, of which more than 90% are unilateral, there is a circumscribed round or oval posterior bowing of the posterior lens capsule, measuring 1 to 5 mm, usually in the area where the hyaloid system of blood vessels originally met with the tunica vasculosa lentis. The cortical lamellae that occupy the bulging part of the lens become progressively disorganized and opaque, possibly because of fluid imbibition through ruptures in the weakened capsule. Some cases have been observed to progress extremely rapidly to total opacification, possibly secondary to blowout of the lentiglobus into the vitreous cavity. If posterior lentiglobus is eccentric and small, it is best observed until progression to a significant opacity involving the

Fig. 9-16. Nuclear cataract.

central visual axis occurs. The presence of central and large defects may be an indication for surgery if associated with high myopic errors of refraction or significant opacification. 9.12 Persistent Hyperplastic Primary Vitreous or Persistence of the Fetal Vasculature Definition

Persistent hyperplastic primary vitreous (PHPV) or persistence of the fetal vasculature (PFV) is a complex malformation of the eye characterized by the presence of remnants of the hyaloid system of blood vessels along with a plaque of fibrovascular tissue behind the lens. PHPV, also referred to as PFV,1 affects the vitreous primarily but also involves the retina, ciliary body, iris, and lens. Elongated ciliary processes converge to and are pulled toward the retrolental fibrovascular tissue. The eye is variably reduced in size, and a cataract may be present. Anterior and posterior varieties of PHPV have been described. Both appear to be on the same continuum of malformations. Congenital falciform fold of the retina may be a manifestation of a posterior form of PHPV but may also be seen in dominant exudative vitreoretinopathy, toxocara canis infection of the eye, and retinal dysplasia such as is seen in the Warburg-Walker syndrome and Norrie disease.1 Diagnosis

PHPV is unilateral in about 90% of cases. The size of the globe varies from normal to moderately decreased, being slightly smaller than normal in the majority of cases (Fig. 9-17). The cornea is clear. The anterior chamber is shallow in smaller eyes because of anterior displacement of the iris/lens diaphragm; this predisposes patients with PHPV to angle-closure glaucoma, which usually develops later in adulthood. Some authors advocate lens extraction to prevent secondary angle-closure glaucoma. The iris may be normal but frequently shows small notches at the pupillary margins, where iridohyaloidal vessels coursed in the developing eye and failed to regress with maturation of iris structures and resorption of the tunica vasculosa lentis. Patent iridohyaloidal vessels may be seen coursing over the anterior iris surface, over the pupillary margin, and over the posterior iris surface to anastomose with vessels in the retrolental membrane. It is thought that such iridohyaloidal vessels are extremely suggestive of PHPV; their presence in a small eye with a white pupillary reflex is diagnostic of this condition.1 The lens may be completely clear or may be cataractous. The fibrovascular plaque may adhere to the posterior lens capsule, and vessels can invade the lens, giving a clinical picture very characteristic of PHPV. The retrolental membrane may contain adipose tissue, cartilage, and smooth muscle tissue. This is thought to be the result of metaplastic changes in tissue of mesenchymal origin. Haddad et al. reported on the clinicopathologic findings in 62 cases of PHPV. The cases were divided into two main groups. Group 1 consisted of 55 unilateral cases not associated with any systemic abnormalities, including 36 eyes (58%) that were considered ‘‘pure cases’’ (Group 1A) and 19 (31%) that disclosed other ocular abnormalities in addition to PHPV (Group 1B). Group 2 consisted of seven (11%) bilateral cases of PHPV accompanied by other ocular and systemic malformations. The most common presenting clinical signs were leukocoria, microphthalmia, and cataract. The main histopathologic features of this condition were outlined, including those responsible for the disastrous results to

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Fig 9-17. Microcornea and microphthalmia in a patient with persistent hyperplastic primary vitreous (PHPV).

the eye (retinal detachment, glaucoma, phthisis bulbi). Several clinical entities were usually mistaken for or associated with PHPV, such as retinoblastoma, congenital cataract, retinal dysplasia, trisomy 13 syndrome, and falciform retinal folds.2 Patients with PHPV present with one of three findings: (1) a small eye since birth, (2) a white pupillary reflex because of the associated cataract or retrolental membrane, or (3) strabismus because of poor vision. Ultrasonography and computed tomography are helpful in the differentiation between PHPV and retinoblastoma in eyes with leukocoria. There is no intraocular calcification in PHPV, and the retrolental mass and/or retinal detachment can be visualized by ultrasonography and by computed tomography with contrast enhancement.3 Retinoblastoma generally occurs in eyes of normal size but has been reported in microphthalmic eyes. Additionally, PHPV and retinoblastoma have rarely coexisted in a microphthalmic eye.4

and appropriate aphakic correction and amblyopia therapy should be instituted. Early surgery may result in relatively good visual results in selected patients.9–11 If the pathology is localized to the anterior segment of the eye, the lens and retrolental membrane are removed through a limbal approach. If significant midvitreal or posterior vitreal components to the PHPV are present, then a combined lensectomy-vitrectomy using a pars-plana surgical approach may be considered.12 Lensectomy probably prevents the development of secondary angle closure glaucoma, which is a source of visual loss and discomfort in these patients with limited visual capabilities and potential. Tractional and rhegmatogenous retinal detachments have been reported in patients with PHPV and are treated surgically as needed. Myopia seems to predict a better visual outcome in patients with PHPV.13 Very rarely, the anterior or posterior lens capsule ruptures in PHPV, and an inflammatory ocular response may be induced.

Etiology and Distribution

References (Persistent Hyperplastic Primary Vitreous)

The incidence of PHPV is unknown, but it is not a very rare condition. PHPV is generally isolated and unilateral without associated congenital malformations. It has, however, been reported in two patients with oculo-dento-osseous dysplasia,5 in one patient with protein C deficiency,6 and in the oculo-palato-cerebral syndrome.7 There is also one report of a family with Rieger anomaly and PHPV in two generations.8 PHPV may be due to a defect in the formation of the secondary vitreous, which is derived from the inner retinal cells starting in the 9th week of gestation. The secondary vitreous fills the developing fetal eye starting from the ocular wall region and progressing centrally. It compresses the regressing primary vitreous, which is probably derived from mesenchyme and contains the hyaloid system of blood vessels that anastomose with the tunica vasculosa lentis anteriorly. A defect in the formation of the secondary vitreous or in the regression of the primary vitreous and of the tunica vasculosa lentis, or a combination of both, may lead to the clinical picture of PHPV. The globe remains small because its growth depends partly on the expansion of the secondary vitreous. Precipitating factors and etiologic agents leading to PHPV have not been identified yet. Familial occurrences of PHPV have been reported in dizygotic twins, in two brothers, and in a mother and son. Prognosis, Prevention, and Treatment

Visual prognosis in eyes with PHPV is generally guarded. Associated cataracts should be extracted in the first few weeks of life,

1. Goldberg MF: Persistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol 124:587, 1997. 2. Haddad R, Font RL, Reeser F: Persistent hyperplastic primary vitreous. A clinicopathologic study of 62 cases and review of the literature. Surv Ophthalmol 23:123, 1978. 3. Mafee MF, Goldberg MF: Persistent hyperplastic primary vitreous (PHPV): role of computed tomography and magnetic resonance. Radiol Clin North Am 25:683, 1987. 4. Irvine AR, Albert DM, Sang DN: Retinal neoplasia and dysplasia. II. Retinoblastoma occurring with persistence and hyperplasia of the primary vitreous. Invest Ophthalmol Vis Sci 16:403, 1977. 5. Traboulsi EI, Faris BM, Der Kaloustian VM: Persistent hyperplastic primary vitreous and recessive oculo-dento-osseous dysplasia. Am J Med Genet 24:95, 1986. 6. Hermsen VM, Conahan JB, Koops BL, et al.: Persistent hyperplastic primary vitreous associated with protein C deficiency. Am J Ophthalmol 109:608, 1990. 7. Frydman M, Weinstock AL, Cohen HA, et al.: Autosomal recessive Peters anomaly, typical facial appearance, failure to thrive, hydrocephalus, and other anomalies: further delineation of the Krause-Kivlin syndrome. Am J Med Genet 40:34, 1991. 8. Storimans CW, Van Schooneveld MJ: Rieger’s eye anomaly and persistent hyperplastic primary vitreous. Ophthalmic Paediatr Genet 10:257, 1989. 9. Anteby I, Cohen E, Karshai I, et al.: Unilateral persistent hyperplastic primary vitreous: course and outcome. J AAPOS 6:92, 2002. 10. Stark WJ, Fagadau W, Lindsey PS, et al.: Management of persistent hyperplastic primary vitreous. Aust J Ophthalmol 11:195, 1983.

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Craniofacial Structures

11. Pollard ZF: Persistent hyperplastic primary vitreous: diagnosis, treatment and results. Trans Am Ophthalmol Soc 95:487, 1997. 12. Dass AB, Trese MT: Surgical results of persistent hyperplastic primary vitreous. Ophthalmology 106:280, 1999. 13. Cheung JC, Summers CG, Young TL: Myopia predicts better outcome in persistent hyperplastic primary vitreous. J Pediatr Ophthalmol Strabismus 34:170, 1997.

9.13 Optic Nerve Hypoplasia Definition

Optic nerve hypoplasia is a nonprogressive, segmental, or diffuse congenital abnormality of one or both optic nerves characterized by a decreased number of axons in the involved nerve, which otherwise has normal glial and supportive mesodermal tissue.1,2 Diagnosis

Optic nerve hypoplasia should be suspected in infants with poor vision and nystagmus, especially those with other neurologic deficits; in older individuals with long-standing, nonprogressive visual impairment of unclear etiology; and in patients with midfacial abnormalities. Males are affected as frequently as females, and bilateral disease is more common than unilateral disease.3,4 Patients with unilateral or asymmetric disease may present with strabismus. Patients with bilateral severe disease usually present with poor vision and nystagmus. Visual acuity may be normal in the presence of visual field defects and mild disease. There is a subset of patients with segmental or sectorial optic nerve hypoplasia.5 In such patients, sometimes born to diabetic mothers,6–9 the superior half of the disc is usually missing, hence the name ‘‘topless’’ optic nerve. Ophthalmoscopically, the nerve head is reduced in size because of the decreased number of axons. There may or may not be a surrounding hypopigmented halo, the so-called double ring sign. The double ring sign indicates that a small optic nerve is present in a wider scleral canal.1 The degree of optic nerve hypoplasia is extremely variable and tends to be more severe in bilateral cases. Mild cases are difficult to diagnose because of problems in measuring optic nerve head diameter and because of the variability in appearance of the optic nerve head in different racial groups and with different degrees of myopia or hyperopia. In cases in which a mild degree of hypoplasia is suspected, fundus photographs can be obtained, and absolute measurements or measurements relative to retinal arterial vessel diameter or to other retinal landmarks such as the distance from the center of the disc to the fovea are made to confirm the diagnosis. Retinal vascular tortuosity is often present, and blunting of the macular and foveal reflexes is due to a decrease in the number of nerve fibers. A variety of visual field defects may be present in patients with optic nerve hypoplasia, depending on the severity of nerve fiber loss. Bitemporal visual field defects and generalized constriction are most commonly seen in severe hypoplasia, whereas inferior altitudinal field defects that spare fixation predominate in segmental hypoplasia.8 Bitemporal field defects may indicate the presence of midline defects in the central nervous system.4,10 Optic nerve hypoplasia should be differentiated from the crowded disc in high hypermetropia; hence, refraction should always be performed. Myopic and astigmatic errors are more often present in patients with ONH than pure hypermetropic errors.11

Also, hypoplastic discs have been incorrectly diagnosed as atrophic discs because of the surrounding pallor of the lamina cribrosa; the nerve tissue itself, however, is pink but smaller than normal. The electroretinogram and electrooculogram are normal and differentiate optic nerve hypoplasia from Leber congenital amaurosis.12 Visual evoked responses are usually reduced in amplitude and correlate with the degree of visual acuity loss. Color vision has not been systematically assessed in patients with optic nerve hypoplasia. Histopathologically, the ganglion cells and optic nerve fibers are reduced in number, but the outer retinal layers are normal. The double ring sign appears to be due to an overgrowth of retinal pigment epithelial cells toward the center of the optic disc.1 The ocular and systemic conditions associated with optic nerve hypoplasia are listed in Table 9-6. Of most interest and significance is the association of optic nerve hypoplasia with structural midline brain abnormalities. Optic nerve hypoplasia is seen in 25% of patients with absence of the septum pellucidum, and 27% of patients with optic nerve hypoplasia have partial or complete absence of the septum pellucidum.4 Septo-optic dysplasia (de Morsier syndrome) is characterized by variable degrees of optic nerve hypoplasia and absence of the septum pellucidum or corpus callosum, mental retardation, spasticity, and impairment of taste and smell13 (Fig. 9-18). Patients with septo-optic dysplasia also have problems learning tasks that require spatial orientation. Pituitary dysfunction and endocrinologic abnormalities may result from hypothalamic maldevelopment.14–16 Hypothyroidism is the most common endocrinologic abnormality in patients with septo-optic dysplasia. Growth hormone deficiency and growth retardation usually become evident in the 3rd or 4th year of life. Diabetes insipidus may also be present. Pituitary dysfunction in patients with septo-optic dysplasia may present as prolonged neonatal hyperbilirubinemia, hypotonia, or infantile hypoglycemia without hyperinsulinemia. In a study of 55 children with optic nerve hypoplasia who underwent magnetic resonance imaging (MRI) of the brain and evaluation of the hypothalamic-pituitary (H-P) axis, 49% of patients had an abnormal septum pellucidum on MRI, and 64% had an H-P axis abnormality. Twenty-seven patients (49%) had endocrine dysfunction, and 23 of these had H-P axis abnormality. The frequency of endocrinopathy was higher in patients with an abnormal septum pellucidum (SP) (56%) than a normal SP (39%). Patients were divided into four groups based on SP and H-P axis appearance: (1) both normal; (2) abnormal SP and normal H-P axis; (3) normal SP and abnormal H-P axis; and (4) both abnormal. The frequency of multiple pituitary hormone deficiency was highest (56%) in Group 4, lower (35%) in Group 3, and even lower (22%) in Group 2. Precocious puberty was most common in Group 2. None of the patients in Group 1 had endocrine dysfunction. Thus, SP and H-P axis appearances on MRI can be used to predict the likely spectrum of endocrinopathy.17 Phillips et al. studied 26 children with optic nerve hypoplasia and pituitary hormone deficiency to determine whether structural abnormalities of the neurohypophysis, as detected by MRI, can be used to diagnose hypopituitarism in children with optic nerve hypoplasia. MRI disclosed posterior pituitary ectopia in 16 of these cases, absence of the pituitary infundibulum and posterior pituitary bright spot in seven, and a normal neurohypophysis in three. Fortyone children with optic nerve hypoplasia and normal endocrinologic function had a normal neurohypophysis. These authors concluded that MRI of the neurohypophysis can predict when congenital hypopituitarism will be associated with optic nerve hypoplasia.18

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Table 9-6. Ocular and systemic conditions associated with optic nerve hypoplasia Syndrome

Prominent somatic features

Causation

Aniridia

None

AD (106200)

Albinism

Absence of skin and hair pigmentation

Heterogeneous

High myopia

None

Unknown

Microphthalmia-uveal coloboma

None

AD (156850)

Aicardi

Infantile spasms, chorioretinal lacunae, retardation

XLD (304050)

Potter

Renal agenesis, pulmonary hypoplasia, oligohydramnios

Unknown

Klippel-Trenaunay-Weber

Asymmetric limb hypertrophy, hemangiomas

Unknown

Facio-auriculo-vertebral spectrum

First and second branchial arch defects

Unknown

Duane retraction

None

Unknown

Meckel

Encephalocele, polydactyly, cystic dysplasia of kidneys, genitourinary abnormalities

AR (249000)

Blepharophimosis

Short palpebral fissures, ptosis, epicanthus inversus, hypogonadism in females

AD (110100)

Chondrodysplasia punctata

Flat facies with low nasal bridge, asymmetric limb shortening, scoliosis, punctate mineralization of epiphyses, follicular atrophoderma

Heterogeneous XLD (302960) AD (118650) AR (215100)

Osteogenesis imperfecta

Fragile bone, blue sclera, joint hyperextensibility, odontogenesis imperfecta

Heterogeneous AR (259410)

13q-

Microcephaly with high nasal bridge, microphthalmia, retinoblastoma, thumb hypoplasia, cardiac defects, genitourinary defects

Chromosomal

Trisomy 18

Prominent occiput, malformed ears, micrognathia, short sternum, cardiac defects, horseshoe kidney, overlapping fingers, intrauterine growth retardation, severe developmental retardation

Chromosomal

Nevus sebaceus of Jadassohn

Midfacial nevus sebaceus, seizures, retardation

Unknown

Midline facial defects

None

Unknown

Etiology and Distribution

Failure of differentiation of the retinal ganglion cell layer between embryonic stages 17 and 19 (12–17 mm in size) has been proposed to explain optic nerve hypoplasia. This necessitates that the ganglion cells be affected selectively, since other cells from the inner neuroblastic retinal layer are normal. This theory also does not account for the associated brain anomalies. Another theory suggests that inadequate target organs, such as in anencephaly or other brain defects associated with optic nerve hypoplasia, prevent the development of ascending pathways such as the optic nerve. Finally, excessive death (apoptosis) of ganglion cells following their overdevelopment may be a plausible pathogenetic mechanism in optic nerve hypoplasia. Possible etiologic factors for the development of optic nerve hypoplasia include maternal diabetes mellitus,19 postmaturity,20 young maternal age,21 and first-born children. Gestational intake of anticonvulsants, quinine, lysergic acid diethylamide, and phencyclidine has been associated with optic nerve hypoplasia. Nearly one-half of patients with fetal alcohol syndrome have optic nerve hypoplasia, and 12.5% of mothers of children with optic nerve hypoplasia admit to alcohol abuse during pregnancy.22 Autosomal dominant inheritance of optic nerve hypoplasia has been reported in five members of one family and in at least one mother-daughter pair.23 Mutations in HESX124–27 and rarely of PAX628 have been associated with optic nerve hypoplasia, and in the former with septo-optic dysplasia. Two patients with partial trisomy 10q24-ter

and optic nerve aplasia have also been reported, indicating the presence of a gene for optic nerve development in that chromosomal region.29 Prognosis, Prevention, and Treatment

Patients with bilateral or unilateral optic nerve hypoplasia should undergo neuroradiologic evaluation for associated brain, pituitary, or other midline cerebral defects. MRI rather than a computed tomography scan should be obtained. Patients with unilateral optic nerve hypoplasia and strabismus should undergo a trial of occlusion therapy for any superimposed amblyopia. Optic nerve hypoplasia is compatible with good visual acuity if the maculopapillary bundle is spared.30 Children with bilateral optic nerve hypoplasia should undergo routine endocrinologic evaluation early in life and periodically thereafter, especially in the presence of suggestive symptomatology. Endocrinologic abnormalities are treated as needed. References (Optic Nerve Hypoplasia) 1. Hotchkiss ML, Green WR: Optic nerve aplasia and hypoplasia. J Pediatr Ophthalmol Strabismus 16:225, 1979. 2. Lambert SR, Hoyt CS, Narahara MH: Optic nerve hypoplasia. Surv Ophthalmol 32:1, 1987. 3. Margalith D, Jan JE, McCormick AQ, et al.: Clinical spectrum of congenital optic nerve hypoplasia: review of 51 patients. Dev Med Child Neurol 26:311, 1984. 4. Acers TE: Optic nerve hypoplasia: septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc 79:425, 1981.

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Craniofacial Structures

Fig. 9-18. Septo-optic dysplasia. Top: optic nerve is hypoplastic and shows the ‘‘double ring sign.’’ Bottom: sagittal brain image shows thinning of the corpus collosum with defects in septum pellucidum. 5. Hoyt CS, Billson FA: Optic nerve hypoplasia: changing perspectives. Aust N Z J Ophthalmol 14:325, 1986. 6. Kim RY, Hoyt WF, Lessell S, et al.: Superior segmental optic hypoplasia. A sign of maternal diabetes. Arch Ophthalmol 107:1312, 1989. 7. Landau K, Bajka JD, Kirchschlager BM: Topless optic disks in children of mothers with type I diabetes mellitus. Am J Ophthalmol 125:605, 1998. 8. Petersen RA, Walton DS: Optic nerve hypoplasia with good visual acuity and visual field defects: a study of children of diabetic mothers. Arch Ophthalmol 95:254, 1977. 9. Hashimoto M, Ohtsuka K, Nakagawa T, et al.: Topless optic disk syndrome without maternal diabetes mellitus. Am J Ophthalmol 128:111, 1999. 10. Rush JA, Bajandas FJ: Septo-optic dysplasia (de Morsier syndrome). Am J Ophthalmol 86:202, 1978.

11. Zeki SM: Optic nerve hypoplasia and astigmatism: a new association. Br J Ophthalmol 74:297, 1990. 12. Sprague JB, Wilson WB: Electrophysiologic findings in bilateral optic nerve hypoplasia. Arch Ophthalmol 99:1028, 1981. 13. De Morsier G: Agenesis du septum lucidum avec malformation du tractus optique. Schweiz Arch Neurol Psychiatry 77:267, 1956. 14. Morishima A, Aranoff GS: Syndrome of septo-optic-pituitary dysplasia: the clinical spectrum. Brain Dev 8:233, 1986. 15. Wilson PW, Easley RB, Bolander FF, et al.: Evidence for a hypothalamic defect in septo-optic dysplasia. Arch Intern Med 138:1276, 1978. 16. Brodsky MC, Phillips PH: Optic nerve hypoplasia and congenital hypopituitarism. J Pediatr 136:850, 2000. 17. Birkebaek NH, Patel L, Wright NB, et al.: Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab 88:5281, 2003. 18. Phillips PH, Spear C, Brodsky MC: Magnetic resonance diagnosis of congenital hypopituitarism in children with optic nerve hypoplasia. J AAPOS 5:275, 2001. 19. Nelson M, Lessell S, Sadun AA: Optic nerve hypoplasia and maternal diabetes mellitus. Arch Neurol 43:20, 1986. 20. Jan JE, Robinson GC, Kinnis C, et al.: Blindness due to optic-nerve atrophy and hypoplasia in children: an epidemiological study (1944– 1974). Dev Med Child Neurol 19:353, 1977. 21. Lippe B, Kaplan SA, LaFranchi S: Septo-optic dysplasia and maternal age. Lancet 2:92, 1979. 22. Stromland K, Pinazo-Duran MD: Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies. Alcohol 37:2, 2002. 23. Skarf B, Hoyt CS: Optic nerve hypoplasia in children. Association with anomalies of the endocrine and CNS. Arch Ophthalmol 102:62, 1984. 24. Carvalho LR, Woods KS, Mendonca BB, et al.: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 112:1192, 2003. 25. Dattani MT, Martinez-Barbera JP, Thomas PQ, et al.: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125, 1998. 26. Tajima T, Hattorri T, Nakajima T, et al.: Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 88:45, 2003. 27. Thomas PQ, Dattani MT, Brickman JM, et al.: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 10:39, 2001. 28. Azuma N, Yamaguchi Y, Handa H, et al.: Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet 72:1565, 2003. 29. Pfeiffer RA, Junemann A, Lorenz B, et al.: Aplasia of the optic nerve in two cases of partial trisomy 10q24-ter. Clin Genet 48:183, 1995. 30. Bjork A, Laurell CG, Laurell U: Bilateral optic nerve hypoplasia with normal visual acuity. Am J Ophthalmol 86:524, 1978.

9.14 Morning Glory Disc Anomaly Definition

The morning glory disc anomaly (MGDA) is an enlarged and excavated optic nerve head, with white glial tissue at its center and a raised annulus of pigmentary chorioretinal changes at its edge.1–3 Diagnosis

The appearance of the nerve head is variable in MGDA, and various degrees of dysplasia may be present. The appearance also depends on the size of the posterior scleral opening, the vascular

Eye

pattern, the amount of gliosis and remnants of the hyaloid system at the center of the disc, and the degree of pigmentation at the edge of the disc (Fig. 9-19).4 The macula is usually dragged nasally to the edge of the disc, and the yellow macular xanthophyll pigment is frequently noticeable at that location. The retinal arterioles and venules emerge in a radial pattern from the enlarged scleral canal and are frequently bridged by vascular arcades close to the optic nerve head.5 Other straight arterioarterial bridging vessels can be seen more peripherally. The majority of cases of MGDA are unilateral with equal involvement of the left and right eyes. Males and females are affected equally. One-half of patients with MGDA present with strabismus. The abnormality is otherwise discovered during routine examination of older children. A large optic nerve head with excessive glial tissue may lead to a

Fig. 9-19. Morning glory disc anomaly. Top: a funnel-shaped excavation at the nerve head with remnants of the hyaloid system at the center of the disc. Bottom: note radiating straight retinal vessels and fibrous tissue in center of disc. The disc diameter is enlarged.

323

white pupillary reflex or leukocoria; hence, MGDA is on the differential list of retinoblastoma and white pupillary reflex. Patients may present with total retinal detachment. Retinal detachment occurs in about 30% of cases.6–8 The detachment is usually nonrhegmatogenous, and its exact etiology is unknown. Communication between the subarachnoid and subretinal spaces with seepage of cerebrospinal fluid under the retina has been postulated as a cause of retinal detachment in MGDA.9,10 There may also be a communication between the vitreous cavity and the subretinal space.11 Spontaneous retinal reattachment has been reported. Rhegmatogenous retinal detachment can also occur.12 Visual impairment is variable in MGDA but is generally substantial, and visual acuity ranges from 20/30 to poor light perception. Poor vision results from retinal and optic nerve dysplasia and hypoplasia but may also be due in part to strabismic or anisometropic amblyopia. Associated ocular anomalies in the same eye include strabismus, retinal detachment, persistence of the hyaloid system, foveal dysplasia, and rarely, pupillary membrane remnants, cataracts, epiretinal membranes, ciliary body cyst, vitreous cyst, microphthalmia, and aniridia.4 Retinal vascular tortuosity, optic pits, microphthalmia, anterior segment dysgenesis, Duane retraction syndrome, and remnants of the pupillary membrane have been reported in the same13 and in the fellow eye. Associated craniofacial abnormalities include hypertelorism, basal encephalocele,14,15 agenesis of the corpus callosum,16 sphenoidal encephalocele,17 and cleft lip and/or palate. Congenital renal abnormalities have also been reported in patients with what has been described as MGDA.18–20 These may have represented cases of the papillorenal syndrome that results from mutations in PAX2.21 This author has noted the MGDA in a boy with preauricular skin tags, patent ductus arteriosus, and unilateral renal agenesis. What has emerged as important associated findings with MGDA are anomalies of the carotid circulation and moyamoya disease.22–27 These progressive vascular malformations can lead to serious central nervous system complications and strokes and are surgically treatable in selected cases. It is of paramount importance to obtain vascular imaging studies such as computed tomography angiography in all patients with MGDA to rule out moyamoya vascular abnormalities. Etiology and Distribution

The morning glory disc anomaly probably results from failure of the posterior sclera and the lamina cribrosa of the optic nerve head to form. This leads to herniation of intraocular contents through the defect and formation of the conical deformity.28 This process interferes with regression of the hyaloid vasculature and derived structures, and remnants of the hyaloid system are hence frequently observed in the center of the malformed optic papilla and sometimes in the vitreous.29,30 It is possible that this process also interferes with closure of the most posterior aspect of the optic fetal fissure leading to a colobomatous component to the MGDA. In some cases it is difficult to distinguish between an optic nerve coloboma resulting from failure of closure of the fetal fissure and MGDA.31,32 Optic pit, MGDA, and peripapillary contractile staphyloma are probably a spectrum of malformations with the same etiology. In peripapillary contractile staphyloma, there probably is myofibroblastic differentiation of some of the mesenchymal tissue at the edge of the disc papilla, leading to contractions that have been observed clinically and recorded by ultrasonography. MGDA is a rare malformation. Many cases are probably misdiagnosed as typical uveal colobomas at the optic disc. Slusher

324

Craniofacial Structures

et al. reported a large kindred in which cavitary optic disc anomalies ranging from optic pits to large, anomalous discs and typical colobomas were inherited in an autosomal dominant fashion.33 The great majority of cases with MGDA or optic pits, however, are isolated, and the recurrence risk in sibs is negligible. Prognosis, Prevention, and Treatment

Visual prognosis is very poor in patients who present with profound visual loss in the affected eye. Careful refraction and treatment of any strabismic or anisometropic amblyopia may result in some regain of vision in rare instances.4 Cryotherapy at the nerve head, scleral buckling, vitrectomy, and retinal tamponade with gas or fluid have been tried for treatment of the retinal detachment that occurs in about 30% of cases; poor visual outcome usually follows, even though retinal reattachment is achieved in some cases.8,10,12,34,35 References (Morning Glory Disc Anomaly) 1. Handman M: Erbliche, vermutlich angeborene zentrale gliose Entartung des Sehnerven mit besonderer Beteiligung der Zentralgefasse. Klin Montasbl Augenheilkd 83:145, 1929. 2. Kindler P: Morning glory syndrome: unusual congenital optic disk anomaly. Am J Ophthalmol 69:376, 1970. 3. Steinkuller PG: The morning glory disk anomaly: case report and literature review. J Pediatr Ophthalmol Strabismus 17:81, 1980. 4. Traboulsi EI, O’Neill JF: The spectrum in the morphology of the socalled ‘‘morning glory disc anomaly.’’ J Pediatr Ophthalmol Strabismus 25:93, 1988. 5. Brodsky MC, Wilson RS: Retinal arteriovenous communications in the morning glory disc anomaly. Arch Ophthalmol 113:410, 1995. 6. Hamada S, Ellsworth RM: Congenital retinal detachment and the optic disk anomaly. Am J Ophthalmol 71:460, 1971. 7. Chang S, Haik BG, Ellsworth RM, et al.: Treatment of total retinal detachment in morning glory syndrome. Am J Ophthalmol 97:596, 1984. 8. Harris MJ, de Bustros S, Michels RG, et al.: Treatment of combined traction-rhegmatogenous retinal detachment in the morning glory syndrome. Retina 4:249, 1984. 9. Irvine AR, Crawford JB, Sullivan JH: The pathogenesis of retinal detachment with morning glory disc and optic pit. Retina 6:146, 1986. 10. Von Fricken MA, Dhungel R: Retinal detachment in the Morning Glory syndrome. Pathogenesis and management. Retina 4:97, 1984. 11. Bartz-Schmidt KU, Heimann K: Pathogenesis of retinal detachment associated with morning glory disc. Int Ophthalmol 19:35, 1995. 12. Ho CL, Wei LC: Rhegmatogenous retinal detachment in morning glory syndrome pathogenesis and treatment. Int Ophthalmol 24:21, 2001. 13. Kawano K, Fujita S: Duane’s retraction syndrome associated with morning glory syndrome. J Pediatr Ophthalmol Strabismus 18:51, 1981. 14. Caprioli J, Lesser RL: Basal encephalocele and morning glory syndrome. Br J Ophthalmol 67:349, 1983. 15. Goldhammer Y, Smith JL: Optic nerve anomalies in basal encephalocele. Arch Ophthalmol 93:115, 1975. 16. Eustis HS, Sanders MR, Zimmerman T: Morning glory syndrome in children. Association with endocrine and central nervous system anomalies. Arch Ophthalmol 112:204, 1994. 17. Koenig SB, Naidich TP, Lissner G: The morning glory syndrome associated with sphenoidal encephalocele. Ophthalmology 89:1368, 1982. 18. Weaver RG, Cashwell LF, Lorentz W, et al.: Optic nerve coloboma associated with renal disease. Am J Med Genet 29:597, 1988. 19. Merlob P, Horev G, Kremer I, et al.: Morning Glory fundus anomaly, coloboma of the optic nerve, porencephaly and hydronephrosis in a newborn infant: MCPH entity. Clin Dysmorphol 4:313, 1995. 20. Torralbo A, Nebro S, Remartinez E, et al.: Morning glory optic disc anomaly associated with chronic renal disease. Nephrol Dial Transplant 10:1762, 1995.

21. Parsa CF, Silva ED, Sundin OH, et al.: Redefining papillorenal syndrome: an underdiagnosed cause of ocular and renal morbidity. Ophthalmology 108:738, 2001. 22. Hanson MR, Price RL, Rothner AD, et al.: Developmental anomalies of the optic disc and carotid circulation. A new association. J Clin Neuroophthalmol 5:3, 1985. 23. Komiyama M, Yasui T, Sakamoto H, et al.: Basal meningoencephalocele, anomaly of optic disc and panhypopituitarism in association with moyamoya disease. Pediatr Neurosurg 33:100, 2000. 24. Krishnan C, Roy A, Traboulsi E: Morning glory disk anomaly, choroidal coloboma, and congenital constrictive malformations of the internal carotid arteries (moyamoya disease). Ophthalmic Genet 21:21, 2000. 25. Bakri SJ, Siker D, Masaryk T, et al.: Ocular malformations, moyamoya disease, and midline cranial defects: a distinct syndrome. Am J Ophthalmol 127:356, 1999. 26. Massaro M, Thorarensen O, Liu GT, et al.: Morning glory disc anomaly and moyamoya vessels. Arch Ophthalmol 116:253, 1998. 27. Taskintuna I, Oz O, Teke MY, et al.: Morning glory syndrome: association with moyamoya disease, midline cranial defects, central nervous system anomalies, and persistent hyaloid artery remnant. Retina 23:400, 2003. 28. Manschot WA: Morning glory syndrome: a histopathological study. Br J Ophthalmol 74:56, 1990. 29. Brown GC, Gonder J, Levin A: Persistence of the primary vitreous in association with the morning glory disc anomaly. J Pediatr Ophthalmol Strabismus 21:5, 1984. 30. Cennamo G, Liguori G, Pezone A, et al.: Morning glory syndrome associated with marked persistent hyperplastic primary vitreous and lens colobomas. Br J Ophthalmol 73:684, 1989. 31. Brodsky MC: Morning glory disc anomaly or optic disc coloboma? Arch Ophthalmol 112:153, 1994. 32. Traboulsi EI: Morning glory disc anomaly or optic disc coloboma? Arch Ophthalmol 112:153, 1994. 33. Slusher MM, Weaver RG Jr, Greven CM, et al.: The spectrum of cavitary optic disc anomalies in a family. Ophthalmology 96:342, 1989. 34. Ridings B, Saracco JB, Escoffier P, et al.: [Treatment of a case of retinal detachment in morning glory syndrome]. J Fr Ophtalmol 11:743, 1988. 35. Matsumoto H, Enaida H, Hisatomi T, et al.: Retinal detachment in morning glory syndrome treated by triamcinolone acetonide-assisted pars plana vitrectomy. Retina 23:569, 2003.

9.15 Optic Pit Definition

Optic pit is an oval, round, triangular, or even slitlike excavation of variable color, depth, and location in the disc substance. Pits may be single or multiple, and the optic nerve head may be normal or increased in size.1–3 Optic pits may be considered as part of a continuum of cavitary malformations of the optic nerve head that includes the different configurations of the morning glory disc anomaly.4 Diagnosis

The diagnosis is made by ophthalmoscopy and may be helped by fluorescein angiography. Pits vary from one-tenth of a disc diameter (0.15 mm) to one-half or more disc diameter in size (Fig. 9-20). They may be white, gray, greenish, or even black and are most often located in the inferotemporal aspect of the disc touching, or distant from, the disc margin. Up to three optic pits have been reported in one disc. Bilateral cases are rare. Serous detachment of the retina in the macular area occurs in more than one-third of patients, usually in the 3rd and 4th decades of life, and is the major cause of visual loss that complicates this congenital malformation that may otherwise go unnoticed.5 The etiology of

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the natural history of optic pits associated with detachment of the macula, Sobol et al. showed that 12 of 15 patients had eventual visual acuity of 20/200 or less.5 The treatment of serous macular detachment from optic pits is difficult. Vitrectomy with gas-fluid exchange has been tried with limited success in reattaching the retina and improving vision.12,13 Laser photocoagulation has been tried in the treatment of both macular detachment and peripapillary neovascularization in this condition.14 There is a macular scleral buckling procedure that consists of fixation of a silastic sponge explant at the posterior pole corresponding to the macula that seems to work well in the majority of patients.15,16 References (Optic Pit)

Fig 9-20. Large central pit of the optic nerve head with tortuosity of retinal vasculature.

the serous detachment is still debated. Lincoff et al. demonstrated that the macular lesion starts as an area of schisis that progresses to a serous macular detachment after the formation of an outer retinal tear.6 Another rare complication is the development of subretinal neovascularization at the disc margin.7 Etiology and Distribution

Gass believes that optic pits are due to anomalous development of the primordial optic nerve papilla and failure of complete resolution of the peripapillary neuroectodermal folds that are part of the normal development of the optic nerve head.8 Other authors have, probably erroneously, attributed the development of pits to failure of closure of the ocular fetal fissure in the region of the nerve head. Although pits and typical chorioretinal colobomas have been reported to coexist, a common etiology for both is highly unlikely. On the other hand, pits have been described in fellow eyes of patients with the morning glory disc anomaly (MGDA);4 and in some members of a family with either pits or optic disc cavitary malformations.9 This author believes that both optic pits and MGDA share a common embryologic etiology. Two families with dominant inheritance of optic pits10,11 and another with cavitary malformations of the optic nerve head have been reported.9 No specific genetic loci have been identified. Prognosis, Prevention, and Treatment

A significant proportion of eyes with optic pits later develop serous macular detachment with loss of visual acuity. In a study of

1. Brown GC, Shields JA, Patty BE, et al.: Congenital pits of the optic nerve head. I. Experimental studies in collie dogs. Arch Ophthalmol 97:1341, 1979. 2. Brown GC, Augsburger JJ: Congenital pits of the optic nerve head and retinochoroidal colobomas. Can J Ophthalmol 15:144, 1980. 3. Brown GC, Shields JA, Goldberg RE: Congenital pits of the optic nerve head. II. Clinical studies in humans. Ophthalmology 87:51, 1980. 4. Traboulsi EI, Jurdi-Nuwayhid F, Torbey NS, et al.: Aniridia, atypical iris defects, optic pit and the morning glory disc anomaly in a family. Ophthalmic Paediatr Genet 7:131, 1986. 5. Sobol WM, Blodi CF, Folk JC, et al.: Long-term visual outcome in patients with optic nerve pit and serous retinal detachment of the macula. Ophthalmology 97:1539, 1990. 6. Lincoff H, Lopez R, Kreissig I, et al.: Retinoschisis associated with optic nerve pits. Arch Ophthalmol 106:61, 1988. 7. Jay WM, Pope J Jr, Riffle JE: Juxtapapillary subretinal neovascularization associated with congenital pit of the optic nerve. Am J Ophthalmol 97:655, 1984. 8. Gass JD: Serous detachment of the macula. Secondary to congenital pit of the optic nervehead. Am J Ophthalmol 67:821, 1969. 9. Slusher MM, Weaver RG Jr, Greven CM, et al.: The spectrum of cavitary optic disc anomalies in a family. Ophthalmology 96:342, 1989. 10. Babel J, Farpour H: [The genetic origin of colobomatous fossae of the optic nerve]. J Genet Hum 16:187, 1967. 11. Stefko ST, Campochiaro P, Wang P, et al.: Dominant inheritance of optic pits. Am J Ophthalmol 124:112, 1997. 12. Schatz H, McDonald HR: Treatment of sensory retinal detachment associated with optic nerve pit or coloboma. Ophthalmology 95:178, 1988. 13. Bartz-Schmidt KU, Heimann K, Esser P: Vitrectomy for macular detachment associated with optic nerve pits. Int Ophthalmol 19:323, 1995. 14. Annesley W, Brown G, Bolling J, et al.: Treatment of retinal detachment with congenital optic pit by krypton laser photocoagulation. Graefes Arch Clin Exp Ophthalmol 225:311, 1987. 15. Georgopoulos GT, Theodossiadis PG, Kollia AC, et al.: Visual field improvement after treatment of optic disk pit maculopathy with the macular buckling procedure. Retina 19:370, 1999. 16. Theodossiadis GP, Theodossiadis PG: The macular buckling technique in the treatment of optic disk pit maculopathy. Semin Ophthalmol 15:108, 2000.

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10 Ear John C. Carey

T

he auditory system is a highly interesting and complex structure. A single integrated anatomic unit serves both hearing and equilibrium. The ear develops as three distinct components: the external ear, the middle ear, and the inner ear. In these introductory comments, the morphogenesis of the three parts of the ear will be summarized in the context of the developmental genes currently known to be vital in ear development. In addition, some of the recently discovered genes, known to be expressed in the inner ear and causative in many syndromic and nonsyndromic forms of deafness in the human, will be tabulated and concisely discussed. This latter set of genetic factors and molecules has amazing homology to the genes causing deafness in the mouse. Moreover, these genes have been identified as a genetic basis of deafness only since 1996. Morphogenesis of the Ear and Crucial Genes

The orchestration of the key events involved in the embryogenesis of the three parts of the ear is remarkable: the embryonic inner ear, eventually going on to form the cochlea and semicircular canals, derives from surface ectoderm and migrates inward. It must connect with the two other distinctive components, the middle ear cavity and the auricle with its meatus, both separate structures and derived from the first and second branchial arch.1,2 The main landmarks that occur in the development of the inner, middle, and outer ear are summarized in Table 10-1. The earliest morphologic evidence of the development of the inner ear occurs at about 22 days as a thickening in the surface ectoderm of both sides of rhombomeres four through six. This is occurring just at the time the neural tube is closing. This thickening, called the otic placode, invaginates and forms the otic vesicle. This placode is a distinct structure and similar to the placodes that form the other sensory organs, the eye and the nose. The signals required to induce the otic placode, the first step in ear development, come from the mesoderm and neural cells. The molecules mediating these events in the mouse and human are still being delineated and are under close investigation. In the chick, FGF-19 is likely the crucial molecule that induces the otic placode. However, what is clear is that in the mouse, Fgfs certainly play a crucial role in otic placode induction, with Fgf-3 from the hindbrain and Fgf-10 from the neural tube adjoining the placode.3,4 The line of evidence that leads to this conclusion comes from knockout experiments in the mouse. Other genes are then required to

maintain differentiation of the placode to the otic vesicle and otocyst. Pax-2, expressed ventromedially, is crucial to the cochlear component of the inner ear, while Nkx-5, expressed dorsolaterally, maintains the semicircular canals. Studies of mice who have knockouts of these two genes show cochlear aplasia and semicircular canal agenesis, respectively.3,4 Other genes expressed in the mouse cochlea in early development are known to be crucial to morphogenesis based on similar types of gene inactivation experiments. These include Six1, Eya1, Bmp4, Tpx1, and Wnt8c.5,6 The integration of these various molecular factors and the morphogenesis of the cochlea and semicircular canals are still being widely investigated. The fact that the fully developed inner ear comprises seven distinct cell types underscores the molecular complexity of its morphogenesis. The middle ear harbors a chain of three ossicles that transmit the vibrations of sound from the environment into the inner ear, where they are then converted to neural impulses. Gene inactivation studies, such as those done in inner ear development, have identified molecular factors needed for the formation of the different components of the middle ear. The signaling molecules, Fgf-8 and endothelin1, likely mediate epithelial-mesenchymal interactions.7 Other genes, including Eya1, Hoxa1, Hoxa2, and Dlx1, are involved in patterning the process of neural crest cells migrating into the region to form the middle ear structures.7 Of note, the tympanic ring (TR), which surrounds the future tympanic membrane, plays a crucial role in directing invagination of the first pharyngeal cleft ectoderm to form the external auditory meatus. Thus, the integration of the connections between the middle ear and the external ear are orchestrated by the TR. The TR needs goosecoid and Prx1 to carry out its pivotal role. Absence of these genes results in an embryo without a TR and, subsequently, the external auditory meatus. This particular malformation, aural atresia, will be discussed in the section on the external ear. Eya1 and Msx1 both are also needed in the middle ear, because gene activation studies of these factors result in significant ossicular chain defects. These two genes are both involved in the causation of human craniofacial syndromes; Eya1 is the causative gene for the brachio-oto-renal syndrome and Msx1 mutations cause dental anomalies. The external ear—the auricle and its connection with the external auditory meatus—develops at approximately 42 days from six proliferations of mesenchyme that occur on both sides of the first pharyngeal cleft. These hillocks arise from the first and second 327

328

Craniofacial Structures Table 10-1. Key landmarks in the development of the ear Time from Conception

Landmarks

21 days

Otic placode invaginates and migrates inward to form the otic vesicle. The vesicle differentiates into three components: the dorsal endolymphatic duct, the expanded central utricle, and the ventral saccule.

28–50 days

The central utricle differentiates to form the three semicircular canals and the ventral saccule increases in size and coils to form the cochlea. These derivatives constitute the membranous labyrinth. The VIII nerve also forms from the otic placode tissue.

9–23 weeks

Condensation of mesenchyme around the membranous labyrinth chondrifies and then ossifies to form the bony labyrinth.

5–8 weeks

The first pharyngeal pouch lengthens and forms the tubotympanic recess, which eventually develops into the tympanic cavity of the middle ear and the eustachian tube. The cartilages of the surrounding first and second pharyngeal arch give rise to the malleus, incus, and stapes. The mandibular process of the first branchial arch is the origin of the malleus, while the cartilage from the maxillary portion of the first branchial arch gives rise to the incus. The stapes derives from cartilage of the second branchial arch. The tympanic ring induces the ectoderm of the first pharyngeal cleft to form the external meatus.

6–8 weeks

The auricle develops from six hillocks, which appear on the adjoining edges of the first and second branchial arch. The cleft in between connects with the external auditory canal from the tympanic ring. The tympanic membrane arises from the tissue that separates the first pharyngeal pouch and the first pharyngeal cleft.

Adapted from Larsen1 and Sadler.2

branchial arch. They proceed to form the auricle and connect with the external auditory meatus, as described above. From knockout experiments, Hoxa1, Hoxa2, and retinoic acid receptors all play a role in external ear morphogenesis.1 As indicated, the processes must be integrated in time and place. The final anatomic unit includes the auricle and its meatus connected to the tympanic membrane (the tympanic ring embeds itself into the temporal bone of the osseous labyrinth), which connects to the three ossicles. This leads to the oval window, which opens into the vestibulocochlear apparatus. Mouse Models for Human Deafness

The sections on the inner ear will discuss the malformations of the vestibular and cochlear organs. Currently, there is an impressive collection of mouse mutants with disorders of hearing and equilibrium that provide models for the study of these genes and

their disordered functional outcome, deafness.8,9 Tables 10-2 and 10-3 summarize a selected group of human deafness conditions, nonsyndromic and syndromic, and tabulates the mouse homologous disorder. The selected group includes many of the conditions that will be discussed in the sections on the inner ear (10.31 and 10.32). Currently, over 80 loci for human deafness have been mapped and over 30 genes for nonsyndromic deafness have been identified, most since 1996. Study of the mouse allows detailed knowledge of the expression of these genes, the interaction of their proteins, and potential clues into pathogenesis. The proteins comprise transcription factors, signaling molecules, signal transduction proteins, and extracellular matrix proteins. One group of proteins that is known to be associated with human deafness is the myosins; three of the myosins have been discovered as causative of human conditions, owing to their corresponding mouse mutants.

Table 10-2. Human nonsyndromic deafness genes and selected corresponding mouse genes and mutations Human Disorder

Human Gene/Locus

Mouse Gene/Locus

Mouse Mutation

DFNB12 (also USH1D)

CDH23, 10q21-q22

Cdh23, 10

Waltzer

DFNA13 (also STL2)

COL11A2, 6p21

Col11a2, 17

Targeted null

DFNA1

DIAPH1, 5q31

Diap1, 18

None

DFNA10

EYA4, 6q23

Eya4, 10

None

DFNA3, DFNB1

GJB2 (CX26), 13q11-q12

Gjb2, 14

Targeted, conditional null Targeted null

DFNA3, DFNB1

GJB6 (CX30), 13q12

Gjb6, 14

DFNA48

MYO1A, 12q13-q14

Myo1a, 10

None

DFNB3

MYO15, 17p11

Myo15, 11

Shaker 2, sh2

DFNA22, DFNB37

MYO6, 6q13

Myo6, 9

Snell’s waltzer, sv

DFNB2, DFNA11 (also USH1B)

MYO7A, 11q13

Myo7a, 7

Shaker 1, sh1

DFN3

POU3F4, Xq21.1

Pou3f4 (Brn4), X

Targeted null; sexlinked fidget, slf

DFNA8/DFNA12/DFNB21

TECTA, 11q22-q24

Tecta, 9

Targeted null

From Jackson Laboratory.11

Ear

329

Table 10-3. Human syndromic deafness genes and corresponding mouse genes and mutations Human Disorder

Human Gene/Locus

Mouse Gene/Locus

Mouse Mutation

USH1D, Usher, type ID (also DFNB12)

CDH23, 10q21-q22

Cdh23, 10

Waltzer, v

USH1B, Usher, type IB (also DFNB2, DFNA11)

MYO7A, 11q13

Myo7a, 7

Shaker 1, sh1

STL3, Stickler, type III

COL11A1, 1p21

Col11a1, 3

Chondro-dysplasia, cho

Alport

COL4A3, 2q36-q37

Col4a3, 1

Targeted null

WS4, Waardenburg-Shah

EDN3, 20q13

Edn3, 2

Lethal spotting, ls

BOR, branchio-oto-renal

EYA1, 8q13

Eya1, 1

Spontaneous—Eya1bor and targeted null

JLNS2, Jervell and Lange-Nielsen, locus 2

KCNE1 (ISK), 21q22

Kcne1 , 16

Targeted null

JLNS1, Jervell and Lange-Nielsen, locus 1

KCNQ1 (KVLQT1), 11p15

Kcnq1, 7

Targeted null

Renal-coloboma

PAX 2, 10q24-q25

Pax2 , 19

Targeted null

WS1, Waardenburg type I WS3, Klein-Waardenburg

PAX3, 2q37

Pax3, 1

Splotch, Sp

WS2A, Waardenburg, type IIA

MITF, 3p14-p12

Mitf, 6

Microphthalmia, mi

PDS, Pendred (also DFNB4)

SLC26A4, 7q31

Slc26a4 12

Targeted null

DGS, DiGeorge anomaly

TBX1, 22q11

Tbx1, 16

Transgene overexpression targeted null

From Jackson Laboratory.11

Myosins are molecules that move along actin filaments. They are known to be involved in various cell functions, such as movement and signal transduction. Understanding their role could provide insight into human deafness and, perhaps, creative strategies for prevention or even treatment. As summarized by Steel and Kros in their seminal paper in 2001,10 the expression patterns in the stereocilia of the hair cells and in the organ of Corti of the cochlea has allowed for the depiction of the array of genes involved in the auditory mechanism. The web page for the hereditary hearing impairment in mice from the Jackson Laboratory11 and the hereditary hearing loss home page at the University of Iowa12 are both valuable resources and provide current listings of the identified genes and loci involved in mouse mutants and human deafness, respectively. References 1. Larsen WJ: Development of the ears. In: Human Embryology, ed 3. Churchill Livingstone, New York, 2001. 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams & Wilkins, Philadelphia, 2004.

3. Pauley S, Wright TJ, Pirvola U, et al.: Expression and function of FGF-10 in mammalian inner ear development. Dev Dyn 227:203, 2003. 4. Wright TJ, Mansour SJ: FGF-3 and FGF-10 are required for mouse otic placode induction. Development 130:3339, 2003. 5. Zheng W, Huang L, Wei ZB, et al.: The role of SIX1 in mammalian auditory system development. Development 130:3989, 2003. 6. Vitelli F, Viola A, Morshima M, et al.: TBX1 is required for inner ear morphogenesis. Hum Mol Genet 12:2041, 2003. 7. Mallo M: Formation of the middle ear: recent progress in development and molecular mechanisms. Dev Biol 231:410, 2001. 8. Ahituv N, Avraham KB: Mouse models for human deafness: current tools for new fashions. Trends Mol Med 8:447, 2002. 9. Avraham KB: Mouse models for deafness: lessons for the human inner ear and hearing loss. Ear Hear 24:332, 2003. 10. Steel KP, Kros CJ: A genetic approach to understanding auditory function. Nat Genet 27:143, 2001. 11. Jacskson Laboratory. Hereditary hearing impairment in mice. http:// www.jax.org/hmr/models.html. 12. University of Iowa. Hereditary hearing loss home page. http://www. uia.ac.be/dnalab.hhh

External Ear John C. Carey, Albert H. Park, and Harlan R. Muntz Structural defects of the external, middle, and inner ear comprise a significant class of congenital anomalies because of their overall frequency and their impact on the people who have them. Most of the recurrent themes that surface in the study of malformations in general will emerge in a discussion of ear malformations: all types of congenital defects from malformations/dysplasias to deformations and disruptions are represented in the study of the ear; state-of-the art developmental biology is typified by the role of neural crest in

branchial arch development and the vast number of genes expressed in cochlear development; the psychological and emotional aspects of coping with congenital disorders, especially the stigma of external ear defects and deafness, emerge as themes in the care of individuals with ear abnormalities. The external ear is an important site for the study of phenotypic variations, mild malformations, and so-called minor anomalies. It was once thought to be an identifier in criminology.1

330

Craniofacial Structures

Fig. 10-1. A. Schematic showing anatomic landmarks of the external ear. B–E. Frontal and lateral views of a male and a female showing level of external ears in relation to the outer canthi of the eyes.

The medically insignificant but helpful morphologic clues that lie in the ear are many. It is of note that all of the common chromosomal syndromes and most of the uncommon ones have a variation or malformation of the ear as a consistent feature. The external ear alterations of Down syndrome and trisomy 18 are examples of this. The evolutionary biology of the external, middle, and inner ear serves as a prototype for the application of this body of knowledge to the study of human malformations. The reader is referred to the papers by Gould2 and Van De Water et al.3 on this theme and to classical works on the anthropology of the external ear.4,5 Sections 10.1 through 10.21 provide a comprehensive listing and review of external ear malformations in humans. Sections 10.22 through 10.33 deal with the middle and inner ear. Figure

10-1 shows the normal anatomy of the external ear and the position of the ear in relation to other facial structures. References 1. Rogers B: Microtic, lop, cup and protruding ears. Plast Reconstr Surg 41:208, 1968. 2. Gould SJ: An earful of jaw. Nat Hist 99(3):12, 1990. 3. Van De Water TR, Maderson PFA, Jaskoll TF: The morphogenesis of the middle and external ear. Birth Defects Orig Artic Ser XVI(4):147, 1980. 4. Martin E, Saller K: Lehrbuch der Anthropologie, vol III. G Fischer Verlag, Stuttgart, 1962, p 2051. 5. Schwarzfischer F: Ohrmuschel. In: Humangenetic, vol 1/2. PE Becker, ed. Georg Thieme Verlag, Stuttgart, 1969, p 163.

Ear

10.1 Microtia/Anotia Definition

Microtia/anotia is a malformation or hypoplasia of the auricle, ranging from a measurably small external ear with minimal structural abnormality, to the ear with major structural alteration, to total absence of the ear (anotia). These anomalies are divided into four types, microtias I to IV. (Lop/cup ear and less significant changes of superior or inferior aspects of the auricle are discussed in Section 10.11.) Diagnosis

The spectrum of microtia represents the most severe malformations of the external ear. The diagnosis is made from physical examination, and most clinicians utilize the classification systems of Meurman1 or Aguillar2 modified from Marks (Fig. 10-2). Type I microtia consists of a generally small pinna that retains most of the overall structure of the normal auricle. Type I blends closely to the lop/cup defect, and clear distinction between it and the lop/cup defect is not made in the otologic literature. In this milder form, the auditory meatus is usually patent, and defects of the ossicular chain are infrequent. Type II microtia is a moderately severe anomaly with a longitudinal mass of cartilage that has some resemblance to the pinna; the rudimentary auricle will be hook-shaped or have an

Fig. 10-2. Microtia I: small ear with usual anatomic components, here with excessive downward folding of superior helix in an infant with Down syndrome (A). Microtia II: vertical mass of cartilage with only superficial resemblance to ear, here with atresia of the external canal and preauricular tag in an infant with Goldenhar syndrome (B). Microtia

331

S or a question mark appearance. Type III microtia represents the prototype of this spectrum and is the most common abnormality in the surgical series, comprising 50–60% of cases (Fig. 10-2C). The ear is usually a rudiment of soft tissue, and the auricle no longer has any resemblance to the normal pinna. It is often called ‘‘peanut’’ shaped. Types II and III microtia are almost always associated with external auditory canal atresia, and about 75% of cases will have some degree of mandibular hypoplasia.3 About 10% of individuals with types II and III microtia will have ipsilateral facial nerve weakness, and about 15% will be labeled as having hemifacial microsomia.4 Type IV microtia consists of anotia, and there is no pinna tissue present at all. In the surgical series of 311 cases reported by Jafek et al.,5 approximately 18% of patients were classified with type I microtia; 20% type II; and 50% type III. Only 3% had anotia (type IV), and the remainder of the series had meatal atresia without external ear defects (see Section 10.3). In larger population series, anotia represents about 10–20% of cases. Microtia types I to III will occasionally be accompanied by a preauricular tag that probably represents the mildest form of the continuum of this defect. The degree of hearing loss in persons with microtia depends on the presence of meatal atresia, middle ear ossicular chain defects, and the occasional occurrence of inner ear dysplasias. In nonsyndromic microtia there is a definite correlation between the degree of external ear defect and the presence of middle ear malformations. Highresolution computed tomography (CT) scanning of the middle and

III: irregular tissue mass without resemblance to external ear, here with atresia of the external canal in a child with Goldenhar syndrome (C). Microtia IV: absence of external ear in a child exposed prenatally to thalidomide (D).

332

Craniofacial Structures

inner ear greatly assists in the diagnosis of these associated defects as well as in the planning of surgery. In infancy and the preschool years, the degree and type of hearing loss can be detected with brainstemevoked response, behavioral testing, and impedance audiometry. Axial and coronal CT scanning are usually deferred until just prior to the planned surgical intervention. The range of associated middle ear ossicular defects is wide and seems not to follow any pattern. Fusion of the malleus to the atresia plate or to the walls of the epitympanic recess is common in individuals with meatal atresia (Section 10.3). About 20–40% of children with microtia/anotia will have an associated defect or an identifiable syndrome pattern.3,6,7 Gorlin et a1.7 and Tewfik and der Kaloustian8 have cataloged the many syndromes that can have microtia as a feature (see also Table 10-4). The most important condition associated with microtia is the oculoauriculo-vertebral (OAV) spectrum. Investigators at the Center for Craniofacial Anomalies at the University of Illinois have meticulously documented the relationship between isolated microtia, ear tags, hemifacial microsomia, Goldenhar syndrome, and the OAV spectrum.9 The range of findings within familial cases of the Goldenhar syndrome and of isolated (apparently nonsyndromic) microtia suggests a continuum; however, it is not clear that all individuals who have isolated microtia always have it as one end of the OAV spectrum. Recently, Llano-Riva et al.10 studied 145 children with microtia, many having features of OAV.12 Because of no difference in the groups of patients, they concluded that microtia is the mild end of expression of the OAV spectrum. Certainly not all of the syndromes in which microtia occurs will exhibit the entire OAV spectrum. Kaye et al.,11 Gorlin et al.,7 and Cohen et al.12 have presented reviews of the OAV spectrum. It is clear from all of this work that this malformation pattern is a condition of etiologic and pathogenetic heterogeneity. Any individual who has apparently isolated microtia (with or without hemifacial microsomia) is a candidate for this diagnosis. In addition to the list of well-delineated syndromes, microtia appears to have other, nonrandom associations. Kaye et al.3 documented a positive association between microtia and cervical spine fusion not necessarily as part of the OAV spectrum. Their data suggest that individuals with isolated microtia should be investigated for the presence of cervical spine abnormalities. One of the most widely discussed associations in pediatrics is the apparent relationship between external ear defects and renal malformations. Other than the occurrence of auricular abnormalities (including microtia) in the many syndromes characterized by both ear and kidney defects, there is no conclusive epidemiologic evidence that an external ear defect is a marker for renal malformation and warrants invasive urologic investigation. This issue is discussed again in detail in connection with low-set ears (see Section 10.9). The most important association with microtia is conductive and sensorineural hearing loss. As pointed out by Jaffe,13 the entire range of microtia as well as other milder ear defects should always bring to mind middle and internal ear abnormalities. Bassila and Goldberg14 found a 16% occurrence of sensorineural hearing loss in individuals with microtia and/or hemifacial microsomia. Naunton and Valvassori15 detected a frequency of 8% of cases, whereas in the Jafek et al.5 cases, none had neural hearing loss. More recently, Calzolari et al.16 found inner ear dysplasia in 10% of cases.16 Certainly inner ear abnormalities and sensorineural hearing loss should be excluded when following individuals with microtia. Etiology and Distribution

A number of epidemiologic investigations worldwide have estimated the birth prevalence of microtia/anotia (Table 10-5). The figures

have usually ranged from one in 3000 to 20,000, with the average estimate at about one to two in 10,000 in the most comprehensive birth defect registries. An investigation in South America reported figures of one in 500 to 3000, depending on the location.17 The frequency in Quito, Ecuador, of one in 500 is the highest recorded figure. Aase and Tegtmeier18 found a one in 2000 birth prevalence among Native Americans. As mentioned earlier, 20–40% of individuals will have microtia associated with other defects. In two recently published large population series, 28–49% of reported cases had microtia associated with other defects, with 6–9% having a welldefined syndrome.19,20 Epidemiologic studies have consistently shown a male to female predominance of about 2:1. In unilateral microtia, the location is right-sided about 60% of the time. In the larger series, about 10% of individuals were affected bilaterally, and about 80% had meatal atresia. The etiology of microtia is heterogeneous. Table 10-4 shows the large number of syndromes, many of which are of single-gene etiology, that consistently include microtia as a component. Microtia types I through IV can also occur as features of chromosome disorders, especially type I microtia in trisomy 21 and types II through IV microtia in trisomy 18 and 13 syndromes. The reader is referred to Tewfik and der Kaloustian8 for an extensive listing of syndromes with external ear defects. Microtia/anotia is a consistent finding in the isotretinoin embryopathy. The discovery that the vitamin A congeners are human teratogens and that they can produce alterations of morphogenesis of the external ear has paralleled a body of work surrounding the role of neural crest in ear development. Microtia and external ear malformations have been produced in various animal models with trypan blue, thalidomide, and the vitamin A congeners. Poswillo21 proposed that the pathogenesis of microtia with associated hemifacial microsomia was due to embryonic hematoma formation in the area of the blood vessels that precede the formation of the stapedial artery stem. It is difficult to explain the entire continuum of the OAV spectrum (lower spinal defects, epibulbar dermoids) as secondary to a vascular disruption. An alteration in cephalic neural crest migration is certainly the most attractive hypothesis to explain the pathogenesis of microtia/anotia currently. Most cases of microtia/anotia are isolated, with no family history, and most large surgical series indicate that less than 10% of the time there is a family history; however, numerous authors have mentioned the occasional occurrence of a positive family history in nonsyndromic microtia. Rollnick and Kaye have documented higher frequencies of first- and second-degree relatives with ear abnormalities in individuals with microtia with or without hemifacial microsomia.9 In their studies, 8% of first-degree relatives had some degree of ear abnormality, including preauricular tags. While most of their patients were classified as having hemifacial microsomia as opposed to isolated microtia, eight of 15 of their cases diagnosed as microtia had a positive family history. Their data suggest that microtia is part of a continuum that extends to hemifacial microsomia and Goldenhar syndrome as mentioned above. These investigators thought that the multifactorial model of causation fits the data best. Looking closer at immediate families in their data set, one can note two kindreds of multiple affected sibs with no other affected relatives, a pattern that might suggest autosomal recessive inheritance. However, there were 19 other pedigrees that showed generation to generation transmission suggestive of dominant inheritance. It is of note that microtia with meatal atresia is listed as an autosomal recessive disorder in the Online Mendelian Inheritance of Man,22 yet a review of familial reports of nonsyndromic microtia

Table 10-4. Syndromes with microtia, types I–IV Syndrome

Prominent Features

Acrofacial dysostosis-cleft lip-triphalangeal thumbs

Mandibular hypoplasia, malar hypoplasia, cleft lip, bifid uvula, hypoplastic thumbs with three phalanges.

Causation Gene/Locus

Unknown

Bixler

Hypertelorism, oral facial clefting

AR (239800)

Branchio-oto-renal

Branchial clefts, ear pits, hearing loss, renal defect

AD EYA1, 8q

CHARGE

Coloboma, Heart defects, Atresia choanae, retarded growth and development, genital anomalies, ear anomalies or deafness

Sporadic (214800) CHD7, 8q12

Coxo auricular

Dislocated hips, abnormal femora

AD (122780)

Diabetic embryopathy

Excessive intrauterine growth; increased risks for CNS, cardiac, spine, and limb defects

Maternal diabetes

Fraser

Cryptophthalmia, syndactyly, Mu¨llerian defects

AR (219000) FRAS1, 4q21

Greig

Macrocephaly, hypertelorism, syndactyly, polydactyly

AD (175700) GLI3, 7p13

Hennekam

Intestinal lymphangiectasia, facial anomalies, developmental delay

AR (235510)

Johnson-McMillen

Alopecia, anosmia, hypogonadism

AD (147770)

Kabuki

Characteristic face, prominent ears, short stature

AD (147920)

Maxillofacial dysostosis

Maxillary hypoplasia, downslanting palpebral fissures, delayed and inarticulate speech

AD (155000)

Meier–Gorlin

Absent patella, short stature, distinctive face

AR (224690)

Mengel

Unusual ear defects, conductive hearing loss, mental retardation, hypogonadism

AR (221300) 16p12

Microtia-congenital heart defect-facial weakness

Microtia, aortic arch anomalies, facial paresis

Uncertain (243440)

Moeschler

Oral cleft, preauricular tags, hemifacial microsomia, thumb/radial defects

AD (141400)

Nager

Mandibular hypoplasia, malar hypoplasia, radial/thumb hypoplasia

AD (154400)

Oculo-auriculo-frontonasal

Frontonasal malformation, hemifacial microsomia

Unknown

Oculo-auriculo-vertebral spectrum

Epibulbar dermoids, vertebral defects, variable heart defects

Heterogeneous AD (164210) AR (257700) 14q

Postaxial acrofacial dysostosis (Miller)

Mandibular hypoplasia, postaxial limb deficiency

Unknown (263750)

Townes–Brock

Ear defects, anorectal malformations, thumb defects

AD (107480) SALL1, 16p12

Treacher Collins

Mandibular hypoplasia, malar hypoplasia, downslanting palpebral fissures, lower lid coloboma, cleft palate

AD (154500) TCOF1, 5q32

Wildervanck

Klippel-Feil anomaly, hearing loss, Duane anomaly

XLD (314600)

Trisomy 21

Flat facies, upslanting palpebral fissures, Brushfield spots, small mouth, short stature, mental retardation

Chromosomal

Trisomy 18

Prenatal growth deficiency, distinctive face/hands, short sternum, heart defect, mental retardation

Chromosomal

Del 4p

Prenatal growth deficiency, hypertelorism, orofacial clefts, mental retardation

Chromosomal

Del 5p

Round face, telecanthus, ear tags, distinctive weak cry, mental retardation

Chromosomal

Del 9p

Characteristic face, hypotonia

Chromosomal

Del 18p

Distinctive face, ptosis

Chromosomal

Del 22q11

Velopharyngeal insufficiency, heart defect, Di-George anomaly

Chromosomal

Prenatal alcohol

Prenatal and postnatal growth deficiency, distinctive face, developmental delay

Prenatal alcohol exposure

Prenatal thalidomide

Preaxial limb defects, internal malformations

Prenatal thalidomide exposure

Prenatal isotretinoin

Anotia, CNS defects, conotruncal malformations

Prenatal isotretinion exposure

333

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Craniofacial Structures

Table 10-5. Selected studies of the birth prevalence of microtia/anotia in various parts of the world Study Group, Location

Year

Per 10,000 Population

Aase, American Indian

1976

5.38

Aase, all New Mexico18

1976

1.34

Castilla and Orioli, Quito, Equador

1986

17.40

Castilla and Orioli, South America17

1986

3.20

Mastroiacova et al., Italy19

1995

1.45

Harris et al., Sweden20

1996

2.35

18

17

20

Harris et al., France

1996

0.76

Harris et al., California, USA20

1996

2.0

Sanchez et al., Venezuela37

1997

3.80

(even excluding the data from Chicago) produced a minimum of 11 reports of generation-to-generation transmission of microtia, some with three-generation pedigrees and one with a five-generation pedigree.23–26 There are also a number of other cases that are labeled as familial hemifacial microsomia that cannot be distinguished from isolated microtia. One of the classic pedigrees cited to support the idea of recessive inheritance of microtia with meatal atresia is that studied by Ellwood et al.27 Yet, in this kindred there was consanguinity, the actual defect was called anotia, and two of the children died in the first few months of life, which suggests a more complicated syndrome, perhaps of recessive inheritance. These data taken together suggest that nonsyndromic microtia with meatal atresia is probably not inherited as a simple autosomal recessive disorder, but rather occurs in many families as an autosomal dominant trait with variable expression and incomplete penetrance. In the dominant familial cases, unilateral and bilateral microtia with or without hemifacial microsomia occur in the same family. Occasionally, some family members simply have the presence of tags. The most parsimonious explanation for the genetics of nonsyndromic microtia is to invoke complex multifactorial causation in most cases, with well-established autosomal dominant inheritance representing a small proportion. Regarding the molecular genetics of familial nonsyndromic microtia, it is reasonable to postulate that a gene predisposing to OAV, hemifacial microsomia, or microtia could be on 14q32 because of linkage in two families.28 It is likely that microtia/anotia can be caused by many different genes and that these genes are on numerous chromosomes. The molecular genetics of this heterogeneous malformation will probably be complicated but could provide a paradigm for studying other complex and multifactorial disorders. Table 10-4 includes our current knowledge on the developmental genes that cause syndromic microtia (e.g., BOR syndrome). Prognosis, Prevention, and Treatment

The impact of microtia/anotia is twofold: stigmatization related to the visible craniofacial defect and hearing loss. The child with microtia often suffers from psychosocial issues related to the visible defect. The microtic ear draws attention to the difference between the two ears, and this can be especially problematic during the elementary school years when conformity and sameness are so important. In addition, some children with microtia will have an adverse effect from hearing loss. The hearing threshold is usually at about 60 dB in an affected ear. This, of course, is of greater concern in the child with the bilateral microtia. Even moderate conductive unilateral hearing loss may be an issue in school performance and

social settings. Ear canal reconstruction or bone conduction amplification for improved hearing should be discussed in detail with the family early so that the implications of improved hearing can be weighed against the risks of the surgical intervention. Children with microtia, either isolated or as part of the OAV anomaly, are frequently evaluated and cared for by craniofacial specialists on a team. The surgical management of microtia is complicated, and numerous surgeons have developed creative approaches to reconstruction. While some otolaryngologists argue for meatal atresia being repaired prior to ear reconstruction, more recently most surgeons have approached external ear surgery first. Certainly the surgical repair should be accomplished by plastic surgeons and otolaryngologists who are used to working together and are experienced in reconstruction. There are two approaches: prosthetic management and auricle reconstruction. Though it is important to offer the family a choice of no intervention, most families will want the child to have a more normal facial appearance. Surgical reconstruction of the external ear is a multistaged endeavor and, as with any surgery, there are risks involved. Prosthetic management requires the diligence of a maxillofacial prosthedontist but has not received as much acceptance in the United States. A prosthetic ear can be made to look very lifelike. Because there are few limitations to thickness, coloration, and revision, the child with prosthesis may actually have a more normal appearance than the child with a reconstructed auricle. Families are often concerned about removing the ear prosthesis for physical activities and cleaning. The prosthesis usually is attached with adhesives or tape, which may be a limitation for the active child. The use of titanium implants to anchor the prosthesis has revolutionized the field of maxillofacial prosthetics. These implants have been used for both dental and facial reconstruction. The titanium implants osseointegrate into the bone and are relatively nonreactive. They have a post that comes through the skin or mucosa upon which the prosthesis can be attached. The use of bone-anchored prostheses eliminates many of the concerns noted in other methods of retention.29,30 Similar to auricular reconstruction, this is also a multistaged operation but is not as invasive.31 The classical surgical reconstruction consists of four stages for auricular reconstruction,2,32,33 followed by canal and middle ear reconstruction. Though there is some controversy as to the best timing for reconstruction, many believe the ideal time is before the child enters first grade, at age 5 to 6 years. The auricle is usually more than 90% of its full size by then. One uses the normal ear to develop a template for the reconstruction. In the case of bilateral atresia, the template can be made from one of the parents’ ears. High-resolution CT is required prior to surgery to delineate the commonly associated ossicular chain defects as well as the anatomy of the facial nerve.34 Regardless of philosophy or staged approach, reconstruction involves the placement of the selected framework (usually a sculpted costal cartilage graft), development of a postauricular sulcus and concha, rotation of the lobule, repair of the atresia and its plate, and the final adjustments of the helix and placement of the auricle. The reconstructed auricle is allowed to heal for a number of months before the canal is reconstructed to ensure the health of the cartilage and flaps. In the past, individuals with unilateral microtia with meatal atresia usually did not have repair of the atresia. However, some investigators feel that the benefits of binaural hearing exceed the risk of surgery, even the risk of damage to the facial nerve. Approach to the associated ossicular chain defects is discussed in the sections on middle ear malformations (Sections 10.22–10.31).

Ear

In meatal atresia there is usually a firm bony union of the malleus with the atretic plate. This needs to be repaired to regain hearing. Also, in most cases of types II through IV microtia, malformations of the malleus and incus are present, and there is a high incidence of facial nerve anomalies in these patients. Thus, families need to be counseled about potential facial nerve injury from surgery. Most series indicate an average of a 30 dB increase postoperatively. Patients who have a relatively intact middle ear will obviously have better results postoperatively than those who have major ossicular chain defects. Hearing restoration can be done using a bone anchored hearing aid (BAHA).35 This uses the osseointegration to place an implant into the mastoid bone. The post is coupled to a device that translates the auditory signal to vibration, working much like the bone conduction hearing aids but with far superior fidelity. It has also shown remarkable improvement for children with unilateral hearing loss.8 There has been reluctance for the insurers to cover the cost of this technology, but it can be offered as an alternative to surgical hearing reconstruction. Complete discussion of aural rehabilitation is beyond the scope of this chapter. It is important to note that children with microtia/anotia require meticulous hearing evaluation in infancy and appropriate audiologic management. Conductive hearing aids are crucial in children with meatal atresia or other structural causes of hearing loss. Preschool programs for infants with mild, moderate, and severe hearing loss exist in most areas of North America, and referral to these programs is important as soon as possible. There is at least one instance of prenatal diagnosis of microtia in a fetus with Treacher Collins syndrome.36 The abnormally small ear was recognized at 17 weeks gestation. Mild forms of type I microtia are probably not able to be diagnosed prenatally. The sensitivity of prenatal ultrasound in the severe forms of microtia is unknown. References (Microtia/Anotia) 1. Meurman Y: Congenital microtia and meatal atresia. Arch Otolaryngol 66:443, 1957. 2. Augilar EF: Auricular reconstruction in congenital anomalies of the ear. Facial Plast Surg Clin North Am 9:159, 2001. 3. Kaye C, Rollnick BR, Hauck WW, et al.: Microtia and associated anomalies: statistical analysis. Am J Med Genet 34:574,1989. 4. Bennun RD, Mulliken IB, Kaban LB, et al.: Microtia: a microform of hemifacial microsomia. Plast Reconstr Surg 76:859, 1985. 5. Jafek BW, Nager GT, Strife I, et al.: Congenital aural atresia: an analysis of 311 cases. Trans Am Acad Ophthalmol Otol 80:588, 1975. 6. Jahrsdoerfer R: Congenital malformations of the ear: analysis of 94 operations. Ann Otol Rhinol Laryngol 89:348, 1980. 7. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 8. Tewfik TD, der Kaloustian VM: Congenital Anomalies of the Ear, Nose, and Throat. Oxford University Press, New York, 1997. 9. Rollnick BR, Kaye CI: Hemifacial microsomia and variants: pedigree data. Am J Med Genet 15:233, 1983. 10. Llano-Riva I, Gonzalez-del Angel A, del Castillo V, et al.: Microtia: a clinical and genetic study at the National Institute of Pediatrics in Mexico City. Arch Med Res 30:120, 1999. 11. Kaye C, Martin AO, Rollnick BR, et al.: Oculoauriculovertebral anomaly segregation analysis. Am J Med Genet 43:913, 1992. 12. Cohen MM, Rollnick BR, Kaye CI, et al.: Oculoauriculovertebral spectrum: an updated critique. Cleft Palate 126:276, 1989. 13. Jaffe BF: Pinna anomalies associated with congenital conductive hearing loss. Pediatrics 57:332, 1976. 14. Bassila MK, Goldberg R: The association of facial palsy and/or sensorineural hearing loss in patients with hemifacial microsomia. Cleft Palate 126:287, 1989.

335 15. Naunton RF, Valvassori GE: Inner ear anomalies: their association with atresia. Laryngoscope 78:1041, 1968. 16. Calzolari F, Garani G, Sensi A, et al.: Clinical and radiological evaluation on children with microtia. Br J Audiol 33:303, 1999. 17. Castilla EE, Orioli IM: Prevalence rates of microtia in South America. Int J Epidemiol 15:364, 1986. 18. Aase LM, Tegtmeier RE: Microtia in New Mexico: evidence for multifactorial causation. Birth Defects Orig Artic Ser XIII(3A):113, 1977. 19. Mastroiacova P, Corchia C, Bott LD, et al.: Epidemiology and genetics of microtia-anotia: a registry-based study on over one million births. J Med Genet 32:453, 1995. 20. Harris J, Kallen B, Robert E: The epidemiology of anotia and microtia. J Med Genet 33:809, 1996. 21. Poswillo D: The pathogenesis of the first and second branchial arch syndrome. Oral Surg 35:302, 1973. 22. Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov. 23. Zankl M, Zang KD: Inheritance of microtia and aural atresia in a family with five affected members. Clin Genet 16:331, 979. 24. Orstavik KH, Medbo S, Mair IWS: Right-sided microtia and conductive hearing loss with variable expressivity in three generations. Clin Genet 38: 117, 1990. 25. Oliveria CA, Pinheiro LC, Gomes MR, et al.: External and middle ear malformations: autosomal dominant genetic transmission. Ann Otol Rhinol Laryngol 98:772, 1989. 26. Gupta A, Patton MA: Familial microtia with meatal atresia and conductive deafness in five generations. Am J Med Genet 59:238, 1995. 27. Ellwood LC, Winter ST, Dar H: Familial microtia with meatal atresia in two sibships. J Med Genet 5:289, 1968. 28. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia: progress of understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638, 2001. 29. Rotenberg BW, James AL, Fisher D, et al.: Establishment of a boneanchored auricular prosthesis (BAAP) program. Int J Pediatr Otorhinolaryngol 66:273, 2002. 30. Westin T, Tjellstrom A, Hammerlid E, et al.: Long-term study of quality and safety of osseointegration for the retention of auricular prostheses. Otolaryngol Head Neck Surg 121:133, 1999. 31. Tietze L, Papsin B: Utilization of bone-anchored hearing aids in children. Int J Pediatr Otorhinolaryngol 58:75, 2001. 32. Brent B: Microtia repair with rib cartilage grafts: a review of personal experience with one thousand cases. Clin Plast Surg 29:257, 2002. 33. Beahm EK, Walton RL: Auricular reconstruction for microtia: part I. Anatomy, embryology, and clinical evaluation. Plast Reconst Surg 109: 2473, 2002. 34. Yeakley JW, Jahrsdoerfer RA: CT evaluation of congenital aural atresia: what the radiologist and surgeon need to know. J Comput Assist Tomogr 20:724, 1996. 35. Snik AF, Mylanus EZ, Cremers CW: The bone-anchored hearing aid in patients with a unilateral air-bone gap. Otol Neurotol 23:61, 2002. 36. Crane IP, Beaver HA: Midtrimester sonographic diagnosis of manbulofacial dysostosis. Am J Med Genet 25:251, 1986. 37. Sanchez O, Mendez JR, Gomez E, et al.: [Clinico-epidemiologic study of microtia]. Invest Clin 38:203, 1997.

10.2 Small Ear The external ear that has normal anatomy or only a minor abnormality of configuration but has a length of 2 standard deviation (SD) or more below the mean is considered small. Ear length is determined by measuring the ear from the superior helix to the lobe. Normal ear length is greater than 30 mm in the full-term baby. There are standards for plotting ear length at birth and in older infants and children (Fig. 10-3).1–5 Small but structurally normal ears are a sign of Down syndrome. Most babies with Down syndrome have mild ear variations,

336

Craniofacial Structures

Fig. 10-3. Curves for normal ear length. Left curve shows growth percentiles from birth to age 14 years. (From Feingold M, Bossert WH: Normal values for selected physical parameters: an aid to syndrome delineations. BDOAS X(13):1, 1974.) Right curve shows mean ear length for males (solid line) and females (dashed line) from birth to age 70 years. (From Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983.)

including defects in the lop/cup ear continuum. However, some simply have a normal-appearing auricle that is small. Only rarely will a newborn with Down syndrome have an ear measuring over 3.1 cm. The external ear, especially the small ear, attains most of its childhood growth by age 5 or 6 years. The etiology and pathogenesis of the small, nonmalformed, nonmicrotic ear are unknown. The physical stigma associated with a small ear is minimal. References (Small Ear) 1. Hall JG, Froster-Iskenius UG, Allanson JE, et al: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 2. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 3. Farkas LG: Anthropometry of the Head and Face. Raven Press, New York, 1994.

10.3 External Auditory Canal Stenosis and Atresia Without Microtia Definition

External auditory canal stenosis or atresia without microtia is narrowing or absence of the external auditory canal without the presence of significant external ear malformations. It is usually called aural atresia by the otologist. Diagnosis

Congenital external auditory canal atresia or stenosis without an external ear malformation or microtia is uncommon. Few reports of this malformation were published before the 1980s. The series of 311 patients with aural atresia reported by Jafek et al. showed that only 24, or about 6%, had atresia without a concomitant microtia.1 Grundfast and Camilon2 reviewed 10 cases and the world literature. The absence of an obvious external malformation hampers early detection, and the average age of diagnosis in their series was 2.5 years, with a range of 2 months to 7 years. Often the practitioner assumes that the narrow or missing ear canal is due to some debris in the canal and

therefore misses the diagnosis. Recognition is obviously made by examination of the ear canal with an otoscope. High-resolution computed tomography (CT) scanning is indicated to assess the presence of an atretic bony plate and the status of associated middle ear ossicular defects.3 Cases with unilateral stenosis or atresia are even more difficult to diagnose than bilateral cases. Atresia of the external meatus may be osseous or membranous. In osseous atresia the tympanic bone is replaced by an atretic plate. Aural atresia (AA) has been classified in various ways. Cremers4 divided AA into three types: in type I there is osseous or membranous atresia of the auditory canal but an almost normal medial aspect of the canal and a normal middle ear. Type II, which accounts for most of the cases, involves a partially or totally atretic ear canal with variable involvement of the middle ear. In type III there is a complete bony meatal atresia, with a very small or absent middle ear cavity. Jahrsdoerfer et al.5 proposed a grading system for AA. This system gives points for the presence of normal structures (e.g., stapes present). Higher scores predict better surgical outcome (see below). Atresia of the auditory canal obviously produces a conductive hearing loss, which is usually of about 60 dB. In the rare patient who has a concurrent inner ear abnormality, there may be a mixed type of loss. As was mentioned in the discussion of microtia/anotia (Section 10.1), sensorineural hearing loss occurs more commonly in association with external and middle ear defects than was originally proposed in the early otolaryngology literature. Isolated external auditory canal atresia/stenosis can occur as a marker for and clue to the deletion 18q syndrome (Table 10-6). Any child with this atresia/stenosis who has other mild malformations, phenotypic variations, or developmental delay should be regarded as possibly having this common chromosomal syndrome. Auditory canal stenosis without microtia is also seen in trisomy 18, in the oculo-auriculo-vertebral spectrum, and in the syndrome reported by Rasmussen et al.6 In the latter condition, congenital vertical talus and hypertelorism occur along with atresia of the external auditory canal. None of the kindred had external ear defects. The condition is inherited as a dominant trait and may represent a submicroscopic 18q deletion.

Ear Table 10-6. Syndromes associated with meatal atresia without microtia Causation Gene/Locus

Syndrome

Prominent Features

Deletion 18q

Distinctive face, tapered fingers

Chromosomal

Rasmussen

Hypertelorism, vertical talus

Uncertain

Trisomy 18

Prenatal growth deficiency, distinctive face/hands, short sternum, congenital heart disease

Chromosomal

Oculo-auriculovertebral spectrum

Epibulbar dermoids, vertebral defects, variable heart defects

Heterogeneous, AD (164210), AR (257700) 14q1

Antley-Bixler

Choanal atresia, characteristic face, humeroradial fusion, femoral bowing

AR (207410) POR, q11

SAMS

Humeroscapular synostosis, club feet

Uncertain (602471)

Etiology and Distribution

Isolated external auditory canal stenosis without microtia is an uncommon defect, accounting for fewer than 10% of all individuals who are evaluated by the otologist with meatal atresia, because most have microtia. No prevalence-at-birth studies are available that provide an estimate of this condition. However, in the Spanish Collaborative Project, a prevalence of 0.19 per 10,000 births, or about two per 100,000, was listed for various rare ear malformations, including atretic or stenosed auditory canals with normal auricle (personal communication: Dr. Maria Luisa Martinez-Frias). This figure is a rough estimate, since it included other uncommon ear malformations. However, the estimate must also be considered to be on the low side since some babies with the condition may not be detected in the newborn period. While in microtia with meatal atresia unilaterality is much more common than bilaterality, in aural atresia without microtia there was equal occurrence of bilateral and unilateral defects.2 Males and females were equally affected; the male predominance found in microtia with meatal atresia was not seen. Because the syndromes showing isolated auditory canal atresia/ stenosis are generally different from those showing microtia with meatal atresia, this defect probably reflects a unique alteration in morphogenesis. It is also of note that, in the few familial cases, the degree and frequency of ossicular chain abnormalities are less than what is usually seen in microtia with meatal atresia. As was noted above, the sex ratio and sidedness differ from those in atresia with microtia. These facts support the notion that this anomaly is a different alteration in morphogenesis. Besides the family reported by Rasmussen et al.6 in whom the meatal atresia occurred as part of a syndrome, three other families have exhibited generation-to-generation transmission, suggesting dominant inheritance. The family in the Robinow and Jahrsdoerfer7 study showed male-to-male transmission, indicating autosomal dominant inheritance in that kindred. Thus, atresia of the auditory canal without microtia is inherited in an autosomal dominant fashion in some of the cases. Recently, Veltman et al.

337

defined a critical region of 5 Mb responsible for AA in the 18q deletion syndrome.8 Prognosis, Prevention, and Treatment

When children have bilateral atresia, bone conduction hearing aids can be placed before the child reaches age 6 months.3,9 Surgery is usually planned for about ages 5 to 6 years. Reconstruction is delayed because pneumatization of the mastoid is not complete until that time. Radiographic evaluation of the middle ear with highresolution CT scanning is important to determine the ossicular chain defects as well as the anatomy of the facial nerve and middle ear cleft. Documentation of a sensorineural component to the hearing loss is also important for prognostic planning. Surgical intervention for auditory canal atresia or stenosis is performed by an experienced otolaryngologist.10 The procedure involves creation of a new ear canal, use of the residual ossicular chain or replacement with an ossicular prosthesis, and creation of a new tympanic membrane using temporalis fascia and split thickness skin graft. Extreme care is needed during dissection of the posterior canal because of the abnormal course of the facial nerve. In general, a postoperative hearing level of 30 dB or better can be achieved in 50–75% of patients with aural atresia.3,9 A hearing level of 20 dB or better is possible in 15–50% of these patients. For patients with unfavorable anatomy (e.g., lack of middle ear pneumatization, facial nerve overlying the oral window), one should consider bone-anchored hearing aid implantation (BAHA) (see Section 10.1). Children with unilateral atresia also require regular otologic assessment. The contralateral ‘‘normal’’ side must be monitored closely for otitis media. These patients are adversely affected from even transient hearing loss involving their functionally hearing ear. The contralateral ‘‘normal’’ side must also undergo hearing testing. References (External Auditory Canal Stenosis and Atresia Without Microtia) 1. Jafek BW, Nager GT, Strife J, et al.: Congenital aural atresia: an analysis of 311 cases. Trans Am Acad Ophthalmol Otol 80:588, 1975. 2. Grundfast KM, Camilon F: External auditory canal stenosis and partial atresia without associated anomalies. Ann Otol Rhinol Laryngol 95:505, 1986. 3. Krowiak E, Grundfast KM: Congenital malformations of the ear. In: Pediatric Otolaryngology, Wetmore RF, Muntz HR, McGill TJ, eds. Thiem, New York, 2000. 4. Cremers CWRJ: Meatal atresia and hearing loss. Autosomal dominant and autosomal recessive inheritance. Int J Pediatr Otorhinolaryngol 8:211, 1985. 5. Jahrsdoerfer RA, Yeakley JW, Aguilar EA, et al.: Grading system for the selection of patients with congenital aural atresia. Am J Otolaryngol 13:6, 1992. 6. Rasmussen N, Johnsen NJ, Thomsen J: Inherited congenital bilateral atresia of the external auditory canal, congenital bilateral vertical talus and increased interocular distance. Acta Otolaryngol 88:296, 1979. 7. Robinow M, Jahrsdoerfer RA: Autosomal dominant atresia of the auditory canal and conductive deafness. Am J Med Genet 4:89, 1979. 8. Veltman JA, Jonkers Y, Nuijten I, et al.: Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. Am J Hum Genet 72:1578, 2003. 9. Declau F, Cremers C, Van de Heyning P: Diagnosis and management strategies in congenital atresia of the external auditory canal. Study Group on Otological Malformations and Hearing Impairment. Br J Audiol 33:313, 1999. 10. Lambert PR, Dodson EE: Congenital malformations of the external auditory canal. Otolaryngol Clin N Am 29:741, 1996.

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Craniofacial Structures

10.5 Large Ear (Macrotia) Definition

Large ear (macrotia) is an alteration in which the length of the auricle is increased above the 97th percentile on standard curves (Fig. 10-5). Diagnosis

Fig. 10-4. Cryptotia. Incomplete separation of the superior and posterior aspects of the pinna from the scalp. (From Aase JM: Diagnostic Dysmorphology. Plenum Press, New York, 1990.)

10.4 Cryptotia Cryptotia is an uncommon defect of the auricle in which there is incomplete separation of the posterior aspect of the superior helix and the adjoining scalp (Fig. 10-4). The diagnosis is made entirely by observation; the examiner simply tugs on the helical fold and discovers the lack of separation. Cryptotia is usually an isolated defect, but it does occasionally occur as part of a syndrome. The Fraser cryptophthalmos syndrome and trisomy 18 are the two most commonly associated entities. Cryptotia is also seen in the Carmi form of epidermolysis bullosa. However, cryptotia usually is nonsyndromic. Unless it is part of a syndrome, this defect is not usually associated with other external, middle, or internal ear changes. Familial cryptotia has been described in one occasion.1 Japanese investigators have emphasized that cryptotia seems to occur much more commonly in Japan than elsewhere in the world.2 The frequency of cryptotia in Japan is one in 400. No other epidemiologic information is available on the nature and determinants of this defect. Plastic surgeons in Japan have developed a number of techniques and approaches for the treatment and repair of cryptotia.2–5 Basically, the repair consists of soft tissue separation and grafts and is usually successful. References (Cryptotia) 1. Hayashi R, Matsuo K, Hirose T: Familial cryptotia. Plast Reconst Surg 91:1337, 1993. 2. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990. 3. Park C: Correction of cryptotia using an external stretching device. Ann Plast Surg 48:534, 2002. 4. Paredes AA Jr, Williams JK, Elsahy NL: Cryptotia. Clin Plast Surg 29:317, 2002. 5. Hirose T, Tomono T, Matsuo K, et al.: Cryptotia: our classification and treatment. Br J Plast Surg 38:352, 1985.

The diagnosis of large ear (macrotia) is made simply by measuring the length of the external auricle. This is accomplished by taking the measurement between the superaurale, which is the highest point of the free margin of the auricle, and the subaurale, which is the lowest portion of the free margin of the ear lobe. This can be done with a standard ruler or tape measure, and the value can be plotted in the available curves, many of which are in standard texts.1,2 At birth, the ear usually measures less than 4.2 cm. The ear grows steadily throughout the first 2 years of life and then slows in growth until age 5 years, when the slowing increases. The large ear is often prominent or protruding. Probably the most important syndrome to consider in individuals with macrotia is the fragile X syndrome. This disorder is rarely noted in infancy and early childhood, so the actual growth curve of the ear in the fragile X syndrome is unknown. However, in the older child, especially in a boy with mental retardation, this is an important marker. There are a number of other syndromes in which macrotia has been recorded, and these have been summarized by Gorlin and coworkers3 and Tewfik and der Kaloustian4 (Table 10-7). Large ears are also found in the oligohydramnios sequence and may be due to external compression.5 Etiology and Distribution

Although no specific prevalence studies have been performed to examine the frequency of large ears, macrotia by definition does occur in 3% of individuals. This, then, is not strictly a malformation but really is an excessive growth phenomenon. However, intrauterine constraint due to oligohydramnios could be a pathogenetic mechanism inducing excessive growth of the ear.5 The large, unfolded, floppy ear is one of the craniofacial features recognized by Potter in the disorder that bears her name, that is, the Potter syndrome (also called oligohydramnios sequence). Prognosis, Prevention, and Treatment

The major impact of macrotia is the stigmatization associated with prominent ears. Surgical reduction of ear size in individuals with macrotia is uncommon. References (Large Ear/Macrotia) 1. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 2. Hall JG, Froster-Iskenius UG, Allanson JE, et al.: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 3. Gorlin RJ, Cohen MM, Hennekan R: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2002. 4. Tewfik TD, der Kaloustian VM: Congenital Anomalies of the Ear, Nose, and Throat. Oxford University Press, New York, 1997. 5. Aase JM: Structural defects as a consequence of late intrauterine constraint, craniotabes, loose skin and asymmetric ear size. Semin Perinatol 7:270, 1983.

Ear

339

Fig. 10-5. Macrotia. Large ear in a 2-month-old infant with microcephaly of unknown cause (A), in a male aged 2 years 9 months with fragile X syndrome (B), and in an adult female carrier of the fragile X chromosome (C). Note the lack of helical folding. Table 10-7. Syndromes that include macrotia Syndrome

Prominent Features

Causation Gene/Locus

Borjeson-Forssman-Lehmann

Coarse face, mental retardation, hypogonadism

XLR (301900) PHF6, Xq26

Fragile X

Long face, large testes, lax joints

XLR (309550) FMR1, Xq27

Langer-Giedion

Microcephaly, exostoses, facial features similar to those in tricho-rhino-phalangeal I

Chromosomal (150230) 8q24

Melnick-Needles

Distinctive face, skeletal changes

XLR (309350) FLNA, Xq28

Pallister-Killian

Pigmentary dysplasia, distinctive face, mental retardation

Chromosomal

Weaver

Distinctive face, macrosomia, camptodactyly

Unknown (277590) Some cases with NSD1 (5q35) mutations

Oligohydramnios

Canthal folds, depressed nasal tip, joint contractures, lung hypoplasia

Heterogeneous

Lamotte

Prenatal growth deficiency, hypertelorism, preaxial polydactyly, distinctive face

AR (245552)

Nance-Horan

Nystagmus, dental anomalies, cataracts, short metacarpal

XLR (302350) NHS, Xp22

10.6 Polyotia True and complete duplication of the external auricle is very rare; many reviewers state that the case of von Bol and de Kleyn1 was the first authentic case of a true duplication defect. In this patient, the infant had a left ear with two external auricles facing each other as a mirror image. Both were fully developed, but a tragus was lacking. Most cases of alleged polyotia are examples of large auricular appendages. The case reported by Gadre et al.2 of an individual with polyotia and the de Lange syndrome is unconvincing in that this

child’s defect appears to be an enlarged accessory appendage. The patient of von Bol and de Kleyn1 had a left-side cleft lip and cleft palate as well as an ocular dermoid, so this individual may have had the oculo-auriculo-vertebral (OAV) spectrum. Recently other cases have been presented.3,4 The birth prevalence of polyotia is obviously low, given only a few widely agreed upon cases. It is of note that the patients of von Bol and de Kleyn1 and Bendor-Samuel et al.3 had no tragus in the duplicated auricles, because some investigators believe that the tragus is the only hillock derived from the first branchial arch.5 This suggests that true polyotia in this case may represent a true duplication of the hillocks that were part of the second branchial arch.

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Craniofacial Structures

The distinction between accessory appendages and true polyotia may be moot if one assumes that auricular appendages are duplicated structures of the auricular hillocks in the first place. Large auricular appendages then would represent duplication of more of the hillocks, with occasional total duplication of the hillocks. Surgical reconstruction has been successful in true polyotia as it is in individuals with auricular appendages.3,4 References (Polyotia) 1. von Bol G, de Kleyn A: Uber einer fall von polyotic. Acta Otolaryngol 1:187, 1918. 2. Gadre AK, Patil DP, Iyer D, et al.: Duplication of the pinna (polyotia) in a case of Brachmann-de Lange syndrome. Br J Plast Surg 40:642, 1987. 3. Bendor-Samuel RL, Tung TC, Chen YR: Polyotia. Ann Plast Surg 34:650, 1995. 4. Ku PK, Tong MC, Yue V: Polyotia—a rare external ear anomaly. Int J Pediatr Otorhinolaryngol 46:117, 1998. 5. Black FO, Myers EN, Rorke LB: Aplasia of the first and second branchial arches. Arch Otolarynol 98:124, 1973.

10.7 Duplication of the External Auditory Meatus Definition

Duplication of the external auditory meatus is a cyst and/or sinus tract located in the preauricular area in close proximity to the external auditory canal, believed to be duplication of the first branchial cleft. Diagnosis

Cysts or sinus tracts representing duplication defects of the first branchial cleft or groove are found in the region of the external auricle and external auditory canal.1,2 Earlier work has classified these defects as either type I or type II.1 Type I defects involve the membranous canal and are histologically epidermoid cysts; these sacs have no cartilage or adnexal structures and course medially, inferiorly, and posteriorly to the pinna. Drainage can occur from the cystic structure, but there is no external pit nor any association with auricular tags. These first branchial cleft sinuses/cysts are internal, and these defects usually present as a mass or abscess. Type II lesions, which are more common than type I, involve apparent duplication of the membranous and cartilaginous portions of the external auditory canal. These cysts/sinuses contain skin with adnexal structures and cartilage and often connect with the auditory canal and extend into the neck. The drainage site is occasionally below the angle of the mandible. Both type I and type II cysts often originate in the external auditory canal. Recurrence of the cyst with secondary infection is common unless the entire sac is removed. Altmann3 refers to these anomalies as colloaural fistulas. These tracts apparently open into the external auditory meatus but usually not into the middle ear. Altmann3 has reviewed some of the unusual colloaural fistulas, including one associated with microtia in which a second tract was attached to the original fistula tract, which extended into the middle ear. In another frequently mentioned case of Virchow’s, the tract actually began at a preauricular appendage and proceeded into the posterior tonsillar pillar just behind the upper tonsil. Most duplication anomalies of the first branchial cleft are isolated features and are not part of a syndrome. Blevins et al.4 reported a patient with Treacher Collins syndrome in their recent

series of four patients. Most of the case reports of this uncommon defect do not document other abnormalities, but two of the patients reviewed by Altmann3 did have microtia. Etiology and Distribution

The frequency of these duplication defects is unknown. Aronsohn et al.2 were able to collect 11 cases seen over a 40-year period at the University of Michigan. Most were children presenting with a mass in the preauricular region. The pathogenesis of this unusual defect is unknown. The hypothesis that these cystic structures represent a duplication anomaly of the first branchial cleft makes sense embryologically, with the type II defects actually having both ectodermal and mesenchymal (cartilaginous) remnants in the structure. Prognosis, Prevention, and Treatment

Surgical removal of the entire sac is important; without this, recurrence is common. This particular point has been emphasized by Aronsohn et al.2 in their review of the University of Michigan experience. Repeated incisions and drainage will occur unless the diagnosis of these defects is made. As is the case in other external ear defects, careful determination of the location of the facial nerve is crucial. These lesions could be mistaken for a branchial cleft related to the second branchial groove. However, the latter lesions are more commonly found in the carotid triangle, and the external opening usually occurs anterior to the sternocleidomastoid muscle. Histologically, the lesions in the second branchial arch cervical cysts do not keratinize, whereas these duplication anomalies of the first branchial cleft do keratinize. Wittekindt et al.5 detailed their surgical experience and expressed concern about the need for adequate incision and drainage procedures because of the risk of recurrent infection. References (Duplication of the External Auditory Meatus) 1. Work WP: Developments of first branchial cleft defects. Laryngoscope 82:1581, 1972. 2. Aronsohn RS, Batsakis JG, Rice DH, et al.: Anomalies of the first branchial cleft. Arch Otolaryngol 102:737, 1976. 3. Altmann F: Malformations of the auricle and the external auditory meatus. Arch Otolaryngol 54:115, 1951. 4. Blevins NH, Byahatti SV, Karmody CS: External auditory canal duplication anomalies associated with congenital aural atresia. J Laryngol Otol 117:32, 2003. 5. Wittekindt C, Schondorf J, Stennert E, et al.: Duplication of the external auditory canal: a report of three cases. Int J Pediatr Otorhinolaryngol 58:179, 2001.

10.8 Synotia/Otocephaly Definition

Synotia/otocephaly is a malformation involving the mandible and external ears, consisting of marked underdevelopment or almost total absence of the mandible and the presence of the external auricles anteriorly and inferiorly, approaching fusion near the midline. This spectrum of defects includes synotia, agnathia, otocephaly, and agnathia-holoprosencephaly. Diagnosis

This complex early defect in craniofacial development is easily diagnosed by inspection on physical examination (Fig. 10-6). The

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Fig. 10-6. Synotia. Sketches of infants with otocephaly showing variable configuration of the ears and other facial structures. (From Gorlin et al.1)

mandible is either totally missing or very small, with the external ears present near the midline in the usual place of the mandible. A very small or absent oral opening is a consistent feature, and there is often persistence of the buccopharyngeal membrane. Because of the respiratory difficulties and the associated central nervous system defects, all children with this malformation have died in the perinatal period. Gorlin et al.1 recently reviewed the literature on this disorder. The facial defect may occur alone or in association with holoprosencephaly. This particular combination is probably a unique developmental defect. Most individuals who have the agnathia-holoprosencephaly defect have cyclopia as opposed to the other holoprosencephalic facies. Since there are only two known recurrences of otocephaly,2,3 and the sibs both had agnathia and holoprosencephaly as part of the disorder, it is difficult to know whether isolated synotia/otocephaly is part of the agnathiaholoprosencephaly continuum. Over 100 cases have been reported in the medical literature. A number of the individuals have other associated malformations, but, as was mentioned above, the combination of agnathia and holoprosencephaly is probably the most important associated defect. Pauli et al.,4 Stoler and Holmes,5 Ozden et al.,6 and others have described cases of agnathia with situs in versus, vertebral defects, and renal malformations. The latter combination may represent a distinct pattern of malformation of unknown etiology. One important observation of agnathia and one of the only occurrences in sibs was made by Pauli et al.2 This family included two sibs, one who had cebocephaly and agnathia and the other who had a milder craniofacial defect with severe micrognathia and arhinencephaly on autopsy. This particular combination of sibs has been widely cited as one of the few examples of familial agnathia/otocephaly among humans. It has recently been documented that this family had an unbalanced chromosome finding involving 6p and 18p.7 One of the stillborn infants in the original series was rekaryotyped and was found to have a derivative chromosome 18 and to be partially trisomic for the distal part of 6p and monosomic for the distal half of 18p. A number of other congenital defects have been reported in cases of agnathia, but no syndrome pattern has emerged other than those mentioned above. Etiology and Distribution

The precise frequency of otocephaly is unknown. There were two cases among 200,000 births in the Spanish Collaborative Project, giving a birth prevalence of approximately one in 100,0005 (personal communication: Dr. Maria Luisa Martinez-Frias). Gorlin et al.1 cited a prevalence of one in 60,000. Various authors have postulated that the basic defect in the pathogenesis of otocephaly is an alteration in neural crest migration. Juriloff et al.8 have described an autosomal recessive version among

mice, who also have holoprosencephaly. Clarke et al.9 have documented the frequency of agnathia, referred to as aglossia, in C57 and C3H mice, to be approximately one in 200. This defect in C57 mice is sporadic. Holoprosencephaly has not been sought in this mutant, although choanal atresia and aglossia are present. Mice heterozygous for Otx2 have otocephaly or agnathia-holoprosencephaly,10 indicating that this is a candidate gene in the human form. Otocephaly has been produced in experimental models in laboratory rodents using streptonigrin, trypan blue, hyperthermia, and X irradiation.11 The defect also occurs spontaneously in sheep, rabbits, and guinea pigs as well as in mice. Prognosis, Prevention, and Treatment

Otocephaly invariably results in death in newborns. As was mentioned above, this is probably due to marked respiratory deficiency resulting from the persistence of the buccopharyngeal membrane and frequent choanal atresia. The association of holoprosencephaly in many of the reported cases also probably adds a factor of lethality to this complicated developmental defect. Prenatal diagnosis by ultrasound has occurred on several occasions.12 Given the severity of morphologic findings in this disorder and its associated malformations, most cases could likely be detected by 16 to 20 weeks of gestation using high-resolution ultrasound. References (Synotia/Otocephaly) 1. Gorlin RJ, Cohen MM Jr: Syndromes of the Head and Neck, ed 3. Oxford University Press, New York, 1990. 2. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosencephaly. Am J Med Genet 14:677, 1983. 3. Porteous ME, Wright C, Smith D, et al.: Agnathia-holoprosencephaly: a new recessive syndrome? Clin Dysmorphol 2:161, 1993. 4. Pauli RM, Graham JM, Barr M: Agnathia, situs inversus and associated malformations. Teratology 23:85, 1981. 5. Stoler JM, Holmes LB: A case of agnathia, situs inversus, and a normal central nervous system. Teratology 46:213, 1992. 6. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn 22:840, 2002. 7. Krassikoff N, Sekhon GS: Letter to the editor: familial agnathiaholoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. Am J Med Genet 34:255, 1989. 8. Juriloff DM, Sulik KK, Roderick TH, et al.: Morphogenesis of spontaneously occurring otocephaly in a mouse mutant. Teratology 21:47A, 1980. 9. Clarke L, Hepworth WB, Carey JC, et al.: Chondrodystrophic mice with coincidental agnathia. Teratology 38:565, 1988. 10. Hide T, Hatakeyama J, Kimura-Yoshida C, et al.: Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development 129:4347, 2002.

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Craniofacial Structures

11. Santana SM, Alvarez SM, Alabern C, et al.: Agnathia and associated malformations. Dysmorphol Clin Genet 1:58, 1987. 12. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathiaholoprosencephaly: three-dimensional imaging by helical computed tomography. Prenat Diagn 21:68, 2001.

10.9 Low-set Ears Definition

Low-set ears are auricles situated low on the lateral face. Diagnosis

The term low-set ears refers to the observation that the auricle or perhaps the meatus is situated low on the individual’s face (Figs. 10-7 and 10-8). This disorder has received much attention in the pediatrics and genetics literature over the last few decades. In fact, the observation of low-set ears is one of the more common observations that the clinician makes when looking at a child who may have a multiple anomalies syndrome. However, the designation of low-set ears is not as useful clinically as is commonly thought. In fact, ‘‘low-set’’ ears are usually due to one of the following four reasons: the ears are small, the ears are posteriorly rotated along their longitudinal axes, the ears are overfolded as in a lop configuration, or the appearance of low-set ears is an illusion due to head tilting or the shape of the cranium. Rarely, an auricle is truly low-set, without posterior rotation. It makes more sense clinically to refer to the more specific observation, that is, small ear, lop ear, or posteriorly rotated ears. However, it is prudent at least to review the different criteria that investigators have used to define this disorder. Farkas1 has indicated that perhaps the best way to look at low-set ears is really to look at the bony meatus and its relationship to the face. He makes a clear and important distinction between ears that are low-set and ears that are posteriorly inclined or posteriorly rotated. Because the ear and its cartilage are a soft tissue structure with many variables, Farkas prefers looking at the relationship of the external meatus to the midface. His criteria for determining low-set ears are as follows: a special profile line is Fig. 10-7. Schematic showing ear placement relative to a horizontal line through the outer canthi of the eyes. Ears are considered low set when the root of the helix is below this line (see also Fig. 10-9). (Courtesy of Dr. Paul R. Dyken, University of South Alabama College of Medicine, Mobile.)

determined (a line connecting the glabella with the most prominent portion of the upper lip), and a perpendicular line is then made from the highest point of the external meatus to this profile line. If this line falls below the upper edge of the alae nasi, the ear canal is low-set. Two other criteria have been suggested in the pediatrics and dysmorphology literature to define low-set ears. The most widely mentioned and cited are those of Feingold and Bossert.2 The technique involves using a piece of radiograph material that is pliable. A series of parallel lines are drawn on the paper, and a line drawn between the inner canthi is extended back to the top of the auricle. The percentage of auricle above the line, or millimeters reached above this line, is recorded, and percentiles are plotted. This measurement obviously depends on the posterior rotation of the auricle as well as the normality of the superior aspect of the pinna. A lop/cup or type I microtia ear would probably fall in the lower percentiles of these curves. Aase3 has suggested that a clinically easy way to measure lowset ears is to take a line that is perpendicular to the lateral aspect of the orbit. This line should cross near the superior attachment of the ear. If it does not, the ear is considered low-set. The syndromes that involve low-set ears obviously overlap with syndromes that produce microtic ears (Table 10-4), lop/cup ear malformation (Table 10-8), and posteriorly rotated ears. As was mentioned in Section 10.1, there is a purported association mentioned in the pediatric and otolaryngology literature of ear and kidney defects. The implication of this association is that, when the clinician sees an ear abnormality, he or she should consider a renal malformation. This particular association is mentioned in most standard pediatrics textbooks and probably has resulted in many children over the last few decades undergoing invasive urologic studies. The question really comes down to the following: is there some special developmental relationship between the external ear and the renal system that is unique and beyond the pleiotropic relationship that exists when ear and kidney malformations are both present as components of heritable syndromes? If there is such a relationship, then one could use an external ear defect as a marker to suggest a kidney malformation. The first mention that the ears and kidneys may be related comes from the concurrence of ear abnormalities and renal malformations in the so-called Potter syndrome. It is now known, of course, that the Potter ‘‘syndrome’’ represents a sequence in which the external, nonrenal defects are secondary to oligohydramnios. This being the case, the ear findings in the Potter syndrome really are secondary to the oligohydramnios, which is secondary to the intrauterine renal oliguria rather than there being some special developmental relationship between the ears and the kidneys. Many of the cases cited suggesting a special developmental relationship between the ears and kidneys were children who had syndromes, often the oculo-auriculo-vertebral spectrum, in which renal malformations sometimes occur.4,5 These papers also reported individuals who would now be considered to have the branchio-oto-renal syndrome. The range of renal defects is usually quite wide, and often they are of minimal medical significance, such as a bifid ureter. Melnick and Myrianthopoulos6 have emphasized the potential relationship between the kidney and the ears. They cite results from the Perinatal Collaborative Project as evidence for such an association; however, it is difficult to conclude from these data that there is any special relationship between the kidneys and the external ear. The odds ratio that is cited involves bifid ureters, and most of the children in the control group would not have undergone a urologic investigation.

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Fig. 10-8. Low-set ears. Measurement of portion of ear (A) and percentage of ear (B) above the level of the eyes. (From Feingold and Bossert.2)

Thus, there is no conclusive epidemiologic evidence of an increased risk of renal malformations associated with ear malformations other than the relationship that exists in known, identifiable syndromes. Recently, Wang et al.7 showed that a renal investigation is only necessary in the patient who has a syndrome in which kidney defects occur. The other problem in this discussion has to do with the issue of what type of ear malformation would suggest a kidney defect in the first place. This could include almost any auricular defect. In the early papers in the otolaryngology literature, there was no distinction between grades of severity that would suggest a kidney problem. Considering simply nonsyndromic microtia, there still appears to be no conclusive evidence warranting routine imaging studies in children with microtia or low-set ears. Etiology and Distribution

Prevalence studies of ear malformations have not recorded low-set ears in particular. Since type I microtia and lop/cup ears fall into this category, one could at least estimate their frequency from those

birth prevalence figures. However, as was mentioned above, the determination of low-set ears is somewhat artificial, so this prevalence figure is not helpful. Posteriorly rotated ears can be defined by percentiles based on data of Farkas.1 References (Low-set Ears) 1. Farkas LG: Anthropometry of the Head and Face in Medicine. Raven Press, New York, 1994. 2. Feingold M, Bossert WH: Normal values for selected physical parameters: an aid to syndrome delineation. Birth Defects Orig Artic Ser X(13):1, 1974. 3. Aase JM: Microtia-clinical observations. Birth Defects Orig Artic Ser XVI(4):289, 1980. 4. Hilson D: Malformations of the ear as a sign of malformation of the genitourinary tract. Br Med J 2:785, 1957. 5. Taylor WC: Deformity of ear and kidney. Can Med Assoc J 93:107, 1965. 6. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9): 1, 1979. 7. Wang RY, Earl DL, Ruder RO, et al.: Syndromic ear anomalies and renal ultrasounds. Pediatrics 108E:32, 2001.

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Craniofacial Structures

10.10 Posteriorly Rotated Ears Definition

Posteriorly rotated ears are a variation of the external ear in which the vertical axis of the ear is rotated posteriorly (Fig. 10-9). An extreme degree of this posterior rotation is sometimes called melotia. Description

Posteriorly rotated ears are an important cause of the commonly cited finding of low-set ears. In fact, the majority of infants who are labeled as having low-set ears either have posteriorly rotated ears or the observation of low-set ears represents an illusion. The diagnosis is made on physical examination. Farkas1 has developed criteria and normal angles for rotation of the external ear. Posteriorly rotated ears are defined as an increased posterior rotation of the auricle on its longitudinal-vertical axis. This angulation is measured by establishing the Frankfurt horizontal (FH), dropping a perpendicular line onto the FH at the ear, and measuring the angulation away from the vertical. Range of normal in schoolaged children is usually between 108 and 208. Melotia is a term used in the older literature to refer to a strikingly posteriorly rotated ear where the actual longitudinal axis of the ear is almost parallel to the body of the mandible and the ear may be situated close to the angle of the mandible on the cheek. Posteriorly rotated ears occur as a nonspecific variation in a number of chromosome conditions, but in particular they are seen in Turner syndrome and Noonan syndrome.2 The etiology and pathogenesis of posteriorly rotated ears as a variation and malformation are unknown. Certainly, the disorder could be perceived as a developmental arrest; that is, the external ear, which normally is situated in some degree parallel to the developing Fig. 10-9. Schematic showing posterior rotation of the ear with the angle (arrow) between the facial plane (C,D) and the long axis of the ear (B) exceeding 208. The ear shown here is also low set, with the attachment of the root of the helix below a horizontal line extending from the outer canthus of the eye (A). (Adapted from Aase.3)

mandible, does not rotate properly to the side of the face. The actual frequency of posteriorly rotated ears is unknown, but, if one uses the percentiles in Farkas’1 curve, 2% of people would fall below the curve by definition alone. Mild degrees of posterior angulation are very nonspecific and common and are not particularly useful in the recognition of syndromes. Posteriorly rotated ears are a variation of ear development that is perceived as stigmatizing or of visual significance to the individual. In the person who has an extreme degree, as in Turner syndrome, reconstructive surgery is an option. References (Posteriorly Rotated Ears) 1. Farkas LG: Anthropometry of the Head and Face. Raven Press, New York, 1994. 2. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 3. Aase JM: Diagnostic Dysmorphology. Plenum, New York, 1990.

10.11 Lop/Cup Ear Anomaly Definition

Lop/cup ear anomaly is an anomaly of the auricle involving a downward folding and deficiency of the superior aspect of the helix, often associated with an exaggerated or overdevelopment of the concha. Lop/cup ear represents underdevelopment or hypoplasia of the superior one-third of the auricle. It is sometimes referred to as constricted ear and overlaps with type I microtia. Diagnosis

The lop/cup ear defect represents one of the common and more important alterations of the external ear. The line of separation between the lop/cup ear and microtia type I is hard to draw, and certainly some ears described as showing type I microtia fall into this group. As was pointed out by Rogers,1 a confusing array of terms has been applied to this class of external auricular defect. Many of the terms are derogatory and pejorative but are used in the literature; examples include bat ears, simple ears, satyr ears, and elf ears. This defect probably represents a continuum of alterations of plical folding of the auricle. It could on some occasions be the result of deforming forces and at other times be a true alteration of the morphogenesis (malformation) of intrinsic muscles and/or cartilage folding. There is no standard definition in the plastic surgery and otolaryngology literature for the lop/cup ear defect, and different authors use the term in different ways. Since Rogers so clearly demonstrated a continuum of ear defects, the present author has chosen to refer to this defect as the lop/cup ear anomaly.1 Tanzer2 has labeled this defect constricted ear and has divided it into groups I through III according to the surgical challenges (Fig. 10-10). Group I defects represent the more traditional lop ear and involve an overfolding of the helix along its superior rim, producing some decrease in height and a flattening of the superior helix/ scapha region. Sometimes the folded helix is so closely adherent to the scapha tissue that it appears to be attached. Group II anomalies are more noticeable and involve both the helix and the adjoining scapha. The lack of cartilage folding involves the crura of the anthelix, and the anthelix itself may be flattened. There is a more striking hood, and the length of the ear is reduced. A prominence or protrusion of the ear is usually found, and there is an exaggerated overdevelopment of the cup-shaped, concave concha. The defect is usually what Rogers has

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Fig. 10-10. Lop/cup ear. This anomaly is characterized by underdevelopment of the superior one-third of the pinna and downward folding of the superior helix. It is closely related to microtia (see Fig. 10-2). (From Aase JM: Diagnostic Dysmorphology. Plenum, New York, 1990.)

called the cup ear and has components of both lop ear and protruding ear.1 Group III of the lop/cup ear defect is a severe version of group II, and the auricle is markedly rolled over the inferior portion of the ear, so the ear is always low-set on the cranium. The term cockleshell ear has been used to refer to this group III defect.

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As in microtia, the lop/cup ear raises the question of hearing loss, but the association is not as frequent. The severe end of the spectrum probably represents a malformation and thus is more commonly associated with middle ear defects, as is microtia, while milder degrees of the defect may more often be a deformation and are rarely associated with middle ear changes. Most affected individuals seeking plastic surgery have the lop/cup ear as an isolated defect and not as part of a well-defined syndrome. No studies actually give a frequency figure of associated malformations. However, in the Spanish Collaborative Project, about 25% of the cases listed as ‘‘dysplastic ear’’ had this as part of a syndrome (personal communication: Dr. Maria Luisa Martinez-Frias). This probably represents at least some estimation of the frequency of this problem occurring as part of a syndrome. Most of the syndromes that include microtia/anotia can also involve this milder auricular abnormality. Table 10-8 lists the syndromes that have lop/cup ear anomaly as a component manifestation and rarely have microtia II through IV. It is important to underscore that the line between milder degrees of microtia and the lop/cup ear defect is not easily drawn. Etiology and Distribution

Because of definitional issues, it is difficult to estimate a precise prevalence-at-birth figure for the lop/cup ear defect. In the Melnick and Myrianthopoulos3 review of the Perinatal Collaborative Project, 61 infants, for a rate of 11.45 in 10,000 or just under one in 1000 infants, were labeled as having ‘‘other malformed pinna.’’ The frequency of the ‘‘dysplastic ear’’ in the Spanish Collaborative Project is 5.47 in 10,000 or just under one in 2000. Thus, a figure of

Table 10-8. Syndromes that include lop/cup ear anomaly (occasionally having microtia types II–IV) Causation Gene/Locus

Syndrome

Prominent Features

Branchio-oto-renal

Branchial sinuses, ear and renal anomalies

AD (113650) EYA1, 8q

Familial blepharophimosis

Blepharophimosis, ptosis, epicanthus inversus, subfertility in females

AD (110100) FOXL2, 3q23

Fraser

Cryptophthalmia, syndactyly, Mu¨llerian defects, renal agenesis

AR (219000) FRAS1, 7q

Kabuki

Distinctive face, cleft palate, short stature

AD (147920)

LADD

Lacrimal (nasolacrimal duct obstruction, auricular (hearing loss and cup-shaped pinnae), dental anomalies (small lateral incisors), digital anomalies (variable)

AD (149730)

Lee

Distinctive face, premature aging, short stature

Uncertain

LMC

Micrognathia, conductive hearing loss

AD

Mengel

Unusual ear defects, conductive hearing loss, mental retardation, hypogonadism

AR (221300)

Oto-facio-cervical

Long face, narrow nose, ear pits, web neck, sloping shoulders, cervical fistulas (?same as branchio-oto-renal syndrome)

AD (166780)

Townes-Brocks

Imperforate anus, triphalangeal thumb and other digital anomalies, absence or fusion of foot bones, hearing loss

AD (107480) SALL1, 16q

Tricho-rhinophalangeal

Sparse hair, prominent nose, epiphyseal dysplasia

AD (190350) TRPS1, 8q24

Trisomy 21

Flat facies, upslanting palpebral fissures, small mouth, short stature, brachydactyly, mental retardation

Chromosomal

Del 4q

Cleft palate, nail defect—second digit, mental retardation

Chromosomal

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about one in 1000 to 2000 gives some idea of the birth prevalence. These figures are in contrast to the Japanese experience. Matsuo and colleagues4 indicated that the frequency of the lop ear was 38.1% at birth and 6.1% at age 1 year. These investigators as well as others in Japan have developed strategies of nonsurgical correction of congenital auricular defects. The fact that the frequency of lop ear actually decreased from the newborn period to the age of 1 year suggests that often the mildest form of this defect is in fact due more to intrauterine constraint that resolves during the 1st year of life. The discrepancy in these figures may also result from the recording of very mild degrees of overfolding of the helix in the Japanese series or from true ethnic differences. These points, however, indicate the difficulties in definition of phenotypic variations of the body, especially of the ear. A precise etiology or pathogenesis of the lop/cup ear defect is not determined in most individuals who have the defect. As was mentioned above, the milder degrees of the lop/cup ear defect may truly be a deformation related to intrauterine compression. The fact that many of the cases in Japan of the so-called lop/cup ear defect resolved supports this notion, as does the recent success in tape attachment and other nonsurgical approaches to these defects.4,5 Nonsyndromic lop/cup ear defects have been seen as an autosomal dominant trait in a number of families; however, the proportion of cases due to an autosomal dominant gene is unknown. Smith and Takashima6 and Zerin et al7 have suggested that the lop/cup ear defects as well as the protruding ear may be due to alterations of plical folding of the cartilaginous ear plate that are, in fact, secondary to changes in the extrinsic and intrinsic ear muscles. These investigators suggest that the ear muscles and perhaps the nerve that innervates the muscles are crucial in determining the form and position of the cartilage of the ear. Their dissections of fetuses with anencephaly, who often have the lop/cup defects, along with experimental evidence in rodents and rabbits suggest that the intrinsic auricular muscles are important for the complicated relief of the external ear. Experimental evidence also shows the importance of neuromuscular factors in external ear development. Chiu et al.,8 working with the auricle of the rat, produced changes in auricular form following neurectomy of the auricular nerve. Based on this work, Smith and Takashima6 suggested that the protruding ear results from an alteration of the posterior auricular muscle, while the lop ear results from an alteration of the superior auricular muscle. Prognosis, Prevention, and Treatment

The major impact of the lop/cup ear defect is visual, a potential stigma for the individual who exhibits the defect. The natural history of the deformations producing a lop/cup ear appearance is for spontaneous resolution, as was emphasized by Graham9 and in the Japanese series.4 The challenge is that it is not always easy to determine which of the defects will resolve and which will persist. Tanzer2 has summarized the surgical approach to the lop/cup ear defect. In this abnormality, not only does the protruding ear need repair, but also restoration of the normally shaped helix scapha and anthelix is necessary. More severe cases may require multistage reconstruction. More recently, Elsahy10 and Park11 have published their modifications of the surgical approach to lop/cup ears that resulted in good outcomes. In the 1980s, the Japanese introduced the concept of nonsurgical correction of congenital ear defects, including the lop/cup ear defect.4 The abnormal folding is corrected by splinting with dental compound using Aluwax. Surgical tapes are also used when appropriate. Utilizing this approach, investigators have emphasized that early correction is critical for outcome. Results are less successful after age 6 weeks, when ear elasticity and form have become better

established. In the Japanese experience, with the high frequency of the lop ear defect, many babies whose ears are splinted undergo this therapy unnecessarily, since over 80% of cases resolve on their own. More recently, Ullmann et al.12 reported their results using early splinting with PuttySoft; 87% were graded as ‘‘excellent.’’ It may be that these milder degrees of lop ear deformity are third-trimester deformational events related to high levels of circulating estrogen. Since no controlled studies are available, and since there are numerous definitional problems regarding the spectrum of the lop/cup ear defect, it is difficult to conclude at this point that nonsurgical correction is the best approach for the more moderate or the severe end of the continuum. References (Lop/Cup Ears) 1. Rogers B: Microtic, lop, cup and protruding ears. Plast Reconstr Surg 41:208, 1968. 2. Tanzer RC: The constricted (cup and lop) ear. Plast Reconstr Surg 55:406, 1975. 3. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9): 1, 1979. 4. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990. 5. Brown FE, Colen LB, Addante RR, et al.: Correction of congenital auricular deformities by splinting in the neonatal period. Pediatrics 78:406, 1986. 6. Smith DW, Takashima H: Ear muscles and ear form. Birth Defects Orig Artic Ser XVI(4):299,1980. 7. Zerin M, Van Allen MI, Smith DW: Intrinsic auricular muscles and auricular form. Pediatrics 69:91, 1982. 8. Chiu DT, Crikelair GF, Moss ML: Epigenetic regulation of the shape and position of the auricle in the rat. Plast Reconstr Surg 63:411, 1979. 9. Graham JM: Smith’s Recognizable Patterns of Human Deformation, ed 2. WB Saunders Company, Philadelphia, 1988. 10. Elsahy NI: Technique for correction of lop/cup ear. Plast Reconstr Surg 85:615, 1990. 11. Park C: Modification of two-flap method and framework construction for reconstruction of atypical congenital auricular deformities. Plast Reconstr Surg 99:1846, 1997. 12. Ullmann Y, Blazer S, Ramon Y, et al.: Early nonsurgical correction of congenital auricular deformities. Plast Reconstr Surg 109:907, 2002.

10.12 Protruding Ear Definition

Protruding ear is a laterally prominent auricle with the usually normally sized ear standing out from the head at an angle of greater than 408. Protruding ear is often considered a variation of the lop/cup ear defect. Diagnosis

This defect is easily recognized by measuring the angle of the posterior aspect of the pinna and the mastoid occipital plane. Farkas has developed standards for this angle of protrusion, and in school-aged children, both male and female, the angle is less than 408. In the protruding ear, the distance from the outer rim of the helix to the mastoid is greater than 2 cm (Fig. 10-11). The prominent ear involves some alteration of plica whereby the angle between the scapha cartilage and the concha cartilage is changed. Usually this relationship is about 908, but in the prominent ear the angle between these cartilages increases to 1308. The anthelix is often flattened, and the protruding ear is usually normal in size but occasionally is larger. It usually appears larger than it is

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Fig. 10-11. Protruding ear. Normal-sized ear, which stands out from the head at an angle of 408 or more. (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.)

because of its lateral prominence. As was mentioned in Section 10.11, the lop/cup ear defect often involves a lateral prominence, and Rogers2 has suggested that the protruding ear is simply the severe end of this continuum. Occasionally, the helical fold is

unraveled in the so-called shell or unraveled ear. As has always been the case in the literature, the definitions of the variations of the external ear are not established, and terminology is often misleading, confusing, and pejorative.

Table 10-9. Syndromes/disorders in which protruding auricle occurs as a feature Causation Gene/Locus

Syndrome

Prominent Features

Aarskog

Hypertelorism, shawl scrotum, short stature

XLR (305400) FGD1, Xp11

Myotonic dystrophy

Long face, myotonia

AD (160900) DMPK, 19q32

Congenital hypotonia phenotype

Hypotonia, ± joint contractures, long face, narrow palate, small jaw

Heterogenous

Anencephaly

As noted

Multifactorial (206500)

Prenatal alcohol

Prenatal and postnatal growth deficiency, distinctive face, developmental delay

Excessive alcohol in utero

Cohen

Distinctive face/teeth, long thin fingers

AR (216550) COH1, 8q22

Tricho-rhino-phalangeal

Sparse hair, prominent nose, brachydactyly, short stature

AD (190350) TRPS1, 8q

Noonan

Distinctive face, webbed neck, pectus excavatum, pulmonic stenosis

AD (163950) PTPN11, 12q

Coffin-Lowry

Coarse face, tapered fingers, pectus carinatum

XL (303600) RSK2, Xp22

Mandibular-facial dysostosis, Toriello type

Mandibular hypoplasia, distinctive face

X-linked

Kabuki

Distinctive face, long palpebral fissures, mental retardation, short stature

Unknown (147920)

Trisomy 21

Distinctive face, brachydactyly, mental retardation

Chromosomal

Trisomy 18

Prenatal growth deficiency, distinctive face/hands, short sternum, congenital heart defects

Chromosomal

Del 4p

Distinctive face, mental retardation, growth deficiency

Chromosomal

45, X

Short stature, distinctive face, webbed neck

Chromosomal

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Most individuals with a protruding ear have it as an isolated anomaly and not as part of a syndrome. Smith and Takashima3 have suggested the laterally prominent ear, like the lop/cup ear, is a sign of alteration of neuromuscular function. Table 10-9 lists a number of syndromes that include a laterally prominent ear. Etiology and Distribution

The birth prevalence of the protruding ear is not available. Most epidemiologic studies examining the frequency of external ear defects have not included this finding, due to the fact that the laterally prominent ear usually becomes more obvious with age. In a Japanese study, protruding ear was recognized to be an acquired defect, and the frequency in the newborn period was less than 1% while it was 5.5% by age 1 year.4 Farkas has also documented the age effect of this ear variation.1 Prognosis, Prevention, and Treatment

As in the lop/cup ear defect, the social stigma of the protruding ear is its major impact. Otoplasty is the standard surgical technique, and a number of strategies to approach the problem have been developed during this century. The basic approach in surgery for protruding ears is to create a prominent anthelix. Various techniques involve the creation of the desired anthelical fold.5 Recently, Brenda et al. presented their approach.6 As in the lop/cup defect, a nonsurgical approach to the correction of this anomaly has also emerged. The basic principle involves the application of surgical tape to the posterior helical rim, affixing it to the temporal region; a headband is often used for reinforcement. A headband alone has also been utilized to correct the prominent ear. Brown et al.7 have placed dental compound in the sulcus between the ear and the scalp to bring about normal anthelical folding. As with the standard technique, the ear is held in position with surgical tape. These nonsurgical approaches are used primarily in the newborn period.

Apparently, this approach has also been effective when utilized as late as age 6 months; however, the later that the strategy is initiated, the longer the period for which taping will be necessary. References (Protruding Ear) 1. Farkas LG: Anthropometry of the Head and Face. Raven Press, New York, 1994. 2. Rogers B: Microtic, lop, cup and protruding ears. Plast Reconstr Surg 41:208, 1968. 3. Smith DW, Takashima H: Protruding auricle: a neuromuscular sign. Lancet 1:747, 1978. 4. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990. 5. Elliott RA: Otoplasty: a combined approach. Clin Plast Surg 17:373, 1990. 6. Brenda E, Marques A, Pereira MD, et al.: Otoplasty and its origins for the correction of prominent ears. J Craniomaxillofac Surg 23:99, 1995. 7. Brown FE, Colen LB, Addante RR, et al.: Correction of congenital auricular deformities by splinting in the neonatal period. Pediatrics 78:406, 1986.

10.13 Stahl Ear Definition

Stahl ear is an abnormal and distinctive extra fold or crus of the anthelix that extends from the superior portion of the anthelix to the upper posterior aspect of the corner of the helix. This extra fold produces a ‘‘crumpled’’ ear appearance. Diagnosis

The diagnosis of the Stahl ear is made simply through an inspection on physical examination. This ear variation is obvious to anyone who has seen the finding (Fig. 10-12). In the literature on the congenital contractural arachnodactyly syndrome, the disorder is

Fig. 10-12. Left: Stahl ear showing a fold extending from the superior portion of the anthelix to the upper posterior corner of the helix. Stahl ear is also called crumpled ear. Right: configuration of the ear after splinting with an Aluwax mold for 1 month. (From Brown et al.4)

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referred to as a ‘‘crumpled ear.’’1 It has also been labeled as the crus antihelicis tertium.2 Apart from its presence in the congenital contractural arachnodactyly syndrome, it is usually an isolated finding and not part of a syndrome. Etiology and Distribution

The Stahl ear was the second most common auricular defect in the Japanese series,3 occurring in 8% of all Japanese newborns, but the finding decreases over time, with a frequency by age 12 months of only 1.3%. It probably represents abnormal plica folding and is another example, like the lop/cup ear defect, of an alteration in intrinsic auricular muscles with secondary effects on ear form. The frequency of Stahl ear is unknown except in the Japanese series. Prognosis, Prevention, and Treatment

The Stahl ear, as with the lop/cup ear, has been of interest to the Japanese investigating the nonsurgical correction of congenital auricular defects. Matsuo et al.3 claim success in most individuals with the Stahl ear when Aluwax and surgical tape are applied in the first few days of life. The abnormal fold is pressed out, and the normal concavite scapha helix is molded. If nonsurgical correction is initiated in the early neonatal period, only 1 week is necessary to change the auricle to its normal shape; the wax is retained for a few weeks to guarantee that the corrected shape remains permanently. Brown and colleagues4 also claim success in the treatment of a Stahl ear using this dental compound and tape. Since in many of the Japanese infants with Stahl ear the defect resolved by itself in the 1st year of life, the exact efficacy of this therapy is unclear. Certainly the experiences of Matsuo et al.3 and Brown et al.4 suggest success, but it is possible that many of these defects would have resolved without the wax and tape. As in the lop/cup ear defect, early intervention is suggested by the authors who use this nonsurgical approach. For individuals who are recognized in later life to have Stahl ears, reconstructive surgery is available. The impact of this variation, however, is minimal. References (Stahl Ear) 1. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 2. Altmann F: Malformations of the auricle and the meatus. Arch Otolaryngol 54:115, 1951. 3. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical congenital auricular deformities. Clin Plast Surg 17:383, 1990. 4. Brown FE, Colen LB, Addante RR, et al.: Correct auricular deformities by splinting in the neonatal. Pediatrics 78:406, 1986.

10.14 Mozart Ear Definition

Mozart ear is a defect of the external auricle consisting of a prominent superior anthelix caused by a fusion of the crura of the anthelix and the crura of the helix. The anomaly is said to have affected Wolfgang Amadeus Mozart and his son. It has also been called the Wildermuth ear. Diagnosis

This variation of the external auricle probably has no medical significance unless it occurs as part of a syndrome. Davies1 and Paton et al.2 have discussed the description and history of this ear defect (Fig. 10-13). It is still unclear whether Mozart had this ear anomaly,

Fig. 10-13. Mozart ear.

but it appears likely that his son, Franz, did. The salient features of the defect include a broad-appearing auricle with a prominent anthelix such that the two crura of the anthelix are fused and are united with the crus of the helix. The concha then is enlarged, and the antitragus is missing or underdeveloped. The ear lobe is underdeveloped or very small. Sometimes the helical fold appears unraveled, altering the relief of the external auricle. Although there is no direct evidence that Mozart himself had the anomaly, the term has taken on such a meaning in the medical literature that it is probably appropriate to retain the eponym, especially since Mozart’s son probably did have the defect. These observations suggest that this ear abnormality is an autosomal dominant trait. Paton and colleagues2 found 13 examples of the Mozart ear in patients about to have reconstructive plastic surgery of the ear. Their work and the work of Davies1 do not cite the occurrence of this finding as part of a generalized syndrome. However, prominence of the anthelix is a consistent finding in the deletion 18q syndrome.3,4 A review of some photographs of children with 18qsuggests that their finding is also part of the continuum of the Mozart ear. The so-called faun ear described in the trisomy 18 syndrome also has components of the Mozart ear. This finding has been noted in the CHARGE syndrome, as well. Etiology and Distribution

Paton and colleagues2 carried out two surveys, one involving 1185 consecutive individuals and the other involving 1092 patients in a medical clinic. They found one case in each group, or about one in 1100 adults with this defect. Although there is no evidence regarding the pathogenesis in this finding, it may be one of the abnormalities of intrinsic auricular muscle development, as in the lop/cup ear defect. It is of note that the three specific syndromes in which the Mozart ear has been noted, trisomy 18, deletion 18q, and CHARGE syndrome, all have narrowed ear canals. There may be some developmental relationship between the Mozart ear and the development of the external ear auditory meatus. Garcia-Cruz et al.4 described a boy with multiple anomalies and the Mozart ear. Prognosis, Prevention, and Treatment

Reconstructive plastic surgery is available for individuals with the Mozart ear. Correction of this defect through a nonsurgical

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approach, that is, splinting or molding using Aluwax, may be an option in the future, although there has been no documented application as yet.

Reference (Darwinian Tubercle)

References (Mozart Ear)

10.16 Prominent Crus of the Helix

1. Davies PJ: Mozart’s left ear, nephropathy and death. Med J Aust 147:581, 1987. 2. Paton A, Pahor AI, Graham GR, et al.: Looking for Mozart ears. Br Med J 293:1622, 1986. 3. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 4. Garcia-Cruz D, Sanchez-Corona J, Ruenes R, et al.: A syndrome with mixed deafness, Mozart ear, middle and inner ear dysplasias. J Laryngol Otol 94:773, 1980.

10.15 Darwinian Tubercle Definition

Darwinian tubercle is a small protrusion on the helix of the auricle just below the margin where the superior helix curves down to the inferior helix, usually at the level of the superior crus of the anthelix (Fig. 10-14).1 Description

This medically insignificant phenotypic variation is easily recognized by the examiner who searches for it. It is documented simply for historic reasons; it is not a marker for any particular syndrome, and it is not known to be associated with middle or internal ear defects. The frequency of the Darwinian tubercle is approximately 1% in population studies. Females are said to show the protrusion more often than males. The tubercle is usually present in fetal life up to about 7 weeks and then disappears. Thus, in infancy and childhood it is a persistence of a pointlike structure that usually resolves. Some evolutionary biologists have suggested that the tubercle of Darwin is at the place where other mammalian ears are pointed. Since a Darwinian tubercle has no visual or cosmetic significance, no treatment is necessary. Prognosis is not an issue, since it is not a marker for other malformations. Fig. 10-14. Darwinian tubercle (arrow), an insignificant feature of external ear anatomy.

1. Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov.

Definition

Prominent crus of the helix is an unusual prominence or posterior flaring of the crus of the helix. Description

The crus of the helix usually extends around inferiorly and posteriorly just into the concha and above the auditory meatus. Usually, this fold ends gradually as it moves above the auditory meatus. Occasionally, there is a striking prominence of this fold, so that it extends back to the anthelix. This disorder produces an unusual-appearing ear configuration; it was described by Aase1 as a ‘‘railroad track ear’’ (Fig. 10-15). The superior aspect of the anthelix and this unusually prominent crus of the helix parallel each other, producing a more prominent cymbal concha. Unusual prominence of the helix has been described in fetal alcohol syndrome and in the Sathre-Chotzen syndrome.1,2 Jaffe3 described an 11-year-old Navajo boy with an unusual flared end of the prominent crus of the helix and an absent external meatus. This individual also had auricular skin tags and conductive hearing loss. Surgical creation of an external meatus improved hearing significantly. The frequency of variations of the crus of the helix is unknown. This finding is probably a variation of plica folding and perhaps alteration of intrinsic auricular muscles, producing this secondary change in form. This particular variation has no stigmatizing impact; its only significance is as a clue to the above-mentioned syndromes. References (Prominent Crus of the Helix) 1. Aase JM: Microtia-clinical observations. Birth Defects Orig Artic Ser XVI(4):289, 1980. 2. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 3. Jaffe BF: Pinna anomalies associated with congenital conductive hearing loss. Pediatrics 57:332, 1976.

10.17 Lobular Defects Definition

Lobular defects are alterations of the form or contour of the ear lobe, including bifid and notched ear lobe (Fig. 10-16), uplifted lobules, antitragus base tag, and thickened ear lobes. Diagnosis

The diagnosis of any of the ear lobe variations described herein is made with visualization on physical examination of the auricular lobule. A notched ear lobe was recorded in one in 300 newborns in Holmes’ unpublished data of minor anomaly prevalence in newborns (personal communication: Dr. Lewis Holmes). A true bifid ear lobe, with two separate lobes, is less common, occurring in only one in 3000 to 4000 infants. These ear lobe findings are usually unilateral and rarely syndromic. The defects usually occur by themselves and are not clues to a malformation syndrome. A tag at the base of the antitragus was described as a dominant trait by Ramirez and Cantu.1 This has also been described in the

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Fig. 10-15. Crumpled ear, with ‘‘railroad track’’ horizontal folding of the anthelix, in two children with contractual arachnodactyly. Ear in B is also retroverted. (Courtesy of Dr. Charles I. Scott, Jr., A.I. DuPont Institute, Wilmington, DE.)

Goldberg-Pashayan syndrome of abnormal ear lobes and ulnar polydactyly.2 Thickened ear lobes are of note in that they were described as an external marker associated with conductive hearing loss and discontinuity between the incus and the stapes. This latter finding has been described in two families and has been referred to as the Escher-Hirt syndrome (see Section 10.24).3

and pathogenesis of these variations of ear lobe development are also unknown. An uplifted ear lobule could be secondary to intrauterine constraint and the shoulder pushing up on the ear lobe. Uplifted ear lobules are also seen as part of the Turner syndrome and perhaps are related to the intrauterine cystic hygroma of that syndrome. Prognosis, Prevention, and Treatment

Etiology and Distribution

The frequency of ear lobe variations has not been determined. As was mentioned above, bifid and notched ear lobes were recorded in the unpublished Boston data on minor anomalies.1 The frequencies of thickened ear lobes or tags of the ear lobes are unknown. The etiology

The significance of these findings is primarily as a clue to syndromes, and rarely are they associated with a need for reconstruction, the exception being extreme alteration of the ear lobes, such as a true bifid lobe or absence of the ear lobe. Park summarized the approach to lower auricular defects.4 References (Lobular Defects)

Fig. 10-16. Cleft ear lobe.

1. Ramirez M, Cantu JM: Two distinct autosomal dominant traits in the pinna. Birth Defects Orig Artic Ser XVIII(3B):243, 1982. 2. Goldberg MJ, Pashayan HM: Hallux syndactyly-ulnar polydactyly abnormal ear lobes: a new syndrome. Birth Defects Orig Artic Ser XII(5): 255, 1976. 3. Escher F, Hirt H: Dominant hereditary conductive deafness through lack of incus stapes junction. Acta Otolaryngol 65:25, 1966. 4. Park C: Modification of two-flap method and framework construction for reconstruction of atypical congenital auricular deformities. Plast Reconstr Surg 99:1846, 1997.

10.18 Auricular Tags Definition

Auricular tags are skin-colored, fleshy appendages represented as nodules or skin protrusions located usually just in front of the tragus of the ear. Diagnosis

Auricular appendages or tags are rather common, mild malformations located usually just in front of the auricle near the tragus (Fig. 10-17).1 These defects vary in size from 1 or 2 mm to several centimeters; they can be pedunculated on a short stalk or sessile.

352

Craniofacial Structures

Fig. 10-17. Preauricular tags in otherwise normal infant (A) and in infant with hemifacial microsomia (B). Postauricular tag in 32-week fetus with tracheoesophageal and genitourinary anomalies (C, D). Skin tag is covered with hair (ST) and is distinctly separate from microtic ear (RE). (Courtesy of Dr. Will Blackburn and N. Reede Cooley, Jr.)

Diagnosis is straightforward, and the disorder is usually not mistaken for any other congenital anomaly. Auricular tags follow an arc-shaped line of predilection from the temple just above the ear to the crus of the helix, then into the concha of the external auditory meatus, and out again just anterior and below the tragus. This line, according to some authors, is a line of junction between the first and second branchial arches. Occasionally, the preauricular tags will extend down from just anterior to the tragus to the angle of the mouth, that is, the oral-tragal line. This second zone corresponds to the line between the maxillary and mandibular portions of the first branchial arch. Tags or appendages in this latter location are more frequently combined with other malformations, such as microtia, and are commonly seen in the oculo-auriculo-vertebral (OAV) spectrum. Also, auricular tags located on the cheek are often associated with a pit or scarlike lesion. Etiology and Distribution

A number of the studies on the frequency of microtia/anotia have also included this mild malformation. Prevalence figures range

from about one in 300 to 1.5%. The Perinatal Collaborative Project reported a prevalence at birth of 17 in 10,000 or about one in 5002, while Holmes’ study in Boston records a frequency of just under 1% (personal communication: Dr. Lewis Holmes). Over 90% of individuals have the tag as a unilateral finding. Although most individuals have this mild malformation as an isolated problem, it may occur as part of a generalized syndrome (Table 10-10). In the Perinatal Collaborative Study, 89 of the 91 children had it as an isolated defect. In a study of 850 school children in Turkey, a tag was detected in 0.47%.3 In the Spanish Collaborative Study, however, approximately 2% of individuals with a preauricular tag had it as part of a syndrome (personal communication: Dr. Maria Luisa Martinez-Frias). Kankkunen and Thiringer4 found a prevalence of five in 1000 live births, and among their 188 cases with auricular tags, 5% had other malformations of the face and ear. Among the neonates in whom the tag was the only defect, 13% were found to have some degree of sensorineural hearing impairment, usually mild to moderate. The authors suggest an association between isolated ear

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Table 10-10. Syndromes that include auricular pits and/or tags Syndrome

Prominent Features

Causation

Branchi-oto-renal (pits)

Brachial sinuses, ear and renal defects

AD (113650) EYA1, 8q

Oculo-auriculo-vertebral spectrum (both)

Epibulbar dermoids, vertebral defects, variable heart defects

Heterogeneous; AD (164210) AD (257700) 14q

Michels syndrome

Oral face clefts, corneal opacities, growth delay

AD (257920)

Oto-facio-cervical (pits)

Ear pits, webbed neck, sloping shoulders

AD (166780)

Moeschler (both)

Thumb/radial defects

AD (141400)

Townes-Brocks (tags)

Anorectal defects, thumb and ear defects

AD (107480) SALL1, 16p12

Autosomal dominant microtia with meatal atresia (tags)

Microtia, atresia of external auditory canal

AD (251800)

Wildervank

Klippl-Feil anomaly, hearing loss, Duane anomaly

X (314600)

Cat eye (both)

Distinctive face, coloboma, anorectal defects

Chromosomal

Del 4p (both)

Distinctive face, mental retardation, growth deficiency

Chromosomal

Del 5p (both)

Round face, telecanthus, ear tags

Chromosomal

Dup 11q and many other chromosomal conditions

Growth delay, mental retardation

Chromosomal

tags and sensorineural hearing loss and recommend routine hearing assessment in all children with preauricular tags. Kugelman et al.5 recently performed renal ultrasound on 108 infants with tags (or pits) and found no increase in renal defects compared to controls. Early anatomists suggested that the auricular appendages resulted from excessive growth of the auricular hillock in the developing ear, perhaps representing a form of duplication of the original six hillocks (see Section 10.6). Occasionally, there is enlargement of the appendages, and they may group together to form a structure that almost resembles an extra auricle. However, as was mentioned in Section 10.6, a true accessory auricle is extremely uncommon, though the term accessory is sometimes used with regard to these mild malformations. As was mentioned in Section 10.1, auricular tags can be the mildest form of familial microtia. They are one of the more common findings in the family studies of microtia and hemifacial microsomia by the Chicago group. In a number of the kindreds with autosomal dominant-appearing microtia with meatal atresia, a preauricular tag is present in a person presumed to have the autosomal dominant gene for microtia. Thus, it is thought to represent the mildest form of variable expression in the dominant trait in those families. In the majority of infants who have no other obvious defect, preauricular tags are isolated, without a positive family history. Kankkunen and Thiringer4 also documented autosomal dominant kindreds showing isolated nonsyndromic ear tags. Prognosis and Treatment

The auricular tag can be removed through an incision around the base. The tag often contains a delicate rod of elastic cartilage, which can extend deeply. Care must be taken not to damage any fibers of the facial nerve that may be running beneath the tag. Removal should be made by a reconstructive surgeon or otolaryngologist who has experience with this malformation.

References (Auricular Tags) 1. Altmann F: Malformations of the auricle and the external auditory meatus. Arch Otolaryngol 54:115, 1951. 2. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9):1, 1979. 3. Beder LB, Kemaloglu YK, Maral I, et al.: A study on the prevalence of accessory auricle anomaly in Turkey. Int J Pediatr Otorhinolaryngol 63:25, 2002. 4. Kankkunen A, Thiringer K: Hearing impairment in connection with preauricular tags. Acta Paediatr Scand 76:143, 1987. 5. Kugelman A, Tubi A, Bader D, et al.: Pre-auricular tags and pits in the newborn: the role of renal ultrasonography. J Pediatr 141:388, 2002.

10.19 Auricular Pits Definition

Auricular pits are pitlike depressions, dimples, or fossae usually just at the anterior margin of the ascending limb of the helix (Fig. 10-18). Pits are also referred to as auricular fistulas. Diagnosis

Altmann1 and Congdon et al.2 have reviewed the anatomy and potential embryogenesis of this common ear defect. The sinuses, fossae, or pits are usually depressions not more than 1 to 3 mm in greatest diameter. Although there are a number of uncommon locations, in over 90% of cases reviewed by Congdon et al.,2 the pits were situated at the anterior margin of the ascending limb of the helix (Fig. 10-18). While most are rather shallow, some can be as deep as 15 mm. A small pigmented mole is sometimes seen near the opening of the dimple. The second most common location is the preauricular region. One of the characteristics of the preauricular pit is that it is sometimes associated with auricular appendages or even with what

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Craniofacial Structures

Fig. 10-18. Preauricular pit (top arrow) associated with retroverted pinna and branchial fistula (bottom arrow) in adult with branchio-oto syndrome (A). Preauricular pits and tag in a 7-month-old infant (B). Preauricular pit and microtia in a 13-month-old infant with Treacher Collins syndrome (C). (Courtesy of Dr. Charles I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.)

appears to be a congenital scar. The preauricular pits are located in the area from the tragus to the corner of the mouth, the area between the maxillary and mandibular portions of the first branchial arch. Other locations include the posterior helicine region (along the rim of the outer helix), the helicolobular region, and within the center aspect of the lobule. An even rarer type is the postauricular pit, which occurs just behind the attachment of the auricle to the temporal region. Altmann1 reviewed the concept of a ‘‘line of predilection’’ and suggested that pits may very well be remnants of the closure of the mandibular and hyoid arch or the mandibular and maxillary portions of the first branchial arch. Congdon et al.2 have also emphasized that the location of these pits seems to be near where the hillocks of His formed. The idea here is that the sinuses may be derived from grooves that are remnants of the closure of these auricular tubercles. They may be elements of a defective closure of the helix or of the branchial clefts. Most auricular pits are isolated defects and are not part of a broader pattern of anomalies. In the Perinatal Collaborative Study, fewer than 10% of individuals had the pit associated with other malformations.3 On the other hand, in the Spanish Collaborative Project, approximately 30% of infants had an associated defect, but only 1% had a recognizable syndrome (personal communication: Dr. Maria Luisa Martinez-Frias). The high frequency of associated malformations in the Spanish study may be due to the close examination of all the babies, including the recording of minor anomalies. Approximately 20% of these pits are bilateral. Numerous syndromes have been described along with which auricular pits are described (Fig. 10-18). The most important and common of these is the branchial-oto-renal syndrome (see Table 10-10). Pits located on the posterior rim of the helix are characteristic of the Beckwith-Wiedemann syndrome (Fig. 10-19). The preauricular pits seen in the oculo-auriculo-vertebral spectrum are part of what was referred to above as congenital scars and also may relate to the development of accessory appendages. Etiology and Distribution

A number of epidemiologic studies have recorded the frequency of auricular pits and depressions. There does seem to be some racial

predilection. These literature studies have been reviewed by Melnick and Myrianthopoulos3 and usually indicate that the birth prevalence is about 1%, with higher frequencies among black and Asiatic children. The frequency in the Perinatal Collaborative Study was just under 1%, with the frequency among blacks being higher than that among whites. As was mentioned above, the majority of pits are unilateral. Auricular pits of the ascending limb of the helix have been described as an autosomal dominant trait. Zou recently found linkage to 8q11 for ear pits as a trait in a Chinese family.4 Some thoughts on pathogenesis were discussed above. Because of the line of predilection of these depressions, it is tempting to postulate that they represent remnants of closure of the auricular hillocks or the closure of the first and second branchial arches. Preauricular pits on the oral-tragal line are probably a

Fig. 10-19. Pits on posterior ear lobe in Beckwith-Wiedemann syndrome. (Courtesy of Dr. H. Eugene Hoyme, Stanford University School of Medicine, Stanford, CA.)

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different alteration of morphogenesis and most likely are part of the continuum of accessory appendages. Prognosis, Prevention, and Treatment

Except for the rare occurrence of secondary infection, medical complications with these findings are uncommon. Reconstructive surgery is an option for preauricular pits. Mandell summarized the surgical issues recently.5 References (Auricular Pits) 1. Altmann F: Malformations of the auricle and the external auditory meatus. Arch Otolaryngol 54:115, 1951. 2. Congdon ED, Rowhanavongse S, Varamisara P: Human congenital auricular and juxtaauricular fossae, sinuses and scars (including the socalled aural and auricular fistulae) and the bearing of their anatomy upon the theories of their genesis. Am J Anat 51:439, 1932. 3. Melnick M, Myrianthopoulos NC: External ear malformations: epidemiology, genetics, and natural history. Birth Defects Orig Artic Ser XV(9):1, 1979. 4. Zou F, Perry Y, et al.: A locus of preauricular fistula arrays to chromosome 8q11. J Hum Genet 48:155, 2003. 5. Mandell DL: Head and neck anomalies related to the branchial apparatus. Otolaryngol Clin N Am 33:1309, 2000.

10.20 Ear Lobe Creases/Pits Definition

Ear lobe creases/pits are transverse linear fissures (creases) or pits in the lobule of the ear. Diagnosis

This alteration of the lobule involves a distinctive linear fissure or crease easily recognized on physical examination (Fig. 10-20). The prenatal onset of congenital ear fissures is most important because of their usefulness in the diagnosis of the Beckwith-Wiedemann syndrome. These ear lobe creases are sometimes called Kerbenohr fissures. They are to be distinguished from the diagonal ear lobe crease that occurs in middle-aged and older adults and that was once thought to be a marker or sign of coronary artery disease. This latter marker will not be reviewed here because it is not a congenital defect, but this topic has been summarized by Jorde et al. Well-defined depressions in the earlobe that resemble pits have been described as an autosomal dominant trait.2 These depressions usually are 3 to 5 cm in diameter and approximately 1 mm in depth. They are sometimes referred to ‘‘natural earring holes.’’ This condition is inherited as an autosomal dominant trait, with variable expressivity and incomplete penetrance. The trait can be both bilateral and unilateral within families. Etiology and Distribution

The frequencies of ear lobe fissures/creases and ear lobe holes/pits are unknown. Ear lobe pits, an autosomal dominant trait, are certainly distinct from autosomal dominant auricular pits, and the two findings are probably mutually exclusive even though they are sometimes discussed together in the otology literature. The frequency of ear lobe creases in the unpublished data from the Boston Minor Anomaly Study is just under 1% for the unilateral finding and approximately one in 300 for the bilateral finding (personal communication: Dr. Lewis Holmes). The deep transverse creases usually seen in Beckwith-Wiedemann syndrome are uncommon as a congenital finding except in that disorder.

Fig. 10-20. Crease on ear lobe associated with macrosomia and macroglossia (Beckwith-Wiedemann syndrome).

The frequency of ear lobe pits or so-called natural earring holes is unknown. The major significance of these findings is as a clue to the Beckwith-Wiedemann syndrome. There is no intrinsic medical significance other than as a diagnostic marker. References (Ear Lobe Creases/Pits) 1. Jorde LB, Williams RR, Hunt SC, et al.: Lack of association of diagonal earlobe crease with other cardiovascular risk factors. West J Med 140:220, 1984. 2. Ramirez M, Cantu JM: Two distinct autosomal dominant traits in the pinna. Birth Defects Orig Artic Ser XVIII(3B):243, 1982.

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Craniofacial Structures

constraint from the longstanding lack of amniotic fluid. It is of note that this particular finding is the primary basis for the so-called ear-kidney association. This alleged association was in fact based on a deformation of the external ear secondary to the oligohydramnios, which was secondary to the intrauterine renal failure, as opposed to an alteration in mesenchymal or cell differentiation (see Section 10.9). Etiology and Distribution

Fig. 10-21. Deformation of the ear. Flattening and crumpling of the ear secondary to intrauterine pressure associated with oligohydramnios. Note the relatively large size of the ear and the interrupted helical fold. (Courtesy of Dr. Will Blackburn and N. Reede Cooley, Jr.)

10.21 Deformation of the Auricle Definition

Deformation of the auricle is an alteration of the form of the external auricle due to unusual mechanical forces on the ear. Diagnosis

The diagnosis of a deformation of the external ear is made by noting an alteration of the form of the auricle in the context of a bona fide history of constraint or intrauterine mechanical forces. The external auricle that is deformed by constraint phenomena in utero can resemble the lop/cup ear defect or can be large and posteriorly rotated (Fig. 10-21). Graham1 has documented a number of examples of alterations of the external ear. Ear variations such as flattening of the ear against the head, overfolding of the helix, and asymmetric growth of the ear should all be considered potential clues to suggest a deformational process. Prolonged oligohydramnios, breech presentation, and uterine malformations are examples of intrauterine phenomena associated with ear deformations. The ear alterations in the Potter syndrome, now recognized as the oligohydramnios sequence, are in fact deformations of the external ear due to the

The exact frequency of deformations of the external ear is unknown. It has been estimated that approximately 2% of liveborn babies will have an extrinsic deformation of late fetal origin. Ear deformations, then, probably occur in a frequency less than that 2% figure. These ear abnormalities can mimic the alterations of intrinsic plical folding, that is, lop/cup ear defect and Stahl ear, but in ear deformations the variation should improve postnatally. Aase2 proposed that prolonged constraint of the external ear actually results in overgrowth, which may be the pathogenetic basis of the ear in the oligohydramnios sequence. Prognosis, Prevention, and Treatment

The natural history of many external ear deformations is postnatal improvement. This applies especially to external ear changes occurring very late in gestation. Perhaps many of the variations of the external ear prevalent among the Japanese (38% for the lop ear and 8% for the Stahl ear) are in fact deformations that mimic alterations of morphogenesis. This may be the reason why many of the external ear defects in the Japanese series improve with time.3 For example, while 38% of infants had a lop ear at birth, only 6% showed this disorder at age 1 year. Ear deformations that involve overfolding lend themselves to the nonsurgical approaches using Aluwax and tape. However, many infants who have reversible ear deformations may be exposed to this taping unnecessarily in that the deformation would have improved on its own. Matsuo et al.3 elect to treat all children, since it is not possible to separate those deformations that will resolve from those that will not resolve. Even in the individual who has a well-documented reason for intrauterine constraint, that is, late oligohydramnios due to leakage or bicornuate uterus, the outcome is not predictable. References (Deformation of the Auricle) 1. Graham JM: Smith’s Recognizable Patterns of Human Deformation, ed 2. WB Saunders Company, Philadelphia, 1988. 2. Aase JM: Structural defects as a consequence of late intrauterine constraint, craniotabs, loose skin and asymmetric ear size. Semin Perinatol 7:270, 1983. 3. Matsuo K, Hayashi R, Kiyono M, et al.: Nonsurgical correction of congenital auricular deformities. Clin Plast Surg 17:383, 1990.

Middle Ear John C. Carey and Albert H. Park Congenital malformations of the middle ear ossicular chain include a wide array of osseous defects of the malleus, incus, and stapes. In this introduction, these defects will be discussed in general. Individual entries for specific middle ear defects and their management will follow.

Interest in these malformations has paralleled developments in the reconstructive surgery of acquired lesions of the middle ear and progress in high-resolution computerized tomography (CT) scanning. Most of the detailed descriptions of the various defects

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have been written in the last 4 decades. Because of the many defects that have been described in all three middle ear bones, one has the impression that there is no pattern to the malformations and that almost any defect can occur in a disorder that involves the middle ear. This notion is not entirely correct, and a few classifications have emerged that are helpful to the clinician. In individuals who have external ear defects, the issue of the potential for a middle ear malformation is always considered. On the other hand, cases involving isolated middle ear defects without an external ear malformation are often not diagnosed or are misdiagnosed as acquired conditions, especially disorders that are unilateral. Funasaka et al.1 have classified ossicular malformations without defects of the external ear into three groups: (1) fixations of the malleus and/or incus, malleoincudal fixations; (2) incudostapedial disconnection; and (3) stapes fixation. While one case can involve all three of these classes of defects, as in Treacher Collins syndrome, most will fall into only one. The Japanese literature abounds with cases of autosomal dominant ossicular defects.2 Cases of this nonsyndromic familial ossicular chain defect are rarely present in the English language literature. In the Japanese literature, individuals in the same family usually have the same type of defect. Familial or autosomal dominantly inherited ossicular defects are usually bilateral, whereas typical ossicular malformations are usually unilateral. Incudostapedial disconnection and/or defects of the incus, either hypoplasia or absence of the long process, appear to be the most common ossicular chain defect in an individual without external ear defects. Congenital fixation of the stapes is probably the most well-known of the three classes of defects, and, because of the dual origin of this important bone, interest in this defect has been high. Stapes ankylosis represents the second most common defect. Fixation of the malleus to either the wall of the tympanic cavity or the incus is commonly seen in meatal atresia. The child with a nonsyndromic ossicular malformation presents with a nonprogressive conductive hearing loss that is present at birth but usually not recognized until later in childhood. The decibel loss is usually in the 40 to 60 range, and the differential diagnosis usually includes acquired hearing loss due to infection and trauma. Audiologic testing, including the tympanogram, will often provide diagnostic clues. The air conduction curve tends to be flat through the midfrequencies while the bone conduction is normal. Impedance audiometry shows changes in the contour of the tympanogram curve, depending on whether there is a defect of discontinuity or fixation. However, the tympanogram is not diagnostic, and further evaluation would be necessary to make a diagnosis. Occasionally, defects of the malleus, especially absence or interruption of the short handle, may be detected on otoscopic examination. High-resolution CT scanning will allow delineation of a number of ossicular chain defects. Swartz et al.3 and more recently Siegert et al.4 have reviewed the radiology of these middle ear defects. Frey5 has also classified middle ear malformations. This categorization includes four groups based on the presence and severity of defects of the external auditory canal. Group 1, the least common form, includes the individual with solitary malformations of the ossicles. The remainder of Frey’s classification (groups 2–4) includes individuals who have middle ear malformations with associated external ear canal defects such as stenosis of the external canal (group 2) and atresia of the external canal (group 3). Group 4 malformations represent the severe end of the spectrum of microtia and meatal atresia with middle ear ossicular chain defects. This classification basically separates individuals with middle ear ossicular defects from those who have the wide range of microtia with

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meatal atresia. Since the overwhelming number of individuals with middle ear malformations are ones who also have external ear malformations, this particular classification is useful to the otologist and radiologist. Teunissen and Cremers6 also proposed a classification of middle ear malformations based on a series of 144 operations. Their classification has four classes: (1) stapes ankylosis; (2) stapes ankylosis with ossicular anomaly; (3) ossicular anomaly with mobile footplate or discontinuity; and (4) aplasia of the round or oval window. In a review on the assessment of individuals with middle ear malformations, Bergstrom7 reported a series of 687 children having congenital hearing loss. Seventeen percent had defects of the conducting mechanism. Only eight of these 117 children had isolated middle ear defects without external ear defects or other malformations. Thus, in this series individuals with nonsyndromic, isolated ossicular chain defects not associated with an external ear malformation were uncommon. Bergstrom, like others, suggests that there are probably many individuals in this group who go undiagnosed. The average age at diagnosis for individuals with congenital conductive hearing loss was 13.4 years, as opposed to 4.2 years in children with associated defects. This figure will clearly become smaller in the future because of universal newborn screening in many areas of the United States and Europe. Nadol8 has separated individuals with middle ear defects into three classes of syndromes: those with progressive hearing loss, including bone dysplasias and connective tissue dysplasias; those with nonprogressive hearing loss, including dysostoses, localized ear defects, and chromosome disorders; and those in which progression of hearing loss is unknown. Nadol8 and Bergstrom7 have compiled the many syndromes associated with ossicular chain defects (see also Table 10-11). As mentioned above, an ascertainment bias probably accounts for the fact that the overwhelming number of individuals in the otology literature have ossicular chain defects as part of a more generalized disorder either of the external and inner ear or as part of an otofacial syndrome. Nadol’s8 classification of disorders that have progressive hearing loss and defects of the middle ear chain includes skeletal dysplasias in which there is postnatal onset of hearing loss. The majority of these conditions fall into the craniotubular dysplasias, including craniometaphyseal dysplasia and frontometaphyseal dysplasia. Autosomal recessive osteopetrosis is the best example of a congenitalonset progressive disorder of conductive hearing loss involving the ossicular chain. This is an intrinsic metabolic disorder of bone. Otosclerosis is the prototypic condition of a postnatal onset disorder of the middle ear bones, while osteogenesis imperfecta is a common example of a syndrome in this grouping. Most of the disorders that fall into the category of nonprogressive hearing loss are congenital malformation syndromes that are in the dysostosis category. These are discussed elsewhere in conjunction with their individual bone defects (see Sections 10.22, 10.23, and 10.24). Other disorders labeled as ‘‘nonprogressive’’ are those that Nadol8 called ‘‘regional defects.’’ These include external, middle, or inner ear malformations; meatal atresia, the X-linked mixed hearing loss with congenital fixation of the stapes; perilymphatic gusher; and Treacher Collins syndrome. Chromosomal disorders are also included. Nadol’s last group consisted of syndromes in which progression was unknown, and these included Apert, otopalatal-digital, and ectrodactyly-ectodermal dysplasia-clefting syndromes. Given that these disorders are all malformation syndromes, it is likely that there is not progression. An accurate prevalence of ossicular chain defects not part of a syndrome cannot be given. If only 7% of individuals with

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congenital hearing loss have isolated, nonsyndromic ossicular defects and the incidence of congenital hearing loss is assumed to be one in 1000, then the incidence could be approximated as one in 14,000. However, this figure has to be an underestimate of the nonsyndromic forms, as mentioned above. The prevalence of individuals with all ossicular malformations is much higher and would approximate the frequency of microtia with meatal atresia because of the high frequency of middle ear defects in microtia. While animal models exist for the study of both external and inner ear defects, middle ear malformations in animals are not as well-described. Altmann9 has reviewed some of the middle ear malformations seen in mammals. Jaskoll10 has conducted investigations of a number of potential teratogens on the development of the chick middle ear. She has listed the teratogens of the middle ear that have been reported in various animal species, including mouse, rat, hamster, monkey, and chick. It is of note that thalidomide induces ossicular chain defects of the middle ear in animal models as it does in the human. Thalidomide is the principal human teratogen recognized to affect the middle ear. A wide range of ossicular chain defects have been reported in infants exposed to thalidomide during the critical period. Vitamin A also alters the middle ear cavity and ossicles in rodents, an important finding since the vitamin A analog, isotretinoin, is a human teratogen. Some authors have proposed that rubella can affect the middle ear as well as the inner ear, but there is little documentation of this. Although maternal diabetes is known to affect external ear development, evidence that it produces middle ear alterations is limited. As mentioned above, there are a number of reports in the Japanese literature of autosomal dominant middle ear ossicular defects. Higashi et al.2 have reviewed a number of the families reported in the Japanese literature. Most defects remain consistent within a single family. There are large Japanese families with autosomal dominant stapes fixation as well as other reports of autosomal dominant incudostapedial disconnection. Higashi et al.2 also reported malleo-incal fixation as a dominant defect. Most of the familial cases have bilateral involvement, although there are a number of exceptions. The genetics of nonsyndromic ossicular malformations have barely been studied. The only citation in the Online Mendelian Inheritance of Man of nonsyndromic middle ear malformations (165680) refers to the above-mentioned report.11 Some of the so-called familial cases of hearing loss may be due to conductive losses in this category. Cases with middle ear defects are often underascertained, and unilateral cases frequently go undetected. With high-resolution CT scanning of the middle ear and newborn screening, the genetic aspects of ossicular chain defects can be better studied in the future. The hearing loss in individuals with middle ear malformation is nonprogressive, of early onset, and conductive in nature. In individuals who have no auditory canal defect or cochlear dysplasia, options for surgical reconstruction of the middle ear are available. Educational intervention for the individual with moderate hearing loss is obviously appropriate. Prior to any surgical intervention and in situations in which surgery is not selected, conductive hearing aids are warranted. Middle ear implantable hearing devices are also a treatment option.12 Individuals with ossicular chain defects have benefited from the many advances in surgery that were developed for otosclerosis, stapes fixation, and acquired defects of the bones secondary to long-standing infection. A number of prosthetic devices and grafting techniques have been developed for reconstruction of the middle ear chain.12 These are discussed in the individual entries for specific defects. Prostheses include the total ossicular replacement

prosthesis and the partial ossicular replacement prosthesis.13,14 Materials used have included titanium, high-density polyethylene sponge, and hydroxyapatite, a dense calcium phosphate ceramic. The House wire is also used in connecting the incus to the oval window. Because of the many advances in the last 3 decades in both the diagnosis and reconstruction of ossicular chain defects, referral to an otologist experienced in this surgery is warranted when evaluating persons with malformations of the auditory conduction system. The following entries on the middle ear discuss the specific defects. References 1. Funasaka A, Abe H, Tozuka G, et al.: Anomalies of the ossicles without malformaton of the external ear. Otol Fukuoka 17:250, 1971. 2. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987. 3. Swartz JD, Glazer AU, Faerber EN, et al.: Congenital middle-ear deafness: CT study. Radiology 159:187, 1986. 4. Siegert R, Weerda H, Mayer T, et al.: High resolution computerized tomography of middle ear abnormalities. Laryngorhinootologie 75:187, 1996. 5. Frey K: Malformations of the middle ear. In: Fundamentals of Ear Tomography. J Jensen, H Rovsing, eds. Charles C Thomas, Springfield, IL, 1971, p 77. 6. Teunissen EB, Cremers CWRJ: Classification of congenital middle ear anomalies: report on 144 ears. Ann Otol Rhinol Laryngol 102:606, 1993. 7. Bergstrom L: Assessment and consequence of malformation of the middle ear. Birth Defects Orig Artic Ser XVI(4):217, 1980. 8. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 9. Altmann F: Congenital atresia of the ear in man and animals. Ann Otol Rhinol Laryngol 64:824, 1955. 10. Jaskoll TF: Morphogenesis and teratogenesis of the middle ear in animals. Birth Defects Orig Artic Ser XVI(7):9, 1980. 11. Online Mendelian Inheritance in Man. http://www.nchi.nlm.nih.gov. 12. Spindel JH: Middle ear implantable hearing devices. Am J Audiol 11:104, 2002. 13. Kartush JM: Ossicular chain reconstruction. Otolaryngol Clin N Amer 27:689, 1994. 14. De La Cruz A: Ossiculoplasty in congenital hearing loss. Otolaryngol Clin N Amer 27:799, 1994.

10.22 Hypoplasia/Aplasia/Malformation of the Malleus Malformations of the malleus include underdevelopment or absence of the malleus, shortening of the handle of the malleus, and alterations of the manubrium (Fig. 10-22). Aplasia or hypoplasia of the malleus is recognized by the detection of congenital hearing loss due to the poor mechanical transmission from the ear drum to the incus. Otoscopic examination will sometimes identify this uncommon bony defect. Clues to the diagnosis can come from the pattern on the tympanogram, but the definitive recognition requires high-resolution CT scanning or surgical exploration, often for other reasons. This defect is associated with microtia with meatal atresia, Treacher Collins syndrome, branchio-oto-renal syndrome, and other less common disorders (Table 10-11).1,2 As in all the ossicular chain defects, exact figures for prevalence do not exist. Hypoplasia/aplasia of the malleus represents one of the less frequent of the ossicular middle ear defects. The goal of surgery is to establish a functional connection from the tympanic membrane and direct it to the incus, stapes, or

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Fig. 10-22. Ossicular chain of the middle ear. A. Normal malleus, incus, and stapes. B. Malformed malleus lacking handle; incus lacking long crus and short process; malleus and incus fused. C. Malleus lacking handle; incus lacking long crus and short process; stapes absent; malleus fused to incus and to lateral wall of attic and atresia plate.

oval window, depending on the status of the other bones.3 A partial ossicular replacement prosthesis or a homograph can be used. A thorough description of prostheses or homographs is provided by Kartush.4 References (Hypoplasia/Aplasia/Malformation of the Malleus) 1. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 2. Bergstrom L: Assessment and consequence of malformation of the middle ear. Birth Defects Orig Artic Ser XVI(4):217, 1980. 3. Jaffe BF: Middle ear isolated anomalies. In: Hearing Loss in Children: A Comprehensive Text. University Park Press, Baltimore, 1977, p 286. 4. Kartush JM: Ossicular chain reconstruction. Otolaryngol Clin N Amer 27:689, 1994.

Fig. 10-23. Fusion of head of malleus to the lateral wall of the attic.

10.23 Fusion Defects of the Malleus Malleus head fixation is the most common isolated malleus anomaly. The malleus may be fused to the incus, the atretic plate (in the case of microtia/meatal atresia), or the superior wall of the tympanic cavity (Figs. 10-22 B and C, and 10-23). In the case of a patent external canal, fixation of the malleus could be diagnosed by the astute clinician who notes the movement of the tympanic membrane while the malleus remains immobile. Fixation of the malleus results in nonprogressive conductive hearing loss with a maximum of 60 dB loss when there is total fixation. Malleus fixation is well-known to otologists in association with otosclerosis. Malleal head fixation, however, can also be a congenital defect as described here. The pathogenesis of this defect has been discussed by Goodhill,1 who proposed a number of mechanisms, including excessive air cell formation in the epitympanum, bony fixation of the anterior malleal ligament, and partial failure of the

epitympanic expansion. Fusion defects of the malleus either to the epitympanum or to the incus are relatively uncommon in the major classes of ossicular chain defects. Fusion of the malleus to the atretic plate commonly occurs with meatal atresia. In the review of the Japanese literature on autosomal dominant chain defects by Higashi et al.,2 one of the families had nonsyndromic malleus and/or incus fixation accompanied by stapes fixation. Fixation defects of the malleus have been described in a number of disorders (Table 10-11). Fixation of the malleus requires mobilization and/or use of a prosthesis (tympanic membrane/malleus to incus). Mobilization of the malleus may be challenging even with curette or microdrill instrumentation. If mobilization is unsuccessful, the incudostapedial joint is separated and the malleus head is amputated and repositioned between the malleus handle and stapes suprastructure. As

Table 10-11. Syndromes with middle ear malformations Syndrome

Causation Gene/Locus

Ossicular Defect(s)

Prominent Features

Osteopetrosis, recessive form

Abnormal bone

Increased bone density, bone marrow failure

AR (259700) CLCN7, 16p13

Achondroplasia

Ossicular chain fusion

Disproportionate short stature, macrocephaly

AD (100800) FGFR3, 4p16

Dyschondrosteosis

Hypoplasia/aplasia of malleus and/or incus, stapes fixation

Forearm shortening, short stature, Madelung defect

AD (127300) SHOX, Xp22

Diastrophic dysplasia

Ossicular fusion

Disproportionate short stature, joint contractures

AD (222600) SLC26A2, 5q32

Osteogenesis imperfecta

Stapes ankylosis

Osseous fragility, blue sclera

AD (166210) Multiple loci

Cleidocranial dysostosis

Incudo-malleal fusion, stapes fixation

Clavicular defect, short stature

AD (119600) CBFA1, 6p21

Symphalangism-brachydactyly

Stapes fixation

Distinctive nose, proximal symphalangism, brachydactyly

AD (186500) NOG, 17q22

Teunissen

Stapes fixation, incus hypoplasia

Brachydactyly, brachytelephalangism, broad thumbs

AD (184460) NOG, 17q22

Dominant symphalangismconductive hearing loss

Stapes fixation

Symphalangism, anomalies of hands and feet

AD (185750)

Forney

Stapes fixation

Joint fusion, mitral insufficiency

AD (157800)

Cleft palate-oligodontia

Stapes fixation

Cleft palate, oligodontia

AR (216300)

X-linked hearing loss

Stapes fixation

Mixed hearing loss, perilymphatic gusher at surgery

XLR (304400) POU3F4, Xq21

Escher-Hirt

Abnormal incudo-stapedial joint

Thickened ear lobules, middle ear malformation

AD (128980)

LMC

Stapes fixation

Lop ears, micrognathia

Unknown

Branchio-oto-renal

Stapes fixation, incus hypoplasia/aplasia, malleus hypoplasia/aplasia, absence of the oval window

Branchial fistulas, ear abnormalities, mixed hearing loss, renal defects

AD (113650) EYA1, 8q

Treacher Collins

Hypoplasia and fusion of malleus and incus, absence of stapes and oval window, stapes fixation

Mandibular hypoplasia, malar hypoplasia, Robin sequence, microtia

AD (154500) TCOF1, 5q32

Oculo-auriculovertebral spectrum

Fusion of the incus and malleus, hypoplasia/aplasia of the ossicles

Epibulbar dermoids, hemifacial microsomia, vertebral defects

Heterogeneous; AD (164210) AD (257700) 14q

Wildervanck

Abnormal ossicles, oval window

Duanne anomaly, Klippel-Feil syndrome, mixed hearing loss, ear defects

Unknown, XLR (314600)

Sellars

Hypoplasia of incus, stapes fixation

Microtia

AD (124690)

Skeletal Dysplasias

Dysostoses

Otofacial Syndromes

Kabuki

Multiple ossicular chain defects

Distinctive face, cleft palate, short stature

AD (147920)

Apert

Various ossicular chain defects

Craniosynostosis, hypertelorism, syndactyly

AD (101200) FGFR2, 10q26

Crouzon

Various ossicular chain defects

Craniosynostosis, hypertelorism

AD (123350) FGFR2, 10q26 (continued)

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Table 10-11. Syndromes with middle ear malformations (continued) Syndrome

Ossicular Defect(s)

Prominent Features

Trisomy 18

Wide range of ossicular defects

Neonatal growth deficiency, distinctive face/hands, short sternum, congenital heart disease

Trisomy 13

Stapes aplasia/hypoplasia, many ossicular defects

Cleft lip/palate, scalp defects, polydactyly, eye defects

45,X

Stapes fixation, stapes hypoplasia/aplasia

Short stature, webbed neck, distinctive facies, gonadal dysgenesis

del 22q

Fused and malformed ossicles

Distinctive face, velopharyngeal insufficiency, heart defects

del 18q

Fused and malformed ossicles

Distinctive face, meatal stenosis or atresia, midfacial hypoplasia, tapered fingers, variable developmental retardation

Causation Gene/Locus

Chromosomal Syndromes

mentioned above, numerous prostheses are available to reestablish ossicular continuity. References (Fusion Defects of the Malleus) 1. Goodhill V: The fixed malleus syndrome: surgical and audiological consideration. Trans Acad Ophthalmol Otolaryngol 70:370, 1966. 2. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987.

10.24 Hypoplasia/Aplasia/Malformation of the Incus Malformations of the incus include underdevelopment or absence of the incus and abnormalities of the lenticular process and long process (Figs. 10-22B and C, and 10-24). As in defects of the malleus, underdevelopment or absence of the incus is diagnosed by the nonprogressive, conductive hearing loss and by high-resolution CT scanning. Defects can be discovered during reconstruction for the problem or for other defects of the middle ear. The range of defects includes absence of the lenticular process, absence of the long process with persistence of the lenticular process and body, absence of the short process and body, and total absence of the incus (Fig. 10-24). This range comprises the class of malformations called incudostapedial disconnection, which represents the most

common middle ear defects seen in one series.1 A variation of this defect was seen by Higashi et al.2 In this family there was unilateral hypoplasia of the long process of the incus producing a conductive hearing loss. Higashi et al.2 also reviewed three other families with apparent autosomal dominant inheritance of an incudostapedial disconnection. This particular continuum of defects has been seen in a number of syndromes, for example, the common disorders of Treacher Collins syndrome, microtia with meatal atresia, trisomy 18, trisomy 13, and Wildervanck syndrome (Table 10-11).3 In addition to these broader patterns of malformation, reports by Escher and Hirt4 and by Wilmont5 delineated an autosomal dominant condition consisting of conductive hearing loss due to an abnormal incudostapedial joint and thickening of the external ear lobes. Teunissen and Cremers6 reported an uncommon condition of brachydactyly, brachytelephalangy, stapes fixation, and hypoplasia of the incus, now known to be caused by mutations of the NOGGIN gene. The ossicular discontinuity due to abnormalities of the incus can be repaired by a partial ossicular replacement prosthesis. References (Hypoplasia/Aplasia/Malformation of the Incus) 1. Swartz JD, Glazer AU, Faerber EN, et al.: Congenital middle-ear deafness: CT study. Radiology 159:187, 1986.

Fig. 10-24. A. Agenesis of incus except for lenticular process; agenesis of a part of anterior crus. B. Malformed incus with only long crus present; stapes solid. C. Agenesis of long crus of incus and the crural arch of the stapes. D. Agenesis of the long crus of the incus. E. Agenesis of short process of the incus, the stapes, and stapedius muscle.

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Craniofacial Structures

2. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Escher F, Hirt H: Dominant hereditary conductive deafness through lack of incus stapes junction. Acta Otolaryngol 65:25, 1966. 5. Wilmont TJ: Hereditary conductive deafness due to incus-stapes abnormalities and associated pinna deformity. J Laryngol 84:469, 1970. 6. Teunissen B, Cremers CWRJ: An autosomal dominant inherited syndrome with congenital stapes ankylosis. Laryngoscope 100:380, 1990.

10.25 Fusion Defects of the Incus The incus may be fused to the malleus, to a portion of the epitympanum and middle ear fossa (Figs. 10-24 B and C), or to the stapes. Making the diagnoses of fusion of the incus to the middle ear cavity or to the malleus is the same as for other ossicular chain defects. The most typical incudostapedial anomalies are fibrous union, absence of the joint or bony fusion. Incudostapedial fusion was the second most common middle ear defect in the Teunissen and Cremer series.1 As mentioned in the above entry, recently Teunissen and Cremers2 described an autosomal dominant condition of stapes fixation, brachydactyly, brachytelephalangy, and, in a few cases, fusion of the short process to the fossa incudis. This fusion defect has also been seen in Winter syndrome, branchio-oto-renal syndrome (incus fused to stapes), and Crouzon syndrome.3 Tympanoplasty may be performed for this and for other forms of bony ossicular fixation.4,5 References (Fusion Defects of the Incus) 1. Teunissen EB, Cremers CWRJ: Classification of congenital middle ear anomalies: report on 144 ears. Ann Otol Rhinol Largyngol 102:606, 1993. 2. Teunissen EB, Cremers CWRJ: An autosomal dominant inherited syndrome with congenital stapes ankylosis. Laryngoscope 100:380, 1990. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Tos M: Tympanoplasty for bony ossicular fixation. Arch Otolaryngol 99:422, 1974.

5. De La Cruz A, Doyle KJ: Ossiculoplasty in congenital hearing loss. Otolaryngol Clin N Am 27:799, 1994.

10.26 Hypoplasia/Aplasia/Malformation of the Stapes Malformations include underdevelopment or absence of the stapes and a wide range of structural alterations of this middle ear ossicle (Figs. 10-22 C, 10-24 A, C, and E, and 10-25). Hypoplasia or aplasia of the stapes are diagnosed using high-resolution computerized tomography. A variety of structural alterations of the shape of the stapes have been described. These include the unicrurate defect, incomplete development of the crura without attachment to the footplate, entire absence of the superstructure of the stapes, and the so-called columella or monopodal stapes.1 The columella type is one of the most common of this group. These defects also can be classified as part of the group of incudostapedial disarticulation defects or disconnection defects. When there are alterations of its superstructure, the stapes is not connected with the incus. The genetics of these malformations are unclear. Most of the information on defects of the stapes involve fixation of the stapes footplate. Sellars and Beighton2 reported a family with an apparently autosomal dominant condition involving type I microtia and absence of the stapes superstructure. In this condition there are varying degrees of hypoplasia of the incus and fixation of the stapes footplate. This particular syndrome is of note, since it seems to comprise a range of findings, including alterations of the long process of the incus, lenticular process of the incus, and stapes superstructure. Variability in the reported family suggests a common denominator in the development in this area of the ossicular chain. The malleus was usually normal. It is of note that the stapes superstructure and perhaps the long process of the incus come from the second branchial arch. Structural alterations of the stapes also occur in Treacher Collins syndrome, oculo-auriculo-vertebral spectrum, Escher-Hirt syndrome, trisomy 13, microtia with meatal atresia, and a number of less common disorders (Table 10-11).3

Fig. 10-25. A. Agenesis of the stapes and stapedius muscle. B. Agenesis of the stapes except for a remnant of the anterior crus; agenesis of stapedius muscle. C. Partial absence of the anterior and posterior crus of the stapes.

Ear

Treatment should center on removing the malformed stapes atraumatically and leaving a mobile footplate. A laser may be helpful in removing an ossified stapedius tendon or abnormal stapes suprastructure. Once accomplished, a prosthesis can be placed from the footplate to either the tympanic membrane, incus (if available), or malleus handle.4,5

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10.27 Congenital Fixation of the Stapes

cular chain. In a series dealing with reconstruction of the middle ear by Scheer,1 16 of 17 patients had a structurally abnormal stapes related to their conductive hearing loss without an abnormal external ear or meatus, and three of these had congenital fixation. In a study of congenital middle ear deafness involving patients with normal external ears, three of 15 had congenital stapes fixation.6 In the series by Teunissen and Cremers, 30% of their 144 cases had congenital stapes ankylosis.7 The etiology of stapes fixation is usually not determined. Most case descriptions in the otology literature provide no family history. However, there are a number of exceptions to this statement, and there has been very little systematic study of the genetic aspects of congenital stapes fixation. The X-linked disorder mentioned above should always be considered, and there are probably more autosomal dominant families than are suspected. There are no studies of parents of individuals with congenital stapes fixation, and unilateral findings could certainly go undetected. Treacher Collins syndrome probably represents the most common of the syndromic disorders in which this defect occurs. Congenital stapes fixation has been seen in individuals with prenatal thalidomide syndrome. None of the other human teratogens has been implicated as a cause of this ossicular defect, but it is plausible that it is a feature of the isotretinoin embryopathy.

Definition

Prognosis, Prevention, and Treatment

Congenital fixation of the stapes is the congenital fusion of the footplate of the stapes to the oval window, thus altering the stapedial-vestibular joint. Congenital stapes footplate fixation is considered in an individual with a nonprogressive conductive hearing loss in which there is no other ossicular chain defect detected on radiography. A definitive diagnosis is made during exploratory tympanotomy. The stapes footplate may be totally or partially fixed on gentle palpation. Absence of the oval window is sometimes associated with stapes ankylosis. When there is total fixation, about 50–100% of the footplate is fixed to the otic capsule. Audiometry will reveal a maximum flat 60 dB conductive loss. About one-fourth of the cases reviewed by Scheer1 had partial fixation with less conductive loss. A historical overview and description of this relatively recently described congenital defect was presented by House2 in 1969. He proposed that congenital fixation of the stapes footplate was due to an abnormality of the differentiation of the annular ligament. The defect is sometimes associated with absence of the oval window, which some otologists feel is the full expression of this morphologic defect of the stapedial-vestibular joint. While the otology literature usually states that family history is negative, there are a number of families reported with an X-linked form associated with the perilymphatic gusher at surgery. In addition, there are a number of autosomal dominant families reported in the Japanese literature.3 Table 10-11 lists a number of syndromes in which congenital stapes fixation occurs. Of special note are the two symphalangism conditions that are due to mutations of NOGGIN and the X-linked disorder of mixed hearing loss with congenital fixation of the stapes footplate and the perilymphatic gusher at the time of surgery. This latter condition has been mapped to the long arm of the X chromosome and is due to mutations of POU4.4,5

Treatment options are dictated by the severity of stapes fixation and the presence of other ossicular anomalies. If stapes fixation is minimal, one can try to mobilize the footplate. House noted good long-term results following stapes mobilization procedures.2 For more extensive stapes fixation, a stapedectomy or stapedotomy procedure is advocated. Proponents have shown good postoperative results with both techniques. Stapedectomy involves complete removal of the footplate; stapedotomy involves creation of a fenestra in the footplate. A prosthesis is then placed for either procedure between the incus and oval window niche. A temporalis fascia graft or trajal perichondrium is typically placed between the prosthesis and oval window niche for stapedectomy procedures to prevent medial migration into the vestibule. The most challenging situation arises when the stapes fixation is associated with incus and malleus abnormalities. In this case, a total ossicular reconstructive prosthesis (TORP) is necessary. It is placed over a temporalis fascia/trajal perichondrium following a stapedectomy procedure. A thin piece of trajal cartilage is then interposed between the TORP and tympanic membrane. Battaglia et al.8 reviewed 21 patients undergoing TORP and stapes footplate removal. Hearing results indicated that 52% have an airbone gap less than 20 dB. House and Teufert9 noted similar results. Awareness of the possibility of the perilymphatic gusher is always necessary prior to surgical intervention. This finding is seen in stapes fixation of various causes, including the X-linked type.

References (Hypoplasia/Aplasia/Malformation of the Stapes) 1. Jaffe BF: Middle ear isolated anomalies. In: Hearing Loss in Children: A Comprehensive Text. BF Jaffe, ed. University Park Press, Baltimore, 1977, p 286. 2. Sellars S, Beighton P: Autosomal dominant inheritance of conductive deafness due to stapedial anomalies, external ear malformations and congenital facial palsy. Clin Genet 23:376, 1983. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Briggs RJS, Luxford WM: Correction of conductive hearing loss in children. Otolaryngol Clin N Am 27:607, 1994. 5. De La Cruz A, Doyle KJ: Ossiculoplasty in congenital hearing loss. Otolaryngol Clin N Am 27:799, 1994.

Etiology and Distribution

The exact frequency of congenital stapes fixation is not known, but it does represent the second most common anomaly of the ossi-

References (Congenital Fixation of the Stapes) 1. Scheer AA: Correction of congenital middle ear deformities. Arch Otolaryngol 85:55, 1967. 2. House HP: Congenital fixation of the stapes footplate. Otolaryngol Clin N Am 2:35, 1969. 3. Higashi K, Yamakawa K, Itani O, et al.: Familial ossicular malformations: case report and review of literature. Am J Med Genet 28:655, 1987.

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Craniofacial Structures

4. Wallis C, Ballo R, Wallis G, et al.: X-linked mixed deafness with stapes fixation in a Mauritian kindred: linkage to Xq probe pDP34. Genomics 3:299, 1988. 5. Brunner HG, van Bennekom A, Lambermon EM, et al.: The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK. Hum Genet 80:337, 1988. 6. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 7. Teunissen EB, Cremers CWRJ: Classification of congenital middle ear anomalies: report on 144 ears. Ann Otol Rhinol Laryngol 102:606, 1993. 8. Battaglia A, McGrew BM, Jackson CG: Reconstruction of the entire ossicular conduction mechanism. Laryngoscope 133:654, 2003. 9. House JW, Teufert KB: Extrusion rates and hearing results in ossicular reconstruction. Otolaryngol Head Neck Surg 125:135, 2001.

10.28 Absence of the Oval Window Nondevelopment of the oval window of the middle ear is usually associated with congenital defects of the stapes, including footplate fixation. Congenital absence of the oval window would usually be recognized at the time of surgery in individuals with conductive hearing loss. In the series of Swartz et al.,1 one individual was recognized by computed tomography. Some otologists feel that congenital stapes fixation is a milder degree of maldevelopment of the stapedial-vestibular joint. Abnormalities of the facial nerve canal and lower ossicular chain, especially the long process of the incus, usually accompany this defect. Commonly the long process of the incus is short and more medially positioned. Some individuals have also had accompanying absence of the round window. The stapes is invariably abnormal. In Lambert’s review2 of seven cases, aplasia of the stapes was present in one case, and structurally abnormal stapes were present in the remaining six cases. Family history data on this disorder are not available. Absence of the oval window has occasionally been seen in Treacher Collins syndrome and in the oculo-ariculo-vertebral spectrum. In addition, individuals with Wildervanck syndrome and 22q11 deletion have been reported with absence of the oval window. This defect is also seen with Mondini dysplasia of the inner ear.3 Absence of both the round window and the stapes has been seen as the middle ear defect in a distinctive dominant syndrome involving limb reduction defects, cardiac arrhythmias, abnormal external ears, and conductive hearing loss. Other than the presence of this finding in some Mendelian syndromes, genetic information is unavailable. As is the case of other middle ear defects, especially congenital stapes fixation, little study of family histories has been accomplished. Congenital absence of the oval window has been reported in cases of prenatal thalidomide syndrome. The frequency of this particular finding is unknown. Lambert’s review2 in 1990 included only seven papers from 1958 to 1990 on this topic. Jahrsdoerfer’s series4 of 13 patients represents the largest to date. This investigator suggested that congenital absence of the oval window may in fact be related to abnormal development of the facial nerve. The surgical challenges to this anomaly are significant given the potential risk to the facial nerve and inner ear. Sterkers and Sterkers have described success with drilling a fenestra above the facial nerve and placing a prosthesis to the incus in six cases.5 Lambert reviewed the outcomes of six patients who underwent vestibulotomios and reconstruction with House wires or a total

ossicular reconstruction prosthesis (TORP).2 Hearing initially improved in four of the six patients but was lost over time. Given the poor surgical outcome and potential morbidity of the procedure, use of hearing aids is recommended. References (Absence of the Oval Window) 1. Swartz JD, Glazer AU, Faerber EN, et al.: Congenital middle-ear deafness: CT study. Radiology 159:187, 1986. 2. Lambert PR: Congenital absence of the oval window. Laryngoscope 100:37, 1990. 3. Nadol JB: Pathoembryology of the middle ear. Birth Defects Orig Artic Ser XVI(4):181, 1980. 4. Jahrsdoerfer R: Congenital malformations of the ear analysis of 94 operations. Ann Otol Rhinol Laryngol 89:348, 1980. 5. Sterkers JM, Sterkers O: Surgical management of absence of the oval window with malposition of the facial nerve. Adv Otorhinolaryngol 40:33, 1988.

10.29 Congenital Cholesteatoma Definition

Congenital cholesteatoma is a cystic epithelial remnant of embryologic origin found medial to an intact tympanic membrane. Diagnosis

While the actual existence of congenital cholesteatoma was once debated in the otology literature, the present consensus is that this disorder does exist. Many children present with conductive hearing loss. An opaque or whitish-appearing mass is typically seen behind the tympanic membrane. Many cases are diagnosed during surgical exploration for the cause of conductive hearing loss. High-resolution computed tomography scanning may detect these lesions as a homogenous mass in the middle ear. The review by McDonald et al.1 indicates that congenital cholesteatomas make up about 2% of all such lesions. Derlacki and Clemis originally established the clinical criteria for diagnosis: (1) no history of otorrhea, perforation, or previous otologic procedures; (2) normal pars tensa and flaccida; and (3) a pearly white mass medial to an intact tympanic membrane. Levenson et al.3 relaxed the criteria by including some children with serious otitis media. The mean age of presentation as reported in more recent reviews is 4.5 years.4,5 There is a male preponderance of nearly 3:1 in recent reports. If allowed to enlarge, these cholesteatomas can erode the ossicles and spread to the attic and antrum. A child with a conductive hearing loss in the absence of serious effusion should be suspected of having a cholesteatoma unless proved otherwise.6 Etiology and Distribution

Von Remak in 1854 (cited in reference 7) suggested that many cholesteatomas may be dermoids originating from epidermal rests formed during embryologic development.7 Michaels in 1988 demonstrated epidermoid tissue in a fetus at 5 to 6 weeks gestation, that apparently involuted by 33 weeks.8 He suggested that this epidermoid tissue, if persistent, could result in primary cholesteatoma located in the anterosuperior portion of the mesotympanum. Other theories such as epithelial implantation, squamous metaplasia from otitis media, or epithelial migration through the tympanic ring have also been considered.9,10 Currently, the epidermal rest theory has been the most widely accepted one.

Ear

Treatment, Prevention, and Prognosis

The treatment of congenital cholesteatoma is surgical removal. The major impact of these lesions, as mentioned above, is ossicular destruction and occasional involvement of the inner ear. The sequence of events is such that they grow, become secondarily infected, and with time produce destruction of the osseous chain and temporal bones. Occasionally, the lesion will recur even after surgery. Surgical strategy depends on the extension of the lesion. Lesions involving the anterosuperior mesotympanum can be removed via an anteriorly based tympanotomy with excellent results. For extensive tumors involving the entire mesotympanic and antrum, a mastoidectomy may need to be performed. In general, the surgeon attempts to preserve as much of the ossicular chain and posterior canal wall as possible without sacrificing the extent of removal. Reexploration is undertaken when the surgeon cannot be certain of residual disease. Ossiculoplasty is usually performed once epithelial removal is complete. References (Congenital Cholesteatoma) 1. McDonald TJ, Cody DT, Ryan RE: Congenital cholesteatoma of the ear. Ann Otol Rhinol Laryngol 93:637, 1984. 2. Derlacki EL, Clemis JD: Congenital cholesteatoma of the middle ear and mastoid. Ann Otol Rhinol Laryngol 74:706, 1965. 3. Levenson MJ, Parisier SC, Chute P, et al.: A review of twenty congenital cholesteatomas of the middle ear in children. Otolaryngol Head Neck Surg 94:560, 1986. 4. Friedberg J: Congenital cholesteatoma. Laryngoscope 104(3 Pt 2):1, 1994. 5. Friedberg J: Congenital cholesteatoma. In: Pediatric Otology and Neurotology. Lalwani AK, Grundfast KM, eds. Lippincott Williams and Wilkins, Philadelphia, 1998, p 284. 6. Chem JM, Schloss MD, Manoukian JJ, et al.: Congenital cholesteatoma of the middle ear in children. J Otolaryngol 18:44, 1989. 7. Curtis AW: Congenital middle ear cholesteatoma: two unusual cases and a review of the literature. Laryngoscope 89:1159, 1979. 8. Michaels L: Origin of congenital cholesteatoma from a normally occurring epidermoid rest in the developing middle ear. Int J Pediatr Otorhinolaryngol 15:51, 1988. 9. Sade J, Babiacki A, Pinkus G: The metaplastic and congenital origin of cholesteatoma. Arch Otolaryngol 96:119, 1983. 10. Aimi K: Role of the tympanic ring on the pathogenesis of congenital cholesteatoma. Laryngoscope 93:1140, 1983.

10.30 Persistence of the Stapedial Artery The stapedial artery is usually present in the early stages of embryonic development of the middle ear and thereafter regresses. Its persistence beyond this point is considered a malformation. Persistence of the stapedial artery is usually diagnosed during middle ear surgery for conductive hearing loss. While there are some radiologic clues on a skull x-ray (absence of the foramen spinosum in the radiograph of the cranial base), it is difficult to diagnose even with carotid angiography. However, recent reports of successful detection with computed tomography scanning have been reported.1 It is also difficult to sort out the various associations with persistence of the stapedial artery, because it is usually found at the time of middle ear surgery and thus, there is clearly an ascertainment bias. It has been seen in individuals with the oculoauriculo-vertebral (OAV) spectrum. In a review by PascualCastroviejo,2 persistence of the stapedial artery was reported in a

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child with an unusual branchial arch abnormality consisting of anotia and trilobulated mass in the area of the pinnae. The persistence of the stapedial artery in this case was demonstrated on arteriography. The frequency of this condition cannot be determined. As of Pascual-Castroviejo’s review,2 there had only been about 20 reported cases. Only a few reports have been published since.1,3 Although the pathogenesis is unclear, the condition does appear to represent the persistence of an artery that usually regresses during embryonic development. The stapedial artery is present in the developing embryo at 35 days as a branch of the hyoid artery. By age 55 to 60 days, the branches of the stapedial artery have become part of the ophthalmic artery, and the arteries originate in the third pharyngeal arch. The trunk of the stapedial artery disappears during the 3rd month of fetal life. It is not clear if the presence of a stapedial artery is developmentally related to the OAV spectrum or to other middle ear defects. It simply may be that this arterial variation occurs in conjunction with other developmental disorders of the external and middle ear. References (Persistence of the Stapedial Artery) 1. Yilmaz T: Persistent stapedial artery; MR angiographic and CT findings. Am J Neuroradiol 24:1133, 2003. 2. Pascual-Castroviejo I: Persistence of the stapedial artery in a first arch anomaly: a case report. Cleft Palate J 20:146, 1983. 3. Pahor AL, Hussain SS: Persistent stapedial artery. J Laryngol Otol 106:254, 1992.

10.31 Highly Placed Jugular Bulb A highly placed jugular bulb is an anomaly of placement of the jugular bulb in which the location of the vascular structure interferes with ossicular chain motion and produces conductive hearing loss. This rare anomaly is sometimes associated with conductive hearing loss.1 A bluish-red mass can be seen in the posterior portion of the middle ear behind the tympanic membrane. A vascular mass is recognized at the time of surgical exploration. A venogram would show distension of the jugular bulb. Because of the rarity and small number of cases of this condition, its association with other malformations or syndromes is unknown. The association of a highly placed jugular bulb with conductive deafness and interference with the osseous chain is uncommon. Moretti1 reviewed the literature on this topic in 1976. The etiology and pathogenesis are unknown. In the case he studied, there was hypoplasia of the contralateral sinuso-jugular system. Other cases can be due to normal variation in the height of the jugular bulb and occasional dehiscence of the floor of the middle ear. Kondoh et al.2 recently documented a case associated with hearing loss. This anomaly is an uncommon cause of unilateral conductive loss due to its involvement with the middle ear chain. Because of the unilateral involvement, vascular surgery would involve decisions about risks versus benefits. References (Highly Placed Jugular Bulb) 1. Moretti JA: Highly placed jugular bulb and conductive deafness. Arch Otolaryngol 102:430, 1976. 2. Kondoh K, Kitahara T, Mishiro Y, et al.: A rare case of the high jugular bulb associated with only hearing ear. (Article in Japanese.) Nippon Jibiinkoka Gakkai Kaiho 105:893, 2002.

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Inner Ear Daryl A. Scott and John C. Carey 10.32 Vestibulocochlear Dysplasias Definition

Vestibulocochlear dysplasias are a continuum of malformations and dysplasias involving the osseous and membranous components of the cochlea, vestibule, and lateral semicircular canals of the inner ear. The normal anatomy of the inner ear is shown in Figure 10-26. Diagnosis

Individuals with vestibulocochlear dysplasias may seek medical attention for hearing loss or vestibular complaints such as dizziness or vertigo. Historically, little could be done to define the anatomy of the inner ear until an individual was deceased and a postmortem examination could be performed. In contrast, modern radiologic techniques can be used to explore the inner ear with relative ease. High resolution computed tomography (CT) in both the axial and coronal views is the standard method of examining the bony labyrinth and internal auditory meatus. Four to five 2 mm axial sections are usually sufficient to exclude congenital dysplasia, with 1 mm sections being obtained if a dysplasia is visualized. Magnetic resonance imaging techniques, including gradient echo, three dimensional Fourrier transformation-constructive interference in the steady state (3-DFT CISS), and fast or turbo-spin echo two-dimensional sequencing heavily weighted with high signal from fluids (T2), are also used for inner ear imaging.1 Dysplasias of the membranous and osseous labyrinth are classified on an anatomic and histologic basis according to schemes that describe a continuum of severity. A classification proposed by Omerod in 1960 is still in common use today.2 This system divides vestibulocochlear dysplasias into four types, each named after the individual who wrote the classical account of that

malformation: (1) Michel aplasia; (2) Mondini-Alexander dysplasia; (3) Bing-Siebenmann dysplasia; and (4) Scheibe dysplasia. Each of these malformations is summarized in Table 10-12 and described in detail below. In 1987, Jackler et al. proposed a second classification system based on the radiographic appearance of various cochlear malformations and the hypothesis that the various morphologic patterns seen in the inner ear result from an arrest of maturation during one the states of inner ear embryogenesis.3 This scheme includes five types: (1) complete labyrinthine aplasia; (2) cochlear aplasia; (3) common cavity; (4) cochlear hypoplasia; and 5) incomplete partition. Each of these malformations is summarized in Table 10-13 and described in detail below. In 1967, Schuknecht proposed a classification system for vestibulocochlear dysplasias similar to Omerod’s.4 In this system Michel and Scheibe types are identical to those proposed by Omerod, but Mondini dysplasia is broadly defined as incomplete development of the bony and membranous labyrinth. Bing-Siebenmann type is deleted, and a milder sembranous cochlear dysplasia (Alexander dysplasia) is added. Michel or Complete Labyrinthine Aplasia

Formation of the inner ear begins during the 3rd week of gestation when a thickening of ectoderm, the otic placode, forms on the lateral surface of the neural tube. Failure of development at this stage results in complete labyrinthine aplasia of the Jackler et al. classification with no development of inner ear structures. Michel aplasia may be bilateral or unilateral and can be seen in conjunction with other abnormalities caused by failure of the otic placode. These include nondifferentiation of the stapes, abnormal course of the facial nerve, hypoplasia of the petrous bone, and abnormal course of the transverses sinus and jugular veins. Michel aplasia is rare and accounted for only about 1% of radiologically apparent cochlear malformations in the report of

Fig. 10-26. Schematics of the bony internal ear (left) and membranous internal ear (right).

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Table 10-12. Omerod’s classification system of vestibulocochlear dysplasias2 Malformation

Description

Associated Disorders

Michel aplasia

Complete lack of inner ear development

Familial autosomal dominant Familial autosomal recessive Anencephaly Klippel-Fiel anomaly Wildervanck Thalidomide embryopathy

Mondini-Alexander dysplasia

Cochlea contains a decreased number of turns and underdevelopment of vestibular structures

Wildervanck Waardenburg Del 22q11 Pendred CHARGE Congenital cytomegalovirus infection Trisomy 18, 13

Bing-Siebenmann dysplasia

Malformation restricted to the membranous labyrinth. Normal bony labyrinth

Jervell and Lange-Nielsen Usher Oculo-auriculo-vertebral spectrum

Scheibe dysplasia

Malformation of the membranous cochlea and saccule. No vestibular involvement and normal bony labyrinth

Waardenburg Congenital rubella infection

Table 10-13. Jackler classification of radiologically apparent vestibulocochlear malformations3 Malformation

Description

Equivalent in Omerod’s Classification

Complete labyrinthine aplasia

Complete lack of inner ear development

Michel aplasia

Cochlear aplasia

Complete lack of cochlear development*

No equivalent

Common cavity

Cochlea and vestibule form a common cavity without internal architecture

Classified by some authors as severe Mondini-Alexander

Cochlear hypoplasia

Small cochlear bud*

Classified by some authors as severe Mondini-Alexander

Incomplete partition

Small cochlea with incomplete or interscalar septum*

Mondini-Alexander

*The vestibule and semicircular canals in cochlear aplasia, cochlear hypoplasia, and incomplete partition may be normal or malformed.

Jackler et al.3 In a recent series by Park et al. of 24 patients with 39 ears involved, four (10%) had the Michel dysplasia.5 Common Cavity Dysplasia

During the 4th week of embryonic development, the otic placode invaginates to form a simple cavity called the otocyst. Arrest at this stage of development results in the persistence of a large cloaca. In the Jackler et al. system, this malformation is designated as the common cavity defect. Common cavity defects represent about 13–25% of vestibulocochlear malformations.3,5 Common cavity dysplasia is associated with increased risk for recurrent otogenic meningitis. Cochlear Aplasia

In the 5th week of embryonic development, three folds form, representing the primordial cochlear, vestibular, and endolymphatic sac appendages. Arrested development of the cochlear bud at this stage would result in cochlear aplasia with complete lack of cochlear development with preservation, but not necessarily normal development, of the semicircular canals and vestibule. Cochlear aplasia is relatively uncommon vestibulocochlear dysplasia and represents only about 3–10% of radiologically apparent cochlear malformations.3,5

Mondini-Alexander Dysplasia or Cochlear Hypoplasia and Incomplete Partition Dysplasia

Between the 5th and 8th weeks of development, the cochlear duct undergoes continuous growth. As the cochlear duct grows the characteristic turns of the cochlear also form. Arrest of development in the 6th week would result in the formation of a rudimentary cochlea, ranging from a small diverticulum to a cochlear bud several millimeters in length. This is classified as cochlear hypoplasia in the Jackler et al. classification scheme.3 Arrest in cochlear development during the 7th week results in a small, flattened cochlea with only 1 to 1.5 turns instead of the 2.5 to 2.75 turns seen at full development. This is referred to as the Mondini-Alexander dysplasia of Omerod’s classification and as incomplete partition in the Jackler et al. classification scheme. The basal turn of the cochlea is usually fully developed, while the upper turns form a common cavity known as the scala communis. Typical findings also include a short cochlear duct, immature auditory and vestibular sense organs and nerves, a large vestibule, a bulbous endolymphatic sac, and malformed semicircular canals that can be wide, small, or missing.6

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Craniofacial Structures

Bing-Siebenmann Dysplasia

In Bing-Siebenmann dysplasia the development of the bony labyrinth is normal, but the membranous portion of the cochlea and semicircular canals are malformed or degenerate. Since the petrous bone and the bony cochlea and vestibule are fully formed, this type of dysplasia cannot be detected radiographically and is not included in the Jackler et al. classification.3 Extensive involvement of the membranous cochlea is typical. The sensory endorgan and tectorial membrane are underdeveloped, and the canal of the cochlea is often collapsed. In cases where the canal of the cochlea is dilated rather than collapsed, the immaturity of the sensory endorgan is attributed to a degenerative process rather than an arrest in development.2 Although Bing-Siebenmann dysplasia is characterized by a greater involvement of the semicircular canals and the vestibular organ than that seen in Scheibe dysplasia, it is likely that BingSiebenmann dysplasia represents a severe form of the more common Scheibe dysplasia. Scheibe or Cochleosaccular Dysplasia

In 1978, Valvassori and Clemis8 described a series of 50 patients, out of 3700 referred for tomographic evaluation, whose vestibular aqueduct was enlarged—1.5 to 8 mm in diameter at the midpoint. Currently a midpoint diameter of greater than 2 mm is typically used for defining large vestibular aqueduct syndrome. Other terms for this abnormality include enlarged—or dilated—vestibular aqueduct and large endolymphatic duct. Individuals with large vestibular aqueducts are at risk for paroxysmal vertigo and progressive sensorineural hearing loss. In one study of 130 children with sensorineural hearing loss, 18 patients had large vestibular aqueducts. Progression of hearing loss was noted in 46% of these patients compared to 35% in the absence of this abnormality.9 Large vestibular aqueducts have been described in association with Pendred and branchio-oto-renal syndrome. In contrast to individuals with large vestibular aqueduct syndrome, about 60% of individuals with Meniere disease have a hypoplastic or narrowed vestibular aqueduct. It is unclear, however, if this abnormality plays a significant role in the disease since it is not present in all affected individuals and is also found in 21% of individuals without Meniere disease.10,11

Scheibe dysplasia represents the mildest end of the spectrum of vestibulocochlear dysplasias and consists of membranous abnormalities primarily of the cochlea with involvement of the saccule. It is also referred to as cochleosaccular dysplasia. In contrast to BingSiebenmann dysplasia, the membranous utricle and semicircular canals are fully formed and functioning. The petrous bone and the bony cochlea and vestibule are fully developed, making radiologic diagnosis impossible. The organ of Corti is often rudimentary with very few sensory cells, and the stria vascularis is degenerate with relatively few vessels. The canal of the cochlea is collapsed and the techtorial membrane is formed but flattened down over the organ of Corti and its supporting cells. In cases where the canal of the cochlea is dilated rather than collapsed, the immaturity of the sensory endorgan is attributed to a degenerative process rather than an arrest in development.2 The degree of development can vary throughout the cochlea, and some areas of the cochlea function sufficiently well to provide some level of hearing.

Internal Auditory Meatus Abnormalities

Semicircular Canal Abnormalities

In retrospective reviews of temporal bone CT scans, between 22% and 31% of children with sensorineural or mixed hearing loss had radiologically detectable vestibulocochlear abnormalities.5,13,14 These abnormalities were more common in children with congenital syndromes than in those with nonsyndromic hearing loss. The true incidence of inner ear malformations in this population is probably higher than given in these series since abnormalities restricted to the membranous labyrinth are not detected on CT scans. Several etiologies have been identified as the cause of inner ear abnormalities: (1) chromosomal abnormalities; (2) single gene disorders; (3) congenital associations; (4) congenital infections; and (5) toxic exposures (see Tables 10-12 and 10-13). Inherited disorders are probably the most common etiology.

During the 6th week of embryonic development, the superior, posterior, and lateral semicircular canals appear as folded invaginations of membrane from the vestibular appendage. Failure of these epithelial folds to form results in complete absence of the involved semicircular canal or semicircular canal aplasia. Over time the central portion of each invagination is resorbed, forming a semicircular duct. Incomplete absorption of the central membrane results in a pocket-shaped semicircular canal that is confluent with the vestibule. Although malformations of the semicircular canals, or semicircular canal dysplasia, can be an isolated defect, they are often associated with cochlear malformations. Semicircular canal abnormalities have been described in a number of hearing loss syndromes, including branchio-oto-renal syndrome, Goldenhar syndrome, Waardenburg syndrome, and CHARGE syndrome. Vestibular Aqueduct Abnormalities

The vestibular aqueduct is a bony canal through which courses the endolymphatic duct. Although most of the membranous labyrinth reaches adult size by the 18th week of fetal life, the vestibular aqueduct continues to grow throughout embryonic life, and the midpoint diameter of the duct is usually between 0.4 and 1.0 mm.7

The cochleovestibular nerve passes through the internal auditory meatus (IAM) along with the facial nerve. Several variations of the internal auditory meatus have been described, including absent, narrowed, widened, ballooned/bulbous, and tapered configurations.12 Absence of the IAM is rare but has been associated with thalidomide embryopathy. Although a narrowed IAM (<2 mm) can be seen in individuals with normal hearing, it is more common in individuals with senorinerural hearing loss and may indicate the hypoplasia or absence of the cochleovestibular nerve. A widened IAM (>8 mm) probably has little significance, except in individuals in whom an acoustic neuroma is suspected. A ballooned/bulbous IAM has been associated with the X-linked deafness perilymphatic gusher. A tapered IAM associated with a common cavity or hypoplastic cochlea has been associated with the formation of spontaneous cerebrospinal fluid fistulae. Etiology and Distribution

Prognosis, Prevention, and Treatment

A reduction in the incidence of inner ear abnormalities caused by congenital infection and toxic exposures may be possible through immunization and patient education programs. A prime example is the dramatic decrease in cases of congenital hearing loss due to rubella infections, which have been associated with Scheibe dysplasia, after the implementation of effective vaccination programs. In the majority of cases, however, prevention is not possible, and medical efforts should be concentrated on preserving residual inner

Ear

ear function, early intervention, timely rehabilitation, and careful monitoring and intervention for potential complications. The majority of individuals with inner ear abnormalities present with hearing loss. Patients with inner ear abnormalities should be discouraged from participating in activities that could result in further damage to the inner ear, such as contact sports, scuba diving, and parachuting. It would also be wise to minimize exposure to ototoxic medications and loud noise. Early diagnosis of hearing loss and appropriate intervention may help to maximize communication potential. Universal newborn screening would detect those patients. Careful monitoring of hearing level throughout life is essential, since individuals with inner ear abnormalities are at an increased risk for progressive hearing loss. Amplification with hearing aids is usually sufficient for auditory rehabilitation in individuals with inner ear abnormalities. In cases where hearing aids prove ineffective, cochlear implantation may provide improved communication outcomes. Multiple case, case series, and literature reviews have been written, which describe the outcomes of cochlear implantation in patients with various inner ear dysplasias. It appears that all degrees of cochlear dysplasia, ranging from incomplete partition to common cavity, can be implanted safely and auditory responses expected.15,16 It should be noted, however, that postoperative speech perception may be highly variable, and intraoperative and postoperative complication may occur. Absolute contraindications to cochlear implantation include Michel aplasia and absence of the auditory nerve. Bony dysplasias of the inner ear are associated with an increased risk of fistulous communication between the subarachnoid space and the middle ear cavity. These communications, called perilymphatic fistulas, can present with cerebrospinal otorhinorrhea or recurrent attacks of meningitis. Parents should be counseled about the early signs and symptoms of meningitis and vaccines against Haemophilus influenzae type B, and invasive pneumococcus should be strongly encouraged. Individuals with inner ear abnormalities are also at risk for perilymphatic fistulas as a result of head trauma or barometric insult. Perilymphatic fistulas are an abnormal connection between the inner and middle ear that allows perilymph fluid to escape into the middle ear compartment. Perilymphatic fistulas usually occur due to tears or ruptures of the oval window annulus, the round window membrane, or both. Symptoms include hearing loss, ranging from mild and fluctuating to sudden and profound; tinnitis; aural fullness; and vestibular symptoms such as vertigo, disequilibrium, lightheadedness, and intolerance to motion. References (Vestibulocochlear Dysplasias) 1. Graham JM, Phelps PD, Mechaels L: Congenital malformations of the inner ear and cochlear implantation in children: review and temporal bone report of common cavity. J Laryngol Otol 114(suppl 25):1, 2000. 2. Omerod FC: The pathology of congenital deafness. J Laryngol Otol 74:919, 1960. 3. Jackler RK, Luxford WM, House WF: Congenital malformations of the inner ear: a classification based on embryonogenesis. Laryngoscope 97(suppl 40):2, 1987. 4. Schuknecht HF: Pathology of sensorineural deafness of genetic origin. In: Deafness in Childhood. McConnell F, Ward PH, eds. Vanderbilt University Press, Nashville, TN, 1967, p 69. 5. Park AH, Kau B, Hutaling A, et al.: Clinical course of pediatric inner ear malformation. Laryngoscope 110:1715, 2000. 6. Schuknecht HF: Mondini dysplasia: a clinical and pathological study. Ann Otol Rhinol Laryngol 89(suppl 65):1, 1980. 7. Pyle GM: Embryological development and large vestibular aqueduct syndrome. Laryngoscope 110:1837, 2000.

369 8. Valvassori GE, Clemis JD: The large vestibular aqueduct syndrome. Laryngoscope 88:723, 1978. 9. Arcand P, Desrosiers M, Dube J, et al.: The large vestibular aqueduct syndrome and sensorineural hearing loss in the pediatric population. J Otolaryngol 20:247, 1991. 10. Sando I, Ikeda M: The vestibular aqueduct in patients with Meniere’s disease. Acta Otolaryngol 97:558, 1984. 11. Sennaroglu L, Yilmazer C, Basaran F, et al.: Relationship of vestibular aqueduct and inner ear pressure in Meniere’s disease and the normal population. Laryngoscope 111:1625, 2001. 12. Phelps PD, Lloyd GAS: Diagnostic Imaging of the Ear, ed 2. SpringerVerlag, London, 1990. 13. Antonelli PJ, Varela AE, Mancuso AA: Diagnostic yield of highresolution computed tomography for pediatric sensorineural hearing loss. Laryngoscope 109:1642, 1999. 14. McClay J, Tandy R, Grundfast K, et al.: Major and minor temporal bone abnormalities in children with and without congenital sensorineural hearing loss. Arch Otolaryngol Head Neck Surg 128:664, 2002. 15. Hoffman RA, Downey LL, Waltzman SB, et al.: Cochlear implantation in children with cochlear malformations. Am J Otol 18:184, 1997. 16. Woolley AL, Jenison V, Stroer BS, et al.: Cochlear implantation in children with inner ear malformations. Ann Otol Rhinol Laryngol 107: 492, 1998.

10.33 Prelingual Hearing Loss Definition

Prelingual hearing loss is a decrease in auditory acuity with onset in infancy or early childhood that produces potential for difficulty in communicating. Diagnosis

Hearing loss is classified as a decrease in auditory acuity and can be classified according to type, severity, and configuration. Types of hearing loss include (1) sensorineural, (2) conductive, and (3) mixed. Sensorineural hearing losses result from disorders of the cochlea or the auditory branch of the VIII cranial nerve. Conductive hearing losses are due to interference with the transmission of sound vibrations to the sensory apparatus. When both sensorineural and conductive hearing loss occur in the same ear, the hearing loss is considered mixed. The severity of hearing loss is divided into four levels: (1) mild, 25 to 40 dB, (2) moderate, 41 to 70 dB, (3) severe, 71 to 90 dB, and (4) profound, greater than 90 dB. Progressive forms of hearing loss are characterized by increasing severity of hearing loss over time in contrast to stable forms where the severity is constant and fluctuation forms where the severity waxes and wanes unpredictably. The extent to which low, middle, and high frequencies are affected determines the configuration of the hearing loss. Concerns of hearing loss in a child may arise from a failed newborn hearing screen, failure to reach developmental milestones, parental concern, or the presence of risk factors for hearing loss. Screening tests based on otoacoustic emission (OAE) or auditory brainstem response (ABR) can help to identify children with hearing loss, but the diagnosis is made by an audiologist after careful administration of a battery of age-appropriate tests to assess the integrity of the auditory system and to estimate the type, degree, and configuration of the hearing loss. Genetic forms of hearing loss can occur in isolation—nonsyndromic—or as a component of a genetic syndrome. Over 300 hearing loss syndromes have been reported. The characteristics

Table 10-14. Common hearing loss syndromes Hearing Loss Syndrome

Clinical Features

Gene or Locus

Alport

Hereditary nephritis (microscopic hematuria and/or proteinuria)

COL4A3 COL4A4 COL4A5

Branchio-oto-renal (BOR)

Preauricular pits, branchial fistulas or cysts, anomalous pinna

EYA1 Second locus at 1q31

Jervell and Lange-Nielsen

Syncopal episodes, prolonged QT interval on electrocardiogram

KVLQT1 KCNE1

Pendred

Thyroid goiter

SLC26A4

Stickler

Cleft palate, Pierre Robin sequence, flat midface, severe myopia, cataracts, marfanoid habitus

COL2A1 COL11A2 COL11A1

Treacher Collins

Downward-slanting palpebral fissures, coloboma of lower eyelid, ear tags, mandibular hypoplasia, anomalous pinna, cleft palate

TCOF1

Usher

Retinitis pigmentosa, vestibular abnormalities (Type 1 and 3)

Type Type Type Type Type Type Type Type Type Type Type

1A 14q32 1B MYO7A 1C USH1C 1D CDH23 1E 21q 1F PCDH15 1G 17q24-25 2A USH2A 2B 3q23-24.2 2C 5q14.3-21.3 3 USH3

Waardenburg

White forelock or premature graying of hair, fused eyebrows, bicolored iris or two eyes of different colors, telecanthus, pigmentary anomalies including partial albinism

Type Type Type Type

I PAX3 II MITF III PAX 3 IV EDNRB, EDN3, SOX10

Table 10-15. Genes responsible for nonsyndromic hearing loss Locus*

Gene

Autosomal Dominant Genes

Locus*

Gene

Autosomal Recessive Genes

DFNA1

DIAPH1, 5q31

DFNA2

GJB3 (Cx31), 1P34

DFNA3

DFNB1

GJB2 (Cx26), 13q11-q12 GJB6 (Cx30), 13q12

GJB2 (Cx26), 13q11-q12 GJB6 (Cx30), 13q12

DFNB2

MYO7A, 11q13.5

DFNB3

MYO15, 17p11.2

DFNA5

DFNA5, 7p15

DFNB4

SLC26A4, 7q31

DFNA6/DFNA14

WFS1, 4p16.1

DFNB6

TMIE, 3p21

DFNA8/DFNA12

TECTA, 11q22-q24

DFNB7/DFNB11

TMC1, 9q13-q21

DFNA9

COCH, 14q12-q13

DFNB8/DFNB10

TMPRSS3, 21q22.3

DFNA10

EYA4, 6q23

DFNB9

OTOF, 2p23-p22

DFNA11

MYO7A, 11q13.5

DFNB12

CDH23, 10q21-q22

DFNA13

COL11A2, 6p21.3

DFNB16

STRC, 15q15

DFNA15

POU4F3, 5q31

DFNB18

USH1C, 11p15.1

DFNA17

MYH9, 22q11.2

DFNB21

TECTA, 11q22-q24

DFNA22

MYO6, 6q13

DFNB22

OTOA, 16p12.2

DFNA28

TFCP2L3

DFNB29

CLDN14, 21q22.3

DFNA36

TMC1, 9q13-q21

DFNB30

MYO3A, 10p11.1

DFNA48

MYO1A, 12q13-q15

DFNB37

MYO6, 6q13

X-Linked DFN3 *As the chromosomal locations—loci—of the various genes responsible for nonsyndromic hearing loss are discovered, they are given specific designators based on their inheritance pattern and their order of discovery. Loci of genes causing autosomal dominant nonsyndromic hearing loss are given the designation DFNA and then numbered sequentially. Autosomal recessive loci have DFNB as their common designator and X-linked loci have DFN as their common designator. As of 2003 there were 51 dominant loci, 39 recessive loci, and eight X-linked loci reported.

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POU3F4, Xq21.1

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of several common syndromes are listed in Table 10-14 and have been thoroughly cataloged by Gorlin et al.1 The genes for many hearing loss syndromes have been identified, and in some cases genetic testing on a research or clinical basis is available. In the past, a diagnosis of nonsyndromic hearing loss was typically made as a diagnosis of exclusion after a careful history, physical exam, and laboratory testing failed to reveal evidence of a hearing loss syndrome or an environmental etiology. The identification of several genes that cause nonsyndromic hearing loss has opened the door for the development of genetic tests for nonsyndromic hearing loss (Table 10-15).2 However, the costeffectiveness of most of these tests, in open populations, is limited by the relatively small percentage of nonsyndromic hearing loss cases that are attributable to a particular gene. A notable exception is genetic testing for mutations in the connexin 26 gene (GJB2), which accounts for about 20–30% of congenital nonsyndromic hearing loss in the United States and is a common cause of nonsyndromic hearing loss worldwide.3,4 Testing for mutation of connexin 26 gene has become routine in the evaluation of infants and children with nonsyndromic hearing loss. Etiology and Distribution

Hearing loss may be caused by a number of environmental and disease-related factors, including viral and bacterial infections, prematurity, hypoxic insults, hyperbilirubinemia, exposure to ototoxic medications, and trauma. However, improvements in health care have resulted in significant reductions in the number of cases attributable to some of these etiologies, and the percentage of hearing loss cases with a genetic etiology continues to rise. In developed nations, at least half of severe childhood hearing loss can be attributed to genetic causes. Seventy percent of hereditary deafness is nonsyndromic. Syndromic forms of hearing loss account for the remaining 30% of inherited cases, or about 15% of the total. Prognosis, Prevention, and Treatment

Early detection and appropriate intervention may help to maximize communication outcomes in individuals with hearing loss. Universal neonatal hearing screening programs are effective in the early identification of many children with congenital hearing loss. Early Detection and Hearing Intervention (EDHI) programs are mandated in more than 35 states in the United States. Diagnosis of severe to profound hearing loss and implementation of early intervention portends better outcomes than diagnosis after 2 years of age. Failure to reach developmental milestones, parental concern, or the pres-

371

ence of risk factors for hearing loss, including stigmata of a hearing loss syndrome, should also trigger formal audiologic testing. Referral to a clinical geneticist is recommended when inherited forms of hearing loss are diagnosed or suspected.5 A clinical geneticist may be helpful in making the diagnosis of a hereditary syndrome when findings are equivocal or subtle. Families can also benefit from counseling available through a clinical geneticist in terms of prognosis and recurrence risk. Protocols for the evaluation of the child with hearing loss have been developed by expert groups.4,6 After hearing loss has been diagnosed, families should be encouraged to explore all available communication options and to choose a method that is consistent with the child’s corrected hearing level and their own willingness to learn new communication skills. Medical interventions may range from auditory amplification with hearing aids to cochlear implantation. The Food and Drug Administration approved cochlear implantation in children in 1990. Currently, over 50% of implants are placed in children. They are usually placed before age 2 years with excellent result in language.7 Limiting medical intervention and adopting a nonverbal form of communication is also a viable option. A large number of national, regional, and local organizations have been formed to provide information and support to families.8 References (Prelingual Hearing Loss) 1. Toriello HV, Reardon W, Gorlin RJ: Hereditary Hearing Loss and Its Syndromes, ed. 2. Oxford University Press, New York, 2004. 2. Van Camp G, Smith R: Hereditary Hearing Loss Homepage. http:// www.uia.ac.be/dnalab/hhh. 3. Green GE, Scott DA, McDonald JM, et al.: Carrier rates in the Midwestern United States for GJB2 mutations causing inherited deafness. JAMA 281:2211, 1999. 4. Kenneson A, Van Naarden Braun K, Boyle C: GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med 4:258, 2002. 5. Tomaski SM, Grundfast K: A stepwise approach to the diagnosis and treatment of hereditary hearing loss. Pediatr Clin N Am 46:35, 1999. 6. Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiology diagnosis of congenital hearing loss. Genet Med 4:162, 2002. 7. Francis HW, Mpankd JK: Cochlear implantation update. Pediatr Clin N Am 50:341, 2003. 8. Cherow E, Dickman DM, Epstein S: Organization resources for families of children with deafness or hearing loss. Pediatr Clin N Am 46:153, 1999.

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11 Nose M. Michael Cohen, Jr.

F

ormation of the nose is entirely dependent on development of the forebrain.1,2 Any insult that prevents the brain’s frontal development may disturb the anatomy of the nose. Nasal development first becomes evident histologically as thickenings of ectoderm, called olfactory placodes, by 26 days postfertilization (stage 12). The placodes are normally widely spaced on the anterolateral aspect of the frontal prominence (Fig. 11-1).1,3 The placodes become distinctive topographically by invaginating to form the nasal pits. With the rapid expansion of the forebrain, the nasal pits appear to converge toward the anterior midline. The lateral rims of the nasal pits (the nasolateral processes) fuse with the maxillary processes, forming the alae nasi. The medial rims of the nasal pits (nasomedial processes) grow faster than the nasolateral processes, extending anteriorly to form the ridge, tip, and columella of the nose and toward the oral plate to form the philtrum and medial portion of the upper lip. The nasomedial process fuses with the maxillary processes, which grow in from the lateral aspect of the face, completing a solid transverse bridge that separates the nose and mouth. The nasal pits become deeper by the overgrowth of the surrounding medial and lateral processes and by further invagination, eventually breaking through into the oral cavity. The anterior nares (nostrils) are now defined at the external opening of the nasal struc-

tures and the posterior nares (choanae) at the point of breakthrough into the oral cavity. The nasal air chamber thereafter becomes separated from the oral chamber by lengthening and fusion of the palatal shelves. Growth of the midfacial structures during the 3rd and 4th months advances the nose beyond the overhanging forehead and obliterates the frontonasal indentation. Further midface advancement continues at a slow pace until adult life. The landmarks for measuring nasal anatomy are shown in Figure 11-2.4 Growth of the nose is most rapid during the first 2 years of life; thereafter, growth assumes a slower rate until the skeleton is mature and then an even slower rate thereafter. Unlike many facial features, the nose continues to grow throughout life. Growth curves for nasal width, height (length), and protrusion and columella length during infancy and childhood are available.5,6

Fig. 11-1. Schematic of embryologic development of the nose and adjacent facial structures. The nasal placodes become evident by day 26 (B); nasal pits form in the placodes during week 5 (C); the lateral rims of the nasal pits merge with the maxillary processes during week 6 (D); the

medial rims of the nasal pits merge with each other, forming the nasomedial process during weeks 6 and 7 (E); and the nasomedial process merges with the maxillary processes to form the upper lip by week 8 (F,G). (Adapted from Patten1 and from Tuchmann-Duplessis and Haegel.3)

References 1. Patten BM: The normal development of the facial region. In: Congenital Anomalies of the Face and Associated Structures. S Pruzansky, ed. Charles C Thomas, Springfield, IL, 1961, p 11. 2. Stark RB, Ehrmann NA: The development of the center of the face with particular reference to surgical correction of bilateral cleft lip. Plast Reconstr Surg 21:177, 1958.

373

374

Craniofacial Structures

Fig. 11-3. Complete absence of the nose.

Fig. 11-2. Top: landmarks of nasal anatomy. Bottom: the configuration of the base, tip, and bridge of the nose as well as the columella, nares, and alae nasi, which vary widely. (From Hall et al.4)

3. Tuchmann-Duplessis H, Haegel P: Illustrated Human Embryology. Springer Verlag, New York, 1982. 4. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, New York, 1989. 5. Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983. 6. Farkas LG, Munro IR: Anthropometric Facial Proportions in Medicine. Charles C Thomas, Springfield, IL, 1987.

11.1 Arhinia Arhinia is absence of the nose. An occasional blind dimple is present where the nostrils should be. Diagnosis is based on clinical inspection (Fig. 11-3). With complete absence of the nose, the site of the external nose is flat and covered with normal skin. The maxilla is hypoplastic, the palate highly arched, and the upper lip normal. The nasal cavity is completely absent, and there is bilateral bony choanal atresia.1 Occasional cases may be associated with microphthalmia, iris coloboma, hypertelorism, meningocele, or submucous cleft palate.2 All cases have been sporadic. The condition is extremely rare. Because of complete obstruction of the nasal air passage, respiratory difficulty and cyanosis occur, especially during feeding. However, the affected infant can survive, adjust to oral breathing, and develop normally. The two patients reported by Gifford et al. had minimal airway and feeding difficulties.3 Surgical establishment of a normal airway can be deferred, and a nasal prosthesis can be constructed. Intelligence is usually normal.

References (Arhinia) 1. Wang MKH: Congenital anomalies of the nose. In: Reconstructive Plastic Surgery, vol II, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1181. 2. Shubich I, Sanchez C: Nasal aplasia associated with meningocele and submucous cleft palate. Ear Nose Throat J 64:259, 1985. 3. Gifford GH Jr, Swanson L, MacCollum OW: Congenital absence of the nose and anterior nasopharynx. Report of two cases. Plast Reconstr Surg 50:5, 1972.

11.2 Unilateral Arhinia, Heminasal Aplasia Unilateral absence of one nostril occurs with an occasional blind dimple where a nostril should be. Unilateral arhinia is a different malformation than cebocephaly, which has a single midline nostril. Diagnosis is based on clinical inspection (Figs. 11-4 and 11-5). One nostril is absent and may be associated with a blind dimple, skin tag, or proboscis. There may be a scar or slight bony tubercle just above the inner canthus. Bony abnormalities in the involved area include absent cribriform plate, nasal septum deviated to the unaffected side, loss of structures of the lateral wall of the nasal chamber on the affected side, absence or hypoplasia of the paranasal sinuses on the affected side, absent nasal bone, and disrupted lacrimal bone. The ipsilateral olfactory tract and bulb are usually absent. The eye on the affected side may be microphthalmic, absent, or have various anomalies. Orofacial clefting has been associated with some cases.1,2 All cases have been sporadic, and the condition is extremely rare. Plastic surgical procedures and/or prosthesis should be considered. Intelligence is usually normal, unless there are associated central nervous system malformations. References (Unilateral Arhinia, Heminasal Aplasia) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001.

Nose

375 2. Wang MKH: Congenital anomalies of the nose. In: Reconstructive Plastic Surgery, vol II, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1181.

11.3 Small Nose

Fig. 11-4. Unilateral absence of the nose associated with absent eye and hypoplastic ear on the same side.

Fig. 11-5. Unilateral absence of the nose associated with nose tag, absent eye with low-set eyebrow, and craniofacial asymmetry.

A small nose measures 2 standard deviations (SD) or more below the mean for one or more standard nasal measurements. Nasal height is a vertical measurement between the base of the columella and the nasion (Fig. 11-2). Nasal width is the horizontal measurement between the outer margins of the alae nasi. Nasal protrusion (depth) is the measurement from the tip of the nose to the base of the columella. Standards for childhood nasal measurements have been published by Hall et al.1 The nose is one of the most variable of facial landmarks.2 In clinical practice the nose is rarely measured, and identification of the small nose is made subjectively. Flattening of the bridge of the nose, hypoplasia of the alae nasi, and anteversion of the nares are anatomic changes that can contribute to the impression that the nose is small. In most cases, the small nose is an isolated finding, representing the lowest 2.5% of the continuous distribution of nose sizes. In general, the configuration of the nose is more helpful in syndrome delineation than is size of the nose. Infants with prenatal exposure to warfarin have small noses with accentuation of the junction of the alae nasi and the tip of the nose (Fig. 11-6). The entire nose is recessed because of midface hypoplasia. In Hallermann-Streiff syndrome the nose is small and pointed, with very little subcutaneous tissue. A similar nose but with more soft tissue in the early years is present in progeria. A small nose with anteversion of the nares occurs in Aarskog, Robinow, de Lange, Williams, Pfeiffer, and a number of other

Fig. 11-6. Small nose with accentuation of the demarcation between the tip of the nose and the alae in an infant exposed prenatally to warfarin.

376

Craniofacial Structures

recognizable syndromes. A small nose with depression of the nasal bridge occurs in acrodysostosis (a form of Albright hereditary dystrophy), in many of the lysosomal storage disorders, and in most skeletal dysplasias that are detectable in the newborn period. The fact that the nose normally tends to have an underdeveloped nasal bridge and anteverted nares early in life lessens the diagnostic usefulness of these findings during this period. Underdevelopment of the alae nasi or a pinched appearance to the nose is present in Johanson-Blizzard, oculodentoosseous, Apert, whistling face, Schwartz-Jampel, Waardenburg, and femoral hypoplasia-unusual facies syndromes. References (Small nose) 1. Hall JG, Froster-lskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, New York, 1989. 2. Goodman RM, Gorlin RJ: Atlas of the Face in Genetic Disorders, ed 2. CV Mosby, St. Louis, 1977.

11.4 Nostril Coloboma

2. Stupka W: The etiology of lateral nasal clefts. Am J Pathol 26:1085, 1950. 3. Stutz L: Angeborene seitliche Nasenspalte verbunden mit gleichseitiger Choanalatresie. Ohrenheik 65:202, 1912. 4. Webster JP, Deming EG: The surgical treatment of the bifid nose. Plast Reconstr Surg 6:1, 1950.

11.5 Bifid Nose The nose may be bifurcated by a central groove (Fig. 11-8). Diagnosis is based on clinical inspection. Ocular hypertelorism with widening of the nasal bridge may be present in many cases.1–3 Median cleft of the upper lip may also occur (Fig. 11-9). This anomaly is present in some cases of frontonasal dysplasia.1 Bifurcation with a central groove in the nose probably results from infolding of the median nasal process. Cases are usually sporadic, and the condition is rare. Surgical repair is the appropriate treatment. References (Bifid Nose)

A nostril coloboma is a triangular cleft involving the ala of the nose. The diagnosis is based on clinical inspection. Lateral nasal clefting usually occurs on one side (Fig. 11-7). Either side may be affected. Bilateral nostril colobomas are rare. Associated anomalies include unilateral anophthalmia, lower lid coloboma, frontal glioma, and ocular hypertelorism.1–4 The defect may be caused by inadequate mesenchyme between the median and lateral portions of the nasal ridge. All cases have been sporadic, and the condition is rare. The appropriate treatment is surgical repair. References (Nostril coloboma) 1. Nash WG: Congenital absence of the right eye and fissure of the nose. Lancet 1:28, 1858.

Fig. 11-7. Nostril coloboma, frontal encephalocele, and ocular hypertelorism.

1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Webster JP, Deming EG: The surgical treatment of the bifid nose. Plast Reconstr Surg 6:1, 1950. 3. DeMyer W: The median cleft face syndrome. Differential diagnosis of cranium bifidum occultum, hypertelorism, and median cleft nose, lip, and palate. Neurology 17:961, 1967.

Fig. 11-8. Bifid nose. Note also the hypoplastic ear and ocular hypertelorism.

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377

has been observed in a father and daughter and in two sisters.3 The treatment is surgical. References (Nostril Atresia) 1. Brown LG: Congenital and hereditary nasal deformity. Proc R Soc Med 22:523, 1929. 2. Panebianco G: Atresia congenita bilaterale incompleita delle narici. Otorinol Ital 27:286, 1929. 3. Washburn AC: Congenital atresia of the anterior nares. Report of two cases in sisters. Arch Otolaryngol 16:789, 1932.

11.7 Choanal Atresia

Fig. 11-9. Bifid nose in association with median orofacial clefting and ocular hypertelorism. (From DeMyer.3)

11.6 Nostril Atresia Nostril atresia is the failure of formation of one nostril. The diagnosis is based on physical examination. The nostril may be closed by membrane, cartilage, or, rarely, bone.1–3 The anomaly is rare, and most cases have been sporadic. However, the condition

Choanal atresia is congenital obstruction of the posterior choana or choanae. The clinical appearance varies widely, from cyanosis and respiratory distress to simple nasal discharge. Diagnosis is based on clinical examination and computed tomography (CT) scans. Bilateral choanal atresia results in complete nasal obstruction with immediate onset of respiratory distress at birth. Unilateral atresia rarely causes respiratory distress; the most common finding is unilateral mucoid discharge. Atresia may be simply membranous, membranous with a bony rim, or completely bony. The condition may be unilateral or bilateral and complete or incomplete.1,2 If a rubber catheter or metal probe cannot be passed more than 32 mm into the nostril, the presumptive diagnosis of choanal atresia can be made. The anomaly may be demonstrated with CT.1,2 The most commonly accepted theory for the pathogenesis of choanal atresia is failure of the nasobuccal membrane to break down. The condition occurs once in approximately 7000 livebirths. The male to female ratio is 1:2 and the unilateral to bilateral ratio is 2:1. Ninety percent are bony, and 10% are membranous. Associated anomalies occur in approximately 50% of the cases and include particularly the CHARGE syndrome (Table 11-1)3–19 Choanal

Table 11-1. Conditions with choanal stenosis or atresia Syndrome

Prominent Features

Causation Gene/Locus

Antley-Bixler4

Craniosynostosis, frontal bossing, humeroradial synostosis, femoral bowing, joint contractures

AR (207410)

Bamforth5

Bifid epiglottis or cleft palate, pili torti, hypothyroidism

Unknown

Braham: hyperostotic dysplasia

Progeroid features, cortical hyperostosis, symphalangism, dentin hypoplasia

Unknown (151050)

CHARGE7

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies or deafness

Sporadic (214800) CHD7, 8q12

Crouzon8

Craniosynostosis, proptosis, midface hypoplasia, beak nose

AD (123500)

Marshall-Smith9

Prominent forehead, growth and developmental failure, accelerated and dysharmonic bone age, early death Craniosynostosis, broad thumbs and halluces

Unknown

Schinzel-Giedion11

Midface retraction, growth and developmental retardation, wormian bones

AR (269150)

Treacher Collins

Lid coloboma, downward-slanting palpebral fissures, malar hypoplasia, ear anomalies, deafness

AD (154500)

Pfeiffer10

AD (101600)

Does not include the reports of Flannery12 (imperforate oropharynx-skeletal anomalies), Salinas et al.13 (craniosynostosis-lid colobomas-lower lip cleft), Seemanova et al.14 (microcephaly-immunodeficiency), Kaplan et al.15 (acro-cranio-facial dysostosis), Hurst et al.16 (cardiac defect-short stature-choanal atresia), Greenberg17 (choanal atresia-absent nipples), Goldblatt and Viljoen18 (radial defectchoanal atresia), and Edwards et al.19 (microphthalmia-microcephaly-brain anomalies).

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Craniofacial Structures

stenosis may also occur in a number of disorders, including hyperostotic skeletal dysplasias that affect the cranium.6,20,21 With unilateral choanal atresia, definitive surgical treatment can be carried out at any time during childhood. With bilateral involvement, an artificial airway is required. Rarely is tracheotomy necessary. Neonates are obligate nosebreathers. Mouthbreathing is a learned response, occurring approximately 4 to 6 weeks after birth. Prognosis is usually good, provided other abnormalities, particularly those of CHARGE syndrome, are not present.1,2 References (Choanal Atresia) 1. Converse JM, Wood-Smith D, Shaw WW: Congenital choanal atresia. In: Reconstructive Plastic Surgery. Principles and Procedures in Correction, Reconstruction and Transplantation, vol 2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1163. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 3. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 4. Escobar LF, Bixler D, Sadove M, et al.: Antley-Bixler syndrome from a prognostic perspective: report of a case and review of the literature. Am J Med Genet 29:829, 1988. 5. Bamforth JS, Hughes IA, Lazarus JH, et al.: Congenital hypothyroidism, spiky hair and cleft palate. J Med Genet 26:49, 1989. 6. Lenz WD, Majewski F: A generalized disorder of the connective tissues with progeria, choanal atresia, symphalangism, hypoplasia of dentine and craniodiaphyseal hypostosis. Birth Defects Orig Artic Ser X(12):133, 1974. 7. Siebert JR, Graham JM Jr, MacDonald C: Pathological features of the CHARGE association: support for involvement of the neural crest. Teratology 31:331, 1985. 8. Cohen MM Jr, MacLean RE: Craniosynostosis, Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 9. Fitch N: The syndromes of Marshall and Weaver. J Med Genet 17:174, 1980. 10. Pfeiffer RA: Associated deformities of the head and hands. Birth Defects Orig Artic Ser XI(5):99, 1975. 11. Donnai D, Harris R: A further case of a new syndrome including midface retraction, hypertrichosis, and skeletal anomalies. J Med Genet 16:483, 1978. 12. Flannery DB: Syndrome of imperforate oropharynx with costovertebral and auricular anomalies. Am J Med Genet 32:189, 1989. 13. Salinas CF, Jorgenson RJ, Strickland A: Case report 38: colobomas of lower lids, malar hypoplasia, antimongoloid slant and clefting. Synd Ident IV(1):5, 1976. 14. Seemanova E, Passarge E, Beneskova D, et al.: Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet 20:639, 1985. 15. Kaplan P, Plauchu H, Fitch N: A new acro-cranio-facial dysostosis syndrome in sisters. Am J Med Genet 29:95, 1988. 16. Hurst JA, Berry AC, Tettenbom MA: Unknown syndrome: congenital heart disease, choanal stenosis, short stature, developmental delay, and dysmorphic facial features in a brother and sister. J Med Genet 26:407, 1989. 17. Greenberg F: Choanal atresia and athelia: methimazole teratogenicity or a new syndrome. Am J Med Genet 28:931, 1987. 18. Goldblatt J, Viljoen D: New autosomal dominant radial ray hypoplasia syndrome. Am J Med Genet 28:647, 1987. 19. Edwards JG, Lampert RP, Hammer ME, et al.: Ocular defects and dysmorphic features in three generations. J Clin Dysmorphol 2:8, 1984. 20. Schaefer B, Stein S, Oshman D, et al.: Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia. Clin Genet 30:381, 1986. 21. Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperostoses. A critical analysis. Birth Defects Orig Artic Ser V(4):78, 1969.

Fig. 11-10. Diprosopia with double nose. (From Gruber.3)

11.8 Polyrrhinia Polyrrhinia is partial or complete duplication of the nose. Diagnosis is based on clinical inspection. Two separate noses each with two nostrils may occur with diprosopia, a condition in which partial duplication of the face occurs (Fig. 11-10). Partial duplication may occur with lesser degrees of facial duplication. Supernumerary nostrils have been described, one above the other.1–3 All cases have been sporadic. The condition is extremely rare. Some cases of facial duplication are incompatible with life. An exception is the case reported by Obwegeser et al.4 in which extraordinary craniofacial reconstruction was carried out successfully. References (Polyrrhinia) 1. Lindsay B: A nose with supernumerary nostrils. Trans Pathol Soc Lond 57:329, 1906. 2. Tawse HB: Supernumerary nostril and cavity. Prac R Sac Med 13:28, 1919. 3. Gruber GB: Diprosopia triorbaria und Prosopothorakopagia (Bin Beitrag zur Frage teratologischer Abbildungen). Zbl Allg Path 108:546, 1966. 4. Obwegeser HL, Weber G, Freihoffei HP, et al.: Facial duplication—the unique case of Antonio. J Max-Fac Surg 6:179, 1978.

11.9 Proboscis Definition

A proboscis is a blind-ended, tubelike structure, commonly located in the midface.

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379

Fig. 11-11. Cyclopia (E, arrowheads) with proboscis (P). (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Diagnosis

Diagnosis is based on clinical inspection. There are four types: holoprosencephalic proboscis, lateral nasal proboscis, supernumerary proboscis, and disruptive proboscis. In holoprosencephaly, proboscis formation is found in many but not all cases of cyclopia (Fig. 11-11). It is formed in all cases of the rarely occurring ethmocephaly (Fig. 1112). In cebocephaly, no proboscis formation occurs per se, but a single-nostril nose is present. With median cleft lip, the nose is extremely underdeveloped, although no proboscis formation occurs.1 Lateral nasal proboscis represents incomplete formation of one side of the nose; it is found instead of a nostril (Fig. 11-13). The proboscis predicts absence of the ipsilateral olfactory tract

and bulb. The patient is frequently otherwise normal, although cleft palate may occur in some instances, and an occasional case has been reported with unilateral microphthalmia. When both nostrils are formed and a proboscis occurs additionally, it represents accessory proboscis formation arising from a supernumerary olfactory placode (Fig. 11-14). Rarely, a lateral proboscis located beyond the limits of the outer canthus has been reported.2–7 Disruptive proboscis formation can occur if an early embryonic hamartoneoplastic lesion arises in the primitive prosencephalon. Figure 11-15 shows bilateral nasal proboscides arising from an early embryonic hypothalamic hamartoblastoma.8 Etiology and Distribution

Fig. 11-12. Ethmocephaly.

With proboscis formation, the lateral nasal process fails to fuse with the median nasal process and with the maxillary process. It is etiologically and pathogenetically heterogeneous. Holoprosencephalic proboscis, lateral nasal proboscis, and supernumerary nasal proboscis are malformations. Proboscis may be considered a disruption when it arises from a hamartoneoplasia affecting the prosencephalon. Holoprosencephaly occurs with a frequency of 0.63 per 10,000 livebirths in nonchromosomal cases; it is obviously higher if chromosomal cases are included (Table 11-2). However, no accurate overall birth prevalence has been determined to date.1 Many cases of holoprosencephaly do not have proboscis formation. Other types of proboscis are rare. Prognosis and Treatment

Prognosis depends on the overall pattern of anomalies. If associated with holoprosencephaly, the prognosis is poor. For nonholoprosencephalic isolated proboscis formation, plastic surgical repair is indicated. References (Proboscis) 1. Cohen MM Jr: Perspectives in holoprosencephaly. Part I. Epidemiology, genetics, and syndromology of holoprosencephaly. Teratology 40:211, 1989. 2. Biber JJ: Proboscis lateralis. A rare malformation of the nose, its genesis and treatment. J Laryngol Otol 63:734, 1949.

380

Craniofacial Structures

Fig. 11-13. Two children with unilateral proboscis and normal nostril on the other side. (Left, courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE; right, courtesy of Dr. T. Coetzee, Pietermaritzburg, South Africa.)

Fig. 11-14. Lateral nasal proboscis in association with cleft lip/ palate. (From McLaren.5)

3. Antoniades K, Baraister M: Proboscis lateralis: a case report. Teratology 40:193, 1989. 4. Wang S, Wang Y, Roy FH: Proboscis lateralis, microphthalmos, and cystic degeneration of the optic nerve. Ann Ophthalmol 15:756, 1983. 5. McLaren LR: A case of cleft lip and palate with ploypoid nasal tubercle. Br J Plast Surg 8:57, 1956. 6. Rontal M, Duritz G: Proboscis lateralis: case report and embryologic analysis. Larynogoscope 87:996, 1977.

Fig. 11-15. Bilateral nasal proboscides. Diffuse pigmentation of the conjunctiva of the right eye is present. The left eye is anophthalmic. Proboscides resulted from disruption by a large, early embryonic, hamartoneoplastic lesion developing between the two cerebral hemispheres. (From Gitlin and Behar.8) 7. Cohen MM Jr, Jirasek JE, Guzman RT, et al.: Holoprosencephaly and facial dysmorphia: nosology, etiology and pathogenesis. Birth Defects Orig Artic Ser VII(7):125,1971. 8. Gitlin G, Behar AJ: Meningeal angiomatosis, arhinencephaly, agenesis of the corpus callosum and large hamartoma of the brain with neoplasia in an infant having bilateral nasal proboscis. Acta Anat 41:56, 1960.

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381

Table 11-2. Conditions with holoprosencephaly Monogenic holoprosencephaly

Aicardi (XLD, 304050) Autosomal dominant holoprosencephaly (AD, 157170) Autosomal recessive holoprosencephaly (AR, 236100) Grote: holoprosencephaly-polydactyly-heart defect (uncertain) Holoprosencephaly-fetal hypokinesia (XLR, 306990) Martin: holoprosencephaly-skeletal anomalies (AD) Meckel (AR, 249000) Steinfeld: limb defects-visceral defects-holoprosencephaly (AD) Velocardiofacial (AD, 19430) Environmental holoprosencephaly

Maternal diabetes Chromosomal holoprosencephaly

Triploidy Trisomies 13, 18 Duplication 3p Deletions 13q, 18p, 7(pter q32) Uncommonly in trisomies 20, 21, 22; duplications or deletions of chromosomes 1,2,5,6,9,11,14,21,22,X; and XXX Holoprosencephaly of unknown cause

Aprosencephaly-radial aplasia-genital defects Hartsfield: holoprosencephaly-ectrodactyly Holoprosencephaly-ectopic cordis-embryonal tumors

Fig. 11-16. Notching of both nostrils in a child with ocular hypertelorism and unilateral microphthalmia. (From Sedano et al.9)

Majewski-like chondrodysplasia Pseudotrisomy 13 Holoprosencephaly-neural tube defect Holoprosencephaly-frontonasal dysplasia From Cohen.1

11.10 Noses of Distinction A number of minor anomalies affect the nose. The nose may be large or small, short or long, thick or thin, symmetric or asymmetric, and curved, humped, or concave. The nostrils may be anteverted. The nasal septum may extend below the alae. The nasal tip may be pointed, round, or broad. The alar wings may be hypoplastic or notched (Fig. 11-16). The nostrils may be of similar size, or one nostril may be larger. The nasal bridge may be high or low and wide or narrow. Rarely, a skin tag may appear on the nose or in close proximity.1,2 Unusual Noses

Wrinkling of the nose (Fig. 11-17) is encountered on occasion and is usually associated with ocular hypertelorism. It may also occur with frontonasal dysplasia. Its pathogenesis is unknown.3 Potato nose, a perjorative term, is used here to describe a condition that is only known by that term in the literature. The

Fig. 11-17. Wrinkling of the nose. (Courtesy of Dr. H. Tsur, Tel Aviv, Israel.)

nose is characterized by marked broadening of a mobile septum, nasal tip, and nasal bridge. The outer wall of the nose has a balloon shape. The nasal bones are absent, and the lateral nasal walls are composed of an ill-defined cartilaginous mass. A tear duct anomaly may be associated. The condition has autosomal dominant inheritence.4 Orangutan nose, a perjorative term, is the only one known to describe an unusual broadening and flattening of the nose. The

382

Craniofacial Structures

Fig. 11-18. Erupted tooth in nostril.

nasal root is short, and the nasal bridge is broad and grooved with a flat nasal tip. The nostrils are widened and directed outward. Hyperpneumatization of the nasal cavity, paranasal sinuses, and mastoids are characteristic. The pharynx is hypoplastic. Myoclonic torsion dystonia is a feature, and the condition probably has autosomal dominant inheritance.5 Nasal teeth occur rarely when a tooth bud develops in the region of the nose (Fig. 11-18). Syndromic Noses

In Binder syndrome, the nasofrontal angle is absent and the nose is hypoplastic with flattening of the alae and nasal tip (Fig. 11-19). Radiographically there is aplasia or hypoplasia of the anterior nasal spine, together with localized maxillary hypoplasia. Although the face may appear ‘‘arhinencephaloid,’’ no brain abnormalities are observed. The sense of smell is completely normal. The overwhelming majority of cases are sporadic.6,7 In chondrodysplasia punctata, the nose is hypoplastic. There are various forms of the

disorder, including an X-linked dominant type, an X-linked recessive type, and an autosomal recessive form.6 Craniometaphyseal dysplasia is a monogenic condition with both autosomal dominant and autosomal recessive forms. Although the condition is present in the zygote, the root of the nose begins to broaden, with an elevated wing of bone gradually extending over the nasal bridge to the zygomas from the 1st year of life until the time of adolescence (Fig. 11-20). Increasing bony sclerosis narrows the nasal lumen, leading to obstruction.6 Craniorhiny combines craniosynostosis with unusual nasal abnormalities. Characteristic features include wide nose, anteverted nostrils, nasal hirsutism, and bilaterally symmetric spherical cystlike formations with small fistulas located just below the nose (Fig. 11-21). Inheritance is autosomal dominant.8 In the de Lange syndrome, primordial growth deficiency occurs together with mental retardation, anomalies of the extremities, and a characteristic facial appearance (Fig. 11-22). Most cases are sporadic. The nose is small with a flat nasal bridge. The nostrils are anteverted. The fetal face syndrome, also known as Robinow syndrome, consists of a characteristic facial appearance, mesomelic brachymelia of the arms, short fingers, and hypoplastic genitalia. An autosomal dominant form of the disorder occurs more commonly than an autosomal recessive form.6 The nose is short and broad, and the nostrils are upturned and anteverted (Fig. 11-23). In the prenatal warfarin syndrome, a characteristic pattern of craniofacial alterations and other defects may be observed. The midface is hypoplastic, with severe underdevelopment of the nose (Fig. 11-6). Choanal atresia may be present.6 Frontonasal dysplasia is characterized by ocular hypertelorism, broad nasal root, lack of nasal tip, widow’s peak, and anterior cranium bifidum occultum. Associated defects may include midline clefting of the nose (Fig. 11-24). The nasal alae may be notched or colobomatous. Most cases are sporadic.6,9 The Hallermann-Streiff syndrome is a distinct disorder consisting of dyscephaly, hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia (Fig. 11-25), and proportionate short stature. Virtually all cases have been sporadic to date.6

Fig. 11-19. Binder syndrome with hypoplastic flattened nose and absence of nasofrontal angle. (Courtesy of Dr. Robert J. Gorlin, University of Minnesota School of Dentistry, Minneapolis.)

Nose

Fig. 11-22. De Lange syndrome. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Fig. 11-20. Craniometaphyseal dysplasia with bony widening of the root of the nose.

Fig. 11-21. Craniorhiny. (From Mindikoglu et al.8)

Fig. 11-23. Fetal face syndrome (Robinow syndrome). Fig. 11-24. Frontonasal dysplasia. (From Sedano et al.9)

383

384

Craniofacial Structures

Fig. 11-25. Hallermann-Streiff syndrome.

Features of the Johanson-Blizzard syndrome include a characteristic facial appearance, severe mental and somatic retardation, sensorineural hearing loss, and malabsorption due to pancreatic insufficiency. The nose is characteristic, with severely hypoplastic or aplastic nasal alae (Fig. 11-26). The disorder has autosomal recessive inheritance.6 The oral-facial-digital-syndrome, type I, is characterized by hyperplastic frenulae, multilobulated tongue, hypoplasia of the nasal alar cartilages, median pseudocleft of the upper lip, asymmetric cleft palate, and various malformations of the digits. In-

Fig. 11-26. Johanson-Blizzard syndrome with hypoplasia of the alae nasi. (Courtesy of Dr. D.W. Day, Dallas, TX.)

heritance is X-linked dominant limited to females and lethal in males. Nasal alar flaring is absent, and in some instances nostril size may be asymmetric, being more hypoplastic on one side.6 In Potter sequence, compression deformities of the face and limbs occur together with pulmonary hypoplasia, wrinkling of the skin, and growth restriction resulting from oligohydramnios. The condition is both etiologically and pathogenetically heterogeneous.6 The nose may be blunted, with a downturned nasal tip (Fig. 11-27). Autosomal dominant rhiny is a localized disorder affecting the midface.8 The nose is extremely short, with upturned small nares facing directly anteriorly (Fig. 11-28).

Fig. 11-27. Craniofacial profile in Potter sequence showing flattened nasal tip and prominent alae nasi. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

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Fig. 11-28. Rhiny. (From Mindikoglu et al.8)

The constellation of broad thumbs and halluces, characteristic facial dysmorphism, growth retardation, and mental deficiency make up the Rubinstein-Taybi syndrome. The overwhelming majority of cases are sporadic.6 The nasal bridge is broad and the nose beaked, with the nasal septum extending below the alae (Fig. 11-29). Trichorhinophalangeal syndrome (TRP) is characterized by cone-shaped epiphyses, sparse and fine hair, bulbous nose with lack of alar flare (Fig. 11-30), and variable growth retardation. Vertical transmission has been demonstrated in a great many families, although horizontal transmission also occurs. It has been conclusively demonstrated that TRP type I is due to deletion of 8q24.12. The more severe TRP type II is due to a larger deletion.6

Fig. 11-30. Trichorhinophalangeal syndrome.

Williams syndrome consists of characteristic facial appearance, mental retardation, growth deficiency, and cardiovascular anomalies.6 The midface is flat, the nasal bridge is depressed, the nares are anteverted, and the philtrum is long (Fig.11-31). References (Noses of Distinction) 1. Cohen MM Jr: Noses nobody knows. Proc Greenwood Genet Center 6:183, 1987.

Fig. 11-29. Rubinstein-Taybi syndrome.

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Craniofacial Structures

References (Deviation of the Nasal Septum) 1. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 2. Gray LP: Deviated nasal septum, incidence and etiology. Ann Otol Rhinol Laryngol 87 (suppl):50, 1978.

11.12 Turbinate Deformity Diagnosis is based on clinical examination. When the nasal septum is displaced, there may be overdevelopment of the inferior or middle turbinates. In addition, if the ethmoid air cells invade the middle turbinate, a rounded bulbous configuration may occur and create nasal obstruction on one side.1 Overdevelopment of the turbinates is compensatory to severe, long-standing displacement of the nasal septum. Surgical repair may be performed for severe involvement. Reference (Turbinate Deformity) 1. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718.

Fig. 11-31. Williams syndrome. (Courtesy of Dr. John M. Opitz, Salt Lake City, UT.)

2. Cohen MM Jr: The Child With Multiple Birth Defects. Raven Press, New York, 1982. 3. Cohen MM Jr: Personal observations. 4. Nieuwenhuijse AC: Continuation of the pedigree of hereditary potato nose (Benjamin-Stibbe). Acta Oto-Laryngol 38:112, 1950. 5. Benedek L, Rakonitz E: Heredopathic combination of a congenital deformity of the nose and of myoclonic torsion dystonia. J Nerv Ment Dis 91:608, 1940. 6. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 7. Olow-Nordenram M: Maxillonasal dysplasia (Binder’s syndrome): a study of craniofacial morphology, associated malformations and familial relations. Swedish Dent J Suppl 47:1, 1987. 8. Mindikoglu AN, Partington MW, Cohen MM Jr: Noses nobody knows—for real: rhiny and craniorhiny. Am J Med Genet 40:250, 1991. 9. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia. J Pediatr 76:906, 1970.

11.11 Deviation of the Nasal Septum The nasal septum is considered to be deviated when it has significant asymmetry. Diagnosis is based on a clinical examination. If septal deviation is significant, particularly in association with turbinate deformity, blockage of the nasal passage may occur on one side.1 Approximately 80% of individuals have at least some deformity of the nasal septum. Significant deviation is much less common.1 Deviation may be due to intrauterine constraint or may result from a birth canal injury. Gray2 found septal deformities in 4% of infants born with normal vaginal deliveries and 13% for difficult deliveries. In contrast, infants delivered by cesarean section rarely had septal deviation. Most newborn nasal deformities are either self-correcting or can be corrected by gentle manipulation.1

11.13 Arrhinencephaly Arrhinencephaly is agenesis of the olfactory tracts and bulbs without more extensive holoprosencephalic involvement. Diagnosis is based on neurologic testing for anosmia, on recognition of a syndrome with absent olfactory tracts and bulbs, or as an autopsy finding. Magnetic resonance imaging scans can be confirmatory, particularly during infancy. Pathogenesis is based on failure of development of the olfactory bulbs. It is etiologically heterogeneous and occurs in various conditions listed in Table 11-3.1 The frequency has been estimated as one in 2500 births. Prognosis depends on diagnosis of the overall condition. Mental deficiency may be a feature in some cases. Other cases may not be compatible with life. Associated malformations may require surgical treatment, depending on various factors.1 Reference (Arrhinencephaly) 1. Cohen MM Jr.: Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and syndromology. Teratology 40:211, 1989.

11.14 Hemangioma of the Nose Hemangioma of the nose is a benign vascular tumor affecting the soft tissues. Diagnosis is based on clinical examination. Hemangiomas may be capillary, cavernous, mixed, hypertrophic, or juvenile (Figs. 11-32 and 11-33). Capillary or mixed hemangiomas are readily diagnosed by the strawberry-reddened skin surface of the lesion on the nose. Pure cavernous lesions may be distinguished by bluish tinge, soft texture, diffuse outline, and collapsibility.1,2 Although hemangiomas commonly occur in the head and neck region, they only infrequently involve the nose.1 Nasal involvement may occur with Sturge-Weber angiomatosis and with Roberts syndrome.

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Table 11-3. Conditions associated with arhinencephaly Syndrome

Prominent features

Causation

Anosmia, isolated, type I

None

XLR

Anosmia, isolated, type II

None

AD

Anosmia-humeroradial synostosis

Humeroradial synostosis, Robin anomaly

Uncertain

Arhinencephaly-Di George

Cardiac defects, absent or hypoplastic thymus and parathyroid

Heterogeneous

Arhinencephaly-Goldenhar

Ocular, auricular, mandibular, and vertebral anomalies

Unknown, but heterogeneous

Campomelic dysplasia

Globular head, cleft palate, bowed long bones, lethal

AR

Chromosome anomalies

Various anomalies and arhinencephaly seen in dup 1q, 6p, 6q, and 16q; tetrasomy 12p; and XXXXY

Chromosomal

Fitch

Absent corpus callosum, hydrocephaly, diaphragmatic defect, ventricular septal defect, absent fingernails

Uncertain

Johnson

Dysplastic ears, deafness, alopecia, hypogonadism

Kallmann, type I

Ocular hypertelorism, mental retardation, hypogonadism, unilateral renal agenesis

XLR

Kallmann, type II

Hypogonadism, diabetes mellitus, deafness

AR

Perrin

Ichthyosis, hypogonadism, mental retardation

XLR

Va´radi

Cleft lip and palate, tongue nodule, polydactyly, heart defect, growth and mental retardation

AR

From Cohen.1

Fig. 11-32. Flat hemangiomatous lesions of midline involving the nose. Patient also had complete absence of all four limbs.

Conservative management with careful observation is the treatment of choice for most lesions, because they tend to regress. Surgical treatment is necessary for rapidly invasive lesions or for those with involvement of contiguous structures causing respiratory embarrassment.1

Fig. 11-33. Hemangioma of nose, causing enlargement.

388

Craniofacial Structures

References (Hemangioma of the Nose) 1. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 2. Wang MKH, Macomber WB: Congenital tumors of the nose. In: Reconstructive Plastic Surgery: Principles and Procedures in Correction, Reconstruction and Transplantation, vol 2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1169.

11.15 Dermoid Cyst of the Nose A dermoid cyst of the nose is a benign tumor containing ectodermal and mesodermal elements. The diagnosis is based on physical examination. Magnetic resonance imaging and computed tomography scanning should be carried out and can detect rare intracranial extension through a bony defect. A dermoid may present as an external nasal mass, an intranasal mass, a dermoid sinus without a cyst, a dermoid cyst without a fistula, or an extracranial/intracranial mass. A dimple, indentation, or pit with an extruding hair occurs commonly. Lesions are firm, noncompressible, and occasionally lobulated.1–3 Dermoids represent embryonic defects. Theories include failure of neuropore closure and abnormal obliteration of the prenasal space. Most cases occur sporadically, although a familial tendency has rarely been reported. Nasal dermoids account for about 10% of all dermoids in the head and neck region. There is a slight male predominance. Complete surgical excision is necessary to prevent progressive expansion, infection, or fistula formation. Plastic surgical reconstruction may be required.1–3 References (Dermoid Cyst of the Nose) 1. Crawford H, Maguire C, Georgiade N, et al.: Dermoid cysts of the nose presentation of 7 cases. Plast Reconstr Surg 16:237, 1955. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 3. Wang MKH, Macomber WB: Congenital tumors of the nose. In: Reconstructive Plastic Surgery: Principles and Procedures in Correction, Reconstruction and Transplantation, vol2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1169.

Fig. 11-34. Frontonasal encephalocele in a 10-month-old infant exposed prenatally to hydantoin.

11.16 Glioma of the Nose A glioma of the nose is a tumor composed of neuroglia at some stage of its development that involves the nose. Diagnosis is based on clinical examination. Computed tomography (CT) or magnetic resonance imaging scans should be used to rule out intracranial involvement. Extranasal gliomas appear most often near the root of the nose. They are smooth, firm, and noncompressible. Intranasal gliomas are reddish, firm, and polypoid. Large gliomas involving the nasal cavity may result in nasal obstruction and septal deviation. Ocular hypertelorism may be associated. Approximately 15% of intranasal gliomas are connected by a fibrous stalk to the dura through the cribriform plate of the ethmoid bone.1–4 The etiology of nasal gliomas is unknown. Males are more frequently affected than females, with a 3:1 ratio. Extranasal lesions occur in 60%, intranasal lesions in 30%, and combined lesions in 10%.2 Surgical intervention is required. An extracranial approach is sufficient unless CT reveals a bony defect in the skull. References (Glioma of the Nose) 1. Dawson RLG, Muir IFK: The fronto-nasal glioma. Br J Plast Surg 8:136, 1955. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718. 3. Walker EA, Resler DR: Nasal glioma. Laryngoscope 73:93, 1963. 4. Wang MKH, Macomber WB: Congenital tumors of the nose. In: Reconstructive Plastic Surgery: Principles and Procedures in Correction, Reconstruction and Transplantation, vol 2, ed 2. JM Converse, ed. WB Saunders Company, Philadelphia, 1977, p 1169.

11.17 Encephalocele Involving the Nose Encephalocele involving the nose consists of herniation of brain tissue through an anterior defect in the skull bones. Diagnosis is by clinical examination together with computed tomography or magnetic resonance imaging. Most cases present in the midline, and some type of bony defect is invariably present (Fig. 11-34). Sincipital encephaloceles may present nasofrontally, nasoethmoidally, or

Nose

nasoorbitally. Large anterior encephaloceles may be associated with ocular hypertelorism. Basal encephaloceles may herniate through the cribriform plate, superior orbital fissure, or posterior clinoid fissure. Lesions may be transethmoidal, sphenoethmoidal, transsphenoidal, and sphenoorbital. Sphenoethmoidal lesions may be associated with hypertelorism and hypothalamic-pituitary dysfunction.1,2 Although the pathogenesis of encephaloceles is not certain, two views predominate. The first is that these neural tube defects are primary malformations, and the second is that they represent disruptive defects secondary to rupture of a distended neural tube. Nasofrontal and basal encephaloceles are very uncommon. Nasal

389

encephaloceles occur in 1 per 35,000 livebirths, but are found in 1 per 6000 births in Southeast Asia. Surgical repair of these defects is required. Prognosis depends on size and extent of the lesion together with associated anomalies. Mental deficiency is common. Associated anomalies occur in 30–40% of cases. References (Encephalocele Involving the Nose) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Hengerer AS, Newburg JA: Congenital malformations of the nose and paranasal sinuses. In: Pediatric Otolaryngology. CD Bluestone, SE Stool, eds. WB Saunders Company, Philadelphia, 1990, p 718.

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12 Lips Marilyn Jones

W

hen reduced to the simplest construct, the human face forms from five mounds of tissue that surround the stomodeum or future mouth. The largest is the central and rostrally located frontonasal process that will give rise to the forehead, the nose, the central portion of the upper lip, and the premaxilla or primary palate. Lateral to the frontonasal process are the paired maxillary processes that form the cheeks, the secondary palate, and the lateral portion of the upper lip. The paired mandibular processes form the lower jaw and lower lip. The maxillary and mandibular processes are derivatives of the first pharyngeal arch. Over the last 10 years much has been learned about the genes that direct the process of facial formation as well as the interactions among cells that populate the face.1–4 In the embryonic disc, the ectodermal layer of the oropharyngeal membrane is dorsally oriented and attached directly to the underlying endoderm (Fig. 12-1). Growth of the overlying neural tissue causes cephalic folding and swings the oropharyngeal membrane into the embryonic interior where it forms the stomodeum (by stage 12, or about 26 days) and persists briefly as the cephalic-most limit of the foregut. Externally, the stomodeum becomes surrounded by the five advancing facial processes outlined above (Fig. 12-2). The mesenchyme that populates the facial primordial derives primarily from neural crest cells migrating from hindbrain neuromere segments just prior to neural tube formation.5 Migration of neural crest cells is spatially and temporally regulated by homeobox genes that create a positional identity for them. Based on interactions with various epithelial and extracellular matrix substances, crest cells give rise to neural, skeletal, connective, dermal, and dental structures in the face. Voluntary muscles of the face derive from paraxial (somatic) mesoderm. A large number of developmental genes, some of which are candidates for nonsyndromic cleft lip and cleft palate, are involved in these processes. At the inferolateral edges of the frontonasal process, nasal placodes begin to invaginate (by stage 11, or about 24 days). The placodes appear to sink into the surrounding tissues as the medial nasal and lateral nasal processes proliferate. By stage 16, or about 37 days, the upper lip has formed on the lateral aspect of the stomodeum. By stage 17, or 41 days, the maxillary process of the first pharyngeal arch has made contact with the medial nasal process of the frontonasal process establishing continuity of the upper lip. This process requires loss of the contacting surface epithelial cells

Fig. 12-1. Schematic of cranial region in stage 10 (A) and stage 12 (B) embryos showing the change in orientation of the oropharyngeal membrane brought about by the cephalic fold. (Reprinted with permission from Moore KL: The Developing Human, ed 4. CV Mosby Co, St. Louis, 1988.)

391

392

Craniofacial Structures

Fig. 12-2. Schematic of facial features of embryos at stages 15 (33 days), 18 (45 days), 21 (52 days), and 23þ (60 days). The lip is a mosaic structure composed of the frontonasal (1), left maxillary (2), left mandibular (3), right mandibular (4), and right maxillary (5)

processes. (Adapted from Tuchmann-Duplessis H, Haegel P: Illustrated Human Embryology, vol 2. Springer-Verlag, New York, 1972, and from Patten BM: Human Embryology, ed 3. McGraw-Hill, New York, 1968.)

(the nasal fin) either through cellular transformation or apoptosis. Failure of this process to occur results in cleft lip. Once continuity is established, the central premaxillary process is invaded by cells from the maxillary process.6 The structure of the philtrum and the characteristic Cupid’s bow configuration of the upper lip are a function of orientation of the labial levators and thickened dermal appendages.7 The palate is formed by the coalescence of three structures: the medial, anterior frontonasal process that forms the primary palate (the premaxillary segment with the four upper incisors as well as the nasal septum) and the two lateral palatal processes projecting from the maxillary part of the first pharyngeal arch. Thus, most of the hard and soft palate is derived from the first arch. After the upper lip has formed, the tongue occupies the stomodeum.8 During the 8th week postconception, growth of the stomodeum and initiation of oromuscular movement drops the tongue below the level of the palatal shelves, allowing horizontal movement of palatal shelf tissue. Contact is rapidly established between the anterior primary palate, the lateral palatal shelves, and the nasal septum. The epithelial tissue covering each of these processes is transformed into mesenchyme, allowing fusion to occur (Fig. 12-3). A number of patterning and signaling genes are involved in this process. The soft palate is invaded by mesenchymal tissue from the first and fourth pharyngeal arch to give rise to the tensor palatini, levator palatini, and uvular muscles, which have complex innervation.9

Facial clefts may be classified either considering pathogenesis (what went wrong during the process of morphogenesis) or etiology (what caused the problem to begin with). Both approaches have relevance with respect to prognosis and recurrence risk. When considering pathogenesis (Fig. 12-4), clefts may be classified either as malformations (errors in normal morphogenesis), deformations (alteration secondary to constraint of a structure that has differentiated normally), disruptions (destruction of a previously normally formed structure), or dysplasias (abnormal organization and growth of cells).10 Malformations are structural abnormalities that represent failures of normal structural development. They are present at birth and do not resolve or improve spontaneously. Most have a multifactorial etiology, as discussed below. Deformations may improve over time as evidenced by the catch-up growth of the chin in many children with Robin type clefts. Disruptions generally have a very low risk for recurrence. Dysplasias need longitudinal follow-up for persistence of the dysplastic process. Neoplasms may develop in some dysplasias. The vast majority of clefts occur as a consequence of malformation. Of these roughly two-thirds will represent failure of the medial nasal and maxillary processes to fuse (cleft lip with or without cleft palate [CL/P]) and one-third will represent failure of the palatal shelves to fuse (cleft palate [CP]). Other mechanisms are represented less frequently. Among over 1700 children presenting to a treatment clinic over a 23-year period in San Diego, 10 children had midline clefts of the lip in association with holoprosencephaly compared

Fig. 12-3. Schematic of closure of secondary palate. (Reprinted with permission from Moore KL: The Developing Human, ed 4. CV Mosby Co, St. Louis, 1988.)

Lips

393

Fig. 12-5. Isolated incomplete median cleft lip (left). Complete median cleft lip associated with holoprosencephaly (right). Fig. 12-4. Pathogenesis of facial clefting.

to ~1000 with CL/P and 500 with CP. The other three mechanisms were represented much less frequently than malformation. In the same population, roughly 100 had clefts classified as Robin type or secondary to micrognathia, 40 had disruptions (amnion rupture sequence or clefts as part of a pattern with a presumptive vascular mechanism), and four had palatal tumors including two nasal gliomas, one teratoma, and one probable epignathus (dysplasia). References 1. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams and Wilkins, Philadelphia, 2004. 2. Sperber GH: Craniofacial embryogenesis: normal developmental mechanisms. In: Understanding Craniofacial Anomalies: The Etiopathogenesis of Craniosynostoses and Facial Clefting. MP Mooney, MI Siegel, eds. Wiley-Liss, Inc., New York, 2002, p 31. 3. Sperber GH: Formation of the primary palate and palatogenesis: closure of the secondary palate. In: Cleft Lip and Palate: From Origin to Treatment. DF Wyszynski, ed. Oxford University Press, New York, 2002, p 5. 4. Moore KL, Persaud TVN, Schmitt W: The Developing Human: Clinically Oriented Embryology. WB Saunders Company, Philadelphia, 1998. 5. LaBonne C, Bronner-Fraser M: Molecular mechanisms of neural crest formation. Annu Rev Cell Dev Biol 15:81, 1999. 6. Viers W: Transmedian innervation of the upper lip: an embryologic study. Laryngoscope 83:1, 1973. 7. Namnoum JD, Hisley KC, Graepel S, et al.: Three-dimensional reconstruction of the human fetal philtrum. Ann Plast Surg 38:202, 1997. 8. Kimes KR, Mooney MP, Siegel MI, et al.: Size and growth rate of the tongue in normal and cleft lip and palate human fetal specimens. Cleft Palate Craniofac J 28:212, 1991. 9. Cohen SR, Chen L, Trotman CA, et al.: Soft palate myogenesis: a developmental field paradigm. Cleft Palate Craniofac J 30:441, 1993. 10. Spranger JW, Benirschke K, Hall JG, et al.: Errors of morphogenesis: concepts and terms. J Pediatr 100:160, 1982.

12.1 Median Cleft Lip Definition

Median cleft lip is the deficiency of the central portion of the lip, including the central vermillion, the philtrum, the premaxilla, and the nasal columella. The defect may range from a subtle notch in the middle of the lip to absence of the premaxilla with a flaplike nose.

holoprosencephaly are increasingly detected with prenatal ultrasonographly.1 The majority of midline clefts of the lip occur as part of the holoprosencephaly sequence.2,3 Early loss of midline structures in the developing prosencephalon causes this pattern of malformation. The phenotype ranges from cyclopia at the severe end of the spectrum, to varying degrees of ocular hypotelorism with a flaplike nose, an absent columella, and midline cleft lip, to a single central incisor. Holoprosencephaly is etiologically heterogeneous and may occur in chromosomal abnormalities (e.g., trisomy 13 and deletion 18p) and single gene disorders (e.g., Smith-Lemli-Opitz syndrome). It may be caused by mutations in a variety of genes important in early brain formation (e.g., sonic hedgehog and zinc finger protein 2) or by teratogenic exposures in early pregnancy (e.g., poorly controlled maternal diabetes). The presence of a midline cleft lip should raise concerns about a serious defect in brain development. Rarely, midline clefts of the lip occur in otherwise normal individuals, in Ellis-van Creveld syndrome, and in the oral-facialdigital syndromes associated with accessory frenulae and lobulations of the tongue. Table 12-1 lists syndromes associated with midline clefts of the lip. Prognosis, Treatment, and Prevention

The most significant factor in determining the outcome of midline cleft lip is the presence of a severe defect in brain development.4 Infants with holoprosencephaly have a reduced lifespan. Survivors have varying degrees of cognitive impairment, seizures, and diabetes insipidus.5 A variety of surgical techniques have been employed for reconstructing the lip depending upon the degree of tissue deficiency. Elias and colleagues outlined a strategy for approaching reconstruction in this population.6 Prevention depends on the etiology of the midline cleft. Holoprosencephaly secondary to poorly controlled maternal diabetes may be prevented with proper management of the diabetes prior to subsequent conception. Prenatal diagnosis with chorionic villus sampling (CVS) or amniocentesis could be offered in cases of chromosome abnormalities. First-degree relatives of infants with holoprosencephaly should be evaluated for minor manifestations such as a single central incisor before genetic counseling is provided. Isolated nonsyndromic midline clefts of the lip are generally sporadic. Prenatal diagnosis with ultrasound has not been reported for isolated midline clefts of the lip. References (Median Cleft Lip)

Diagnosis

The diagnosis is easily made by physical examination at the time of birth (Fig 12-5). Midline clefts of the lip in association with

1. Blaas HG, Eriksson AG, Salvesen KA, et al.: Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 19:24, 2002.

394

Craniofacial Structures

Table 12-1. Syndromes commonly featuring midline cleft lip Causation Gene/Locus

Syndrome

Prominent features

Branchio-oculo-facial

Cervical aplasia cutis congenita, pseudoclefts, eye defects

AD (113620)

Ellis-van Creveld

Short limbs, nail dysplasia, polydactyly, cardiac defects

AR (225500) EVC, 4p16

Frontonasal malformation

Hypertelorism, widow’s peak, bifid nose

Usually sporadic

Holoprosencephaly

Cyclopia, hypotelorism, premaxillary agenesis

AD (142945) SHH, 7q36 AD (157170) SIX3, 2p21 AD (142946) TGIF, 18p11 Trisomies 13, 18; del 7q, 13q, 18p, dup 3p, maternal diabetes

Hydrolethalis

Hydrocephaly, crossed polydactyly, cardiac defect

AR (236680) 11q23-25

OFD syndromes

Oral frenulae, lobulated tongue, digital anomalies

XLD (311200) CXorf5, Xp22 AR (252100)

Diagnosis

2. DeMyer W: Median facial malformations and their implications for brain malformations. Birth Defects Orig Artic Ser XI(7): 155, 1975. 3. Lacbawan FL, Muenke M: Central nervous system embryogenesis and its failures. Pediatr Dev Pathol 5:425, 2002. 4. Plawner LL, Delgado MR, Miller VS, et al.: Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain. Neurology 59:1058, 2002. 5. Barr M Jr, Cohen MM Jr: Holoprosencephaly survival and performance. Am J Med Genet 89:116, 1999. 6. Elias DL, Kawamoto HK Jr, Wilson LF: Holoprosencephaly and midline facial anomalies: redefining classification and management. Plast Reconstr Surg 90:951, 1992.

12.2 Cleft Lip With or Without Cleft Palate (CL/P) Definition

Cleft lip with or without cleft palate is a defect in the upper lip just lateral to the philtral pillar on the affected side, resulting from Fig. 12-6. Complete bilateral cleft lip and palate (left). Complete unilateral cleft lip and palate (right).

failure of the medial nasal process to establish continuity with the maxillary process. The subtlest manifestation of cleft lip may be a fibrous band of scarlike tissue along the philtral ridge. More typically, there is an obvious gap between the premaxillary and lateral aspects of the upper lip with flattening of the nasal alar rim on the affected side and deviation of the nasal septum toward the noncleft side.

The diagnosis is made on physical examination at the time of birth (Figs. 12-6 and 12-7). Increasingly, clefts of the lip and primary palate (alveolus) are detected prenatally using twodimensional and three-dimensional imaging.1,2 Multiple studies over the last 30 years have documented the frequency with which clefts occur in association with other anomalies. All have confirmed that cleft palate (CP) is more frequently associated with other defects than CL/P, which in turn is more associated than is cleft lip (CL) alone. Methodologic differences among studies make it very difficult to compare specific numbers. In FoghA˚ndersen’s 1942 data, roughly 10% of affected individuals had associated defects.3 Numbers typically less than 15% have been seen in studies of CL/P that depended upon birth certificates or review of medical records to document the associated defects.4,5 With improved ability to document the frequency of minor as well as major malformations, frequencies ranging from 14–45% were documented despite the fact that most clinic-based populations did not include newborns with clefts as part of conditions with limited survival.6–9 Rigorous birth defects surveillance programs have published frequencies of associated defects with CL/P ranging from 26.2% to 36.8%.10,11 Gorlin’s authoritative text documents well over 300 syndromes, sequences, and associations in which CL/P may represent one feature.12 The clinical importance of recognizing associated malformations is that anomalies do not occur together at random. Clustering suggests the presence of a pattern of malformation of significance with respect to prognosis, recurrence risk, or both. Table 12-2 lists the more common conditions associated with CL/P. Etiology and Distribution

Table 12-3 sets forth population-based characteristics of CL/P. For the past 30 years, the multifactorial threshold model has been widely accepted as the explanation for the familial clustering of facial clefts. The model assumed that liability to a discrete birth defect such as CL/P or CP was determined by the additive effect of many genetic and environmental factors, each of which had a small but equal individual impact. According to the model, an overt

Lips

Fig. 12-7. Incomplete bilateral cleft lip (left). Incomplete bilateral cleft lip (right) with overt cleft below the right nostril and occult cleft below the left nostril.

phenotype occurred when a threshold was exceeded, converting a continuous liability for a specific defect into an all-or-none expression of a malformation.13 Although the model accounted for the less than 100% concordance of defects in monozygotic (MZ) twins, the impact of gender and the degree of malformation on recurrence risk, and the nonlinear decline in risk to relatives depending on the degree of relationship, complex segregation analysis has suggested that the multifactorial model is not biologically true. Rather, CL/P is most likely determined by a small number (two to eight) of genes acting in a multiplicative fashion and in conjunction with specific environmental risk factors. Each locus is estimated to increase the risk for first-degree relatives three- to sixfold.14–16 New approaches to complex trait analysis afforded by major advances in the fields of genetics and molecular biology have allowed identification of several genes with major impact on nonsyndromic clefting. Interestingly, some of these genes cause a mixed cleft phenotype (cleft palate alone and cleft lip with or without cleft palate in affected members of the same family). Genes conferring susceptibility for clefting have been identified through a variety of strategies, including linkage or association studies, cloning of chromosomal break points, Mendelian models, animal models, and human and mouse expression studies.17 The five genes of greatest interest currently include PVRL1 (identified through a Mendelian phenocopy), TBX22 (identified through a Mendelian phenocopy, see cleft palate below), MSX1 (evaluated because of the phenotype in the mouse knockout), FGFR1 (identified through linkage and chromosomal abnormality mapping a different phenotype), and IRF6 (identified through a Mendelian phenocopy). A polymorphism in transforming growth factor alpha (TGFa) on chromosome 2p13 was the earliest gene associated with nonsyndromic CL/P in humans.18 The gene was initially selected because of its role in CP in the mouse. Since the first report, multiple confirmatory and nonconfirmatory studies have been published reflecting the difficulty with association studies in general as well as population differences among the study samples.19 Several reports link polymorphisms in TGFa with an increased risk for CL/P in the face of maternal cigarette smoking.20,21 Other studies have failed to confirm this interaction.22 Homozygous mutations in the poliovirus receptorlike 1 gene (PVRL1) at 11q23-24 have been shown to cause cleft lip/palate– ectodermal dysplasia, an autosomal recessive disorder with high prevalence on Margarita Island in the Caribbean Sea.23 Heterozygous mutations in the same gene, whose product functions as a cell–cell adhesion molecule in keratinocytes, also accounted for nonsyndromic CL/P in an adjacent population in Venezuela.24

395

Mutations in the gene MSX1, a homeobox gene on chromosome 4p16.1, have been shown to cause Witkop syndrome, an autosomal dominant condition with mixed clefting, hypodontia, and nail dysplasia.25 Although early association studies between MSX1 and CL/P yielded mixed results, more recent reports have documented an association between CL/P and MSX1 if the clinical phenotype included missing teeth outside of the cleft region.26–28 Mild nail hypoplasia may be seen in affected patients. Deletion of MSX1 may account for the high frequency of clefts in children with deletion 4p. Mutations in MSX1 may account for 2% of cases of CL/P. The gene may also be a modifier locus. Mutations in fibroblast growth factor receptor 1 (FGFR1) at 8p11 have recently been identified as part of the search for the cause of autosomal dominant Kallmann syndrome. Using linkage and overlapping interstitial deletions in two affected individuals, Dode´ et al. found that FGFR1 emerged as a candidate for Kallmann syndrome, which is associated with anosmia (secondary to absence of the olfactory bulbs and tracts) and hypogonadotrophic hypogonadism (secondary to deficiency of gonadotropin-releasing hormone). CL/P, CP, and hypodontia are occasional features of Kallmann syndrome. Inactivating mutations in FGFR1 account for Kallmann syndrome, whereas activating mutations in the same gene produce craniosynostosis.29 The frequency with which mutations account for nonsyndromic CL/P and CP remains to be determined. It is possible that mutations in FGFR1 underlie the olfactory deficits previously documented in boys with facial clefts.30 Mutations and deletions in transcription factor interferon regulatory factor 6 (IRF6) located at 1q32-41 have been shown to account for Van der Woude syndrome and popliteal pterygium syndrome, two of the more frequently encountered recognizable patterns of malformation occurring among the CL/P and CP populations.31 Van der Woude syndrome is the prototype Mendelian disorder with clefting and lip pits, the only other manifestation of this single gene disorder. Recently, a polymorphism (V2741 allele) in IRF6 has been documented to track with the cleft phenotype in varied populations of individuals with CL/P but not CP.32 Variations in IRF6 may account for 5% of nonsyndromic cleft lip and palate. Interestingly, hypodontia and mixed clefting are characteristics of IRF6 mutations. Mutations in p63, the gene responsible for ectrodactylyectodermal dysplasia-clefting syndrome (EEC), Hay-Wells syndrome, and split hand–split foot malformation, have not been identified in patients with nonsyndromic clefts. 33 Polymorphisms in transforming growth factor beta (TGFb) on chromosome 14q24 have been investigated because cleft palate is a consistent finding in the knockout mouse model.34 Results in human populations have been mixed. Likewise, inconsistent results have been published in studies of the methylene tetrahydrofolate reductase (MTHFR) gene on chromosome 1p36, the retinoic acid receptor alpha (RARA) gene on chromosome 17q21.1, the proto-oncogene BCL3 on chromosome 19q13.1, and the gamma-aminobutyric acid receptor (GABRB3) on chromosome 15q11.2.35–39 Multiple environmental factors are known to interfere with lip and palate development in experimental systems, including isotretinoin, anticonvulsants, smoking, alcohol, corticosteroids, and nutritional factors. Population studies in humans have documented fairly convincingly an association between nonsyndromic clefting and exposure to maternal cigarette smoking, maternal diabetes, a variety of anticonvulsant agents (phenytoin, valproic acid, trimethadione, and primidone), folic acid antagonists, and

396

Craniofacial Structures Table 12-2. Syndromes commonly featuring cleft lip with or without cleft palate alone Prominent features

Causation Gene/Locus

Down

Flat face, small ears, cardiac defects, single transverse palm crease

Trisomy 21

Trisomy 13

Aplasia, cutis congenita, heart defect, omphalocele, polydactyly

Trisomy 13

Trisomy 18

Growth deficiency, petite facies, camptodactyly, short sternum

Trisomy 18

Del 4p

Hypertelorism, short philtrum, scalp defect, ear pit

Del 4p

Del 22q (VCFS, DiGeorge)

Short palpebral fissures, small ears, alar hypoplasia, conotruncal cardiac defect

Del 22q11.22

Aarskog

Short stature, shawl scrotum, round face

XLR (305400) FGD1, Xp11

Basal cell nevus

Jaw keratocysts, basal cell carcinomas, bifid ribs

AD (109400) PTCH, 9q22.3

CHARGE

Ocular colobomas, choanal atresia, micropenis, cardiac defect

AD (214800) CHD7, 8q12

Coffin-Siris

Sparse scalp hair, coarse facies, hirsutism, nail hypoplasia

Uncertain (135900)

Syndrome

Chromosomal Disorders

Single Gene Disorders

Distal arthrogryposis, type 2

Camptodactyly, dimples

AD (114300)

EEC

Ectrodactyly, ectodermal dysplasia

AD (129900) P63, 3q27

Fryns

Diaphragmatic hernia, coarse face, digital hypoplasia

AR (229850)

Opitz

Hypertelorism, hypospadias

XLD (300000) MID1, Xp22 AD (145410) 22q11.2

Popliteal pterygium

Lip pits, popliteal web, genital anomalies

AD (119500) IRF6, 1q32-41

Van der Woude

Lower lip pits

AD (119300) IRF6, 1q32-q41

Waardenburg

White forelock, deafness, iris heterochromia

Type 1: AD (193500) PAX3, 2q35 Type 2: AD (193510) MITF, 3p13

Other

Amnion rupture

Ring constrictions, limb amputations, cephaloceles

Sporadic

FAV/OAV spectrum

Microtia, ear tags, cardiac defect, epibulbar dermoid

Usually sporadic

Alcohol

Microcephaly, short palpebral fissures

Alcohol

Anticonvulsants

Microcephaly, coarse facies, cardiac defects, nail hypoplasia

Hydantoin, valproic acid, trimethadione

Maternal diabetes

Heart defect, caudal regression

Poorly controlled diabetes

Teratogens

corticosteroids.40–51 Clefts are a consistent feature among the multiple anomalies induced by isotretinoin exposure.52 Clefts represent one feature of the fetal alcohol syndrome. Heavy maternal drinking has been associated with an increased risk for nonsyndromic CL/P,53,54 whereas lower levels of alcohol consumption have not.55 No environmental agent induces clefting with every exposure; thus, current research is focused on the genetic factors that underlie susceptibility to teratogen-induced malformation. Since poverty in and of itself appears to increase the risk for CL/P, nutritional factors are under investigation.56

Prognosis, Treatment, and Prevention

For nonsyndromic CL/P, the outcome with appropriate treatment is excellent. Reconstruction is accomplished in a staged fashion as an individual grows and develops, mandating longitudinal followup. Treatment decisions necessarily weigh aesthetic and speech concerns against issues of facial growth.57–60 The former dictate early repair, because there is some evidence that speech results are better if repair of the palate is performed prior to 1 year of age. In contrast, study of facial growth in untreated adult Sri Lankans

Lips Table 12-3. Epidemiologic characteristics of cleft lip with or without cleft palate Characteristic

Summary Information

Prevalence

One per 1000 total births

Geographic variation

High prevalence in Australia (Aborigines), Canada, the Far East Lower prevalence in Southern Europe and Africa

Racial/ethnic differences

In general, populations of Asian origin have higher rates than Caucasians, who have higher rates than Africans

Gender differences

M/F 2:1

Laterality

Two-thirds of unilateral defects are left-sided

Temporal trends

Mostly stable rates over time

Maternal age

No convincing maternal age effect when syndromic cases are meticulously excluded

Birth weight/ gestational age

Lower mean birth weight in some studies; no convincing increase in prematurity

Twinning

No clear increase in twins MZ twin concordance rate is 6–1 9 times higher than DZ concordance rate DZ twin same as full siblings

Familial patterns

Familial cases 15–25% Sibling recurrence 3–5%

Data from references 4, 6, 9, 10, 14, 16, 51, 56, 90, 91.

with CL/P demonstrated that the unoperated maxilla for the most part grows normally.61 A variety of strategies have been proposed to optimize the outcome, given these two warring factors. Although much literature has been written on the subject of treatment, there is a paucity of randomized control trials to compare treatment protocols in any standardized way. Data from a sixcenter international collaborative project have documented better outcomes in multidisciplinary centers using a few experienced operators and relatively simple protocols as opposed to centers with multiple providers and no consistent approach to treatment, at least if facial growth and dental relationships were used as the objective measure of outcomes.62–64 It is beyond the scope of this chapter to address treatment comprehensively. Parameters of care for affected children have been published by the American Cleft Palate-Craniofacial Association.65 The 2002 text edited by Wyszynski covers the subject comprehensively.66 The first step in treating an infant with CL/P is to establish feeding.67,68 Otherwise normal infants with clefts have normal rooting, latching, sucking, and swallowing reflexes. With the exception of those infants with Robin-type clefts, they are not at risk for aspiration, although nasopharyngeal reflux is nearly universal if the secondary palate is cleft. A variety of devices have been invented to feed infants with CL/P. All use a squeeze mechanism to circumvent the decrease in suction caused by the cleft. With appropriate support, breast-feeding is possible in some infants.69 In a prospective randomized study, breast-feeding immediately following lip repair posed no problem for wound disruption and promoted better growth.70 Middle ear problems are frequent and may present as recurrent infection or reduced middle ear compliance with hearing loss. Ventilation tubes are commonly placed in conjunction with either the lip or the palate repair. Breast milk may provide some protection against otitis media.71

397

The goal of the initial lip repair in a unilateral cleft is to align the vermillion, establish muscle continuity across the upper lip, reconstruct the philtral pillar, and reposition the alar cartilages, although considerable variation in technique exists.72 In a bilateral cleft lip, the alar cartilages may be repositioned for reconstruction of the columella at the time of the initial repair.73 The goal of the palate repair is to generate length and mobility in the palate such that air can be directed through the oral cavity during speech production. Many children require speech therapy after surgery. Up to 25% may need secondary palatal surgery to address residual velopharyngeal insufficiency. The defect in the alveolus (at the junction of the primary and secondary palates) is reconstructed using autologous bone from the iliac crest, calvarium, or rib.74 There is considerable controversy as to the timing of this procedure. The applicability of bone substitutes is being explored. Revisions of the lip and nose are typically considered prior to kindergarten, in preadolescence, and after completion of facial growth.75 Two studies of linear growth in children with nonsyndromic CL/P documented mildly reduced stature compared to population norms.76,77 Most children with nonsyndromic CL/P function in regular classes in school and have normal psychosocial adjustment, despite the fact that a wide variety of learning and emotional issues have been identified in this population.78 Comprehensive assessments have demonstrated subtle cognitive differences between CL/P subjects and noncleft controls.79,80 Some of these differences can be measured as quantitative measures on magnetic resonance scanning of the brain.81 Brain imaging is not standard in the evaluation of an otherwise normal child with CL/P; however, comprehensive neurodevelopmental testing should be considered in any child with CL/P who is struggling in school. No testing is yet available to identify genes conferring susceptibility to CL/P. Avoidance of environmental factors known to increase the risk, such as cigarette smoking, is a mainstay of prevention. Although preconception folic acid supplementation is known to reduce the risk of occurrence and recurrence of neural tube defects, the role of folic acid in prevention of CL/P remains controversial.82–84 Supplementation at the 0.4mg level currently recommended by the Center for Disease Control and Prevention is suggested. Although the multifactorial-threshold model for CL/P has been challenged as addressed above, families are still counseled with respect to recurrence risk based upon the empirical data from which the model derived. Table 12-4 outlines recurrence risk for both CL/P and CP.13 Cleft lip and palate is increasingly recognized on prenatal ultrasound.85–87 As with other malformations, the natural history of a prenatally identified CL/P is different from one identified in the newborn period, with a much higher proportion having chromosome abnormalities, serious defects in brain development, or patterns of malformation.88 In a small series of prenatally diagnosed CL/P fetuses (no other anomalies noted and normal chromosomes) the risk that an affected infant would have other anomalies was 10%.89 References (Cleft Lip With or Without Cleft Palate) 1. Chmait R, Pretorius D, Jones M, et al.: Prenatal evaluation of facial clefts with two-dimensional and adjunctive three-dimensional ultrasonography: a prospective trial. Am J Obstet Gynecol 187:946, 2002. 2. Stoll C, Clementi M, Euroscan study group: Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe. Ultrasound Obstet Gynecol 21:543, 2003.

398

Craniofacial Structures

Table 12-4. Risks of cleft lip and cleft lip/palate given several family situations Risk to next child Proband has CL/CP (%)

Proband has CP (%)

There are no other affected relatives

4

2

There is an affected relative

4

7

Affected child also has another malformation

2

2

Situation

Parents not affected and

4

–

Parents not affected but have two affected children

Parents are related

9

1

One parent affected, no child affected

4

6

One parent affected, one child affected

17

15

Adapted in part from Fraser.13

3. Fogh-A˚ndersen P: Inheritance of Hare Lip and Cleft Palate. Arnold Busck, Nordisk Forlag, Copenhagen, 1942. 4. Fraser GR, Calnan JS: Cleft lip and palate. Seasonal incidence, birth weight, birth rank, sex, site, associated malformations, and parental age. Arch Dis Child 36:420, 1961. 5. Knox G, Braithwaite F: Cleft lips and palates in Northumberland and Durham. Arch Dis Child 38:66, 1963. 6. Welch J, Hunter AGW: An epidemiological study of facial clefting in Manitoba. J Med Genet 17:127, 1980. 7. Rollnick BR, Pruzansky S: Genetic services at a center for craniofacial anomalies. Cleft Palate J 18:304, 1981. 8. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, et al.: Anomalies associated with cleft lip, cleft palate, or both. Am J Med Genet 20: 585, 1985. 9. Jones MC: Etiology of facial clefts: Prospective evaluation of 428 patients. Cleft Palate J 25:16, 1988. 10. Croen LA, Shaw GM, Wasserman CR, et al.: Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983–1992. Am J Med Genet 79:42, 1998. 11. Stoll C, Alembik Y, Dott B, et al.: Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37:41, 2000. 12. Gorlin RJ, Cohen MM, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 13. Fraser FC: The genetics of cleft lip and palate. Am J Hum Genet 22:36, 1970. 14. Farrall M, Holder SE: Familial recurrence pattern analysis of cleft lip with or without cleft palate. Am J Hum Genet 50:270, 1992. 15. Mitchell LE, Risch N: Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Am J Hum Genet 51:323, 1992. 16. Mitchell LE, Christensen K: Analysis of the recurrence patterns for nonsyndromic cleft lip with or without cleft palate in the families of 3,073 Danish probands. Am J Med Genet 61:371, 1996. 17. Spritz RA: The genetics and epigenetics of orofacial clefts. Current Opinion Pediatr 13:556, 2001. 18. Ardinger HH, Buetow KH, Bell GI, et al.: Association of genetic variation of the transforming growth factor alpha gene with cleft lip and palate. Am J Hum Genet 45:348, 1989. 19. Mitchell LE: Transforming growth factor alpha locus and nonsyndromic cleft lip with or without cleft palate. A reappraisal. Genet Epidmiol 14:231, 1997. 20. Shaw GM, Wasserman CR, Lammer EJ, et al.: Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 58:551, 1996.

21. Beaty TH, Maestri NE, Hetmanski JB, et al.: Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992-1996. Cleft Palate Craniofac J 34:447, 1997. 22. Christensen K, Olsen J, Norgaard-Pedersen B, et al.: Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991–1994. Am J Epidemiol 149:248, 1999. 23. Suzuki K, Hu D, Bustos T, et al.: Mutations of PVRL1, encoding a cellcell adhesion molecule/herpes receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet 25:427, 2000. 24. So¨zen MA, Suzuki K, Tolarova MM, et al.: Mutation on PVRL1 is associated with sporadic, nonsyndromic cleft lip/palate in northern Venezuela. Nat Genet 29:141, 2001. 25. Jumlongras D, Bei M, Stimson JM, et al.: A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet 69:67, 2001. 26. van den Boogaard MJH, Dorland M, Beemer FA, et al.: MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 24:342, 2000. 27. Jezewski PA, Vieira AR, Nishimura C, et al.: Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet 40:399, 2003. 28. Slayton RL, Williams L, Murray JC, et al.: Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J 40:274, 2003. 29. Dode´ C, Levilliers J, Dupont JM, et al.: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33:463, 2003. 30. Richman RA, Sheehe PR, McCanty T, et al.: Olfactory deficits in boys with cleft palate. Pediatrics 82:840, 1988. 31. Kondo S, Schutte BC, Richardson RJ, et al.: Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32:285, 2002. 32. Zucchero T, Cooper M, Caprau D, et al.: Am J Hum Genet 73S:162, 2003. 33. Barrow LL, van Bokhoven H, Daack-Hirsch S, et al.: Analysis of the p63 gene in classical EEC syndrome, related syndromes, and nonsyndromic orofacial clefts. J Med Genet 39:559, 2002. 34. Kaartinen V, Voncken JW, Shuler C, et al.: Abnormal lung development and cleft palate in mice lacking TGF beta-3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415, 1995. 35. Shaw GM, Rozen R, Finnell RH, et al.: Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip. Am J Med Genet 80:196, 1998. 36. Gaspar DA, Matioli SR, Pavanello RC, et al.: Evidence that BCL3 plays a role in the etiology of nonsyndromic oral clefts in Brazilian families. Genet Epidemiol 23:364, 2002. 37. Scapoli L, Martinelli M, Pezzetti F, et al.: Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Hum Genet 110:15, 2002. 38. Mitchell LE, Murray JC, O’Brien S, et al.: Retinoic acid receptor alpha gene variants, multivitamin use, and liver intake as risk factors for oral clefts: a population-based case-control study in Denmark, 1991–1994. Am J Epidemiol 158:69, 2003. 39. van Rooij IA, Vermeij-Keers C, Kluijtmans LA, et al.: Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate? Am J Epidemiol 157:583, 2003. 40. Abrishamchian AR, Khoury MJ, Calle EE: The contribution of maternal epilepsy and its treatment to the etiology of oral clefts: a population based case-control study. Genet Epidemiol 11:343, 1994. 41. Rodriguez-Pinilla E, Martinez-Frias ML: Corticosteroids during pregnancy and oral clefts: a case-controlled study. Teratology 58:2, 1998. 42. Lieff S, Olshan AF, Werler M, et al.: Maternal cigarette smoking during pregnancy and the risk of oral clefts in newborns. Am J Epidemiol 150: 683, 1999. 43. Chung KC, Kowalski CP, Kim HM, et al.: Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg 105:485, 2000.

Lips 44. Hernandez-Diaz S, Werler MM, Walker AM, et al.: Folic acid antagonists during pregnancy and the risk of birth defects. N Eng J Med 343:1608, 2000. 45. Lorente C, Cordier S, Goujard J, et al.: Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational exposure and congenital malformation working group. Am J Public Health 90:415, 2000. 46. Park-Wyllie L, Mazzotta P, Pastuszak A, et al.: Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62:385, 2000. 47. A˚berg A, Westbom L, Ka¨lle´n B: Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Develop 61:85, 2001. 48. Pradat P, Robert-Gnansia E, Di Tanna GL, et al.: Contributors to the MADRE database. First trimester exposure to corticosteroids and oral clefts. Birth Defects Res Part A Clin Mol Teratol 67:968, 2003. 49. Matalon S, Schechtman S, Goldzweig G, et al.: The teratogenic effect of carbamazepine: a meta-analysis of 125 exposures. Reprod Toxicol 16:9, 2002. 50. Vieira AR, Orioli IM, Murray JC: Maternal age and oral clefts: a reappraisal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94:530, 2002. 51. Shaw GM, Croen LA, Curry CJ: Isolated oral cleft malformations: association with maternal and infant characteristics in a California population. Teratology 43:225, 1991. 52. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid embryopathy. N Eng J Med 313:837, 1985. 53. Werler MM, Lammer EJ, Rosenberg L, et al.: Maternal alcohol use in relation to selected birth defects. Am J Epidemiol 134:691, 1991. 54. Munger RG, Romitti PA, Daack-Hirsch S, et al.: Maternal alcohol use and risk of orofacial cleft birth defects. Teratology 54:27, 1996. 55. Meyer KA, Werler MM, Hayes C, et al.: Low maternal alcohol consumption during pregnancy and oral clefts in offspring: the Slone Birth Defects Study. Birth Defects Res Part A Clin Mol Teratol 67:509, 2003. 56. Clark JD, Mossey PA, Sharp L, et al.: Socioeconomic status and orofacial clefts in Scotland, 1989 to 1998. Cleft Palate Craniofac J 40: 481, 2003. 57. Peterson-Falzone SJ: The relationship between timing of cleft palate surgery and speech outcome: what have we learned and where do we stand in the 1990s? Semin Orthod 2:185, 1996. 58. Mølsted K, Asher-McDade C, Brattstro¨m V, et al.: The RPS. A sixcenter international study of treatment outcome in patients with clefts of the lip and palate: Part 2. Craniofacial form and soft tissue profile. Cleft Palate Craniofac J 29:398, 1992. 59. Kirschner RE, LaRossa D: Cleft lip and palate. Otolaryngol Clin North Am 33:1191, 2000. 60. Rohrich RJ, Love EJ, Byrd HS, et al.: Optimal timing of cleft palate closure. Plast Reconstr Surg 106:413, 2000. 61. McCance AM, Roberts-Harry D, Sherriff M, et al.: A study model analysis of adult unoperated Sri Lankans with unilateral cleft lip and palate. Cleft Palate J 27:146, 1990. 62. Shaw WC, Asher-McDade C, Brattstro¨m V, et al.: The RPS. A sixcenter international study of treatment outcome in patients with clefts of the lip and palate: Part 1. Principles and study design. Cleft Palate Craniofac J 29:393, 1992. 63. Molsted K: Treatment outcome in cleft lip and palate: issues and perspectives. Crit Rev Oral Biol Med 10:225, 1999. 64. Mars M, Asher-McDade C, Brattstro¨m V, et al.: A six-center international study of treatment outcome in patients with clefts of the lip and palate: Part 3. Dental arch relationships. Cleft Palate Craniofac J 29:405, 1992. 65. Parameters for evaluation and treatment of patients with cleft lip/ palate or other craniofacial anomalies. American Cleft Palate-Craniofacial Association. Cleft Palate Craniofac J 30(suppl):S1, 1993. 66. Wyszynski DF, ed: Cleft Lip and Palate: From Origin to Treatment. Oxford University Press, New York, 2002.

399 67. Wyszynski DF, Sarkozi A, Vargha P, et al.: Birth weight and gestational age of newborns with cleft lip with or without cleft palate and with isolated cleft palate. J Clin Pediatr Dent 27:185, 2003. 68. Clarren SK, Anderson B, Wolf LS: Feeding infants with cleft lip, cleft palate, or cleft lip and palate. Cleft Palate J 24:244, 1987. 69. Fisher JC: Feeding children who have cleft lip and palate. West J Med 154:207, 1991. 70. Darzi MA, Chowdri NA, Bhat AN: Breast feeding or spoon feeding after cleft lip repair: a prospective, randomized study. Br J Plast Surg 49:24, 1996. 71. Paradise JL, Elster BA, Tan L: Evidence in infants with cleft palate that breast milk protects against otitis media. Pediatrics 94:853, 1994. 72. Schendel SA: Unilateral cleft lip repair—state of the art. Cleft Palate Craniofac J 37:335, 2000. 73. Mulliken JB: Repair of the bilateral complete cleft lip and nasal deformity—state of the art. Cleft Palate Craniofac J 37:342, 2000. 74. Vig KW: Alveolar bone grafts: the surgical/orthodontic management of the cleft maxilla. Ann Acad Med Singapore 28:721, 1999. 75. Cutting CB: Secondary cleft lip nasal reconstruction: state of the art. Cleft Palate Craniofac J 37:538, 2000. 76. Duncan PA, Shapiro LR, Soley RL, et al.: Linear growth patterns in patients with cleft lip or palate or both. Am J Dis Child 137:159, 1983. 77. Cunningham ML, Jerome JT: Linear growth characteristics of children with cleft lip and palate. J Pediatr 131:707, 1997. 78. Endriga MC, Kapp-Simon KA: Psychological issues in craniofacial care—state of the art. Cleft Palate Craniofac J 36:3, 1999. 79. Broder HL, Richman LC, Matheson PB: Learning disability, school achievement, and grade retention among children with cleft: a twocenter study. Cleft Palate Craniofac J 35:127, 1998. 80. Nopoulos P, Berg S, VanDemark D, et al.: Cognitive dysfunction in adult males with non-syndromic clefts of the lip and/or palate. Neuropsychologia 40:2178, 2002. 81. Nopoulos P, Berg S, Canady J, et al.: Structural brain abnormalities in adult males with clefts of the lip and/or palate. Genet Med 4:1, 2002. 82. Tolarova M, Harris J: Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 51:71, 1995. 83. Shaw GM, Nelson V, Carmichael SL, et al.: Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies? Epidemiology 13:625, 2002. 84. Botto LD, Olney RS, Erickson JD: Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet 125C:12, 2004. 85. Forrester MB, Merz RD, Yoon PW: Impact of prenatal diagnosis and elective termination on the prevalence of selected birth defects in Hawaii. Am J Epidemiol 148:1206, 1998. 86. Grandjean L, Larroque D, Levi S, et al.: The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J Obstet Gynecol 181:446, 1999. 87. Jones MC: Prenatal diagnosis of cleft lip and palate: detection rates, accuracy of ultrasonography, associated anomalies, and strategies for counseling. Cleft Palate Craniofac J 39:169, 2002. 88. Berge SJ, Plath H, von Lindern JJ, et al.: Natural history of 70 fetuses with a prenatally diagnosed orofacial cleft. Fetal Diagn Ther 17:247, 2002. 89. Jones MC: The risk that an apparently isolated cleft lip with or without cleft palate will be associated with anomalies that impact outcome: follow-up of 32 cases ascertained through prenatal diagnosis. Proc Greenwood Genet Center 19:122, 2000. 90. Global strategies to reduce the health-care burden of craniofacial anomalies: report of WHO meetings on International Collaborative Research on Craniofacial Anomalies, Geneva, Switzerland 5-8 November 2000. Park City, Utah, 24-26 May 2001. Geneva, Switzerland: WHO, Human Genetics Program, 2002. 91. Sipek A, Gregor V, Horacek J, et al.: Facial clefts from 1961 to 2000— incidence, prenatal diagnosis and prevalence by maternal age. Ceska Gynekol 67:260, 2002.

400

Craniofacial Structures

12.3 Cleft Palate Definition

Incomplete fusion of the palatal shelves on either side of the midline results in cleft palate (CP). Abnormalities in closure occur posterior to the incisive foramen and thus derive from problems in the secondary rather than primary palate. Clefts may involve the hard and soft palates or the soft palate alone, or may be submucous in nature, involving muscle discontinuity with an intact overlying mucosa. Diagnosis

Overt clefts of the secondary palate are readily identified on physical examination in the newborn period, provided the oral cavity is adequately examined (Fig. 12-8). In wide clefts, the vomer bone is clearly visualized in the midline. Clefts may have a V-shaped or U-shaped appearance. Hanson and Smith distinguished U-shaped palatal defects from more typical V-shaped clefts and postulated that U-shaped clefts might be deformational defects occurring when the tongue was retropositioned in the oral cavity secondary to micrognathia such that palatal closure was mechanically blocked.1 The Robin sequence (micrognathia, cleft palate, and glossoptosis) was offered as evidence of this hypothesis. Both U-shaped and V-shaped clefts have been noted in association with micrognathia.2 In hindsight, this is not surprising given the phenotypes associated with the genetic abnormalities that may underlie CP alone. In the author’s experience, it is usually possible to distinguish classical Robin-type clefts from V-shaped clefts with micrognathia and some airway issues. This observation has been born out by Printzlau and Andersen in a review of Robin sequence in Denmark.3 Although etiologically heterogeneous, the triad of features (U-shaped cleft palate, micrognathia, and glossoptosis) constituted a well-defined pattern readily identified in the newborn period. Shprintzen et al. documented that well over half of infants with the Robin sequence as the presenting problem have an underlying diagnosis, with 50% having Stickler syndrome as a specific diagnosis.4 Both Stickler syndrome and deletion 22q11.2 (velocardiofacial syndrome) occurred commonly in the series reported by van den Elzen et al.5

Fig. 12-8. Isolated V-shaped cleft palate (left). U-shaped cleft palate associated with micrognathia and glossoptosis (right).

Submucous clefts are more problematic and are frequently not identified at birth. Infants with submucous clefts of the palate present with frequent nasal regurgitation of fluids, recurrent ear infections, and/or velopharyngeal insufficiency. The diagnosis of a submucous cleft rests on the triad of (1) notching of the posterior border of the hard palate, (2) muscular diastasis with mucosal integrity, and (3) a bifid uvula. Roughly 2% of the population may have an isolated bifid uvula.6 Cleft palate has been diagnosed indirectly prenatally based on the finding of severe micrognathia in images assessing the fetal profile.7 The ‘‘cleft palate’’ frequently referenced in the prenatal diagnosis literature is actually the primary palate or alveolar ridge, not the secondary palate. Posterior structures are very difficult to visualize with current technology. As outlined above, the frequency with which clefts occur in association with other anomalies is much greater than initially recognized. Virtually all studies have confirmed that CP is more frequently associated with other defects than cleft lip with or without cleft palate (CL/P), no matter what the methodology used to identify associated defects (birth or medical record review, birth defect surveillance study, or ongoing clinical evaluation). Emanuel and colleagues documented a 40% rate of associated defects among children with CP alone ascertained through birth and hospital record review compared to 24% with CL/P.8 Surveys of clinic populations that afford the ability to document the frequency of minor as well as major malformations have published numbers ranging from 55–61% despite the exclusion of newborns with clefts as part of conditions with limited survival.4,9,10 Among carefully evaluated patients with submucous clefts of the palate, 77% will have an associated abnormality.4 Rigorous birth defects surveillance programs have documented frequencies of associated defects with CP ranging from 46.7–51.7%.11,12 Gorlin’s text documents the numerous syndromes, sequences, and associations in which CP may represent one feature.13 The clinical importance of recognizing associated malformations has been reviewed above. Table 12-5 lists some common conditions associated with CP. Of particular note is the frequency with which the disorders of type 2 collagen (Stickler syndrome and spondyloepiphyseal dysplasia congenita) occur in the population. In the author’s series, over 5% of all children presenting for treatment with CP will have Stickler syndrome. Early recognition of this condition is critical to monitor patients for the devastating ocular

Table 12-5. Syndromes commonly featuring cleft palate alone Syndrome

Prominent features

Causation Gene/Locus

Chromosomal Disorders Del 22q (VCFS, DiGeorge)

Short palpebral fissures, small ears, alar hypoplasia, conotruncal cardiac defects

22q11.22

Down

Flat face, small ears, cardiac defects, single transverse palmar creases

Trisomy 21

Beckwith

Overgrowth, macroglossia, hemihypertrophy, omphalocele

Multiple mechanisms perturb imprinted loci 11p15

Branchio-oto-renal

Cup ears, ear pits, branchial arch remnants, Mondini defect

AD (113650) EYA1, 8q13

Campomelic dysplasia

Short bowed tibias with dimpling, flat face, sex reversal

AD (114290) SOX9, 17q24-q25

CHARGE

Ocular colobomas, choanal atresia, micropenis, cardiac defects

AD (214800) CHD7, 8q12

Cleft palate-ankyloglossia

Ankyloglossia

XLR (303400) TBX22, Xq21

De Lange

Growth deficiency, hirsutism, limb defects, cardiac defects

Sporadic (122470) NIPBL, 5p13.1

Diastrophic dysplasia

Short limb dwarfing, hitch-hiker thumb, scoliosis

AR (222600) SLC26A2, 5q32-33

Distichiasis-lymphedema

Double row of eyelashes, peripheral edema, cardiac defects

AD (153400) FOXC2, 16q24

Multiple pterygium

Multiple pterygia, short neck, scoliosis with vertebral defects

AR (265000)

Nager

Radial limb defects, ear malformation, zygomatic hypoplasia

AD (154400)

Oralfacial digital type 1

Lobulated tongue, oral frenula, milia, alopecia

XLD (311200) CXORF5, Xp22

Otopalato digital type 1

Broad nasal root, deafness, broad distal phalanges

XLR (311300) FLNA, Xq28

Popliteal pterygium

Lip pits, popliteal web, genital anomalies

AD (119500) IRF6, 1q32-q41

Rapp-Hodgkin ectodermal dysplasia

Coarse dry hair, anhidrosis, alopecia

AD (129400) P63, 3q27

SED congenita

Short limb dwarfing, myopia, pulmonary hypoplasia

AD (183900) COL2A1, 12q13

Smith-Lemli-Opitz

Ptosis, hypospadias, 2–3 toe syndactyly

AR (270400) DHCR7, 11q12-13

Stickler

Flat face, myopia, Robin sequence (non-ocular form)

AD (108300) COL2A1, 12q13 AD (604841) COL11A1, 1p21 AD (184840) COL11A2, 6p21.3

Treacher Collins

Microtia, zygomatic hypoplasia, micrognathia

AD (154500) TCOF1, 5q32-33

Van der Woude

Lower lip pits

AD (119300) IRF6, 1q32-q41

Single Gene Disorders

Other FAV/OAV spectrum

Microtia, ear tags, cardiac defects, epibulbar dermoid

Usually sporadic

Kabuki

Large palpebral fissures, fetal finger pads, cardiac defect

Sporadic

Mobius sequence

Sixth and seventh cranial nerve palsy, clubfoot, other cranial nerve palsy

Sporadic

Anticonvulsants

Microcephaly, coarse facies, cardiac defects, nail hypoplasia

Hydantoin

Alcohol

Microcephaly, short palpebral fissures, smooth philtrum

Alcohol

Retinoic acid

Anotia, conotruncal cardiac defect, brain defect

Isotretinoin

Teratogens

401

402

Craniofacial Structures

complications that may occur.14 Although many affected infants will have flat facial profiles, micrognathia, and the Robin sequence, ophthalmologic evaluation to screen for early onset myopia is warranted when the diagnosis is suspected. Etiology and Distribution

Table 12-6 sets forth population-based characteristics of CP. As discussed above in greater detail, segregation analyses have challenged the multifactorial/threshold model for clefting, although fewer studies have specifically addressed cleft palate alone.15–17 In general, linkage and association studies have been more problematic in CP than in CL/P, probably reflecting heterogeneity in the populations under investigation. Beaty et al.18 documented an association between MSX1 and isolated CP, later confirmed by Fallin et al.19 Mutations in MSX1, FGFR1, and IRF6 produce mixed clefting phenotypes (discussed above) and may account for a proportion of nonsyndromic CP. The most interesting gene thus far identified with specificity for CP is TBX22, mutations which are responsible for X-linked cleft palate with ankyloglossia.20 Recent investigations in broader populations have suggested that inactivating mutations in TBX22 may account for 2–4% of nonsyndromic CP in North America and Brazil, but not the Philippines.21 The most convincing environmental agent associated with nonsyndromic CP is maternal cigarette smoking.22 It is the author’s belief that the difficulty in demonstrating teratogenicity as well as genetic associations in the CP population relates to heterogeneity within nonsyndromic CP and to pitfalls in identifying which individuals are truly nonsyndromic. Prognosis, Treatment, and Prevention

For nonsyndromic CP the outcome with appropriate treatment is excellent. As discussed in detail above, establishing oral feeding is the first step in treatment. Children with CP are at increased risk for middle ear effusions and otitis media. Speech, language, and facial growth are monitored after the palate is repaired, with appropriate intervention (speech therapy/orthodontic treatment) if problems are identified. Not all submucous clefts of the palate require surgical management. Repair is usually reserved for those associated with velopharyngeal incompetence or recurrent otitis media.23,24 Although most children with nonsyndromic CP func-

Table 12-6. Epidemiologic characteristics of cleft palate alone Characteristic

Summary Information

Prevalence

One per 2000 total births

Geographic variation

Higher in Australia, Scandinavia, Scotland, France

Racial/ethnic differences

Slightly higher in Asians

Gender differences

Slight preponderance of F

Temporal trends

Mostly stable rates over time

Maternal age

No evidence for maternal age effect when syndromic cases are meticulously excluded

Birth weight/gestational age

Lower mean birth weight in some studies; no convincing increase in prematurity

Twinning

No clear increase in twins DZ concordance rate same as full siblings

Familial patterns

Familial cases 10% Sibling recurrence 2–3

tion in regular classes in school, a significant number have language impairment and reading disabilities.25,26 Neurodevelopmental testing should be considered for any child who struggles in school. Although the multifactorial-threshold model for CP is likely not correct, as addressed above, families are still counseled with respect to recurrence risk based on the empirical data from which the model derived. Table 12-4 outlines recurrence risk for CP. Currently, no tests of genetic susceptibility are available. Prevention focuses on avoidance of exposure to agents, such as cigarette smoking, known to increase the risk. Prenatal diagnosis using ultrasound can be considered for those syndromic cases in which severe micrognathia is a consistent feature.27 References (Cleft Palate) 1. Hanson JW, Smith DW: U-shaped palatal defect in the Robin anomaly: developmental and clinical relevance. J Pediatr 87:30, 1975. 2. Rintala A, Ranta R, Stegars T: On the pathogenesis of cleft palate in the Pierre Robin syndrome. Scand J Plast Reconstr Surg 18:237, 1984. 3. Printzlau A, Andersen M: Pierre Robin sequence in Denmark: A retrospective population-based epidemiological study. Cleft Palate Craniofac J 41:47, 2004. 4. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, et al.: Anomalies associated with cleft lip, cleft palate, or both. Am J Med Genet 20: 585, 1985. 5. Van den Elzen AP, Semmekrot BA, Bongers EM, et al.: Diagnosis and treatment of the Pierre Robin sequence: results of a retrospective clinical study and review of the literature. Eur J Pediatr 160:47, 2001. 6. Lindemann G, Riss B, Sewerin I: Prevalence of cleft uvula among 2732 Danes. Cleft Palate J 14:226, 1977. 7. Pilu F, Romero R, Reece EA, et al.: The prenatal diagnosis of Robin anomalad. Am J Obstet Gynecol 154:630, 1986. 8. Emanuel I, Culver BH, Erickson JD, et al.: The further epidemiological differentiation of cleft lip and palate: a population study of clefts in King County, Washington, 1956-1965. Teratology 7:271, 1973. 9. Rollnick BR, Pruzansky S: Genetic services at a center for craniofacial anomalies. Cleft Palate J 18:304, 1981. 10. Jones MC: Etiology of facial clefts: prospective evaluation of 428 patients. Cleft Palate J 25:16, 1988. 11. Stoll C, Alembik Y, Dott B, et al.: Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37:41, 2000. 12. Croen LA, Shaw GM, Wasserman CR, et al.: Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983–1992. Am J Med Genet 79:42, 1998. 13. Gorlin RJ, Cohen MM, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 14. Snead MP, Yates JR: Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353, 1999. 15. Chung CS, Ching GHS, Morton NE: A genetic study of cleft lip and palate in Hawaii. II. Complex segregation analysis and genetic risks. Am J Hum Genet 26:177, 1974. 16. Demenais F, Bonaiti-Pelie J, Briard ML, et al.: An epidemiological and genetic study of facial clefting in France. II Segregation analysis. J Med Genet 21:436, 1984. 17. Clementi M, Tenconi R, Forabosco P, et al.: Inheritance of cleft palate in Italy. Evidence for a major autosomal recessive locus. Hum Genet 100:204, 1997. 18. Beaty TH, Wang H, Hetmanski JB, et al.: A case-control study of nonsyndromic oral clefts in Maryland. Ann Epidemiol 11:434, 2001. 19. Fallin MD, Hetmanski JB, Park J, et al.: Family-based analysis of MSX1 haplotypes for association with oral clefts. Genet Epidemiol 25:168, 2003. 20. Moore GE, Ivens A, Chambers J, et al.: Linkage of an X-chromosome cleft palate gene. Nature 326:91, 1987. 21. Marcano ACB, Doudney K, Braybrook C, et al.: TBX22 mutations are a frequent cause of cleft palate. J Med Genet 41:68, 2004. 22. Wyszynski DF, Duffy DL, Beaty TH: Maternal cigarette smoking and orofacial clefts: a meta-analysis. Cleft Palate Craniofac J 34:206, 1997.

Lips 23. Pensler JM, Bauer BS: Levator retropositioning and palatal lengthening for submucous clefts. Plast Reconstr Surg 82:765, 1988. 24. Ysunza A, Pamplona MC, Mendoza M, et al.: Surgical treatment of submucous cleft palate: a comparative trial of two modalities for palatal closure. Plast Reconstr Surg 107:9, 2001. 25. Richman LC, Eliason MJ, Lindgren SD: Reading disability in children with clefts. Cleft Palate J 25:21, 1988.

403 26. Richman LC, Eliason M: Type of reading disability related to cleft type and neuropsychological patterns. Cleft Palate J 21:1, 1984. 27. Vettraino IM, Lee W, Bronsteen RA, et al.: Clinical outcome of fetuses with sonographic diagnosis of isolated micrognathia. Obstet Gynecol 102:801, 2003.

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13 Tongue Robert J. Gorlin

I

am surprised at how often one encounters the faulty perception that ‘‘the mouth begins at the tonsils.’’ In the medical curriculum, because little to no time is allocated to disorders of the mouth, we will devote some effort to the elucidation of this subject. The mouth can be easily examined digitally using a 22 gauze, a good light, and a mouth mirror. The tongue is the most important soft tissue structure within the oral cavity. Speech, deglutition, some taste (sweet, salt, bitter, sour, metallic, and so forth [most taste is really smell]), and participation in the immune system (through the lingual tonsils) are its main functions. During embryonal development, if the tongue fails to descend to its normal position and the mandible is small, the tongue will interfere with the approximation of the palatal shelves (processes) in the midline. These shelves form the secondary palate; if tongue interference occurs, the palate will be cleft. Abnormal embryonal development of the tongue may produce alterations in the formation of the thyroid gland, with resultant ectopia (lingual thyroid). Alterations in tongue formation (absence of fungiform and circumvallate papillae) may be associated with lack of taste sensation as in familial dysautonomia (Riley-Day syndrome). Midline clefting of the mandible may be associated with absent, cleft, or adherent tongue. Tongue enlargement, as in Beckwith-Wiedemann syndrome, will influence tooth position and alignment. In addition, microstomia will be present if the tongue is nearly absent, as in hypoglossia-hypodactyly syndromes or in otocephaly. Speech alterations may be present in cases of marked ankyloglossia; diastema of mandibular incisors occurs in cases of thick lingual frenulum with insertion into the anterior labial mucosa. The normal anatomy of the oral floor is altered by the formation of dermoid cysts and salivary gland hamartomas associated with cleft or maldeveloped tongue.

Embryology/Anatomy

At about the end of the 4th embryologic week, a somewhat rhomboidal elevation is seen, behind the buccopharyngeal membrane, in the floor of the pharynx just rostral to the foramen cecum (the depression from which the thyroid gland arises). This unpaired tubercle (tuberculum impar) or median tongue bud is soon joined on each side by lateral lingual tubercles. The posterior third of the tongue is formed by two elevations that develop caudal to the foramen

cecum: the copula (hypobranchial eminence) and the still more caudal epiglottal swelling. The second arch plays no role in tongue development. The muscles of the tongue are derived from myoblasts that migrate from the myotomes of occipital somites. Connective tissue, lymphatics, and blood vessels of the tongue (and possibly some muscle fibers) are derived from the branchial arch mesenchyme. The tongue is usually considered to have two parts: the anterior two-thirds of the tongue (the oral portion), which is separated from the posterior third (the pharyngeal portion) by the sulcus terminalis. The tongue surface becomes covered with papillae, beginning around day 54. Both vallate and foliate papillae appear earliest and have a relationship to the terminal branches of the glossopharyngeal nerve. The fungiform papillae, also scattered over the same area but fewer in number, arise somewhat later embryologically, having a relationship to the termination of the chorda tympani branch of the facial nerve. The filiform papillae covering the dorsum of the anterior two-thirds of the tongue appears after week 12. The vallate papillae appear along the sulcus terminalis and the foliate papillae on the posterolateral surface of the tongue. The sensory nerve supply to the anterior two-thirds of the tongue is from the lingual branch of the mandibular division of the trigeminal nerve. The taste buds of the anterior two-thirds of the tongue are innervated by the chorda tympani branch of the seventh nerve. The foliate papillae and the posterior one-third of the tongue are innervated by the glossopharyngeal nerve. The superior laryngeal branch of the vagus nerve supplies a small area of the tongue just anterior to the epiglottis, and, as indicated earlier, the muscles of the tongue are supplied by the hypoglossal nerve, except for the palatoglossus, which is supplied by the vagus. The tongue has two groups of muscles: extrinsic and intrinsic. The extrinsic group (genioglossus, hypoglossus, styloglossus, and palatoglossus) are responsible for the gross positioning of the tongue. The intrinsic muscles (superior and inferior longitudinal muscles and transverse and vertical muscles) govern its shape.1 Excellent review of molecular embryology are those of Yamane et al.2 and Jung et al.3 References 1. Velcek FT, Klatz DH, Hill CH: Tongue lesions in children. J Pediatr Surg 14:238, 1979. 405

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2. Yamane A, Mayo MI, Bringas P Jr, et al.: TGF-alpha, EGF, and their cognate EGF receptor are co-expressed with desmin during embryonic, fetal and neonatal myogenesis in mouse tongue development. Dev Dyn 209:353, 1997. 3. Jung HS, Oropeza V, Thesleff I: Shh, Bmp-2, Bmp-4 and Fgf-8 are associated with initiation and patterning of mouse tongue papillae. Mech Develop 81:179, 1999.

13.1 Aglossia, Hypoglossia, Microglossia Aglossia, hypoglossia, and microglossia cover the range of total to partial absence of the tongue. Diagnosis is established on clinical inspection. Aglossia is an inaccurate term because some tongue remnants are always present (hypoglossia), with the rudimentary tongue located at the level of the genioglossal processes (Fig. 13-1). The tongue bud generally is capable of some movement that is accentuated laterally and anteriorly by the muscular folds of the oral floor. Isolated aglossia (hypoglossia) is very rare.1 It forms part of the oromandibular-limb hypogenesis group of syndromes and is seen specifically in hypoglossia-hypodactylia and Moebius syndromes.2–8 Persistence of the buccopharyngeal membrane or remnants of it has been frequently associated with aglossia.9 Brecht and Johnson5 reported a case of complete mandibular agenesis with microstomia, choanal atresia, cleft soft palate, persistence of the buccopharyngeal membrane, and almost total aglossia. There is no evidence that heredity plays an etiologic role in this condition. All examples of hypoglossia-hypodactylia and Moebius syndrome (oromandibular-limb hypogenesis) have been sporadic. Rarely, hypoglossia may be found without hypodactyly. There is usually reduction of mandibular incisors to but a single one. The mandible is severely constricted.6 Situs inversus7 and anterior maxillo-mandibular fusion8 have also been found. The prevalence of this tongue malformation is extremely rare.4 No therapy exists for this condition. Patients are capable of achieving an acceptable level of speech.

Fig. 13-1. Rudimentary malformed tongue in hypoglossiahypodactyly syndrome.

Fig. 13-2. Absence of the lingual frenulum.

References (Aglossia, Hypoglossia, Microglossia) 1. Bousten M, Mercier J, Delaire J: Les syndromes malformatifs oromandibulaires et des membres. Rev Stomatol Chir Maxillofac 88:168, 1987. 2. Chicarilli ZN, Polayes IM: Oromandibular limb hypogenesis syndromes. Plast Reconstr Surg 76:13, 1985. 3. Hall BD: Aglossia-adactylia. Birth Defects Orig Artic Ser VII (7):233, 1971. 4. Schuhl JF: Aglossia-adactylia. Review of the literature. Ann Pediatr 33:137, 1986. 5. Brecht K, Johnson CM: Complete mandibular agenesis. Arch Otolaryngol 111:132, 1985. 6. Yamada A, Konno N, Imai Y, et al.: Treatment of hypoglossia-hypodactyly without extremity anomalies. Plast Reconstr Surg 106:274, 2000. 7. Amor DJ, Craig JE: Situs inversus totalis and congenital hypoglossia. Clin Dysmorphol 10:47, 2001. 8. Arshad AR, Goh CS: Hypoglossia congenita with anterior maxillomandibular fusion. Br J Plast Surg 47:139, 1994. 9. Grippaudo FR, Kennedy DC: Oromandibular-limb hypogenesis syndromes: A case of aglossia with an intraoral band. Br J Plast Surg 51: 480, 1998.

The tongue originates from the first, third, and fourth pharyngeal arches. The two lateral lingual swellings and a median swelling (tuberculum impar), which form the anterior two-thirds of the tongue, are derived from the first arch. During early stages of development, the tongue is fused to the floor of the mouth. Separation is achieved by extensive cellular degeneration, the frenulum being the only remaining tissue in this area. Absence of the frenulum occurs when the cellular degeneration extends beyond the normal limits. Absence of the frenulum has been reported in the aglossia-adactylia syndrome.1 Review of the literature failed to disclose isolated cases of this condition. We have observed the occurrence of absent lingual frenulum in two sisters and their mother. Absence of the lingual frenum has been reported in Ehlers-Danlos syndrome, type 12 and in a variant of Rapp-Hodgkin syndrome.3 Prognosis is excellent. References (Absence of Lingual Frenulum)

13.2 Absence of Lingual Frenulum Complete absence of lingual frenulum with the ventral surface of the tongue folding in the floor of the mouth can occur (Fig. 13-2).

1. Schuhl FJ: Aglossia-adactylia. Review of the literature. Ann Pediatr 33:137, 1986. 2. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001, p 517. 3. Kantaputra PN, Pruksachatkunakorn C, Vanittanakom P: RappHodgkin syndrome with palmoplantar keratoderma, glossy tongue,

Tongue

407

congenital absence of the lingual frenum and sublingual caruncles. Am J Med Genet 79:343, 1998.

13.3 Macroglossia Macroglossia denotes enlargement of the tongue, some cases having congenital etiology and others acquired. Enlargement may produce airway obstruction and be associated with noisy breathing, drooling, slurred speech, difficult swallowing, spreading of teeth, and open bite. Pressure of the teeth on the tongue may cause marginal scalloping1 (Table 13-1). An enlarged tongue, from whatever cause, may be especially distressing to parents because the child may appear mentally retarded. Vogel et al.1 have classified tongue enlargement into two categories: (a) true macroglossia and (b) relative macroglossia. True macroglossia, in turn, is divided into congenital and acquired causes. Congenital causes, described elsewhere in this section, include hemangioma and lymphangioma. Muscular enlargement would include such disorders as hemihyperplasia (hemihypertrophy) (Fig. 13-3),2 and Beckwith-Wiedemann syndrome.3–5 Glycogen storage disease type II (Pompe disease); mucopolysaccharidoses (MPS) I, II, and VI; mannosidosis; and I-cell disease are among the systemic diseases associated with tongue enlargement.6 Neoplastic enlargement (various hamartomas and choristomas, cysts, and neurofibromatoses) is discussed extensively elsewhere in this section (see also Table 13-2).7,8 Acquired macroglossia includes such categories as neoplasms (lymphoma, carcinoma), systemic disorders (amyloidoses), and local reactive change (angioneurotic edema) (Table 13-2). Relative macroglossia refers to a tongue that appears large in spite of its normal size. This is usually due to a malfunction of the tongue for any of various reasons (e.g., jaw underdevelopment, lingual dystonia). Again, relative macroglossia has been divided into congenital (trisomy 21, cretinism) and acquired (edentulousness, myxedema) causes (Table 13-3).9,10 Many quite diverse conditions can produce a large tongue, and there have been a number of classifications that have attempted to encompass all known causes of tongue enlargement.1 One of the better recent publications addressing this problem is that of Vogel et al.1 As they point out, clinical presentation is variable. Depending on the size of the tongue and on the nature of the disorder, the infant can exhibit noisy breathing, have difficulty with

Fig. 13-3. Macroglossia associated with hemihyperplasia. (Courtesy of Dr. James E. Vogel, Johns Hopkins Hospital, Baltimore, MD.) Table 13-2. Clinical classification of true macroglossia Congenital

Vascular malformation (lymphatic, venous, capillary) Muscular enlargement (hemihypertrophy, Beckwith-Wiedemann syndrome) Systemic disorder (mucopolysaccharide storage disorders) Tumor (dermoid cyst, rhabdomyoma) Acquired

Tumor (lymphoma, epidermoid carcinoma) Table 13-1. Clinical presentations of macroglossia

Systemic disorder (amyloidosis, gigantism) Local reactive change (edema, vascular congestion)

Airway obstruction Noisy breathing

From Vogel et al.1

Difficulty with chewing/swallowing Drooling

Table 13-3. Causes of relative macroglossia

Slurred speech

Congenital

Perception of mental retardation

Systemic disorder (Down syndrome, cretinism)

Widened interdental spaces Scalloping/crenations

Acquired

Open-bite deformity/mandibular prognathism

Functional (postoperative maladaptation)

Dry/cracked tongue

Elevation (Ludwig’s angina, edentulous)

Ulceration/secondary infection/hemorrhage

Systemic disorder (myxedema)

From Vogel et al.1

From Vogel et al.1

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swallowing, and drool, and have open bite, wide interdental spaces, and slurred speech. If the tongue enlargement is massive, the dorsal surface may be dried, cracked, ulcerated, infected, or hemorrhagic. Anterior wedge resection usually is adequate to reduce tongue size.11 References (Macroglossia) 1. Vogel JE, Mulliken JB, Kaban LB: Macroglossia: a review of the condition and a new classification. Plast Reconstr Surg 78:715, 1986. 2. Wittman A: Macroglossia in acromegaly and hypothyroidism. Virchows Arch A 373:353, 1977. 3. Salman RA: Oral manifestations of Beckwith-Wiedemann syndrome. Spec Care Dentist 8:23, 1988. 4. Arons MS, Solataire GB, Grunt JA: The macroglossia of BeckwithWiedemann syndrome. Plast Reconstr Surg 45:341, 1970. 5. McManamny DS, Barnett JS: Macroglossia as a presentation of Beckwith’s syndrome. Plast Reconstr Surg 75:170, 1985. 6. Nyhan WL: Understanding inherited metabolic disease. Clin Symp 32:1, 1980. 7. Ayres WW, Delaney AJ, Backer MH: Congenital neurofibromatous macroglossia associated in some cases with von Recklinghausen’s disease. Cancer 5:721, 1952. 8. Basma NJ, Robin PE: Hemimacroglossia associated with plexiform neurofibromatosis. J Laryngol Otol 101:743, 1987. 9. Ardran GM, Harker P, Kemp FH: Tongue size in Down syndrome. J Ment Defic Res 16:160, 1972. 10. Farkas LG, Munro IR, Kolar JC: Abnormal measurements and disproportions in the face of Down syndrome patients. Plast Reconstr Surg 75:159, 1985. 11. Rizer FM, Schechter GL, Richardson MA: Macroglossia: etiologic considerations and management techniques. Int J Pediatr Otorhinolaryngol 8:225, 1985.

13.4 Bifid Tongue Clefting of the anterior tongue constitutes a bifid tongue. In bifurcation of the tongue tip, the degree of splitting varies from patient to patient. Differentiation must be made between true and false bifid tongue, the latter being observed during tongue protrusion in individuals with ankyloglossia (Cupid’s bow). Isolated bifid tongue is rare, but it can be associated with cleft mandible and various syndromes.1 In the oral-facial-digital syndromes, the Fig. 13-4. Bifid tongue and hyperplastic frenula that traverse the mucobuccal fold in oral-facial-digital syndrome type I. (Courtesy of Dr. M. Perko, Zurich, Switzerland.)

tongue may be bifid, trifid, or tetrafid (Fig. 13-4). Other considerations occasionally associated with bifidity of the tongue tip are median mandibular cleft, mandibulofacial dysostosis, and cleft palate.2–4 Bifid tongue has also been associated with natal teeth and hearing loss5 and with oral duplication.1 The tongue, anterior to the circumvallate papillae, is formed from two lateral tubercles derived from the first branchial arch that fuse in the midline between the 4th and 5th embryonal weeks. Failure of fusion of the tubercles causes cleft (bifid or lobulated) tongue. Sedano and Freyte6 reported a prevalence of 5.3 per 1000 or one affected per 189 school-aged Mexican children. There is a higher proportion of boys affected, with a prevalence male to female ratio of approximately 2:1.7 Bifid tongue can be corrected with plastic surgery. References (Bifid Tongue) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Matheny M, Hall B, Manaligod JM: Otolaryngologic aspects of oralfacial-digital syndrome. Int J Pediatr Otorhinolaryngol 53:39, 2000. 3. Chidzonga MM, Shija JK: Congenital median cleft of the lower lip, bifid tongue with ankyloglossia, cleft palate and submental epidermoid cyst: report of a case. J Oral Maxillofac Surg 46:809, 1988. 4. Nocini PF, Urbani G, Manfrani F, et al.: Bifid tongue associated with other maxillofacial pathology. Minerva Stomatol 36:511, 1987. 5. Darwish S, Sastry KA, Ruprecht A: Natal teeth, bifid tongue and deaf mutism. J Oral Med 42:49, 1987. 6. Sedano HO, Freyte IC: Clinical orodental malformations in Mexican children. Oral Surg 68:300, 1989. 7. Almeida LE, Ulbrich L, Togni F: Mandible cleft: report of a case and review of the literature. J Oral Maxillofac Surg 60:681, 2002.

13.5 Fissured Tongue, Scrotal Tongue, Lingua Plicata Definition

Fissured tongue, scrotal tongue, and lingua plicata are multiple linear fissures of various depths on the dorsal surface of the tongue with variation of clinical appearance of lingual papillae (Fig. 13-5).

Fig. 13-5. Fissured tongue. Can be found in the normal population and has no significance.

Tongue

Diagnosis

On careful examination, most tongues present some degree of furrowing. Diagnosis of fissured tongue can be achieved by asking the patient to push the tip of the tongue against the anterior mandibular teeth, because during this maneuver the fissures become accentuated. A single central groove in the midline of the tongue is not considered a fissured tongue. Kullaa-Mikkonen1,2 and Kullaa-Mikkonen and Sorvari3,4 proposed two types of fissured tongue: (1) fissured tongue with normal-appearing filiform papillae and (2) so-called fissured tongue syndrome (FTS) characterized by fissured tongue with smooth-surfaced papillae preceded by geographic tongue. In FTS, geographic and fissured tongue are believed to be different manifestations of the same condition and to have autosomal dominant inheritance with variable penetrance. The tongue may become fissured and/or lobulated in patients with pernicious anemia or with Sjo¨gren syndrome. Fissured tongue is seen in 30% of patients with trisomy 21 and is part of MelkerssonRosenthal syndrome.5 Some authors have postulated that fissured tongue may be a mucosal manifestation of generalized pustular psoriasis.6,7 Hietanen et al.8 and Dawson6 found fissured tongue in 9.5% of patients with psoriasis. Considering that oral psoriasis is rare and that fissured tongue is seen in the general population with a prevalence that varies from 0.5% to 50% (according to the population examined), it is safe to assume that the 9.5% prevalence for fissured tongue in psoriatic patients probably represents a chance association and not a true oral manifestation of psoriasis. Etiology and Distribution

Fissured tongue is thought to have multifactorial etiology.9 It has been suggested that a combination of impaired immunologic mechanism and gastrointestinal disease (malabsorption) may play roles in the production of FTS.1 Based on the assumption that both generalized pustular psoriasis and fissured tongue are thought to be multifactorial in etiology with genetic predisposition being one of the factors, Hubler7 has suggested that the two entities may share genes. Prevalence values for fissured tongue have ranged from 3.2 to 538 affected per 1000 examined individuals,9–16 with this diversity of values being attributed to the possibility of one or more etiologic factors being present to a greater or lesser degree in the populations examined. Sedano et al.,15 in a recent survey of 43,000 school-aged Mexican children, reported a statistically significant difference between the prevalences in boys (168.3 per 1000) and girls (145.2 per 1000). This finding has been noted earlier.9–11,13 Aboyans and Ghaemmaghami17 reported no increase in the incidence of fissured tongue with age, but Sedano et al.15 found a prevalence value of 140.9 per 1000 for children aged 6 to 10 years and a prevalence of 193.0 per 1000 in children aged 11 to 14 years. This finding tends to agree with those of Chosack et al.11 and Halperin et al.,12 who reported a steady rise in the prevalence of fissured tongue with increasing age. Prognosis and Treatment

Prognosis is excellent. The condition does not require treatment. In occasional cases in which the fissures are extremely deep, superimposed infection with Candida albicans can occur. In those cases, antimycotic therapy and proper oral hygiene will effect a cure.

409

References (Fissured Tongue, Scrotal Tongue, Lingua Plicata) 1. Kullaa-Mikkonen A, Pentilla I, Kotilainen R, et al.: Hematological and immunological features of patients with fissured tongue syndrome. Br J Oral Maxillofac Surg 25:481, 1987. 2. Kullaa-Mikkonen A: Familial study of fissured tongue. Scand J Dent Res 96:366, 1988. 3. Kullaa-Mikkonen A, Sorvari TE: Lingua fissurata. A clinical, stereomicroscopic and histopathological study. Int J Oral Maxillofac Surg 15:525, 1986. 4. Kullaa-Mikkonen A, Sorvari TE: A scanning electron microscopic study of fissured tongue. J Oral Pathol 15:93, 1986. 5. Powell FC: Glossodynia and other disorders of the tongue. Dermatol Clin 5:687, 1987. 6. Dawson TAJ: Tongue lesions in generalized pustular psoriasis. Br J Dermatol 91:419, 1974. 7. Hubler WR Jr: Lingual lesions of generalized pustular psoriasis. Report of five cases and a review of the literature. J Am Acad Dermatol 11:1069, 1984. 8. Hietanen J, Salo OP, Kanerva L, et al.: Study of the oral mucosa in 200 consecutive patients with psoriasis. Scand J Dent Res 92:50, 1984. 9. Redman RS: Prevalence of geographic tongue, fissured tongue, median rhomboid glossitis and hairy tongue among 3,611 Minnesota schoolchildren. Oral Surg 30:390, 1970. 10. Bouquot JE, Gundlach KKH: Odd tongues: the prevalence of common tongue lesions in 23,616 white Americans over 35 years of age. Quintessence Int 17:719, 1986. 11. Chosack A, Zadik D, Eidelman E: The prevalence of scrotal tongue and geographic tongue in 70,359 Israeli schoolchildren. Community Dent Oral Epidemiol 2:253, 1974. 12. Halperin V, Kolas S, Jefferies KR, et al.: Occurrence of Fordyce glands, benign migratory glossitis, median rhomboid glossitis and fissured tongue in 2,478 dental patients. Oral Surg 6:1072, 1953. 13. Kullaa-Mikkonen A, Mikkonen M, Kotilainen R: Prevalence of different morphologic forms of the human tongue in young Finns. Oral Surg 53:152, 1982. 14. Sawyer DR, Taiwo EO, Mosadomi A: Oral anomalies in Nigerian children. Community Dent Oral Epidemiol 12:269, 1984. 15. Sedano HO, Carreon Freyre I, Garza de la Garza ML, et al.: Clinical orodental malformations in Mexican school aged children. Oral Surg 68:300, 1989. 16. Von Neuschulz B, Klammt J: Untersuchungen zur Lingua plicata. Zahn Mund Kieferheilkd 74:472, 1986. 17. Aboyans V, Ghaemmaghami A: The incidence of fissured tongue among 4,009 Iranian dental outpatients. Oral Surg Oral Med Oral Pathol 36:34, 1973.

13.6 Glossopalatine Ankylosis (Ankyloglossum Superius) Glossopalatine ankylosis involves a frenulum of variable thickness extending from the dorsal surface of the tongue to the hard palate or the maxillary alveolar ridge. The diagnosis is self-evident on intraoral clinical inspection. The frenulum is generally attached to the anterior portion of the tongue, the tongue tip being cleft. If there is cleft palate, the tongue may be attached to the nasal septum. Differentiation from persistent buccopharyngeal membrane is made on the basis of location, the latter being at the posterior portion of the tongue and at the level of the anterior tonsillar pillars. In glossopalatine ankylosis, the tongue is attached to the hard palate or to the maxillary alveolar ridge. The lingual attachment generally occurs in the anterior part of the tongue. Glossopalatine ankylosis is generally associated with other congenital anomalies such as cleft palate, ankyloglossia superior

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Craniofacial Structures

Fig. 13-6. Ankyloglossia superior syndrome. Child has a small mouth, attachment of the tongue to the hard palate, and reduction anomalies of the digits. (Courtesy of Dr. H. Gima, Okinawa, Japan.)

syndrome, underdeveloped mandible, and hypoplastic upper lip (Fig. 13-6).1–4 Hall5 and Gorlin et al.3 have included glossopalatine ankylosis as one of the findings in hypoglossia-hypodactyly or oromandibular-limb hypogenesis syndromes. This is borne out in the case of Zennano et al.6 Plastic surgery is used to liberate the tongue, with excellent results. References (Glossopalatine Ankylosis [Ankyloglossum Superius]) 1. Chicarilli ZN, Polayes IM: Oromandibular limb hypogenesis syndromes. Plast Reconstr Surg 76:13, 1985. 2. DeConinck A, Deleise M: Ankylose palato-linguale conge´nitale avec anomalies des extre´mitie´s. Acta Stomatol Belg 72:89, 1975. 3. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 4. Gima H, Yamashiro M, Tomoyose Y: Ankyloglossum superius syndrome. J Oral Maxillofac Surg 45:158, 1987. 5. Hall BD: Aglossia-adactylia. Birth Defects Orig Artic Ser VII(7):233, 1971. 6. Zennano O, Chabrol A, Mullon MH, et al.: Ankyloglossum superius. Rev Laryngol Otol Rhinol 1131:55, 1992.

13.7 Ankyloglossia: Tongue-tie, Partial Ankyloglossia, Total and Lateral Ankyloglossia Definition

Isolated partial ankyloglossia is characterized by a frenulum of variable size, generally located on the midventral surface of the tongue, that extends from the lingual gingival mucosa to nearly the tip of the tongue (Fig. 13-7). This frenulum restricts tongue

Fig. 13-7. Ankyloglossia. The lingual frenulum is attached to the mandibular gingiva. Minor adhesions of this type do not cause speech abnormalities.

movement and generally does not allow protrusion of the tip of the tongue beyond the vermilion border of the lower lip. Diagnosis

The diagnosis is established by clinical inspection. The presence of a thick, short ventral frenulum, with inability to protrude the tongue, is quite indicative of isolated partial ankyloglossia. When the tongue is protruded, the short frenulum creates a small notch on the tongue tip, mimicking a minor case of bifid tongue. In extreme cases of tongue-tie, minor alterations in speech may be present when articulating one or more tongue tip sounds such as t, d, l, th, and s.1 Partial (simple) attachment or tongue-tie comprises the majority of cases of ankyloglossia.

Tongue

Total and/or lateral ankyloglossia are rare conditions in which the tongue is extensively fused to the oral floor or alveolar gingiva. Patients with extensive ankyloglossia have presented with associated anomalies of the limbs. We suggest that these cases represent a form of oromandibular-limb hypogenesis syndrome. Ankyloglossia has been reported to be associated with the oral-facial-digital syndrome I and cleft mandible.2,3,14,15 Ankyloglossia has also been combined with cleft palate in Icelandic, Canadian, and German kindreds. In the Icelandic families, the males are all affected while only 70% of female carriers are affected. The gene maps to Xq21.31-q21.33.13 Etiology and Distribution

The tongue originates from the first, third, and fourth pharyngeal arches. The two lateral lingual swellings and a medial swelling (tuberculum impar) that form the anterior two-thirds of the tongue are derived from the first arch. During early stages of development, the tongue is fused to the floor of the mouth. Separation is achieved by extensive cellular degeneration, the frenulum being the only remaining tissue in this area. Ankyloglossia occurs when the resorption process is not completed. Although several authors have suggested autosomal dominant inheritance, in our view single gene inheritance of simple tongue-tie is untenable. The association of X-linked cleft palate and simple ankyloglossia is an obvious exception.4,13 De Porte and Parkhurst5 found 99 cases of ankyloglossia among 273,604 live births in New York State excluding New York City. McEnery and Gaines6 found four cases among 1000 children with speech defects, and Green7 reported 12 cases of tongue-tie among 40,000 children with speech defects. Sedano8 reported 8.3 cases per 1000 among Mexican school-aged children, the prevalence among males being 1.6 times that of females, values higher than those of previous reports.9–15

411

11. Sedano HO, Carreon Freyre I, Garza de la Garza ML, et al.: Clinical orodental malformations in Mexican school aged children. Oral Surg 68:300, 1989. 12. Wright JE: Tongue-tie. J Paediatr Child Health 31:276, 1995. 13. Braybrook C, Warry G, Howell G, et al.: Physical and transcriptional mapping of the X-linked cleft palate and ankyloglossia (CPX) critical region. Hum Genet 108:537, 2001. 14. Almeida LE, Ulbrich L, Togni F: Mandible cleft: report of a case and review of the literature. J Oral Maxillofac Surg 60:681, 2002. 15. Armstrong AP, Waterhouse N: Tessier 30 median mandibular cleft: case report and literature review. Br J Plast Surg 49:536, 1996.

13.8 Median Rhomboid Glossitis Median rhomboid glossitis is a somewhat rhomboid reddish area in the midline of the dorsum of the tongue, immediately anterior to the circumvallate papillae (Fig. 13-8). Its long axis lies in the median raphe. It usually measures about 1.52.5 cm. Although usually flat, it can be raised above the surface from 2 to 5 mm and may be fissured or mammilated. The pink or rosy color is due to an absence of filiform papillae and is not primarily inflammatory. Earlier investigators proposed that median rhomboid glossitis was due to persistence of the tuberculum impar, an unpaired structure arising between the first and second pharyngeal arches and normally overgrown by the lateral lingual tubercles. If the tuberculum impar is not overgrown, the persistent embryonal structure would give rise to a rhomboidal plaque. Theoretically, the anomaly could be somewhat anteriorly displaced and of any shape. More recent investigators have suggested that the condition is not congenital.1–4 Baughman1 believed that it was an inflammatory, infectious, or degenerative process that occurred only in adults. Redman,5 however, reported its occurrence in children. Farman et al.4 found Candida in about one-half of the cases, but did not

Prognosis and Treatment

Prognosis is excellent. Plastic surgery can be carried out in extreme cases to improve pronunciation. Surgery is indicated in cases of lateral and total ankylosis. References (Ankyloglossia) 1. Williams WN, Waldron CM: Assessment of lingual function when ankyloglossia (tongue-tie) is suspected. J Am Dent Assoc 110:353, 1985. 2. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 3. Russell AG, Staley CE: Congenital cleft mandible. J Oral Surg 19:257, 1961. 4. Bjo¨rnsson A, Arnason A, Tippet P: X-linked cleft palate and ankyloglossia in an Icelandic family. Cleft Palate J 26:3, 1989. 5. De Porte JV, Parkhurst E: Congenital malformations and birth injuries among the children born in New York State outside of New York City, in 1940–1942. NY State J Med 45:1097, 1945. 6. McEnery ET, Gaines FP: Tongue-tie in infants and children. J Pediatr 18:252, 1941. 7. Green JS: Anomalies of the speech mechanism and associated voice and speech disorders. NY State J Med 45:605, 1945. 8. Sedano HO: Congenital oral anomalies in Argentinian children. Community Dent Oral Epidemiol 3:61, 1975. 9. Catlin FI, De Haan V: Tongue-tie. Arch Otolaryngol 94:548, 1971. 10. Sawyer DR, Taiwo EO, Mosadomi A: Oral anomalies in Nigerian children. Community Dent Oral Epidemiol 12:2269, 1984.

Fig. 13-8. Median rhomboid glossitis. The lozenge-shaped bald area on the midline of the tongue extends to the sulcus terminalis.

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Craniofacial Structures

indicate a cause-and-effect relationship. Cooke2 was more certain of candidal etiology. However, the oral candidal organisms are so common that we are skeptical concerning the relationship. It may be that the disorder is developmental and that the area, being devoid of papillae, is more susceptible to hosting candidal organisms.6–8 Its reported frequency has ranged from one per 90 to 400 individuals. There appears to be a male to female ratio of 3:1 but no racial predilection.5,9–11 Microscopically, there is absence of filiform papillae. The epithelium is hyperplastic with marked downgrowth. Some serous salivary glands exhibit squamous metaplasia with epithelial pearl formation (pseudoepitheliomatous hyperplasia), which may erroneously be diagnosed as squamous cell carcinoma. A chronic inflammatory infiltrate is usually seen in the subepithelial layer, and often there is vascular dilation. Prognosis is excellent. No treatment is needed.

5. Chen YR, Noordhoff MS: Duplication of stomadeal structures. Report of three cases with literature review and suggestion for classification. Plast Reconstr Surg 84:733, 1989. 6. Lu CY, Teng RJ, Hou JW, et al.: Bifid tongue associated with midline cleft palate, mandible, cervical vertebrae, and linea alba. Eur J Pediatr 157:86, 1998.

References (Median Rhomboid Glossitis) 1. Baughman RA: Median rhomboid glossitis. A developmental anomaly? Oral Surg 31:56, 1971. 2. Cooke BE: Median rhomboid glossitis: candidiasis and not a developmental anomaly. Br J Dermatol 93:399, 1975. 3. Delemarre JFM, van der Waal I: Clinical and histopathologic aspects of median rhomboid glossitis. Int J Oral Surg 2:203, 1973. 4. Farman AG, van Wyck CW, Staz J, et al.: Central papillary atrophy of the tongue. Oral Surg 43:48, 1977. 5. Redman R: Prevalence of geographic tongue, fissured tongue, median rhomboid glossitis and hairy tongue among 3,611 Minnesota schoolchildren. Oral Surg 30:390, 1970. 6. Van der Wal N, van der Waal I: Candida albicans in median rhomboid glossitis. Int J Oral Maxillofac Surg 15:322, 1986. 7. Van der Waal I, Beemster G, van der Kwast WA: Median rhomboid glossitis caused by Candida? Oral Surg 47:31, 1979. 8. Ullmann W, Hoffman M: Glossitis rhombica mediana. Eine Studie an 4422 dermatologisch Patientin. Hautarzt 32:571, 1981. 9. Halperin V, Kolas S, Jefferis K, et al.: Occurrence of Fordyce spots, benign migratory glossitis, median rhomboid glossitis and fissured tongue in 2,478 dental patients. Oral Surg 6:1072, 1953. 10. Schaumann BF, Peagler F, Gorlin RJ: Minor craniofacial anomalies among a Negro population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 29:566, 729, 1990. 11. Wright BA: Median rhomboid glossitis. Oral Surg 46:806, 1978.

13.9 Double Tongue Double tongue has been part of oral duplication on many occasions. The reader is referred to Gorlin et al.1 for more complete discussion. Examples are those of Calomeni and Jordan,2 Bartholdson et al.,3 Britto et al.,4 Chen and Noordhoff,5 and Lu et al.6 Cleft palate often accompanies double tongue. We suspect this overlaps bifid tongue. References (Double Tongue) 1. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 2. Calomeni AA, Jordan JE: Multiple congenital defects. J Am Dent Assoc 107:432, 1983. 3. Bartholdson L, Hellstrom SO, Soderberg O: A case of double tongue. Scand J Plast Reconstr Hand Surg 25:93, 1991. 4. Britto JA, Ragoowansi RH, Sommerlad BC: Double tongue, intraoral anomalies, and cleft palate. Cleft Palate Craniofac J 37:410, 2000.

Fig. 13-9. Lingual thyroid presenting as a mass located at the foramen cecum. (Courtesy of Dr. M. R. Kamat, Riyadh, Saudi Arabia.)

Fig. 13-10. Enhanced axial CT scan shows homogeneous mass of a lingual thyroid (arrows) at the base of the tongue. (From Willinsky et al.5)

Tongue

413

Fig. 13-11. A and B. 131I scintigraphy in frontal and lateral planes showing a functional lingual thyroid at tongue base and absence of functional thyroid at normal site. C. Biopsy material from a lingual mass shows thyroid tissue covered by normal-appearing mucosa. (From van der Wal et al.10)

13.10 Lingual Thyroid Definition

Lingual thyroid is a nodule of variable size composed of normal thyroid tissue located on the dorsal surface of the tongue in the midline at the level of the foramen cecum or within the body of the tongue (Fig. 13-9). Diagnosis

Lingual thyroid should be suspected when a mass or nodule is located at the level of the foramen cecum in front of the terminal sulcus of the tongue. Nevertheless, differential diagnosis includes various tongue neoplasms, hamartomas, choristomas, and lingual tonsillitis.1,2 Radioactive iodine 123 or technitium 99m scanning and computed tomography scans will demonstrate the presence of thyroid tissue at the lingual location (Fig. 13-10).3–5 A biopsy procedure is not indicated unless it has been proven that the patient has a normally located and functional thyroid gland. Lingual thyroid generally presents as a round, purplish nodule 2 to 3 cm in diameter. Occasionally it can be hemorrhagic and, if very large, may displace the epiglottis.6 Ninety percent of cases occur at the level of the foramen cecum, but some patients may present thyroid tissue embedded in the body of the tongue, sublingually or rarely in the anterior portion of the tongue.7 Rarely, there is dual ectopic thyroid.26 On palpation the mass is firm and encapsulated. This aids in differentiation from lingual tonsillitis, which is soft and friable.1 In females, lingual thyroid increases in size during times of marked endocrine activity such as puberty, pregnancy, and menopause.8 It is during those periods that the majority of cases in women have been detected. Some patients may have obstructive problems such as dysphagia (50%), dysphonia (44%), or dyspnea (28%).5–9 Over 70% of patients with lingual thyroid have total absence of the normally located thyroid gland (Fig. 13-11). Infants with lingual thyroid may present symptoms of hypothyroidism.10 Etiology and Distribution

The thyroid gland is formed during weeks 3 to 4 of embryonal development by invagination of proliferating endoderm in the

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Craniofacial Structures

floor of the pharynx at the level of the future foramen cecum on the dorsal surface of the tongue, between the tuberculum impar and the copula. This tissue descends in front of the pharyngeal gut but remains attached to the tongue by a thin evanescent canal known as the thyroglossal duct. Ectopic thyroid tissue can be found at different levels of the duct, from the tongue base to the neck. Failure of descent of this epithelial proliferation results in ectopic thyroid. Over 400 cases of this anomaly have been reported in the literature with a female to male ratio of 4 to 5:1.6,10,11 Residual thyroid tissue is found in the vicinity of the foramen cecum in 10% of 200 routine autopsies, with equal distribution among the sexes. Baughman12 reported identical findings (9.8%) in 184 biopsies, but in a study of 100 autopsies, Soames13 did not find evidence of thyroid tissue in the tongue. Williams et al.14 reported the frequency of lingual thyroid at 1.3 per 10,000 births. Nearly all examples of lingual thyroid have been isolated. However, there are a few examples in siblings.15–17 Sensorineural hearing loss has been an associated finding in a few cases.18,19 Prognosis and Treatment

Occasional cases of a benign neoplasm arising in a lingual thyroid have been reported.2 Adenocarcinoma developing in the lingual thyroid has been reported in several instances, as has goiter.10,11,20,21 Airway obstruction, especially in children, has been observed in several cases.4,7,9 Myxedema will develop after surgical removal of the lingual thyroid if there is no orthopic gland. Thyroiditis can occur in the normal thyroid gland, when present, following surgical ablation of the ectopic lingual thyroid. Surgery is indicated only if the lingual thyroid is extremely large or if it does not respond to suppressive medical therapy with thyroxine or ablation with radioactive iodine.4 Laser surgery has been used to avoid profuse hemorrhage, as there is high vascularity of the lingual thyroid.9 Autotransplantation of the ectopic thyroid has been reported to have a 30% success rate.22 The rectus abdominis muscles or the neck are chosen as an autotransplant site because of easy access.23 Thyroglossal duct cyst refers to a cyst that develops from persistence and dilation of the embryonic thyroglossal tract. Although the tongue arises at the foramen cecum, the cyst usually presents below the tongue at the level of the hyoid bone. It has occasionally been noted in the oral floor.28 Rarely, there is familial occurrence of thyroid anomalies.15,16,24,25 Blandino et al.27 elegantly discuss magnetic resonance imaging findings. References (Lingual Thyroid) 1. Puar RK, Pura HS: Lingual tonsillitis. South Med J 79:1126, 1986. 2. Soni NK, Chatterji P: An unusual tumor mistaken as a lingual thyroid. J Laryngol Otol 98:1055, 1984. 3. Miller JH: Lingual thyroid gland: sonographic appearance. Radiology 156:83, 1985. 4. Kansal P, Sakati N, Rifai A, et al.: Lingual thyroid. Diagnosis and treatment. Arch Intern Med 147:2046, 1987. 5. Willinsky RA, Kassel EE, Cooper PW, et al.: Computed tomography of lingual thyroid. J Comput Assist Tomogr 11:182, 1987. 6. Baldwin RL, Copeland SK: Lingual thyroid and associated epiglottitis. South Med J 81:1538, 1988. 7. Chanin LR, Greenberg LM: Pediatric upper airway obstruction due to ectopic thyroid: classification and case reports. Laryngoscope 98:422, 1988. 8. Kalan A, Tariq M: Lingual thyroid gland: clinical evaluation and comprehensive management. Ear Nose Throat J 78:340, 1999. 9. Maddern BR, Werkhaven J, McBride T: Lingual thyroid in a young infant presenting as airway obstruction: report of a case. Int J Pediatr Otorhinolaryngol 16:77, 1988.

10. Van der Wal N, Wiener JD, van der Waal I: Lingual thyroid. A clinical and postmortem study. Int J Oral Maxillofac Surg 15:431, 1986. 11. Koch CA, Picken C, Clement SC, et al.: Ectopic lingual thyroid: an otologic emergency beyond childhood. Thyroid 10:511, 2000. 12. Baughman RA: Lingual thyroid and lingual thyroglossal tract remnants— a clinical and histopathologic study with review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 34:781, 1972. 13. Soames JV: A review of the histology of the tongue in the region of the foramen cecum. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 36:220, 1973. 14. Williams ED, Toyn CE, Harach HR: The ultimobranchial gland and congenital thyroid abnormalities in man. J Pathol 159:135, 1989. 15. Orti E, Castells S, Qazi GH, et al.: Familial thyroid disease. Lingual thyroid in two siblings and hypoplasia of the thyroid lobe in a third. J Pediatr 78:675, 1971. 16. Kaplan M, Kauli R, Raviv U, et al.: Hypothyroidism due to ectopy in siblings. Am J Dis Child 131:1264, 1977. 17. Rosenberg T, Gilboa Y: Familial thyroid ectopy and hemiagenesis. Arch Dis Child 55:639, 1980. 18. Elidan J, Christin R, Gay I: Lingual thyroid, sensorineural hearing loss and mental retardation: a coincidental association? Laryngol Otol 97:539, 1983. 19. Wetke R: Struma baseos linguae og bilateral perceptiv ha¨rensaettelse. Ugeskr Laeger 151:2734, 1989. 20. Fish J, Moore RM: Ectopic thyroid tissue and ectopic carcinoma: a review of the literature and report of a case. Ann Surg 157:212, 1963. 21. Weider DJ, Parker W: Lingual thyroid. Ann Otol Rhinol Laryngol 86:841, 1977. 22. Potdar GG, Desai PB: Carcinoma of lingual thyroid. Laryngoscope 81:427, 1971. 23. Al-Samarrai AYI, Crankson SJ, Al-Jobori A: Autotransplantation of lingual thyroid into the neck. Br J Surg 75:287, 1988. 24. Klin B, Serour F, Fried K, et al.: Familial thyroglossal duct cyst. Clin Genet 43:101, 1993. 25. Castillo-Toucher S, Castillo P: Autosomal dominant inheritance of thyroglossal duct cyst. Clin Genet 45:111, 1994. 26. Hazarika P, Siddiqui SA, Pujary K, et al.: Dual ectopic thyroid. J Laryngol Otol 112:393, 1998. 27. Blandino A, Salvi L, Scribano E, et al.: MRI findings in thyroglossal duct cysts. Eur J Radiol 11:207, 1990. 28. Dolata J: Thyroglossal duct cyst in the mouth floor: an unusual location. Otolaryngol Head Neck Surg 110:580, 1994.

13.11 Choristoma of Tongue: Enterogenous Cyst of Tongue Definition

An enterogenous cyst of the tongue is a cystic mass containing gastric or intestinal mucosa located in the tongue. A choristoma is a mass of tissue that is histologically normal for a part of the body other than the site at which it is located. The term choristoma derives from the Greek choristos—separated—and is used to indicate displaced or heterotopic tissue. Diagnosis

Heterotopic islands of gastric mucosa or enterogenous cysts (often called intestinal duplications) have been found in the esophagus, small intestines, mediastinum, vitelline duct, pancreas, gallbladder, and Meckel diverticulum and are dealt with in Sections 25.3 and 35.4 of this volume. Here, we will deal only with oral cysts lined by gastric or intestinal epithelium. The choristomatic cyst may be entirely enclosed within the body of the tongue or oral floor, or it may communicate with the surface (Fig. 13-12). The cystic wall may be composed partly (or rarely totally)

Tongue

415

Fig. 13-12. Choristoma of the tongue. Left: newborn infant with large cystic tongue preventing closure of the jaws. Right: microscopic view of the cyst lined with nonciliated columnar epithelium. (Courtesy of Dr. P. Arcand, Hospital Sainte-Justine, Montreal.)

of gastric mucosa of the type seen in the body and fundus of the stomach. Both parietal and chief cells may be found. Rarely there is associated pancreatic tissue. Often there is a smooth muscle coat. Intestinal or even esophageal mucosa may line the cyst and, upon occasion, gastric and intestinal mucosa. Rarely cartilage and pancreatic tissue has been found.

Where there is connection of the cyst to the oral cavity, the tubelike structure descending into the cyst is lined by stratified squamous epithelium with sebaceous glands emptying into it. Several authors have described a lingual epithelial-lined tube surrounded by sebaceous glands but without gastric or intestinal epithelium. Sebaceous glands, as an isolated finding, may be found in the same area.6 Respiratory epithelium and/or dermoid cyst may also be found.7

Etiology and Distribution

Prognosis and Treatment

The origin of the heterotopic gastric or intestinal epithelium is not known. It may be derived from misplacement of embryonal rests of undifferentiated mucosa. The tongue arises from the floor of the pharynx in the region of the first three pharyngeal (branchial) arches. In the embryo of 3 to 4 weeks, the undifferentiated primitive endoderm lies adjacent to the anlage of the tongue. In the fusion of the lateral lingual tubercles to form the anterior two-thirds of the tongue, rests may become entrapped. Lingual cysts lined by stratified and/or ciliated or nonciliated columnar epithelium are probably related embryologically, since the primitive foregut epithelium has the ability to differentiate along all these lines. Among the 65 cases of gastric or enterogenous cysts of the tongue, there is at least a male to female sex predilection of 3:1. The anterior two-thirds of the tongue was involved in most cases, the oral floor, hypopharynx, and submandibular salivary gland in decreasing order.1–8 A similar lesion has been reported in the lip.1

Prognosis is excellent. Recurrence following surgical removal or CO2 laser is unknown. References (Choristoma of Tongue: Enterogenous Cyst of Tongue) 1. Gorlin RJ, Myers SL: Gastrointestinal cyst of the tongue: a possible duplication cyst of foregut origin? J Oral Maxillofac Surg 55:629, 1997. 2. Daley TD, Wysocki GP, Lovas GL, et al.: Heterotopic gastric cyst of the oral cavity. Head Neck Surg 7:168, 1984. 3. Wurster CF, Ossoff RH, Rao MS, et al.: Heterotopic gastric mucous of the tongue. Otolaryngol Head Neck Surg 93:92, 1985. 4. Arcand P, Granger J, Brochu P: Congenital dermoid cyst of the oral cavity with gastric choristoma. J Otolaryngol 17:219, 1988. 5. Kinoshita Y, Honma Y, Otuka T, et al.: Gastrointestinal mucosal cyst of the oral cavity. J Oral Maxillofac Surg 52:1203, 1994. 6. Kovero O: A sebaceous gland in the dorsal surface of the tongue. Int J Oral Maxillofac Surg 18:206, 1989.

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7. Mirchandani R, Sciubba J, Gloster ES: Congenital oral cyst with heterotopic gastrointestinal and respiratory mucosa. Arch Pathol Lab Med 113:1301, 1989. 8. Willner A, Feghali J, Bassila M: An enteric duplication cyst occurring in the anterior two-thirds of the tongue. Int J Pediatr Otorhinolaryngol 21:169, 1991.

13.12 Choristoma of Tongue: Epidermoid Cyst of Tongue An epidermoid cyst of the tongue is a cystic mass that is lined with squamous epithelium. There are a few examples of lingual cysts lined by nonkeratinizing stratified squamous epithelium. These cysts are to be differentiated from dermoid cysts of the oral floor.1–5 We believe that these cysts are related to enterogenous cysts and to those that are lined by respiratory epithelium, that is, by incorporation of pluripotential embryonal rests. Excellent prognosis follows simple surgical excision. References (Choristoma of Tongue: Epidermoid Cyst of Tongue) 1. Goldberg AF: Dermoid cyst of the tongue. J Oral Surg 23:649, 1965. 2. Quinn JH: Congenital epidermoid cyst of anterior half of tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 13:1283, 1960. 3. Valtonen H, Nuuitinen J, Karla J, et al.: Congenital dermoid cysts of the tongue. J Laryngol Otol 100:965, 1986. 4. Dahlman B, Livaditis A: Congenital cyst of anterior half of tongue. Z Kinderchir 29:244, 1980. 5. Correa MS, Fonoff Rde N, Ruschel HC, et al.: Lingual epidermal cyst: case report in an infant. Pediatr Dent 25:591, 2003.

13.13 Choristoma of Tongue: Cyst Lined with Respiratory Epithelium or Nonciliated Columnar Epithelium A cystic mass of the tongue that contains respiratory epithelium is another type of choristoma. As with the more numerous enterogenous cysts of the tongue, cysts lined by either ciliated or nonciliated epithelium are entirely enclosed within the body of the tongue. Like enterogenous cysts, these cysts represent incorporation of epithelial rests having the potential of differentiating into this form of epithelium. The same explanation may be given for those lingual cysts lined by nonkeratinized stratified squamous epithelium. It should be remembered that the primitive foregut gives rise to parts of both the digestive system and the respiratory tract.1–9,12 A combination dermoid and bronchogenic cyst has been noted, as have an odd cyst of the mandible with respiratory epithelium resulting from postsurgical implant, and a congenital cystadenoma.10–13 Prognosis is excellent. Simple surgical removal is curative. References (Choristoma of Tongue: Cyst Lined with Respiratory Epithelium or Nonciliated Columnar Epithelium) 1. Crawley DE, Miller RH: Enterocystoma of the head and neck. Otolaryngol Head Neck Surg 91:492, 1983. 2. Constantinides CG, Davies MOQ, Cywes S: Intralingual cysts of foregut origin. S Afr J Surg 20:227, 1982. 3. Kim YS, Ahn SK, Lee SH: Sublingual foregut cyst. J Dermatol 25:476, 1998. 4. Boue´ DR, Smith GA, Kraus HF: Lingual bronchogenic cyst in a child. Pediatr Pathol 14:201, 1994.

5. Manor Y, Buchner A, Peleg M, et al.: Lingual cyst with respiratory epithelium: an entity of debatable genesis. J Oral Maxillofac Surg 57:124, 1999. 6. Akerson H, Granger J, Brochu P: Congenital dermoid cyst of the oral cavity with gastric choristoma. J Oral Surg 32:117, 1974. 7. Arcand P, Granger J, Brochu P: Congenital dermoid cyst of the oral cavity with gastric choristoma. J Otolaryngol 17:219, 1988. 8. Ohama K, Asano S, Tsukahara Y, et al.: An unusual alimentary duplication cyst at the floor of the mouth—a proposal of new criteria for alimentary duplications. Z Kinderchir 41:45, 1986. 9. Dahlman B, Livaditis A: Congenital cyst of the anterior half of the tongue. Z Kinderchir 29:244, 1980. 10. Obiechina AE, Arotiba JT, Ogenbiyi T: Coexisting congenital sublingual dermoid and bronchogenic cyst. Br J Oral Maxillofac Surg 37:58, 1999. 11. Koutlas IG, Gillum RB, Harris MW, et al.: Surgical (implantation) cyst of the mandible with ciliated respiratory lining. J Oral Maxillofac Surg 60:324, 2002. 12. Naidoo LCD: Median lingual cyst: review of the literature and report of a case. J Oral Maxillofac Surg 55:172, 1997. 13. Kacker A, de Serres LM: Congenital cystadenoma of the tongue in a neonate: case report with review of the literature. Int J Pediatr Otorhinolaryngol 60:83, 2001.

13.14 Choristoma of Tongue: Brain Tissue in Tongue Extracranial localization of brain tissue is not rare, being most often found in ovarian and testicular teratomas. However, nonteratomatous extracranial brain tissue is relatively uncommon, most examples being nasal gliomas. A few have been found in the oropharynx or palate. None has involved extension to the cranial cavity. There are few convincing examples of heterotopic brain tissue in the tongue (Fig. 13-13).1–12 While heterotopic brain tissue may be viewed as teratomatous, only neuroectodermal elements are present. These consist of glia and ependymal cells. A more likely explanation is displacement of neural elements in the floor of the anterior oral pharynx prior to the closure of the secondary palate. This is compatible with the finding of palatal defect in those with ectopic brain tissue in the nasopharynx. Most have caused dysphagia. Prognosis is excellent. Simple surgical removal is curative.

Fig. 13-13. Choristoma of the tongue. Microscopic view of a lingual inclusion nodule showing heterotopic brain tissue (glial elements) near the overlying stratified squamous epithelium. (From Bychkov et al.1)

Tongue

References (Choristoma of Tongue: Brain Tissue in Tongue) 1. Bychkov V, Gatti WM, Fresco R: Tumor of the tongue containing heterotopic brain tissue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 66:71, 1988. 2. Knox R, Pratt M, Garvin AJ, et al.: Heterotopic lingual brain in the newborn. Arch Otolaryngol Head Neck Surg 115:630, 1989. 3. Ofodile FA, Aghadiuno PO, Oyemade O, et al.: Heterotopic brain in the tongue. Plast Reconstr Surg 69:120, 1982. 4. Landini G, Kitano M, Urago A, et al.: Heterotopic central neural tissue of the tongue. Int J Oral Maxillofac Surg 19:334, 1990. ¨ ber Glioma linguae. Frankfurt Z Pathol 26:214, 1922. 5. Peterer F: U 6. Yokahama S, Nakayama I, Yamashita H, et al.: Heterotopic brain of the tongue. Acta Pathol Jpn 36:1327, 1986. 7. Abdelsayed RA, Wetherington RW, Bent JP III, et al.: Glial choristoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:215, 1999. 8. Garcia-Prats MD, Rodriguez-Peralto JL, Carello R: Glial choristoma of the tongue. J Oral Maxillofac Surg 52:977, 1994. 9. Strome SE, McClatchey K, Kileny PR, et al.: Neonatal choristoma of the tongue containing glial tissue: diagnosis and surgical considerations. Int J Pediatr Otorhinolaryngol 33:265, 1995. 10. Halfpenny W, Odell EW, Robinson PD: Cystic and glial mixed hamartoma of the tongue. J Oral Pathol Med 30:368, 2001. 11. Wallach SG, Weiss PR, Llena JF: Glioma of the tongue. Plast Reconstr Surg 100:1245, 1997.

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12. Morita N, Harada M, Sakamato T: Congenital tumors of heterotopic nervous system tissue in the oral cavity. Report of two cases. J Oral Maxillofac Surg 51:1030, 1993.

13.15 Choristoma of Tongue: Chondroma and Osteoma Definition

Chondroma and osteoma are benign cartilaginous or bony growths of the tongue. Diagnosis

The lingual chondroma, in contrast to the osteoma, can arise any place within the tongue, but most often is on or adjacent to a lateral margin or is mid-dorsum (Fig. 13-14). They are usually hard and are characterized by slow growth and considerable mobility. Sizes have ranged from 0.3 to 4.5 cm. Differential diagnosis of choristomas located on the posterior dorsum includes lingual thyroid, hyperplastic lingual tonsils, and neoplasm of minor salivary glands. Those on the lateral border of the tongue embrace so-called traumatic fibroma, granular cell schwannoma (myoblastoma), and neural tumors, whereas those on the ventral surface include tumors of minor salivary gland

Fig. 13-14. Choristoma of the tongue. Left: two separate chondromas of the lateral border of the tongue of a 35-year-old woman. Unlike osteomas, chondromas can occur at any site on the tongue. Right: photomicrograph showing cartilaginous tissue with overlying connective tissue and epithelium. (From Landini et al.3)

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Craniofacial Structures

origin, mucous retention phenomena (mucoceles), lipomas, and various neural tumors. The reports of chondromas of the tongue by Ramachandran and Viswanathan1 and by Plessier and Leroux-Robert2 appear to be examples of choristomas associated with oral-facial-digital syndrome type 1. Etiology and Distribution

Branchial arch cartilages related to the anterior two-thirds of the tongue are derived from Meckel cartilage. Elastic cartilage is found in the epiglottis and in some laryngeal cartilages. Since Landini et al.3 found elastic cartilage, the origin of the choristoma might be from proliferation of ectopic rests of elastic cartilaginous tissue probably from (a) the larynx or (b) proliferation of pluripotential mesenchymal cells of the tongue. While Gentscheff 4 found approximately 30% of both children and adults to have cartilage rests in the tongue on postmortem examination; van der Wal and van der Waal5 found neither bone nor cartilage in 113 autopsies. Cartilaginous tumors of the tongue are rare, there being no more than 40 reports. Of these, about 65% were composed of pure cartilage, the rest being osteocartilaginous.6–11,17 About 50 cases of osteoma of the tongue have been reported.5,10,12–16 Although presenting most often in the 3rd to 4th decades of life, the lingual osteoma is clearly a choristoma, not a neoplasm (Fig. 13-15). In 65%, it arises at or around the foramen cecum. About 25% arise in the lateral margins of the tongue. There is at least a female to male predilection of 3:1. Sizes have ranged from 0.5 to 2.0 cm.

¨ ber Skelettreste in der menschlichen Zunge. Virchows 4. Gentscheff C: U Arch [Anat] 293:129, 1934. 5. Van der Wal N, van der Waal I: Osteoma or chondroma of the tongue: a clinical and postmortem study. Int J Oral Maxillofac Surg 16:713, 1987. 6. Piattelli A, Fioroni M, Orsini G, et al.: Osteochondromatous choristoma of the tongue. J Oral Maxillofac Surg 58:1320, 2000. 7. Wesley RK, Zielinski RJ: Osteochondroma of the tongue. Clinical and histopathologic considerations. J Oral Surg 36:59, 1978. 8. Weitzner S, Stimson PG, McClendon JL: Cartilaginous choristoma of the tongue. J Oral Maxillofac Surg 45:185, 1987. 9. Segal K, Katsav Y, Sidi J, et al.: Chondroma of the tongue: report of two cases. Ann Otol Rhinol Laryngol 93:271, 1984. 10. Tohill MJ, Green JG, Cohen DM: Intraoral osseous and cartilaginous choristomas: report of three cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 63:506, 1987. 11. Yasuoka T, Handa Y, Watanabe F, et al.: Chondroma of the tongue. J Maxillofac Surg 12:188, 1984. 12. Main DMG: Osseous polyp of the tongue: osteoma or choristoma? Br Dent J 156:285, 1984. 13. Krolls SO, Jacoway JR, Alexander WN: Osseous choristomas (osteomas) of intraoral soft tissues. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 32:588, 1971. 14. Engel P, Cherrick HM: Extraosseous osteomas of the tongue. J Oral Med 31:99, 1976. 15. Ishikawa M, Mizukoshi T, Notani K, et al.: Osseous choristoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 76:561, 1993. 16. Vered M, Lustig JP, Buchner A: Lingual osteomas: a debatable entity. J Oral Maxillofac Surg 56:9, 1998. 17. Mosqueda-Taylor A, Gonzalez-Guevara M, de la Piedre-Garza JM, et al.: Cartilagenous choristomas of the tongue. J Oral Path Med 27: 283, 1998.

Prognosis and Treatment

Surgical removal ensures complete cure. Recurrence is unknown. References (Choristoma of Tongue: Chondroma and Osteoma) 1. Ramachandran K, Viswanathan R: Chondroma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 25:487, 1968. 2. Plessier P, Leroux-Robert J: Dysembryoplasies linguales multiples a contenu cartilagineux. Ann Anat Pathol 9:432, 1932. 3. Landini G, Kitano M, Urago A, et al.: Chondroma and osteochondroma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 68:206, 1989.

13.16 Congenital Dermoid Cyst A congenital dermoid cyst is a cyst of the tongue in which the cavity is lined by stratified squamous epithelium with sebaceous epithelium and/or sweat glands in the cyst wall. Very few examples are known of such cysts in the anterior tongue (Fig. 13-16). Of all dermoid cysts, about 7% occur in the head and neck, with most examples involving the oral floor. Although related, they are not further considered in this section.

Fig. 13-15. Choristoma of the tongue. Left: osteoma of the tongue occurring near the foramen cecum, as is the usual case. Right: photomicrograph of lingual osteoma showing thin epithelial and connective tissue cover over a well-rounded and highly mature bony nodule. (From van der Wal and van der Waal.5)

Tongue

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Fig. 13-16. Dermoid cyst of tongue. Left: cystic tongue mass lined with keratinizing squamous epithelium. Right: sebaceous glands within the cyst wall. (From Flom et al.1)

As in the case of dermoids of the oral floor, it has been assumed by most investigators that the lingual dermoid arises from entrapment of epithelium during fusion of the first branchial arches. The anterior tongue arises from two lateral lingual tubercles that fuse and incorporate an unpaired tubercle.1–6 References (Congenital Dermoid Cyst) 1. Flom GS, Donovan TJ, Landgraf JR: Congenital dermoid cyst of the anterior tongue. Otolaryngol Head Neck Surg 100:602, 1989. 2. Mathur SK, Meron PRN: Dermoid cyst of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 50:217, 1980. 3. Velcek FT, Klotz DH, Hill CH, et al.: Tongue lesions in children. J Pediatr Surg 14:238, 1979. 4. Smolansky SJ, Cardinal JP, Saffos RO: Lingual dermoid cysts. Ear Nose Throat J 58:240, 1979. 5. Ruggieri M, Tine A, Rizzo R, et al.: Lateral dermoid cyst of the tongue. Int J Pediatr Otorhinolaryngol 30:79, 1994. 6. Reddy VS, Radhakrishna K, Rao PLNG: Lingual dermoid. J Pediatr Surg 26:1389, 1991.

13.17 Hamartoma: Lymphangioma of the Tongue Lymphangioma of the tongue consists of benign nodular masses of clear lymph-filled vesicles of various sizes elevated above the surface of the tongue. Some rupture, and others become papil-

lomatous, somewhat resembling granulation tissue. One can often see capillary tufts within the vesicles. Hamartoma refers to a benign, oddly arranged focal collection of histologically normal tissue indigenous to an area. Presenting very early in infancy, lymphangiomas usually grow slowly and remain essentially quiescent. Some are localized but more often are diffuse and involve the dorsal rather than the ventral surface. Involvement may be unilateral or bilateral. Some lesions bleed following minor trauma. There is no sex predilection. In about 40%, the lymphangioma may involve more than half the tongue, resembling granulation tissue (Fig. 13-17). The anterior two-thirds of the tongue is usually the preferred site, but it may involve other parts of the oral cavity (lip, cheeks, oral floor) or extend to the epiglottis or mediastinum. In about 5%, the lymphangioma is associated with cystic hygroma. Deeper examples can be complicated by glossitis, especially those that extend beyond the lips, in which cases the tongue appears dry, cracked or fissured, and hemorrhagic.1–6 Trauma and/or infection may suddenly cause enlargement (macroglossia) and severe pain. Occasionally there is associated fever. The macroglossia may make for airway obstruction, difficult mastication, drooling, dysphagia, deformity of mandible, and altered speech. Macroglossia may occur on either a permanent or an intermittent basis. Microscopically, the tumor consists of endothelial-lined cystic spaces filled with lymph, a few lymphocytes, and red blood cells.

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ence with speech, dental occlusion, and mastication. Unlike cutaneous angiomas, involution of the lingual hemangioma does not occur.2–8 We could find little to document frequency in infancy. Some series indicate that congenital angiomas of the tongue are relatively common lesions, others that they are rare. We hold the latter view. Depending on size, location, and type of involved tissue, resection or elimination of the hemangioma can be simple or quite challenging. For small, superficial lesions, argon laser therapy is quite effective. For larger lesions, the CO2 laser has been employed. Embolization has been employed for nonresectable hemangiomas or in preparation for surgery to lessen operative bleeding.2 Intralesional injection with steroids is less effective. Fig. 13-17. Superficial lymphangioma causing macroglossia. Note densely packed yellowish, red, or bluish-black vesicular elements more marked on distal portion of tongue. (From Brandrup.6)

The spaces are located within a stroma of thin fibrous connective tissue. It should be remembered that macroglossia is a nonspecific finding and can be associated with various congenital cysts or tumors, congenital anomalies (lingual thyroid), congenital hypothyroidism, and Beckwith-Wiedemann syndrome or can be acquired early in infancy (e.g., glycogen storage disease type II, GM1 gangliosidosis, Hurler syndrome). Surgery and/or laser photocoagulation are the treatments of choice. Radiation therapy and electrodessication are not recommended. References (Hamartoma: Lymphangioma of the Tongue) 1. Balakrishnan A, Bailey CM: Lymphangioma of the tongue. A review of pathogenesis, treatment and the use of surface laser photocoagulation. J Laryngol Otol 105:924, 1991. 2. Litzow TJ, Lash H: Lymphangiomas of the tongue. Proc Mayo Clin 36:229, 1961. 3. White MA: Lymphangioma of the tongue. ASDC J Dent Child 54:280, 1987. 4. Rice JP, Carson SH: A case report of lingual lymphangioma presenting as recurrent massive tongue enlargement. Clin Pediatr 24:47, 1985. 5. Postlethwaite KR: Lymphangiomas of the tongue. Br J Maxillofac Surg 24:63, 1986. 6. Brandrup F: Lymphangioma circumscriptum of the tongue. Dermatologica 153:191, 1976.

13.18 Hamartoma of the Tongue: Hemangioma Hemangiomas of the tongue are benign vascular tumors and may be capillary, cavernous, venous, or mixed with lymphangioma.1 They occur in various sizes, as small as a pea or as large as a child’s fist. They may be flat or rounded, red-purple to deep red, and superficial or deep, extending into the tongue muscle. Some seem to stop abruptly at the midline. Most become evident in the newborn period and grow pari passu with the child. Technically, one should include telangiectasias (hereditary hemorrhagic telangiectasia) and Sturge-Weber syndrome. Microscopically, there is a proliferation of endothelial-lined spaces that contain erythrocytes. In those that are superficial, trauma may produce bleeding or ulceration. With marked tongue enlargement, there is often interfer-

References (Hamartoma of the Tongue: Hemangioma) 1. Giunta J, Shklar G, McCarthy PL: Diffuse angiomas of the tongue. Arch Otolaryngol Head Neck Surg 93:83, 1971. 2. Brown DA, Smith JD: Late complication of congenital hemangiomas of the tongue. Head Neck Surg 9:299, 1987. 3. Vankova´ B, Barinka L: Haemangiomas of the tongue. Acta Chir Plast 29:242, 1987. 4. Rieblova´ V: Haemangiomas. Acta Chir Plast 24:219, 1982. 5. Gardner AF: Tumor and tumor-like lesions of the oral cavity in infants and children. J Dent Child 31:42, 1964. 6. Parkin JL, Dixon JA: Argon laser treatment of head and neck vascular lesions. Otolaryngol Head Neck Surg 93:211, 1985. 7. Shklar G, Meyer J: Vascular tumors of the mouth and jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 19:335, 1965. 8. Velcek FT, Klatz DH, Hill CH: Tongue lesions in children. J Pediatr Surg 14:238, 1979.

13.19 Hamartoma of the Tongue: Mixed Type (Mesenchymoma) A mixed-type hamartoma of the tongue is a benign tumor of the tongue that contains an oddly arranged and focal overgrowth of mixed tissue elements indigenous to the area.1–7 The hamartoma appears as a spherical mass covered by normal oral mucosa. It has limited growth capacity, does not invade surrounding tissues, and may arise in any area of the body. The color reflects the specific composition (mucous salivary glands, adipose tissue, nerves, smooth muscle, connective tissue, blood vessels) of the hamartoma. It is difficult to separate this lesion from the so-called benign mesenchymoma of the tongue.12 An osteolipoma is an example.8 Most occurrences have been found incidentally, often due to interference with feeding, and most have been located at the base of the tongue in the foramen cecum area.1–6,9,10,13,15 Exceptions to this are the one or more lingual hamartomas in several of the oralfacial-digital syndromes. The child described by Ishii et al.7 probably had oral-facial-digital syndrome type 1 (OFD1). The female child with an erroneous diagnosis of ectrodactyly-ectodermal dysplasia syndrome surely had OFD1.11 Lipoma of the tongue is rarely congenital14 but occurs principally near the surface in the mid-dorsum. All mixed type hamartomas have been successfully removed by surgical means. References (Hamartoma of the Tongue: Mixed Type) 1. Demuth RJ, Johns DF: Recurrent aspiration pneumonitis in a cleft palate child with hamartoma of the tongue. Cleft Palate J 18:299, 1979.

Tongue 2. Freedman PD, Chou MD, Diner H, et al.: Benign mesenchymoma of the oral soft tissues. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 53:606, 1982. 3. Herzog S, Bressman J, Giglio JA: Tongue mass in an infant. J Oral Maxillofac Surg 44:463, 1986. 4. Tashihara J, Oda A, Takahashi Y, et al.: Fibrous hamartoma of the tongue. Int J Pediatr Otorhinolaryngol 33:17, 1995. 5. Ide F, Shimoyama T, Horie N: Angiomyolipomatous hamartoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85:581, 1998. 6. Takimoto T, Yoshizaki T, Umeda R: Hamartoma of the tongue. Int J Pediatr Otorhinolaryngol 18:157, 1989. 7. Ishii P, Takemori S, Suzuki J: Hamartoma of the tongue. Arch Otolaryngol 88:171, 1968. 8. Piattelli A, Fioroni M, Iezzi G, et al.: Osteolipoma of the tongue. Oral Oncol 37:468, 2001. 9. Kobayashi A, Amagasa T, Okada N: Leiomyomatous hamartoma of the tongue. J Oral Maxillofac Surg 59:337, 2001. 10. Goldsmith P, Soames JV, Meikle D: Leiomyomatous hamartoma of the posterior tongue. J Laryngol Otol 109:1190, 1995. 11. Hanna R, Argenyi ZB, Benda JA: Hamartoma of the tongue in an infant with a primary diagnosis of ectrodactyly-ectodermal dysplasia– cleft lip and palate syndrome. J Cutan Pathol 21:173, 1994. 12. Smith BC, Ellis GL, Meis-Kindblom JM, et al.: Ectomesenchymal chondromyxoid tumor of the anterior tongue. Nineteen cases of a new clinicopathologic entity. Am J Surg Pathol 19:519, 1995. 13. Owen G, Berry T, Bicknell P: Hamartoma of the tongue. J Laryngol Otol 107:363, 1993. 14. Yonezawa H, Harada K, Enomoto S: Congenital lipomatoid mass of the tongue. Int J Oral Maxillofac Surg 29:138, 2000. 15. Zalal GH, Patterson K, Cotton RT: Congenital tumors of the dorsum of the tongue. Int J Pediatr Otorhinolaryngol 28:219, 1994.

13.20 Congenital Teratoma A congenital teratoma of the tongue is a tumor that contains elements from all three germ layers. Most often immature neuroectodermal present; however, cartilage, bone, skin, cystlike structures lined by stratified squamous epithelium, pseudostratified ciliated columnar epithelium, intestinal epithelium, muscle, and nerve have been found. These congenital growths, unlike those of the ovary and/or testicle, appear to be uniformly benign. We have tabulated less than a dozen examples. Teratoma, in a few cases, has been within the body of the tongue, but occasionally has been attached to the base of the tongue by a pedicle or to the side of the tongue. They may be so large as to fill the mouth completely (Fig. 13-18). There does not appear to be any sex predilection. Although teratomas are thought to arise in the developing blastomere, some cells being displaced or separated, it is possible that normal muscle-forming cells migrating from the occipital myotomes have been accompanied by neuroectodermal and other cells. In a few examples, a second teratoma has been found in the proximate area.1–8 There is excellent prognosis following surgical excision. In spite of the rule (regarding ovarian teratomas) that the greater the immaturity and amount of neuroepithelium, the poorer the prognosis, there is overwhelming evidence that lingual teratomas are not malignant. Elevated carcinoembryonic antigen and alpha-fetoprotein levels have been found. In some cases urinary vanillyl mandelic acid and dopamine levels have also been increased.

421

Fig. 13-18. Massive tongue enlargement caused by a teratoma. (Courtesy of Dr. A. E. Rodin, Xenia, OH.)

References (Congenital Teratoma) 1. Rodin AE, Singula P: Teratoma of the tongue at birth. Pediatr Pathol 3:291, 1985. 2. Ashley JV, Shafer AD: Teratoma of the tongue in a newborn. Cleve Clin Q 50:34, 1983. 3. Lalwani AK, Engel TL: Teratoma of the tongue: a case report and review of the literature. Int J Pediatr Otorhinolaryngol 24:261, 1992. 4. Grier EA, MacNerland RH: Benign teratoma of the tongue. Ill Med J 132:43, 1967. 5. Mahour GH, Landing BH, Wooley MM: Teratomas in children: clinicopathologic studies in 133 children. Z Kinderchir 23:365, 1978. 6. Wood GH, Williams JE: Rare tumor of the tongue in a newborn child. Eye Ear Nose Throat Monthly 31:83, 1952. 7. Miller AP, Owens JB Jr: Teratoma of the tongue. Cancer 19:1583, 1966. 8. Uchida K, Urata H, Suzuki H: Teratoma of the tongue in neonates: report of a case and review of the literature. Pediatr Surg Int 14:79, 1998.

13.21 Abnormal Tongue Movements and Excessive Mobility of the Tongue Variations in the voluntary movement and configuration of the tongue are possible (Fig. 13-19). The ability to curl up the lateral borders of the tongue is called tongue-tubing or tongue-curling, whereas curling the lateral borders of the tongue downward is inverse tongue-tubing. Tongue-upfolding is the capacity to extend the tongue beyond the lips and to fold the tip back upon the body of the tongue without the aid of the teeth.19 Tongue-rolling is the ability to roll or twist the tongue from side to side. To trefoil the tongue refers to the ability to deform the anterior tongue at will into a cloverleaf

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Craniofacial Structures

Fig. 13-19. Lingual calesthenics. A. Tongue-tubing, a trait seen in 65% of the populace. B. Ability to flip-flop the tongue is found in 35%. C. About 7% are able to touch the nose with the tip of the tongue. D. Hyperextensible tongue seen in 50% of those with Ehlers-Danlos

syndrome (Gorlin sign). E. Tongue-upfolding. This trait, accomplished without the use of the teeth, is relatively rare. F. Trefoiling of the tongue. G. Inverse tongue-tubing. H. Placing the tongue into the nasopharynx.

pattern. Excessive mobility refers to the ability to place the tip of the tongue behind the soft palate into the nasopharynx. Another ‘‘talent of mobility’’ is that of touching the tip of the nose with the tip of the tongue or, still further, extending it into the nostrils. Tongue-tubing or tongue-curling can be done by about 65– 70% of the white population.1 Several authors have indicated that this ability does not have single gene inheritance.2–4 Discordance in identical twins has varied from 15–20% in various studies.2,3 To the best of our knowledge, there has been no study on the epidemiology of inverse tongue-tubing. Tongue-upfolding has been found in 2–3% of the population.5–8 Whitney9 reported that about

1.5% had the ability to upfold the tongue with the aid of the teeth, but only one per 600 individuals could do this to the extended tongue. Bat-Miriam,10 studying Ethiopian tribes, noted that 3–10% could upfold the tongue. While this trait has been seen in several generations, most cases are sporadic and we doubt single gene inheritance.11 Tongue-rolling can be accomplished by about 35% of the population. It, too, has occurred in several generations, but the vast majority of cases are sporadic. Martin18 suggested that there was no genetic basis for tongue-rolling. Approximately 2.5% can trefoil the tongue, according to Gahres.12 This is far more common than has been found in our experience. We have noted

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11. Hirschhorn HH: Transmission and learning of tongue gymnastic ability. Am J Phys Anthropol 32:451, 1970. 12. Gahres EE: Tongue rolling and tongue folding and other hereditary movements of the tongue. J Hered 43:221, 1952. 13. Hoch MO: Clover-leaf tongues. J Hered 40:132, 1949. 14. Matzker J: Abnorme Beweglichkeit der Zunge. HNO 14:181, 1977. 15. Stuart-Low W: Case showing an unusually large and long tongue. Proc R Soc Med (Laryngol Sect) 2:111, 1909. 16. Cinar F, Uzun L, Ugur MB, et al.: An unusual movement of the tongue. Plast Reconstr Surg 113:773, 2004. 17. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 18. Martin NG: No evidence for a genetic basis of tongue rolling or hand clasping. J Hered 66:179, 1975. 19. Cohen MM Jr: Lingual lesions and liabilities. Am J Med Genet 47:762, 1993. 20. Hennekam RCM: Lingua cochlearis in multiple pterygium syndrome. Am J Med Genet 47:761, 1993.

Fig. 13-20. Pigmented fungiform papillae.

this ability in siblings and in several generations, but, again, most cases are sporadic.8–12 There are no data available concerning the ability to place the tip of the tongue into the nasopharynx, but it is rare.13–16 The ability to touch the tip of the nose with the tongue is manifest in about 7% of the white population but apparently occurs with considerable frequency (approximately 50%) in those with Ehlers-Danlos syndrome type I (Gorlin sign).17 Lingua cochlearis refers to a spoon-shaped alteration in the tongue tip in multiple pterygium syndrome.20 References (Abnormal Tongue Movements and Excessive Mobility of the Tongue) 1. Urbanowski A, Wilson J: Tongue curling. J Hered 38:365, 1947. 2. Matlock P: Identical twins, discordant in tongue rolling. J Hered 43:24, 1952. 3. Reedy JJ, Szczes T, Downs TD: Tongue rolling among twins. J Hered 62:125, 1971. ¨ ber die Fa¨higkeit, die Zunge um die La¨ngsachse zu rollen. 4. Vogel F: U Acta Genet Med Gemellol 6:225, 1957. 5. Hsu TC: Tongue upfolding (a newly recognized hereditary character in man). J Hered 39:187, 1948. 6. Lee JW: Tongue-folding and tongue rolling in an American Negro population sample. J Hered 46:289, 1955. 7. Lee JW: A study of the inheritance of certain tongue characteristics in 72 pairs of Negro twins. J Hered 47:17, 1956. 8. Wooldridge HR: Relationship of marked mandibular arch symmetry and the ability to perform certain unusual tongue movements. Am J Orthodont 44:65, 1958. 9. Whitney DD: Tongue tip overfolding. J Hered 40:19, 1949. 10. Bat-Miriam M: A survey of some genetical characters in Ethiopian tribes. IX. Tongue folding and tongue rolling. Am J Phys Anthropol 20:198, 1962.

13.22 Pigmented Fungiform Papillae and Other Lingual Pigmentations Pigmented fungiform papillae of the tongue are relatively common in African Americans. They have rarely been noted in Asians and Whites (Fig. 13-20).1–3,6,7 Microscopic sections have shown multiple melanophages in the upper lamina propriae of the tongue. Rarely the pigmentation may be more diffuse,4,5 unrelated to Peutz-Jeghers syndrome, Addison disease, or minocycline therapy. Holzwanger et al.1 noted that 25–30% of black people have pigmented papillae versus 1% of white people. References (Pigmented Fungiform Papillae and Other Lingual Pigmentations) 1. Holzwanger JM, Rudolph RI, Heaton CL: Pigmented fungiform papillae of the tongue, a common variant of oral pigmentation. Int J Dermatol 13:403, 1974. 2. Kaplan BS, Hurley HJ: Prominent pigmented papillae of the tongue. Arch Dermatol 95:394, 1967. 3. Isogai Z, Kanzaki T: Pigmented fungiform papillae of the tongue. J Am Acad Dermatol 29:489, 1993. 4. Menni S, Boccardi D: Melanotic macules of the tongue in a newborn. J Am Acad Derm 44:1048, 2001. 5. Anavi Y, Mintz S: Unusual physiologic melanin pigmentation of the tongue. Pediatr Dermatol 9:123, 1992. 6. Ahn SK, Chung J, Lee SH, et al.: Prominent pigmented fungiform papillae of the tongue. Jap J Clin Dermatol 47:1009, 1993. 7. Oh CK, Kim MB, Jang HS, et al.: Pigmented fungiform papillae of the tongue in an Asian male. J Dermatol 27:350, 2000.

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14 Teeth Rena N. D’Souza, Hitesh Kapadia, and Alexandre R. Vieira

T

he presence of a complete and functional dentition is critical to the overall health and well-being of an individual. In fact, the size, shape, color, and alignment of teeth are determining characteristics of facial expression and impart uniqueness to each human. Individuals who lack a full complement of teeth as a result of disease, trauma, or genetic disorders often endure emotional hardship due to compromised facial aesthetics. Costly and sometimes complex dental care is needed to restore normal structure and function to dentition. Since teeth are critical for the proper mastication of complex food substances, inefficient grinding compromises digestion by salivary enzymes and may result in digestive problems. As seen in older individuals who have lost teeth to periodontal disease or dental caries, speech is often affected, as is vertical dimension and facial aesthetics. Anthropologists and paleontologists rely on the importance of teeth in evolution because they are the best-preserved organs in fossils. In fact, studies of fossilized teeth have revealed much about the behavior and feeding habits of humans and their ancestors. The presence of enamel, the hardest substance in the human body, on the crowns of teeth makes them indestructible and valuable resources for forensics. For developmental biologists, the forming tooth organ is a useful paradigm for organogenesis, offering a means to study how shape, size, and position are determined and how specialized mineralized tissues are formed. Notwithstanding these critical functions, the importance and uniqueness of teeth are frequently overlooked by health professionals. This chapter reviews the physical and histologic features of normal dentition and describes classic and modern literature about the cellular and molecular processes that result in a fully formed tooth. As a logical progression, disorders that affect the patterning of dentition, in particular those involving changes in the number, size, and shape of teeth, will be outlined. This will be followed by an overview of disorders that affect the mineralized matrices of teeth, namely enamel, dentin, and cementum. Since the development of dentition is not complete until teeth emerge from within their bony crypts into the oral cavity, it is justifiable to include a section on normal and abnormal tooth eruption.

The authors acknowledge the important contribution of Ronald J. Jorgenson to the first edition of this text, which provided the basis for this chapter.

During the past decade, several advances in understanding the molecular biology and genetics of tooth development have been made and genes that are responsible for the major disorders of dentition have been identified. General Description

In humans, teeth represent approximately 20–25% of the total surface area of the oral cavity or mouth. In contrast to the monophyodont dentition present in rodents, human dentition is a succedaneous dentition with two sets of teeth: a deciduous set that predominates from ages 6 months to 6 years and a permanent set that predominates from age 12 years onward. Between ages 6 and 12 years, teeth of both sets can be present and the dentition is said to be mixed. The word deciduous refers to the fact that the teeth exfoliate with time; primary is an acceptable alternative to deciduous and indicates the sequence of eruption. The word permanent refers to the lifelong status of the ‘‘adult’’ teeth. An acceptable alternative is secondary to reflect their place in the sequence. Teeth are described in terms that reflect their position, function, or morphology (Fig. 14-1). The shape of each tooth is closely adapted to its function. The incisors are shovel-shaped with thin, flat edges that are used for biting or incising. The canines are used for tearing tough food. The premolars with their sharp cusps are used for shredding. The molars, each with four to five flat cusps, are used for grinding the shredded food passed backward from the premolars. For heterodont mammalian dentition, the general dental formula in each quadrant is three incisors, one canine, four premolars, and three molars. In humans, one incisor and two premolars have been lost, while rodents have lost two incisors, the canine and premolars.1 There are 20 deciduous teeth and 32 permanent teeth (Fig. 14-1). The deciduous complement consists of two incisors, one canine, and two molars in each quadrant (a quadrant is half an arch). The permanent complement consists of two incisors, one canine, two premolars, and three molars in each quadrant. In ordinary circumstances, the deciduous teeth are smaller than permanent teeth that will eventually replace them and are consequently widely spaced. Permanent teeth that replace deciduous teeth are said to be succedaneous (ensuing): the premolars succeed the deciduous molars; the permanent molars, having no predecessors, are correctly termed nonsuccedaneous teeth. 425

426

Craniofacial Structures

old. Alternatively, the observations that point to mutations in two independent genes, MSX1 and PAX9, which both dominantly affect premolar and molar formation, suggests that each tooth family or ‘‘clone’’ may require a different genetic code or combination of genes during development. This selectivity may be best explained by the clone theory. Parts of Teeth

Fig. 14-1. Orientation of teeth in dental arches.

Patterning of Dentition

From an evolutionary genetic standpoint, mammalian dentition is considered a segmental or sequentially arranged organ system whose members are arrayed in specific number and in regionally differentiated locations along the linear axes of the jaws.2 For developmental biologists, the model of tooth development offers a useful paradigm for studying patterning and morphogenesis or the determination of position, size, shape, and number. Much of our understanding about the patterning of dentition comes from mouse studies. The use of transgenesis, gene targeting, expression analyses, and functional in vivo and in vitro tooth recombinations as well as bead implantation assays has greatly increased our understanding about the molecular mechanisms that influence the patterning of murine dentition. While there is good left–right symmetry in human dentition, anterior–posterior and buccal–lingual symmetries are highly varied, suggesting a patterning gradient along these axes. Two theories have been proposed to explain the patterning of dentition. The field theory assumes that all tooth primordia are initially identical and that varying concentrations of chemical morphogens create gradients of patterning in different regions of the jaws. The finding of an anterior–posterior (A–P) gradient of retinoic acid concentration in the developing murine mandible lends some support to the field theory.3 An alternate theory, the clone model, proposes that each family of teeth arises from a distinct group of neural crest stem cells that retain positional identity as they migrate to the arches.4 The role of Hox genes in controlling positional information along the A–P axis in Drosophila and other vertebrates has lent credibility to the clone theory.5 Furthermore, it has been shown that the final position of odontogenic mesenchyme in the maxilla and mandible is determined by the original position of these cells in the neural crest as well as the time when the cells migrate out of the crest, thus supporting the clone theory over the field theory.6 As will be evident from the following discussion on tooth agenesis, it is unclear which of the two theories explains some of the more consistent patterns of human tooth agenesis. For example, missing lateral incisors are often associated with second premolar agenesis, suggesting that teeth that are last to develop in a given morphogenetic field may fall below a developmental thresh-

Teeth are composed of crowns and roots. The crowns comprise the exposed portions of the teeth and are covered by enamel. Under the enamel is a thick layer of dentin and a soft central core, the pulp chamber. The terminology used to identify different surfaces and structural components of teeth is described in Fig. 14-2. Enamel is the hardest calcified structure in vertebrates and covers the crowns of the teeth. It varies from 2 to 3 mm in thickness over the bulkiest parts of the cusp to a knife-edge thickness at the cementoenamel junction. Because enamel is acellular, it is nonvital and cannot regenerate except by superficial remineralization. The latter happens as a result of an exchange of mineral ions that occurs on the surface of enamel. Enamel varies from translucent to yellowgrey in color, but most of the hue of enamel-covered crowns is the result of the dentin being visible through the enamel. Teeth that have a thin layer of enamel appear more yellow, to reflect the color of dentin. This is common in individuals of Asian descent. Enamel formation is described conceptually as occurring in three phases. The secretory phase is marked by the deposition of an organic matrix by ameloblasts. At this stage, these cells are called presecretory and secretory ameloblasts. They are elongated cells that show nuclear polarity and secretory organelles.7,8 In the second phase of mineralization, nucleation or crystal formation occurs. As crystals elongate the final phase of maturation of enamel matrix occurs. At this stage, the organic matrix, in particular amelogenin, is degraded by proteinases. The degradative products of amelogenins are reabsorbed back into the ameloblasts.9,10 The principal classes of enamel matrix proteins are amelogenin, ameloblastin, enamel, tuftelin, a metalloproteinase called enamelysin (MMP-20), a serine proteinase called enamel matrix serine proteinase 1 (EMPSP1), and traces of dentin sialophosphoprotein (DSPP). As will be discussed later, enamel malformations involve mutations in genes that encode some of these matrix proteins.11 The major constituents of enamel are rods, rod sheaths, and an interrod substance. The rods consist of networks of organic particles around which apatite crystals are coalesced. Each rod is surrounded by a sheath that is less highly calcified than the rod proper. The nature of the interrod structure is not well-known, although it is well-accepted that this area of enamel facilitates the spread of dental caries toward dentin.8,12 The dentin constitutes the bulk of the tooth. It is a living tissue that has many of the physical and chemical properties of

Fig. 14-2. Component parts of teeth.

Teeth

bone. The dentin is yellow in color and far less brittle than the enamel. The formation of dentin follows the same principles that guide the formation of other hard connective tissues in the body, namely cementum and bone. The first requirement is the presence of highly specialized cells that can synthesize and secrete a highly specialized organic matrix that is capable of accepting biologic apatite or mineral.13 Other prerequisites include a rich vascular supply and high levels of the enzyme alkaline phosphatase. Dentinforming cells or odontoblasts begin to secrete a predentin extracellular matrix (ECM). They retreat in a pulpal direction but remain connected to the matrix as it is being formed through cell extensions called odontoblastic processes. The organic predentin matrix is converted into a mineralized layer of dentin through a highly complex process that begins some distance away from the odontoblastic cell bodies. The outermost layer of dentin, which is the first layer to be formed, is the mantle dentin; the remainder is the circumpulpal dentin.14,15 Excellent reviews by Linde and Goldberg16 and Butler and Ritchie17 detail the composition of dentin matrix and the process of dentinogenesis. The organic phase of dentin is composed of proteins, proteoglycans, lipids, various growth factors, and water. Among the proteins, collagen is the most abundant and offers a fibrous matrix for the deposition of carbonate apatite crystals. The collagens that are found in dentin are primarily type I collagen with trace amounts of type V collagen and some type I collagen trimer. The importance of type I collagen as a key structural component of dentin matrix is illustrated by the inherited dentin disorder called dentinogenesis imperfecta (DGI) that is discussed later in this chapter. An important class of dentin matrix proteins is the noncollagenous proteins (NCPs).17 The dentin-specific NCPs are dentin phosphoproteins (DPP) or phosphophoryns and dentin sialoprotein (DSP). After type I collagen, DPP is the next most abundant of dentin matrix proteins and represents almost 50% of the dentin ECM. DPP is a polyionic macromolecule that is rich in phosphoserine and aspartic acid. Its high affinity for type I collagen as well as calcium makes it a strong candidate for the initiation of dentin mineralization. DSP accounts for 5–8% of the dentin matrix and has a relatively high sialic acid and carbohydrate content. Its role in dentin mineralization is unclear at the present time. For several years it was believed that DSP and DPP were two independent proteins encoded by different genes. DPP and DSP are specific cleavage products of a larger precursor protein that was translated from one large transcript.18 This single gene encoding for DSP and DPP is named dentin sialophosphoprotein (DSPP). The importance of DSPP in dentin formation was recently underscored with the discovery that mutations in this gene are responsible for the underlying dentinal defects seen in dentinogenesis imperfecta (DGI).19,20 The DGI locus maps to human chromosome 4 within q13-21 where several other dentin ECM genes reside. A second category of NCPs with Ca-binding properties is classified as mineralized tissue-specific because they are found in all the calcified connective tissues, namely dentin, bone, and cementum. These include osteocalcin (OC) and bone sialoprotein (BSP). A serine-rich phosphoprotein called dentin matrix protein 1 (Dmp-1), whose expression was first described as being restricted to odontoblasts,21 was later shown to be expressed by osteoblasts and cementoblasts22,23 and by brain cells. Other NCPs in this group include osteopontin (OP) and osteonectin (SPARC). The fourth category of dentin NCPs is not expressed in odontoblasts but is primarily synthesized in the liver

427

and released into the circulation. An example of a serum-borne protein is a2HS-glycoprotein. Diffusible growth factors that appear to be sequestered within dentin matrix constitute the fifth group of dentin NCPs. This group includes the bone morphogenetic proteins (BMP), insulinlike growth factors (IGF), and transforming growth factor beta (TGF-b).24 The pulp occupies the pulp chamber (the core of the crown) and the root canals. The incisal or occlusal surface of the pulp chamber is the roof. Projections along the mesial and distal aspects of the roof are the pulp horns. The apical surface of the pulp chamber is the floor and serves as the exit point for the nerves and vessels that traverse the root canals. Blood and lymph vessels are found in the pulp, as are sensory and motor nerves. The only sensation the pulp is able to transmit is pain. The bulk of the pulpal tissue is a loose connective tissue that contains cells of many types, fibroblasts, and the odontoblasts. Somatic stem cells from the dental pulp of a deciduous molar are capable of regenerating several tissues when transplanted in vivo. Cementum is another calcified tissue of mesodermal origin. The cementum covering the apical third of the root is cellular (contains cementocytes), while that of the remaining two-thirds is acellular. Cementum is less resorptive than bone, a fact that undoubtedly is related to its role in anchoring teeth and allowing teeth to move through bone during eruption. Development of Teeth

Teeth develop in distinct stages that are easily recognizable at the microscopic level. Hence, stages in odontogenesis are described in classic terms by the histologic appearance of the tooth organ. From early to late, these stages are described as the lamina, bud, cap, and bell (early and late) stages of tooth development.25,26 Recent advances made in the understanding of the molecular control of tooth development have led to the development of new terminology to describe tooth development as occurring in four phases: initiation, morphogenesis, cell or cytodifferentiation, and matrix apposition (Fig. 14-3). The dental lamina marks the first morphologic sign of the initiation of tooth development and is visible around 5 weeks of human development. At this stage, cells in the dental epithelium and underlying ectomesenchyme are dividing at different rates, the latter more rapidly. The inductive influence of the dental lamina to dictate the fate of the underlying ectomesenchyme has been confirmed by several researchers.27 The bud stage is characterized by the continual growth of cells of the dental lamina and ectomesenchyme. The latter is condensed and termed the dental papilla. At this stage, the inductive or tooth-forming potential is transferred from the dental epithelium to the dental papilla. The transition from the bud to the cap stage is an important step in tooth development because it marks the onset of crown formation. The tooth bud assumes the shape of a cap that is surrounded by the dental papilla. The ectodermal compartment of the tooth organ is referred to as the dental or enamel organ. The enamel organ and dental papilla become encapsulated by another layer of mesenchymal cells called the dental follicle that separate the tooth organ papilla from the other connective tissues of the jaws. A cluster of cells called the enamel knot is an important organizing center within the dental organ and is important for the formation of cusps.28,29 The enamel knot expresses a unique set of signaling molecules that influence the shape of the crown as well as the development of the dental papilla. Similar to the fate of signaling centers in other organizing tissues like the developing limb bud, the enamel knot

428

Craniofacial Structures

Fig. 14-3. Signaling in tooth development. Schematic description of the diffusible signals and transcription factors involved in epithelialmesenchymal interactions during mouse tooth development. Growth factors and morphogens involved are the bone morphogenetic proteins (BMP), fibroblast growth factors (FGF), Sonic hedgehog (SHH), and

Wingless protein (WNT). Several molecules function throughout odontogenesis. In humans, mutations in PITX2, SHH, MSX1, and PAX9 have been associated with Rieger syndrome, solitary median maxillary central incisor, premolar/third molar agenesis, and molar oligodontia, respectively. (Reprinted with permission from Thesleff.33)

undergoes programmed cell death or apoptosis after cuspal patterning is completed at the onset of the early bell stage. The dental organ next assumes the shape of a bell as cells continue to divide but at differential rates. A single layer of cuboidal cells called the external or outer dental epithelium lines the periphery of the dental organ, while cells that border the dental papilla and are columnar in appearance form the internal or inner dental epithelium. The latter gives rise to the ameloblasts, cells responsible for enamel formation. Cells located in the center of the dental organ produce high levels of glycosaminoglycans that are able to sequester fluids as well as growth factors that lead to its expansion. This network of star-shaped cells is named the stellate reticulum. Interposed between the stellate reticulum and the internal dental epithelium is a narrow layer of flattened cells, termed the stratum intermedium, that express high levels of alkaline phosphatase. The stratum intermedium is believed to influence the biomineralization of enamel. In the region of the apical end of the tooth organ, the internal and external dental epithelial layers meet at a junction called the cervical loop. At the early bell stage, each layer of the dental organ has assumed special functions and exchanges molecular information that leads to cell differentiation at the late bell stage. The dental lamina that connects the tooth organ to the oral epithelium gradually disintegrates at the late bell stage. At the future cusp tips, cells of the internal dental epithelium stop dividing and assume a columnar shape. The most peripheral cells of the dental papilla organize along the basement membrane and differentiate into odontoblasts, the

dentin-forming cells. At this time, the dental papilla is termed the dental pulp. After the first layer of predentin matrix is deposited, cells of the internal dental epithelium differentiate into ameloblasts or enamel-producing cells. As enamel is deposited over dentin matrix, ameloblasts retreat to the external surface of the crown and are believed to undergo programmed cell death. In contrast, odontoblasts line the inner surface of dentin and remain metabolically active throughout the life of a tooth. Root formation then proceeds as epithelial cells proliferate apically and influence the differentiation of odontoblasts from the dental papilla as well as cementoblasts from follicle mesenchyme. This leads to the deposition of root dentin and cementum, respectively. In multirooted teeth, certain portions of the root sheath grow more rapidly than the remainder, producing tonguelike extensions. When the extensions (two in two-rooted and three in three-rooted teeth) meet, the position of the root furcation is established. The dental follicle that gives rise to components of the periodontium, namely the periodontal ligament fibroblasts, alveolar bone of the tooth socket, and the cementum, also plays a role during tooth eruption, which marks the end phase of odontogenesis. In summary, tooth development is regulated by temporally and spatially restricted, reciprocal interactions between epithelial and mesenchymal compartments, and the potential to dominate tooth development shifts back and forth between epithelium and mesenchyme. The chronology of human tooth development is summarized in Tables 14-1 A and B.

Teeth

429

Table 14-1A. Developmental chart of deciduous teeth34

Tooth

Initiation (wk in utero)

Calcification Begins (wk in utero)

Crown Formation at Birth (38–42 wk)

Crown Complete (mo)

Eruption (mo)

Exfoliation (yr)

Lower central incisor

6–7

13–16

3/5

1–3

6–10

5–6

Lower lateral incisor

7

14–16

3/5

2–3

10–16

6–7

Upper incisors

7

14–16

5/6 central

2–3

8–13

6–7

2/3 lateral Canines

7.5

1/3

9

16–20

9–10

First molars

8

14.5–17

Cusps united, occlusal surface complete, 1/2–3/4 crown height

6

12–16

10–11

10

16–23

Cusps united, 1/4 crown height

10–12

23–30

12

Second molars

15–18

Table 14-1B. Developmental chart of permanent teeth34

Initiation

Calcification begins

Crown complete (yr)

Eruption (yr)

4–5

6–7

Mandible

Central incisor

20–22 wk IU

3–4 mo

Lateral incisor

21–22 wk IU

3–4 mo

4–5

7–8

Canine

20–26 wk IU

4–5 mo

6–7

9–11

First premolar

38–42 wk IU

1.75–2 yr

5–6

10–12

Second premolar

7.5–8 mo

2.25–2.5 yr

6–7

11–12

First molar

15–17 wk IU

Second molar

8.5–9 mo

Third molar

3.5–4 yr

Central incisor Lateral incisor Canine

Birth 2.5–3 yr

2.5–3

6–7

7–8

11–13

8–10 yr

12–16

17–25

20–22 wk IU

3–4 mo

4–5

7–8

21–22 wk IU

3–4 mo

4–5

8–9

21–26 wk IU

4–5 mo

6–7

11–12

First premolar

38–42 wk IU

1.25–1.75 yr

Second premolar

7.25–8 mo

Maxilla

First molar

3.5–4 wk IU

Second molar

8.5–9 mo

Third molar

3.5–4 yr

2–2.5 yr Birth 2.5–3 yr 7–9 yr

5–6

10–11

6–7

10–12

2.5–3

6–7

7–8

12–13

12–16

17–25

IU ¼ in utero.

In recent years significant advances have been made in understanding the molecular mechanisms that determine the site of tooth initiation.30,31 Fig. 14-3 shows that a number of transcription factors, signaling molecules (i.e., growth factors and their receptors), and extracellular matrix molecules are expressed in the mesenchyme of the first branchial arch. Several lines of evidence indicate that synergistic and antagonistic interactions of signaling molecules are recursively utilized in tooth development.30–32 Clinical Considerations

Congenital malformations of the teeth can be more clearly understood by considering tooth development in stages of initiation and proliferation, morphogenesis, and matrix apposition. The dental lamina initiates tooth development. If the lamina is not formed or its early organization is abnormal, initiation will not occur and teeth will not develop at all (anodontia). If only portions of the lamina are

physically disrupted, initiation is disrupted in focal areas and only teeth in that area will not develop (hypodontia). Of course, some disruptive factors may cause overactivity of the lamina, resulting in hyperdontia (supernumerary teeth). After initiation, the separate tooth buds proliferate at their predetermined paces. Interference with proliferation also leads to hypodontia. Histodifferentiation follows the initial steps of proliferation. Cell types (ameloblasts and odontoblasts, for instance) are established during the histodifferentiation stage. If the inner dental epithelium does not differentiate properly, it cannot stimulate odontoblast formation, and tooth development will be arrested. If odontoblasts fail to differentiate properly, they cannot stimulate ameloblast formation and no enamel will form. Abnormal dental structure, poorly organized and formed, results from abnormal differentiation. Differential growth of parts of the dental organ (morphodifferentiation) accounts for the basic size and shape of teeth.

430

Craniofacial Structures

Abnormal morphodifferentiation leads to microdontia, macrodontia, globodontia, supernumerary cusps, and other abnormalities. Apposition refers to the deposition of the matrix of dentin and enamel. Once the cells of the inner dental epithelium have stimulated the underlying mesenchyme to form odontoblasts, the odontoblasts lay down a layer of predentin. Mineralization begins after sufficient predentin is present. The various types of dentin dysplasia are probably defects of predentin deposition. After a small amount of predentin has formed, ameloblasts begin to secrete the enamel matrix and continue to do so until the predetermined size of the crown has been reached. Too little enamel matrix leads to hypoplastic types of enamel dysplasia. After the enamel matrix is laid down, it is mineralized; disruptions at this stage of development lead to hypocalcified types of enamel dysplasia. Maturation of the hard matrix follows appositional growth. Interference with maturation leads to such manifestations as hypomature forms of enamel dysplasia. Future Challenges and Directions

The molecular basis for malformations of human teeth is beginning to be delineated; however, there remains much to be resolved in the area of genotype-phenotype correlations. How locus-specific mutations affect phenotypic changes as measured by tooth shape, position, size, and number is poorly understood. The availability of improved dental diagnostic and genomic tools along with sophisticated mouse transgenesis will greatly add to our knowledge of how allele-specific alterations influence patterns of inheritable disease. Although tooth malformations compromise emotional wellbeing and impose significant financial burdens on patients and their families, these conditions are not life threatening. Therefore, the identification and diagnosis of multigenerational families segregating disorders affecting dentition offers an exciting avenue for research on the genetic etiology of dental diseases. The legacy of inheritable anomalies of human dentition will continue to provide a unique and powerful system for studying the genetic pathways that control the development of human dentition. Knowledge about normal and abnormal tooth development and eruption is essential in the postgenomic area as emerging technologies of biomimetics and tissue engineering are applied to the field of regenerative dental medicine. The next decade will benefit from these advances as they can be well-applied to the bioengineering of animal and human tooth structures through the use of either embryonic or adult (somatic) stem cells. These multipotential cells can be derived from bone marrow stroma as well as from tissues derived from individual layers of embryonic tooth organs or the intact tooth germ itself.35–37 Stem cell populations existent in deciduous teeth that are shed have also shown the potential to form mineralized tooth structures like dentin and bone and to regenerate nerve tissues as well.38–40 References 1. Thesleff I, Pispa J: The teeth as models for studies on the molecular basis of the development and evolution of organs. In: Molecular Basis of Epithelial Appendage Morphogenesis. Chuong CM, ed. International Thomson Publishing Services Ltd, London, 1998, p 157. 2. Weiss K, Stock D, Zhao Z, et al.: Perspectives on genetic aspects of dental patterning. Eur J Oral Sci 106(suppl 1):55, 1998. 3. Kronmiller JE, Beeman CS: Spatial distribution of endogenous retinoids in the murine embryonic mandible. Arch Oral Biol 39:1071, 1994. 4. Osborn JW: Morphogenetic gradients: fields versus clones. In: Development, Function and Evolution of the Teeth. Butler PM, Joysey KA, eds. Academic Press, NY, 1978, p 171.

5. Hunt P, Krumlauf R: Hox codes and positional specification in vertebrate embryonic axes. Annu Rev Cell Biol 8:227, 1992. 6. Imai H, Osumi-Yamashita N, Ninomiya Y, et al.: Contribution of earlyemigrating midbrain crest cells to the dental mesenchyme of mandibular molar teeth in rat embryos. Dev Biol 176:151, 1996. 7. Boyde A: Enamel. In: Handbook of Microscopic Anatomy, vol 6, Teeth. Oksche A, Vollrath L, eds. Springer-Verlag, Berlin, 1989. 8. Fincham AG, Moradian-Oldak J, Simmer JP: The structural biology of the developing dental enamel matrix. J Struct Biol 126:270, 1999. 9. Hubbard MJ: Enamel cell biology. Towards a comprehensive biochemical understanding. Connect Tissue Res 38:17, 1998; discussion 35. 10. Simmer JP, Fincham AG: Molecular mechanisms of dental enamel formation. Crit Rev Oral Biol Med 6:84, 1995. 11. Smith CE, Nanci A: Overview of morphological changes in enamel organ cells associated with major events in amelogenesis. Int J Dev Biol 39:153, 1995. 12. Warshawsky H, Nanci A: Stereo electron microscopy of enamel crystallites. J Dent Res Spec No:1504, 1982. 13. Fujisawa R, Kuboki Y: Preferential adsorption of dentin and bone acidic proteins on the (100) face of Hydroxyapatite crystals. Biochem Biophys Acta 1075:56, 1991. 14. Butler WT, Bhown M, Brunn JC, et al.: Isolation, characterization and immunolocalization of a 53-kDal dentin sialoprotein (DSP). Matrix 12: 343, 1992. 15. Butler WT: Dentin matrix proteins and dentinogenesis. Connect Tissue Res 33:59, 1995. 16. Linde A, Goldberg M: Dentinogenesis. Crit Rev Oral Biol Med 4:679, 1993. 17. Butler WT, Ritchie H: The nature and functional significance of dentin extracellular matrix proteins. Int J Dev Biol 39:169, 1995. 18. MacDougall M, Simmons D, Luan X, et al.: Dentin phosphoprotein and dentin sialoprotein are cleavage products expressed from a single transcript coded by a gene on human chromosome 4. Dentin phosphoprotein DNA sequence determination. J Biol Chem 272:835, 1997. 19. Zhang X, Zhao J, Li C, et al.: DSPP mutation in dentinogenesis imperfecta Shields type II. Nat Genet 27:151, 2001. 20. Xiao S, Yu C, Chou X, et al.: Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nat Genet 27:201, 2001. 21. George A, Sabsay B, Simonian PA, et al.: Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J Biol Chem 268:12624, 1993. 22. D’Souza RN, Cavender A, Sunavala G, et al.: Gene expression patterns of murine dentin matrix protein 1 (Dmp1) and dentin sialophosphoprotein (DSPP) suggest distinct developmental functions in vivo. J Bone Miner Res 12:2040, 1997. 23. Hirst KL, Simmons D, Feng J, et al.: Elucidation of the sequence and the genomic organization of the human dentin matrix acidic phosphoprotein 1 (DMP1) gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II. Genomics 42:38, 1997. 24. Smith AJ, Lesot H: Induction and regulation of crown dentinogenesis: embryonic events as a template for dental tissue repair? Crit Rev Oral Biol Med 12:425, 2001. 25. Ten Cate AR: Oral Histology: Development, Structure, and Function, ed 5. Mosby, St. Louis, 1998. 26. Avery JK: Oral Development and Histology. Mosby Year Book, St. Louis, 1987. 27. Mina M, Kollar EJ: The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol 32:123, 1987. 28. Jernvall J, Kettunen P, Karavanova I, et al.: Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. Int J Dev Biol 38:463, 1994. 29. Jernvall J, Aberg T, Kettunen P, et al.: The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 125:161, 1998.

Teeth 30. Peters H, Balling R: Teeth. Where and how to make them. Trends Genet 15:59, 1999. 31. Jernvall J, Thesleff I: Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 92:19, 2000. 32. Thesleff I: The genetic basis of normal and abnormal craniofacial development. Acta Odontol Scand 56:321, 1998. 33. Thesleff I: Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Science 116:1647, 2003. 34. Cameron AC, Widmer RP: Handbook of Paediatric Dentistry, ed 2. Mosby, London, 1998, p 355–356. 35. Young CS, Terada S, Vacanti JP, et al.: Tissue engineering of complex tooth structures on biodegradable polymer scaffolds. J Dent Res 81:695, 2002. 36. Duailibi MT, Duailibi SE, Young CS, et al.: Bioengineered teeth from cultured rat tooth bud cells. J Dent Res 83:523, 2004. 37. Ohazama A, Modino SA, Miletich I, et al.: Stem-cell-based tissue engineering of murine teeth. J Dent Res 83:518, 2004. 38. Gronthos S, Mankani M, Brahim J, et al.: Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 97:13625, 2000. 39. Gronthos S, Brahim J, Li W, et al.: Stem cell properties of human dental pulp stem cells. J Dent Res 81:531, 2002. 40. Miura M, Gronthos S, Zhao M, et al.: SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 100:5807, 2003.

14.1 Tooth Agenesis Definition

Tooth agenesis is the congenital lack of one or more of the deciduous or permanent teeth. It is classified as a clinically and genetically heterogenous condition that affects specific groups of teeth. It is the most common developmental anomaly in humans. The third molars, for instance, are congenitally absent so commonly that surveys of tooth agenesis frequently exclude this tooth type for consideration. The literature uses several terms to describe tooth agenesis that are based on the number of teeth involved. Oligodontia is the agenesis of six or more permanent teeth, whereas absence of less than

431

six teeth is referred as hypodontia. Anodontia refers to the absence of all deciduous and permanent teeth (Fig. 14-4). Diagnosis

A tooth is considered congenitally absent when it is not present clinically (erupted) or radiographically (unerupted) at an age when it is expected to be present. The extent to which tooth agenesis is manifested varies widely and can be presented as the only phenotypic feature (isolated) or associated with other anomalies or as part of a syndrome. Among the several developmental anomalies involving human dentition, the field of tooth agenesis has shown the most progress. The genetic etiology of tooth agenesis has received much attention in recent years, and as Tables 14-2 to 14-5 describe, several genes and underlying mutations have been reported to cause tooth agenesis. Many of these discoveries have been guided by knowledge about the genes involved in murine tooth development, in particular those that are important for the initiation of odontogenesis. Etiology and Distribution

Tooth agenesis occurs more frequently among a few specific teeth (lateral incisors, second premolars, and third molars), with 10– 25% of the population affected. Familial tooth agenesis is transmitted as autosomal dominant, autosomal recessive, and X-linked conditions but can also show no clear segregation pattern. Affected members within a family often exhibit significant variability with regard to the location, symmetry, and number of teeth involved. Residual teeth can vary in size, shape, or rate of development. The permanent dentition is more affected than the primary dentition. Animal models suggest that specific genetic factors might be involved with specific types of teeth during development. Mice with targeted null mutations of both Dlx-1 and Dlx-2 homeobox genes do not develop maxillary molar teeth, but the incisors and mandibular molars are normal. In contrast, among mice with mutant activin ßA (a member of the transforming growth factor (TGF) ß superfamily), incisors and mandibular molar teeth fail to develop

Fig. 14-4. Congenitally missing teeth. Intraoral photographs and panoramic radiographs from a normal 11-year-old male individual (A,B,C) and his 19-year-old affected brother, (D,E,F). A,B,C. Normal mixed primary and permanent dentition. Note the impacted maxillary central incisor and the presence of permanent first and second molars (arrows). Crowns shown in B were placed on the primary molars after the radiograph was taken. D,E,F. Affected individual with the following anomalies: peg-shaped lateral incisors; reduced mesiodistal widths and conical shape of permanent teeth; overretained primary second molars and mandibular central incisors. Notably, permanent mandibular central incisors and all permanent teeth distal to the first premolars are congenitally missing (solid arrows).

432

Craniofacial Structures Table 14-2. Isolated tooth agenesis Phenotype

Causation Gene/Locus

Hypodontia1

Polygenic Possibly MSX1, PAX9, TGFA, others

Hypodontia with anomalous shape of pulp chambers and pulp canals2

AR (602639) 16q12.1

Oligodontia with preferential agenesis of second premolars and third molars3

Sporadic (106600) PAX9, 14q12–q13

Oligodontia with preferential agenesis of second premolars and third molars4,5

AD (106600) MSX1, 4p16.1

Oligodontia with preferential molar agenesis6–13

AD (106600) PAX9, 14q12–q13

Oligodontia with preferential molar agenesis14

AD (106600) MSX1, 4p16.1

Severe oligodontia including deciduous and permanent molar agenesis8

AD (106600) PAX9, 14q12–q13

Table 14-3. Tooth agenesis associated with other defects or diseases Phenotype

Causation Locus/Genes

Anodontia and strabismus15

AD, Unknown

Asphyxiating thoracic dystrophy and oligodontia16

Chromosomal (208500) Deletion, 12p11.21–p12.2

Cleft lip and palate and hypo-dontia outside the cleft area17

Polygenic Possibly MSX1, TGFB3, others

Coloboma of macula with type B brachydactyly and oligodontia18

Sporadic (120400)

Hypodontia and Dupuytren contracture19

AD (126900) with incomplete penetrance

Leukodystrophy and oligodontia20

AR (607694)

Medullary sponge kidney and anodontia of permanent dentition21

AR

Oligodontia and colorectal cancer22

AD AXIN2

Oligodontia and congenital sensorineural hearing loss23,24

AR (221740)

Oligodontia and polycystic ovaries25

AR

beyond a rudimentary bud, whereas maxillary molar teeth develop normally. The mice lack whiskers and have defects in the secondary palates, including cleft palate. In humans, mutations in MSX1 and PAX9 have been associated with tooth agenesis, but those mutations probably cause only a very few cases. However, the pattern of tooth agenesis from these mutations is remarkable, with PAX9 causing preferential agenesis of molars and MSX1 causing preferential agenesis of second premolars and third molars. The majority of the tooth agenesis cases are probably multifactorial with many genes involved.206 Epidemiologic characteristics of tooth agenesis are listed in Table 14-6. Prognosis, Treatment, and Prevention

Unless agenesis of one or more teeth is associated with a syndrome, prognosis is good. The unavoidable dental consequences of tooth agenesis include malocclusion due to improper position of the

teeth, deficient growth of the alveolar processes associated with the missing teeth, and excess space within the dental arches. The availability of space results in drifting, tipping, and supraeruption of the adjacent or opposing teeth. In molar oligodontia, the functional atrophy in alveolar ridge height is easily recognizable. Syndromic and nonsyndromic forms of tooth agenesis that involve multiple teeth result in significant aesthetic, emotional, and financial burdens placed on families faced with the ordeal and costs associated with restoring the dentitions of several affected family members. The average cost for the restoration of dentition in patients affected with severe forms of tooth agenesis approximates $50,000 to $60,000 per individual. Although clinicians have long observed hypodontia and oligodontia, the early diagnosis, preventive or interceptive dental measures, and treatment options for this condition have been extremely limited. The number and type of missing teeth as well as individual skeletal proportions and aesthetic considerations generally dictate treatment regimens. Therapy is phasic, complicated, and lengthy, involving at least two dental specialists. Orthodontic appliances are ideal for the repositioning of existing teeth and the consolidation of space for either a fixed or removable prosthesis. However, when several teeth are missing, as seen in molar oligodontia, orthodontic correction is followed by bone augmentation procedures to increase the bone mass prior to the placement of implants. With the exception of syndromic cases of anodontia, molar oligodontia presents with the most severe of dental complications. There are no useful preventive measures for tooth agenesis, and prenatal diagnosis is impossible or considered by many to be unwarranted. In theory, anodontia can be detected prenatally by ultrasound examination. It is doubtful that a couple would choose to modify the course of a pregnancy for isolated anodontia, making prevention a moot point. References (Tooth Agenesis) 1. Vieira AR, Meira R, Modesto A, et al.: MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res 83:723, 2004. 2. Ahmad W, Brancolini V, Ul Faiyaz MF, et al.: A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1. Am J Hum Genet 26:987, 1998. 3. Mostowska A, Kobielak A, Biedziak B, et al.: Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. Eur J Oral Sci 111:272, 2003.

Table 14-4. Syndromes with tooth agenesis as a component Syndrome

Prominent Features

Causation Locus/Gene

Autosomal Dominant Conditions

Acrofacial dysostosis, type Nager26,27

Limb deformities, severe micrognathia and malar hypoplasia (can also be autosomal recessive)

(154400) 9q32, 1q12–q21

Acrofacial dysostosis, type Palagonia28

Oligodontia, short stature, frizzy hair with aplasia cutis verticis, hand anomalies, unilateral cleft lip, some vertebral anomalies (can also be X-linked dominant)

(601829)

Adenomatous polyposis of the colon29,30

Adenomatous polyps of the colon and rectum, congenital hypertrophy of the retinal pigment epithelium, dental anomalies

(175100) APC, 5q21-q22

ADULT31–33

Ectrodactyly, syndactyly, nail dysplasia, hypoplastic breasts and nipples, intensive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, loss of permanent teeth

(103295) p63, 3q27

Alagille34,35

Eye anomalies, cardiovascular anomalies, abnormal vertebrae, cognitive problems, typical facies, hypodontia, oral xanthomas

(118450) JAG1, 20p12

Ankyloplepharon-ectodermal defects-cleft lip/palate36,37

Coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; cleft lip/palate

(106260) p63, 3q27

Axenfeld-Rieger38–43

Eye, dental, and umbilical anomalies

(180500) PITX2, 4q25–q26 FOXC1, 6p25 13q14

Book44

Congenitally missing premolars, narrow palate, severe functional hyperhidrosis of the hands and feet, small hands, hypoplastic nails

(112300)

Branchio-oculo-facial45

Branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, premature aging

(113620)

Choanal atresia with maxillary hypoplasia, prognathism, and hypodontia46

Bilateral choanal atresia, tall forehead, maxillary hypoplasia, prognathism, hypodontia

Ectodermal dysplasia 347,48

Mild hypotrichosis, mild hypodontia, and variable degrees of hypohidrosis (can also be autosomal recessive)

(129490) EDAR, 2q11–q13

Ectrodactyly-ectodermal dysplasia-clefting49–51

Lobster-claw anomalies of hands and feet, lacrimal duct anomalies with ocular complications, cleft lip/palate (most cases are sporadic)

(129900) (EEC1) 7q11.2–q21.3 (EEC2) 19p13–q13 (EEC3) p63, 3q27

Ehlers-Danlos type VI52–54

Ocular, muscular, and skin defects; abnormal maxilla; occasional hypodontia and/or smaller teeth sizes

(225400) PLOD1, 1p36.3–p36.2 (continued)

433

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Hair-nail-skin-teeth dysplasias55

Large number of rare disorders involving binary, ternary, or quaternary combination of hair, nails, skin appendages, and teeth anomalies (can also be autosomal recessive or X-linked)

(125640, 257980, 262020, 272980, 275450)

Hallermann-Streiff56

Birdlike facies with hypoplastic mandible and beaked nose, proportionate dwarfism, hypotrichosis, microphthalmia, dental anomalies, congenital cataract

(234100)

Hypodontia with orofacial clefts57

Cleft lip and palate, cleft palate alone, oligodontia with preferential agenesis of second premolars and third molars

(106600) MSX1, 4p16.1

Kallmann58,59

Hypogonadotropic hypogonadism, anosmia, bimanual synkinesia, cleft lip or palate, multiple dental agenesis

(147950) FGFR1, 8p11.2–p11.1

KBG60

Short stature, characteristic facies, mental retardation, skeletal anomalies, oligodontia, macrodontia

(148050)

LADD61

Aplasia or hypoplasia of the puncta with obstruction of the nasal lacrimal ducts; ear, dental, and hand anomalies

(149730)

Limb-mammary62,63

Severe hand/foot anomalies and hypoplasia/aplasia of the mammary gland and nipple, lacrimal-duct atresia, nail dysplasia, hypohidrosis, hypodontia, cleft palate with or without bifid uvula

(603543) p63, 3q27

Niikawa-Kuroki (Kabuki)64–66

A peculiar face, characterized by eversion of the lower lateral eyelid, arched eyebrows with sparse or dispersed lateral onethird, depressed nasal tip, and prominent ears; skeletal anomalies, dermatoglyphic abnormalities, mild to moderate mental retardation; postnatal growth deficiency, heart defects, dental anomalies

(147920)

Oculodentodigital dysplasia67,68

Bilateral microphthalmos, abnormally small nose, hypotrichosis, dental anomalies, fifth finger camptodactyly, syndactyly of the fourth and fifth fingers, missing toe phalanges

(164200) GJA1, 6q21-q23.2

Oligodontia, microcephaly, short stature, characteristic facies69

Microcephaly, short stature, characteristic facies, oligodontia

Unknown

Otodental dysplasia70

Sensorineural hearing loss, dental anomalies, missing premolars

(166750)

Popliteal pterygium71,72

Cleft lip/palate, paramedian mucous cysts of the lower lip, webbing of the lower limbs, digital and genital anomalies

(119500) IRF6, 1q32-q41

(continued)

434

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Scalp-ear-nipple73

Abnormality of the scalp, ears, nipples, tooth agenesis, and renal anomalies

(181270) Unknown

Shopf-Schulz-Passarge74,75

Keratosis palmoplantaris with cystic eyelids, hypodontia, hypotrichosis (can also be autosomal recessive)

(224750) 17q24

Ulnar-mammary76–78

Posterior (ulnar or postaxial) limb deficiencies and/or duplications, mammary gland hypoplasia, apocrine dysfunction, and dental and genital abnormalities

(181450) TBX3, 12q24.1

Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly79,80

Congenital hypotrichosis, uncombable hair, associated with juvenile cataracts, retinal pigmentary dystrophy, oligodontia, and brachymetacarpy

(191482)

Van der Woude71,72,81–84

Lip pits, cleft of lip/palate, hypodontia

(119300) IRF6, 1p34

Witkop (tooth-and-nail)85

Missing teeth and poorly formed nails

(189500) MSX1, 4p16.1

Agonadism, XY, with mental retardation, short stature, retarded bone age, and multiple extragenital malformations86

Minor anomalies: peculiar face, hypodontia, short neck, inverted nipples, thoracolumbar scoliosis, ‘‘dysplastic’’ hips, partial clinodactyly/syndactyly of the toes

Unknown

Amelogenesis imperfecta and platyspondyly87

Mild growth retardation, platyspondyly, vertebral defects, pectus carinatum, limited extension at the elbows, amelogenesis imperfecta, oligodontia

(601216) Unknown

Bardet-Biedl88–94

Mental retardation, pigmentary retinopathy, polydactyly, obesity, hypogenitalism

Multiple loci

Blepharo-cheilodontic95

Cleft lip and/or palate, ectropion of the lower eyelids with ocular hypertelorism, and dental anomalies

(119580)

Brachymetapody-anodontia-hypotrichosis-albinoidism96

Congenital anodontia, small maxilla, short stature, little hair growth, albinoidism, multiple ocular abnormalities

(211370)

Cerebellar hypoplasia with endosteal sclerosis97

Ataxia and developmental delay, microcephaly, short stature, oligodontia, strabismus, nystagmus, congenital hip dislocation

(213002)

Cleft lip/palate, congenital contractures, ectodermal dysplasia, and psychomotor and growth retardation98

Typical facies, congenital contractures, orofacial clefts, oligodontia and other teeth anomalies (may also be X-linked)

(301815)

Cleft lip/palate-ectodermal dysplasia99,100

Anhidrosis, hypotrichosis, dental anomalies, dysplasia of nails, cleft lip and palate, deformity of the fingers and toes, malformation in the genitourinary system, popliteal perineal pterygium, syndactyly

(225000) PVRL1, 11q23–q24

Autosomal Recessive Conditions

(continued)

435

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Cleft palate, stapes fixation, and oligodontia101

Cleft palate, stapes fixation, oligodontia

(216300)

Cockayne102–104

Dwarfism, precociously senile appearance, pigmentary retinal degeneration, optic atrophy, deafness, disproportionately long limbs with large hands and feet and flexion contractures of joints, marble epiphyses in some digits, photosensitivity, mental retardation

(216400) XPB, XPD, XPG, CSA, CSB

Cranioectodermal dysplasia105

Dolichocephaly; sparse, slow-growing, fine hair; epicanthal folds; hypodontia and/or micro-dontia; brachydactyly; narrow thorax

(218330)

Dermatoosteolysis, Kirghizian type106

Recurrent skin ulceration, arthralgia, fever, fistulous osteolysis around joints, oligodontia, nail dystrophy, keratitis with visual impairment or blindness

(221810)

Dysosteosclerosis107

Anterior fontanel tends to remain open, oligo-dontia, progressive mental retardation, oto-sclerosis, intracerebral calcifications (can also be X-linked)

(224300)

Ectodermal dysplasia, Margarita Island type100,108

Scanty eyebrows and eyelashes; sparse, short, and dry scalp hair; dental anomalies; cleft lip/palate; syndactyly of fingers and toes; onychodysplasia

(225060) PVRL1, 11q23-q24

Ellis-van Creveld109–111

Skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth

(225500) EVC, EVC2

Epidermolysis bullosa112–116

Dystrophy of the nails, nonscarring blistering of skin, mild skin atrophy, hypodontia

(226650) COL17A1, LAMA3, LAMB3, LAMC2, ITGB4

Gorlin-Chaudhry-Moss117

Craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies, patent ductus arteriosus, normal intelligence

(233500)

Hanhart118–120

Aglossia, adactylia; is often associated with missing mandibular incisors, hypertrophy of salivary glands (most cases are sporadic)

(103300)

Hennekan lymphangiectasia-lymphedema121

Intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia, and face; severe mental retardation; facial anomalies

(235510)

Johanson-Blizzard122

Aplasia or hypoplasia of the nasal alae, congenital deafness, hypothyroidism, postnatal growth retardation, mental retardation, midline ectodermal scalp defects, microdontia or absent permanent teeth

(243800)

Leukomelanoderma, infantilism, mental retardation, hypodontia, hypotrichosis123

Mental retardation, leukomelanoderma, hypotrichosis, hypodontia

(246500)

(continued)

436

Table 14-4. Syndromes with tooth agenesis as a component (continued)

Syndrome

Prominent Features

Causation Locus/Gene

MULIBREY nanism124,125

Anomalies of MUscle, LIver, BRain, and EYe

(253250) TRIM37, 17q32–q23

Odontotrichomelic126

Tetramelic deficiency, ectodermal dysplasia, deformed pinnae

(273400)

Polydactyly, postaxial, with dental and vertebral anomalies127

Postaxial polydactyly and other abnormalities of the hands and feet, hypoplasia and fusion of vertebral bodies, dental anomalies

(263540)

Progeria128,129

Precocious senility of a striking degree; death from coronary artery disease is frequent and may occur before 10 years of age

(176670) LMNA, 1q21.2

Pycnodysostosis130

Deformity of the skull, maxilla, and phalanges; osteosclerosis; fragility of bone; dental anomalies

(265800) CTSK, 1q21

Richieri-Costa and Pereira131

Robin sequence, cleft mandible, limb anomalies

(268305)

Rothmund-Thomson132,133

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

(268400) RECQL4, 8q24.3

Spondyloepimeta-physeal dysplasia with abnormal dentition134

Generalized platyspondyly with epiphyseal and metaphyseal involvement, thin tapering fingers with accentuated palmar creases, abnormal dentition (oligodontia and pointed incisors)

(601668)

Mental retardation with peculiar pugilistic nose, large ears, tapered fingers, drumstick terminal phalanges by radiograph, and pectus carinatum. Other complications: premature death, progressive kyphoscoliosis, spinal stenosis, drop attacks, abnormalities in dentition, hearing loss, ocular abnormalities, excess of psychiatric illness in carrier females

(303600) RSK2, Xp22.2-p22.1

Males: characteristic facies; teeth often missing or misshapen; fine, sparse hair; and skin is thin, glossy, smooth, and dry with hypohidrosis. Females: sparse, thin scalp hair and mosaic patchy distribution of body hair; abnormal teeth; mild hypohidrosis

(305100) ED1, Xq12-q13.1

X-Linked Conditions

Coffin-Lowry135–139

Ectodermal dysplasia 1140–142

Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum143

(225040)

(continued)

437

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Faciogenital dysplasia144–148

Ocular hypertelorism, anteverted nostrils, broad upper lip, escrotum anomalies, occasional dental anomalies

(305400) FGD1, Xp11.21

Focal dermal hypoplasia149

Atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, multiple papillomas of the mucous membranes or skin, digital anomalies, oral anomalies, ocular anomalies, mental retardation

(305600)

Frontometaphyseal dysplasia150

Marked frontal hyperostosis, underdeveloped mandible, cryptorchidism, subluxated radial heads, metaphyseal dysplasia

(305620) FLNA, Xq28

Incontinentia pigmenti151

Disturbance of skin pigmentation sometimes associated with a variety of malformations of the eye, teeth, skeleton, and heart

(308300) NEMO, Xq28

Mulvihill-Smith152

Low-birth-weight dwarfism with mild to moderate mental retardation, striking multiple pigmented nevi, lack of facial subcutaneous fat

(176690)

Oculofaciocardio-dental153–155

Cataracts, micro-phthalmia, oligodontia, radiculomegaly, septal heart defects

(300166) BCL6 corepressor (BCOR)

Orofaciodigital, type I156,157

Clefts of the jaw and tongue, other malformations of the face and skull, malformations of the hands and teeth, mental retardation

(311200) CXORF5, Xp22.3-p22.2

Otopalatodigital types I and II150,158

Conduction deafness, cleft palate, characteristic facies, generalized bone dysplasia; type II is more severe

(311300, 304120) FLNA, Xq28

W159

Mental retardation with frontal prominence; anterior cowlick; hypertelorism; antimongoloid orbital slant; broad, flat nasal bridge; midline notch of upper lip and submucous cleft of the hard palate; absent upper central incisors; limited motion at the elbow; pes cavus

(311450)

Short stature, hypotelorism, prognathism, hypodontia

(607095)

Down161–165

Mental retardation, typical facies, heart defects, short stature, dental anomalies

(190685) Trisomy 21

Glossopalatine ankylosis166

Glossopalatine ankylosis, cleft palate, limb anomalies, hypoplastic mandible, incisor hypodontia

Hemimaxillofacial dysplasia167

Unilateral enlargement of maxillary alveolar bone and gingival associated with tooth agenesis, facial asymmetry

Chromosomal and Other Conditions

Anauxetic dysplasia160

(continued)

438

Teeth

439

Table 14-4. Syndromes with tooth agenesis as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Oroacral, Verloes-Koulischer type168

Absence of the medial part of the upper alveolar ridge, including the gingiva, frenulum, and tooth buds for the maxillary incisors and canines

(603446)

Sener169

Frontonasal dysplasia, dilated Virchow-Robin spaces, hypodontia, buccal frenula

(606156)

Unusual facies, oligodontia, and precocious choroid calcifications170

Minor digital anomalies, telecanthus, broad and flattened nasal bridge, mild ocular proptosis, small nose with anteverted nostrils, microretrognathia

(603589)

Williams-Beuren171

Typical facies, mental retardation, growth deficiency, cardio-vascular anomalies, infantile hypercalcemia

(194050) 7q11.23

Wolf-Hirschhorn172

Severe growth retardation and mental defect, microcephaly, typical facies, closure defects (cleft lip or palate, coloboma of the eye, cardiac septal defects)

(194190) Chromosomal Del 4p16.3

Table 14-5. Solitary maxillary central incisor defects Causation Gene/Locus

Type of Defect Associated

Isolated defect173

AD (147250) SHH, 7q36

7q36.1 deletion174

Chromosomal Del 7q36.1

18p deletion or r(18)175–178

Chromosomal Del 18p or ring 18

CHARGE179,180

Multifactorial (214800)

Hypophyseal short stature and cleft lip181

Unknown

Holoprosencephaly182–194

Heterogeneous (236100) SHH, 7q36 SIX3, 2p21 TGIF, 18p13 ZIC2, 13p32 PTCH, 9q22.3 Other loci and chromosomal causes

Table 14-6. Epidemiologic Characteristics of Tooth Agenesis Characteristic

Summary Information 207

Frequency (primary dentition)

1.4%

Frequency (permanent dentition, excluding third molars)208,209

1.6–10%

Ethnic differences210

Frequencies are higher in Asians and lower in African-descent populations compared to Europeans

Gender differences211,212

M/F 2:3

1,213,214

Familial patterns

Approximately 35% are familial cases Sibling recurrence 1–9%

Iris coloboma and hypomelanosis of Ito183

Unknown

Klippel-Feil195–197

AD (148900) 8q22.2

Microphthalmia and hypopituitarism198

Unknown

Precocious puberty and hypothalamic hamartoma199

Unknown

Short stature and choanal atresia200

Unknown

Short stature and ocular coloboma201

Unknown 202,203

Unusual forms of ectodermal dysplasia

Unknown

VACTERL179,204

Sporadic (192350)

XXX syndrome205

Trisomy X

Monozygotic twin concordance 89%

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180.

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203.

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204. Wesley RK, Hoffman WH, Perrin J, et al.: Solitary maxillary central incisor and normal stature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 46:837, 1978. 205. Miura M, Kato N, Kojima H, et al.: Triple-X syndrome accompanied by single maxillary central incisor: case report. Pediatr Dent 15:214, 1993. 206. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003. 207. Whittington BR, Durward CS: Survey of anomalies in primary teeth and their correlation with the permanent dentition. N Z Dent J 92:4, 1996. 208. Eidelman E, Chosack A, Rosenzweig KA: Hypodontia prevalence among Jewish populations of different origin. Am J Phys Anthrop 39:129, 1973. 209. Graber LW: Congenital absence of teeth: a review with emphasis on inheritance patterns. J Am Dent Assoc 96:266, 1978. 210. Muller TP, Hill IN, Petersen AC, et al.: A survey of congenitally missing permanent teeth. J Am Dent Assoc 81:101, 1970. 211. Bergstrom K: An orthopantomographic study of hypodontia, supernumeraries and other anomalies in school children between the ages of 8-9 years: an epidemiological study. Swed Dent J 1:145, 1977. 212. Brook AH: A unifying aetiological explanation for anomalies of human tooth number and size. Arch Oral Biol 29:373, 1984. 213. Markovic M: Hypodontia in twins. Swed Dent J Suppl 15:153, 1982. 214. Spoonhower C, Valiathan M, Hans MG, et al.: Familial aggregation of congenital hypodontia. In: International Association for Dental Research 82nd General Session Program Book, 2004, p 149.

14.2 Supernumerary Teeth Definition

Supernumerary teeth is the presence of more than the normal complement of deciduous (20) and permanent teeth (32). Diagnosis

Supernumerary teeth can be diagnosed by the actual count, clinically or radiographically. Teeth in excess of the normal complement are named according to their location: mesiodens are located on the palatal side of the maxillary central incisors; supernumerary canines and premolars are located at the normal sites for such teeth; paramolars are located buccal to the first, second, and third molars; and distomolars (fourth molars) are located distal to the third molar in line with the dental arch. There may also be lingual, intradental, and interradicular supernumerary teeth. Supernumerary teeth may be fused with teeth in the normal complement. Supernumerary teeth can present as the only phenotypic feature (isolated), in association with other anomalies (such as tooth agenesis or orofacial clefts), or as part of a syndrome.1–3 Etiology and Distribution

Syndromes with supernumerary teeth as a component are listed in Table 14-7. There is evidence that related etiologic factors contribute to supernumerary teeth, tooth agenesis, and orofacial clefts.3,33,34 Differences in the mesiodistal width of central incisors depending on unilateral or bilateral occurrence of mesiodens and the report of gemination of a deciduous incisor on the same side of a mesiodens support the theory of the split in the tooth bud inducing the development of supernumerary teeth over that of a local hyperactivity of the dental lamina.33 Single and double supernumeraries occur in 90% of cases, and multiple supernumeraries in 10% of cases.35 Epidemiologic characteristics of supernumerary teeth are listed in Table 14-8.

Prognosis, Treatment, and Prevention

Supernumerary teeth may interfere with the eruption of teeth in the normal complement or may cause their malalignment. Unless they are features of a syndrome, prognosis is good. They are easily extracted, even if they are impacted. There are no preventive measures. References (Supernumerary Teeth) 1. Finn SB: Clinical Pedodontics. WB Saunders Company, Philadelphia, 1967, p 477. 2. Mercuri LG, O’Neill R: Multiple impacted and supernumerary teeth in sisters. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 50:293, 1980. 3. Ranta R: Numeric anomalies of teeth in concomitant hypodontia and hyperodontia. J Craniofac Genet Dev Biol 8:245, 1988. 4. Joslyn G, Carlson M, Thliveris A, et al.: Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66:601, 1991. 5. Nishisho I, Nakamura Y, Miyoshi Y, et al.: Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665, 1991. 6. Mundlos S, Otto F, Mundlos C, et al.: Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773, 1997. 7. Zhou G, Chen Y, Zhou L, et al.: CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia. Hum Mol Genet 8:2311, 1999. 8. Wynne SE, Aldred MJ, Bartold PM: Hereditary gingival fibromatosis associated with hearing loss and supernumerary teeth—a new syndrome. J Periodontol 66:75, 1995. 9. Franc¸ois J: A new syndrome: Dyscephalia with bird face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, microphthalmia and congenital cataract. Arch Ophthalmol 60:842, 1958. 10. Gorlin RJ, Anderson RC, Blaw ME: Multiple lentigines syndrome: complex comprising multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness, and autosomal dominant hereditary pattern. Am J Dis Child 117:652, 1969. 11. Munshi A, Munshi AK: Leopard syndrome—report of a variant case. J Indian Soc Pedod Prev Dent 17:5, 1999. 12. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiple-lentigines/ LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389, 2002. 13. Giedion A: Das tricho-rhino-phalangeale syndrome. Helv Paediatr Acta 21:475, 1966. 14. Ludecke HJ, Schaper J, Meinecke P, et al.: Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. Am J Hum Genet 68:81, 2001. 15. Bork K, Stender E, Schmidt D, et al.: Familiaere kongenitale hypotrichose mit ‘unkaemmbaren haaren,’ retina-pigmentblattdystrophie, juveniler katarakt und brachymetakarpie: eine weitere entitaet aus der gruppe der ektodermalen dysplasien. Hautarzt 38:342, 1987. 16. Silengo M, Lerone M, Romeo G, et al.: Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly: report of a new patient with additional findings. Am J Med Genet 47:931, 1993. 17. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck. Oxford University Press, New York, 2001, p 1117. 18. Gurrieri F, Sammito V, Ricci B, et al.: Possible new type of oral-facialdigital syndrome with retinal abnormalities: OFDS type (VIII). Am J Med Genet 42:789, 1992. 19. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 20. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999.

Teeth

445

Table 14-7. Syndromes with supernumerary teeth as a component Syndrome

Prominent Features

Causation Gene/Locus

Adenomatous polyposis of the colon4,5

Adenomatous polyps of the colon and rectum, congenital hypertrophy of the retinal pigment epithelium, dental anomalies

(175100) APC, 5q21–q22

Cleidocranial dysplasia6,7

Persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, supernumerary teeth, vertebral malformations

(119600) CBFA1 (RUNX2), 6p21

Gingival fibromatosis, hearing loss, and supernumerary teeth8

Gingival overgrowth at the time of deciduous tooth eruption, hearing loss, supernumerary teeth, hypertelorism

Unknown

Hallermann-Streiff9

Birdlike facies with hypoplastic mandible and beaked nose, proportionate dwarfism, hypotrichosis, microphthalmia, dental anomalies, congenital cataract

(234100)

LEOPARD10–12

Multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, sensorineural deafness, delayed secondary sexual characteristics, supernumerary teeth

(151100) PTPN11, 12q24.1

Trichorhino-phalangeal types I and III13,14

Sparse hair, beaked nose, long upper lip, super-numerary teeth, severe metacarpophalangeal shortening

(190350, 190351) TRPS1 18q24.12

Uncombable hair, retinal pigmentary dystrophy, dental anomalies, brachydactyly15,16

Congenital hypotrichosis and uncombable hair, associated with juvenile cataracts, retinal pigmentary dystrophy, oligodontia, brachymetacarpy

(191482)

Unusual facies, digital anomalies, supernumerary teeth17

Prominent forehead with widow’s peak, supernumerary teeth, subglottic tracheal hypoplasia, brachydactyly, club foot, clinodactyly

AD

Oral-facial-digital with retinal anomalies18

Mild mental retardation; small notch in the upper lip; highly arched palate with bifid tongue; supernumerary lower canine bilaterally; lobulated, hamartomatous tongue; multiple frenula (could also be X-linked)

(258865)

Rothmund-Thomson19,20

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

(268400) RECQL4, 8q24.3

Steroid dehydrogenase deficiency21

Supernumerary teeth, steroid dehydrogenase deficiency

Unknown

Cataract-dental22–28

Dense nuclear cataracts and frequently microcornea with mesiodens and incisor anomalies

(302350) Xp22.13

Focal dermal hypoplasia29

Atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, and multiple papillomas of the mucous membranes or skin, digital anomalies, oral anomalies, ocular anomalies, mental retardation

(305600)

Orofaciodigital, types I, III30–32

Clefts of the jaw and tongue, other malformations of the face and skull, malformation of the hands and teeth, mental retardation

(311200, 258850) CXORF5, Xp22.3–p22.2

Autosomal Dominant Conditions

Autosomal Recessive Conditions

X-Linked Conditions

21. Lyngstadaas SP, Crossner CJ, Nazer H, et al.: Severe dental aberrations in familial steroid dehydrogenase deficiency: a new association. Clin Genet 49:249, 1996. 22. Bixler D, Higgins M, Hartsfield J Jr: The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females. Clin Genet 26:30, 1984. 23. Bergen AAB, ten Brink J, Schuurman EJM, et al.: Nance-Horan syndrome: linkage analysis in a family from the Netherlands. Genomics 21:238, 1994. 24. Stambolian D, Bond A, Lewis RA, et al.: Linkage studies in the Nance Horan syndrome using eight polymorphic DNA probes from the short arm of X chromosome. Cytogenet Cell Genet 51:1085, 1989.

25. Zhu D, Alcorn DM, Antonarakis SE, et al.: Assignment of the NanceHoran syndrome to the distal short arm of the X chromosome. Hum Genet 86:54, 1990. 26. Stambolian D, Favor J, Silvers W, et al.: Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance-Horan syndrome, on the mouse X chromosome. Genomics 22:377, 1994. 27. Toutain A, Dessay B, Ronce N, et al.: Refinement of the NHS locus on chromosome Xp22.13 and analysis of five candidate genes. Eur J Hum Genet 10:516, 2002. 28. Burdon KP, McKay JD, Sale MM, et al.: Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe

446

Craniofacial Structures

Table 14-8. Epidemiologic characteristics of supernumerary teeth Characteristic

Summary Information

Frequency (primary dentition)36

<0.1%

Frequency (permanent dentition)37–39

1–5%

Ethnic differences37–39

No remarkable differences in frequency among populations

Gender differences39–42

M/F 2:1 in Europeans; 4:1 in Africans; 5.5:1 in Japanese; and 6.5:1 in Chinese

Familial patterns33

Approximately 30% are familial cases

29. 30. 31. 32. 33. 34. 35. 36.

37. 38. 39.

40. 41. 42.

congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet 73:1120, 2003. Hall EH, Terezhalmy GT: Focal dermal hypoplasia syndrome. J Am Acad Dermatol 9:443, 1983. Sugarman GI, Katakia M, Menkes JH: See-saw winking in a familial oral-facial-digital syndrome. Clin Genet 2:248, 1971. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. Stellzig A, Basdra EK, Komposch G: Mesiodentes: incidence, morphology, etiology. J Orofac Orthop 58:144, 1997. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003. Scheiner MA, Sampson WJ: Supernumerary teeth: a review of the literature and four case reports. Aust Dent J 42:160, 1997. Whittington BR, Durward CS: Survey of anomalies in primary teeth and their correlation with the permanent dentition. N Z Dent J 92:4, 1996. Clayton JM: Congenital dental anomalies occurring in 3,557 children. J Dent Child 23:206, 1956. Niswander JD, Sajuku C: Congenital anomalies of teeth in Japanese children. Am J Phys Anthropol 21:569, 1963. Primo LG, Wilhelm RS, Bastos EPS: Frequency and characteristics of supernumerary teeth in Brazilian children: consequences and proposed treatments. Rev Odontol Sa˜o Paulo 11:231, 1997. Hogstrum A, Andersson L: Complications related to surgical removal of anterior supernumerary teeth in children. J Dent Child 54:341, 1987. So LLY: Unusual supernumerary teeth. Angle Orthod 60:289, 1990. Umweni AA, Osunbor GE: Non-syndromic multiple supernumerary teeth in Nigerians. Odontostomatol Trop 25:43, 2002.

14.3 Microdontia Definition

Microdontia is a tooth that is much smaller than its contralateral homolog or a tooth of the same group from an opposing arch (mandibular central incisors are exceptions), a tooth that does not ‘‘fill’’ its space in the dental arch, or a tooth that appears small because of absence of expected shape (peg shaped, conical, or tapered). There are anatomic standards, of course, but the criteria stated above are the most useful to the clinician. Diagnosis

Microdontia is diagnosed by simple observation or measurement. Standards for tooth size have been published (Table 14-9), but mi-

crodontia is usually determined subjectively. Microdontia may affect only a few teeth, usually homologous teeth such as the maxillary lateral incisors, or may be generalized. It may be an isolated trait, may be associated with tooth agenesis or orofacial clefts, or may be one feature in syndromes.1–6 Etiology and Distribution

Syndromes with microdontia as a component are listed in Table 1410. It is likely that microdontia is a variable expression of tooth agenesis and therefore is probably multifactorial in etiology. The more severe the tooth agenesis, the smaller the size of the tooth formed.3 Individuals with agenesis of one upper lateral incisor present with a 13-fold increased risk of having microdontia involving the contralateral upper lateral incisor. Also, cases with molar agenesis have a fourfold increased risk of having microdontia involving an upper lateral incisor. The suggestive association between molar agenesis and microdontia of the upper lateral incisor provides evidence that incisors and molars share some developmental genetic mechanisms, which appear to be independent from those that regulate premolar development.85 This is in agreement with the pattern of tooth agenesis seen from the mutations in PAX9 and MSX1 in humans. PAX9 causes oligodontia with preferential agenesis of molars, while MSX1 causes oligodontia with preferential agenesis of second premolars and third molars.86 The reported frequency of pegged teeth in the deciduous dentition is 0.2%, while the frequency in the permanent dentition is 1–2% among those of European descent and 6.2% among Japanese.87–89 Prognosis, Treatment, and Prevention

There are no morbid features associated with isolated microdontia. Malalignment of adjacent teeth and malocclusion may occur, depending on the site and extent of microdontia. Treatment usually consists of reshaping the tooth with composite resin or crowning. There are no useful preventive measures for microdontia. References (Microdontia) 1. Schalk-van der Weide Y, Bosman F: Tooth size in relatives of individuals with oligodontia. Arch Oral Biol 41:469, 1996. 2. Carretero Quezada MGC, Hoeksma JB, van de Velde JP, et al.: Dental anomalies in patients with familial and sporadic cleft lip and palate. J Biol Buccale 16:185, 1988. 3. Brook AH, Elcock C, al-Sharood MH, et al.: Further studies of a model for the etiology of anomalies of tooth number and size in humans. Connect Tissue Res 43:289, 2002. 4. Lidral AC, Reising BC: The role of MSX1 in human tooth agenesis. J Dent Res 81:274, 2002. 5. McKeown HF, Robinson DL, Elcock C, et al.: Tooth dimensions in hypodontia patients, their unaffected relatives and a control group measured by a new image analysis system. Eur J Orthod 24:131, 2002. 6. Lammi L, Halonen K, Pirinen S, et al.: A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Eur J Hum Genet 11:866, 2003. 7. Renner RP: An Introduction to Dental Anatomy and Esthetics. Quintessence, Chicago, 1985. 8. Hay RJ, Wells RS: The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition. Br J Derm 94:287, 1976. 9. McGrath JA, Duijf PHG, Doetsch V, et al.: Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet 10:221, 2001. 10. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996.

Teeth

447

Table 14-9. Average sizes of permanent and deciduous teeth Permanent Heighta

Widthb

Deciduous Heighta

Widthb

Maxillary

Central incisors

10.5

8.5  7.0

6.0

6.5  5.0

Lateral incisors

9.0

6.5  6.0

5.6

5.0  4.0

10.0

7.5  8.0

6.5

7.0  7.0

Canines First premolars

8.5

7.0  9.0

—

—

Second premolars

8.5

7.0  9.0

—

—

First molars

7.5

10.0  11.0

5.1

7.3  8.5

Second molars

7.0

9.0  11.0

5.7

8.2  10.0

Third molars

6.5

8.5  10.0

—

—

9.0

5.0  6.0

5.0

4.2  4.0

Mandibular

Central incisors Lateral incisors Canines

9.5

5.5  6.5

5.2

4.1  4.0

11.0

7.0  7.5

6.0

5.0  4.8

First premolars

8.5

7.0  8.0

—

—

Second premolars

8.0

7.0  8.0

—

—

First molars

7.5

11.0  10.5

6.0

7.7  7.0

Second molars

7.0

10.5  10.5

5.5

9.9  8.7

Third molars

7.0

10.0  9.5

—

—

a

Height of crown in cm. Mesiodistal width  buccolingual (buccopalatal) width in cm. Modified from Renner.7

b

11. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000. 12. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 13. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 14. Saadi I, Semina EV, Amendt BA, et al.: Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034, 2001. 15. Borges AS, Susanna R Jr, Carani JCE, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 16. Jorgenson RJ, Dowben JS, Dowben SL: Autosomal dominant ectodermal dysplasia. J Craniofac Genet Dev Biol 7:403, 1987. 17. Monreal AW, Ferguson BM, Headon DJ, et al.: Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22:366, 1999. 18. Hyland J, Ala-Kokko L, Royce P, et al.: A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers-Danlos syndrome type VI. Nature Genet 2:228, 1992. 19. Ha VT, Marshall MK, Elsas LJ, et al.: A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. J Clin Invest 93:1716, 1994. 20. Heikkinen J, Toppinen T, Yeowell H, et al.: Duplication of seven exons in the lysyl hydroxylase gene is associated with longer forms of a repetitive sequence within the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet 60:48, 1997. 21. Freire-Maia N: Ectodermal Dysplasia. A Clinical and Genetic Study. Liss, New York, 1984, p 251.

22. Niikawa N, Matsuura N, Fukushima Y, et al.: Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565, 1981. 23. Lo IFM, Cheung LYK, Ng AYY, et al.: Interstitial dup(1p) with findings of Kabuki make-up syndrome. Am J Med Genet 78:55, 1998. 24. Milunsky JM, Huang XL: Unmasking Kabuki syndrome: chromosome 8p22-8p23.1 duplication revealed by comparative genomic hybridization and BAC-FISH. Clin Genet 64:509, 2003. 25. Gillespie FD: A hereditary syndrome: ‘dysplasia oculodentodigitalis.’ Arch Ophthalmol 71:187, 1964. 26. Paznekas WA, Boyadjiev SA, Shapiro RE, et al.: Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408, 2003. 27. Levin LS, Jorgenson RJ, Cook RA: Otodental dysplasia: a ‘new’ ectodermal dysplasia. Clin Genet 8:136, 1975. 28. Kantaputra PN, Kinoshita A, Limwonges C, et al.: A Thai mother and son with distal symphalangism, hypoplastic carpal bones, microdontia, dental pulp stones, and narrowing of the zygomatic arch: a new distal symphalangism syndrome? Am J Med Genet 109:56, 2002. 29. Bork K, Stender E, Schmidt D, et al.: Familiaere kongenitale hypotrichose mit ‘unkaemmbaren haaren,’ retina-pigmentblattdystrophie, juveniler katarakt und brachymetakarpie: eine weitere entitaet aus der gruppe der ektodermalen dysplasien. Hautarzt 38:342, 1987. 30. Silengo M, Lerone M, Romeo G, et al.: Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly: report of a new patient with additional findings. Am J Med Genet 47:931, 1993. 31. Jumlongras D, Bei M, Stimson JM, et al.: A nonsense mutation in MSX1 causes Witkop Syndrome. Am J Hum Genet 69:67, 2001. 32. Sulisalo T, Makitie O, Sistonen P, et al.: Uniparental disomy in cartilage-hair hypoplasia. Eur J Hum Genet 5:35, 1997. 33. Ridanpaa M, van Eenennaam H, Pelin K, et al.: Mutations in the RNA component of RNase MRP cause a pleitropic human disease, cartilagehair hypoplasia. Cell 104:195, 2001.

Table 14-10. Syndromes with microdontia as a component Syndrome

Prominent Features

Causation Gene/Locus

Autosomal Dominant Conditions

Ankyloblepharon-ectodermal defects-cleft lip/palate8,9

Coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; cleft lip/palate

(106260) p63, 3q27

Axenfeld-Rieger10–15

Eye, dental, and umbilical anomalies

(180500) PITX2, 4q25-q26 FOXC1, 6p25 13q14

Ectodermal dysplasia 316,17

Mild hypotrichosis, mild hypodontia, variable degrees of hypohidrosis (can also be autosomal recessive)

(129490) EDAR, 2q11-q13

Ehlers-Danlos type VI18–20

Ocular, muscular, and skin defects; abnormal maxilla; occasional hypodontia and/or smaller teeth sizes

(225400) PLOD1, 1p36.3–p36.2

Hair-nail-skin-teeth dysplasias21

Large number of rare disorders involving binary, ternary, or quaternary combination of hair, nails, skin appendages, and teeth anomalies (can also be autosomal recessive or X-linked)

(125640, 257980, 262020, 272980, 275450)

Niikawa-Kuroki (Kabuki)22–24

A peculiar face, characterized by eversion of the lower lateral eyelid, arched eyebrows with sparse or dispersed lateral one-third, depressed nasal tip, prominent ears, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate mental retardation, postnatal growth deficiency, heart defects, dental anomalies

(147920)

Oculodento-digital dysplasia25,26

Bilateral microphthalmos, abnormally small nose, hypotrichosis, dental anomalies, fifth finger camptodactyly, syndactyly of the fourth and fifth fingers, missing toe phalanges

(164200) GJA1, 6q21–q23.2

Otodental dysplasia27

Sensorineural hearing loss, dental anomalies, missing premolars

(166750)

Symphalangism, Kantaputra type28

Distal symphalangism, microdontia, dental pulp stones, narrowed zygomatic arch

(606895)

Uncombable hair, retinal pigmentary dystrophy, dental anomalies, brachydactyly29,30

Congenital hypotrichosis and uncombable hair, associated with juvenile cataracts, retinal pigmentary dystrophy, oligodontia, and brachymetacarpy

(191482)

Witkop (tooth-and-nail)31

Missing teeth and poorly formed nails

(189500) MSX1, 4p16.1

Cartilage-hair hypoplasia32–35

Short-limbed dwarfism due to skeletal dysplasia, sparse hair, dental anomalies, lymphopenia, anemia, neutropenia

(250250) RMRP, 9p21–p12

Cleft lip/palate, congenital contractures, ectodermal dysplasia, and psychomotor and growth retardation36

Typical facies, congenital contractures, orofacial clefts, oligodontia and other teeth anomalies (may be X-linked)

(301815)

Cleft lip/palate-ectodermal dysplasia37,38

Anhidrosis, hypotrichosis, dental anomalies, dysplasia of nails, cleft lip and palate, deformity of the fingers and toes, malformation in the genitourinary system, popliteal perineal pterygium, syndactyly

(225000) PVRL1, 11q23–q24

Autosomal Recessive Conditions

(continued)

448

Table 14-10. Syndromes with microdontia as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Cranioectodermal dysplasia39

Dolichocephaly; sparse, slow-growing, fine hair; epicanthal folds; hypodontia and/or microdontia; brachydactyly; narrow thorax

(218330)

Ectodermal dysplasia, Margarita Island type38,40

Scanty eyebrows and eyelashes; sparse, short, and dry scalp hair; dental anomalies; cleft lip/palate; syndactyly of fingers and toes; onychodysplasia

(225060) PVRL1, 11q23–q24

Ellis-van Creveld41–43

Skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth

(225500) EVC, EVC2

Gorlin-Chaudhry-Moss44

Craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies, patent ductus arteriosus, normal intelligence

(233500)

Immunoosseous dysplasia, Schimke type45–47

Combination of spondyloepiphyseal dysplasia and numerous lentigines; microdontia and other dental abnormalities; slowly progressive immune defect; immune-complex nephritis, which leads to death at about age 8 years

(242900) SMARCAL1

Larsen48,49

Bilateral dislocation of the knees, pes cavus, cylindrically shaped fingers, characteristic facies (can also be autosomal dominant)

(150250) FLNB

Microcephalic osteodysplastic dwarfism, type II50,51

Dwarfism, microcephaly, characteristic facies, bone anomalies, microdontia

(210720)

Odontotrichomelic52

Tetramelic deficiency, ectodermal dysplasia, deformed pinnae

(273400)

Polydactyly, postaxial, with dental and vertebral anomalies53

Postaxial polydactyly and other abnormalities of the hands and feet, hypoplasia and fusion of vertebral bodies, dental anomalies

(263540)

Rothmund-Thomson54,55

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

(268400) RECQL4, 8q24.3

Spondyloepimetaphyseal dysplasia with abnormal dentition56

Generalized platyspondyly with epiphyseal and metaphyseal involvement, thin tapering fingers with accentuated palmar creases, abnormal dentition (oligodontia and pointed incisors)

(601668)

Coffin-Lowry57–61

Mental retardation with peculiar pugilistic nose, large ears, tapered fingers, drumstick terminal phalanges by radiograph, and pectus carinatum Other complications: premature death, progressive kyphoscoliosis, spinal stenosis, drop attacks, abnormalities in dentition, hearing loss, ocular abnormalities, excess of psychiatric illness in carrier females

(303600) RSK2, Xp22.2–p22.1

Ectodermal dysplasia 162–64

Males: characteristic facies; teeth often missing or misshapen; fine, sparse hair; skin is thin, glossy, smooth, and dry with hypohidrosis Females: sparse, thin scalp hair and mosaic patchy distribution of body hair; abnormal teeth and mild hypohidrosis

(305100) ED1, Xq12–q13.1

Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum65

Severe mental retardation, macrocephaly, hypertelorism, short and downward slanting eyelids, small nose and mouth, dysplastic and low-set ears, swallowing difficulties, reduced sweating, sparse scalp hair, delayed dentition, small teeth with defective enamel

(225040)

X-Linked Conditions

(continued)

449

450

Craniofacial Structures

Table 14-10. Syndromes with microdontia as a component (continued) Causation Locus/Gene

Syndrome

Prominent Features

Faciogenital dysplasia66–70

Ocular hypertelorism, anteverted nostrils, broad upper lip, escrotum anomalies, occasional dental anomalies

(305400) FGD1, Xp11.21

Focal dermal hypoplasia71

Atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, multiple papillomas of the mucous membranes or skin, digital anomalies, oral anomalies, ocular anomalies, mental retardation

(305600)

Incontinentia pigmenti72

Disturbance of skin pigmentation sometimes associated with a variety of malformations of the eye, teeth, skeleton, and heart

(308300) NEMO, Xq28

Johanson-Blizzard73

Aplasia or hypoplasia of the nasal alae, congenital deafness, hypothyroidism, postnatal growth retardation, mental retardation, midline ectodermal scalp defects, and microdontia or absent permanent teeth

(243800)

Orofaciodigital, type I74,75

Clefts of the jaw and tongue, other malformations of the face and skull, malformation of the hands and teeth, and mental retardation

(311200) CXORF5, Xp22.3–p22.2

Down76–81

Mental retardation, typical facies, heart defects, short stature, dental anomalies

(190685) Trisomy

Microcephaly, macrotia, and mental retardation82

Microcephaly, mental retardation, huge ears with very large lobules, median frenulum of the upper lip, ptosis, microdontia, bilateral ureterohydronephrosis secondary to vesicoureteral reflux (can be autosomal dominant or X-linked)

(602555)

Microcephalic osteodysplastic primordial dwarfism with tooth abnormalities83

Growth retardation, opalescent and rootless teeth, severe microdontia, hypoplastic alveolar process, unerupted teeth, long second toes

(607561)

Williams-Beuren84

Typical facies, mental retardation, growth deficiency, cardiovascular anomalies, infantile hypercalcemia

(194050) 7q11.23

Chromosomal and Other Conditions

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43. Ruiz-Perez VL, Tompson SWJ, Blair HJ, et al.: Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet 72:728, 2003. 44. Gorlin RJ, Chaudhry AP, Moss ML: Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies—a new syndrome? J Pediatr 56:778, 1960. 45. Lundman MD, Cole DEC, Crocker JFS, et al.: Schimke immunoosseous dysplasia: case report and review. Am J Med Genet 47:793, 1993. 46. Fonseca MA: Dental findings in the Schimke immuno-osseous dysplasia. Am J Med Genet 93:158, 2000. 47. Boerkoel CF, Takashima H, John J, et al.: Mutant chromatin remodeling protein SMARCAL1 causes Shimke immuno-osseous dysplasia. Nat Genet 30:215, 2002. 48. Larsen LJ, Schottstaedt ER, Bost FC: Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 37:574, 1950. 49. Krakow D, Robertson SP, King LM, et al.: Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 36:405, 2004. 50. Karasik JB, Garcia DM, Pritzker H, et al.: Deletion of 1q21-q24 in a patient with features of microcephalic osteodysplastic primordial dwarfism, type II (MOPDII). Am J Hum Genet 51(suppl):A82, 1992. 51. Lin HJ, Sue GY, Berkowitz CD, et al.: Microdontia with severe microcephaly and short stature in two brothers: osteodysplastic primordial dwarfism with dental findings. Am J Med Genet 58:136, 1995.

Teeth 52. Freire-Maia N. A newly recognized genetic syndrome of tetramelic deficiencies, ectodermal dysplasias, deformed ears and other anomalies. Am J Hum Genet 22:370, 1970. 53. Rogers JG, Levin LS, Dorst JP, et al.: A postaxial polydactyly-dental-vertebral syndrome. J Pediatr 90:230, 1977. 54. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 55. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999. 56. Rao V, Morton RE, Young ID: Spondyloepimetaphyseal dysplasia and abnormal dentition in siblings: a new autosomal recessive syndrome. Clin Dysmorphol 6:3, 1997. 57. Trivier E, De Cesare D, Jacquot S, et al.: Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384:567, 1996. 58. Jacquot S, Merienne K, De Cesare D, et al.: Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. Am J Hum Genet 63:1631, 1998. 59. Manouvrier-Hanu S, Amiel J, Jacquot S, et al.: Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome. J Med Genet 36:775, 1999. 60. Hunter AGW: Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet 111:345, 2002. 61. Simensen RJ, Abidi F, Collins JS, et al.: Cognitive function in CoffinLowry syndrome. Clin Genet 61:299, 2002. 62. Zonana J, Gault J, Davies KJP, et al.: Detection of a molecular deletion at the DXS732 locus in a patient with X-linked hypohidrotic ectodermal dysplasia (EDA), with the identification of a unique junctional fragment. Am J Hum Genet 52:78, 1993. 63. Kere J, Srivastava AK, Montonen O, et al.: X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 13:409, 1996. 64. Monreal AW, Zonana J, Ferguson B: Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet 63:380, 1998. 65. Fryns JP, Chrzanowska K, van den Berghe H: Hypohidrotic ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum. J Med Genet 26:520, 1989. 66. Aarskog D: A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J Pediatr 77:856, 1970. 67. Pasteris NG, Cadle A, Logie LJ, et al.: Isolation and analysis of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative, rho/ rac guanine nucleotide exchange factor. Cell 79:669, 1994. 68. Orrico A, Galli L, Falciani M, et al.: A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome). FEBS Lett 478:216, 2000. 69. Schwartz CE, Gillessen-Kaesbach G, May M, et al.: Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome. Eur J Hum Genet 8:869–874, 2000. 70. Lebel RR, May M, Pouls S, et al.: Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene. Clin Genet 61:139, 2002. 71. Goltz RW, Peterson WC Jr, Gorlin RJ, et al.: Focal dermal hypoplasia. Arch Dermatol 86:708, 1962. 72. The International Incontinentia Pigmenti Consortium: Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature 405:466, 2000. 73. Johanson AJ, Blizzard RM: A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 79:982, 1971. 74. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. 75. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. 76. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866.

451 77. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 78. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977. 79. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 80. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 81. Shapira J, Chaushu S, Becker A: Prevalence of tooth transposition, third molar agenesis, and maxillary canine impactation in individuals with Down syndrome. Angle Orthod 70:290, 2000. 82. Verloes A, Lesenfants S, Philippet B, et al.: Microcephaly, macrotia, unusual mimics and mental retardation syndrome: new syndrome or variant of de Lange type 2 syndrome. Genet Couns 7:277, 1996. 83. Kantaputra PN: Apparently new osteodysplastic and primordial short stature with severe microdontia, opalescent teeth, and rootless molars in two siblings. Am J Med Genet 111:420, 2002. 84. Ewart AK, Morris CA, Atkinson D, et al.: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11, 1993. 85. Barbosa ARS, Modesto A, Meira R, et al.: Molar agenesis is associated with abnormalities of superior lateral incisors. In: International Association for Dental Research 82nd General Session Program Book, 2004, p 194. 86. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003. 87. Saito T: A genetic study on the degenerative anomalies of deciduous teeth. Jpn J Hum Genet 4:27, 1959. 88. Schulze C: Developmental abnormalities of the teeth and jaws. In: Thoma’s Oral Pathology. Gorlin RJ, Goldman HM, eds. Mosby, St. Louis, 1970. 89. Sumiya Y: Statistical study on dental anomalies in the Japanense. J Anthropol Soc Nippon 67:171, 1959.

14.4 Macrodontia Definition

Macrodontia is a tooth that is much larger than its contralateral homolog or teeth from the same group from an opposing arch (the maxillary central incisors are exceptions); a tooth that ‘‘overfills’’ its space in the dental arch, crowds out adjacent teeth, or is rotated to accommodate its size; or a tooth that appears large because of exaggerated dimension. Fused teeth (joining of two teeth by the pulp tissue and dentin) and germination (budding of a second tooth from one tooth germ) might fit well into the later category. Diagnosis

Macrodontia is diagnosed by simple observation or measurement and comparison with standards for tooth size (Table 14-9). Even though there are anatomic standards, the criteria stated above are the most useful to the clinician. Macrodontia is usually an isolated trait but can be accompanied by other dental anomalies or occur as part of a syndrome.1–3 Also, patients with supernumerary teeth present significantly larger teeth compared to the general population.4 Etiology and Distribution

Syndromes with macrodontia as a component are listed in Table 14-11. Because of the association with sexual chromosome anomalies, it appears that there are dental growth-promoting factors on both the X and the Y chromosomes. The promoting effect of the Y chromosome on tooth growth seems to be stronger than that of the

452

Craniofacial Structures

Table 14-11. Syndromes with macrodontia as a component Causation Gene/Locus

Syndrome

Prominent features

KBG5

Short stature, characteristic facies, mental retardation, skeletal anomalies, oligodontia, macrodontia

AD (148050)

Polydactyly, postaxial, with dental and vertebral anomalies6

Postaxial polydactyly and other abnormalities of the hands and feet, hypoplasia and fusion of vertebral bodies, dental anomalies

AR (263540)

Oculofaciocardio-dental7–9

Cataracts, microphthalmia, oligodontia, radiculomegaly, septal heart defects

XL (300166) BCL6 corepressor (BCOR)

47, XXY (Klinefelter)10

Tall stature, delayed speech in 50% of the cases, behavior disorders

(314240) Chromosomal

47, XYY11,12

Tall stature, 1/3 of the cases will present with delayed speech or language development, higher risk for criminal behavior

(314240) Chromosomal

Hemihyperplasia13,14

The enlarged area may vary from a single digit, a single limb, or unilateral facial enlargement to involvement of half the body

Sporadic (235000) 11p15

X chromosome.10 Occasionally, exaggerated tooth size is seen in conjunction with absence of an adjacent tooth, suggesting that the large tooth may be fusion of two adjacent teeth. The frequency of macrodontia is unknown; it is certainly rare.

13. Gorlin RJ, Meskin LH: Congenital hemihypertrophy. J Pediatr 61:870, 1962. 14. West PMH, Love DR, Stapleton PM, et al.: Paternal uniparental disomy in monozygotic twins discordant for hemihypertrophy. J Med Genet 40:223, 2003.

Prognosis, Treatment, and Prevention

There are no morbid features associated with isolated macrodontia. Malalignment of adjacent tooth and malocclusion can occur, depending on the site and extent of macrodontia. Treatment may be indicated for aesthetic reasons. There are no useful preventive measures for macrodontia. References (Macrodontia) 1. Ekman-Westborg B, Julin P: Multiple anomalies in dental morphology: macrodontia, multituberculism, central cusps, and pulp invaginations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 38:217, 1974. 2. Ritzau M, Carlsen O, Kreiborg S, et al.: The Ekman-Westborg-Julin syndrome: report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:293, 1997. 3. Yoda T, Ishii Y, Honma Y, et al.: Multiple macrodonts with odontoma in a mother and son—a variant of Ekman-Westborg-Julin syndrome. Report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85:301, 1998. 4. Brook AH, Elcock C, al-Sharood MH, et al.: Further studies of a model for the etiology of anomalies of tooth number and size in humans. Connect Tissue Res 43:289, 2002. 5. Herrmann J, Pallister PD, Tiddy W, et al.: The KBG syndrome—a syndrome of short stature, characteristic facies, mental retardation, macrodontia amd skeletal anomalies. Birth Defects Orig Artic Ser XI(5), 1975. 6. Rogers JG, Levin LS, Dorst JP, et al.: A postaxial polydactyly-dentalvertebral syndrome. J Pediatr 90:230–235, 1977. 7. Shepard MK: An unidentified syndrome with abnormality of skin and hair. Birth Defects Orig Artic Ser VII(8):353, 1971. 8. Hayward JR: Cuspid gigantism. Oral Surg Oral Med Oral Path Oral Radiol Endod 49:500, 1980. 9. Gorlin RJ, Marashi AH, Obwegeser HL: Oculo-facio-cardio-dental (OFCD) syndrome. Am J Med Genet 63:290, 1996. 10. Alvesalo L, Portin P: 47,XXY males: sex chromosomes and tooth size. Am J Hum Genet 32:955, 1980. 11. Alvesalo L, Osborne RH, Kari M: The 47,XYY male, Y chromosome, and tooth size. Am J Hum Genet 27:53, 1975. 12. Alvesalo L, Kari M: Size and deciduous teeth in 47, XYY males. Am J Hum Genet 29:486, 1977.

14.5 Abnormalities of Tooth Shape Definition

Abnormalities of tooth shape occur in the crowns or roots of teeth. Crown form may be entirely distorted with the loss of the usual cusp and groove relationships (globodontia), or the crowns may have abnormal or supernumerary cusps (referred as talon cusps for incisors and canines and supernumerary cusps for premolars and molars) or invaginations (dens invaginatus). Shovel-shaped incisors are yet another variation of crown shape. Roots may be foreshortened or bent (dilacerated), or there may be supernumerary roots. The pulp chambers can be vertically enlarged (taurodontia). Diagnosis

Globodontia, talon cusps, supernumerary cusps, dens invaginatus, shovel-shaped incisors, dilacerations, supernumerary roots, and taurodontia may occur as isolated traits or be associated with tooth agenesis, supernumerary teeth, microdontia, or macrodontia. More than one abnormality of tooth shape can be present in the same case. Abnormalities of tooth shape can be part of various syndromes. Short stature is often described as accompanying abnormalities of tooth shape.1–15 Globodontia can be the only obvious feature in someone with otodental dysplasia, an autosomal dominant trait that presents with sensorineural hearing loss and dental anomalies.16 Abnormalities of crown shape are determined clinically. Dilacerated and supernumerary roots and taurodontia can be determined by radiographs. Etiology and distribution

Syndromes with shovel-shaped and other incisor abnormalities as a component are listed in Table 14-12, and those with globodontia or supernumerary cusps as a component are listed in Table 14-13, and those with taurodontia as a component are listed in Table 14-14. Globodontia is probably not seen as an isolated trait. It is found in otodental dysplasia, an autosomal dominant syn-

Teeth

453

Table 14-12. Syndromes with shovel-shaped and other incisor abnormalities as a component Syndrome

Prominent Features

Causation Gene/Locus

Rubinstein-Taybi17–22

Mental retardation, broad thumbs, and facial abnormalities; 90% of the cases present with talon cusps

AD (180849) CREBBP, 16p13.3

Orofaciodigital type II23,24

Poly-, syn-, and brachydactyly, lobate tongue with papilliform protuberances, angular form of the alveolar process of the mandible, supernumerary sutures in the skull, neuromuscular disturbances, cleft palate, and talon cusps

AR (252100)

Cataract-dental25–31

Dense nuclear cataracts and frequently microcornea with mesiodens and incisors of Hutchinson

XL (302350) Xp22.13

Incontinentia pigmenti32,33

Disturbance of skin pigmentation sometimes associated with a variety of malformations of the eye, teeth, skeleton, and heart

XL (308300) NEMO, Xq28

47, XXY (Klinefelter)34,35

Tall stature, delayed speech in 50% of the cases, behavior disorders, occasional shovel-shaped incisors

(314240) Chromosomal

47, XYY36,37

Tall stature, 1/3 of the cases will present with delayed speech or language development, higher risk for criminal behavior, occasional shoved-shaped incisors

(314240) Chromosomal

Down38–42 (190685)

Mental retardation, typical facies, heart defects, short stature, dental anomalies

Trisomy 21

Congenital syphilis43

Skin ulcers, rashes, fever, weakened or hoarse crying sounds, swollen liver and spleen, yellowish skin, anemia, bone deformities, incisors of Hutchinson

Prenatal infection

Sturge-Weber19,44,45

Nevus flammeus of the face, angioma of the meninges, glaucoma, occasional talon cusps

Sporadic (185300) 4q, chromosome 10

Table 14-13. Syndromes with globodontia or supernumerary cusps as a component Causation Gene/Locus

Syndrome

Prominent Features

Otodental dysplasia16

Sensorineural hearing loss, dental anomalies, missing premolars

AD (166750)

Cartilage-hair hypoplasia46–49

Short-limbed dwarfism due to skeletal dysplasia, sparse hair, dental anomalies (supernumerary cusps), lymphopenia, anemia, neutropenia

AR (250250) RMRP, 9p21–p12

Rothmund-Thomson50,51

Atrophy, pigmentation, telangiectasia, juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism, dental anomalies, soft tissue contractures, proportionate short stature, anemia, osteogenic sarcoma

AR (268400) RECQL4, 8q24.3

drome, and in Rothmund-Thomson syndrome, an autosomal recessive condition.16,50,51 The etiology of supernumerary cusps is unknown, although the differences in the prevalences of such abnormality among males and females suggest a multifactorial trait (male to female ratio is 1:2). Supernumerary cusps have a prevalence in the population as high as 47.6%.15 Dens invaginatus is probably a multifactorial trait with higher frequencies in those of Chinese, Japanese, Native Americans, and Eskimos, compared to European and African descents.15,90–93 Shovel-shaped incisors are more common among Native Americans, Inuit, and Asian populations (60–75%) compared to other ethnic groups, and it is probably a multifactorial trait.94 The cause for dilacerated and supernumerary roots is unknown; however, roots can be dilacerated as a consequence of trauma to erupting teeth. The supernumerary roots may be due to the dis-

turbances of the Hertwig’s epithelial root sheath forming the root.95,96 Taurodontia can be caused by a delay in the formation of horizontal extensions of Hertwig epithelial root sheath, whose invagination determines the position of the pulpal floor. Taurodontia has been reported in 0.5% of those of Japanese descent, 0.57–3.2% of those of European descent, and 4.37% of those of African descent. It is probably a multifactorial trait, although there have been a few reported families in which it appears to be transmitted in an autosomal dominant fashion.97 Prognosis, Treatment, and Prevention

None of the abnormalities discussed above is morbid or progressive. At most, they complicate certain types of dental treatment: endodontics (root canal therapy) and extractions. Prevention is not possible or necessary.

454

Craniofacial Structures

Table 14-14. Syndromes with taurodontia as a component Syndrome

Causation Gene/Locus

Prominent Features

Autosomal Dominant Conditions

Apert52–58

Skull malformation (acrocephaly of brachysphenocephalic type) and syndactyly of the hands and feet of a special type (complete distal fusion with a tendency to fusion also of the bony structures)

(101200) FGFR2, 10q26

Axenfeld-Rieger52,59–64

Eye, dental, and umbilical anomalies

(180500) PITX2, 4q25–26 FOXC1, 6p25 13q14

Basal-cell nevus52,65,66

Basal cell nevi; medulloblastoma; congenital thoracic scoliosis; astrocytoma with severe hydrocephalus; the palms and soles may show pits; bridging of the sella turcica; mild mandibular prognathism; lateral displacement of the inner canthi; frontal and biparietal bossing; odontogenic keratocysts of the jaws; kyphoscoliosis; bifid, missing, fused, and/or splayed ribs; imperfect segmentation of cervical vertebrae; characteristic lamellar calcification of the falx cerebri; ovarian fibromata and lymphomesenteric cysts, which tend to calcify; short fourth metacarpal

(109400) PTCH2, 9q22.3

Ectodermal dysplasias52

Large number of disorders characterized by hair, skin, dental, and nail anomalies (can also be autosomal recessive or X-linked)

Genes for the most common forms have been identified

Otodental dysplasia52

Sensorineural hearing loss, dental anomalies, including missing premolars

(166750)

Trichodentoosseous52,67,68

Enamel hypoplasia and hypocalcification with associated strikingly curly hair

(190320) DLX3

Pyramidal molar roots, taurodontia, fused molar roots, juvenile glaucoma, unusual upper lip

(200970)

Dyskeratosis congenita52,70–74

Cutaneous pigmentation, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in most cases

(305000) DKC1, Xq28

Fragile X52,75–78

Moderate to severe mental retardation, macroorchidism, large ears, prominent jaw, high-pitched and jocular speech

(309550) FMR1, Xq27.3

Orofaciodigital, type I52,79,80

Clefts of the jaw and tongue, other malformations of the face and skull, malformation of the hands and teeth, mental retardation

(311200) CXORF5, Xp22.3–p22.2

47, XXY (Klinefelter)81

Tall stature, delayed speech in 50% of the cases, behavior disorders

(314240) Chromosomal

49, XXXXY81

Mild microbrachycephaly, ocular hypertelorism, up-slanting palpebral fissures, epicanthic folds, strabismus, myopia, low broad nasal bridge, poorly modeled ears, short neck, taurodontia

Chromosomal

Down52,82–86 (190685)

Mental retardation, typical facies, heart defects, short stature, dental anomalies

Trisomy 21

Dyschondrosteosis52,87–89

Typical deformity of the distal radius and ulna and proximal carpal bones, mesomelic dwarfism

Pseudo-autosomal genes SHOX or SHOXY

Autosomal Recessive Conditions

Ackerman69

X-Linked Conditions

Chromosomal and Other Conditions

References (Abnormalities of Tooth Shape) 1. Stoy PJ: Taurodontism associated with other dental abnormalities. Dent Pract Dent Rec 10:202, 1960. 2. Haunfelder D: Ein beitrag zu den molaren mit prismatischen wurzeln (sog. taurodontismus). Dtsch Zahnarztbl 21:419, 1967. 3. Stenvik A, Zachrisson BU, Svatun B: Taurodontism and concomitant hypodontia in siblings. Oral Surg Oral Med Oral Path Oral Radiol Endod 33:841, 1972. 4. Moller KT, Gorlin RJ, Wedge B: Oligodontia, taurodontia and sparse hair—a syndrome. J Speech Hear Disord 38:268, 1973.

5. Saulk JJ Jr, Delaney JR: Taurodontism, diminished root formation and microcephalic dwarfism. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 36:231, 1973. 6. Gorlin RJ, Cervenka J, Moller K, et al.: Malformation syndromes: a selected miscellany. Birth Defects Orig Artic Ser XI(2):39, 1975. 7. Garner DG, Girgis SS: Taurodontism, short roots and external resorption associated with short stature and small head. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 44:271, 1977. 8. Casamassimo PS, Nowak AJ, Ettinger RL, et al.: An unusual triad: microdontia, taurodontia, and dens invaginatus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 45:107, 1978.

Teeth 9. Witkop CP Jr, Jaspers MT: Teeth with short thin dilacerated roots in patient with short stature. A dominantly inherited trait. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 54:553, 1982. 10. Davidson LE, Woolass KF: Severe hypodontia in an eight-year-old child. Br Dent J 158:215, 1985. 11. Ireland EJ, Black JP, Scures CC: Short roots, taurodontia, and multiple dens invaginatus. J Pedodontics 11:164, 1987. 12. Bazopoulou-Kyrkanidou E, Dacou-Voutetakis C, Nassi H, et al.: Microdontia, hypodontia, shortbulbous roots and root canals with strabismus, short stature, and borderline mentality. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 74:93, 1992. 13. Kantaputra PN, Gorlin RJ: Double dens invaginatus of molarized maxillary central incisors, premolarization of maxillary lateral incisors, multituberculism of mandibular incisors, canines and first molar, and sensorineural hearing loss. Clin Dysmorphol 1:128, 1992. 14. Shaw L: Short root anomaly in a patient with severe short-limbed dwarfism. Int J Paediatr Dent 5:249, 1995. 15. Kocsis GS, Marcsik A, Ko´tai EL, et al.: Supernumerary occlusal cusps on permanent human teeth. Acta Biol Szeged 46:71, 2002. 16. Levin LS, Jorgenson RJ, Cook RA: Otodental dysplasia: a ‘new’ ectodermal dysplasia. Clin Genet 8:136, 1975. 17. Rubinstein JH, Taybi H: broad thumbs and toes and facial abnormalities. Am J Dis Child 105:588, 1963. 18. Gardner DG, Girgis SS: Talon cusps: a dental anomaly in the Rubinstein-Taybi syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 47:519, 1979. 19. Davies PJ, Brook AH: The presentation of talon cusp: diagnosis, clinical features, associations and possible aetiology. Br Dent J 160:84, 1986. 20. Petrij F, Giles RH, Dauwerse HG, et al.: Rubinstein-Taibi syndrome caused by mutations in the transcriptional coactivator CBP. Nature 376:348, 1995. 21. Murata T, Kurokawa R, Krones A, et al.: Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in RubinsteinTaybi syndrome. Hum Mol Genet 10:1071, 2001. 22. Bartsch O, Locher K, Meinecke P, et al.: Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J Med Genet 39:496, 2002. 23. Mohr OL: A hereditary lethal syndrome in man. Avh Norske Videnskad Oslo 14:1, 1941. 24. Goldstein E, Medina JL: Mohr syndrome or oral-facial-digital II: report of two cases. J Am Dent Assoc 89:377, 1974. 25. Bixler D, Higgins M, Hartsfield J Jr: The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females. Clin Genet 26:30, 1984. 26. Bergen AAB, ten Brink J, Schuurman EJM, et al.: Nance-Horan syndrome: linkage analysis in a family from the Netherlands. Genomics 21:238, 1994. 27. Stambolian D, Bond A, Lewis RA, et al.: Linkage studies in the Nance Horan syndrome using eight polymorphic DNA probes from the short arm of X chromosome. Cytogenet Cell Genet 51:1085, 1989. 28. Zhu D, Alcorn DM, Antonarakis SE, et al.: Assignment of the NanceHoran syndrome to the distal short arm of the X chromosome. Hum Genet 86:54, 1990. 29. Stambolian D, Favor J, Silvers W, et al.: Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance-Horan syndrome, on the mouse X chromosome. Genomics 22:377, 1994. 30. Toutain A, Dessay B, Ronce N, et al.: Refinement of the NHS locus on chromosome Xp22.13 and analysis of five candidate genes. Eur J Hum Genet 10:516, 2002. 31. Burdon KP, McKay JD, Sale MM, et al.: Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet 73:1120, 2003. 32. Tsutsumi T, Oguchi H: Labial talon cusp in a child with incontinentia pigmenti achromians: case report. Pediatr Dent 13:236, 1991. 33. The International Incontinentia Pigmenti Consortium: Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature 405:466, 2000.

455 34. Alvesalo L, Portin P: 47,XXY males: sex chromosomes and tooth size. Am J Hum Genet 32:955, 1980. 35. Kirveskari P, Alvesalo L: Shovel shape of maxillary incisors in 47,XXY males. Proc Finn Dent Soc 77:79, 1981. 36. Alvesalo L, Osborne RH, Kari M: The 47,XYY male, Y chromosome, and tooth size. Am J Hum Genet 27:53, 1975. 37. Alvesalo L, Kari M: Size and deciduous teeth in 47, XYY males. Am J Hum Genet 29:486, 1977. 38. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866. 39. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 40. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977. 41. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 42. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 43. Modesto A, Portella W, Souza IPR: Sı´filis congeˆnita: relato de um caso na FO.UFRJ. Rev Odontopediatr 1:209, 1992. 44. Debicka A, Adamczak P: Przypadek dziedziczenia zespolu Sturge’aWebera. Klin Oczna 81:541, 1979. 45. Huq AHMM, Chugani DC, Hukku B, et al.: Evidence of somatic mosaicism in Sturge-Weber syndrome. Neurology 59:780, 2002. 46. Sulisalo T, Makitie O, Sistonen P, et al.: Uniparental disomy in cartilage-hair hypoplasia. Eur J Hum Genet 5:35, 1997. 47. Ridanpaa M, van Eenennaam H, Pelin K, et al.: Mutations in the RNA component of RNase MRP cause a pleitropic human disease, cartilagehair hypoplasia. Cell 104:195, 2001. 48. Bonafe L, Schmitt K, Eich G, et al.: RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet 61:146, 2002. 49. Rindanpaa M, Ward LM, Rockas S, et al.: Genetic changes in the RNA components of RNase MRP and RNase in Schmid metaphyseal chondrodysplasia. J Med Genet 40:741, 2003. 50. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 51. Kitao S, Shimamoto A, Goto M, et al.: Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82, 1999. 52. Jorgenson RJ: The conditions manifesting taurodontism. Am J Med Genet 11:435, 1982. 53. Slaney SF, Oldridge M, Hurst JA, et al.: Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet 58:923, 1996. 54. Oldridge M, Lunt PW, Zackai EH, et al.: Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Hum Mol Genet 6:137, 1997. 55. Passo-Buenos MR, Richieri-Costa A, Sertie AL, et al.: Presence of the Apert canonical S252W FGFR2 mutation in a patient without severe syndactyly. J Med Genet 35:677, 1998. 56. Lajeunie E, Cameron R, El Ghouzzi V, et al.: Clinical variability in patients with Apert’s syndrome. J Neurosurg 90:443, 1999. 57. Oldridge M, Zackai EH, McDonald-McGinn DM, et al.: De novo Aluelement insertions in FGFR2 identify a distinct pathological basis for Apert syndrome. Am J Hum Genet 64:446, 1999. 58. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. 59. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392, 1996.

456

Craniofacial Structures

60. Perveen R, Lloyd IC, Clayton-Smith J, et al.: Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 41:2456, 2000. 61. Nishimura DY, Searby CC, Alward WL, et al.: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 68:364, 2001. 62. Priston M, Kozlowski K, Gill D, et al.: Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 10:1631, 2001. 63. Saadi I, Semina EV, Amendt BA, et al.: Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034, 2001. 64. Borges AS, Susanna Junior R, Carani JCE, et al.: Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil. J Glaucoma 11:51, 2002. 65. Gorlin RJ, Goltz RW: Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib: a syndrome. New Eng J Med 262:908, 1960. 66. Smyth I, Narang MA, Evans T, et al.: Isolation and characterization of human Patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol Genet 8:291, 1999. 67. Price JA, Bowden DW, Wright JT, et al.: Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum Mol Genet 7:563, 1998. 68. Price JA, Wright JT, Kula K, et al.: A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. J Med Genet 35:825, 1998. 69. Ackerman JL, Ackerman AL, Ackerman AB: Taurodont, pyramidal and fused molar roots associated with other anomalies in a kindred. Am J Phys Anthropol 38:681, 1973. 70. Heiss NS, Knight SW, Vulliamy TJ, et al.: X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 19:32, 1998. 71. Knight SW, Heiss NS, Vulliamy TJ, et al.: X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet 65:50, 1999. 72. Vulliamy TJ, Knight SW, Heiss NS, et al.: Dyskeratosis congenita caused by a 3-prime deletion: germline and somatic mosaicism in a female carrier. Blood 94:1254, 1999. 73. Heiss NS, Megarbane A, Klauck SM, et al.: One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC). Genet Couns 12:129, 2001. 74. Knight SW, Vulliamy TJ, Morgan B, et al.: Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis. Hum Genet 108:299, 2001. 75. Kremer EJ, Pritchard M, Lynch M, et al.: Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711, 1991. 76. De Boulle K, Verkerk AJMH, Reyniers E, et al.: A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet 3:31, 1993. 77. Lugenbeel KA, Peier AM, Carson NL, et al.: Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome. Nat Genet 10:483, 1995. 78. Wang YC, Lin ML, Lin SJ, et al.: Novel point mutation within intron 10 of FMR-1 gene causing fragile X syndrome. Hum Mutat 10:393, 1997. 79. Fenton OM, Watt-Smith SR: The spectrum of the oro-facial-digital syndrome. Br J Plast Surg 38:532, 1985. 80. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 68:569, 2001. 81. Komatz Y, Tomoyoshi T, Yoshida O, et al.: Taurodontism and Klinefelter’s syndrome. J Med Genet 15:452, 1978. 82. Down JL: Observations on an ethnic classification of idiots. Clin Lect Rep London Hospital 3:249, 1866. 83. Lejeune J, Gautier M, Turpin R: Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci 248:1721, 1959. 84. Mikkelsen M: Down’s syndrome cytogenetic epidemiology. Hereditas 86:45, 1977.

85. Hook EG: Epidemiology of Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 11. 86. Thuline HC, Pueschel SM: Cytogenetics in Down syndrome. In: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences. Pueschel SM, Rynders JE, eds. Ware Press, Cambridge, 1982, p 133. 87. Shears DJ, Vassal HJ, Goodman FR, et al.: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 19:70, 1998. 88. Grigelioniene G, Eklof O, Ivarsson SA, et al.: Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia. Hum Genet 107:145, 2000. 89. Huber C, Cusin V, Merrer M, et al.: SHOX point mutations in dyschondrosteosis. J Med Genet 38:323, 2001. 90. Sumiya Y: Statistic study on dental anomalies in the Japanese. J Anthropol Soc Nippon 67:215, 1959. 91. Merril RG: Occlusal anomalous tubercles on premolars of Alaskan Eskimos and Indians. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 17:484, 1964. 92. Yip WK: The prevalence of dens invaginatus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 38:80, 1974. 93. Lin LC, Roan RT: Incidence of dens evaginatus investigated from three junior middle schools at Kaohsiung City. Formosan Sci 34:113, 1980. 94. Hrdlicka A: Shovel-shaped teeth. Am J Phys Anthropol 3:429, 1920. 95. Kannan SK, Suganya, Santharam H: Supernumerary roots. Indian J Dent Res 13:116, 2002. 96. Kamat SS, Kumar GS, Raghunath V, et al.: Permanent maxillary central incisor impaction: report of two cases. Quintessence Int 34:50, 2003. 97. Jorgenson RJ, Salinas CF, Shapiro SD: The prevalence of taurodontism in a select population. J Craniofac Genet Dev Biol 2:125, 1982.

14.6 Dental Malocclusion Definition

Dental malocclusion consists of teeth that are not properly aligned in the arch for a reason other than skeletal discrepancy. Malocclusion results from abnormal relationships of the different components of the maxillofacial complex. Malocclusion can be of dental origin or due to skeletal discrepancy. Skeletal malocclusions occur when the maxilla and/or the mandible are not properly aligned in relation to the skull or when the maxilla and mandible are misaligned relative to each other. Some malocclusions involve a dental and skeletal component. Diagnosis

Dental malocclusion can be diagnosed clinically. It can be associated with trauma, caries, oral habits (thumb finger, pacifier), tooth agenesis, supernumerary teeth, microdontia, macrodontia, and abnormalities of tooth shape. Dental malocclusion can also have no apparent cause. Some syndromes with malocclusion have no other dental anomalies. Etiology and Distribution

Syndromes with malocclusion as a component are listed in Table 14-15. Dental malocclusion may be caused by genetic and environmental factors. In pure ethnic stocks, such as Melanesians of the Philippine islands, malocclusion is almost nonexistent. However, in heterogeneous populations, the incidence of jaw discrepancies and occlusal disharmonies is significantly greater.21 Highest rates of normal occlusion are reported in British (67.3%), followed by European descent North-Americans (51%), Lebanese (40.3%), NorthAmerican Indians (34.5%), Egyptians (34.33%), and Swedish (10%).

Teeth

457

Table 14-15. Syndromes with malocclusion as a component Syndrome

Causation Gene/Locus

Prominent Features

Autosomal Dominant Conditions

Brachydactyly type B11

Involvement of the distal phalanges, nail aplasia, coloboma of the macula, characteristic facies, renal agenesis, double uterus and vagina, mixed hearing loss, high-arched palate, crowed teeth, supernumerary ribs

(113000) ROR2, 9q22

Marfan2–10

Increased height; disproportionately long limbs and digits; anterior chest deformity; mild to moderate joint laxity; vertebral column deformity (scoliosis and thoracic lordosis); narrow, highly arched palate with crowding of the teeth

(154700) FBN1, 15q21.1

Prader-Willi11–17

Diminished fetal activity, profound poor muscle tone, feeding problems in infancy, underdeveloped sex organs, short stature and retarded bone age, small hands and feet, delayed developmental milestones, characteristic facies, cognitive impairment, onset of gross obesity in early childhood due to insatiable hunger, tendency to develop diabetes in adolescence and adulthood when weight was not controlled

(176270) Pat del 15q11-q13 Mat UPD 15

Susceptibility to infection, vomiting, coarse features, macroglossia, flat nose, large clumsy ears, widely spaced teeth, large head, big hands and feet, tall stature, slight hepatosplenomegaly, muscular hypotonia, lumbar gibbus, radiographic skeletal abnormalities, dilated cerebral ventricles, lenticular opacities, hypogammaglobulinemia, ‘‘storage cells’’ in the bone marrow, vacuolated lymphocytes in the bone marrow and blood

(248500) MANB

Autosomal Recessive Conditions

Mannosidosis, Alpha, lysosomal18–20

However, dental malocclusion rates are higher in Swedish (83%), followed by North-American Indians (53%), Lebanese (35.5%), Egyptians (33.3%), European-descent North-Americans (26%), and British (13.7%). Skeletal discrepancy, which is more influenced by population mix, is higher in Egyptians (31.6%), followed by Lebanese (24.2%), European-descent North-Americans (23%), British (19%), North-American Indians (10.5%), and Swedish (7%).22–27 No differences between males and females have been noted for dental malocclusion.27 A relationship exists between certain discrete malpositions of the permanent canine and tooth agenesis. Studies indicate significantly elevated prevalence rates for tooth agenesis in association with palatally displaced canine, mandibular lateral incisor–canine transposition, and maxillary canine–first premolar transposition. Like tooth agenesis, these three positional anomalies involving the canine have been reported in families and appear to be under strong genetic control.28–41 Palatally displaced canine occurs in 1–3% of the population, mandibular lateral incisor–canine transposition in 0.03%, and maxillary canine–first premolar transposition in 0.25%.42–48 Maxillary canine–first premolar transposition has a higher frequency in Down syndrome.49 Dental transposition is indicative of faulty field gene function, which would explain why there is an increased occurrence of tooth agenesis on either side of transposed teeth. This may also explain the fact that teeth in the critical marginal areas of dental lamina, lateral incisors, second premolars, and third molars are the most vulnerable for tooth agenesis.21 MSX1 and PAX9, which have been associated with preferential agenesis of posterior teeth, might be involved in the genetic control of positional anomalies involving the canine.41,50 Prognosis, Treatment, and Prevention

Dental malocclusion is not a morbid trait. It may pose aesthetic problems that might lead to lower self-esteem. Other possible con-

sequences are periodontal disease and temporomandibular joint problems. Orthodontic treatment is recommended and usually successful. Preventive and interceptive orthodontics is possible and desirable. Prevention through other techniques is not possible. References (Dental Malocclusion) 1. Oldridge M, Fortuna AM, Maringa M, et al.: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24:375, 2000. 2. Dietz HC, Cutting GR, Pyeritz RE, et al.: Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337, 1991. 3. Hayward C, Keston M, Brock DJH, et al.: Fibrillin (FBN1) mutations in Marfan syndrome. Hum Mutat 1:79, 1992. 4. Dietz HC, McIntosh I, Sakai LY, et al.: Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics 17:468, 1993. 5. Hewett DR, Lynch JR, Smith R, et al.: A novel fibrillin mutation in the Marfan syndrome which could disrupt calcium binding of the epidermal growth factor-like module. Hum Mol Genet 2:475, 1993. 6. Hayward C, Porteous MEM, Brock DJH: Identification of a novel nonsense mutation in the fibrillin gene (FBN1) using nonisotopic techniques. Hum Mutat 3:159, 1994. 7. Dietz HC, Pyeritz RE: Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet 4:1799, 1995. 8. Hayward C, Brock DJH: Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Hum Mutat 10:415, 1997. 9. Hayward C, Porteous ME, Brock DJH: Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: report of 12 novel mutations. Hum Mutat 10:280, 1997. 10. Silva DB, Freitas FCN, Vieira AR, et al.: Sı´ndrome de Marfan: caracterı´sticas clı´nicas, implicac¸o˜es dentais e relato de caso. J Bras Odontoped Odonto Bebeˆ 2:230, 1999.

458

Craniofacial Structures

11. Prader A, Labhart A, Willi H: Ein syndrom von adipositas, kleinwuchs, kryptorchismus und oligophrenie nach myatonieartigem zustand im neugeborenenalter. Schweiz Med Wschr 86:1260, 1956. 12. Buiting K, Greger V, Brownstein BH, et al.: A putative gene family in 15q11-13 and 16p11.2: possible implications for Prader-Willi and Angelman syndromes. Proc Nat Acad Sci 89:5457, 1992. 13. Buiting K, Dittrich B, Gross S, et al.: Molecular definition of the Prader-Willi syndrome chromosome region and orientation of the SNRPN gene. Hum Mol Genet 2:1991, 1993. 14. Buiting K, Dittrich B, Gross S, et al.: Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170, 1998. 15. Ohta T, Gray TA, Rogan PK, et al.: Imprinting-mutation mechanisms in Prader-Willi syndrome. Am J Hum Genet 64:397, 1999. 16. Ming JE, Blagowidow N, Knoll JHM, et al.: Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting. Am J Med Genet 92:19, 2000. 17. Buiting K, Gross S, Lich C, et al.: Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 72:571, 2003. 18. Nilssen O, Berg T, Riise HMF, et al.: Alpha-mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet 6:717, 1997. 19. Gotoda Y, Wakamatsu N, Kawai H, et al.: Missense and nonsense mutations in the lysosomal alpha-mannosidase gene (MANB) in severe and mild forms of alpha-mannosidosis. Am J Hum Genet 63:1015, 1998. 20. Berg T, Riise HMF, Hansen GM, et al.: Spectrum of mutations in alpha-mannosidosis. Am J Hum Genet 64:77, 1999. 21. Mossey PA: The heritability of malocclusion: part 2. The influence of genetics in malocclusion. Br J Orthod 26:195, 1999. 22. Goose DH, Thomson DG, Winter FC: Malocclusion in schoolchildren of the west Midlands. Br Dent J 102:174, 1957. 23. Grewe JM, Cervenka J, Shapiro BL, et al.: Prevalence of malocclusion in Cheppewa Indian children. J Dent Res 47:302, 1968. 24. Ingervall B: Prevalence of dental and occlusal anomalies in Swedish conscripts. Acta Odontol Scand 32:83, 1974. 25. El-Mangoury NH, Mostafa YA: Epidemiologic panorama of dental occlusion. Angle Orthod 60:207, 1990. 26. Tipton RT, Rinchuse DJ: The relationship between static occlusion and functional occlusion in a dental school population. Angle Orthod 16:57, 1991. 27. Saleh FK: Prevalence of malocclusion in a sample of Lebanese schoolchildren: an epidemiological study. East Mediterr Health J 5:337, 1999. 28. Racek J, Sottner L: Contribution to the heredity of retention of canine teeth. Cesk Stomatol 77:209, 1977. 29. Peck L, Peck S, Attia Y: Maxillary canine-first premolar transposition, associated dental anomalies and genetic basis. Angle Orthod 63:99, 1993. 30. Peck S, Peck L, Kataja M: The palatally displaced canine as a dental anomaly of genetic origin. Angle Orthod 64:249, 1994. 31. Peck S, Peck L: Classification of maxillary tooth transpositions. Am J Orthod Dentofacial Orthop 107:505, 1995. 32. Peck S, Peck L, Kataja M: Prevalence of tooth agenesis and peg-shaped maxillary lateral incisor associated with palatally displaced canine (PDC) anomaly. Am J Orthod Dentofacial Orthop 110:441, 1996. 33. Peck S, Peck L, Kataja M: Site-specificity of tooth agenesis in subjects with maxillary canine malpositions. Angle Orthod 66:473, 1996. 34. Pirinen S, Arte S, Apajalahti S: Palatal displacement of canine is genetic and related to congenital absence of teeth. J Dent Res 75:1346, 1996. 35. Peck S, Peck L: Palatal displacement of canine is genetic and related to congenital absence of teeth. J Dent Res 76:728, 1997. 36. Peck S, Peck L, Hirsh G: Mandibular lateral incisor-canine transposition in monozygotic twins. J Dent Child 64:409, 1997. 37. Sottner L: Our concept of inheritance of tooth retention from the aspect of molecular biology and genetics. Cesk Stomatol 97:43, 1997.

38. Peck S, Peck L, Kataja M: Mandibular lateral incisor-canine transposition, concomitant dental anomalies and genetic control. Angle Orthod 68:455, 1998. 39. Plunkett DJ, Dysart PS, Kardos TB, et al.: A study of transposed canines in a sample of orthodontic patients. Br J Orthod 25:303, 1998. 40. Shapira Y, Kuftinec MM: Maxillary tooth transpositions: characteristic features and accompanying dental anomalies. Am J Orthod Dentofacial Orthop 119:127, 2001. 41. Peck S, Peck L, Kataja M: Concomitant occurrence of canine malposition and tooth agenesis: evidence of orofacial genetic fields. Am J Orthod Dentofacial Orthop 122:657, 2002. 42. Ro¨hrer A: Displaced and impacted canines. Int J Orthod Oral Surg Radiogr 15:1003, 1929. 43. Dachi SF, Howell FV: A survey of 3874 routine full-mouth radiographs. II. A study of impacted teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 14:1165, 1961. 44. Niczky E, Mu¨ller K, Slavik J: Transposition. Cesk Stomatol 67:227, 1967. 45. Shah RM, Boyd MA, Vakil TF: Studies of permanent tooth anomalies in 7,886 Canadian individuals. I: impacted teeth. J Can Dent Assoc 44:262, 1978. 46. Ja¨rvinen S: Mandibular incisor-cuspid transposition: a survey. J Pedod 6:159, 1982. 47. Sandham A, Harvie H: Ectopic eruption of the maxillary canine resulting in transposition with adjacent teeth. Tandlaegebladet 89:9, 1985. 48. Hirschfelder U, Petschelt A: Impaction of teeth from an orthodontic point of view. Dtsch Zahna¨rztl Z 41:164, 1986. 49. Shapira J, Chaushu S, Becker A: Prevalence of tooth transposition, third molar agenesis, and maxillary canine impactation in individuals with Down syndrome. Angle Orthod 70:290, 2000. 50. Vieira AR: Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res 82:162, 2003.

14.7 Enamel Dysplasia Definition

Enamel dysplasia is any abnormality of enamel formation. These defects affect the quality or quantity of enamel and can be divided into those that are influenced by environmental factors and those that are idiopathic or genetic in origin. Many environmentally related factors can contribute to alterations of enamel. These are listed in Table 14-16.1 Amelogenesis imperfecta (AI) collectively refers to the group of hereditary enamel malformations that occur in the absence of a systemic disorder. Diagnosis

Environmental defects affecting enamel typically manifest as hypoplasia, diffuse opacities, or demarcated opacities.1 Since environmental factors affect only the teeth that are developing at the time of the insult, few teeth or only one dentition may be involved. The affected enamel may be localized or present on many teeth, with varying degrees of involvement on each affected tooth. Hereditary dysplasias typically affect all the teeth of both dentitions, though there are exceptions. A common pattern seen in environmental dysplasias with an insult of short duration is dysplastic, horizontal bands of enamel. The location of the bands can be correlated to the stage of tooth development at the time of the insult and the width to the time interval of the insult. In instances where genetic dysplasias localize, the resulting defect is in a vertical direction because of the manner in which amelogenesis occurs (apex to occlusal direction).2

Teeth Table 14-16. Environmental factors associated with enamel dysplasias1

459

Systemic

enamel dysplasia similar to that of other debilitative diseases or may cause a general discoloration of the enamel as a consequence of pigment deposition during amelogenesis.3

Birth-related trauma

Turner Hypoplasia

Chemicals

Trauma to deciduous teeth or periapical inflammation of an overlying primary tooth may interfere with amelogenesis of succedaneous teeth. The interference leads to hypoplasia or hypocalcification of the enamel of the permanent teeth in a distribution dependent on the extent of the trauma or infection or on the stage of development of the permanent tooth. Traumatic dysplasia affects the permanent incisors more often than other teeth, because injuries to the deciduous incisors are common during childhood. Infectious dysplasia affects premolars more often than other teeth because of the frequency of abscesses under deciduous molars. Permanent molars are least likely to be affected by overlying periapical inflammatory processes since they do not replace a deciduous tooth.3

Chromosomal abnormalities Infections Inherited diseases Malnutrition Metabolic disorders Neurologic disorders Local

Local acute mechanical trauma Electric burn Irradiation Local infection

Etiology and Distribution Natal dysplasia

Horizontal bands of enamel hypocalcification, hypomaturation, or hypoplasia may be seen across the surfaces of teeth that are developing at the time of birth: the middle third of the deciduous incisors and cuspids and the tips of the canines and molars. The trauma of birth or the physiologic changes that occur at birth are responsible for these lines. They are most often found in the deciduous dentition and their presentation is not easily visible. A similar pattern of enamel defects involving the cuspids, bicuspids, and second molars is seen when the traumatic insult occurs around the age of 4 to 5 years.1,3 Ingestional Dysplasia

Severe vitamin D deficiency can cause enamel dysplasia in the typical horizontal distribution. Ingestion of more than 1.8 parts per million (ppm) of fluoride in water also causes enamel hypoplasia. While only 10% of those ingesting 1.8 ppm are affected, 90% of those ingesting 6 ppm or more are affected. The dysplasia varies from mottling of the enamel to hypocalcification and hypoplasia. Even when an entire tooth surface is mottled because of long-term ingestion of fluoride, there are superimposed horizontal lines across the surface that demarcate periods of high and low ingestion.3 Debilitative Dysplasia

Prolonged debilitative disorders are capable of causing a pattern of enamel dysplasia that is also known as fever hypoplasia. While the eruptive diseases of childhood most commonly cause debilitative dysplasia, any serious illness, with or without fever, during the period of tooth development may do so. The extent of the dysplasia (width of the dysplastic horizontal line) reflects the duration of the disease, and the pattern of the dysplasia (number and type of teeth affected) reflects the approximate age at the time of the disease. The dysplasia is usually bilateral, as homologous teeth on the left and right sides are affected equally. Debilitative diseases with prenatal effect on enamel development include congenital syphilis and rubella. Rh incompatibility, when severe enough to cause erythroblastosis fetalis, may cause

Hypoplasia Caused by Antineoplastic Therapy

An emerging cause of enamel dysplasia is therapeutic radiation or chemotherapy used in the treatment for pediatric cancer. The extent of dysplasia is directly related to the age of the individual at treatment, the type of therapy administered, and the dose and field of radiation, if used.1 Amelogenesis imperfecta

AI is a collective term used to describe a group of conditions that demonstrate developmental alterations in enamel structure without systemic involvement. Though a number of classification systems currently exist, the most widely accepted was proposed by Witkop and Sauk and is based predominantly on the observed phenotype.4 Four major types of AI have been identified based on clinical and histologic characteristics of enamel: 1) hypoplastic, 2) hypomaturation, 3) hypocalcified, and 4) hypomaturation-hypoplastic (Fig. 14-5). This organization scheme is correlated to a disturbance in one of the phases of amelogenesis: 1) secretion of an organic matrix, 2) mineralization of the matrix, and 3) maturation of enamel. The four major groups are subsequently subdivided into 15 subtypes based primarily on phenotype and, secondarily, by mode of inheritance (Table 14-17).5 The complexity of the diagnosis for amelogenesis imperfecta implies genetic heterogeneity. There are currently two genes implicated in the pathogenesis of AI. The first genetic association was the discovery of the amelogenin gene in the p21.1-22.3 region of the X chromosome. The second defect was found in the enamelin gene on chromosome 4q21. Both of these genes encode proteins that contribute to the formation of the enamel matrix during amelogenesis. As advances are made in determining the genetic etiology of the various forms of AI, a classification system based on the specific molecular defect rather than the observed phenotype may emerge.6 To date, seven types of hypoplastic AI have been described.1 They are all characterized by an inadequate deposition of enamel matrix. Smooth hypoplastic AI may be inherited as an autosomal dominant trait or as an X-linked dominant one. In autosomal dominant AI, the enamel is thin, smooth, and white and contrasts with the dentin on radiographs. The teeth are small and somewhat conical. In the X-linked dominant type, the enamel in males is thin, smooth, and brown and contrasts with the dentin on X-rays, while the enamel in females shows alternate vertical bands of normal and abnormal enamel.

460

Craniofacial Structures

Fig. 14-5. Amelogenesis imperfecta. A. Intraoral photograph of patient afflicted with amelogenesis imperfecta. Note the small crown size of the permanent teeth (arrow) and consequent open contacts (*). B. Radiograph of the affected teeth, revealing generalized enamel agenesis on erupted as well as unerupted teeth.

Rough hypoplastic AI is inherited in an autosomal dominant manner. The enamel is thin, rough, and yellow-brown and contrasts with dentin on radiographs. There are two types of pitted hypoplastic AI. In one type, the pitting is inherited in an autosomal dominant manner and is generalized, although vertical orientation of the pits may be seen and the labial surfaces are more frequently pitted than the lingual surfaces. In the other type, the pitting is limited to the middle third of the crown and is distributed horizontally. This pattern of localized pitting has been characterized in cases inherited in both

an autosomal dominant and recessive fashion.3 In the autosomal recessive enamel agenesis pattern, there is a total lack of enamel formation. The surface of the dentin is rough and an anterior open bite is occasionally seen.1 In hypomaturation AI, the deposition and initial mineralization of the enamel matrix is normal. There is, however, a defect in the maturation of the enamel structure.1 To date, four types of hypomaturation AI have been described. Pigmented hypomature AI may be inherited as an autosomal recessive or an X-linked recessive trait. The enamel in males with either type is normally thick, yellowbrown, and soft and does not contrast with the dentin on radiographs. The enamel in females with the autosomal recessive form is identical to that in males. By contrast, X-linked recessive form in females shows alternate vertical bands of normal and hypomature enamel. Localized hypomature AI, typically inherited as an autosomal dominant trait, is believed to also occur as an X-linked trait.1 It is characterized by white, opaque enamel over the incisal and occlusal two-thirds of the teeth. The distribution of the defect is horizontal, contrary to the normal vertical distribution observed in other genetic dysplasias, leading to the descriptive term snow-capped teeth.3 In the hypocalcified form of AI, the enamel matrix is deposited normally but fails to mineralize to any significant extent.1 Two types of hypocalcified AI have been identified. One is inherited as an autosomal dominant trait, and the other as autosomal recessive. The enamel of both types is normally thick, yellow-brown and friable and appears moth-eaten on radiographs.3 The hypomaturation/hypoplastic form of AI demonstrates both enamel hypoplasia and hypomaturation. Though the two identified patterns are similar, they are differentiated by the thickness of enamel and the overall tooth size. The hypomaturation/hypoplastic pattern is characterized by enamel hypomaturation, where the enamel appears mottled yellow-white to yellow-brown. This is accompanied by varying degrees of taurodontism. The hypoplastic/hypomaturation form of AI has thin enamel as a hallmark feature and also demonstrates hypomaturation.1 AI affects approximately one in 1500 Americans of Caucasian background, with autosomal dominant hypocalcified AI accounting for 40% of all cases. While the frequency of AI among Americans of other racial backgrounds has not been reported, there is no

Table 14-17. Classification of amelogenesis imperfecta5 Type

Pattern

Specific Features

Inheritance

Genetic Defect

IA

Hypoplastic

Generalized pitted

AD

Unknown

IB

Hypoplastic

Localized pitted

AD (104500)

Enamelin (ENAM)

IC

Hypoplastic

Localized pitted

AR (204650)

Unknown

ID

Hypoplastic

Diffuse smooth

AD (104500)

Enamelin (ENAM)

IE

Hypoplastic

Diffuse smooth

XLD (300391)

Amelogenin(AMELX)

IF

Hypoplastic

Diffuse rough

AD

Unknown

IG

Hypoplastic

Enamel agenesis

AR

Unknown

IIA

Hypomaturation

Diffuse pigmented

AR (204700)

Unknown

IIB

Hypomaturation

Diffuse

XLR (301100)

Amelogenin (AMELX)

IIC

Hypomaturation

Snow capped

X-linked

Unknown

IID

Hypomaturation

Snow capped

AD

Unknown

IIIA

Hypocalcified

Diffuse

AD

Unknown

IIIB

Hypocalcified

Diffuse

AR

Unknown

IVA

Hypomaturation-hypoplastic

Taurodontism

AD (104510)

Unknown

IVB

Hypoplastic-hypomaturation

Taurodontism

AD

Unknown

Teeth Table 14-18. Syndromes with enamel dysplasia as a feature3

461

Dysplasia Type

14.8 Dentin Dysplasia

Amelo-onycho-hypohidrotic

Hypocalcification/hypoplasia

Definition

Oculodentoosseous dysplasia

Hypoplasia

Trichodentoosseous

Hypocalcification/hypoplasia

Tuberous sclerosis

Pitted hypoplasia

Dentin dysplasia is an abnormal formation of dentin. The dysplasia may manifest in the absence of a systemic disorder or in conjunction with other anomalies and have either an environmental or genetic origin. Environmentally induced dentin dysplasias include pigmentary and physiologic dysplasia. Dentinogenesis imperfecta (DI) refers to one of the inherited dentin dysplasias that presents without a systemic component. This includes types I and II dentin dysplasia; DI types I, II, and III; pulpal dysplasia; and fibrous dysplasia of the dentin.

Syndrome

Autosomal Dominant Conditions

EEC

Hypoplasia

Ectodermal dysplasia, Basan type

Hypocalcification

Autosomal Recessive Conditions

Morquio syndrome (MPS-IV)

Hypoplasia

Vitamin D–dependent rickets

Rough hypoplasia

Kohlschutter

Hypoplasia

Pigmentary Dysplasia

McGibbon

Aplasia

Epidermolysis bullosa (AR type)

Pitted hypoplasia

Pigmentary dysplasia can be seen clinically because of the translucent nature of the overlying enamel. Erythropoietic porphyria causes red-brown discoloration of the teeth; in primary teeth the pigmentation (porphyrin deposition) may involve all layers, whereas in permanent teeth the pigmentation is predominantly in the dentin and cementum. Erythroblastosis fetalis (hemolytic disease of the newborn) causes yellow-green pigmentation; again, the enamel may be affected, but the heaviest pigmentation (deposition of hemolyzed fetal blood products) is in the dentin. Tetracycline causes a yellow to yellow-brown discoloration of dentin. Agents and compounds that may discolor fully formed teeth include silver amalgam (black), copper (blue-green), nickel and chromium (green), lead (brown), bismuth (gray-blue), oil of cloves (brownblack), bilirubin (green), hemin and hematin (blue-black), methemoglobin (red-brown), and hematoidin (orange). Physiologic processes through which fully formed teeth may become discolored include internal resorption (pink), pulp disease (gray-black), and dental caries (color dependent on staining agent to which dentin is exposed).

X-Linked Conditions

Amelocerebrohypohidrotic

Hypoplasia

Pseudohypoparathryoidism

Pitted hypoplasia

Focal dermal hypoplasia

Hypoplasia

evidence that it differs greatly from that among Caucasians. Enamel dysplasia is also seen as a component of many syndromes of genetic and environmental origin. These are summarized in Table 14-18.3 Prognosis, Treatment, and Prevention

Enamel dysplasia, while not inconsequential, has a generally good prognosis. Other tooth layers are not affected, and the teeth can be maintained for a lifetime. Whether it is environmental or genetic in etiology, enamel dysplasia is easily and successfully treated, albeit the necessary restorative dentistry may be expensive. Sealants, composite restorations, crowns, and other restorative techniques work well and are used interchangeably, depending on the site and extent of the dysplasia.3 Enamel dysplasia of environmental origin can be prevented by avoiding the known cause. Enamel dysplasia of genetic origin can be dealt with through genetic counseling. While most couples may not modify family planning because of a risk for AI, some will; those who do not can be alerted through counseling of the risks so that prognosis is improved by early diagnosis and treatment.3 References (Enamel Dysplasia) 1. Neville BW, Damm DD, Allen CM, et al.: In: Oral and Maxillofacial Pathology, ed 2. WB Saunders Company, Philadelphia, 2002, p 49. 2. Jorgensen RJ, Yost C: Etiology of enamel dysplasias. J Pedodontol 6:315, 1982. 3. Jorgenson RJ: Teeth. In: Human Malformations and Related Anomalies, ed 1. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 383. 4. Witkop CJ, Sauk JJ: Heritable defect of enamel. In: Oral Facial Genetics. RE Stewart, GH Prescott, eds. CV Mosby, St. Louis, 1976, p 151. 5. Witkop CJ: Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. J Oral Pathol 17:547, 1988. 6. Aldred MJ, Savariarayan R, Crawford PJM: Amelogenesis imperfecta: a classification and catalogue for the 21st century. Oral Dis 9:19, 2003.

Physiologic Dysplasia

Most physiologic dysplasias are seen as exaggerated developmental lines on histologic sections. Dentinogenesis Imperfecta

The types of DI (Table 14-19) can be differentiated by clinical and radiographic features (Fig. 14-6). In classical DI (DI-IA), the teeth are yellow-brown to blue-gray in color and appear translucent. The crowns are bulbous because of an exaggerated constriction at the cementoenamel junction. The pulp chambers of some primary teeth and all secondary teeth are obliterated by atypical dentin. The obliteration is progressive, beginning before eruption and continuing afterwards. The roots are excessively tapered and foreshortened. Histopathologic studies reveal (1) absence of extensions of dentinal tubules into the enamel, (2) smooth (not scalloped) dentin-enamel junctions, and (3) abnormal dentinal tubules. In DI-IB, the teeth are also yellow-brown to blue-gray in color and appear translucent. Crown shape is like that of DI-IA, but the pulp chambers of primary teeth, rather than being obliterated, are excessively large. There is very little dentin, with most of the pulplike inner portion of the teeth consisting of coarse collagen bundles. In DI-II, also called radicular dentin dysplasia or rootless teeth, the crowns are normal in color and shape. The pulp chambers are virtually obliterated, but there are crescent-shaped radiolucencies in

462

Craniofacial Structures

Table 14-19. Classification of dentinogenesis imperfecta (DI)1–3 Type

Features

Alternative Classification

Genetic Defect

IA

Obliterated appearance, obliterated pulps, exaggerated coronal constriction

Shields II (125420)

Dentin sialo-phosphoprotein (DSPP)

IB

Similar to IA, but pulp chambers of deciduous teeth are enlarged

DI Brandywine type, Shields III (125500)

Likely dentin matrix acidic phospho-protein-1 (DMP1)

II

Obliterated pulp (crescent-shaped radiolucencies), foreshortened roots, premature loss of teeth

Dentin dysplasia I (125400)

Unknown

III

Opalescence of deciduous teeth, thistle-tube pulp chambers

Dentin dysplasia II, pulpal dysplasia (125420)

Dentin sialo-phosphoprotein (DSPP)

IV

Obliterated pulps, fibrous dentin

Fibrous dysplasia of dentin

Unknown

the central portions of the teeth. The roots are virtually absent, leading to premature ‘‘loosening’’ and loss of teeth. There are also multiple periapical radiolucencies around most roots. Histopathologic studies reveal that, in fact, the pulp is absent, having been replaced by regularly formed, eumorphous concretions. In DI-III, also termed coronal dentin dysplasia, the color of the crowns of the primary teeth resembles that of DI-I, but the crowns of the secondary teeth are normal in color and shape. On radiographs the pulp chambers of affected teeth resemble the

Fig. 14-6. Dentinogenesis imperfecta (DGI). A. Intraoral photograph of patient afflicted with DGI. Note the discoloration and extensive loss of tooth structure. B. Radiograph of the affected teeth, revealing bulbous crowns, obliterated pulp chambers, and narrowed root canals. (Courtesy of Dr. Nadarajah Vigneswaran, University of Texas Health Science Center, Houston, TX.)

thistle-tube glassware used in chemistry laboratories. Roots are well formed, and there is seldom premature tooth loss. In DI-IV, the crowns of teeth are also normal in size and shape, as are the pulp chambers, but pulpal tissue is obliterated by atypical dentin, and the dentin itself is abnormal in histopathologic study. Etiology and Distribution

DI-I is a relatively common disorder, affecting approximately one in 8000 individuals. It has recently been linked to mutations in the dentin sialophosphoprotein (DSPP) gene on chromosome 4q21.4 The gene product is cleaved into two dentin-specific matrix proteins, dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). DPP, a highly acidic protein, is the major noncollagenous component of dentin, being solely expressed by the ectomesenchymal-derived odontoblast cells of the tooth. Unique to all of the reported cases of DI-I, all patients have a positive family history (have affected progenitors), and all patients whose ancestry can be traced are descended from the population in a particular province in France. DI-IA is inherited as an autosomal dominant trait, with virtually complete penetrance and remarkably little variation in expression. Variation is so minimal, in fact, that its occurrence (e.g., enlarged pulp chambers of primary teeth) is evidence that favors the existence of DI-IB. DI-IB is largely limited to a triracial isolate in the United States, although it has recently been reported among Ashkenazi Jews. Linkage analysis revealed the most likely candidate gene for DI-IB in a branch of the Brandywine kindred was dentin matrix acidic phosphoprotein-1.5 These results again were consistent with the hypothesis that DI-I and DGI-III are allelic or the result of mutations in two tightly linked genes, DSPP and DMP1. DI-II is more rare than DI-I, occurring in only one in 100,000 persons. The mutation rate for the DI-II gene seems low and clinical variation is minimal. While the primary defect is unknown, it has been suggested that the epithelial component of the root sheath invaginates too early in development and causes root aplasia. DI-III is less common than the other dentin dysplasias, having been reported in only a few families. It is an autosomal dominant disorder in which mineralization of the dentin of the primary teeth is abnormal. On the basis of the phenotypic overlap and shared chromosomal location with dentinogenesis imperfecta type I, it has been proposed that the two conditions are allelic. A missense mutation (encoding an aspartic acid to tyrosine change) was reported in DSPP in a family with dentin dysplasia type II.6 The substitution in the hydrophobic signal peptide domain caused a failure of translocation of the encoded proteins into the

Teeth

endoplasmic reticulum. It is hypothesized that this would likely lead to a loss of function of both DSP and DPP. DI-IV is the rarest of the dentin dysplasias, having been reported in a single family as an autosomal dominant trait. The primary defect underlying this disorder is unknown. Prognosis, Treatment, and Prevention

Individuals affected by DI-I are prone to lose teeth because the inherent weakness at the dentin-enamel junction causes the enamel to fracture, thereby exposing the more delicate, underlying dentin to occlusal forces and cariogenic agents. Any treatment that protects the dentin should prove effective. Stainless steel crowns and other types of full crown coverage are adequate. Dental restorations, such as amalgam fillings and gold inlays, are likely to fail. Individuals with DIII lose their teeth because excessive mobility leads to periodontal disease or exfoliation. Short of extractions and prostheses, treatment is not effective. DI-III and DI-IV do not predicate the loss of teeth. Prevention is possible only through family planning by affected individuals. References (Dentin Dysplasia) 1. Shields ED, Bixler D, EI-Kafrawy AM: A proposed classification for heritable human dentine defects with a description of a new entity. Arch Oral Biol 18:543, 1973. 2. Jorgenson RJ: Problems in nomenclature of craniofacial disorders. J Craniofac Genet Dev Biol 9:7, 1989. 3. Jorgenson RJ: Teeth. In: Human Malformations and Related Anomalies. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 383. 4. Patel PI: Soundbites. Nat Genet 27:129, 2001. 5. MacDougall M, Jeffords LG, Gu TT, et al.: Genetic linkage of the dentinogenesis imperfecta type III locus to chromosome 4q. J Dent Res 78:1277, 1999. 6. Rajpar MH, Koch MJ, Davies RM, et al.: Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization. Hum Mol Genet 11:2559, 2002.

14.9 Cementum Dysplasia Cementum dysplasia is a neoplastic disease that is described here because it is relatively common and its neoplastic nature is not always recognized at discovery. At the time of discovery, cementum dysplasia often resembles hypercementosis or fibrous dysplasia of the adjacent alveolar bone. Cementum is the most poorly understood layer of the teeth. Nonetheless, three entities should be mentioned here: concrescence, familial cementoma, and cementum dysplasia. Concrescence is simply the fusion of adjacent teeth by cementum only. Concrescence is probably caused by nothing more than close approximation of the roots of developing teeth. Its frequency in the population has not been well-established. Familial cementomas are neoplastic lesions that appear in all four quadrants, a combination that is thought to be inherited as an autosomal dominant trait. Only a few families have been reported. Cementum dysplasia is a neoplastic process that is found in two to three individuals per 1000 in the general population. Females are more commonly affected than males and blacks more commonly than whites. Mandibular anterior teeth are more commonly affected than other teeth.

463

Each of these disorders is benign, requires no treatment, and cannot be prevented. Each may complicate extraction of affected teeth that have to be removed for other reasons.1 Reference (Cementum Dysplasia) 1. Jorgenson RJ: Teeth. In: Human Malformations and Related Anomalies. Stevenson RE, Hall JG, Goodman RM, eds. Oxford University Press, New York, 1993, p 383.

14.10 Abnormalities of Tooth Eruption Definition

Abnormalities of tooth eruption can be early, delayed, or a lack of tooth eruption. All of these conditions can manifest independently or as a component of an underlying disorder. The normal eruption sequence for each tooth is shown in Tables 14-1A and 14-1B. Ordinarily, the deciduous teeth erupt between ages 6 months and 2 years in the following sequence: incisors, 6 to 9 months; first molars, 12 to 14 months; canines, 16 to 18 months; and second molars, 20 to 24 months. The permanent teeth ordinarily erupt between ages 6 and 21 years in the following sequence: first molars and lower central incisors, 6 to 7 years; lower lateral incisors, 7 to 8 years; upper lateral incisors, 8 to 9 years; lower canines, 9 to 10 years; premolars, 10 to 12 years; upper canines, 11 to 12 years; second molars, 12 to 13 years; and third molars, 17-21 years. Small variations from these eruption patterns are common and may even be familial. Teeth in females generally erupt earlier than those in males. Natal Teeth

Natal teeth are those that are present at birth or erupt within the first month. While natal teeth are most commonly lower central incisors, other teeth may erupt early or the natal teeth may be supernumerary (predeciduous). Natal teeth may be inherited in an autosomal dominant fashion.1 They occur in roughly one in 3000 newborns.2 Natal teeth are found in cyclopia, Ellis-van Creveld syndrome, Hallermann-Streiff syndrome, pachyonychia congenita, PallisterHall syndrome, short rib-polydactyly type II, and WiedemannRautenstrauch syndrome. Eruption Delays or Impaction

Developmental delays in tooth eruption are most commonly attributed to mechanical interferences caused by supernumerary teeth, crowding, soft tissue impaction, or odontogenic tumors and cysts. Ankylosis typically occurs after partial eruption of the tooth into the oral cavity; it is defined as the fusion of cementum or dentin to alveolar bone due to cellular changes in the periodontal ligament caused by trauma and other pathologies. When the tooth becomes ankylosed, it appears to submerge in relation to adjacent teeth that continue to erupt. Eruption failure and delayed eruption are conditions that do not naturally involve ankylosis and are associated with craniofacial dysostosis, hypothyroidism, hypopituitarism and several genetic and medical syndromes.3–6 Eruption defects can also present as a component of various syndromic conditions and are summarized in Table 14-20. Primary failure of eruption (PFE) is characterized by a localized failure of eruption of permanent posterior teeth and lacks any systemic involvement. The affected teeth are nonimpacted,

464

Craniofacial Structures

nonankylosed, and fully formed, but are unable to reach the occlusal plane presumably due to a primary defect in the eruption mechanism itself. Attempts to close the resultant ‘‘open bite’’ orthodontically often result in ankylosis of PFE-affected teeth.7 (Fig. 14-7)

Prognosis, Treatment, and Prevention

Most natal teeth are firmly imbedded and pose no risk to the neonate. Those that are loose should be extracted to avoid aspiration. Delayed eruption can have considerable consequence on ultimate

Table 14-20. Syndromes with tooth eruption defects as a feature6 Causation Gene/Locus

Syndrome

Eruption Phenotype

Cleidocranial dysplasia

Delayed eruption

AD (600211) RUNX2/CBFA1, 6p21

Osteopetrosis

Failure of eruption

AR and AD TRAF6

GAPO

Failure of eruption

AR

Osteopathia striata with cranial sclerosis

Failure of eruption in some cases

AD

Osteoglophonic dysplasia

Failure of eruption of 28 teeth

AD

Singleton-Merten

Dysplastic development with delayed eruption of 28 teeth

AD possibly

Aarskog

Delayed eruption

XLR (305400) FGDY1, Xp21.1

Acrodysostosis

Delayed tooth eruption (23% of cases)

AD (101800)

Albright hereditary osteodystrophy

Delayed eruption

AD (103580) GNAS, 20q13.2

Apert

Delayed and ectopic eruption

AD (101200) FGFR2

Chondroectodermal dysplasia (Ellis–van Creveld)

Delayed eruption and partial anodontia

AR (225500) Several mutations in the EVC gene

Cockayne

Delayed eruption

AR CSB (ERCC6) gene (helicase)

De Lange

Delayed eruption

AD NIPBL, 5p13.1

Dubowitz

Delayed eruption and hypodontia

AR possibly

Frontometaphyseal dysplasia (Gorlin-Cohen)

Delayed eruption and retained deciduous teeth

AD (304120) FLNA, Xq28

Goltz (Focal dermal hypoplasia)

Delayed eruption and hypodontia with hypoplastic teeth

XLD, lethality in hemizygous males

Hunter

Delayed eruption

XL (309900) IDS, Xq28

Incontinentia pigmenti

Delayed eruption and hypodontia in 80%

XLD, lethality in males NEMO, Xq28 heterogeneous

Killian/Teschler-Nicola

Delayed eruption

Mosaic tetrasomy 12p in skin fibroblasts

Levy-Hollister

Delayed eruption of 18 teeth

AD

Maroteaux-Lamy mucopolysaccharoidosis (MPS VI)

Delayed eruption with small teeth

AR (253200) ASB, 5q11–q13

Osteogenesis imperfecta, type I

Delayed eruption and dysplastic teeth

AD COL1A1, COL1A2

Progeria (Hutchinson-Gilford)

Delayed eruption of 18 and 28 teeth and hypodontia of 28 teeth

AR (176670) LMNA, 1q21.2

Pyknodysostosis

Delayed eruption and occasional anodontia

AR (265800) CTSK, 1q21

Primary failure of eruption*

Failure of 28 teeth to erupt partially or completely

*Not associated with overt systemic disease.

Teeth

465

occlusion. The choices of treatment for impacted teeth include longterm observation, orthodontically assisted eruption, transplantation, or surgical removal. The presence of infection, nonrestorable carious lesions, cysts, tumors, or destruction of adjacent teeth necessitates surgical removal of the affected teeth.8 None of the conditions affecting tooth eruption is preventable. References (Abnormalities of Tooth Eruption) 1. Bodenhoff J, Gorlin RJ: Natal and neonatal teeth; folklore and fact. Pediatrics 32:1087, 1963. 2. Jorgenson RJ, Shapiro SD, Salinas CF, et al.: Intraoral findings and anomalies in neonates. Pediatrics 69:577, 1982. 3. Sauk JJ: Genetic disorders involving tooth eruption anomalies. In: The Biological Mechanisms of Tooth Eruption and Root Resorption. Davidovitch Z, ed. EBSCO Media, Birmingham, 1988, p 171. 4. Gorlin RJ, Cohen MM, Levin LS: Syndromes of the Head and Neck, ed 3. Oxford University Press, New York, 1990. 5. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders Company, Philadelphia, 1997. 6. Wise GE, Frazier-Bowers S, D’Souza RN: Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med 13:323, 2002. 7. Proffit WR, Vig KW: Primary failure of eruption: a possible cause of posterior open-bite. Am J Orthod 80:173, 1981. 8. Neville BW, Damm DD, Allen CM, et al.: Oral and Maxillofacial Pathology, ed 2. WB Saunders Company, Philadelphia, 2001, p 49.

Fig. 14-7. Primary failure of eruption. Intraoral photograph (A), dental models (B), and panoramic radiograph (C) showing nonankylosed, submerged upper left posterior quadrant and resulting posterior lateral open bite (arrows).

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Part IV Neuromuscular Systems

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15 Brain Alasdair G.W. Hunter

T

he anatomy of the developing central nervous system (CNS) dominates embryonic topography in much the same way that function of the mature CNS dominates postnatal actions and behavior. The CNS is represented initially as an ectodermal plate, stretching the length of the dorsum of the embryonic disc.1–4 The margins of the plate become elevated during developmental stages 8–9 (days 18–20) and eventually roll into a tube during developmental stages 10–12 (days 22–26). Closure of the tube begins at the level of the third somite and progresses bidirectionally from that point. The brain develops from the neural tube rostral to somite 4 and the spinal cord caudal to this level. The segmental nature of the brain is superficially obscured by three major flexures and the markedly discordant growth of its different parts. Three anatomical regions may be identified. The forebrain (prosencephalon) differentiates into the midline diencephalon (thalamus and hypothalamus) and the telencephalon (cerebral hemispheres). The midbrain (mesencephalon) forms the rostral part of the brain stem and the colliculi. The hindbrain (rhombencephalon) forms the caudal portion of the brain stem, the pons, and the cerebellum. Cranial nerves I and II derive from the forebrain; III and IV, from the midbrain; and V–XII, from the hindbrain. It is easier to envision the segmental nature of the spinal cord because of the egress and entrance of spinal nerves at the level of each somite. Complex interrelationships exist through which the CNS influences the development of other organ systems during embryogenesis. Perhaps only the hematopoietic system and the kidneys are exempt from major CNS influence during development. So extensive are the developmental interrelationships that it is tempting to assign to the central nervous system a place of preeminence among the body systems. With the exception of its dependence on the cardiovascular system, the developing CNS is influenced by other systems in only a limited way. This is primarily because many vital functions (nutrition, oxygenation, waste disposal, production of growth factors, protection against mechanical injury), which will become the major responsibility of

Acknowledgements: The author thanks Doctors C. Jiminez, V. Briggs, S. Grahavoc, L. Auruch, W. Blackburn, and Mr. N.R. Cooley Jr. for providing and helping to select illustrations for chapters 15–17.

different systems, are carried out during embryogenesis by the maternal host and placenta. The developing CNS is subject to all of the processes that lead to anomalies.2–8 The presence of anomalies may be obvious at birth or may become evident later because of developmental impairment or neurologic dysfunction. Virtually all visible chromosome aberrations alter mental capability and may cause specific malformations. Exempted from this generalization are most structural and numerical aberrations of the sex chromosomes. It is likely that each chromosome contains numerous genes that participate in brain formation and maintenance of its structure and function. Likewise, environmental insults of a wide variety can affect brain development or damage the brain after development is essentially complete. Radiation, certain infections, metabolic derangements, and a number of drugs and chemicals are the best known of these environmental influences. Vascular insults, placento-amniotic disruptions, the process of twinning, and mechanical forces contribute further to the number of CNS anomalies. As with all developing systems, the CNS becomes progressively resistant to influences from the environment. Defects of neural tube closure are the most common CNS malformations and are among the most common of all major anomalies.3–10 Neural tube defects are usually obvious at birth or present in early infancy. This is not the case with many CNS malformations whose presence are not suspected until seizures, developmental impairment, obstruction of CSF flow, or mass effect prompts imaging of the central nervous system. Malformations are the leading cause of death in infancy and lethal anomalies of the CNS are among the most common of these.11 Disturbances of individual genes and molecular pathways that account for a number of malformations of the CNS have been identified during the past decade. Considerable progress has been made in delineating the molecular causes of holoprosencephaly and lissencephaly, and some progress has been made as well in understanding hydrocephaly, agenesis of the corpus callosum, cerebellar dysgenesis, and other CNS anomalies.12–20 As notable as these advances are, more remains to be learned than we know at present. Most disappointing has been the failure to identify major genes that predispose to neural tube defects. The cranium and vertebral column prevent casual inspection of the CNS. To be sure, certain anomalies of the CNS can be predicted with some accuracy from associated clinical 469

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Neuromuscular Systems

features—for example, holoprosencephaly can be predicted from abnormal midface development, small brain size from cranial measurement, some cases of lissencephaly from facial features, and so forth.21–23 Until recently, however, detailed observations on the anatomy of the CNS could only be made at autopsy, although a limited view could be obtained through invasive tests such as arteriography and pneumoencephalography. Most CNS structures can now be visualized by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Ultrasound is most useful prenatally and during the early months of life when the anterior fontanel is open. MRI has become the procedure of choice for imaging brain and spinal cord anatomy and has revolutionized our thinking about several classes of CNS malformation. References 1. O’Rahilly R, Mu¨ller F: Developmental Stages in Human Embryos. Carnegie Institution of Washington, Publication 637, 1987. 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott, Williams and Wilkins, Baltimore, 2004, pp 90, 433. 3. O’Rahilly R, Mu¨ller F: Human Embryology and Teratology, ed 3. Wiley-Liss, New York, 2001, p 395. 4. Lemire RJ, Loeser JD, Leech RW, et al: Normal and Abnormal Development of the Human Nervous System. Harper and Row, Hagerstown, 1975. 5. Norman MG, McGillivray BC, Kalousek DK, et al.: Congenital Malformations of the Brain. Oxford Univ Press, New York, 1995. 6. Warkany J, Lemire RJ, Cohen MM, Jr: Mental Retardation and Congenital Malformations of the Central Nervous System. Year Book Medical Publishers, Chicago, 1981. 7. Melnick M: Current concepts of the etiology of central nervous system malformations. BDOAS XV(3):19, 1979. 8. Myrianthopoulos NC: Our load of central nervous system malformation. BDOAS XV(3):1, 1979. 9. Hall JG, Friedman JM, Kenna BA, et al.: Clinical, genetic and epidemiological factors in neural tube defects. Am J Hum Genet 43:827, 1988. 10. National Birth Defects Prevention Network: 2004 Congenital Malformations Surveillance Report. Birth Defects Res (Part A) 70:553, 2004. 11. Centers for Disease Control and Prevention: Infant mortality statistics from the 2001 period linked birth/infant death data set. Nat Vital Stat Rep 52:1, 2003. 12. Roessler E, Belloni E, Gaudenz K, et al.: Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357, 1996. 13. Muenke M, Cohen MM Jr.: Genetic approaches to understanding brain development: holoprosencephaly as a model. Ment Retard Dev Disabil Res Rev 6:15, 2000. 14. Kato M, Dobyns WB: Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 12:R89, 2003. 15. des Portes V, Francis F, Pinard J-M, et al.: Doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet 7:1063, 1998. 16. Hong SE, Shugart YY, Huang DT, et al.: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26:93, 2000. 17. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359, 2002. 18. Jouet M, Rosenthal A, Armstrong G, et al.: X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 7:402, 1994. 19. Jackson AP, McHale DP, Campbell DA, et al.: Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 63:541, 1998.

20. des Portes V, Boddaert N, Sacco S, et al.: Specific clinical and brain MRI features in mentally retarded patients with mutations in the Oligophrenin-1 gene. Am J Med Genet 124A:364, 2004. 21. Croen LA, Shaw GM, Lammer EJ: Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet 64:465, 1996. 22. Aicardi J: Diseases of the Nervous System in Childhood, ed 2. Mac Keith Press, London, 1998, p 90. 23. Jones KL, Gilbert EF, Kaveggia EG, et al.: The Miller-Dieker syndrome. Pediatrics 66:277, 1980.

15.1 Microcephaly Definition

Microcephaly is a cranial vault that is smaller than normal. Since growth of the cranium depends on the forces of an expanding brain, microcephaly is an indicator of an undersized brain. Thus, in defining microcephaly one is in reality attempting to define a lower limit for normal brain size. Although a number of parameters, including the use of cranial height, width, and length, may more accurately reflect brain volume, in clinical practice microcephaly is defined in terms of age- and sex-appropriate curves of occipitofrontal circumference (OFC). There is some difference of opinion about whether the lower limit should be defined as 2 or 3 SD below the mean.1,2 The more liberal 2 SD is used in this discussion because it is consistent with usual clinical practice and it shows good correlation with symptomatology. OFC is a dynamic measure, and it is not uncommon for the centile to fall over time from normal to 2 SD and below. However, the use of such a definition, which by its nature includes 2.5% of the population, requires a cautious approach when assessing its significance. Some authors use the term micrencephaly when small brain size is due to a primarily developmental abnormality and the term true micrencephaly when the small brain is the only pathology.3 That distinction is not made in this discussion. Diagnosis

To identify microcephaly requires an accurate measurement of maximum head circumference, which is then compared with appropriate age- and sex-matched controls4 (Fig. 15-1). There may also be some argument for using ethnically matched data. Adult head size centiles should be used after age 18 years.5 Measurement of OFC is best obtained by using a tape that does not stretch and by placing the tape around the cranium at a level just above the supraorbital ridges and at the opisthocranion. However, the tape should be adjusted up and down to ensure that maximum circumference of the skull is obtained, while at the same time excluding ears, braids, and the like from the measurement.4 Any marked deviation from normal skull shape can affect the measurement. For example, dolichocephaly will increase the head circumference. When there is doubt, length, width, and cranial height measurements6 and cranial radiographic studies may substitute (Fig. 15-2).7 A study of neonates showed a correlation between OFC and brain volume estimated by computed tomography (CT) of 0.55 (p < 0.003) and demonstrated that below an OFC of 33.5 cm a lower OFC strongly predicted a reduced brain volume.8 Microcephaly differs from most of the topics in this chapter in that it is not a primary malformation but rather a sign of a small

Brain

Fig. 15-1. Four-month-old infant with microcephaly, pancytopenia, intracranial calcifications and seizures. This X-linked condition closely mimics the disorder caused by prenatal cytomegalovirus infection.

brain (Fig. 15-3). The underlying pathogenesis may reflect the normal population variation of brain volume or a broad spectrum of genetic or acquired insults that may act prenatally, perinatally, or postnatally to inhibit brain development and, ultimately, size. The traditional approach to the classification of microcephaly has separated genetic from non-genetic causes. The latter are often referred to as acquired or secondary. However, these terms have

Fig. 15-2. Cranial radiograph of 14-year-old male with microcephaly of unknown cause. Note the marked craniofacial disproportion.

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also been used to describe post-natal onset microcephaly, that is, to contrast with congenital microcephaly. Although primary is usually used to define isolated genetic microcephaly, it has been used to contrast acquired or secondary microcephaly. These terms are avoided in this section. We are on the threshold of a new understanding of microcephaly, and the driving forces are careful application of neuroimaging9–11 and the mapping and cloning of genes related to the development of the brain.12,13 Some of the most exciting progress has been in the area of isolated microcephaly without evident acquired cause. In 1998 Barkovich et al.9 reported that most children with the isolated finding of an OFC  3 SD at birth had fewer than the normal number of gyri, sulci about one-half the normal depth, absent tertiary sulci, and a normal or decreased cortical thickness. At first, this was called microlissencephaly; but Hanefeld10 pointed out that this was an inappropriate term and suggested oligogyric microcephaly, which is now used interchangeably with microcephaly with simplified gyral pattern (MSG).11 Barkovich et al.9 distinguished a subset of patients (group 1) who, despite their severe microcephaly and MSG, had a relatively mild clinical course with a normal newborn examination, normal tone or mild corticospinal tract signs, and uncommon and readily controlled seizures. Difficulties with feeding and weight gain were frequent but early milestones were mildly delayed and many walked by 24 months and developed some language ability. Other children with MSG (originally groups 2–5; now group 211) have a much more severe clinical course and their magnetic resonance imaging (MRI) scan may show delayed myelination, hypoplasia of the brainstem or cerebellum, or increased extra-axial spaces. These children present as newborns with abnormal neonatal reflexes, spasticity, poor feeding and failure to thrive. The subsequent course is one of severe spastic quadriplegia, intractable seizures, and profound mental retardation. Agenesis of the corpus callosum may occur in both groups. Based on his personal review of unpublished ‘‘data on several of the families studied’’ Dobyns11 believes that the families mapped with autosomal recessive isolated microcephaly (traditionally primary microcephaly) correspond to his Group-1-MSG. Furthermore, he considers that the time has come to make this a diagnosis of inclusion, rather than exclusion, and proposes a birth OFC of  3 SD, a low sloping forehead, MSG brain pattern, and lack of extracranial malformations as diagnostic criteria. He suggests that parents of these children be counseled that there is a 25% recurrence risk. Although this conclusion may be correct, and there are families with clear autosomal recessive inheritance,9,14,15 not all authors would go that far, and this author does not consider the current published data adequate to draw any conclusion. In the original paper9 there were 17 patients from 14 families and no data were provided that would allow for a segregation analysis. Three cases were from one highly inbred family and another two were siblings. Mochida and Walsh12 distinguished what they called microcephaly vera, in which the brain is the only affected organ and it is small but with normal architecture. On pathologic study the architecture may be normal or show depletion of cortical layers II and III and of the germinal zone near the ventricles. The clinical course is really not distinct from Group-1 MSG, and the overlap between the two conditions and their respective relationship to the mapped and cloned microcephaly genes13,16,17 remains to be clarified. Microcephaly vera has also been used to describe patients whose MRI is compatible with MSG.18 In the interim it is unlikely that any classification of microcephaly will withstand the test of time, but Fig. 15-4 provides

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Neuromuscular Systems

Fig. 15-3. Vertical and lateral views of opened cranium of a microcephalic fetus showing severe brain hypoplasia and external hydrocephaly. Note the absence of olfactory nerves and a central cleavage line on the cerebral surface in the vertical view. The incised falx is retracted posteriorly. The absence of gyral development is noted in both views (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

a framework on which to approach the diagnosis of microcephaly. By considering these categorical items individually, one is unlikely to overlook important details of history and physical examination. And, as molecular information becomes more directly applicable, the approach will allow appropriate selection of cases for study. To determine the precise etiology of a case of microcephaly remains one of the most challenging tasks in medicine. The patient is often not seen until some time after birth, when microcephaly is recognized during an investigation of an associated developmental delay and by which time much important historical information has been lost and some laboratory tests are no longer appropriate. The need for a detailed family history is axiomatic. The history includes a careful search for consanguinity and measurement of the head size of the parents and siblings.

Standard inquiries with respect to the specific pregnancy should include its planning; any attempts to terminate; the timing and quantity of the consumption of alcohol, medications, and other drugs; chronic and acute maternal illnesses, fevers and rashes; and any other intervention or treatment. Information about the activity of the fetus and any complications of labor and delivery may also be useful. The timing of the onset of microcephaly is an important detail. While routine obstetric ultrasound more and more provides prenatal information about head growth, it is ironic that the simple measurement of birth OFC is often missing from the newborn examination. The simple fact that the head was small at birth can eliminate perinatal and postnatal etiologies. However, it must be stressed that the converse does not hold; a normal birth

Fig. 15-4. A categorical pathway that may aid the diagnosis/classification of patients with microcephaly. Solid line could be an example of isolated (pure microcephaly) with affected sibs. Dotted line might represent an infection such as rubella.

Brain

OFC does not eliminate either genetic microcephaly or a prenatally acquired cause. Careful examination of the patient may uncover minor anomalies (such as disturbed hair patterning) that could be evidence of an early prenatal disturbance; or a particular appearance with associated anomalies may suggest a specific syndrome. The details of further investigations will depend on the presence or absence of historical clues and/or associated malformations. Further investigation may include laboratory testing for maternal phenylketonuria, prenatal infection, and chromosome aberrations. Neuroimaging is important, both to detect major intracranial malformations and to better determine the nature of the small brain. In one recent study of non-syndromic microcephaly, 62% of the patients had an abnormal neuroimaging study, and the presence of a detectable abnormality correlated with the severity of the developmental delay.19 When the OFC was between 2 and 2.99 SD, 43% of patients had an abnormality demonstrated on scanning, as compared with 80% when the OFC was  3 SD. It has long been known that an important proportion of isolated, unexplained microcephaly is genetic, most often autosomal recessively inherited. Several authors have attempted to identify clues that will help to pinpoint genetic microcephaly cases, and this information will remain germane until genetic testing becomes available to clinical practice, and even then may help to select appropriate cases for study. Penrose20 noted decreased skull height and width, short stature, prominent ears, a normal face, stooped posture, furtive movements, and a lack of associated sensory or motor signs. Baraitser21 stressed that the microcephaly was usually congenital, confirmed the clinical characteristics, and noted some sparing of personality. Qazi and Reed22 emphasized that consanguinity, increased pregnancy wastage, negative history, presence at birth (50%), lack of significant neurologic problems, relatively normal early milestones, and a higher rate of subnormal intellect in first-degree relatives were associated with the familial cases. Sujatha et al.23 used segregation analysis to support the validity of these criteria, although their study suggested that not all patients thus defined have autosomal recessive microcephaly. Certainly isolated genetic microcephaly occurs in the absence of a characteristic appearance and in the absence of any specific personality.22,24 Equally important, patients whose clinical features include paresis, seizures, visual disturbances, and lack of speech and ambulation may have a genetic basis for their condition. Brandon et al.24 documented a high rate of spastic diplegia in genetic microcephaly. Tolmie et al.25 found spastic quadriplegia, seizures, and profound retardation in five of nine families with isolated genetic microcephaly. Thus, while craniofacial appearance, lack of neurologic signs, negative history for etiologic events, and microcephaly at birth may suggest a genetic etiology, they are not proof of such a cause. Furthermore, a significant neurologic impairment or a normal OFC at birth does not rule out a genetic cause. This heterogeneity extends to autosomal dominant isolated microcephaly. Haslam and Smith26 first reported four families with normal stature, indistinct phenotype, and borderline to mild retardation. Since then similar families, as well as those with more severe retardation and with normal intellect, have been reported27–29; they serve to emphasize the need to examine family members and to be cautious when discussing prognosis. It is probable that moderate and more severe retardation occur on an autosomal dominant basis but are genetically lethal. The prenatal diagnosis of microcephaly is subject to the ability to accurately measure and define a small brain when

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present, and the gestational timing at which the microcephaly occurs. Cervenak et al.30 in a study of 24 pregnancies found a very poor correlation between a biparietal diameter of  3 SD, measured a few days before term, and the presence of postnatal microcephaly. However, there were no false-positive predictions when the OFC was less than 4 SD, the head perimeter (HP) less than 5 SD, the HP/abdominal perimeter less than 3 SD, or the femur length to HP greater than þ3 SD. Errors in gestational dating or the occurrence of intrauterine growth retardation (IUGR) can also compromise diagnosis. A careful search should be made for additional morphologic anomalies of the brain, and the finding of large subarachnoid spaces, a rudimentary ventricular shape,31 or shortness of the frontal lobe32 may predate measurable microcephaly. A discrepancy of signal size generated from vertebral versus carotid branches on transvaginal sonography with power Doppler was reported in two cases31 but not confirmed in two others,33 perhaps reflecting etiologic heterogeneity. Fetal MRI may add further definition where ultrasound has raised an initial concern.34 The major difficulty with the prenatal diagnosis of microcephaly is that often it does not become apparent until after the second trimester and thus cannot be detected until well into the third trimester.35,36 The distribution of causes of microcephaly that is detected prenatally is likely to vary with gestation and family history, and to be different from that ascertained at birth. Indeed, den Hollander et al.37 found that 25 of 30 prenatal cases were part of a complex problem, thus pointing to the need for a careful wholebody fetal examination. Table 15-1 lists a large number of conditions with microcephaly and associated malformations. Conditions in which there is usually a significant associated brain malformation (e.g., cerebellar hypoplasia, lissencephaly) are included under the specific malformation entry and not under microcephaly. Similarly, conditions in which there is a clear postnatal abiotrophy or metabolic disease are excluded. For most syndromes little is known about the underlying structure of the brain. Etiology and Distribution

Anything that impairs growth and integrity of the brain from the time of its early development to the end of the rapid postnatal growth period may lead to microcephaly. The causes are myriad, and the same agent may act in different ways at different times to cause microcephaly. For example alcohol can act to cause both neuronal migrational abnormalities and excess apoptosis. Developmental and degenerative causes of microcephaly can be both genetic and environmental (extrinsic); but, it can be generally assumed that evidence of the destruction of a normally developed brain is not genetic. However, if fetal inherited thrombophilias are proven to cause vascular disruptive changes, then even this rule will have its exception.528 Developmental problems may be suspected if there are associated extracranial malformations, or if the brain shows an associated primary anomaly such as holoprosencephaly, MSG, or is simply small with a normal appearing architecture. Microcephaly with extracranial anomalies may lead to the recognition of a known or unknown genesis syndrome (Table 15-1). Developmental microcephaly may be intrinsic (in most cases genetic) to the embryo or be extrinsic resulting from a variety of potential agents. At this time it is not clear whether all cases of MSG and microcephaly vera are genetic or whether there are non-genetic phenocopies. Twelve of the 14 families with MSG reported by Barkovich et al.9 had no positive family history, but the number of

Table 15-1. Syndromes in which microcephaly has been reported Syndrome

Prominent Features

Causation Gene/Locus

Abidi: X-linked mental retardation38

Variable short stature, prominent ears, cleft lip/palate, small testes, moderate to severe mental retardation

XLR Xq12-q21

Ablepharon-macrostomia39

Virtual to complete absence of upper and lower lids, failed lip fusion, abnormal nasal alae, corneal damage, absent lanugo, hypoplastic nipples, some cases with cryptophthalmos, absent zygomatic arch, abnormal genitalia

AR (200110) One father with minor signs

Absent abdominal musclesmicrophthalmia40

Wide sutures and fontanel, telecanthus, epicanthus, flat nose, low-set small ears, cleft palate, narrow chest, bifid sternum, low umbilicus, hypoplastic genitalia, joint laxity

AR

Acanthosis nigricans-short stature41

IUGR, prominent long nose with high bridge, small mandible and ears, hearing loss, small hands and feet, cryptorchidism, dislocated radial heads

AR or XLR

Achalasia-adrenocorticalalacrima42

In addition to this known association, brothers displayed microcephaly, ataxia, delayed development, and optic atrophy

AR (231550) 12q13

Achalasia-microcephaly43

Moderate to severe mental retardation, achalasia leading to pulmonary complications that respond to treatment

AR (200450)

Acrocraniofacial-Kaplan type44

Telecanthus, downslanting palpebrae, ptosis, ear anomalies and pits, high nasal bridge, cleft palate, micrognathia, broad tips to digits, proximal thumb, developmental delay. One of two sibs microcephalic.

AR (201050)

Acrofacial dysostosis-Catania type45

IUGR, postnatal growth and mild developmental retardation, malar hypoplasia, tall forehead, widow’s peak, carious teeth, short 1st and 5th fingers, interdigital webbing

AD (101805)

Acrofacial dysostosisPalomeque type46

IUGR, postnatal growth and severe mental retardation, severe maxillary and mandibular hypoplasia, downslanting palpebrae, colobomata, abnormal ears, significant four-limb anomalies with pedunculated thumbs

Unknown

Acrometageria47

Single patient with short stature, beaked nose, skin atrophy on limbs and poor subcutaneous fat, fine thin hair, hyperextensible joints. No excess chromosome breakage. Stated as microcephalic but no measurements reported.

Unknown

Acro-renal-ocular-thumb48

Variable eye anomalies including colobomata; thumb changes ranging from limited flexion and hypoplastic tip to preaxial polydactyly/severe hypoplasia; mild renal anomalies; OFC inconsistently recorded; one of three measured at 3rd centile

AD (102490)

ACTH deficiency-face dysmorphia565

Prenatal and postnatal growth failure, moderate mental retardation, severe micrognathia, cleft palate, atrial septal defect, hypospadias, hearing loss

Unknown

Adducted thumbsmyopathic face49

Craniosynostosis, mental retardation, myopathy, swallowing problems, palatal anomalies, downslanting palpebrae, ophthalmoplegia, limited movement of large joints, early death

AR (201550)

Adrenal hypoplasia-growth hormone deficiency-skeletal anomalies50

Developmental delay, partial androgen resistance, early dental eruption, flat nasal bridge, abnormal helices, high palate, short limbs, delayed bone age, hip dysplasia

Unknown

Albinism-digital anomalies51

Sloped forehead, oculocutaneous albinism, deficient/hypoplastic distal fingers and great toe

AR (203340)

Albinism-immunodeficiencymicrocephaly52

Tyrosine positive oculocutaneous albinism, granulocytopenia, intermittent thrombocytopenia, protruding midface, unusual hair, mild mental retardation

AR (203285)

Alcohol, prenatal53

IUGR, postnatal growth failure, developmental delay, fine motor dysfunction, short palpebrae, maxillary hypoplasia, short nose, thin and smooth upper lip, small distal phalanges

In utero exposure to alcohol

Al-Gazali-leprechaun-like54

Insulin resistance, hypoglycemia, variable growth pattern, some microcephalic, hyperteloric, low nasal bridge, thick lips, prominent nipples, large genitalia, large extremities, brachydactyly

AR (246200)

Alopecia-congenital seizures55

Intractable neonatal seizures, hypertonia, hyperreflexia, profound psychomotor delay, sparse hair follicles, mild hyperkeratosis, gyral changes, reduced cortical neurons

AR

Alopecia-keratosis follicularis-dwarfism56

Square face, micrognathia, long philtrum, delayed teeth, severe psychomotor delay, seizures

XLR

Alopecia-mental retardationMoynahan57

Universal atrichia, any hair at birth soon lost, short stature, delayed puberty, severe retardation

AR

Alopecia-shawl scrotum58

Postnatal onset sparse scalp hair, eyebrows, and lashes; protruding ears; hair follicles containing hair remnants with surrounding fibrosis

AR

Alopecia-skeletal anomalies59

IUGR, growth failure, turricephaly, prominent nose, large ears, contractures, clinodactyly, short middle phalanges, vertebral and other bone fusions, mental retardation

AR (203550)

(continued)

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Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Upswept hair, bitemporal narrowness, hypoplastic supraorbital ridges, eyebrow flare, hypertelorism, high/cleft palate, micrognathia, low and rotated ears, short stature, delayed development

AR? (600325)

Amish-lethal microcephaly17

Congenital microcephaly, possible MSG type, and lethal within a year. Isolated marked elevation of 2-ketoglutaric acid when well. 1/500 Amish births

AR (607196) SLC25A19, 17q25.3

Anemia-abnormal appearance-short stature61

Growth and developmental delay, ptosis, epicanthus, mid-face hypoplasia, small jaw, cupped ears, small penis, delayed puberty

AR?

Angelman62

Broad-based gait, arms abducted, unprovoked laughter, seizures, vertical skull base, occipital groove, macrostomia, prognathia, tongue protrusion, moderate to severe developmental delay

Mat del 15q11-q13 (75%) Pat UPD (5%) UBE3A (<5%)

Anophthalmia-postnatal growth failure63

IUGR, FTT, anophthalmia or related eye anomalies, large fontanels, abnormal ears, hypertelorism, over-riding digits, hypotonia, small genitalia, developmental delay, consanguinity

AR

Anonychia congenitamicrocephaly64

Normal intelligence and appearance; absent to very hypoplastic nails; variable wide-spaced teeth. Single family.

AR?

Anterior chamber cleavagecerebellar hypoplasia65

Postnatal microcephaly, dense hair, broad nose with low bridge, wide cupid-bow mouth, shield chest, tracheostenosis, congenital hypothyroidism, cerebellar hypoplasia, anterior chamber eye anomalies

Unknown (601427)

Apple peel atresia-ocular anomalies-microcephaly66

Marked microcephaly, developmental delay, variable eye anomalies include anterior chamber and microphthalmia, apple peel jejunal atresia

AR (243605)

Armendares: retinitis pigmentosacraniosynostosis67

Postnatal growth delay, craniostenosis, atypical retinitis pigmentosa, micrognathia, ptosis, epicanthus, telecanthus, short nose, clinodactyly

Unknown

Arthrogryposis-jaw and finger contractures68

Microstomia, micrognathia, groove above chin, high palate, large ears, hand contractures, metacarpophalangeal subluxation, talipes equinovarus, dislocated hip

AD (121070)

Asphyxiating thoracic dysplasia variant69

Thoracic and pelvic changes like Jeune asphyxiating thoracic dysplasia, asymmetric cupped ribs, some bony changes cleared, mental retardation (possibly chance concurrence of microcephaly/MR with Jeune)

AR

Asymmetric crying face70

Developmental delay and postnatal growth failure in a child whose mother and maternal grandmother were also microcephalic with asymmetric crying face, and whose maternal aunt had microcephaly, asymmetric crying face, mental retardation, and cleft palate

AD (125520)

Ataxia-ocular telangiectasiachromosome instability71

Onset of psychomotor regression in infancy; ataxia, dysarthria; increased sporadic chromosomal breaks, especially chromosome 7; timing of onset of microcephaly unclear

Unknown

ATR-1672

Alpha-thalassemia, macro- or microcephaly, broad forehead, hyperteloric, low nasal bridge, irregular teeth, genital anomalies

AD (141750) 16p13.3

ATR-X73

Flat face with low nasal bridge, hypertelorism, epicanthus, inverted ‘‘V’’ upper lip, large mouth, small teeth, everted lower lip, short stature, genital anomalies, hemoglobin H disease with HbH bodies

XLR (300032) XNP, Xq13

Ataxia-short stature-DNA repair74

Microcephaly and growth failure from infancy; moderate mental retardation; initially clumsy, later onset of dysarthria, nystagmus, and ataxia. Decreased DNA excision repair.

Unknown

Baller-Gerold-RothmanThompson-like75

IUGR infant with overlapping features of the syndromes; parents cousins; unusual appearance, short forearms, obesity, hypoplastic thumbs, craniostenosis

AR?

Bartsocas-Papas: popliteal pterygium76

Ankyloblepharon, corneal ulcers, syngnathia, cleft lip/palate, nasal hypoplasia, absence/syndactyly of hands and feet, pterygia, genital anomalies, highly lethal

AR (263650)

Battaglia: coarse face-joint laxity-seizures77

Severe developmental delay, somewhat coarse face, full lips, everted lower lip, initial hypotonia, abnormal posture, hip and knee flexion, lax joints, delayed bone age and thin diaphyses

AR?

Bavinck: eye anomalies-short stature78

Short stature, mild retardation, prominent and narrow forehead, epicanthus, cataract, other eye anomalies, abnormal external ears, short nose with thick alae, small hands

AD

Bawle-Horton: microcephaly27

A number of families have autosomal dominant microcephaly, sometimes with additional findings of unknown specificity; variable mental retardation, soft facial signs, short stature

AD

Aminopterin-like

60

(continued)

475

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Benzodiazepine, prenatal

Low nasal bridge, short nose, short palpebral fissures, epicanthus, small mandible, flat upper and full lower lips, cleft/high palate, developmental delay, mild cortical dysplasia

In utero exposure to benzodiazepine

Bindewald: Fallot spectrummild dysmorphia80

Tetralogy of Fallot/double outlet RV, severe growth and mental retardation, hirsute forehead, large ears, micrognathia, mild 2-4 toe syndactyly, plantar creases

AR (601127)

Blepharophimosis-epicanthus inversus-microcephaly81

Blepharophimosis, ptosis, epicanthus inversus; the BPES syndrome (types I and II) are due to FOX2 mutations. Cases with microcephaly may be a contiguous gene syndrome.

Del 3q23

Blepharophimosis-radial hypoplasia-cardiac82

Hypertelorism, blepharophimosis, micrognathia, hypoplastic left heart, camptodactyly, radial hypoplasia, developmental delay

Unknown

Blepharophimosis-radioulnar synostosis83

Microcephaly, blepharophimosis, ptosis and radioulnar synostosis in two unrelated patients

Unknown

Bo¨rjeson-ForssmanLehmann84

Central obesity, narrow palpebrae, large ears, short stature, moderate to severe retardation, kyphosis, short neck, post-pubertal hypogonadism

XLR (301900) PHF6, Xq26-q27

Bowen-conradi85

Lethal syndrome with IUGR, micrognathia, prominent nose, rocker-bottom feet, joint restriction, clouded cornea, most cases reported in Hutterites

AR (211180)

Brachy/camptodactyly-short stature86

Short stature, hypotelorism, maxillary hypoplasia, micrognathia, hamate-capitate and semilunar-pyramidal fusion, 2-5 distal metacarpal hypoplasia, proximal phalanges very underdeveloped

Unknown

Brachycephalosyndactylycataract87

Postnatal onset microcephaly, normal IQ, hypertelorism, ptosis, microcornea, coloboma, downslanting palpebrae, malar flatness, retrognathia, low and rotated ears, linear skin depigmentation, duplicated hallucal nails

Unknown

Brachydactyly A2-diabetes88

Hypoplastic thumbs and halluces, short index fingers with absent middle phalanges, learning problems, small genitalia, delayed puberty

AR (211369)

Brachydactyly-nail dysplasia89

Type B brachydactyly, coarse face with synophrys and hirsutism, crowded teeth, abnormal helices, kyphosis, variable syndactyly of toes and fingers, mental retardation

XLD probable (603396)

Brachyphalangy-tibial aplasia-polydactyly90

Scalp defect, short palpebrae, blocked nasolacrimal ducts, small nose, small jaw, cleft ear lobules, preauricular tags, abnormal fingers, postaxial polydactyly of feet

Unknown

Braeger: ischiadic hypoplasiapolydactyly91

IUGR, developmental delay, hypertelorism, epicanthus, short nose, hypospadias, four-limb postaxial polydactyly, hypogammaglobulinemia, small ischia. Single case, consanguinity

Unknown

Branchio-oculo-facial92

Microcephaly and delayed development inconsistent, prominent philtral pillars, broad nose and nasal tip, ocular coloboma, branchial clefts, post auricular linear scar

AD (113620)

BRESHECK93

Microhydrocephaly with fused thalami, growth and mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR or XLR

Brittle cornea-joint hyperextensibilty94

Similar to ED VI. Blue sclera, keratoglobus with risk of globe rupture, lax joints, normal lysyl-hydroxylase. Sister in a sib-pair with consanguineous parents was microcephalic

AR (229200)

Buntix: microbrachycephalyradioulnar synostosis95

Short stature, short philtrum, pigmentary retinopathy, radioulnar synostosis. Consanguinity

AR

Burton: microcephaly-short stature96

Normal to borderline intelligence, simple protruding ears, nystagmus/esotropia, stature 3 to 6 SD

AD (156580)

Calcified basal gangliamicrophthalmia308

Mild mental retardation, microphthalmia, cataract, peaked nose with prominent root, high palate, micrognathia; single case

Unknown

CAMFAK97

Congenital cataracts and microcephaly, hypertonia, progressive kyphoscoliosis, hip dysplasia, demyelinization similar to Cockayne.

AR?

Camptodactyly-Guadalajara type98

IUGR, restriction at elbows and interphalangeal joints, short stature, wide forehead, epicanthic folds, telecanthus, microphthalmia, short and anteverted nares, abnormal pinnae, frontal and ethmoid sinus agenesis, bony anomalies

AR (211910)

Canescence-joint laxity99

Profound retardation, ligamentous laxity, thin skin, short stature, droopy lower eyelids, prominent eyes, premature graying

AR

Carbamazepine, prenatal100

Generally uncommon mild findings of growth delay, upslanting palpebrae, short nose, and hypoplastic nails; more severe reports of spina bifida, microcephaly, developmental delay; one case of radial microbrain

Prenatal exposure

79

(continued)

476

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Carey-Fineman-Ziter

Robin sequence, Moebius phenotype, muscle hypoplasia, downslanting palpebrae, ptosis, low and rotated ears

AR (254940)

Carpenter-Waziri102

Coarse facial appearance, full eyebrows, depressed nasal bridge, open mouthed, widely spaced teeth, short stature, moderate developmental delay, brachydactyly with wide distal phalanges

XLR (300032) XNP, Xq13

Castriota-Scanderberg: acrodysplasia103

IUGR, proportionate short stature, absent/hypoplastic clavicles, poor pubic ossification, hypoplastic/absent clavicles, brachydactyly

Unknown

Cataracts-aberrant oral frenula104

Growth proportionately <3rd centile, epicanthus, cataracts, ptosis, upslanting palpebrae, small and anteverted nose, multiple oral frenula; borderline to normal intelligence

AD

Cataract-autonomic neuropathy105

Microcephaly, narrow forehead, congenital cataracts, progressive autonomic dysfunction with variable age of onset of gut motility and hypotensive problems, sensory and motor involvement, severe developmental delay

AR

Cataracts-renal tubular necrosis106

Congenital cataracts, early onset seizures, significant developmental delay, spongy breakdown of gray and white matter, cerebellar dysplasia, histiocytic infiltration and necrotic foci in kidneys

AR (218900)

Caudal appendage-short terminal phalanges107

Monozygous twin with ‘‘tail,’’ short stature, short terminal phalanges, mixed deafness, developmental delay, initial normal OFC, arrested hydrocephalus, then microcephaly

Unknown

Cerebellar ataxia-optic atrophy108

Congenital spasticity, ataxia and optic atrophy, severe mental retardation, growth failure, abnormal osmophilic skin EM pattern

AR

Cerebellar hypoplasiaendosteal sclerosis109

Developmental delay, oligodontia, small teeth, congenital hip dislocation, sclerosis of long bones and vertebrae, stenosis of medullary space

AR

Cerebral aneurysmscalcification110

Short stature, delayed development, seizures, symmetric calcification of basal ganglia, thalami, and dentate, pulmonary emphysema, cirrhosis. Three male sibs, two microcephalic

AR or XLR

Cerebro-arthro-digital111

Extreme IUGR, microcephaly or hydrocephaly, fat cheeks, short upturned nose, small and inturned mouth, bud-like digits, hypoplastic to absent nails, sacral agenesis and skeletal anomalies

Unknown

Cerebro-costo-mandibular112

Micrognathia, cleft palate, glossoptosis, rib gaps, absent 12th rib, variable developmental delay and microcephaly (11/28), high mortality; variable inheritance

Variable (117650)

Cerebro-oculo-facioskeletal113

Prominent nasal root, large ears, deep-set eyes, narrow palpebrae, microphthalmia, cataract, camptodactyly, progressive postnatal growth failure, inanition, death in infancy

AR (214150) CKN2, 10q13 XPG, 13q33 EM9, 19q13.2-q13.3

COFS-osteopetrosis114

Congenital contractures, hypotonia, postnatal growth failure, prominent nasal bridge, micrognathia, muscular degeneration, early death

Unknown

Cerebro-oculo-genital115

Microphthalmia, corneal opacity, severe developmental delay, small phallus, hypospadias, marked microcephaly or hydranencephaly, absent corpus callosum

XLR (309800)

Cerebro-oculo-skeletalrenal116

Optic atrophy, absence of retinal vessels, seizures, growth and developmental delay, elongated clavicles, cupped ribs, mild platyspondyly, rhizomelia, schizencephaly, nephritis/nephrosis

Unknown (200995)

Cerebro-renal-digital117

Pterygium coli, postaxial polydactyly hands and feet, dysplastic kidneys, vaginal agenesis, polysplenia (family ‘‘G’’ of report)

AR

Ceroid-lipofuscinosiscongenital118

Rare conatal presentation of microcephaly and neuronal ceroid-lipofuscinosis, seizures, hyperactive reflexes

AR (204200)

Cervical ribs-preaxial polydactyly119

Male proband with urethral obstruction, congenital heart, IUGR, anal atresia, micropenis, spinal defects; female sibs and mother with cervical ribs, missing ribs; one with Sprengel anomaly

XLD? (601389)

Cervical vertebral fusionshort stature120

Mild retardation, sloping forehead, beaked nose, ptosis, prominent eyes, low-set ears, malar hypoplasia, micrognathia, funnel chest; cervical spine fusion, instability, compression; consanguinity

AR (251250) XLR

Choanal stenosis-hypotheliabranchial fistulae121

Bilateral choanal stenosis, broad forehead, prominent nose, branchial fistulae, lacrimal duct stenosis, hypothelia, hearing loss, growth and speech delay; consanguinity

AR?

Choanal stenosis-short stature122

Short nose, epicanthus, long philtrum, thin upper lip, atrial and ventricular septal defects, developmental delay

AR (214800)

101

(continued)

477

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Chondrodysplasia-joint dislocations123

Growth failure, joint dislocations, club feet, kyphoscoliosis, finger flexion, prominent eyes, low nasal bridge, glaucoma, epiphyseal changes

AR (215200)

Chondrodysplasia-pseudohermaphroditism124

IUGR, growth retardation, hypoplastic irides, optic disc colobomas, micromelia, narrow chest, hypoplastic scapulae, trapezoid vertebrae, short hand bones. One case a 46,XY female with cerebellar hypoplasia

AR? (600092)

Chondrodysplasia punctatadel Xp22.32125

Nasal hypoplasia, generalized ichthyosis, mild mental retardation, behavioral difficulties, stippled epiphyses, mixed hearing loss. Described as mildly microcephalic

XLR Xp22.32

Chorioretinopathymicrocephaly-AR126

Microphthalmia, chorioretinopathy, optic atrophy, short stature, cutis marmorata, mental retardation

AR (251270)

Chorioretinopathymicrocephaly-AD127

Microphthalmia, persistent embryonic remnants, chorioretinal dysplasia, myopic astigmatism, developmental delay

AD (156590)

Chromosome abnormalities128

Microcephaly is a nonspecific finding in a large number of chromosome deletion and/ or duplication syndromes

Chromosome imbalance

Chromosome instabilityMaraschio129

Primary amenorrhea, Wolff-Parkinson-White, follicular thyroid adenoma, slightly bulbous nose, small jaw, low IgG subclasses, high level of spontaneous chromosome aberrations

AR?

Chromosome instabilityWegner130

Normal development, small jaw, epicanthus, high palate, areas of depigmentation, anal stenosis/atresia, low IgA level, defective T-cells, cellular hypersensitivity to x-rays and bleomycin

AR (251260)

Chudley: facial-obesityhypogonadism131

One of four patients microcephalic; moderate to severe mental retardation, short stature, bitemporal narrowing, almond-shaped palpebrae, anteverted nares, inverted ‘‘V’’ upper lip, macrostomia, hypogonadism

XLR (309490)

Cleft lip/palate-hypodipsic hyponatremia132

Single case. Bilateral cleft lip/palate, possible hypothalamic defect with hypodipsic hyponatremia, hyperlipemia, microcephaly, growth and developmental delay

Unknown

Cleft mandible-athetosis133

Prominent forehead, small midface, prominent mandible with cleft and absent incisors, preauricular tag, coloboma, hypotonic becoming athetoid

Unknown

Cleft lip/palate congenital megacolon134

Cleft lip and/or palate, mental retardation, variable microcephaly, short stature, other variable minor anomalies

AR

Coffin-Siris135

Growth failure, scalp hypotrichosis, body hypertrichosis, fingernail hypoplasia, absent/hypoplastic terminal phalanx, developmental delay, hindbrain anomalies

AD? (135900)

Coffin-unusual facearthritis136

Growth and developmental delays, small and anteverted nose, long and smooth philtrum, thin upper lip, probable sensorineural deafness, onset arthritis in infancy

AR

Cohen137

Mid-childhood-onset obesity, mental retardation, high nasal bridge, downslanting fissures, prominent nasal root, large ears, chorioretinal dystrophy, narrow hands and feet

AR (216550) COH1, 8q22-q23

Colobomas-clefting-mental retardation138

Microbrachycephaly and short stature, colobomas of iris and retina, ptosis, cleft lip and palate, developmental delay

AR or XLR

Colobomatous microphthalmia-cerebellar hypoplasia139

Microcephalic at birth, microphthalmia, iris coloboma, cataracts, optic nerve hypoplasia, high palate, cerebellar hypoplasia. Single case, parental consanguinity

AR?

Congenital contracturesshort stature314

Severe developmental delay, short stature, severe scoliosis, congenital contractures, myopia, ptosis, beaked nose, dental anomalies

Unknown

Congenital heart defectsskeletal changes140

Growth failure, hypotonia, delayed development, seizures, aortic hypoplasia, atrial and ventricular septal defects, micropenis, redundant forehead and neck skin, postaxial polydactyly

AR or XLR

Congenital heart defectsunusual face141

Delayed growth and development, seizures, prominent ear lobes with pits/creases, anteverted nares, high palate, lacrimal duct stenosis, thyroglossal cyst, tetralogy of Fallot, short thick feet

AR or XSLR

Congenital muscular dystrophy-cataracts142

Mild developmental delay, slowly progressive merosine positive dystrophy, normal neuroimaging, abnormal ERG, hyperpigmented fundus

AR

Congenital myopathy-bullous skin eruption143

Myopathy, bullous skin eruption, secretory diarrhea, zinc deficiency, postnatal growth failure, mild developmental delay, hearing loss, congenital heart defect

AR

Congenital progeria: PettyWiedemann144

IUGR, congenital microcephaly, wide sutures, persistent fontanel, sparse hair, progeroid face, poor subcutaneous fat, lax and wrinkled skin, delayed growth, normal mental development

Unknown

(continued)

478

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Conotruncal heartmicrophthalmia145

Microbrachycephaly reported (case 2) but not documented, minor ear anomalies, unusual appearance (no photos), small mouth, microphthalmia, tetralogy of Fallot or truncus arteriosis

AR

Corneal dystrophy-ichthyosis nigrans146

Annular corneal dystrophy, ichthyosis nigrans, myopia, photophobia

Unknown

Cortada: acromesomelic anomalies-dental arch contraction147

Contracted dental arches, hypodontia, bowed radii, hypoplastic ulnar styloid, acromicria, small feet, hypotelorism, epicanthus, profound retardation

AR

Cranioectodermal dysplasiaSensenbrenner148

Dolichocephaly, frontal bossing, sparse and fine hair, dental anomalies, marked brachydactyly, short narrow thorax, pectus excavatum, one case microcephalic and one macrocephalic of 14

AR (218330)

Craniofacial dysostosisdiaphyseal hyperplasia149

Rhizomelic short stature, brachydactyly, hypoplastic malar region, prominent eyes, small mandible, large fontanel closes early, fractures, thick cortex of long bones, thin skull, Wormian bones

AD (122900)

Craniosynostosis-absent fibula150

Coronal synostosis, lacrimal duct stenosis, intraabdominal testes, short stature, reduced span, microbrachycephaly, hypodontia, normal intelligence

AR (218550) XLR

Craniosynostosis-anal anomaly-porokeratosis151

Coronal synostosis, imperforate/anterior anus, hypospadias; postnatal onset of spreading porokeratosis; no FGFR1, 2 or 3 mutations

AR or XLR (603116)

Craniosynostosis-colobomasplit hand152

Upslanting palpebrae, paranasal folds, high palate, micrognathia, iris colobomata, syndactyly toes 2-5, asymmetric split hand, perineal hypospadias, severe retardation

Unknown

Craniosynostosishumeroradial-aplastic thumbs153

IUGR, marked microcephaly, ridged sutures, prominent eyes with short palpebrae, micrognathia, elbow and knee flexion contractures, absent thumbs, bilateral humeroradial synostosis, hydranencephaly

Unknown

Craniosynostosis-limb reduction-clefting154

Mid facial hypoplasia, cleft lip/palate, auricular anomalies, hypertelorism, radial/ fibular aplasia, short stature (patient looked similar to SC-phocomelia, no chromosome puffing noted)

AR?

Crouzon-marked microcephaly155

U-shaped palate, shallow orbits, posteriorly rotated ears, glaucoma, craniostenosis and growth failure (facial appearance supports primary suture involvement, possibly same as Crouzon)

Unknown

Cutaneous hypo- and hyperpigmentation-spastic paraparesis156

Mental retardation, gray hair as infant, hypopigmented patches, freckles and cafe-aulait spots, progressive spastic paraparesis, muscle wasting, long nose, retrognathia

AR (270680)

Cutis laxa (male lethal)157

Delayed growth and development, lax ligaments, dislocated hips, open fontanel, downslanting palpebral fissures, urinary tract anomalies; all 14 cases so far are female

AR (219200)

Cutis laxa-short umbilical cord158

Initial increased OFC becoming microcephalic, marked cutis laxa and hypertonia at birth diminishing with time, epicanthus, telecanthus, low nasal bridge and anteverted nares. Single case

Unknown

Cutis verticis gyrata-retinitis pigmentosa159

Primary cutis verticis gyrata, prominent supraorbital ridges, hypertelorism, progressive RP, cataracts, sensorineural deafness, kyphoscoliosis, developmental delay

XLR or AR (605685)

Cytomegalovirus, prenatal infection160

Asymptomatic to severe CNS changes. May include IUGR, microcephaly, intracranial calcification, hydrocephaly, chorioretinal changes, deafness

Prenatal infection

Czeizel-Lowry: cataractmicrocephaly161

Mild microcephaly, postnatal nuclear cataract, severe developmental delay, Pertheslike hip changes; CT showed bilateral symmetric hypodensities in pallidum and corpus striatum

AR (212540)

Da Silva: mental retardationmicrocephaly162

Severe mental retardation, postnatal growth failure, preauricular skin tag, camptodactyly, nasal skin tag, club feet, increased tone, pulmonary infections, hypoplastic corpus callosum, lethal

AR

Deafness-male pseudohermaphroditism163

IUGR, hypertelorism, ptosis, small nose, microtia, micrognathia, cleft palate, hypospadias, small penis, shawl scrotum, mental retardation, feeding and respiratory problems

AR

De Barsy164

IUGR, growth failure, progeroid appearance, large ears, clouded cornea, thin lips, cutis laxa and atrophic skin, hypotonia, lax small joints, mental retardation

AR

De Lange165

IUGR, synophrys, short nose, anteverted nares, prominent philtrum, thin upper lip with downward ‘‘V’’ at midpoint, proximal thumbs, ulnar ray defects, severe retardation usual, milder form recognized

AD (122470) NIBPL, 5p13.1 (continued)

479

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Delozier-Blanchet: microcephalyhypogenitalism166

Amphora-shaped face, microcephaly with nystagmus, spasticity, obesity and hypogenitalism, severe mental retardation

AR or XLR

De Moor: frontonasal dysplasia167

Sporadic cases of growth and developmental failure, mild frontonasal dysplasia, congenital heart disease (TOF/aortic stenosis), mild genital anomalies

Unknown

D’ercole: short staturecongenital heart168

IUGR, growth and developmental retardation, congenital heart, oval face with high palate and furrowed tongue, delayed puberty

XLR

Desmosterolosis169

IUGR, downslanting palpebral fissures, low nasal bridge, thick alveolar ridges, gingival nodules, congenital heart defect, ambiguous genitalia, variability includes case with macrocephaly and another with microcephaly, abnormal cholesterol biosynthesis

AR (602398) DHCR24 1p33-p33.1

Digito-renal-cerebral170

Absent distal phalanges of fingers and toes, cystic dysplasia and other renal anomalies

AR (222760)

Adults described with variable microcephaly and mental retardation, broad-based gait, truncal ataxia, intention tremor, athetoid posturing, dysarthria, short stature

AR (224050)

Distal aphalangia-extra metatarsal172

Variable asymmetric distal aphalangia, hand and foot syndactyly, duplication of 4th metacarpal, short stature, borderline intelligence

AR

Distal arthrogryposis-mental retardation173

Postnatal onset microcephaly, frontal and parietal bossing, high narrow forehead, narrow chest, retrognathia, narrow and pointed nose, adducted thumbs, tapered and contracted fingers

AR?

Dolichospondylic dysplasia174

Short stature, beaked nose, epicanthus, rotated ears, scoliosis, thin gracile metacarpals, tall vertebral bodies, mild retardation to borderline IQ, mild microcephaly. Single case, not to be confused with dolichospondyly described in syndromes such as 3-M.

Unknown

DOOR175

Sensorineural deafness, onychodystrophy, osteodystrophy with absent distal phalanges, mental retardation. A severe, often lethal, form may have elevated 2-oxoglutarate

AR (220500)

Duane anomaly-ASDmicrocephaly176

Duane retraction in association with short neck, spastic paraplegia, atrial septal defect and microcephaly; not dysmorphic

Unknown

Dubowitz177

IUGR, short stature, sparse hair, sloped forehead, small palpebral fissures, ptosis, telecanthus, broad nose, palate anomalies, micrognathia, eczematoid skin

AR (223370)

Drayer: microcephalydigital178

Hypertelorism, blepharophimosis, low set ears, brachydactyly 2-5, proximal thumbs, short 3–5 toes, short stature, developmental delay

AR

Dwarfism-bowed femurs179

IUGR, disproportionate short stature, hypotelorism, upslanting palpebrae, prominent clavicles, narrow chest, flexion contractures of major joints and fingers, irregular flared metaphyses, coronal cleft vertebrae

Unknown

Dwarfism-delayed sexual maturation180

Severe mental retardation, proportionate short stature, infantile genitalia, delayed bone age, no specific facial signs; possible parental consanguinity

AR or XLR

Dwarfism-enamel hypoplasia-diabetes181

Congenital microcephaly, growth and mental retardation, onset of diabetes in infancy, small wide-spaced teeth with enamel hypoplasia. The two sisters had elevated alanine, pyruvate, and lactate.

AR

Dwarfism-microcephalyhydrocephaly182

Sloping forehead with marked microcephaly, no developmental progress, short and cupped ribs, mildly flat vertebrae, postmortem hydrocephalus, one sib with absent corpus callosum

AR

Dwarfism-tall vertebrae183

Prenatal proportionate short stature with hypertelorism, prominent supraorbital ridges, triangular face, tall and narrow vertebrae, slender tubular bones

AD (126950)

Dyserythropoiesesmicrocephaly-IUGR325

IUGR, postnatal growth failure with mild liver dysfunction and chronic diarrhea, significant neonatal jaundice, aniso/microcytosis, abnormal iron metabolism with ringed sideroblasts

AR/XLR?

Dyskeratosis congenita184

Unusual case of autosomal recessive form with severe microcephaly, mental retardation, and cerebellar hypoplasia, in addition to usual nail dystrophy, mucosal and skin pigment changes, and bone marrow failure

AR?

Ear-patella-short stature185

Microtia, micrognathia, small mouth with thick lips, developing high narrow nose, high forehead, short stature, absent patella, dislocating elbows, several bony anomalies, and delayed bone age

AR (224690)

Ectodermal dysplasia-ocular: Wallis-Beighton186

Mental and growth retardation, blindness due to microcornea and sclerocornea, narrow nasal bridge, flared nostrils, short upper lip, broad alveolar ridge, prominent ears, fine and sparse hair, barrel-shaped upper incisors

Disequilibrium

171

(continued)

480

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Ectrodactyly-deafness

Similar to EEC with ectodermal dysplasia, typical ectrodactyly, submucous cleft palate, Mondini anomaly causing sensorineural deafness, vertical talus

AD (220600) 7q21.1-q21.3

Ectrodactyly-ectodermal dysplasia-clefting188

Typical ectrodactyly (central reduction); ectodermal changes may include skin, hair, nails, and teeth; cleft lip/palate, lacrimal duct, and urogenital anomalies; developmental delay in 7% and microcephaly in 2% of cases

AD (129900) p63, 3q27 7p11.2-q21.3, Chr 19

Ellis: microcephaly-heartrenal189

IUGR, severe microcephaly, small ears, pre-auricular pits, short palpebral fissures, hypoplastic alae, cleft palate, redundant neck skin folds, varied congenital heart defects, lung segmentation defects, unilateral renal agenesis, high lethality, brain in one sib small with reduced gyri, hydranencephaly-like in one

AR (601355)

Elmer: anterior chamberlentigenes-marfanoid190

Axenfeld anomaly, Rieger anomaly, posterior embryotoxon, mild mental retardation, lentigines on the back, marfanoid habitus; two males complete situs inversus; parental consanguinity

AR

Epiphyseal dysplasia-retinitis pigmentosa191

Short stature; variable mild retardation; hypertelorism; optic atrophy; limited elbow extension; small, flat, irregular epiphyses; wide lumbar pedicles

AR

Evans: microcephalyhypotelorism192

Normal intelligence, hypotelorism, malar hypoplasia; one of six had Axenfeld anomaly

AD (156580)

Facial anomalies-hypoplastic genitalia193

Prenatal onset, IUGR, severe retardation, low upswept hairline, prominent glabella, large abnormal ears, hydronephrosis, camptodactyly, lethal (prenatal diagnosis possible), consanguinity

AR or ?XLR

Facio-digital-genital-Kuwait type194

Variable short stature with normal development, Aarskog-like face with hypertelorism, anteverted nares, long and deep philtrum, long neck and sloped shoulders, broad hand with mild interdigital webbing and hyperextensibility, microcephaly recorded but frequency not documented

AR (227330)

Fallot complex-mental and growth retardation195

Severe growth and developmental delay, large and protruding ears, slightly upslanting palpebral fissures, high palate, micrognathia, cutaneous toe syndactyly, longitudinal plantar crease

AR

Familial microcephalyTolmie type 2196

Neonatal microcephaly, severe generalized seizures, spasticity, and profound mental retardation

AR

Fanconi pancytopenia197

Short stature, radial ray defects, skin pigment anomalies, variable-onset aplastic anemia/leukemia, urogenital anomalies, increased baseline and clastogen-induced chromosome breakage

AR (227650) FAA, 16q24.3 (60–65%) BRCA2, 13q12.3 FACC, 9q22.3 (8%) FANCD2, 3p25.3 FANCE, 6p22-p21 (13%) FANCF, 11p15 FANCG, 9p13

Feingold: mesobrachyphalangytracheoesophageal fistula198

Grecian nose, telecanthus, prominent occiput, micrognathia, tracheoesophageal fistula, duodenal atresia, 2-3 toe syndactyly, hypoplasia middle phalanges 2nd and 5th fingers, normal development, resembles del (13q22-qter)

AD

Feingold: short stature-cleft palate-ear anomalies199

Similarities to Goldenhar syndrome; facial asymmetry, thin ear helices, broad nasal bridge, cleft palate, gingival hypertrophy, prominent alveolar ridges, short fingers, spina bifida occulta, mild mental retardation; single case

Unknown

Feinstein: partial alopeciapersonality traits200

Sparse scalp, body, eyebrow, and eyelash hair, lighter in color than family; harsh, deep voice; thick, protruding ears; microcornea and marked hypermetropia; hyperkinetic, mischievous, cheerful, self confident, and outgoing

Unknown

Fernhoff: short stature-malar/ mandibular hypoplasia201

Single case, IUGR, significant micrognathia, cleft soft palate, petite face, narrow palpebral fissures, epicanthic folds, small low-set ears, overlapping fingers with bilateral fixed flexion deformities of the 3rd, 4th, and 5th proximal interphalangeal joints, small pituitary, absence of the cerebellar external granular layer

Unknown

Fetal alcohol202

Variable pre- and postnatal growth failure, short palpebral fissures, malar hypoplasia, short nose, smooth philtrum, thin upper lip, small distal phalanges and nails, cardiac malformations, vertebral anomalies, strawberry hemangioma

In utero alcohol exposure

Fetal brain disruption203

Marked microcephaly with overlapping sutures, scalp rugae, and severe mental retardation resulting from a variety of disruptive causes including thromboembolism, infection, and fetal trauma

Disruption

187

(continued)

481

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Fibular deficiency-mental retardation204

IUGR, hypertelorism, downslanting palpebral fissures, high and narrow forehead, anteverted nares, short philtrum, small mouth, mental retardation, fibular remnant, short, bowed tibia; mild, variably short metacarpals, metatarsals, and proximal phalanges of the toes

Unknown

Filippi: unusual faciessyndactyly205

Low birth-weight, growth failure, severe retardation, prominent forehead, prominent nasal root with specific shape to root, syndactyly 3-4 fingers and 2-4 toes, characteristic metacarpophalangeal profile

AR (272440)

Floating-Harbor206

IUGR, speech delay with normal motor development, bulbous nose with wide columella, deep-set eyes, short philtrum, thin lips, triangular face, short neck, brachy/ clinodactyly; microcephaly an inconsistent sign

Sporadic (136140)

Focal dermal hypoplasia207

Coloboma, microphthalmia, dental hypoplasia and abnormal eruption, linear skin hypoplasia with hyperpigmentation, atrophic macules, extruding areas of fat; developmental delay and microcephaly are variable findings

XLD (305600) Xp22.31

Frydman: V-esotropiablepharophimosis208

Short stature, borderline microcephaly, blepharophimosis, ptosis, strabismus, variable telecanthus, short palpebrae, V-esotropia with upward gaze paralysis, 2-3 toe syndactyly

AR (210745)

Fryns-Verresen: IUGRcoloboma-microcephaly209

IUGR, sloping forehead, low-set ears, microphthalmia, iris coloboma, cataracts, corneal clouding, congenital heart; absent left kidney, ureter, and ductus deferens in one male, hypospadias, anal stenosis; female sib had unilateral cleft lip/palate; perinatally lethal

AR

Funduscopic anomalies without retardation210

Variable funduscopic changes as in Gardner syndrome; fine granular pigment with hyperpigmented spots and areas of atrophy, patchy chorioretinal atrophy

AR

German: peculiar face-growth retardation211

Reduced intrauterine movement, dolichocephaly, long face, long and smooth philtrum, downslanting fissures, large nose and ears, mild camptodactyly, cleft palate, mental retardation, lethal

AR

Gillessen-Kaesbach: polycystic kidneysbrachymelia212

Potter type 1 polycystic kidneys, microbrachycephaly, short and full neck, hypertelorism, upslanting palpebral fissures, flat nasal tip, smooth philtrum, fleshy and posteriorly rotated ears, short limbs, rocker-bottom feet, brachydactyly, congenital heart defect, and other intra-abdominal anomalies

AR

Giuffre: microcephalyradioulnar synostosis213

Radio-ulnar synostosis, 5th finger clinodactyly, mild finger cutaneous syndactyly, cubitus valgus. Original cases of normal intelligence; similar sporadic cases since reported with mild delay.

AD

Golabi: short stature-brittle hair214

Postnatal onset microcephaly, growth and developmental retardation, narrow triangular face, upslanting palpebral fissures, epicanthus, telecanthus, prominent ears; seizures, atrial septal defect, brittle hair, and large central incisors variable features

XLR

Goldblatt: genitopatellar215

Hypoplastic/absent patella, contractures of major joints, short stature, cupped ears, flat nasal bridge, mid-face hypoplasia, micrognathia, crossed renal ectopia, scrotal hypoplasia; 4 of 7 cases with absent corpus callosum

Unknown (606170)

GOMBO216

Named for growth retardation, ocular abnormalities, microcephaly, brachydactyly, oligophrenia; has prominent nose, dental anomalies, aged skin, 5th finger, clinodactyly, prognathism. Original cases found to be 46,XY, ish der(3),t(3;22) (p25;q13).

Partial 3p monosomy and 22q trisomy (233270)

Goniodysgenesis-short stature217

Growth and mental retardation, downslanting palpebral fissures, Rieger anomaly, epicanthus, preauricular pits, possible cardiac valve defects

AD? (138770)

GRANDDAD218

IUGR, sparse scalp hair, prematurely aged face, postnatal growth failure, normal development, triangular face, deep-set eyes, hypermetropia, prominent nasal septum, hypoplastic alae, poor fat, 2 of 7 microcephalic

Unknown

Green: anal-renalsyndactyly219

Postnatal growth failure, anal stenosis, unilateral renal agenesis, variable 2-5 toe syndactyly; adult had broad forehead, narrow nose, and ventricular septal defect

AD

Grix: broad thumbshyperostosis220

Large thumbs and halluces, neonatal hyperostosis, puffy eyelids, high nose, bulbous tip, bifid tongue tip, psychomotor delay, hypertonic, postnatal growth failure, hypertrichosis

AR or SLR

Growth failureencephalopathy-endocrine221

Postnatal onset microcephaly and growth failure, high bossed forehead, flat occiput, upslanting palpebral fissures, high palate, small pointed chin, cortical atrophy; one sib with septum pellucidum cyst, stereotypic movements

AR

Growth hormone deficiencyadvanced bone/sexual maturation222

Severe microcephaly, short stature, advanced skeletal and sexual maturation, limited extension at elbows, isolated growth hormone deficiency; one of the two brothers was mentally retarded

XLR or AR

(continued)

482

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Grubben: short-dentaleczema223

Pre- and postnatal growth and developmental delay, hypotonia; small, widely spaced or missing teeth, eczematous skin rash; small, puffy hands and feet with tapering digits; partial agenesis of the corpus callosum or ventriculomegaly; selective IgG2 subclass deficiency a possible marker

AR (233810)

Gurrieri: retardationseizures-skeletal224

IUGR, postnatal growth and developmental delay, deep-set eyes, short philtrum, kyphosis, joint laxity, seizures, cerebral atrophy; 1 of 4 sibs truly microcephalic, minor pelvic and spine anomalies

AR (601187)

Gustavson: blind-deafspasticity225

Generally lethal in first year, severe sensorineural hearing loss, large malformed ears, optic atrophy, restricted movement of the large joints, spasticity, seizures. One severely affected girl

XLR Xq26

Halal: microcephaly cleft palate226

Mild developmental delay, retinal pigment anomaly, hypotelorism, prognathism, variable camptodactyly affecting distal interphalangeal joints of fingers 2-5

AD or XLD

Halal-Silver227

Mild de Lange-like gestalt, short stature, thin build, mild synophrys, long eyelashes, depressed nasal bridge, long philtrum, thin lips, micrognathia, cryptorchidism, metatarsus adductus, dermatoglyphic anomalies

AD (112370)

Hallerman-Streiff228

Short stature, fronto-parietal prominence, microphthalmia, cataracts, thin pointed nose, hypodontia, natal teeth, skin atrophy, hypotrichosis

AD; most are new mutations (234100)

Hall-Riggs: coarse faceskeletal dysplasia229

Progressive metaepiphyseal disorder with severe retardation, flat nasal bridge, large lips, brachydactyly, short arms; microcephaly may be of postnatal onset

AR (234250)

Hamel: X-linked retardationheart defect230

Short stature, long narrow face, sunken eyes, malar hypoplasia, anomalous and protruding ears, broad nasal bridge and bulbous tip, micrognathia becoming prognathic, cleft palate and uvula, Fallot complex, atrial and septal defects, hypospadias

XLD (300463) PQBP1, Xp11.23

Hennekam-RenckensWennen231

Single case with short stature, mental retardation, total alopecia, optic atrophy, severe myopia, full lips, fleshy nose with prominent nasolabial grooves. Subject’s sweating was normal, and she had apparently normal teeth.

Unknown

Hepatic cirrhosis-unusual face232

Growth and mental retardation, triangular face, prominent eyes, hypoplastic alae, pinched nose, skin pigment changes, trident hands, abnormal toes, aminoaciduria

AR

Herpes, prenatal233

About 5% of neonatal herpes is acquired in utero: variable clinical spectrum may include cutaneous, ocular, and CNS lesions; about one-half have an encephalitis that can cause microcephaly or hydranencephaly

Prenatal infection with herpes virus

Herrick: multisystem atrophy234

Perinatally lethal with cerebellar hypoplasia, brainstem atrophy, degeneration of the basal ganglia and the thalamus, sudanophilic staining in macrophages and astrocytes of the white matter, flexion contractures, hypertonia

AR

Hirschsprung-cleft palate235

Mild retardation, hypertelorism, synophys, prominent nose, poor hair growth, hypotonic

AR (235730) SMADIP1, 2q22

Hirschsprung-cleft palatedigital236

Profound growth and developmental failure, myoclonic seizures, short segment Hirschsprung, cleft soft palate, distal digital hypoplasia, 5th finger clinodactyly, 3-4 toe syndactyly

AR

Hirschsprung-microcephalyretardation237

Large nose, prominent ears, deep set and large eyes, infero-nasal coloboma, short philtrum, developmental delay, CT evidence of defective neuronal migration (2 cases with agenesis of corpus callosum)

AD del 2q22-q23

HIV III infection, prenatal238

There is no current evidence to suggest a dysmorphic syndrome associated with HIV III; postnatal growth failure and microcephaly are secondary to chronic illness and CNS infection

Intrauterine or conatal infection

HMC239

Hypertelorism (marked), narrow palpebral fissures, microtia with choanal stenosis, cleft lip/palate, broad bifid nose, mild renal anomalies, ?congenital heart defect

AR (239800)

Holmes-Gang: club footretardation240

Large anterior fontanel, epicanthus, short and anteverted nose, short upper lip, severe equinovarus, propositus had renal hypoplasia; shown to be allelic with ATRX

XLR (301040) XNP, Xq13

Houlston: glomerulonephritismarfanoid habitus241

Mental retardation, marfanoid habitus with joint laxity and arachnodactyly, focal glomerulonephritis; one sister developed acute myeloblastic leukemia at 17 years; parental consanguinity

AR (248760)

Humoral immunodeficiencyface-limb242

Humoral immunodeficiency, arched eyebrows, hypoplastic nares, macrostomia with thin lips, triphalangeal thumbs, hypoplastic thenar eminence, mild delay; single case

Unknown

(continued)

483

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Hunter-McAlpine

Oval face, almond-shaped eyes, ptosis, small nose, downturned mouth, short stature, retardation, brachydactyly with characteristic metacarpo-phalangeal profile, craniostenosis, elbow limitation

dup 5q35-qter

Hurst: craniostenosis-ear anomalies244

Short stature; atretic auditory meati; small abnormal ears; micrognathia; small mouth; short neck; camptodactyly; delayed bone age; dislocated radial heads; abnormal clavicles, patellae, and glenoid fossa

Unknown

Huson: spondyloepiphyseal dysplasia tarda— microcephaly245

Spondyloepiphyseal dysplasia tarda, developmental delay, broad nasal root, short philtrum, full lips, rhizomelic shortness of limbs, broad chest, short sternum, mild radiologic findings of SED

AR (600093)

Hutteroth: absent thumbs246

Developmental delay, congenital heart defect, wide forehead, flat occiput, narrow high palate, absent thumbs, elbow restriction, radio-ulnar synostosis, bowing, 3-4 finger syndactyly, short stature

Unknown

Hyams: cerebral palsyglaucoma247

Sisters with spastic cerebral palsy, later onset glaucoma, mild developmental delay; parental consanguinity

AR

Hydantoin, prenatal248

Soft signs of short nose with broad base, telecanthus, ptosis, short neck, wide mouth, mild IUGR/developmental delay, distal digit hypoplasia; microcephaly not a common finding

In utero exposure to hydantoin

3-hydroxybutaric aciduria249

Poor fetal movement, triangular face, short sloping forehead, bitemporal narrowness, prominent philtrum

AR

Hypogonadism-short stature250

Hypergonadotrophic hypogonadism, narrow forehead, synophrys, abnormal pinnae, early tooth loss

AR (251200)

Hypogonadism-short statureobesity251

Mental retardation, short stature, micropenis, hypotonia, narrow forehead, normal sized hands with ulnar deviation and minor finger anomalies (similar to Bo¨rjeson-Forssman-Lehmann)

XLR

Hypomelanosis of Ito252

Causally nonspecific neurocutaneous disorder with hypopigmented skin, usually in streaks or whorls and following the lines of Blaschko; may be associated with hypertrichosis, eye and CNS malformations

Various mosaic karyotypes

Hypoparathyroiddysmorphism253

Congenital hypoparathyroidism, seizures, growth and developmental retardation, deep-set eyes, beaked nose with low bridge, long philtrum, thin upper lip, micrognathia, medullary stenosis

AR (241410) 1q42-43

Hypoplastic right heartmultiple congenital anomalies254

A cluster of infants with unusual rate of associated malformations included microcephaly (10/14), Pierre Robin (2), low set ears (4), arrhinencephaly (1)

Unknown

Ichthyosis-digital anomalies255

One of two sibs microcephalic, growth and developmental delay, epicanthus, full lateral eyelids, lower lip groove, minor ear anomalies, flexion deformities, hypoplastic toes and nails

AR (258840)

Ichthyosis-microcephalydeafness256

Congenital ichthyosis, spastic quadriplegia, severe developmental delay, myoclonus, deafness, high palate; pair of MZ twins

Unknown

Imaizumi-Kuroki: radial raydwarfism257

IUGR, postnatal growth and developmental delay, triangular face, short palpebrae, prominent eyes, sparse hair, deep philtrum, hypoplastic radii, absent thumbs and first metacarpals. Single case

Unknown

Immunodeficiencychromosome instability258

Growth failure, mental retardation, cafe´-au-lait spots, chromosome instability reflected by 7;14 rearrangements. Cells did not complement some patients of Seemanova et al260 (see Immunodeficiency-normal intelligence) but did complement other reported cases.

AR (251260) Nibrin/p95, 8q21

Immunodeficiencymalformations259

Postnatal growth and developmental delay, large protruding ears, sloping forehead, prominent beaked nose, hypoplastic patellae, eczema, defective hemotaxis, transient hypogammaglobulinemia, hypogonadism

AR or XLR (251240)

Immunodeficiency-normal intelligence260

Congenital microcephaly, receding forehead, upslanting palpebrae, long straight nose, small mandible, short stature, hypogammaglobulinemia, decreased cellular immunity, respiratory infections, and lymphoreticular malignancy

AR (251260)

Inbal: myopathy-lactic acidosis-anemia261

Myopathy with abnormal mitochondrial inclusions, lactic acidosis, sideroblastic anemia, mental retardation, normal face with long philtrum. Age of onset of the microcephaly unclear

AR (600462)

Intermittent hyperpnea-wide mouth262

Profound mental retardation, wide mouth, thick fleshy lips, broad beaked nose, abnormal EEG, intermittent hyperpnea equivalent to Joubert (one of two microcephalic)

Unknown

243

(continued)

484

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Intestinal atresia-ocular anomalies263

Apple peel intestinal atresia, variable microphthalmia, corneal clouding, shallow anterior chamber, irregular dilated pupils, epicanthus, mild delay, microcephaly progressive from birth

AR

Ippel: cataracts-retinitis pigmentosa264

Microcephaly may be postnatal, mild to moderate mental retardation, congenital sutural cataracts, middle or late childhood onset of retinitis pigmentosa

AR

Iris colobomataventriculomegaly265

Pre- and postnatal growth retardation, developmental delay, iris colobomata, dilated ventricles, spasticity, and abnormal immunoglobulin levels

AR

Ives: microcephalymicromelia266

IUGR, perinatal death, fused elbows, forearm shortened with single long bone, two to four digits on hands

AR (251230)

Jaffer: arachnodactyly-chest deformity267

Short stature and developmental delay, hypertelorism, prominent jaw, high arched palate, pectus carinatum, joint laxity, spondylolisthesis, scoliosis, mitral valve prolapse

Unknown

Janssen: cystic hygromarenal-syndactyly268

Early lethal, anterior cystic hygroma, eyelid fusion, hypertelorism, upslanting palpebral fissures, broad nose with depressed bridge, micrognathia, renal dysplasia, bicornuate uterus, clitoromegaly, cutaneous syndactyly of toes 4 and 5

AR

Jejunal atresia-ocular-sex reversal564

Jejunal atresia, aberrant right tracheobronchus, corectopia, iris stromal hypoplasia, peripheral anterior synechia, 46,XY sex reversal

Unknown

Johanson-Blizzard269

Scalp defects, hypoplastic alae nasi, hypodontia, microdontia, deafness, exocrine pancreatic dysfunction, IUGR, short stature, ano-rectal anomalies, normal to retarded intelligence

AR (243800)

Jones: blepharophimosisabnormal ears270

Short stature, mild developmental delay, brachymicrocephaly, small ears with overfolded helix, sparse medial eyebrows, epicanthic folds, small and upslanting palpebral fissures, malar hypoplasia, long philtrum, narrow palate; single case

Unknown

Jorgenson: ptosis blepharophimosis271

Facial asymmetry, ptosis, blepharophimosis, retardation; three unrelated children, variable additional minor digital and arm anomalies

Unknown

Juberg-Hayward272

Cleft lip/palate, hypoplastic columella and alae, hypoplastic and distally placed thumbs, short stature, hypodontia, elbow anomalies, 2-3 toe syndactyly

AR/?AD (216100)

Juberg-Hellman: female limited seizures273

The prevalence of microcephaly and its age of onset is unclear; early development normal to 4–18 months; onset of seizures and developmental delay limited to females

XLD female limited Xp23

Judge: porokeratosiscraniosynostosis274

Microbrachycephaly, postnatal erythematous, reticulate facial rash with poikiloderma and focal crusting of the scalp and ears; symmetrical, demarcated, erythematous, hyperkeratotic plaques with raised, brown hyperkeratotic margins on forearms, dorsum hands, thighs and knees; craniosynostosis, hypospadias, hypotrichosis

AR?

Kabuki275

Variable developmental delay, hypotonia, long palpebral fissures with everted lateral 1/3 of the lower lid, ptosis, broad nasal tip, cleft/high-arched palate, prominent ear lobes, congenital heart and renal anomalies, prominent fetal finger pads, joint hypermobility, patellar dislocation, premature thelarche

Uncertain (147920)

Kapur-Toriello276

Variable growth failure, retardation, microphthalmia, coloboma, bulbous nasal tip with underhanging columella, cleft lip/palate, minor ear anomalies, constipation, gut malrotation, congenital heart defects

AR (244300)

Kaufman: oculocerebrofacial277

Microcornea, strabismus, pale discs, small teeth, minor external ear anomalies, thin fingers, micrognathia, neonatal respiratory problems, mental retardation

AR (244450)

Kawashima: deafness-ear anomalies278

Facial asymmetry, prominent glabella, thick protruding lower lip, micrognathia, low-cupped ears, mild retardation; variable, asymmetric mixed, or sensorineural deafness

AD (156620) XLD

KBG279

Short stature, mental retardation, low hairline, large maxillary central incisors, round face, high nasal bridge and bulbous tip, cervical ribs, vertebral anomalies, finger syndactyly

AD (148050)

Kelly: microcephaly-digital anomalies280

Severe retardation, sloping forehead, prominent nose, small jaw, scoliosis, decreased elbow extension and supination, short 4th and 5th metacarpals, complete syndactyly toes 4-5, and partial syndactyly of toes 2-4

XLR or AR

Kondoh281

Pre- and postnatal growth retardation, sparse hair, widow’s peak, bushy eyebrows, ptosis, pear-shaped nose with narrow alae, long philtrum, thin upper lip, interphalangeal and knee contractures, atopic dermatitis

AR (606242)

Kozlowski: wrinkly skin-hip dislocation282

IUGR, bilateral congenital hip dislocation, thin skin with wrinkling over the hands, umbilical hernia, hypotonia, advanced pneumatization of the paranasal sinuses, and pseudoepiphyses of the 2nd metacarpals

AR

(continued)

485

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Kraus-Rupert

Microcephaly, hypogonadism, obesity, 2-4 toe syndactyly, prominent ears

Probable AR

Labrune-Assathiany: progressive vitiligo284

Growth and developmental delay, beaked nose, high narrow palate, late childhood onset progressive vitiligo, macrogenitosomia, double meatus. Single case, consanguinity.

Unknown

Langer-Giedion285

Mild to severe retardation, large protruding ears, bulbous nose with ‘‘tented’’ alae, long simple philtrum, cone-shaped epiphyses, exostoses of long bones (some clinical correlation with size of chromosome deletion)

(150230) del(8q) TRPS1 and EXT1, 8q24.12-24.13

Lathosterolosis383

Variable Smith-Lemli-Opitz–like signs in two cases published to date but unique intracellular storage of mucopolysaccarides and lipids in liver and non-neuronal cells of CNS

AR (607330) SC5D, 11q23.3

Lenz microphthalmia286

Developmental delay, external ear anomalies, ptosis, cleft lip/palate, sloped shoulders, clavicle hypoplasia, syndactyly, camptodactyly, thumb anomalies, renal anomalies

XLR (309800) Xq27-q28

Leprechaunism287

IUGR, growth failure, adipose deficiency, prominent eyes, thick lips, gingival hyperplasia, large phallus, hirsutism, infections, insulin-binding defect, death

AR (246200) insulin receptor gene, 19p13.3

Lethal multiple pterygium288

Fetal death, cutaneous joint webbing, frequent cystic hygroma and hydrops, growth failure; marked heterogeneity. One case report with hypoplastic cerebellum and immature spinal cord tracts.

AR

Lethal progeroid-osteolysis289

Growth and developmental delay, severe micrognathia, glossoptosis, patchy hyperpigmented skin, still joints, progeroid appearance, high forehead, slightly beaked nose, sparse hair, hypoplastic distal phalanges. Single case.

Unknown

Leukotriene C4-synthesis deficiency290

Progressive developmental delay and hypotonia, hyporeflexia, decreased motor conduction velocities, early death, broad nasal root, epicanthus, absent CSF leukotriene C4 and raised LTB4. Parental consanguinity in the case.

AR

Ligase IV291

Growth and/or developmental delay, Seckel-like face, pancytopenia, variable skin signs can include photosensitivity, hypothyroid; cells show radiosensitivity due to DNA ligase IV deficiency

AR (606593) LIG4, 13q22-q34

Lindstrom: IUGRdwarfism292

Severe retardation, seizures, cleft lip, small pointed chin, lens opacity on slit-lamp examination, simple ear helix, short neck, camptoclinodactyly of fifth fingers, acrocyanosis

AR

Livido reticularis-snub nose293

Profound mental retardation, short stature, livedo reticularis, snub nose, diastasis recti, hypoplastic nails both fifth toes; deletion Yq11-ter found in the father

Unknown

Low birth weight-dwarfismdysgammaglobulinemia294

IUGR, growth and developmental delay, joint hyperextensibility, brachydactyly, single flexion crease fifth fingers, calcaneovalgus, recurrent bacterial infections, elevated IgA

AR

Macroepiphyses-wrinkled skin295

Club feet, long fingers, lax joints, aged appearance, wrinkled hands, dry coarse hair, pectus excavatum, osteopenia, multiple fractures, enlargement of joints, normal development

Unknown (248010)

Macular bullous dystrophyretardation296

IUGR, postnatal growth failure; maculo-papulous skin rash, vesicles filled with clear fluid on sun-exposed areas; short tapering fingers, nail dystrophy; permanent loss of scalp hair in the first year; corneal opacity, glaucoma, cataract; hypogenitalism, diabetes mellitus

XLR (302000) Xq26-qter

Madokoro: short palpebraemicrognathia297

Severe microcephaly, downslanting palpebrae, hypertelorism, epicanthus, delayed development, small mouth, cleft palate

AR

Mandibulofacial dysostosisthoracic deformities507

Growth retardation, mandibulofacial dysostosis, thoracic deformity; one brother with asplenia, the other with gallbladder aplasia

AR/XLR?

Marden-Walker298

Delayed motor development, blepharophimosis, low-set and malformed ears, cleft palate, micrognathia, renal microcysts or cystic dysplastic kidney, joint contractures, arachnodactyly, camptodactyly, kyphoscoliosis, congenital heart malformations; likely heterogeneous

AR (248700)

Marion-Mayers: face dysmorphia-IUGR299

Significant IUGR, hypotonia and delayed development, metopic prominence, high nasal root, low-set ears, downturned mouth, triangular face, phonation anomalies

AR?

Martsolf 300

Brachycephaly, cataracts, malar hypoplasia, prognathism, pouting lower lip, hypogonadism, aged appearance, short palms, broad finger tips, mental retardation

AR (212720)

283

(continued)

486

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Mastocytosis-microtia

Short stature, developmental delay, facial asymmetry, frontal bossing, upslanting palpebrae, broad nasal bridge with hypoplastic alae, microtia, scoliosis; consanguinity

AR? (248910)

Maternal hyperthermia302

Impact varies with timing, must be sustained and
398C; microcephaly in about 10%; heterotopias; microphthalmia, contractures, micrognathia (causal association not proven in prospective studies)

In utero hyperthermia

Maternal hyperphenylalaninemia303

IUGR, mental retardation, seizures, congenital heart defects, cleft palate, cervical vertebral anomalies, strabismus, 80% risk of microcephaly in untreated pregnancies

In utero hyperphenylalaninemia

Matsoukas: oculararticular304

Growth and developmental retardation, multiple joint dislocations, short palpebrae, hypertelorism, high palate, small mouth, microphthalmia, corneal sclerosis

AD

Me´garbane´: elbows-tibiadeafness-cataracts305

Mental retardation, sensorineural deafness, cataracts, scoliosis, bowed tibiae, dislocated elbows, short fourth metacarpals, calcaneum valgus

AR

Me´garbane´: joint dislocationabnormal skin306

Delayed growth, severe retardation, ptosis, prominent and low-set ears, beaked nose, joint laxity with dislocations, delayed bone age, abnormal blood vessel walls in skin; consanguinity

AR or XLR

Me´garbane´-LeMerrerKallab307

Growth retardation, hypertelorism, downslanting palpebrae, ptosis, broad nasal tip, short and webbed neck, low posterior hairline, seizures, cerebral atrophy

AR

Megalocornea-mental retardation309

Short stature, hypotonia, moderate to severe mental retardation, occasional ataxia/ choreoathetosis, seizures, possible macrocephaly

AR (249310)

MEHMO310

Severe developmental delay, early onset seizures, prenatal microcephaly, obesity, short stature, narrow forehead, facial telangiectasias, simple ears with large lobules, downturned mouth, cryptorchidism, micropenis, edematous hands and feet, tapered fingers

XLR Xp21-Xp22

Mehta: heart-ptosishypodontia311

Sagittal synostosis, ptosis, blepharophimosis, prominent ears, prominent lower lip, small and abnormally shaped teeth, long fingers and toes, generalized joint laxity, total anomalous pulmonary venous drainage. Single case, similar to Mutchinick; see entry this table.

Unknown

Mental retardationosteosclerosis312

Profound retardation, progressive osteosclerosis, short and narrow frontal and occipital areas, prominent supraorbital ridges, cataract, gray teeth, prominent ears, saber chins

Unknown

Mesobrachyphalangytracheoesophageal fistulaRett–like508

Similar to Feingold-mesobrachyphalangy-tracheoesophageal fistula198 with regression, autistic signs, seizures, stereotypic hand movements

Unknown

Methylmercury, prenatal313

Severe neurologic disturbance with postnatal growth failure, spasticity, pyramidal and cerebellar signs, seizures, mental retardation, microcephaly in 60%

Prenatal exposure

Microcephaly-cardiacdigital315

Growth retardation, hypertelorism with broad nasal bridge, cleft or pseudocleft lip, distally placed thumbs, variable mild 2nd and 5th digit hypoplasia and mild skin syndactyly

AD (600987)

Microcephalycardiomyopathy316

Mental retardation, abnormal ear helix, 5th finger clinodactyly, sandal gap, non-progressive dilated cardiomyopathy, may have stippled pigment in retina

AR (251220)

Microcephaly-cleftingpreauricular tags317

Growth and developmental retardation, sparse eyebrows, short and upslanting palpebrae, epicanthus, short nose with anteverted nares, thin upper lip, micrognathia, preauricular pits/tags, long thin fingers, abnormal nipples

Unknown

Microcephaly-coarse faceskeletal318

Growth and developmental delay, prominent eyebrows, broad nose, large mouth with full lips, hirsute, delayed bone age, scoliosis, variable and mild skeletal anomalies

AR (601352)

Microcephaly-cortical blindness-polydactyly319

Growth and developmental delay, recurrent infections, prominent forehead, short nose, micrognathia, postaxial polydactyly, cortical blindness

AR (218010)

Microcephaly-cubitus valgus320

Mental retardation, midchildhood-onset obesity, strabismus, malar hypoplasia, short philtrum, multiple nevi, marked cubitus valgus, clinodactyly of great toes

XLR?

Microcephaly cutis verticis gyrata-edema321

Progressive microcephaly, cutis verticis gyrata, seizures, developmental delay, optic atrophy, cortical blindness, coloboma, onset hepatosplenomegaly and lymphedema in infancy, ventricular dilatation, abnormal granulation of white cells

AR

Microcephaly-deafness322

Short stature, severe mental retardation, deafness, seizures, spastic/ataxic movement, reduced/immature cells in cerebral layers III and IV; heterozygotes have dull mentality

XLR (309590)

Microcephaly-gray matter heterotopia324

Severe psychomotor delay and seizures, sloping forehead, tall stature, obesity; short wide hands and feet, mild quadriparesis, laminar heterotopias in centrum ovale

AR?

301

(continued)

487

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Microcephaly-lethal arthrogryposis326

Polyhydramnios and premature stillbirth, high forehead, upslanting palpebrae, absent glabellar angle, hypoplastic alae nasi, hypoplastic thenar eminence, severe joint restrictions

AR

Microcephalylymphedema327

Congenital lymphedema of hands and feet, prominent upper helix, epicanthus, flat nasal bridge; heterogeneity with some cases showing retinal changes

AD (152950)

Microcephalylymphedema328

Male with prenatal microcephaly and scalp rugae, female with microcephaly and scoliosis; both with mental retardation (distinct from benign AD form)

Unknown

Microcephaly-myopia (Achermann-Largo)329

Delayed development and bone age, short stature, bitemporal narrowness, epicanthus, periorbital fullness, full cheeks, pouting lower lip

AR or XLR

Microcephaly-nonpigmented retinopathy330

Timing of microcephaly unclear, developmental delay, early onset of visual impairment with pale optic discs, nystagmus, ERG with normal a-waves and attenuated b-waves

AR

Microcephaly-normal intelligence331

Short stature, receding forehead, upslanting palpebrae, epicanthus, long nose, high bridge, wide spaced teeth, high palate (no evident immunodeficiency but one death from leukemia and one from bronchopneumonia)

AR (251260)

Microcephaly-normal intelligence-digital332

Normal intelligence, short palpebrae, variable thumb hypoplasia, short 2nd and 5th middle phalanges, small feet, sandal gap, interdigital syndactyly, short first metacarpal with thin proximal end

AD (602585)

Microcephaly-normal intelligence-oligodontia333

Absent 3rd molars and mandibular permanent 2nd molars; single case

Unknown

Microcephaly-normal intelligence-retinal pigment334

Average to low average intelligence, small ears, cafe´-au-lait spots, normal visual acuity, numerous flat brown hyper- and tan-gray hypopigmented retinal patches

AR or XLR (145290)

Microcephaly-osteoplastic dysplasia335

Postnatal growth failure, normal intelligence, large fontanelle, beaked nose, brachydactyly, platyspondyly, odontoid hypoplasia, coned and ivory digital epiphyses, accessory metacarpal ossification centers

Unknown

Microcephaly-osteodysplastic primordial dwarfism336

Type I and II and Taybi-Lindes are equivalent. Marked IUGR, prominent nose, micrognathia, sloped forehead, alopecia, dry skin, contractures, early death, variety of skeletal changes

AR (210710)

Microcephaly-posterior rib gaps337

Severe microcephaly with sloping forehead, posteriorly rotated and low-set ears, prominent eyes, downslanting palpebrae, large nose, full lips, rib hypoplasia with posterior rib gaps, other bony hypoplasias, contractures

AR? (603394)

Microcephaly-short radius or tibia338

Severe developmental delay, short stature, hypotelorism, strabismus, epicanthus, short first metacarpals and/or tibia, long and dorsally flexed fingers and toes. One brother had anal atresia, one pulmonary artery atresia.

AR or XLR

Microcephaly-tapetoretinal degeneration339

Postnatal microcephaly, severe developmental delay, tapetoretinal degeneration, variable spasticity and muscle wasting; some patients with dystonic signs

AR (602685) 15q24

Microcephaly-tetralogy of Fallot-hydronephrosis323

Severe developmental delay, short stature, seizures, inappropriate laughter, telecanthus, hydronephrosis; long face, nose, and philtrum; prominent ears

AR or XLR

Microhydranencephaly340

Microhydranencephaly, resembles fetal disruption, severe growth and developmental delay, sloping forehead, exophthalmia, micrognathia, spastic quadriplegia, joint contractures, athetosis, respiratory and skin infection

AR (605013) 16p13.3-12.1

Micromelic short statureknee subluxation341

IUGR, FTT with vomiting, natal tooth, short neck, frontal bossing, thin sparse hair, hypertelorism, blue sclera, cleft palate, hypoplastic genitalia, small hands, camptoclinodactyly

Unknown

Microphthalmia-abnormal thumb/hallux342

IUGR, mild to moderate developmental delay, clinical anophthalmia, blepharophimosis, bitemporal narrowing, long face, cleft palate, adducted and hypoplastic thumbs with small nails, short in-turned halluces; single case

Unknown

Microphthalmia-absent abdominal muscles343

Growth and developmental delay, wide fontanels, telecanthus, narrow palpebrae, V-shaped eyebrows, flat nose with small nares, small ears, wide-spaced nipples, bifid sternum, deficient abdominal muscles

AR

Microphthalmia-colobomamicrocephaly344

Growth and developmental delay, mild facial dysmorphia with broad nasal bridge, long philtrum and high palate, colobomatous microphthalmia, congenital heart defects, radiographic anomalies

AR

Microphthalmia-corneal opacity345

Thick eyebrows, small nose, long philtrum, thin upper lip, small and low-set anomalous pinnae, seizures, hypertonicity, psychomotor delay, glycinuria

AR? (2515000) (continued)

488

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Microphthalmiaectrodactyly-prognathism346

Blindness, foot ectrodactyly, digitized thumbs, central cleft lip. Case with t(6;13)(q21;q12) that disrupted sorting nexin 3

AD? (601349) SNX3, 6q21

Microphthalmia-linear skin defects347

May have other CNS anomalies including septum pellucidum cyst, ACC, colpocephaly and hydrocephaly; microphthalmia, sclerocornea, linear dermal aplasia usually of the head and neck

del Xp22.3 (309801) XLD male lethal Xp22.3

Microphthalmia-retinal folds348

Variable syndrome with mental retardation, small cornea, falciform vitreoretinal folds, perinatal pedal edema

AD or XLD (180060)

Miles-Carpenter349

Asymmetric face, ptosis, strabismus, short palpebral fissures, joint hypermobility, camptodactyly of fingers and toes, rocker-bottom feet, excess of fingertip arches

XLD (309605) Xq21.31

Mitral valve prolapseasthenic habitus350

Mental retardation, mitral valve prolapse, flat nasal tip with small alae, high palate, pectus excavatum, short and slender hands. A single case with microcephaly resembled those without.

Unknown

Mixed sclerosing bone dysplasia351

Developmental delay, osteopoikilosis, melorheostosis, developmental delay, overfolded helices, beaked nose, short philtrum, thin upper lip, prominent chin, multiple pigmented nevi

Unknown

Mosaic variegated aneuploidy352

Severe microcephaly, frequent eye and renal malformations, variable but usually significant developmental delay, in vitro mosaic trisomy for different chromosomes, premature chromatid separation, endoduplication, high risk of malignancy

AR (257300) BUBIB, 15q15

Mubashir: situs inversusretardation353

Profound mental retardation, growth failure, situs inversus, long face with posteriorly rotated ears, hypertelorism, ptosis, anteverted nares, hypoplastic alae, long philtrum, tented upper lip, brachydactyly, mild interdigital webbing, short fourth and fifth metacarpals, cerebellar/brain stem migration disorder

Unknown

Multicore myopathyaganglionosis354

Developmental delay and microcephaly by  9 mos, short stature, ptosis, low anterior hairline, long nose with high bridge, small jaw, pharyngeal webbing, Hirschsprung, cerebellar dysfunction, multicore myopathy

Unknown

Mulvihill-Smith355

IUGR, short stature, retardation, broad forehead, lack of subcutaneous facial tissue, hypodontia, sensorineural deafness, small jaw, pigmented nevi, abnormal IgG, T-cell dysfunction

AD (176690)

Muscular build-rhizomeliacataracts356

IUGR, severe microcephaly with borderline intelligence, sparse hair and eyebrows, cataracts, hypotelorism, short and bowed legs, hypertrophic muscular build, micropenis, hypoplastic scrotum

AR?

Mutchinick-unusual face357

Developmental delay, brachycephaly, sloping forehead, hypertelorism, closed short palpebrae, photophobia, broad straight nose, wide mouth, hyperconvex thumbnails

AR

Myhre-unusual face358

Large simple ears and downturned mouth, maxillary hypoplasia, prognathism, lax joints, scoliosis, large ulnar styloid, short stature, retardation

AR

Nakata: cleft palate-lateral synechiae359

Mild to moderate mental retardation, short stature, triangular face, prominent ears with abnormal antihelix, large and upslanting palpebrae, cleft palate or uvula, lateral oral synechiae, everted lower lip

AR

Neonatal axonal dystrophy360

Neonatal onset; rapid deterioration; hearing loss; dystrophic axons; demyelination; cortical blindness with pyramidal, extrapyramidal, and bulbar signs

AR (256600)

Neonatal infantile spasms361

Refractory seizures with hypsarhythmia, progressive microcephaly, and lethal outcome

AR

Nephrotic syndromeinfantile spasms362

Developmental delay; early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits; areas of microgyria, cortical layer fusion; floppy ears, hiatal hernia, flexion contractures

AR (251300)

Nezelof: arthrogryposis-renal and hepatic disease363

Joint contractures, muscle atrophy, proximal thumbs, obstructive jaundice, variable liver histology, renal tubular degeneration and/or nephrocalcinosis; reported with microcephaly, corpus callosum anomalies

AR (301820)

Nicholaides-Baraitser: retardation-sparse hair364

Severe developmental delay, short stature, sparse hair, lack of subcutaneous tissue, triangular face, coarse features, thick lips, swollen interphalangeal joints, short 4th and 5th metacarpals with coned epiphyses

Unknown (601358)

Nijmegen breakage365

Growth and variable intellectual impairment, sloping forehead, prominent mid-face and long nose, large and abnormal pinnae, upslanting palpebrae, cafe´ au lait spots, immunodeficiency, chromosome breakage and rearrangements of chromosomes 7 and 14

AR (251260) NBS1, 8q21

Norrie366

Variable microcephaly and normal to severe mental retardation, progressive ocular pseudoglioma, opaque corneae, cataract, sensorineural deafness in one third, narrow nasal bridge, flat malar region, thin upper lip

XLR (310600) NPD, Xp11 (continued)

489

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Nowaczyk: IUGR-pigmentary retinopathy367

Severe IUGR, developmental and growth delay, large fontanel, prominent forehead, aged facial appearance, short palpebrae, choanal atresia, small mandible, large hands with long fingers, no subcutaneous fat, peripheral retinal pigmentary changes, radiographic anomalies

Unknown

Obesity-growth hormone deficiency368

Growth and developmental delay, truncal obesity, unusual fat distribution in mammary and submammary areas, mild hypotelorism, small nostrils, cleft lip/palate, aggressive; single case

Unknown

Obesity-short stature (X-linked)369

Delayed development, low implantation of thumbs

XLR

Oculocerebralhypopigmentation370

Severe developmental delay, spasticity, generalized hypopigmentation, gingival hyperplasia, opacified and vascularized cornea; some cases with cardiac, renal and CNS anomalies including Dandy-Walker cyst

AR (257800)

Oculocutaneous albinismgrowth hormone371

Short stature, isolated growth hormone deficiency, mild hypopigmentation, nystagmus, large teeth, high palate, micrognathia, long philtrum, 2-3 toe syndactyly. The female of two sibs was microcephalic.

AR?

Oculodentoosseous372

Microcephaly and retardation are occasional signs; microphthalmia, microcornea, short palpebrae, thin nose and hypoplastic alae, enamel hypoplasia, 4-5 finger and 3-4 toe syndactyly, fine and sparse hair

AD (164200) GJA1, 6q22-q24 (Connexin 43)

Oculo-palato-cerebraldysplasia373

IUGR, short stature, hypotonia, bulbous nose, cleft palate, large and pointed ears, small hands and feet, microphthalmia, persistent hyperplastic primary vitreous, hypermobile joints, soft skin

AR (257910)

Ohdo374

Retardation, blepharophimosis, mild microphthalmia, ptosis, hypoplastic teeth, variety of congenital heart defects, cryptorchidism; one report of agenesis of the corpus callosum

AR (249620)

Okamoto: microcephalyclefting-hydronephrosis375

Severe growth and mental retardation, malar hypoplasia, hypertrichosis, synophrys, flat nasal bridge, short and anteverted nose, cleft palate, open mouth, webbed neck, hydronephrosis, congenital heart

Unknown

Olivopontocerebellar hypoplasia-dysmorphia376

Like trisomy 18 with prominent occiput, overlapping fingers, rocker-bottom feet; neurologic signs of spasticity, extra-pyramidal dyskinesia, absent voluntary motor responses, marked pontocerebellar hypoplasia, progressive cerebral atrophy

AR (277470)

Opitz: C-trigonocephaly377

Progressive microcephaly, small nose with broad root and anteverted nares, long and simple philtrum, attached frenulum, anomalous pinnae, upslanting palpebrae, abnormal joints, contractures, nevi, hemangiomas, cardiac defects

AR (211750)

Oral-facial digital-retinal378

Variable retardation, short stature, chorioretinal atrophy, lateral pseudocleft, high arched palate, multiple oral frenula, bifid/lobulated/hamartomatous tongue, mild brachydactyly, zygodactyly, broad hallux, bifid terminal phalanges of toes 1-3

AR? (258865)

Orstavik: aplasia cutisretinal-brain379

Aplasia cutis on scalp and abdomen, broad bulbous nose, small chin, long philtrum, hypoplasia to absence of fingers with the nails attached to metacarpals, ventricular dilatation and cerebral atrophy, variable thalamic calcification. Male had agenesis of the corpus callosum.

AR

Osteogenesis imperfectacataracts380

Hypertelorism, low-set ears, blue sclera, bowed lower limbs, soft calvarium, fractures at birth, lethal, few large or absent gyri

AR (259410)

Osteoporosispseudoglioma381

Microphthalmia, anterior chamber and vitreoretinal anomalies, fractures and deformities, short stature, mental retardation, thin sparse hair, micrognathia

AR (259770) LRP5, 11q13.4

Oto-palatal-digital II382

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia

XLR (311300) FLNA, xq28

Paes-Alves: pseudopapilledemaskeletal384

External auditory stenoses, mixed deafness, small pinnae, hypotelorism, downslanting palpebrae, pseuodopapilledema, blepharophimosis, abnormal tooth color, micrognathia, mild finger skin syndactyly, short metacarpals, palmar keratosis, abnormal feet

AR (264475)

Palant: toe anomaliesunusual face385

Severe retardation; cleft palate; almond shaped, deep-set eyes; upslanting and narrow palpebral fissures; bulbous nasal tip; broad distal phalanges of toes; 2-3 toe syndactyly; 4-5 toe camptodactyly; short stature

AR (260150)

Partington: microcephalydistinctive face386

Pre- and postnatal growth delay, mild developmental delay, friendly, thick eyebrows, short nose with hanging columella, full cheeks

AR

Parietal foraminabrachymicrocephaly387

Contiguous gene syndrome involving parietal foramina (ALX4), multiple exostosis (EXT2), with variable craniofacial dysostosis and developmental delay

del 11p11.2 (continued)

490

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Periodic alternating nystagmus-microcephaly388

Growth and developmental retardation, congenital periodic alternating nystagmus with decreased visual acuity, prominent ears, cerebellar hypoplasia

Unknown

Peters anomaly-colobomatacontractures389

Peters anomaly, chorioretinal colobomata, falciform retinal fold, and arthrogryposis multiplex; two unrelated males whose mothers had a flu-like illness in the 4th week of gestation

Unknown

3-phosphoglycerate dehydrogenase390

Growth and psychomotor retardation, hypertonia, seizures, polyneuropathy, hypogonadism, occasional cataracts, adducted thumbs

AR (601815) 1q12

Pierpont: plantar lipomatosis-unusual face391

Developmental delay, prominent forehead, malar hypoplasia, square nasal tip, anteverted nares, thin upper lip, wide spaced teeth, central palatal ridge, congenital fat pads on anteromedial heels, prominent fetal finger tip pads, deep palmar/ plantar grooves

Unknown

Pilodentoungular dysplasia392

Delayed development; thin, sparse scalp hair; dystrophic nails, severest on fingers; thin skin on hands; blue sclera; retrognathia, high palate, hypodontia

Unknown

Pilotto: clefting-vertebral defects393

Mental retardation, infections, cleft lip/palate, hypertelorism, abnormal pinnae, high nasal bridge, short neck, vertebral anomalies, hypoplastic external genitalia

Unknown

Pitt-Hopkins394

Severe developmental delay, voluntary overbreathing, variable microcephaly, prominent nose with wide bridge and flared nares, macrostomia, thick and fleshy lips, finger clubbing, seizures, cerebellar hypoplasia

Uncertain

Pitt-Rogers-Danks395

IUGR, delayed development, downslanting palpebral fissures, prominent eyes, short upper lip, hypoplastic labia, extra palmar and digital creases

(262350) del 4p16.3

Poland anomalymicrocephaly396

Possibly chance association of microcephaly, typical symbrachydactyly, and ipsilateral pectoral hypoplasia

Unknown

Polysyndactyly-ptosis397

Short stature, mental retardation, pre- and postaxial polysyndactyly, dacryostenosis, high palate, fusion of incisors, brachyphalangy; parents consanguineous

Uncertain

Porphyria-acute intermittent, homozygote398

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) homozygote

Prader-Willi399

Almond-shaped eyes with or without upslanting palpebrae, early severe hypotonia, variable short stature and delay, early obesity, small hands and feet by midchildhood, hypogonadism

Pat del 15q11-q13 Mat UPD 15q (176270)

Preaxial polydactylyclefting400

Bifid thumb, cleft lip/palate, short stature, seizures, clinodactyly of 5th fingers, delayed development, consanguinity in the one case

Uncertain

Premature aging-short stature401

IUGR, progressive loss of subcutaneous tissue, small jaw, prominent ears, high ‘‘piping’’ voice, broad forehead, hypospadias, hypodontia, fine and sparse hair, sensorineural deafness

Unknown

Premaxillary agenesismidline cleft402

Mental retardation, cleft lip/palate, hypotelorism, downslanting palpebrae, chronic constipation, absent maxillary incisors

AD (157170)

Primordial dwarfismcataracts403

Growth and developmental retardation, enamel hypoplasia, delayed bone age, brachymesophalangy, large down-turned mouth

AR (251190)

Progeria-Giannotti type404

Progeroid face, frontal bossing, upslanting palpebrae, blepharophimosis, poor subcutaneous fat, large nose, thin lips. Son also had microcephaly and mild developmental delay

Uncertain (602249)

Proptosis-Pierre Robin405

Dolichocephaly; hirsute forehead; low posteriorly rotated ears; wide nasal bridge and alae; clenched hand with 2nd finger over 3rd; hypospadias; seven whorls

Unknown

Pseudo-Down406

Short stature and developmental delay with facial characteristics suggestive of Down syndrome but with normal dermatoglyphics and karyotype

AR (264450)

Pseudoprogeria/HallermanStreiff 407

Congenital absence of eyebrows and eyelashes; early-onset spasticity and delay; later glaucoma, optic atrophy; presenile appearance; ptosis, downslanting palpebrae; micrognathia

AR (200130) XLR

Pseudo-TORCH408

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; similar to, and may be allelic with, Aicardi-Goutieres and Cree encephalitis

AR (251290)

Pterygia-short stature409

Trigonocephaly, hypertelorism, epicanthus, small jaw, low and rotated ears, thin fingers with syndactyly, hypogonadism, growth failure and retardation, neck and elbow pterygia, crura knees

AD (177980)

Ptosis-subvalvular aortic stenosis410

Ptosis, downslanting palpebrae, hypertelorism, short nose with broad bridge, small mouth, high palate, bifid uvula, pectus, high-pitched voice

XLD or AD (continued)

491

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Radial microbrain

Brain weights of 16–50 g at term, variable acromicria and nephropathy, overall reduction by about 30% in neurons that have normal vertical distribution and appearance; deficit of the total number of vertical cell columns (radial-neuronal-glial units), perhaps from too few proliferative neuronal-glial units in the germative zone

AR

Radial ray-ulnar hypoplasiaretardation509

Developmental delay, short stature, absent thumbs, ulnar hypo/aplasia, cryptorchidism, micropenis. Single case

Unknown

Radioulnar synostosis-short stature412

Mild developmental delay, bilateral radioulnar synostosis, short stature, thoracic scoliosis; two sporadic cases with consanguinity in one

AR?

Raine dysplasia413

Short neck, craniofacial disproportion, wide fontanels, small nose with low root, dysplastic pinnae, small mouth, arthrogryposis, micrognathia, bone sclerosis, prenatal fractures

AR

Ramban-Hasharon: glycosylation defect IIc414

Severe developmental delay, short stature, minor face dysmorphia, variable craniostenosis, cortical atrophy, seizures, recurrent infections, neutrophil motility defect, absent red blood cell H antigen

AR (266265) FUCT1, 11p11.2

Reardon: microcephalyblepharophimosis415

Developmental delay, short palpebrae, ptosis, large ears; possible variant of Ohdo

AR?

Renal/Mu¨llerian duct hypoplasia-craniofacial510

Severe developmental delay, large anterior fontanel, tall and broad forehead, hypertelorism, small nose, short philtrum, renal malformations, absent uterus, dimples at the elbows and wrists, delayed bone age, hypoplastic distal phalanges

AR (266810)

Renpenning416

Moderate microcephaly, short stature, moderate to severe retardation, small to normal testicular size, normal ears

XLR (309500) PQBP1, Xp11.2

Respiratory chain deficiencycraniofacial malformations417

A variety of respiratory chain defects can cause pre- and postnatal growth retardation, and variable craniofacial dysmorphia including round face with high forehead, flat philtrum, short neck, hypoplastic middle and distal phalanges

AR and mitochondrial

Retinal detachment-acral anomalies418

IUGR, growth failure, profound retardation, rudimentary distal phalanges of fingers, absent distal creases, small toes 2-5, rudimentary nails

AR

Retinitis pigmentosa-mental retardation511

Mild to moderate mental retardation, retinitis pigmentosa, myopia, cataract; female carriers of normal intelligence, some had evidence of retinitis pigmentosa; possible contiguous gene syndrome

XLR Xp21-q21

Rett419

Typically presents in females after initial normal development and OFC; developmental arrest by about 18 mos, followed by regression and microcephaly; hand wringing; hyper/hypoventilation; occasional severe perinatal encephalopathy in males. Severe type with infantile spasms due to mutations in CDKL5.

XLD (312750) MECP2, Xq28

Rhizomelic chondrodysplasia punctata-type I420

Symmetric proximal shortness of humeri and femora, flat face, low nasal bridge, cataract, ichthyotic skin changes, coronal cleft vertebrae, punctate epiphyseal and extraepiphyseal calcification, peroxisomal defect

AR (215100) PEX7, 6q22-q24

Rhizomelic chondrodysplasia punctata-type II421

Equivalent phenotype to type I but lacks a peroxisomal defect biochemical profile

AR DHAPAT, Chr 1

Richeri-Costa: acro-frontofacio-nasal512

Microbrachycephaly, posteriorly rotated ears, hypertelorism, broad nose with midline groove and bilateral blind ending pit on nasal tip, hypospadias, 3-4 finger syndactyly, broad thumbs and halluces, consanguinity

AR (201181)

Richieri-Costa: microbrachycephalylumbosacral422

Mental retardation, short stature, long thin face with hypoplastic midface, cleft lip, obtuse mandibular angle, prominent chin, pelvic and lumbosacral modeling anomalies

AR

Roberts-SC phocomelia423

Growth failure, variable retardation, cleft palate, clouded cornea, hypoplastic nasal/ear cartilage, phocomelia, oligodactyly, silvery hair, penis/clitoris enlarged, centromere separation

AR (268300) ESCO2, 8p21

Robin sequence-aniridiagrowth delay513

Severe growth and developmental delay, triangular face, aniridia, micrognathia, cleft palate, delayed dental eruption, long and tapering fingers. Affected sib pair

Uncertain

Rothmund-Thompson424

Microcephaly and developmental delay are occasional findings; IUGR and postnatal growth failure, poikiloderma, hyperkeratosis, photosensitivity; sparse hair, premature graying; juvenile zonular cataract; micro/anodontia; nail dystrophy; probable heterogeneity

AR (268400) RECQL4, 8q24.3

Rubella, prenatal425

Defects depend on timing of infection from first to mid-second trimester; IUGR, growth and developmental retardation, deafness, cataracts, microphthalmia, chorioretinitis, patent ductus and peripheral vessel stenosis, signs of congenital infection

Prenatal infection with rubella virus

411

(continued)

492

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Rubinstein-Taybi

Mental retardation, short stature, downslanting palpebrae, hypoplastic maxilla, narrow palate, beaked nose, septum extending below alae, abnormal auricles, broad angulated thumbs and great toes

AD (268600) microdeletions (11%) CREB, 16p13.3

Ruvalcaba427

Mental retardation, short stature, downslanting palpebrae, small nose, narrow maxilla, thin vermillion, pectus carinatum, thin skin, short metacarpals, phalangeal tufting

AR (180870)

Salinas: atypical clefting428

Acrocephaly, craniosynostosis, lower lid colobomata, inner lid margin granulationlike tissue, no medial lashes, choanal atresia, redundant midfacial skin, cleft palate

Unknown

Saul: salt and pepper pigment429

Scattered hyper- and hypopigmentation, midface hypoplasia, prognathism, scoliosis, choreoathetosis, seizures, severe mental retardation, overtubulated bones

AR

Say: cleft palate-large ears430

Short stature, hypoplastic toenails and nipples, tapering fingers with hypoplastic tips, proximal thumbs, marked micrognathia, hypospadias

AD (181180)

Scalp defects-polythelia431

Developmental delay, cutis aplasia of the scalp, protruding ears, wide nasal bridge and alar base, thin upper lip, micrognathia, polythelia

AD

Schachter: hypotelorismsmall mouth-prognathism514

Short stature, developmental delay, small and low-set ears, hypotelorism, epicanthus, strabismus, cataracts, small and cupid-bow–shaped mouth, prognathism, 3-4 finger syndactyly, abnormal skin pigmentation

Unknown

Schimke: immuno-osseous dysplasia432

Usually normal intellect with childhood onset of disproportionately short trunk, mild craniofacial dysmorphia, defective cellular immunity with immune complex nephropathy; variant with microcephaly and retardation

AR (242900) SMARCAL1, 2q35

Schlichtemeier: multiple coagulation defects515

Mental retardation, congenital hypotonia, mild hypertelorism, arched eyebrows, prominent teeth, narrow hands with long fingers; variable blood vessel anomalies including hemorrhage, narrowness, tortuosity, aneurysm and thrombosis; abnormalities of multiple anticlotting factors

AR (216550)

Sclerocornea-short stature433

Postnatal growth failure, short limbs, small hands and feet, microphthalmia, sclerocornea, coloboma, delay beyond expectation for visual impairment; like Peters-plus

AR?

Seckel434

Severe IUGR, proportionate growth failure, severe mental retardation, receding forehead and chin, downslanting palpebrae, prominent curved nose, dislocated radial head

AR (210600) ATR, 3q22.1-q24, SCKL2, 18p11.31q11.2

Seckel-like, ataxiaendocrinopathy435

Proportionate primordial dwarfism, gonadal insufficiency (testicular atrophy, ovarian aplasia), insulin resistance, onset of goiter in teens, progressive ataxia, mental retardation

AR

Seckel-like, MajoorKrakauer436

IUGR, extreme micrognathia, dysplastic low and rotated ears, beak-like nose, prominent eyes, absent gyral pattern (subject to early prenatal diagnosis)

AR

Seckel-like, osteodysplastic types I and III437

Seckel face but disproportionate dwarfism with short limbs; type I, short bowed humerus and femur; type III, long clavicles, cervical arch clefts, lumbar platyspondyly; difference may be part of an age-dependent spectrum

Unknown

Seckel like-pancytopenia516

Sloping forehead, micrognathia, prominent midface, slightly hooked nose, onset of pancytopenia in infancy, increased chromosome breakage and mitomycin C sensitivity, seizures, cryptorchidism, hypoplastic scrotum, glandular hypospadias, hyper- and hypo-pigmentation, ‘‘spindle-shaped’’ fingers

Unknown (600546)

Seckel-like, premature senility438

Normal birth weight, developmental delay, sloping forehead and chin, prominent nose, ptosis, nystagmus, early graying and alopecia, low-set ears, atrophic epidermis

Unknown

Seckel-like, short limbs439

Severe IUGR, growth failure, small forehead, some nasal prominence, disproportionate limb shortness, brachymesophalangy and metacarpy, femoral metaepiphyseal changes

AR (210720)

Setlies: temporal forceps marks517

Temporal cutis aplasia, upslanting eyebrows, absent eyelashes of upper or lower lids, double eyelashes upper lid, narrow palpebrae, excess periorbital skin, floppy eyelids, ptosis, full nasal tip, scar-like vertical ridge on the chin; single report with microcephaly

AR/AD (227260)

Seidel: microcephaly440

IUGR, growth and developmental delay, hypotonia, receding hairline, broad lateral eyebrows, long eyelashes, flat nasal tip, microdontia, large ears with crus anomalies, pectus excavatum, cutis laxa, mild skeletal anomalies

AR or XLR

Sequeiros-Sack: linear skin atrophy441

Congenital crusted erosions and blisters of skin and tongue that heal to reticulated scars, scarring alopecia, variable anonychia; microcephaly and developmental delays in a subset of cases

Unknown

426

(continued)

493

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Severe microcephaly-absent pyramidal tracts442

Sloping forehead, hypertelorism, broad nasal tip, micrognathia, absent pyramidal tracts, dysplastic inferior olives, microphthalmia, joint contractures

AR

Severe microcephaly-choreacataracts518

Early onset of choreiform movement, cataracts, sensorineural deafness, profound mental retardation

Unknown

Short stature-cleft mandibleradial ray443

Short stature, microstomia, micrognathia, cleft lower alveolar ridge, laryngeal anomalies, variable radial ray defects; OFC not recorded in many of ten case reports but one documented case of microcephaly

AR (268305)

Short stature-deafnessclefting-digital444

IUGR, frontal bossing, short premaxilla, Pierre-Robin, prominent nose, sensorineural deafness, myopia, small hands and feet with digital angulation due to accessory triangular phalanges; single case

Unknown

Short stature-skin pigment anomalies445

Growth failure, hypertonia, distal finger camptodactyly, hypoplastic third toes and terminal 5th digit, chorioretinitis, optic atrophy, cafe´-au-lait and other pigment changes

Unknown

Skeletal dysplasia-CNS degeneration446

Postnatal growth failure, short limbs, variable postnatal microcephaly, short and anteverted nose, short neck, small thorax, platyspondyly with wafer-thin vertebrae, progressive encephalopathy, early death

AR (602613)

Skeletal dysplasia-Robin anomaly-polydactyly447

Postnatal microcephaly, developmental delay, abnormal pinnae with stenotic canals, prominent forehead, small mouth, micrognathia, cleft palate, broad and varus thumbs, valgus halluces, postaxial hexadactyly of the feet, skeletal anomalies

Unknown

Slender bone osteodysplasiapituitary-retinopathy519

Postnatal growth and developmental delay, dysmorphic appearance, pigmentary retinopathy, pituitary hypoplasia, growth hormone deficiency, micropenis; like type III osteodysplastic primordial dwarfism but no IUGR; single case

Unknown

Smith-Fineman-Myers448

Dolichocephaly, upslanting palpebrae, hyperopia, decreased frontonasal angle and nasolabial folds, patulous lower lip, flat philtrum, micrognathia, pale with freckles, short, delayed development, seizures (some may be X-linked alpha thalassemia without hemoglobin H bodies)

XLR (309580) XNP, Xq13 Heterogeneity

Smith-Lemli-Opitz449

Postnatal growth failure, mental retardation, narrow forehead, ptosis, epicanthus, broad anteverted nasal tip, broad alveolar ridges, micrognathia. Severe end of spectrum has more marked genital and internal anomalies, and postaxial polydactyly

AR (270400) DHCR7, 11q12-q13

Smith-Magenis450

Short stature, square and broad face, upslanting palpebrae, deep-set eyes, full cheeks, depressed and broad nasal root, marked malar hypoplasia, fleshy and tented upper lip, bulky philtral pillars, characteristic and possibly unique behaviors (nail yanking, body insertions)

(182290) del 17p11.2

Spastic paraplegia-optic atrophy-sex reversal451

Spastic paraplegia with normal cognition, optic atrophy, poor vision, XY-sex reversal

AR (603117)

Sparse hair-seizures452

Sparse hair on scalp and brows growing at normal rate, moderate retardation, generalized seizures

AD or AR?

Spondyloepiphyseal dysplasia-retinal dystrophy453

IUGR, postnatal growth and developmental delay, anteverted nares, long philtrum, thin upper lip, upslanting palpebrae, epithelial dysplasia, retinal dystrophy, variable immunodeficiency

AR (300258) XLR

Stimmler: enamel hypoplasiadiabetes454

Severe retardation, dwarfism, early-onset insulin-dependent diabetes, small teeth with enamel hypoplasia, ataxia, alaninuria

AR (202900)

Stoll: congenital heartneurofibromatosis520

Ear asymmetry, long nose, short philtrum, prominent lower lip, multiple cafe´-au-lait spots, complex congenital heart defect, phaeochromocytoma, consanguinity; concurrence of a syndrome with NF1?

AR?

Sutherland-Haan: microcephaly-spastic diplegia455

IUGR, short stature, brachycephaly, lean build, mild to moderate spasticity, small testes, delayed puberty, anal stenosis/atresia

XLR (309470) PQBP1, Xp11.2

Tall stature-infraauricular creases456

Postnatal microcephaly and developmental delay, hypotonia, flat midface and philtrum, mildly tented upper lip, advanced bone age, horizontal crease below ear lobes. Single case

Unknown

Tapetoretinal degeneration457

Growth and developmental delay, sensorineural deafness, severe joint laxity with dislocations and scoliosis, hypotonia, short stature

Unknown

TAR-like458

IUGR with borderline microcephaly at birth, small nose, anteverted nares, cataracts, glaucoma, malar hypoplasia, rhizomelia, radial aplasia, five digits both hands, low platelets; consanguinity

AR?

(continued)

494

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Temtamy: brachydactylyhyperphalangism521

Short stature, mild developmental delay, deafness, low-set ears, mid-face hypoplasia, arched eyebrows, synophrys, narrow nose, small mouth, micrognathia, dental anomalies, shawl scrotum, short hands, proximally placed and abducted thumbs, various clinical and radiographic hand and foot anomalies

Unknown

Tetra-amelia-ectodermal dysplasia459

Postnatal microcephaly, tetra-amelia, upslanting palpebrae, abnormal lacrimal ducts, prominent and bulbous nose, preauricular pits, hypotrichosis, absent medial clavicle

AR (273390)

Theile: unusual face460

Severe retardation, small nose with broad bridge, epicanthus, narrow palpebrae, high palate, low-set ears, cryptorchidism

Unknown

Thrombocytopenia-skeletalcardiac461

Stenotic ear canals, hypertelorism, pallor of optic disc, prominent nose, prognathism, high palate, ventricular and atrial septal defect, tapering phalanges, partial zygodactyly of fingers, carpal fusion

Unknown

Toluene embryopathy462

Abnormal hair pattern, narrow bifrontal diameter, deep-set eyes, short palpebral fissures, small midface, low-set ears, small nose, micrognathia, blunt finger tips, small nails, hypotonia, hyperreflexia

In utero exposure to toluene

Toriello: branchial arch463

Downslanting fissures, high palate, low protruding ears, hearing loss, slight neck web, cryptorchidism, subvalvular pulmonic stenosis

XLR (301950)

Torres-Aybar: microcephalycardiac defect464

Two sisters with developmental delay, large patent ductus, ear anomalies, deafness, broad nasal bridge, nail hypoplasia, delayed dentition; brother with dextrocardia

AR?

Toxoplasmosis465

Spectrum of disease includes IUGR, developmental delay, hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, hearing loss

Prenatal infection

Trichodental dysplasiamicrocephaly466

Fine, dry, and slow-growing hair; hypodontia and peg-shaped teeth; single case reported with microcephaly and mental retardation

AD? (601453)

Trichothiodystrophyichthyosis467

Low birth weight, short stature, mental retardation, aged look, nail dysplasia, cataracts, osteosclerosis, brittle hair showing alternating light and dark bands under polarization, cystine deficiency in hair. Mutations in the helicase subunits of TFIIH.

AR (601675) ERCC3, 2q21 ERCC2, 19q13.2q13.3

Trigonocephalyhypospadias468

Moderate retardation, high palate, hooked nose, posteriorly rotated ears, maxillary hypoplasia, ‘‘beaked’’ nails

AR (241760) XLR

Trigonocephalymicrognathia-zygodactyly522

Trigonomicrocephaly, large ears, severe and asymmetric micrognathia, atrioventricular septal defect, vertebral anomalies, cutaneous syndactyly of hands and feet, cafe´-au-lait-spots; single case

Unknown

Trigonocephaly-short stature-developmental delay469

IUGR, hypotelorism, posteriorly rotated ears, 5th finger clinodactyly

XLR (314320)

Trimethadione, prenatal470

Mental retardation, abnormal helices, cleft lip/palate, heart defects, renal anomalies, hypospadias, 2/40 were microcephalic

Prenatal exposure

Troyer-like523

Developmental delay, marfanoid appearance with normal stature, evidence of peripheral muscle atrophy with fasciculation in males and electrical evidence of neuropathy in females; EMG and nerve biopsy in the males suggested an axonal neuropathy

AR

Tsukahara-Sugio: micromelia-microcephaly471

Borderline developmental and growth delay, variable mild microcephaly and trigonocephaly, narrow bifrontal diameter, upslanting palpebrae, anteverted nares, micrognathia, small hands

AD (603572)

t(X;Y) female-linear skin defects-microphthalmia472

Linear, erythematous skin defects; variable microphthalmia, anterior chamber defects, sclerocornea; short stature; congenital heart defects; variable corpus callosum defect

del Xp22 (309801)

Type A1 brachydactylydwarfism473

Delayed growth and development, ptosis, epicanthus, bulbous nose, mesomelia, short digits, hypoplastic toenails, severe myopia, chronic otitis media

Unknown

Upper limb-cardiovascular474

Delayed growth and development, hypertelorism, high palate, small mandible, low-set ears, asymmetric limb hypoplasia, radioulnar synostosis, congenital heart Sparse hair, large fontanel, macroglossia, saddle nose, high palate, short stature, flat acetabulae, digitalized thumb, bifid terminal phalanx, pulmonic stenosis, developmental delay

Unknown

Moderate mental retardation, small and malformed pinnae, telecanthus, epicanthic folds, flat and broad nose, wide mouth, camptodactyly/clinodactyly of the fingers, mild skin syndactyly; similarities with blepharo-naso-facial syndrome

Unknown

Urbach: short humeri475

Van Maldergem: blepharonaso-facial-hand524

AR (268250)

(continued)

495

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Varicella

Variable IUGR, seizures, wide spectrum of development, cortical atrophy, chorioretinitis, limb and/or digit hypoplasia, cutaneous scarring; high mortality, infection between 8–20 weeks

In utero infection

Vasquez: hypogonadismgynaecomastia525

Moderate mental retardation, short stature, variable brachycephaly, micrognathia, obesity, hypogonadism, clinodactyly/camptodactyly of the hands369

XLR (309590)

Velo-cardio-facial477

Long narrow face, retrognathia, prominent nose with hypoplastic tlip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart; especially conotruncal defects

AD (192430) del 22q11 del 10p

Ventricular extrasystolehyperpigmentation478

Ventricular extrasystoles, short stature, small mandible, absent mandibular first molars, patchy areas of hyperpigmentation

AD (133750)

Verloes: male pseudohermaphroditismmu¨llerian526

Short stature, mental retardation, coarse face with deep-set eyes, microphthalmia, full lips; males with genital ambiguity, persistent mu¨llerian structures, obesity. One sib had anal atresia and a sacral spina bifida.

AR (600122)

Viljoen-van Vuuren: broad thumbs and toes479

Microbrachycephaly, growth and developmental retardation, downslanting palpebrae, large ears, prominent nose, malar hypoplasia, broad thumbs and toes, hyperextensible interphalangeal joints

AR

Vitamin A, prenatal480

Spontaneous abortion, microtia, microphthalmia, anophthalmia, congenital heart, limb reduction defects, thymic hypoplasia, jaw hypoplasia, hydrocephalus

In utero exposure

Vohwinkel: mutilating keratoma plus481

Diffuse hyperkeratosis of palms and soles, constriction of phalanges, starfish-shaped dorsal hyperkeratosis of hands and feet; may have hearing loss, alopecia, nail anomalies; single case with long face, clefting, and microcephaly

AD (124500)

Warfarin, prenatal482

Significant developmental delay, small and grooved nose with depressed bridge, stippled epiphyses, mild nasal hypoplasia, short fingers; other CNS defects reported

In utero exposure ARSE inhibition

Weaver-Hansma: microcephaly-cataracts483

Growth and developmental delay, cataracts, optic nerve hypoplasia, malar hypoplasia, epicanthus, short anteverted nose, fair skin, hypoplastic toenails

AR?

Weaver-Williams: unusual face-weight deficiency484

Mental retardation, decreased subcutaneous tissue and muscle, prominent ears, small downturned mouth, malformed teeth, cleft palate, downsloping ribs, bone hypoplasia

AR

Wiedemann: fibrolipomatoid hamartoma485

Mild mental retardation; short stature; long furrowed tongue; round to lobular tongue and alveolar surface; white to yellow brown, congenital tumour-like polypoid growths

AR?

Wiedemann: microcephalygrowth retardation527

Mental retardation, short stature, hypotonia, unusual cry, hypoplastic optic nerves, irregular fundal pigmentation, complete 3-4 skin syndactyly of the fingers, mild 1-2 syndactyly of the toes, congenital heart defect

Unknown

Wiedemann-retardation unusual face486

Narrow palpebral fissures and alae nasi; large mouth; low, prominent, simple ears; small mandible, broad wrists; syndactyly of fingers 2-5; brachytelephalangy

Unknown

Wiedemann: thumb anomaly-short stature487

Developmental delay, downslanting palpebrae, low-set ears, small chin, short stature, stubby and broad thumbs and toes, micropenis, scrotal hypoplasia

AD or XLD

Wiedemann: unusual faceanal atresia488

Low-set cupped ears with folded helix, downslanting palpebrae, ptosis, thin upper vermillion, short stature, developmental delay

Unknown

Williams489

Mild microcephaly and growth failure, short palpebrae, stellate irises, periorbital fullness, anteverted nares, full lips, supravalvular aortic stenosis, friendly personality; oligogyric microcephaly reported. Contiguous gene syndrome.

AD (194050) 7q11.2

Winter: distinctive face-broad thumbs and toes490

Frontal cowlick, midface hypoplasia, deep-set eyes, convex nasal profile, small ears, mandibular overbite, broad thumbs and toes, mild developmental delay

AD or XLD

Wolcott-Rallison491

Neonatal or early infancy onset diabetes mellitus, epiphyseal dysplasia, growth retardation; microcephaly an occasional finding

AR (226980) EIF2AK3, 2p12

Woods-Huson: microcephaly-syndactyly492

Severe developmental delay, growth failure, broad and hirsute forehead, broad nasal bridge with prominent columella and hypoplastic alae, long and narrow toes, dystonic movements, 3-4 finger syndactyly

AR (272440)

Worster-Drought: supraorbital paresis493

Variably severe suprabulbar paresis impairing orbicularis oris, tongue, soft palate, larynx, and pharyngeal muscles; a subset have developmental delay and microcephaly

AD (185480)

Wrinkly skin494

IUGR, developmental delay, hypotonia, winged scapulae, hip dysplasia, joint hyperextension, wrinkled skin on dorsum hands and feet, secondary plantar and palmar creases, hypoelasticity, prominent veins

AR (278250) 2q32

476

(continued)

496

Brain

497

Table 15-1. Syndromes in which microcephaly has been reported (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cutaneous sun sensitivity and early carcinomas, corneal changes, 18% progressive neurologic change; DNA repair defect with heterogeneity shown by complementation studies

AR (278800) ERCC6, 10q11

X-linked complex spastic paraplegia-Claes496

Borderline microcephaly with severe mental retardation, hyperreflexia, hypertonia, and muscle hypoplasia of lower limbs, facial hypotonia, shuffling gate

XLR Xp21.1-Xq21.3 or Xq23-Xq27.1

XLMR-Christianson497

Mild microcephaly, profound mental retardation, no speech, ophthalmoplegia, truncal ataxia, lowered life expectancy, cerebellar and brain stem ‘‘atrophy’’; females may show delay

XLR (300243) Xq24-q27

XLMR (MRX14)-Gendrot498

Nonsyndromic moderate to severe mental retardation with mild microcephaly, seizures, prominent ears, macroorchidism

XLR Xp11.22-Xq11.2

XLMR-growth hormone deficiency499

Variable microcephaly, short stature, high palate, dental crowding, gynecomastia, clinodactyly, infantile behavior, isolated growth hormone deficiency

XLR SOX3, Xq24-q27.3

XLMR-Hyde-Forster500

Two severely retarded male maternal half-sibs whose maternal aunts had learning problems; coarse facial features, brachycephaly, plagiocephaly; one was microcephalic

XLR (300064)

XLMR-ophthalmoplegiadeafness501

Postnatal microcephaly, growth and mental retardation, childhood onset of choreoathetosis and spasticity, external ophthalmoplegia, variable neurosensory deafness

XLR (312840)

X-linked microcephalymicrophthalmia-genital hypoplasia502

Congenital cataracts, microcornea, microphthalmia, short and upslanting palpebrae, large ears, thin upper lip, downturned mouth, genital hypoplasia, growth failure

XLR

Young-Simpson503

Developmental and growth delay, hypothyroidism, small and low-set ears, blepharophimosis, bulbous nasal tip, tented upper lip, congenital heart defects

Unknown

Yunis-Varon: cleidocranial dysostosis504

Wide anterior fontanel; sparse scalp hair; short philtrum; narrow palate; micrognathia; thin lips; absent/hypoplastic thumbs, great toes, clavicles; distal toe/finger aphalangia

AR (216340)

Zerres: postnatal microcephaly-syndactyly505

Mental retardation, postnatal onset growth failure and microcephaly, 2-5 finger and 1-4 toe syndactyly, brachymesophalangy of fingers 2-5, sparse hair, short nose, poor philtrum, small penis

Unknown

Zlotogora-Dagan: thumb anomalies506

IUGR, growth and developmental delay, aplastic or malpositioned thumb, amenorrhea, azoospermia, some with skin hyperpigmentation; occasionally other anomalies, including case with holoprosencephaly

Uncertain

Xeroderma pigmentosum

495

at risk siblings was not given. In a study of a population selected for consanguinity and an OFC between 4 SD and 14 SD, 38 of 56 showed linkage to one of the five, then known, isolated genetic microcephaly (MCPH) loci.13 As these and related genes are cloned16 and testing can be applied, it will be interesting to see how often such genes account for this form of microcephaly in the general population of non-consanguineous, simplex families. To date, six loci for true (primary) microcephaly have been mapped (MCPH1– MCPH6) and the genes for MCPH1 (Microcephalin),566 MCPH5 (ASPM),567 MCPH3 (CDK5RAP2), and MCPH6 (CENPJ)568 have been found. It should be kept in mind that an intrinsic fetal metabolic disease can have a developmental impact and lead to prenatalonset microcephaly.17 Degenerative conditions show progressive neurologic signs and may be accompanied by increasingly severe microcephaly. Most are genetic and include the broad spectrum of early-onset metabolic and abiotrophic diseases. However, post-infection complications, such as subacute sclerosing panencephalitis or early postnatal exposure to toxins such as lead, may also cause the degeneration of a previously normal brain. Microcephaly may accompany gross disruptive abnormalities such as craniofacial amniotic bands, but more often it represents a subtler clinical situation. Major disruption of blood supply will likely give rise to clastic lesions, and perinatal hypoxia may also leave a characteristic footprint on neuroimaging. The pregnancy

and perinatal history may lend important clues, and invasive prenatal diagnostic procedures may occasionally give rise to vascular disruption.529,530 In a study of children with learning disability, respiratory distress syndrome and intraventricular hemorrhage were the perinatal factors most strongly associated with microcephaly.531 The type of microcephaly and the associated clinical signs will vary with the ascertainment, and there is an interesting contrast between prenatal and newborn cases. In a prenatally ascertained series of 30 cases with a mean gestation of 28 weeks, more than half the fetuses were small for dates.37 Five had isolated microcephaly, five had holoprosencephaly, seven had a chromosome anomaly, six had a known genetic syndrome, and seven had multiple anomalies. Thus in 83%, the microcephaly was part of a complex problem. Dalgren and Wilson came to a similar conclusion after a retrospective review of 21 infants with a prenatal diagnosis of microcephaly that had been confirmed postnatally.532 The common etiologies included infection, complications of monochorionic twinning, genetic syndromes, and chromosome anomalies. In contrast, in a case-control study of infants whose microcephaly was ascertained through the systematic measurement of 19,000 consecutive newborns, only 4 (6.2%) of those with an OFC of  2 SD were considered dysmorphic or had a major malformation.533 One malformation syndrome and one metabolic disease were recognised, and the infants with microcephaly did not have an excess of minor anomalies.

498

Neuromuscular Systems

Any attempt to study the prevalence of microcephaly is challenged by a discouraging array of methodologic problems, and some of these have been discussed by Leviton et al.534 The prevalence of microcephaly is highly dependant on the age at ascertainment. Second trimester studies will miss many conditions that become apparent toward term; newborn ascertainment will not include those whose microcephaly has a peri- or postnatal onset. The study of an adult population will miss severe cases that have died and is likely to be biased toward a selected population, such as those with a learning disability.531 The causal mix of microcephaly should show a temporal change as certain causes are largely eliminated (congenital rubella) and others are introduced (gestational cocaine use) or are modified through improved pediatric and obstetric care, or by interventions such as prenatal screening for major malformations and chromosome abnormalities. The study of Vargas et al.533 verified the cranial measurements of the 850 infants in the lowest quartile from their study of 19,000 neonates. They found 106 with a confirmed OFC  2 SD below the mean, giving a birth prevalence of microcephaly of 5.5/1000 (0.55%). The prevalence was well below the statistically expected 25 per 1000, which suggests either a significant skew from the normal distribution or that the OFC charts in use are not representative of the current population. There does not appear to be a good current estimate of the rate of isolated genetic microcephaly. A 1955 Japanese study estimated the prevalence to be 1/25,000 to 1/50,000 livebirths.535 A broad range of intrauterine exposures to medications, drugs, chemicals, and infections, including cytomegalovirus, toxoplasma, rubella, and other viruses, may lead to microcephaly (Table 15-1). It is not the intention to review here the evidence for and against the various putative environmental teratogens. Instead, comments are limited to a few factors that are of particular contemporary interest. That pregnant women should not be exposed to x-rays has been indoctrinated into all medical practitioners. The accepted maximal in utero exposure to radiation is 0.05 Gy (5 rads). In assessing risk, it is paramount to distinguish diagnostic from therapeutic radiation. All single diagnostic procedures involve less than 0.05 Gy,536and the true threshold for malformation is likely significantly higher. The critical period for exposure is between 8 and 15 weeks, although there is evidence that high-dose radiation later in gestation can be harmful to the brain. Data on high exposure derive mainly from survivors of Hiroshima and anecdotal clinical experience. Microcephaly is the single major malformation associated with atomic bomb survivors, and children exposed within 1500 m of the hypocenter had an average OFC of 1.1 cm less than unexposed controls at the age of 17 years.537 The exposure of five survivors with the most severe intellectual impairment ranged between 0.69 Gy and 1.76 Gy.539 Reports of effects at levels as low as 0.10 Gy have involved unusually high neutron levels. Neutrons carry 5 to 20 times the radiation weighting factor of standard gamma or x-rays.539 There has been no evidence of an increase of microcephaly following in utero exposure to fallout from Chernobyl.540 Therapeutic radiation can expose the fetus to teratogenic levels. Case reports of infants with microcephaly include ocular changes that have been associated with radiation following maternal radiation therapy.541 Careful abdominal shielding may reduce fetal exposure by up to 50% and increase the margin of safety when maternal treatment of certain tumors is required.537 Guidelines to the systematic documentation and assessment of in utero radiation exposure have been published and can be followed in individual cases.542

At present, there is no evidence that diagnostic obstetric ultrasound is harmful to the developing brain. There is a single report of a developmentally delayed, microcephalic child with sacral agenesis born to a mother who received therapeutic ultrasound, and McLeod and Fowlow caution against this type of embryonic exposure.543 Microcephaly may occur due to in utero exposure to a number of drugs (Table 15-1), but two substances merit further discussion. Vitamin A deficiency and excess have long been known to be potent teratogens in animals, and an embryopathic effect in humans was anticipated when these compounds were introduced for the treatment of cystic acne (isotretinoin) and psoriasis (etretinate). Despite package warnings, the education of physicians about the potential hazards, and efforts to control prescriptions, the inevitable in utero exposures occurred, with a resultant high rate of spontaneous abortion and fetal abnormality.544 Typical malformations of the central nervous system include microcephaly/ hydrocephaly, posterior fossa cysts, and cortical blindness, and these are found associated particularly with ear, thymic, and cardiovascular malformations. Isotretinoin has a short half-life, and the outcome is favorable if exposure is discontinued by 4 weeks before the last menstrual period. The half-life of etretinate is months and therefore raises concern even for preconceptional exposure. There have been a few case reports of infants exposed to topical tretinoin who have had malformations compatible with retinoid teratogenicity.545 Vitamin A is available across the counter, without a pregnancy warning label, and in some cases with doses as high as 25,000 to 100,000 IU, although the recommended daily allowance is in the range of 5000 IU. Vitamin A may also have a role in reducing the chance of vertical transmission of HIV. Human malformations have been associated with doses as low as 25,000 IU/day, and a study that was criticized on methodologic grounds raised concerns about doses as low as 10,000 IU/day.546 Mulder et al.546 were able to produce subtle evidence of neural crest disturbance in mice with a single dose of 10 mg (29,000 IU)/kg administered at critical day 9 (human weeks) postconception. The conservative approach would be to advise against doses greater than 10,000 IU/day in women who may become pregnant. The fact that a single center was able to report on 505 newborns exposed during intrauterine life to illicit drugs547speaks to the magnitude of the problem in society today. Cocaine has emerged as an agent that causes fetal damage and is associated with spontaneous abortion, abruptio placenta, prematurity, stillbirth, and IUGR. In extreme cases, vascular damage may lead to the fetal brain disruption sequence,203 and abnormalities of vasculature and neuronal migration have been observed at autopsy.548 Several studies have shown an increased rate of microcephaly in exposed infants, variably estimated to be eight-fold greater than in controls, or up to 20% of cases.547,549–552 Neonatal neurologic signs and symptoms are considered to be a drug effect, rather than withdrawl,547and long-term developmental consequences have been noted. Comparison with other illicit drugs,547and studies that have controlled for confounding variables, confirm that the pathology is due to cocaine and not sociodemographic factors.549 Abuse of alcohol,53 solvents such as toluene553 and gasoline,554 and poisons such as methylmercury313 and carbon monoxide555 can result in microcephaly, in some cases with severe neurologic signs and mental retardation. Prognosis, Treatment, and Prevention

Microcephaly is a reflection of a small brain, and the outlook for a patient, which can range from normal to profound mental retardation, will vary with the nature and severity of the underlying

Brain

pathology. Every effort should be expended to determine a specific etiology and to define any associated intra- and extracranial malformations. As greater numbers of syndromes with microcephaly are defined, and their long-term outcomes become known, it should be increasingly possible to provide an expected range of developmental potential and/or neurologic complications. The paucity of associated neurologic signs and relatively normal early developmental milestones of some forms of autosomal recessive microcephaly have been alluded to. Microcephaly is strongly correlated with developmental delay. Nelson and Deutschberger556 analyzed data from the U.S. Collaborative Perinatal Project and found that children with microcephaly (2 SD) at 1 year of age had a 50% chance of having an IQ of < 80 at age 4 years. However, one-half of the children had IQ scores above this level. In a follow-up at age 7 years of children ascertained from the same cohort, Dolk557 found that 51% of the children with OFC below 3 SD had an IQ of < 70, and 17% were between 71 and 80. In those children with OFC below 2 SD, rates were 11% and 28%, respectively. In the absence of a specific diagnosis, a cautious approach should be taken toward predicting developmental potential simply on the basis of microcephaly. By definition, when using a cut-off value of 2 SD below the age-, sex-, and gestation-appropriate means, 2.5% of the population is expected to fall below this level and presumably many will simply reflect the lower range of normal OFC. Comparison with first-degree relatives may suggest this possibility. The further that the OFC falls below the mean, the greater is the risk of mental retardation. Current dogma is that the child with microcephaly whose head continues to grow parallel to the normal centiles has a better prognosis than does the child whose OFC continues to fall from normal. Good practice requires the clinician to consider the relative proportions of body measurements such as height, weight, and OFC to each other. Therefore, it is relevant to consider the question of ‘‘relative microcephaly,’’ that is, a head size that falls within the normal range but is disproportionately small when compared with the patient’s length or weight centiles. OFC and weight are correlated during the first year of life, but Brennan et al.558 found that infants whose head circumferences were significantly disproportionate relative to their weights, but were between the 10th and 90th centiles, were not at increased risk for an adverse outcome. A similar study with respect to length would be of interest, as adult OFC has been shown to correlate with height.5 The prospect for primary treatment and reversal of symptomatic microcephaly remains problematic. By the time the abnormality has been recognized, the causative factor is usually no longer operative, the damage has been done, and one is left to provide appropriate family, paramedical, and developmental support. Glazier et al.559 have pointed to the possibility of undiagnosed functional bladder anomalies in patients with severe delay associated with microcephaly and have suggested that such patients undergo a urologic evaluation. An important proportion of symptomatic microcephaly is the result of teratogenic events such as exposure to toxins, infections, and anoxia. Development and promotion of vaccination, and specific diagnostic intervention when infection is suspected, can have a significant benefit. There has been some success in increasing general public awareness about the hazards of ingesting alcohol and related substances during pregnancy, although perhaps one must be less sanguine about the prospects of influencing those who practice substance abuse. Infants born to women with untreated maternal phenylketonuria have a 93% risk for mental retardation and a 72% risk

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for microcephaly but barriers remain to the prevention of this problem.560 Abdel-Salam and Czeizel561 reported a 40–50% reduction in the prevalence of isolated microcephaly among the offspring of women who took pharmacologic doses of folic acid (6 mg/day) and iron (50 mg/day). However, their definition of microcephaly was < 10%, no comparisons of the development of the children were provided, and clearly questions arise as to possible negative effects at this level of supplementation. Thorough investigation and, when appropriate, genetic counseling should be offered to all families. Notwithstanding sophisticated advances in clinical, molecular, and neuroimaging approaches to diagnosis, it is not always possible to distinguish reliably between a genetic and nongenetic etiology in patients who have a negative family history and isolated microcephaly. Earlier empiric recurrence risk estimates may well be too low, but a risk of about 20% appears appropriate, although some would routinely counsel unexplained, isolated microcephaly as autosomal recessive.11 Advances in prenatal ultrasound and, in some centers, MRI neuroimaging have greatly improved the ability to detect malformations associated with specific syndromes, accompanying brain abnormalities, and subtle biometric differences in the fetal brain that may predate the appearance of measurable microcephaly.31,32 Concerns remain about positive and negative predictive values, and caution should be exercised in offering ultrasound as a basis for the prenatal diagnosis of microcephaly. This is especially true in the case of syndromes or situations where there is no precedent of successful and timely diagnosis. Detectable cerebral architectural changes or growth failure of the head may not occur until after such time as termination of the pregnancy would normally be available. An approach to the ultrasound diagnosis of microcephaly has been outlined by Romero et al.562 and can be modified with some of the newer information. The case reported by Winter et al.563 is a reminder that not all apparent microcephaly bodes a poor prognosis, and this must be kept in mind when microcephaly is detected in utero and there is no other abnormality in the pregnancy and no significant family history. It was suggested that the fetus suffered microcephaly on the basis of in utero constraint from a bicornate uterus and showed subsequent normal postnatal development and catch up of the OFC. Amniocentesis should be offered when there is a risk of a recurrent chromosome abnormality or enzymopathy. There has been remarkable recent progress in the identification of genes responsible for several types of isolated microcephaly11–13,568 and for many syndromes with microcephaly (Table 15-1). Careful evaluation of patients and families should allow the selective use of current molecular techniques in some cases. However, further technological advances are needed before a molecular screening approach can be applied to individual cases of unexplained isolated microcephaly. Multiplex families with isolated microcephaly, and patients with concurrent balanced translocations and microcephaly, may continue to aid in the isolation of causative genes. Qazi and Reed22 reported a high rate of subnormal intelligence among the close relatives of patients with isolated genetic microcephaly, and if confirmed in families with proven mutations, this might prove useful in selecting families for mutational studies. References (Microcephaly) 1. Hecht F, Kelly JV: Little heads, inheritance and early detection. J Pediatr 95:731, 1979. 2. Goodman RM, Gorlin RJ: The Malformed Infant and Child. Oxford University Press, New York, 1983, p 7.

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3. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 271. 4. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989, p 80. 5. Bushby KM, Cole T, Matthews JN, et al.: Centiles for adult head circumference. Arch Dis Child 67:1286, 1992. 6. Gooskens RHJM, Gielen CCAM, Hanlo PW, et al.: Intracranial spaces in childhood macrocephaly: comparison of length measurements and volume calculations. Dev Med Child Neurol 30:509, 1988. 7. Lusted LB, Keats TE: Atlas of Roentgenographic Measurements, ed 3. Year Book Medical, Chicago, 1972, p 30. 8. Lindley AA, Benson JE, Grimes C, et al.: The relationship in neonates between clinically measured head circumference and brain volume estimated from head CT-scans. Early Hum Dev 56:17, 1999. 9. Barkovich AJ, Ferriero DM, Barr RM, et al.: Microlissencephaly: a heterogeneous malformation of cortical development. Neuropediatrics 29:113, 1998. 10. Hanefeld FA: Oligogyric microcephaly. Neuropediatrics 30:102, 1999. 11. Dobyns WB: Primary microcephaly: new approaches for an old disorder. Am J Med Genet 112:315, 2002. 12. Mochida GH, Walsh CA: Molecular genetics of human microcephaly. Curr Opinion Neurol 14:151, 2001. 13. Roberts E, Hampshire DJ, Pattison L, et al.: Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J Med Genet 39:718, 2002. 14. Peiffer A, Singh N, Leppert M, et al.: Microcephaly with simplified gyral pattern in six related children. Am J Med Genet 84:137, 1999. 15. Sztriha L, Al-Gazali LI, Varady E, et al.: Autosomal recessive microcephaly with simplified gyral pattern, abnormal myelination and arthrogryposis. Neuropediatrics 30:141, 1999. 16. Jackson AP, Eastwood H, Bell SM, et al.: Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136, 2002. 17. Kelley RI, Robinson D, Puffenberger EG, et al.: Amish lethal microcephaly: A new metabolic disorder with severe congenital microcephaly and 2ketoglutaric aciduria. Am J Med Genet 112:318, 2002. ¨ ztu¨rk MH, Aydingoz U ¨ , et al.: CT and MRI of micro18. Yelgec¸ S, O cephalia vera. Paediatr Neuroradiol 40:332, 1998. 19. Custer DA, Vezina LG, Vaught DR, et al.: Neurodevelopmental and neuroimaging correlates in nonsyndromal microcephalic children. J Dev Behav Pediatr 21:12, 2000. 20. Penrose LS: Microcephaly. Folia Hered Pathol 5:79, 1956. 21. Baraitser M: The Genetics of Neurologic Disorders. Oxford University Press, Oxford, 1985, p 22. 22. Qazi QH, Reed TE: A problem in diagnosis of primary versus secondary microcephaly. Clin Genet 4:46, 1973. 23. Sujatha M, Kumari CK, Murty JS: Segregation frequency in microcephaly. Hum Genet 81:388, 1989. 24. Brandon MWG, Kirman BH, William CE: Microcephaly. J Ment Sci 57:637, 1959. 25. Tolmie JL, McNay M, Stephenson JBP: Microcephaly: genetic counselling and antenatal diagnosis after the birth of an affected child. Am J Med Genet 27:583, 1987. 26. Haslam RHA, Smith DW: Autosomal dominant microcephaly. J Pediatr 95:701, 1979. 27. Newbury-Ecob RA, Young ID. Dominant inheritance of microcephaly, short stature and congenital dislocation of the hips. Clin Dysmorphol 2:34, 1993. 28. Rossi LN, Candini G, Scarlatti G, et al.: Autosomal dominant microcephaly without mental retardation. Am J Dis Child 141:655, 1957. 29. Ramirez ML, Rivas F, Cantu JM: Silent microcephaly: a distinct autosomal dominant trait. Clin Genet 23:281, 1983. 30. Chervenak FA, Rosenberg J, Brightman RC: A prospective study of the accuracy of ultrasound in predicting fetal microcephaly. Obstet Gynecol 69:908, 1987. 31. Pilu G, Falco P, Milano V, et al.: Prenatal diagnosis of microcephaly assisted by vaginal sonography and power Doppler. Ultrasound Obstet Gynecol 11:357, 1998.

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509 465. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 681. 466. Giannotti A, Diglio MC, Albertini G, et al.: Sporadic trichodental dysplasia with microcephaly and mental retardation. Clin Dysmorphol 4:334, 1995. 467. Toelle SP, Valsangiacomo E, Botthauser E: Trichothiodystrophy with severe cardiac and neurological involvement in two sisters. Eur J Pediatr 160:728, 2001. 468. Goldblatt J, Wallis C, Viljoen D: A new hypospadias-mental retardation syndrome in three brothers. Am J Dis Child 141:1168, 1987. 469. Say B, Meyer J: Familial trigonocephaly associated with short stature and developmental delay. Am J Dis Child 135:711, 1981. 470. Feldman GL, Weaver DD, Lourien EW: The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child 131:1389, 1977. 471. Tsukahara M, Sugio Y: New dominant syndrome of microcephaly, facial abnormalities, micromelia, and mental retardation. J Hum Genet 43:224, 1998. 472. Paulger BR, Kraus EW, Pulitzer DR, et al.: Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck. Pediatr Dermatol 14:26, 1997. 473. Tsukahara M, Azuno Y, Kajii T: Type A1 brachydactyly, dwarfism, ptosis, mixed partial hearing loss, microcephaly, and mental retardation. Am J Med Genet 33:7, 1989. 474. Tamari I, Goodman RM: Upper limb-cardiovascular syndromes: a description of two new disorders with a classification. Chest 65:632, 1974. 475. Urbach D, Hertz M, Shine M, et al.: A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet 29:83, 1986. 476. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 576. 477. Mitnick RJ, Bello JA, Shprintzen RJ: Brain anomalies in velo-cardiofacial syndrome. Am J Med Genet 54:100, 1994. 478. Char F, Douglas JE, Dungan WT: Familial multiforme ventricular extrasystoles with short stature, hyperpigmentation and microcephalya new syndrome. Birth Defects Orig Artic Ser XI(5):63, 1975. 479. Viljoen DL, Kallis J, Voges S, et al.: An apparently new mental retardation syndrome in three elderly sisters. Clin Genet 40:6, 1991. 480. De Wals P: Surveillance of retinoic acid embryopathy. Teratology 40:274, 1989. 481. Sensi A, Bettoli V, Zampino E, et al.: Vohwinkel syndrome (mutilating keratoderma) associated with craniofacial anomalies. Am J Med Genet 50:201, 1994. 482. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 4. WB Saunders, Philadelphia, 1988, p 568. 483. Weaver DD, Hansma DI: An apparent new autosomal recessive syndrome with microcephaly, unusual facial appearance, eye anomalies, hypotonia and developmental delay. Proc Greenwood Genet Center 7:162, 1988. 484. Weaver OD, Williams CPS: A syndrome of microcephaly, mental retardation, unusual facies, cleft palate and weight deficiency. Birth Defects Orig Artic Ser XIII(3B):69, 1977. 485. Wiedemann HR, Grosse K-R, Dibbern H: An Atlas of Characteristic Syndromes: a Visual Aid to Diagnosis. Wolfe Medical Publications Ltd, London, 1985, p 48. 486. Wiedemann HR, Grosse K-R, Dibbern H: An Atlas of Characteristic Syndromes: a Visual Aid to Diagnosis. Wolfe Medical Publications Ltd, London, 1985, p 322. 487. Nevin NC, Stewart FJ, Corkey CW, et al.: Microcephaly with large anterior fontanelle, generalized convulsions, micropenis, and distinct anomalies of the hands and feet. Another example of Wiedemann syndrome? Clin Genet 46:205, 1994. 488. Zampino G, Balducci F, Mariotti, et al.: Growth and developmental retardation, ocular ptosis, cardiac defect, and anal atresia: confirmation of the ROCA-Wiedemann syndrome. Am J Med Genet 90:358, 2000. 489. Faravelli F, D’Arrigo S, Bagnasco I, et al.: Oligophrenic microcephaly in a child with Williams syndrome. Am J Med Genet A 117:169, 2003.

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490. Winter RM: Distinctive autosomal or X-linked dominant syndrome of microcephaly, mild developmental delay, short stature, and distinctive face. Am J Med Genet 47:917, 1993. 491. Biason-Lauber A, Lang-Muritano M, Vaccoro T, et al.: Loss of kinase activity in a patient with Wilcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 51:2301, 2002. 492. Woods CG, Crouchman M, Huson SM: Three sibs with phalangeal anomalies, microcephaly, severe mental retardation, and neurological abnormalities. J Med Genet 29:500, 1992. 493. Palton MA, Baraitser M, Brett EM: A family with congenital suprabulbar paresis (Worster-Drought syndrome). Clin Genet 29: 147, 1986. 494. Kreuz FR, Wittwer BH: Del(2q)—cause of the wrinkly skin syndrome? Clin Genet 43:132, 1993. 495. Kraemer KH, Lee MM, Scotto J: Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123:241, 1987. 496. Claes S, Deviendt K, Van Goethem G, et al.: Novel syndromic form of X-linked complicated spastic paraplegia. Am J Med Genet 94:1, 2000. 497. Christianson AL, Stevenson RE, van der Meyden CH, et al.: X-linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia and cerebellar atrophy in a large South African kindred is localized to Xq24-q27. J Med Genet 36:759, 1999. 498. Gendrot C, Ronce N, Toutain A, et al.: X-linked mental retardation exhibiting linkage to DXS255 and PGKP1: a new MRX family (MRX14) with localization in the pericentromeric region. Clin Genet 45:145, 1994. 499. Raynaud M, Ronce N, Ayrault A-D, et al.: X-linked mental retardation with isolated growth hormone deficiency is mapped to Xq22-Xq27.2 in one family. Am J Med Genet 76:255, 1998. 500. Hyde-Forster I, McCarthy G, Berry AC: A new X linked syndrome with mental retardation and craniofacial dysmorphism? J Med Genet 29:736, 1992. 501. Schimke RN, Horton WA, Collins DL, et al.: A new X-linked syndrome comprising progressive basal ganglion dysfunction, mental and growth retardation, external ophthalmoplegia, postnatal microcephaly and deafness. Am J Med Genet 17:323, 1984. 502. Seemanova´ E, Lesny I: X-linked microcephaly, microphthalmia, microcornea, congenital cataract, hypogenitalism, mental deficiency, growth retardation, spasticity: possible new syndrome. Am J Med Genet 66:179, 1996. 503. Masuno M, Imaizumik I, Okada T, et al.: Young-Simpson syndrome: further delineation of a distinct syndrome with congenital hypothyroidism, congenital heart defects, facial dysmorphism, and mental retardation. Am J Med Genet 84:8, 1999. 504. Hughes HE, Partington MW: The syndrome of Yunis and Varon— report of a further case. Am J Med Genet 14:539, 1983. 505. Zerres K, Rietschel M, Rietschel E, et al.: Postnatal short stature, microcephaly, severe syndactyly of hands and feet, dysmorphic face, and mental retardation: a new syndrome? J Med Genet 29:271, 1992. 506. Zlotogora J, Dagan J, Ganen A, et al.: A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism. J Med Genet 34:813, 1997. 507. Delb W, Lipfert S, Henn W: Mandibulofacial dysostosis, microcephaly and thorax deformities in two brothers: a new recessive syndrome? Clin Dysmorphol 10:105, 2001. 508. Shetty AK, Chatters R, Tilton AH, et al.: Syndrome of microcephaly, mental retardation, and tracheoesophageal fistula associated with features of Rett syndrome. J Child Neurol 15:61, 2000. 509. Wieczorek D, Koster B, Gillessen-Kaesbach G: Absence of thumbs, a/ hypoplasia of radius, hypoplasia of ulnae, retarded bone age, short stature, microcephaly, hypoplastic genitalia, and mental retardation. Am J Med Genet 108:209, 2002. 510. Davee MA, Moore CA, Bull MJ, et al.: New syndrome? Familial occurrence of renal and Mullerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay. Am J Med Genet 44:293, 1992. 511. Aldred MA, Dry KL, Knight-Jones EB, et al.: Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa. Am J Hum Genet 55:916, 1994.

512. Teebi AS: Naguib-Richieri-Costa syndrome: hypertelorism, hypospadias, and polysyndactyly syndrome. Am J Med Genet 44:115, 1992. 513. Poole AE, Saal HM: RAG syndrome. In: Birth Defects Encyclopedia. Buyse ML, ed. Blackwell Scientific Pub, Cambridge, 1990, p 1457. 514. Hall BD: Schachter syndrome (hypotelorism, small cupid bow mouth, prognathism, abnormal ears, mental retardation): report of a second case. Am J Hum Genet 49(Suppl):139, 1991. 515. Schlichtmeier TL, Tomlinson GE, Kamen BA, et al.: Multiple coagulation defects and the Cohen syndrome. Clin Genet 45:212, 1994. 516. Woods CG, Leversha M, Rogers JG: Severe intrauterine growth retardation with increased mitomycin C sensitivity: a further chromosome breakage syndrome. J Med Genet 32:301, 1995. 517. Frederick DR, Robb RM: Ophthalmic manifestations of Setleis forceps marks syndrome: a case report. J Pediatr Ophthalmol Strabismus 29: 127, 1992. 518. Plomp AS, Baraitser M, Slaney SF, et al.: Severe microcephaly, choreiform movements, cataracts and sensorineural deafness in two patients: a new syndrome? Clin Dysmorphol 9:11, 2000. 519. Maclean K, Ambler G, Flaherty M, et al.: A variant microcephalic osteodysplastic slender-bone disorder with growth hormone deficiency and a pigmentary retinopathy. Clin Dysmorphol 11:255, 2002. 520. Stoll C, Alembik Y, Dott B: Complex congenital heart disease, microcephaly, pheochromocytoma and neurofibromatosis type I in a girl born from consanguineous parents. Genet Couns 6:217, 1995. 521. Temtamy SA, Meguid NA, Ismail SI, et al.: A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol 7:249, 1998. 522. Al-Sannaa N, Forrest CR, Teebi AS: Trigonomicrocephaly, severe micrognathia, large ears, atrioventricular septal defect, symmetrical cutaneous syndactyly of hands and feet, and multiple cafe-au-lait spots: new acrocraniofacial dysostosis syndrome? Am J Med Genet 101:279, 2001. 523. Farah S, Sabry MA, Al-Shubaili AFK, et al.: A possible new Troyer-like syndrome. Am J Hum Genet 59:A92, 1996. 524. Van Maldergem L, Wetzburger C, Verloes A, et al.: Mental retardation with blepharo-naso-facial abnormalities and hand malformations: a new syndrome? Clin Genet 41:22, 1992. 525. Vasquez SB, Hurst DL, Sotos JF: X-linked hypogonadism, gynaecomastia, mental retardation, short stature, and obesity—a new syndrome. J Pediatr 94:56, 1979. 526. de Die-Smulders C, Van Schrojenstein L, de Valk H, et al.: Confirmation of a new MR/male pseudohermaphroditism syndrome, Verloes type. Genet Couns 5:73, 1994. 527. Wiedemann HR. A further microcephaly-growth deficiency-retardation syndrome. In: An Atlas of Clinical Syndromes: A Visual Aid to Diagnosis, ed 2. Wiedemann HR, Kunze J, Grosse F-R, et al., eds. Wolfe Publishing Ltd, London, 1992, p 172. 528. Voudris KA, Skardoutsou A, Vagiakou EA: Congenital microcephaly in two infants with the factor V Leiden mutation. J Child Neurol 17:905, 2002. 529. Villo N, Beceiro J, Cebrero M, et al.: Fetal brain disruption sequence in a newborn with a history of cordocentesis at 21 weeks gestation. Arch Dis Child Fetal Neonatal Ed 84:63, 2001. 530. Sherer DM, Salifia CM: Midtrimester amniocentesis of a twin gestation complicated by immediate severe bradycardia with subsequent associated fetal anomalies. Am J Perinatol 13:347, 1996. 531. Watemberg N, Silver S, Harel S, et al.: Significance of microcephaly among children with developmental disabilities. J Child Neurol 17:117, 2002. 532. Dalgren L, Wilson RD: Prenatally diagnosed microcephaly: a review of etiologies. Fetal Diagn Ther 16:323, 2001. 533. Vargas JE, Allred EN, Leviton A, et al.: Congenital microcephaly: phenotypic features in a consecutive sample of newborn infants. J Pediatr 139:210, 2001. 534. Leviton A, Holmes LB, Allred EN, et al.: Methodologic issues in epidemiologic studies of congenital microcephaly. Early Hum Dev 69:91, 2002. 535. Konai T, Kishimoto K, Ozaki Y: Genetic study of microcephaly based on Japanese material. Am J Hum Genet 7:51, 1955.

Brain 536. Toppenberg KS, Hill DA, Miller DP: Safety of radiographic imaging during pregnancy. Am Fam Physician 59:1813, 1999. 537. Greskovich JF Jr, Macklis RM: Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 27:633, 2000. 538. Miller RW: Discussion: severe mental retardation and cancer among atomic bomb survivors exposed in utero. Teratology 59:234, 1999. 539. Radiation—quantities and units of ionizing radiation. Canadian Centre for Occupational Health and Safety. http://www.ccohs.ca/ oshanswers/phys_agents/ionizing.html 540. Gustavson KH, Jagell S, Blomquist HK, et al.: Microcephaly, mental retardation and chromosomal aberrations in a girls following radiation therapy during late fetal life. Acta Radiol Oncol 20:209, 1981. 541. Preliminary evaluation of the impact of the Chernobyl radiological contamination on the frequency of central nervous system malformations in 18 regions of Europe. The EUROCAT Working Group. Paediatr Perinatol Epidemiol 2:253, 1988. 542. Mossman KL, Hili LT: Radiation risks in pregnancy. Obstet Gynecol 60:237, 1982. 543. McLeod DR, Fowlow SB: Multiple malformations and exposure to therapeutic ultrasound during organogenesis. Am J Med Genet 34:317, 1989. 544. Rosa FW, Wilk AL, Kelsey FO: Teratogen update: vitamin A cogeners. Teratology 33:355, 1986. 545. Selcen D, Seideman S, Nigro MA: Otocerebral anomalies associated with topical tretinoin use. Brain Dev 22:218, 2000. 546. Mulder GB, Manley N, Grant J, et al.: Effects of Vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study. Teratology 62:214, 2000. 547. Rahbar F, Fomufod A, White D, et al.: Impact of exposure to phencyclidine (PCP) and cocaine on neonates. J Natl Med Assoc 85:349, 1993. 548. Kesrouani A, Fallet C, Vuillard E, et al.: Pathologic and laboratory correlation in microcephaly associated with prenatal cocaine exposure. Early Hum Dev 63:79, 2001. 549. Singer LT, Salvator A, Arendt R, et al.: Effects of cocaine/polydrug exposure and maternal psychological distress on infant birth outcomes. Neurotoxicol Teratol 24:127, 2002. 550. Leobstein R, Koren G: Pregnancy outcome and neurodevelopment of children exposed in utero to psychoactive drugs: the Motherisk experience. J Psychiatry Neurosci 22:192, 1997. 551. HadeedAJ, Siegel SR: Maternal cocaine use during pregnancy: effect on the newborn infant. Pediatrics 84:205, 1989. 552. Fulroth R, Phillips B, Durand DJ: Perinatal outcome of infants exposed to cocaine and/or heroin in utero. Am J Dis Child 43:905, 1989. 553. Hersh J, Podruch P, Rogers G: Toluene embryopathy. Proc Greenwood Genet Center 4:98, 1985. 554. Hunter AGW, Thompson D, Evans JA: Is there a fetal gasoline syndrome? Teratology 20:75, 1979. 555. Schardein JL: Chemically Induced Birth Defects. Marcel Dekker, New York, 1985, p 754. 556. Nelson KB, Deutschberger J: Head size at one year as a predictor of four year IQ. Dev Med Child Neurol 12:487, 1970. 557. Dolk H: The predictive value of microcephaly during the first year of life for mental retardation at seven years. Dev Med Child Neurol 33:974, 1991. 558. Brennan TL, Funk SG, Frothingham TE: Disproportionate intra-uterine head growth and developmental outcome. Dev Med Child Neurol 27:746, 1985. 559. Glazier DB, Cummings KB, Barone JG: Urodynamic evaluation of profound microcephaly in children. Br J Urology 80:825, 1997. 560. MMWR Report: Barriers to dietary control among pregnant women with phenylketonuria-United States, 1998-2000. Morb Mort Wkly Rep 51:117, 2002. 561. Abdel-Salem G, Czeizel AE: A Case-control study of microcephaly. Epidemiology 11:571, 2000. 562. Romero R, Pilu G, Jeanty P, et al.: Prenatal Diagnosis of Congenital Anomalies. Appleton & Lang, Norwalk, CT, 1987, p 54. 563. Winter RM, Dearlove J, Jolly H, et al.: Apparent microcephaly caused by bicornuate uterus. Br Med J 286:1640, 1983. 564. Keegan CE, Vilain E, Mohammed M, et al.: Microcephaly, jejunal atresia, aberrant right bronchus, ocular anomalies, and sex reversal. Am J Med Genet 125A:293, 2003.

511 565. Kajantie E, Otonkoski T, Kivirikko S, et al.: A syndrome with multiple malformations, mental retardation, and ACTH deficiency. Am J Med Genet 126A:313, 2003. 566. Trimborn M, Bell SM, Felix C, et al.: Mutations in Microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet 75:261, 2004. 567. Kumar A, Blanton SH, Babu M, et al.: Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations. Clin Genet 66:341, 2004. 568. Bond J, Roberts E, Springell K, et al.: A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37: 353, 2005.

15.2 Megalencephaly Definition

Megalencephaly is a brain weight/volume ratio greater than the age-appropriate 98th centile (or >2 SD above the mean), because of a true hyperplasia or overproduction of parenchyma.1 Generally megalencephaly is accompanied by macrocephaly (an occipitofrontal circumference—OFC—greater than the 98th centile). Adult head circumference has been found to correlate with height,2,3 and it is important that appropriate centile graphs are used.3 However, most cases of macrocephaly do not reflect underlying megalencephaly, so it is important to exclude hydrocephalus, cerebral edema, neoplasia, fluid collection, and a thickened calvarium.4 Megalencephaly is further divided into an anatomic type (developmental) and a metabolic type. The latter includes various storage and degenerative encephalopathies. With the exception of a small number of metabolic encephalopathies in which megalencephaly can be an important early sign, this summary is restricted to the anatomic form. Diagnosis

In most cases a patient with megalencephaly will be ascertained because of macrocephaly. In the past, confirmation was based on the weight of the brain drained of cerebrospinal fluid (CSF). The advent of neuroradiographic methods has made possible in vivo diagnosis. In most cases, anatomic megalencephaly is apparent at birth, and the head continues to be enlarged but grows at a rate parallel to the upper percentiles. A pattern of head growth that crosses centiles is more suggestive of a disturbance of CSF dynamics or a storage disorder, but it may also be seen in anatomic megalencephaly.5 In most cases of megalencephaly, a careful history and examination will suggest the likely diagnostic category, and neurologic evaluation, including CT and MRI, can be used to define the specific anatomy. Linear neuroimaging measurements have been used most often to estimate the ventricular and subarachnoid spaces and thus to determine the presence or absence of megalencephaly. More complex methods have been developed to better estimate the true parenchymal volume more precisely. Gooskens et al.6 applied one such method and were able to confirm megalencephaly in only three of eight patients in whom that diagnosis had been made using the traditional linear measurements. In contrast, the methods did agree well for the diagnosis of communicating hydrocephalus. Gooskens et al.7 also obtained a relatively poor correlation (r ¼ 0.59) between the OFC and their estimate of brain volume. The correlation was poorest the greater the head shape deviated from a circle (e.g., dolichocephaly, brachycephaly). A better correlation (r ¼ 0.72) with brain volume was obtained for the product of OFC squared

512

Neuromuscular Systems

and head height. The latter was measured with sliding callipers as the distance from the vertex to the line connecting the auditory canals. Tramo et al.8 found that OFC did correlate with forebrain volume, area of the corpus callosum, and cortical surface area. For most purposes, macrocephaly in the absence of a thickened cranial vault, hydrocephalus, tumor, or acute pathology is accepted as due to a megalencephaly. However, it has become clear that a significant proportion of children with the relatively common condition of benign macrocephaly (vide infra) have increased subarachnoid9 and/or Virchow-Robin10 spaces rather than true megalencephaly. Few patients with syndromic macrocephaly have been subject to rigorous estimates of brain size, and the presence of megalencephaly remains problematic for the majority of syndromes associated with a large head. With this caveat, Table 15-2 lists syndromes in which macrocephaly is present and neuroimaging has yet to demonstrate another consistent cause for the increased OFC. Mild hydrocephalus and megalencephaly can coexist,7 and some syndromes in which a mild degree of hydrocephaly does not appear to account for the macrocephaly are included. The POSSUM1 and London1 databases were used extensively, but not exclusively, to ascertain syndromes; but many syndromes so identified are not included. Excluded are conditions in which undefined macrocephaly appeared to be a chance or occasional finding of no diagnostic importance, accompanied a specific brain malformation that is considered elsewhere in this chapter, was a reflection of intracerebral storage, or was likely due to abnormal thickness of the cranial vault. Many syndromes (e.g., most of the lethal chondrodysplasias) are described as having relative macrocephaly, that is, an OFC of normal size for age but out of proportion to a small stature; but, for most, there is as yet no evidence of true brain abnormality. These syndromes, as well as case reports of conditions reported to have a ‘‘large head’’ but where no, or normal, OFC measurements are provided, are not included. The most common type of megalencephaly is benign, familial, and most often free from associated anomalies (benign familial megalencephaly—BFM). Thus, among the most important investigations of a patient is measurement of the OFCs of other family members. These measurements, together with an appropriate history and physical examinations, may be all that is required to point to BFM. However, newer clinical and neuroimaging studies have added complexity to the understanding of BFM. The traditional view that BFM is an autosomal dominant condition with male predominance1 has been challenged by Arbour et al.155 They showed that although parents and siblings of patients had an increased mean OFC, the distribution of measurements was unimodal, not bimodal as would be expected from a simple autosomal dominant trait. Those authors found further support for their argument in their analysis156 of the results of Miles et al.,157 and point out that the imposition of an arbitrary cut-off of >2 SD above the mean onto a continuous variable (OFC) can lead to apparent autosomal dominant inheritance in some families. Petersson et al.158 have provided support for the multifactorial inheritance of megalencephaly. In some families, the macrocephaly may be accompanied by ventriculomegaly, but the increased OFC persists in the presence of shunting procedures.5,157 In a study of 20 children with benign macrocephaly, Alper et al.9 found that 13 had enlarged arachnoid spaces and 7 had true megalencephaly. Although the former group tended to be younger, the groups did not differ with respect to parental history of macrocephaly. It is not clear whether such families represent simple anatomic variation or different conditions. Similarly, Cole and Hughes47 identified six patients from a study of

Sotos syndrome, who had macrocephaly, some characteristic facial and physical features (see Table 15-1), and resembled a number of their first- and second-degree relatives. Again, it is not universally agreed that this condition differs from BFM. DeRosa et al.160 reported the prenatal diagnosis of BFM and emphasized the need to carefully assess the family in such cases; it appears that the onset of megalencephaly was between 21 and 32 weeks gestation. It is important to consider the possibility of a subdural fluid accumulation in a child presenting with macrocephaly and pericerebral fluid collection visible on CT. Vanderschueren et al.161 demonstrated that CT may fail to detect a second fluid layer characteristic of a concurrent subdural collection. They found that macrocephaly associated with a subdural collection correlated with age under 5 months, acute clinical signs, and absence of a family history of macrocephaly. The observation of an excess of macrocephaly among children with autism162 has stirred a great deal of interest and further study. Macrocephaly has been shown to be an independent risk factor for autism, and macrocephaly is significantly more common among the parents of both macrocephalic and non-macrocephalic autistic propositi.157,162 Among autistic children, macrocephaly is not associated with developmental level, severity of autistic signs, gender, seizure prevalence, dysmorphia, or recurrence risk,157,163 although children with macrocephaly appear less likely to have a family history of attention deficit hyperactivity disorder157 and tend to be older.164 The diagnosis of the individual syndromic forms of megalencephaly will depend largely on the associated manifestations, and in some cases an increased OFC may be a presenting sign. It is important to emphasize that many of the syndromes in Table 15-2 may only occasionally present with a large head and/or that their associated intracranial findings have not been well documented. There is a need for much more information on specific syndromes; it is not uncommon to find a statement that the patient had a large, or relatively large, head but that the OFC is not recorded. Often in syndromic megalencephaly, a variety of gyral and structural anomalies, neuronal heterotopias, and abnormal and/or overproduction of specific cell types will be seen.6 Friede1 believes that cases of diffuse glial overgrowth published prior to 1940 represented well-differentiated infiltrating tumors. Unilateral megalencephaly, or hemimegalencephaly, is an uncommon condition characterized by a diffuse enlargement of one-half of the brain, which shows shallow sulci, wide gyri, loss of separation of the cell layers, subcortical neuronal heterotopias, and scattered giant neurons (neuronal hypertrophy) (Fig. 15-5).165 The condition may represent the extreme of the spectrum of cortical dysplasias (see Section 15.5). MRI is well suited to demonstrating the sulcal and gyral anomalies, in addition to the increased thickness of the cortical ribbon.165 Kato et al.166 studied the brain from four patients and found hypertrophy of the white matter with an increase in glial cells and reduction in the cortex. They demonstrated an excess epidermal growth factor like immunoreactivity in astrocytes and posited that it had a role in the overgrowth of the affected side, although the staining did not differ between the two sides of the brain. O’Kusky et al.167 showed that the total number and type of synapsis per unit of brain volume was normal in hemimegalencephaly, but that given the overall increased brain thickness that the total number of synapses in a radial column of cortex would be increased. Affected children may have a large and sometimes asymmetric head and usually have a poor prognosis, often with a grossly abnormal electroencephalogram (EEG), intractable seizures, hemiparesis, and mental retardation.

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly Syndrome

Prominent Features

Causation Gene/Locus

3-methylglutaconic aciduria type 111

Macrocephaly, delayed development of speech, motor delay, and symptomatic hypoglycemia variable; elevated 3-methylglutaconic acid in the urine; defect of 3-methylglutaconylCoA hydratase

AR (250950) AUH, Chr. 9

Achondroplasia12

Rhizomelic short stature, low nasal bridge, prominent forehead, trident hand, short cranial base, small foramen magnum, narrowed lumbar interpeduncular distance, short tubular bones; megalencephaly may relate to mild undetected hydrocephalus

AD (100800) FGFR3, 4p16.3

Adams-Oliver variantpolymicrogyria13

Cutis aplasia of scalp and transverse limb reduction in one sib who also had postnatal macrocephaly; both sibs had polymicrogyria; consanguinity

AR?

Alexander disease14

Megalencephalic leukodystrophy with psychomotor delay, spasticity, seizures, demyelination, degeneration of astrocytes, Rosenthal fibers, typical MRI findings

AR (203450) NDUFB1, 11q13 GFAP, 17q21

Al-Gazali: webbed neck-face dysmorphia15

Growth and developmental delay, short webbed neck, low-set ears, downslanting palpebrae, arched eyebrows, hypoplastic supraorbital ridges, large nose, pectus carinatum/excavatum, cardiac septal defects, 5th finger clinodactyly; one of four had hydrocephaly

AR

Alpha thalassemia-mental retardation-deletion16

Mild to moderate mental retardation, macrocephaly or microcephaly, tall/broad forehead, hypertelorism, horizontal to downslanting palpebrae, initially depressed nasal bridge, crowded/irregularly spaced teeth, talipes equinovarus, cryptorchidism

Microdeletion

Aminopterin sine aminopterin–like17

Severe mental retardation, prominent forehead, hypertelorism, downslanting palpebrae, simple philtrum, thin nose with thick septum, short neck, low posterior hairline, mild cutaneous syndactyly, progressive camptodactyly, postaxial polydactyly of hands

AR

Anophthalmiahypopituitarism-renal18

Micro/anophthalmia, cleft lip/palate, absent pituitary, nephronopthisis, delayed development, reduced cerebral white matter, multiple small porencephalic cysts; father had large head

Unknown

Anophthalmia-nasal proboscis19

Macrocephaly, hydrocephalus, craniosynostosis, anophthalmia and proboscis-like nose. 1 of 2 unrelated girls had frontal encephalocele

Unknown (605627)

Apert20

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS anomalies include corpus callosum, limbic system, gyri, heterotopia, and others

AD (101200) FGFR2, 10q25.3-q26

Ataxia-telangiectasia21

Immunodeficiency, visceral and cutaneous vascular anomalies and telangiectasia, cerebellar ataxia, hypoplasia of cerebellar granular and ganglion cells (megalencephaly uncommon?)

AR (208900) ATM, 11q22.3

Atelosteogenesis-boomerang dysplasia22

Spectrum of lethal chondrodysplasia, variable macrocephaly, flat and low nasal bridge, micrognathia, short neck, micromelia, bowed limbs, broad array of radiologic changes, multinucleated giant cells in cartilage

AD (108720, 112310) FLNB, 3p14.3

Atkin: Coffin-Lowry–like face23

Square forehead, prominent supraorbital ridges, hypertelorism, downslanting palpebrae, thick lips, dental anomalies, macroorchidism, short stature, mental retardation

XLD (300431)

Bagatelle-Cassidy: macrocephaly-shortdeafness24

Prominent forehead, delayed closure anterior fontanelle, hypertelorism, sparse frontal hair, downslanting palpebrae, relatively short limbs, normal radiographs

Unknown

Bannayan-Riley-Ruvalcaba25

Frontal bossing, downslanting palpebrae, delay in early motor and speech development; diffuse mesodermal hamartomas (lipomas and hemangiomas), which may be aggressive (see Cowden)

AD (153480) PTEN, 10q22-23

Bardet-Biedl26

Short stature, obesity, developmental delay, retinal dystrophy, eye anomalies, brachydactyly, postaxial polydactyly, renal anomalies, small genitalia in males, macrocephaly an occasional finding; overlap with McKusick-Kaufman on 20p12 (MKKS)

AR (209900) BBS1, 2q31 BBS2, 3p13-p12 BBS3, ARL6, 4q27 BBS4, 11q13 BBS5, 15q22.3-q23 MKKS, 16q21 BBS7, 20p12

Basal cell nevus27

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomas, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 1p32 PTCH2, 9q22.3

Basal cell carcinomahypotrichosis-milia28

Coarse and sparse scalp hair, thinned eyebrows and eyelashes, milia in childhood, excess sweating; similar to nevoid basal cell carcinoma syndrome with basal cell carcinomas in early adulthood

AD (109390)

Beveridge: macrocephalyabnormal pigment29

Protuberant abdomen, enlarged liver, large hands and feet, hoarse voice, sparse hair, brittle nails, palmar creases described as ‘‘dirty orange,’’ not carotenemic, nodules on dorsum of hands; dyskeratosis congenita, increased pigmentation in the basal epidermal layers

Unknown

(continued)

513

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Bo¨rjesson-ForssmanLehmann-like30

Moderate developmental delay, short stature, obesity, partial alopecia, large ears, round face, deep-set eyes, narrow palpebrae, prominent upper and lower lips, small jaw

AD

Brachytelephalangyanosmia31

Square forehead, small nose, telecanthus, thin upper lip, short stature, anosmia, normal CT, hypogonadotrophic hypogonadism.

AD or XLD (113480)

Campomelic dysplasia32

Mean OFC at birth 37 cm, micrognathia, flat nasal bridge, cleft palate, bowed femur and tibia, narrow chest, respiratory distress, laryngomalacia, cardiac and renal defects common, ambiguous genitalia in most males; characteristic radiographic changes

AD (114290) SOX9, 17q24q-25

Cantu: hypertrichosisosteochondrodysplasia33

Congenital hypertrichosis and coarse face, macrosomia, broad nasal bridge, long philtrum, full mouth, narrow shoulders and chest, broad ribs, platyspondyly, flared metaphyses, pelvic anomalies

AR (239850)

Cardio-facial-cutaneous34

Facial appearance resembles Noonan syndrome; sparse, friable, curly hair; bitemporal narrowness; dry and hyperkeratotic skin; frequent ptosis, strabismus, and nystagmus; pulmonary stenosis most common congenital heart defect

AD (115150)

Carey-Fineman-Ziter35

Developmental and growth delay, feeding difficulty, facial weakness, ptosis, downslanting palpebrae, ophthalmoplegia, cleft palate, brachydactyly, initial macrocephaly becoming microcephalic

AR (254940)

Char: patent ductus arteriosus36

Variable developmental delay; facial signs including low-set ears, ptosis, short philtrum, patulous lips; patent ductus arteriosus; digital anomalies

AD(169100) TFAP2B, 6p12

Chromosome (1)(q42-qter) trisomy37

Prominent forehead, large fontanel, flat nasal bridge, micrognathia, low-set ears, facial capillary hemangioma, cardiac malformation

Partial trisomy

Chromosome del(2)(q37qter)38

Developmental delay, frontal bossing, low nasal bridge, cardiac defect, repetitive behavior

Partial deletion

Chromosome del(4)(q33qter); dup (7)(q34-qter)39

Moderate developmental delay, behavioral problems, face dysmorphia, iris colobomas, supernumerary nipples

Partial deletion/ trisomy

Chromosome dup(4)(p16.3)40

Mild to moderate developmental delay, overgrowth, abundant hair, coarse face, bushy eyebrows, synophrys, prominent supraorbital ridges, small and anteverted nose, square jaw

Partial trisomy

Chromosome del (5)(q35.3)41

Excess pre- and postnatal nuchal thickness, telecanthus, flat and low nasal bridge, short fingers, atrial septal defect, narrow chest, slow motor milestones

Partial deletion

Chromosome dup (7)(q11.23)42

Postnatal macrocephaly, developmental delay, hypertonic legs with hyperreflexia, prominent forehead, downslanting palpebrae, long philtrum, high palate, low-set ears, normal ventricles, white matter hypodensities

Partial trisomy

Chromosome inv dup(8)(p12p23)43

Mild developmental delay, mild facial signs, frontal bossing, malformed pinnae, thin upper lip, everted lower lip, high palate, coloboma, cardiac defects, scoliosis, absent corpus callosum, cerebral atrophy; 3/21 macrocephalic

Partial trisomy

Chromosome 14 maternal disomy44

Short to above-normal stature, developmental delay to normal intelligence, premature puberty in both sexes, hydrocephalus, cleft uvula, hyperextensible joints

Disomy

Chromosome del (19)(q13.2)-DiamondBlackfan45

Diamond-Blackfan red cell aplasia, hypotonia, tall and wide forehead, hypertelorism, epicanthus, macrocephaly, developmental delay

Partial deletion

Cleidocranial dysplasia46

Macrobrachycephaly, wide fontanel with delayed closure, short stature, hypo/aplasia clavicles, midface hypoplasia, persistent primary dentition, delayed dental eruption, other dental anomalies

AD (119600) RUNX2, 6p21

Cole-Hughes: macrocephaly47

Macrocephaly, variable developmental delay, square face, frontal bossing, narrow parietal region, malar underdevelopment, long philtrum

AD (153470)

Complex I deficiency48

Variety of clinical presentations include Leigh syndrome, lactic acidosis, cardiomyopathy, and macrocephaly with progressive leukodystrophy

AR (252010) NDUFU1, NDUFS1,2,4,7,8 5q11.1, heterogeneity, also mitochondrial

Cortez-Lacassie: ectodermal dysplasia49

Agenesis of distal phalanges with hypoplastic nails, abnormal thumbs, absent toenails, absent palmar creases, small lower teeth, curly hair

Unknown

Costello50

Short stature, mental retardation, loose redundant skin on hands and feet, hyperextensible fingers, nasal and perioral papillomata, thick facial features, epicanthus, ptosis; elevated risk of neoplasia; may have true postnatal macrocephaly

AD (218040) 22q13.1

Cowden hamartomas51

Macrocephaly early marker with second-decade onset, facial papules, oral papillomas, acral and palmoplantar keratosis, cutaneous fibromas, gastrointestinal polyps, thyroid anomalies, fibrocystic breast disease, significant risk for malignancies

AD (158350) PTEN, 10q22-23 (continued)

514

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cranioectodermal dysplasiaSensenbrenner52

Dolichocephaly, frontal bossing, sparse and fine hair, dental anomalies, marked brachydactyly, short narrow thorax, pectus excavatum. One case microcephalic and one macrocephalic of 14

AR (218330)

Craniofacial-conodysplasia53

Frontal bossing, flat nasal bridge, telecanthus, midface hypoplasia, prognathism, ventricular dilatation, stenosis of foramen magnum, cone-shaped epiphyses of thumb and index fingers, short proximal phalanges of thumb and middle phalanges of the 2nd and 5th fingers; resembles acrodysostosis

AD

Cronkite-Canada: infantile polyposis54

Juvenile intestinal polyps from stomach to rectum, hypotonia, hepatosplenomegaly, proteinlosing enteropathy, alopecia, nail dystrophy, clubbing

Unknown (175500) 10q22.3-q24.1 or 18q21.1?

Cutis marmoratamacrocephaly55

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous haemangiomas of the skin, and developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects

Unknown (602501)

Cutis marmoratalymphangiectasia56

Prenatal overgrowth, flat nasal bridge, high palate, four-limb postaxial polydactyly, faint cutis marmorata, thick subcutaneous tissues, lymphedema of feet, vascular ectasia of gut, linear skin pigmentation

Unknown

Der Kaloustian: radioulnar synostosis-hypotonia57

Macrodolichocephaly, developmental delay, radio-ulnar synostosis, long and narrow face, prominent nasal bridge, high palate, structural renal anomalies

AR (266255)

Desmosterolosis58

Rhizomelia, short and malformed ribs, osteosclerosis, hypoplastic nasal bridge, cleft palate, gingival nodules, ambiguous genitalia; cardiac, gut, and renal anomalies; immature gyral pattern, hypoplastic corpus callosum; elevated desmosterol

AR (602398) DHCR24, 1p33-p31.1

Dinno: pseudomarfanoid59

Dislocated lenses, hypertelorism, downslanting palpebrae, arachnodactyly, increasingly abnormal bone density, ‘‘bone-within-bone’’ appearance to metacarpals; variable signs include communicating hydrocephalus, high palate, a pectus carinatum, joint laxity, abnormal capital femoral epiphyses

AD

Encephalocraniocutaneous lipomatosis60

Developmental delay common; lipodermoids of the conjunctiva, sclera, and eyelids; lipomas of cranium or face; intracranial pathology includes cerebral atrophy, porencephalic cysts, intracranial calcification

Unknown (176920)

Facio-oculo-acoustic-renal61

Developmental delay, large fontanel, hypertelorism, severe myopia, sensorineural deafness, proteinuria, diaphragmatic hernia; part of spectrum? (see OMIM 222448)

AR (227290)

Fragile X62

Long face with prominent jaw; thick nasal bridge; ears appear large; macroorchidism; mild connective tissue dysplasia includes lax skin and joints, kyphoscoliosis, and mitral prolapse; mental retardation and hyperactivity in males with >200 repeats, and generally milder symptoms in females

XLD (309550) FMR1, Xq28

Fryer: overgrowth63

Asymmetric postnatal overgrowth, increased bone age, large and prominent ears with pointed helices, long fingers with prominent joints, severe scoliosis; single case

Unknown

Fryns: macrocephaly-unusual face-spastic paraplegia64

Broad and high forehead, deep-set eyes, short philtrum, large mouth, spastic paraplegia

AR (600302)

Fryns: mental retardationcraniofacial dysmorphism65

Moderate to severe mental retardation, coarse face, hypertelorism, high palate, dental anomalies, one case short stature (similar to Atkin syndrome)

AR? (Authors state AD)

Glutaric aciduria type 166

Acute or subacute onset of encephalopathy from 3 months to 3 years, persistent dystonicdyskinesis and later psychomotor dysfunction with cerebral atrophy; macrocephaly may predate signs; increased urine glutaric, 3-OH glutaric and glutaconic acid

AR (231670) GCDH, 19p13.2

Glutaric aciduria type 267

Macrocephaly early sign, cryptorchidism, hypospadias; most show initial normal health and development; signs can include respiratory distress, hypoketotic hypoglycaemia, sweaty-foot odor, seizures, dystonic cerebral palsy; aliphatic mono- and dicarboxylic acids, sarcosine, glycine conjugates in blood and urine; abnormal electron transfer flavoprotein (ETF) or ETFubiquinone oxidoreductase (ETF-dehydrogenase)

AR (331680) ETF-dehydrogenase 15q23-25, 19q13

Goldblat-Singer: gingival fibromatosis-distinctive face68

Normal intelligence, synophrys, full eyebrows, hypertelorism, downslanting palpebrae, small and anteverted nares, gingival hypertrophy, cupid’s bow mouth

AR (228560)

Greig cephalopolysyndactyly69

Variable postaxial hand and preaxial toe polysyndactyly, telecanthus, hypertelorism, low and wide nasal root

AD (175700) GLI3, 7p13

Halal: progressive macrocephaly-hamartomas70

Normal birth OFC, developmental delay, muscle wasting, hyperteloriam, subcutaneous angiolipomas, congenital heart defect, cutis marmorata, telangiectasias, broad thumbs and halluces. Single case; consanguinity

Unknown PTEN spectrum? (continued)

515

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Heide: osteoporosisblindness71

Osteoporosis, wormian bones, frontal bossing, brachytelephalangy, hyperextensible joints, congenital blindness, mental retardation

AR

Hemihypertrophyhemimegalencephalypolydactyly72

Hemimegalencephaly, cutis marmorata, hemihypertrophy of face and limbs, 3-4 syndactyly and post-axial polydactyly of hands, polydactyly of left foot with 2-3 toe syndactyly, widesandal gap; single case

Unknown

Hidrotic ectodermal dysplasia-natal teeth73

Thin and sparse, slow-growing hair; variable natal teeth, premature loss of secondary dentition; flexural crease acanthosis nigricans; some heat intolerance; mild nail dystrophy

AD (601345)

Hirschsprunghemimegalencephaly74

Right-sided hemimegalencephaly, Hirschsprung disease; later onset seizures, status epilepticus, left hemiparesis; single case

Unknown

Hockey: XLMR-precocious puberty75

General overgrowth, advanced bone age, muscular, early development normal but two naternal uncles later considered retarded, premature puberty, mother of the proband obese with acanthosis nigricans, and a 46,XX,del(15)(q11-13) karyotype

XLR

Hypertelorism-short limbsdeafness76

Postnatal macrocephaly with mild ventriculomegaly, persistent anterior fontanel, prominent forehead, hypertelorism, downslanting palpebrae, sparse frontal hair, relatively short limbs

Unknown

Hypochondroplasia77

Rhizomelic short stature, slightly prominent forehead, decreased elbow extension and forearm supination, radiology similar but milder than achondroplasia; heterogeneity; macrocephaly associated with FGFR3 mutations

AD (146000) FGFR3, 4p16.3

Hypomelanosis of Ito78

Extremely variable syndrome of linear and swirled hypopigmentation, occasional asymmetry, microphthalmia and eye anomalies common, CNS anomalies include migrational abnormalities or isolated macrocephaly

Some AD (146150) Some have chromosome mosaicism

Immunodeficiencycentromere instability79

Mental retardation, variable macrocephaly, hypertelorism, flat nasal bridge, epicanthus, protruding tongue, small jaw; centromeric instability chromosomes 1, 9, and 16; variable immunodeficiency including combined, hypogammaglobulinaemia and low T-lymphocytes

AR (242860) 20q11-13

Ischiospinal dysostosis-rib gaps-nephroblastomatosis80

Nephromegaly due to nephroblastomatosis, rib gaps, vertebral ossification defects, hypoplastic ischia

Uncertain

Kaler: sparse hairosteopenia81

Developmental delay, OFC at 97%, prominent forehead, blue sclerae, hypertelorism, lax joints, sparse hair, frequent fractures, osteopenia of the long bones (this is likely geroderma osteodysplastica)

AR (259690)

Keiport82

Prominent forehead, hypertelorism, large and high-bridged nose, wide terminal phalanges, deafness

Uncertain

Klinefelter83

Patient with Klinefelter syndrome, tetralogy of Fallot, megalencephaly characterized by polymicrogyria and large pyramidal neurons

47,XXY karyotype

Klippel-Trenaunay-Weber84

Various hemangiomatous lesions, may involve limbs, skin, and internal organs; random hypertrophy of body parts

Unknown (149000)

L-2 hydroxyglutaric aciduria85

Variable clinical signs from normal with later regression to early-onset infantile spasms, hypsarrhythmia, seizures, action myoclonus, choreoathetosis, mental retardation, and macrocephaly; white matter changes on MRI; L-2 hydroxyglutaric aciduria

AR (236792)

Laryngeal stenosis-shortarthropathy86

Short limbs, deep-set eyes, malar flatness, trismus, campto/brachydactyly, progressive arthropathy; one of three said to be macrocephalic but no measurements

Unknown

Laxova-basal ganglia87

Cogwheel rigidity, parkinsonian tremors, postural changes, slurred speech, shuffling gait, OFC may be large at birth, variable mental retardation, L-DOPA no benefit

XLR (311510) Xq28

LeMarec: mesomelia88

Single case with brachymesomelia, club feet, frontal bossing, flat nasal bridge, symmetric ulnar and radial hypoplasia

Unknown

Linear nevus sebaceous89

Linear nevus sebaceous, variable hemihypertrophy with or without intracranial anomalies, pachygyria (megalencephaly and hemimegalencephaly useful marker for neurologic involvement)

Unknown (163200)

Lujan: marfanoid90

Tall stature, asthenia, long and narrow face, high palate, small jaw, double row of teeth, variable mental retardation, hyperextensible joints, pectus, atrial septal defect, absent corpus callosum

XLR (309520)

Macrocephaly-bowed limbs-vertebral91

Dolichomacrocephaly, ‘‘beaten copper’’ skull, congenital bowed long bones, hypertelorism; bowing improved with age

AR (211355)

Macrocephaly-cavum septum pellucidum92

Macrobrachycephaly, developmental delay, cavum septum pellucidum and cavum vergae

Uncertain (continued)

516

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Macrocephaly-cerebral atrophy-seizures93

Progressive cerebral atrophy, abnormal white matter on MRI, hypoplastic corpus callosum, increased third and lateral ventricles

AR/XLR?

Macrocephalydisproportionate tall stature94

Mild to moderate developmental delay, tall with long thorax and straight back but relatively short limbs, moderate hypotonia, high and narrow forehead, upswept frontal hair, wide and short ears, hypotelorism, blepharochalasis

AD

Macrocephaly-facio-skeletal95

Dolichomacrocephaly, hyperextensible joints, eccentric pupils, mild to moderate developmental delay, pectus carinatum, kyphoscoliosis, blue sclera, Dandy-Walker cyst

Uncertain

Macrocephaly-spastic paraplegia96

Developmental delay, progressive spasticity, short neck, broad chest, truncal obesity, broad and high forehead, deep-set eyes, short philtrum, prominent upper central incisors, alveolar ridges, megacisterna magna

AR (600302)

Macrocephaly-tremor97

Macrocephaly, slow tremor of head, trunk, and/or limbs developing before age 5 years; other neurologic and endocrine signs common; distortion of third ventricle by space occupying lesion or aqueduct stenosis

Sporadic

Mangano: macrosomiamental retardation98

Variable developmental delay, overgrowth, large hands and feet, coarse face, thick eyebrows

AD

Mascaro: follicular hamartomas-alopecia-joint laxity99

Old facial appearance, delayed closure of fontanels, dental malocclusion, joint hypermobility, alopecia, hypohidrosis, hyperelastic skin, follicular hamartomas, hepatomegaly, growth hormone deficiency, severe left pulmonary artery hypoplasia; consanguinity

AR

Megalencephalic leukodystrophy-subcortical cysts100

Diffuse swelling of cerebral white matter, spongiform leukodystrophy, large subcortical cysts in frontal and temporal lobes; onset in infancy, slowly progressive motor deterioration, cerebellar ataxia, seizures

AR(604004) MLC1, 22qter

Megalencephaly-benign familial101

No associated anomalies, most common type of megalencephaly

AD (155530)

Megalencephaly-hamartomas

See Bannayan-Riley-Ruvalcaba

AD PTEN

Megalencephaly-mega corpus callosum102

Mental retardation, no motor development, prominent forehead, low nasal bridge, large eyes; MRI evidence of megalencephaly, a broad corpus callosum, ‘‘enlarged’’ white matter, focal increased thickness of thick gray matter, pachygyric appearance, wide Sylvian fissures

Unknown

Megalencephaly-spasticataxia103

Progressive megalencephaly and dysmyelination, spasticity, ataxia, seizures; normal intellect, senses, and cranial nerves; consanguinity

AR? (212905)

Megalocornea-macrocephalymental retardation104

Macrocephaly, mental retardation, megalocornea, large and fleshy ears, long and tapering fingers, variable obesity and scoliosis

Unknown (249310)

MOMES105

Developmental delay, maxillary hypoplasia, prognathism, blepharophimosis, ptosis, abducens palsy, dental crowding, lateral deviation of halluces, coned epiphyses of toes

AR (606772)

MOMO106

Mental retardation, prominent forehead, hypertelorism, downslanting palpebrae, broad nasal root, truncal obesity, retinal coloboma, glaucoma

Unknown (157980)

Moreno: gigantism107

Large at birth, advanced bone age, loose skin, prominent supraciliary ridges, deep-set eyes, limited joint movement (same as Weaver syndrome?)

Unknown

Muller: cerebral malformationhypertrichosis108

Hypertelorism, telecanthus, microphthalmia, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS findings in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Multiple epiphyseal dysplasia-edemamacrocephaly109

Normal stature, mild developmental delay, frontal bossing, short neck, hypertelorism, flat malar regions, flat epiphyses of long bones, mild metaphyseal flaring, mild frontal atrophy, variable lymphedema of the hands and legs

AR (607131) 15q26

Multiple pterygium-XY gonadal dysgenesis110

Cranial asymmetry, frontal bossing, small and low-set ears, micrognathia, partial finger zygodactyly, webbed neck, contractures and webbing at major joints. Single case

Unknown

Nephritis-macrocephalydeafness111

Hereditary nephritis and sensorineural hearing loss similar to Alport syndrome but with macrocephaly and mental retardation

XLR (301050) COL4A5, Xq22.3

Neuro-facio-digito-renal112

Mental retardation, high forehead, cowlick, hypertelorism, short and angulated ears, abnormal thumb, broad halluces, unilateral renal agenesis (similar to FG syndrome but without constipation and anal and joint abnormalities)(see also OMIM 222448 and 227290)

Uncertain (256690)

Neurofibromatosis113

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudarthrosis, and diverse complications of tumors. Two cases with hemimegalencephaly without hamartomas and heterotopias did well

AD (162200) neurofibromin, 17q11.2 (continued)

517

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Nokelainen: cerebral atrophyabnormal white matter114

Severe developmental delay, high forehead, small and concave nose with low bridge, tented mouth, gingival hyperplasia, downslanting palpebrae, seizures; patchy T-2–weighted periventricular increased signal intensity

XLR/AR?

Noonan115

Variable mental retardation and short stature, ptosis, downslanting palpebrae, low/abnormal ears, short/webbed neck, sternal malformation, pulmonary valve stenosis/dysplasia

AD (163950) PTPN11, 12q22

Noonanneurofibromatosis116

Noonan-like facial appearance, short/webbed neck, short stature, hypotonia and variable developmental delay in association with manifestations of neurofibromatosis; some cases shown to have neurofibromatosis mutations

AD (193520)

Optic disc druzenmegalencephaly117

Macrocephaly, pseudopapilledema due to optic disc drusen; one of four isolated cases had cleft lip and palate

Unknown

Orstavik: macrocephalyepilepsy-autism118

Developmental delay, high forehead, full eyebrows, short philtrum, epilepsy, autism; megalencephaly demonstrated at autopsy

Uncertain

Osteopathia striata-cranial sclerosis119

Macrocephaly may be presenting sign although CT may be consistent with cerebral atrophy; macrocephaly likely due to cranial sclerosis

AD/XLD? (166500)

Osteosclerotic-osteochondrodysplasia120

Lethal micromelic osteosclerotic osteochondrodysplasia with IUGR, marked platyspondyly, poor modelling and metaphyseal flaring, frontal bossing, low nasal bridge, pulmonary hypoplasia; absence of gray/white matter demarcation; hypercellular cortical and trabecular bone marrow fibrosis, dilated rough endoplasmic reticulum

AR (603393)

Overgrowth-vertebral fusion131

Normal intelligence, round face, hypertelorism, downslanting palpebrae, broad nasal bridge, maxillary hypoplasia, short philtrum, large mouth, thin lips, irregular vertebral end plates and disc spaces were most marked anteriorly, progressive vertebral fusion

Unknown

Parietal foramina-clavicular hypoplasia132

High prominent forehead, sloping parietal area and abrupt angle at occiput, mild mid-face hypoplasia, hypertelorism, lacrimal duct occlusion, short nasal septum, external ear anomalies, sloping shoulders (isolated parietal foramina with mutations of ALX4 and MSX2)

AD (168550)

Pena-Shokier without IUGR123

Hydramnios, small and immobile mouth, choanal atresia, low and angulated ears, pterygia, camptodactyly; normal CNS microscopy in one case

XLR or AR

Periventricular nodular heterotopia, bilateral124

Bilateral periventricular nodular heterotopias, usually mild phenotype with onset of frequent seizures age 4–25 years; pair of MZ twin sisters reported with BPNH, macrocephaly, and no neurologic signs

XLD (300049) filamin A FLNA, Xq28

Perlman: hamartomas125

Renal hamartomas, nephroblastomatosis, fetal gigantism, deep-set eyes, broad nasal bridge, low-set ears, everted lower lip, bifid sternum, neonatal death

AR (267000)

Pfeiffer-Hirschfelder-Rott: acromesomelia126

Ptosis, telecanthus, ureteral stenosis, acromesomelia, aplasia of distal ulna, bowed radii, dislocation of radial heads, short proximal phalanges and 2nd–5th metacarpals, modelling and fusion defects of metacarpals/metatarsals, wrists, and ankles

Unknown

Posterior fossa anomaliesleukodystrophy127

Macrosomia, developmental delay, prominent forehead, hypertelorism, flat nasal bridge, narrow palate, 4-5 clinodactyly of fingers, 2-4 toe syndactyly, central hypotonia, absent reflexes lower limbs with distal hypertonia. One sib had vermis aplasia and Dandy-Walker variant, the other a mega cisterna magna.

AR

Programmed cell death anomaly128

Normal intelligence and MRI, cutaneous syndactyly of hands and feet, stenotic auditory canals, hypoplastic lacrimal ducts, short palpebrae, small teeth, prominent jaw, mixed hearing loss

Unknown

Proteus129

Marked and asymmetric overgrowth that can lead to a range of complications; skin changes include linear verrucous epidermal nevi, intradermal nevi, shagreen patches, hemangiomas, lipomas, patchy dermal hypoplasia, characteristic hyperplastic and pebbly plantar overgrowth; frequent ocular problems. Some PTEN mutations claimed, but cases questioned.183

Uncertain (176920) 1q11-q25

PTEN-associated VATERlike-macrocephaly130

Bilateral thumb hypoplasia, 13 pairs of ribs, tracheoesophageal fistula, static ventriculomegaly; no other signs of PTEN spectrum

AD PTEN, 10q22-q23

Pyruvate carboxylase deficiency131

Typically a Leigh-like picture with onset by 6 months, vomiting and growth failure, lactic acidosis; cases with macrocephaly may represent a subset of patients

AR (266150) 11q13.4-q13.5

Richieri-Costa132

IUGR, broad nasal root, downslanting palpebrae, hypertelorism, joint restriction, hypoplastic digits, fused and missing ribs

Uncertain

Riley-Smith

See Bannayan-Riley-Ruvalcaba

AD PTEN

Robinow: fetal face133

Prominent forehead, wide mouth, small nose, hypertelorism, micropenis, variable mesomelic shortness, vertebral defects, oral clefts

AD (180700), AR (268310) ROR2, 9q22 (continued)

518

Table 15-2. Syndromes primarily with anatomic (developmental) macrocephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Ruvalcaba-Myhre-Smith

See Bannayan-Riley-Ruvalcaba

AD PTEN

Schorderet: Robinow-like134

Macrocephaly, short forearms, hypertelorism, hepatosplenomegaly; one patient with hemiand fused vertebrae and scoliosis, the other a bifid rib; male with ambiguous genitalia, had a mosaic 45,X/46,X,dic(Y)/47,X,dic(Y),dic(Y) karyotype

AR (268310)

Short and broad hallucesmacrocephaly135

Short and broad great toes, proximally placed thumbs, mild developmental delay; single case

Unknown

Simpson-Golabi-Behmel136

Macrocephaly in 1/3, postnatal overgrowth, thick lips, large mouth, dental malalignment, prominent jaw, short neck, hoarse voice, hepatosplenomegaly, cardiac anomalies, cryptorchidism, broad hands and feet, some cases of delayed development

XLR (312870) Glypican 3, Xq26

Simpson-Golabi-Behmeltype 2137

A severe form; neonates are hydropic; low-set and posteriorly rotated ears; hypertelorism; short broad nose; short neck; redundant skin; limb and skeletal anomalies; marked neurologic impairment; lethal

XLR (300209) Xp22

Sotos: Cerebral gigantism138

Early overgrowth with large hands and feet, prominent and high forehead, downslanting palpebrae, long and prominent chin, high palate, somatomedian initially high and falls during first year, variable developmental delay

AD (117550) NSD1, 5q35

Sotos-Goldstein variant139

Looks like Sotos; authors consider marked hypotonia, nystagmus, and improving development distinctive

AD

Sotos-Blackett variant140

Some Sotos-like features, variable retardation, accelerated growth, precocious puberty, may show ventricular enlargement

AD

Teebi: overgrowth141

Developmental delay, prenatal overgrowth, advanced bone age, loose skin, joint laxity, thin and hypopigmented hair, downslanting palpebrae, dental anomalies, prominent fingertip pads; consanguinity

AR (277590)

Thanatophoric dysplasia142

Micromelic; short-limbed lethal dwarfism with a few survivors beyond 1 year; achondroplasia-like face; excess skin folds; ‘‘H’’ or ‘‘U’’ appearance of vertebrae on AP view; bowing and metaphyseal flare of long bones; very short, broad, small tubular bones, brain abnormalities, megalencephaly, prominent dysmorphic temporal lobes, abnormal dentate gyrus, stenosis of foramen magnum and spinal canal, narrow spectrum of mutations

AD (187600) FGFR3, 4p16

Tollner: polydactyly-visceral anomalies143

Hypertelorism, bilateral cleft lip/palate, macroglossia, hepatosplenomegaly, accessory lobe of right lung, horseshoe kidney, complex congenital heart defect, heptadactyly of hands, preaxial polysyndactyly of feet, micropenis, hydrocephalus, ependymal cysts, polygyria, leptomeningeal fibrosis. Single case

Unknown

Toriello: macrocephalyHirshsprung144

Single case with facial asymmetry, high palate, 13 pairs of ribs, broad and short hands, short distal phalanges

Unknown

Toriello: oculo-ectodermal145

Cutis aplasia of scalp, epibulbar dermoids, patchy skin hyperpigmentation; additional findings may include keloid, preauricular tag, epicanthus, strabismus; similar to linear nevus sebaceous

Unknown

Turner: XLMRmacrocephaly146

Moderate X-linked mental retardation, macrocephaly in males and some carrier females; holoprosencephaly a possible expression of the gene in males

XLD Xp21-q21

Turnpenny-Thwaites: rhizomelic short stature147

Pre- and postnatal growth failure, rhizomelia, high forehead, frontal bossing, malar flatness, small nose, macrostomia, gingival hypertrophy, thin lips, clitoral hypoplasia; single case

Unknown

Van Benthem148

Severe retardation, dolichocephaly, high palate, chest and spinal anomalies, arachnodactyly, hypospadias, testicular agenesis in one case, respiratory infection

XLR probable

Weaver149

High broad forehead, broad nasal root, telecanthus, micrognathia, large ears, accelerated growth and bone age, hypotonia, camptodactyly prominent finger pads

AR/AD (277590) Heterogeneity, 5q35 Some with NSD1 mutations

Wiedemann: dwarfismblepharophimosis150

Primordial dwarfism, macrodolichocephaly, low-set ears, downslanting palpebrae, blepharophimosis, cryptorchidism, delayed bone age; single case

Unknown

Wiedemann: megalencephaly-mental retardation151

Two male sibs with delayed closure of fontanel, deep-set eyes, small and pointed chin, mental retardation, large penis and testes; another sib had heart defects and megalencephaly

XLD or AD

Wiedemann: tibial ray defect152

Trigonocephaly, small and downslanting palpebrae, micromelia, asymmetric lower limb anomalies, tibial hypoplasia, high-level preaxial polydactyly of the foot

Uncertain

XLMR-macrocephalymacroorchidism153

Macrocephaly variable, seizures, triangular face, blue eyes, prominent jaw, macroorchidism, monotonous speech; females may show developmental delay

XLD Xq12-q21

Zimmerman-Laband154

Variable developmental delay, coarse features, hepatosplenomegaly, hirsutism; later onset gingival fibromatosis, joint hyperlaxity, nail hypoplasia; cases with cardiomyopathy

AD (135500) 3p21.2 or 8q24.3?

519

520

Neuromuscular Systems

Fig. 15-5. Gross pathological appearance of hemimegalencephaly in a child with a large flank lymphangioma but no vascular changes in the brain. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

A patient with high-output cardiac failure due to isolated hemimegalencephaly was reported by Walters et al.168 Although usually an isolated finding, hemimegalencephaly has also been reported in association with hemihypertropy, which, when it includes the head, has a poor prognosis. The hemihypertrophy may be limited to the craniofacies.169 There is no specific information as to whether the brain pathology in patients with hemifacial hypertrophy is similar to that of isolated hemimegalencephaly. Etiology and Distribution

The true prevalence of megalencephaly is not known. Marked variations in rates reported from autopsy studies, from 1/1146 to 1/50,000, may in part be explained by the standards of normal used for comparison, as well as by the handling of the brain prior to weighing. By statistical definition, 2.5% of the population are macrocephalic. In a follow-up study of an initial cohort of 150,229 boys, Pedersson et al.158 calculated gestational week and birth weight corrected centile curves for OFC. Because OFC was reported as whole centimeters in the study, the 98th centile was defined within a 1cm zone. Of 144,273 neonates with no malformations, 732 (1/197; 0.5%) were above the 98th centile and 3,555 (1/40.6; 2.46%) were within the 98 centile zone. However, the proportion of macrocephalic individuals who have anatomic megalencephaly will vary with the population studied and with the investigations carried out. Lorber and Priestly5 studied 557 children with macro-

cephaly and considered 126 (23%) of them to be megalencephalic. Seventeen of the latter had a specific associated syndrome; the majority of the remainder appeared to have benign familial megalencephaly. Gooskens et al.6 proposed a category of megalencephaly that they called ‘‘dynamic’’ to reflect a possible etiologic basis in a transient disturbance of CSF hemodynamics. In some cases of BFM and also in a variety of syndromes there is some evidence of mild ventricular dilation or subarachnoid fluid collection.159 Indeed, at least one study suggests that increased subarachnoid spaces may be the predominant MRI finding in BFM.9 Hartel et al.184 reported male and female siblings with progressive macrocephaly and dilated Virchow-Robin spaces. Gooskens et al.7 demonstrated the concurrence of true megalencephaly with communicating hydrocephalus. The etiology of BFM, at least in cases in which there is true megalencephaly, may simply represent brains at the upper limit of the distribution curve. Current arguments in favor of mutifactorial inheritance would support this interpretation, which is not contradicted by the idea that ‘‘bigger may not be better.’’ There is no known pathologic change in the brain, and it is not clear whether the increased size reflects overproduction of cells or glial fibers, or perhaps a diminution in programmed cell death. Knowledge about the cause of the megalencephaly, and indeed of its very presence, is fragmentary for most of the syndromes listed in Table 15-2. The majority of the conditions are rare; many represent single case reports. Frequently (notably those with cerebral dysfunction), disturbed neuroanatomy, including heterotopias, polymicrogyria, and abnormal cortical lamination, may be seen. The macrocephaly in neurofibromatosis 1 appears to be due to an increase in total, including frontal, white matter.170 Generalized cortical dysplasia of the type more often seen in hemimegalencephaly was reported in two girls with megalencephaly who presented with seizures at age 3 and 4 years,171 respectively, and it has also been reported in the cutis marmorata-macrocephaly association (Table 15-2). Prendiville et al.172 showed MRI evidence of subclinical, and apparently transient, brain involvement in nine of ten infants with neonatal lupus. One child had findings, including increased subarachnoid spaces, compatible with BFM. This may have been coincidence but does raise the question as to whether some cases of benign macrocephaly might have an inflammatory cause. In a study of C57BL/6 mice with maternal exposure to human influenza virus at day 9 of pregnancy, Fatemi et al.173 showed a significant increase in brain size and decrease in ventricular size in the exposed cohort. This appeared due primarily to an increase in pyramidal and non-pyramidal cell density. As adults the offspring also exhibited abnormal behaviour, suggesting the possibility of prenatal infection as a cause for megalencephaly. Prognosis, Treatment, and Prevention

Clearly the prognosis for the child with megalencephaly is highly dependent on the underlying pathogenesis and on any associated neurodevelopmental anomalies. When history, physical examination, and selective investigations lead to a specific syndrome diagnosis, prognosis can best be estimated on the basis of previous experience with that condition. As discussed, most individuals with anatomic megalencephaly do not have an associated syndrome. De Meyer4 introduced the concept of an optimum human brain size, with the relationship of intelligence to brain size represented by an inverted ‘‘U’’, with microcephaly at one extreme and megalencephaly at the other. He referred to data from the National Institutes of Health

Brain

Collaborative Perinatal study that, although indicating a shift toward increasing intelligence with increasing OFC, showed a decline beyond a specific point. Both the nature of the groups studied and the detail of their assessment will affect population-based estimates of the prognosis of children with megalencephaly. Lorber and Priestley7 studied patients referred for assessment of macrocephaly, and 109 of 126 megalencephalic children had no syndrome diagnosis. The concept of BFM was recognized late in the study (i.e., many parents were not examined), but 49 patients had parents with confirmed macrocephaly, and six others were affected by their histories. Ninety-six of the children were considered normal, six normal but below average, and seven clearly retarded. The retarded children were characterized by having additional positive family or personal history and/or clinical findings. No mention was made of fragile X studies. These data suggest a good prognosis for BFM. However, data from studies of non-referred children with macrocephaly suggest there is an increased risk for difficulties, some of which may be subtle. In their cohort study, Petersson et al.158 found that the odds ratio for low intelligence scores was 1.32 (CI 1.1-1-38) for the 732 children with an OFC >98th centile compared with those with an OFC in the normal range. The odds ratio for mental retardation was 1.31 but did not reach significance. A multivariate analysis comparing 20 children with macrocephaly with 19 normencephalic siblings and 16 age-matched controls showed a main effect of macrocephaly on psychometric measures.174 Univariate analysis confirmed poorer performance of the macrocephalic children on a number of measures including visuomotor control and integration, motor speed, bilateral coordination, and naming fluency. Arbour et al.155 noted that the macrocephalic propositi with psychomotor impairment had larger heads and a more frequent history of birth difficulty, thus raising the concern that some of the problems may be acquired and preventable. A cohort study of boys born with macrocephaly found an odds ratio of 5.44 (CI 1.11-52.15) for the development of autism,163 an association that has already been discussed. Gherpelli et al.175 followed 17 boys and one girl with congenital macrocephaly associated with increased subarachnoid spaces to the mean age of 56 months. They found that two (11%) had significant neurodevelopmental problems, but also that the macrocephaly had resolved in 45% of cases. This association can also usefully be examined from the starting point of children selected because of a syndrome and/or developmental problem. The association of macrocephaly with autism has been discussed,157,162–164and most studies have not shown an association with the specific pattern or severity of the autism. However, Deutsch and Joseph176 noted that autistic children with macrocephaly were more likely to show a discrepancy between their non-verbal and verbal abilities. Smith177 measured the OFC in children referred as ‘‘learning disabled’’ ( < 10th centile of achievement relative to expectation) and compared them with age- and sex-matched controls. An excess of macrocephaly was found in the learning disabled group. A more detailed study of a non-referred group in the regular school resource program found a similar excess of macrocephaly, but not of minor anomalies, among the children in the resource program compared with their controls.178 Resource children with macrocephaly showed lower achievement than normocephalic resource children, and a pattern of macrocephaly and similar learning problems was noted in several of their families. During evaluation of children with developmental delay, Neri et al.179 identified a group of 42 nondysmorphic children (39 male), selected for length and/or OFC

521

above the 75%, who presented with sporadic occurrence, a high prevalence of muscular hypotonia, advanced bone age, obesity, and seizures. Nineteen had an OFC
97 centile, and neuroimaging showed no major anomalies although some had a degree of ventriculomegaly. With the exception of two affected sisters, the families were negative for mental retardation, and the parents did not show overgrowth. Although parental OFCs were not discussed, the authors suggest this may be a heterogeneous overgrowth/ macrocephaly condition associated with mild developmental delay. With respect to specific syndromes, Bale et al.,2 by comparing height corrected OFC in propositi and their affected siblings with neurofibromatosis (NF1), concluded that it was a true macrocephaly syndrome. In contrast, they surmised that macrocephaly in nevoid basal cell carcinoma syndrome was related to proband status. Moore et al.180 carried out quantitative neuroanatomical measurements on 52 propositi with NF1 and demonstrated significantly greater total brain volume, most notably of the gray matter, in NF1. Gray matter volume and size of the corpus callosum was negatively correlated with performance on academic measures. Patients with Duchenne muscular dystrophy (DMD) are at significant risk for intellectual impairment. Appleton et al.181 found relative macrocephaly among a group of 64 patients with DMD, and although 12 had absolute macrocephaly, there was no correlation between OFC or true macrocephaly and intellectual abilities. Hemimegalencephaly has been reported in association with several syndromes including NF1, tuberous sclerosis, linear sebaceous nevus, and Klippel-Trenauny-Weber and has an almost uniformly poor prognosis. However, two patients with NF1 and hemimegalencephaly, and who lacked heterotopias or hamartomas, did well.182 Treatment of children with megalencephaly is directed toward palliation of the associated complications or malformations of specific syndromes, and provision of developmental services and support as required. All megalencephalic/macrocephalic children merit a careful history, including that of the family, and physical examination. For otherwise normal children, especially with a proven family history of benign megalencephaly, neuroradiologic studies are unnecessary. However, in light of the several studies showing that these children are at increased risk for neurodevelopmental problems, attention should be paid to the potential for learning disabilities. Some children with hemimegalencephaly may benefit from multilobar cortical resections and/or hemispherectomy for the control of intractable seizures. Prevention is largely directed toward syndromic anatomic megalencephaly and known metabolic causes. Genetic counselling, selective reproductive options, and targeted ultrasound directed at the detection of specific malformations or growth patterns are available. References (Megalencephaly) 1. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 273. 2. Bale SJ, Amos CI, Parry DM, et al.: Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I. Am J Med Genet 40:206, 1991. 3. Bushby KMD, Cole T, Matthews JNS, et al.: Centiles for adult head circumference. Arch Dis Child 67:1286, 1992. 4. De Meyer W: Megalencephaly: types, clinical syndromes, and management. Pediatr Neurol 2:321, 1987. 5. Lorber J, Priestley BL: Children with large heads: a practical approach to diagnosis in 557 children, with special reference to 109 children with megalencephaly. Dev Med Child Neurol 23:494, 1981.

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Brain 154. Robertson SP, Lipp H, Bankier A: Zimmermann-Laband syndrome in an adult. Long-term follow-up of a patient with vascular and cardiac complications. Am J Med Genet 78:160, 1998. 155. Arbour LA, Watters GV, Hall JG, et al.: Multifactorial inheritance of non-syndromic macrocephaly. Clin Genet 50:57, 1996. 156. Fraser FC, Arbour LA: Association of non-syndromic macrocephaly with autism. Am J Med Genet 104:342, 2001. 157. Miles JH, Hadden LL, Takahashi TN, et al.: Head circumference is an independent clinical finding associated with autism. Am J Med Genet 95:339, 2000. 158. Petersson S, Pedersen NL, Schalling M, et al.: Primary megalencephaly at birth and low intelligence level. Neurology 53:1254, 1999. 159. Asch AI, Myers GI: Benign familial macrocephaly: report of a family and review of the literature. Pediatrics 57:535, 1976. 160. DeRosa R, Lenke RR, Kurczynski TW, et al.: In utero diagnosis of benign fetal macrocephaly. Am J Obstet Gynecol 161:690, 1989. 161. Vanderschueren WG, Demaerel PH, Smet MH, et al.: CT and MRI in infants with pericerebral collections and macrocephaly: benign enlargement of the subarachnoid spaces versus subdural collections. AJNR Am J Neuroradiol 14:855, 1993. 162. Stevenson RE, Schroer RJ, Skinner C, et al.: Autism and macrocephaly. Lancet 349:1744, 1997. 163. Bolton PF, Roobol M, Allsopp L, et al.: Association between idiopathic infantile macrocephaly and autism spectrum disorders. Lancet 358: 726, 2001. 164. Fombonne E, Roge B, Claverie J, et al.: Microcephaly and macrocephaly in autism. J Autism Dev Disord 29:113, 1999. 165. Kalifa GL, Chiron C, Sellier N, et al.: Hemimegalencephaly: MR imaging in five children. Radiology 165:29, 1987. 166. Kato M, Mizuguchi M, Sakuta R, et al.: Hypertrophy of the cerebral white matter in hemimegalencephaly. Pediatr Neurol 14:335, 1996. 167. O’Kusky JR, Akers M-A, Vinters HV: Synaptogenesis in hemimegalencephaly: the numerical density of asymmetric and symmetric synapses in the cerebral cortex. Acta Neuropathol 92:156, 1996. 168. Walters BC, Burrows PE, Musewe N, et al.: Unilateral megalencephaly associated with neonatal high output cardiac failure. Child Nerv Syst 6:123, 1990. 169. Dean ICS, Cole GF, Appleton RE, et al.: Cranial hemihypertrophy and neurodevelopmental prognosis. J Med Genet 27:160, 1990. 170. Cutting LE, Cooper KL, Koth CW, et al.: Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHA. Neurology 59:1388, 2002. 171. Marchal G, Anderman F, Tampieri D, et al.: Generalized cortical dysplasia manifested by diffusely thick cortex. Arch Neurol 46:430, 1989. 172. Prendiville JS, Cabral DA, Poskitt KJ, et al.: Central nervous system involvement in neonatal lupus erythematosus. Pediatr Dermatol 20:60, 2003. 173. Fatemi SH, Earle J, Kanodia R, et al.: Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol 22:25, 2002. 174. Sandler AD, Knudsen MW, Brown TT, et al.: Neurodevelopmental dysfunction among nonreferred children with idiopathic megalencephaly. J Pediatr 131:320, 1997. 175. Gherpelli JL, Scaramuzzi V, Manreza ML, et al.: Follow-up study of macrocephalic children with enlargement of the subarachnoid space. Arq Neuropsiquiatr 50:156, 1992. 176. Deutsch CK, Joseph RM: Breif report: Cognitive correlates of enlarged head circumference in children with autism. J Autism Dev Disord 33:209, 2003. 177. Smith RD: Abnormal head circumference in learning disabled children. Dev Med Child Neurol 23:626, 1981. 178. Smith RD, Ashley J, Hardesty RA, et al.: Macrocephaly and minor congenital anomalies in children with learning problems. Dev Behav Pediatr 5:231, 1984. 179. Neri G, Steindl K, Mazzei A, et al.: Nonsyndromal overgrowth in males with mild psychomotor delay. Am J Med Genet 79:291, 1998. 180. Moore BD 3rd, Slopis JM, Jackson EF, et al.: Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status. Neurology 54:914, 2000.

525 181. Appleton RE, Bushby K, Gardner-Medwin D, et al.: Head circumference and intellectual performance of patients with Duchenne muscular dystrophy. Dev Med Child Neurol 33:884, 1991. 182. Cusmai R, Curatolo P, Mangano S, et al.: Hemimegalencephaly and neurofibromatosis. Neuropediatrics 21:179, 1990. 183. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003. 184. Hartel C, Bachmann S, Bonnemann C, et al.: Familial megalencephaly with dilated Virchow-Robin spaces in magnetic resonance imaging: an autosomal recessive trait? Clin Dysmorphol 14:31, 2005.

15.3 Aprosencephaly/Atelencephaly Definition

Aprosencephaly/atelencephaly is the absence of all but remnants of structures derived from the prosencephalon or the telencephalon but with an intact cranial vault. Atelencephaly is considered a less severe form of aprosencephaly. In the latter, both telencephalic and diencephalic structures are involved (Fig. 15-6),1 whereas in atelencephaly, the diencephalic structures have developed but the cerebral hemispheres are either absent or represented by small remnants. The distinction is not absolute, and intermediate forms have been described.2 This author does not consider it useful, at present, to define those cases with a prosencephalic remnant as pseudo-aprosencephaly, thus reserving the term aprosencephaly for examples with no evidence of prosencephalic development.3 Diagnosis

The clinical presentation of aprosencephaly/atelencephaly is that of marked craniofacial disproportion due to extreme microcephaly, prominent supraorbital ridges, a sharply sloping forehead, and an intact cranium that may have redundant scalp folds. In aprosencephaly, there is involvement of structures derived from the diencephalon and of the facial components that are dependent on early prechordal mesoderm. Thus, the optic globes, mammillary bodies, hypothalamus, and posterior pituitary (hypophysis) are abnormal or absent, and the face is similar to the severe end of

Fig. 15-6. Sketch of aprosencephaly showing vestigial prosencephalon and normal cerebellum. A. Prosencephalon remnant. B,C. Cerebellum. (After Laurie et al.5)

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the holoprosencephaly spectrum,1,4,5 including cyclopia with no proboscis and extreme nasal hypoplasia with apparent absence of the ethmoid.4,5 The case reported by Goldsmith et al.6 is unusual in the lack of holoprosencephalic facial features.7 In atelencephaly the eyes are present, palpebral fissures are often upslanting, and there may be hyper- or hypotelorism.8,9 The nose is essentially normal in appearance. An exception was the patient with atelencephaly and a holoprosencephalic face described by Young et al.10 from among a series of patients with sirenomelia. Brain weights of near-term infants have ranged from 8 to 105 g. Those who survive the newborn period may have a highpitched cry, tetraparesis, vomiting, primitive reflexes, and disturbed temperature regulation.4,9 Anterior chamber dysgenesis was reported in one long surviving infant.4 The EEG may not show activity at usual amplification and consists of low-voltage thetadelta activity. Seizures, presumably originating in disorganized diencephalic remnants, have been recorded.11 It may be difficult to confirm the diagnosis with postnatal ultrasound because of a closed fontanel and the short intracranial distances. Prenatal diagnosis of atelencephaly by ultrasound is possible, and it can be distinguished from other causes of abnormal head shape and extreme microcephaly.12–14 Neuroimaging readily demonstrates the absence of cerebral structures, and autopsy can provide confirmation of the specific pathology. In atelencephaly the diencephalon is normal, with a nubbin of tissue representing more cephalad structures, whereas in aprosencephaly there is either no evidence of the prosencephalon3 or a vestigial prosencephalic remnant. The more caudad structures including the cerebellum are usually reported as normal except for some variation in size and shape and the absence of the pyramidal tracts.8,9 However, Harris et al.2 made the interesting observation in their first patient that the cerebellum, which had appeared grossly normal, was histologically virtually unrecognizable and consisted mainly of white matter. Thus, cerebellar anomalies may be more common than previously thought. The two siblings reported by Florell et al.14 both had a grossly abnormal cerebellum and may represent a specific autosomal recessive syndrome. Sergi and Schmitt3 described two cases. In one they found evidence of what they interpreted as a remnant of a collapsed forebrain vesicle, while in the second there was no evidence that the prosencephalon had ever developed, the cerebellum was absent, and there were associated gut anomalies. They argued that the

former case represents an intermediate between aprosencephaly/ atelencephaly and holoprosencephaly, to be called pseudo-aprosencephaly or vesicular forebrain, and that the second example is true aprosencephaly/atelencephaly. Certainly it is important that these types of pathological details are recorded. However, at present there does not appear to be any difference in the types of malformations associated with cases with and without a forebrain remnant, and there does not appear to be any great advantage to further complicating the nomenclature. Atelencephaly and aprosencephaly (inclusive of associated craniofacial signs) may occur in isolation or may be associated with other anomalies. Ippel et al.7 provided a tabular summary of the anomalies and malformations associated with 20 cases of aprosencephaly/atelencephaly from the literature and added one case of their own. If one discounts findings, such as adrenal hypoplasia, which may simply be secondary to the underlying brain pathology, then the types of malformations are similar for the two conditions. A possible exception is congenital heart disease that was noted in four of 11 cases of aprosencephaly but was not reported among the 10 cases of atelencephaly. The concurrence of aprosencephaly and atelencephaly with genital, gut, cardiac, and distal limb malformations has been called the XK-aprosencephaly/ atelencephaly syndrome (Table 15-3). In some cases, associated genital hypoplasia may simply be secondary to the CNS disturbance, particularly of the hypothalamic/pituitary region. In one retrospective study of children with ambiguous genitalia, a significant proportion of males were found to have associated CNS disturbance or malformations.15 Two reports of the XK-aprosencephaly syndrome yet again raise the debate over syndrome nomenclature and ‘‘lumping’’ versus ‘‘splitting.’’ Laurie et al.16 reported a term infant with hypoplastic genitalia and thumbs who had a mildly holoprosencephalic face, normal-sized hydranencephalic cranial cavity, and significant cerebellar pathology. Townes et al.17 described male twins with anencephaly and a female sibling with severe alobar holoprosencephaly. The child with holoprosencephaly was macrocephalic, lacked thumbs, and had three syndactylous digits on both hands. In neither of these reports was the brain malformation that of aprosencephaly or atelencephaly (both are included in the table of Ippel et al.7), but the cases may well represent part of the spectrum of this causally unknown syndrome. Further support for a causal overlap between atelencephaly and holoprosencephaly is provided

Table 15-3. Syndromes with aprosencephaly/atelencephaly Syndrome

Prominent Features

Causation Gene/Locus

Aprosencephalycerebellar dysgenesis14

Absent telencephalon and pyramidal tracts, rudimentary diencephalic and mesencephalic structures, primitive cerebellar hemispheres, evidence of abnormal neuronal migration, retinal dysplasia, normal optic globes, CNS perivascular mesenchymal proliferation; consanguinity

AR?

Holoprosencephaly-fetal hypokinesia18

Extreme IUGR and microcephaly by 2nd trimester, sloped forehead, micrognathia, short neck, flexed elbows, thumbs, hips; extended fingers, knees; lung hypoplasia, severe brain disorganization may include cerebellum, brain stem, and cellular architecture; one case may have had aprosencephaly

XLR

XK-aprosencephaly/ atelencephaly7

Absence deformities of upper limbs ranging from hypoplastic thumbs to absent radial ray; male genitalia hypoplastic to cloacal anogenital opening, imperforate anus, VSD, hypoplastic adrenals, diaphragmatic hernia.

Unknown, one case with r(13)6

Chromosome del(13)(q22;q31)26

One case with atelencephaly; various CNS anomalies including holoprosencephaly, cystic 4th ventricle, agenesis of caudal vermis; coloboma iris/microphthalmus

deletion

Brain

by their occurrence in two cases associated with deletions of 13q (Table 15-3). Molecular confirmation of this overlap comes from the report of a sibship with holoprosencephaly-aprosencephaly/ atelencephaly and a SIX3 gene mutation.28 Hockey et al.18 reported a sex-linked recessive syndrome of fetal hypokinesia, joint contractures, extreme microcephaly, and holoprosencephaly. The brain of one patient was described as lacking the anterior telencephalon, the prosencephalon, and the diencephalon, a condition verging on anencephaly. Labrune et al.19 considered the third of six cases they described with brain and limb defects to have the XK-aprosencephaly syndrome. The brief description described the CNS as resembling a primitive neural tube, with essentially an absent hindbrain and only a few lamellar-like cerebellar structures, again supporting the concept of a spectrum of maldevelopment. In contrast, Siebert et al.20 undertook a careful comparison of the craniofacial features of atelencephaly, anencephaly, and holoprosencephaly and concluded that they probably involved different developmental fields, perhaps related in a hierarchical fashion. They did not have a case of holoprosencephalic facies-atelencephaly for study. A case of syndromic aprosencephaly with cerebellar hypoplasia, a Rathke’s cleft cyst, and an ependymal and pigmented epithelial cyst has been reported.21 It was speculated that the ependymal cyst might be the equivalent of the dorsal cyst of holoprosencephaly. Etiology and Distribution

There has not been any attempt to determine the prevalence of aprosencephaly/atelencephaly. There have been an additional seven cases reported3,19,22–25 since the summary by Ippel et al.,7 for a total of 25, if one excludes the patients of Laurie et al.,16 Townes et al.,17 and Labrune et al.19 It is likely that not all cases are recognized and that some are mislabeled as anencephaly or microcephaly. In the series of 41 patients with prosencephalic malformations studied by Sergi and Schmitt,3 there were 36 that seem to clearly fit the holoprosencephaly spectrum, and two had aprosencephaly/atelencephaly. If holoproencephaly occurs at a rate of about 3/10,000 (see Section 15.4), then an estimate of the prevalence of aprosencephaly/atelencephaly would be 1/60,000. The embryologic origin of aprosencephaly must date from after closure of the neural plate and before division of the prosencephalon into the diencephalon and the telencephalon in the fifth week. Atelencephaly postdates this separation and thus does not involve the eyes and other diencephalic structures. Altered cranial morphology is considered secondary to the underlying brain abnormality. Pathologic studies in a 21-week-old fetus showed rounded, primitive, germinal matrix-like cells that formed rosettes and some heterotopias.12 At term the pathological findings in the prosencephalic remnants have varied. In some there have been the occasional neuron, calcospherites, and gliomesenchymal scar tissue suggestive of a destructive process of unknown etiology.8,9,21 In other cases,3,24 the findings are compatible with arrested development. Harris et al.2 described a proliferative vasculopathy in one of their cases and suggested that this could be a causative, rather than a secondary phenomenon. Most cases have been sporadic, but the presence of concurrent severe cerebellar dysplasia requires that autosomal recessive inheritance be considered. The association of two cases with deletions of 13q suggests deficiency of one or more genes in this region may result in these malformations,6,26 and there is the recent report of a causative, maternally inherited, SIX3 mutation.28 Holoprosencephaly is associated with maternal diabetes, and the fact that the mother of the patient reported by Kajantie et al.25 was a long-standing insulin-dependent diabetic raises the possibility that this illness may also be etiologic in aprosencephaly. Two further

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mothers were exposed to first-trimester radiation, and two had prior induced abortions. Sulik et al.27 provide evidence of straindependent production of holoprosencephaly/aprosencephaly anomalies in presomite mouse embryos exposed to low-dose all-trans retinoic acid, although the conclusions were based upon craniofacial appearance and brain studies were not provided. Prognosis, Treatment, and Prevention

Stillbirth or immediate postnatal death is common, but survival to age 14 months has occurred twice.4,9 Surviving infants make no significant developmental progress and may have temperature instability, seizures, a high-pitched cry, spasticity, and continuation of primitive reflexes. No treatment beyond that required for comfort is indicated. The abnormality may be detected during routine or targeted ultrasound.12–14 Good quality chromosome studies are warranted, especially in the presence of associated malformations. Given evidence for the involvement of 13q it would be of interest to look for disruption and/or deletion of ZIC2 in any subsequent cases. No direct preventive measure is known. References (Aprosencephaly/Atelencephaly) 1. Martin RS, Carey JG: A review and case report of aprosencephaly and the aprosencephaly syndrome. Am J Med Genet 11:369, 1982. 2. Harris CP, Townsend JJ, Norman MG, et al.: Atelencephalic aprosencephaly. J Child Neurol 9:412, 1994. 3. Sergi C, Schmitt HP: The vesicular forebrain (pseudo-aprosencephaly): a missing link in the teratogenic spectrum of the defective brain anlage and its discrimination from aprosencephaly. Acta Neuropathol 99:277, 2000. 4. Adkins WN, Kaveggia EG: Sporadic case of apparent aprosencephaly. Am J Med Genet 3:311, 1979. 5. Laurie IW, Nedzved MK, Lazjuk GI, et al.: Aprosencephaly-atelencephaly and the aprosencephaly (XK) syndrome. Am J Med Genet 3:303, 1979. 6. Goldsmith CL, Tawagi GF, Carpenter BF, et al.: Mosaic r(13) in an infant with aprosencephaly. Am J Med Genet 47:531, 1993. 7. Ippel PF, Breslau-Sideruius EJ, Hack WWM, et al.: Atelencephalic microcephaly: a case report and review of the literature. Eur J Pediatr 157:493, 1998. 8. Garcia CA, Duncan C: Atelencephalic microcephaly. Dev Med Child Neurol 19:227, 1977. 9. Iivanainen M, Haltia M, Lydecken K: Atelencephaly. Dev Med Child Neurol 19:663, 1977. 10. Young ID, O’Reilly KM, Kandall CH: Etiological heterogeneity in sirenomelia. Pediatr Pathol 5:31, 1986. 11. Danner R, Shewman DA, Sherman MP: Seizures in an atelencephalic infant. Arch Neurol 42:1014, 1985. 12. Siebert JR, Warkany J, Lemire RJ: Atelencephalic microcephaly in a 21 week human fetus. Teratology 34:9, 1986. 13. Tick DB, Greenberg F, Reiter A, et al.: Prenatal detection of telencephalic hypoplasia. Proc Greenwood Genet Center 9:127, 1990. 14. Florell SR, Townsend JJ, Klatt EC, et al.: Aprosencephaly and cerebellar dysgenesis in sibs. Am J Med Genet 63:542, 1996. 15. Hunter AGW: Diagnosis in persons referred for cytogenetic studies because of abnormalities of the external genitalia. Proc Greenwood Genet Center 7:136, 1988. 16. Laurie IW, Nedzved MK, Lazjuk GI, et al.: The XK-aprosencephaly syndrome. Am J Med Genet 7:231, 1980. 17. Townes PL, Reuter K, Rosquete EE, et al.: XK aprosencephaly in sibs. Am J Med Genet 29:523, 1988. 18. Hockey A, Crowhurst J, Cullitz G: Microcephaly, holoprosencephaly, hypokinesia-second report of a new syndrome. Prenat Diagn 8:683, 1988. 19. Labrune P, Trioche P, Fallet-Bianco C, et al.: Severe brain and limb defects with possible autosomal recessive inheritance: a series of six cases and review of the literature. Am J Med Genet 73:144, 1997. 20. Siebert JR, Kokich VG, Warkany J, et al.: Atelencephalic microcephaly: craniofacial anatomy and morphologic comparisons with holoprosencephaly and anencephaly. Teratology 36:279, 1987.

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21. Kim TS, Cho S, Dickson DW: Aprosencephaly: review of the literature and report of a case with cerebellar hypoplasia, pigmented epithelial cyst and Rathke’s cleft cyst. Acta Neuropathol 79:424, 1990. 22. al-Gazali LI, Bakalinova D, Bakir M, et al.: XK-aprosencephaly. Clin Dysmorphol 7:143, 1998. 23. Oostra RJ, Baljet B, Verbeeten BW, et al.: Congenital anomalies in the teratological collection of Museum Vrolik in Amsterdam, The Netherlands. III: primary field defects, sequences, and other complex anomalies. Am J Med Genet 80:46, 1998. 24. Kakita A, Hayashi S, Arakawa M, et al.: Aprosencephaly: histopathological features of the rudimentary forebrain and retina. Acta Neuropathol 102:110, 2001. 25. Kanjantie E, Ammala P, Salonen R: A fetus suggesting an extension of the XK-aprosencephaly spectrum phenotype. Clin Dysmorphol 11:299, 2002. 26. Towfighi J, Ladda RL, Sharkey FE: Purkinje cell inclusions and ‘‘atelencephaly’’ in 13q- chromosomal syndrome. Arch Pathol Lab Med 111:146, 1987. 27. Sulik KK, Dehart DB, Rogers JM, et al.: Teratogenicity of low doses of alltrans retinoic acid in presomite mouse embryos. Teratology 51:398, 1995. 28. Pasquier L, Dubourg C, Gonzales M, et al.: First occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation and phenotype/genotype correlation in our series of SIX3 mutations. J Med Genet 42:e4, 2005

15.4 Holoprosencephaly Definition

Holoprosencephaly is a spectrum of malformations of the midline of the prosencephalon that relates to varying degrees of failure of its sagittal division into the cerebral hemispheres, transverse cleavage into diencephalon and telencephalon, and the horizontal budding of the olfactory bulbs and tracts. Arhinencephaly was the term first used to describe these disorders, but it has largely been abandoned as too specific in its reference to the olfactory system and inaccurate in that the greater part of the rhinencephalon remains intact. The terms holotelencephaly1 and telencephalosynapsy 2 have been advocated, but holoprosencephaly (HPE), coined by DeMyer and Zeman,3 is generally accepted today, notwithstanding the protest that holo is inappropriate because it means ‘‘complete, entire, or perfect.’’4 Arhinencephaly connotes specific absence of the olfactory nerves, tracts, and tubercles, and it may occur as part of the HPE spectrum or as an isolated malformation. Likewise, commissural and septal defects are natural consequences of HPE but also occur on their own and in association with different syndromes and malformations unrelated to HPE. Although classic HPE shows a continuum of severity, discrete categorization into alobar, semilobar, and lobar types is helpful for diagnostic and descriptive purposes, and these terms are in wide use today. The alobar variety may be further classified into pancake, cup, or ball, depending on the degree of development of the forebrain upward to cover the dorsal surface of the holoventricle. In the interhemispheric variant of HPE (syntelencephaly), the basal forebrain, anterior frontal lobes, and occipital regions are normally separated, but there is an abnormal cerebral hemispheric fusion of the posterior frontal and parietal regions, and the Sylvian fissure connects across the midline in most cases.5 Leech and Shuman6 recognized a malformation in which there is a T-shaped telodiencephalic ventricle, agenesis of the septum pellucidum and corpus callosum and, with the exception of the hypothalamic plate, good preservation of diencephalic structures. They proposed that this holotelencephaly resulted from abnormal telencephalic rather than prosencephalic development.

It has been suggested that a classification that considers the degree of separation of the deep gray nuclei and associated CNS anomalies may provide an improved correlation with clinical outcome,7 and it is anticipated that the descriptive anatomical classification of HPE will be supplanted once the molecular basis of HPE is fully understood.8,9 Diagnosis

Holoprosencephaly is thought to occur because of defective induction of the rostral neural tube by the prechordal mesoderm and mesio-basal forebrain or as a result of excessive cell death in this region.10,11 The forebrain hypoplasia that leads to HPE is mirrored in a continuum of midline facial anomalies ranging from cyclopia without a proboscis to a small forehead with hypotelorism (Figs. 15-7 and 15-8). Kjaer and Fischer Hansen12 demonstrated that all HPE-associated craniofacial malformations were related to a triangle bounded posteriorly by the sella tursica and antero-laterally by the orbits. The severity of the facial malformations correlated with the severity of the underlying skeletal changes. The correlation of facial anomalies with HPE is not absolute but, unlike cases involving any other intracranial malformation, the majority of cases of HPE can be diagnosed by physical examination. An understanding of the facial spectrum is therefore paramount.13,14 Cyclopia is the most severe malformation and consists of a single midline orbit that can be anophthalmic, monophthalmic, or contain synophthalmic ocular structures (see Fig. 15-8A). A proboscis, representing remnants of nasal structures, is usually present and situated above the orbit. Ethmocephaly is the least common facial subtype and consists of a proboscis separating severely hypoteloric orbits, usually with marked microphthalmia (Fig. 15-9). Both ethmocephaly and cyclopia display trigonocephaly and predict alobar HPE. In cebocephaly a small, flattened nose with a single nostril is situated below hypoplastic, hypoteloric orbits (see Fig. 15-8C). Less severe in the spectrum (see Fig. 15-8D) is median cleft lip, called by some premaxillary agenesis. In fact, even in the more severe forms, in which there is no median cleft because the midface hypoplasia allows midline fusion of the maxillary processes, the lateral maxillary incisors may be present, suggesting that the lateral nasal processes participate in the midline fusion.15 In this condition the nose is small and flat, and there is hypotelorism and often trigonocephaly.

Fig. 15-7. Spectrum of facial anomalies in holoprosencephaly.

Brain

529

Fig. 15-8. A. Cyclopia with unitary ocular structure in a newborn infant. Note absence of all nasal structures. (Courtesy of Dr. C.I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.) B. Cyclopia with synophthalmia of the ocular structures and proboscis. (Courtesy of Dr. C.I. Scott, Jr., A.I. duPont Institute, Wilmington, DE.) C. Typical

facial appearance of cebocephaly. D. Eighteen-month-old male infant with holoprosencephaly. Facial features include hypotelorism, upslanted palpebral fissures, and premaxillary agenesis. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Both cebocephaly and median cleft lip are usually associated with alobar HPE, but milder brain involvement is also seen. There are exceptions to the strong correlation between these severe (cyclopia-cebocephaly) facial anomalies and the presence of HPE. Cohen6 used the data of Roach et al.16 to state that severe HPE is associated with a diagnostic face 80% of the time. There may have been ascertainment bias in these data due to the

presence of facial anomalies, which could lead to a correlation that is somewhat higher than might occur if all cases of HPE could be ascertained. The converse, cases with craniofacial signs suggestive of HPE but with normal brains or different brain anomalies, have also been reported.7,17–19 This variability likely results from differences in the timing and/or specificity in the timing of the embryologic disturbance. For example, the three siblings with

530

Neuromuscular Systems

Fig. 15-9. Facial photograph of an infant showing the unusual combination of ethmocephaly and agnathia.

a normal facial appearance and alobar holoprosencephaly reported by Barr and Cohen20 suggest a gene acting on the prosencephalon, but either sparing the origin of the frontonasal and mesencephalic neural crest cells or acting after their separation. Several minor craniofacial anomalies may be seen alone or in combination with HPE, and although the strength of the association with HPE is less, they may still serve as important markers in family studies or to direct investigations in a child with developmental delay. Premaxillary agenesis (PMA) was discussed as part of the HPE craniofacial spectrum, but this anomaly is well described in otherwise normal, or developmentally delayed, individuals without HPE. Cohen21 has stressed that, in the absence of HPE, patients with PMA have a normal OFC and intraocular distances. The association of a single maxillary central incisor (SCMI) with HPE has received particular attention because it can occur as a form fruste of HPE in families with autosomal dominant HPE.22 SCMI is a common finding in association with congenital nasal pyriform aperture stenosis (CNPAS), which is itself often seen in HPE. SCMI and CNPAS may occur alone or together in otherwise normal individuals, although there is a strong correlation with their presence and short stature, and functional and structural pituitary anomalies.23 Of 51 cases of SMCI and/or CNPAS reviewed by Lo et al.,23 only one patient had documented HPE, although four other families (six cases) had a positive family

history of HPE. The finding of a missense mutation in sonic hedgehog (SHH), which has not been reported in full-blown HPE, raises the possibility that certain mutations may mildly disrupt this pathway and thus represent a mild expression of HPE. Kjaer et al.24 studied the palatal structure in 11, mostly alobar, fetuses with HPE who had facial signs ranging from cyclopia to mild philtral (short) anomalies. The premaxilla, including the primary portion of the hard palate, was abnormal in all cases. Although a study of brains of children ascertained through the palatal anomalies has yet to be reported, this may prove to be a useful craniofacial marker of HPE. Martin and Jones25 found that the superior labial frenulum was absent in 88% (15/17) of cases distributed across the HPE craniofacial-brain spectrum. Presence of the frenulum was associated with presence of the philtral pillars; when present in HPE, the frenulum may be abnormally thick. There are no data as to the occurrence of this anomaly in the general population or in other CNS anomalies. Other less severe facial abnormalities that may accompany HPE but are not pathognomonic include trigonocephaly, small forehead and microcephaly, hypotelorism, small and flat nose, and unilateral cleft lip.26 Hypertelorism is often mentioned as accompanying HPE, but Fitz27 states that mention of hypertelorism as being associated with HPE is based on a statement by DeMyer and Zeman3 that it might occur and that he was unaware of any actual reports. However, Jellinger et al.,28 from a retrospective review of autopsies, reported that two of eight cases of semilobar and one of nine of lobar HPE were hyperteloric. No measurements or photographs were provided, and, in the absence of some secondary phenomenon like hydrocephalus, it is difficult to account for hypertelorism with any of the current embryologic theories of HPE. One patient with HPE and hypertelorism had facial involvement with the amniotic band syndrome, which may have led to the hypertelorism.29 Some of the syndromic HPEs listed in Table 15-4 may include hypertelorism. Fitz27 has said that, in the absence of the typical facial appearance of HPE, patients with HPE and trigonocephaly do not have a closed, sclerotic, metopic suture as is seen in primary craniosynostosis. He therefore recommended against investigating otherwise normal-appearing children with craniosynostotic trigonocephaly to rule out HPE. Ben-Hur et al.18 reported relatives of patients with HPE who had midline cleft and bifid uvula. However, until relatives who have only bifid uvula are reported with recurrence of HPE, it remains speculative as to whether relatives of patients with HPE, who themselves have bifid uvula, are at risk to bear children with HPE. Hypotelorism, anosmia, and endocrine dysgenesis have also been reported in relatives of patients with HPE. Hypognathia/agnathia is a rare malformation that can occur by itself, but has some propensity to be associated with HPE and midline visceral anomalies.13 Most patients with HPE do not have agnathia, and there is no apparent correlation between the severity of the mandibular underdevelopment and that of the brain. However, the appearance of the upper midface retains its predictive value with respect to the prosencephalon. Cyclopia without a proboscis is the most common form of HPE that accompanies agnathia.13 The patient illustrated in Figure 15-9 is, thus, unusual in that he illustrates ethmocephaly, the least common form of HPE face, in association with agnathia. In the absence of clinical hypognathia, Mieden15 found abnormalities of muscle anatomy in the areas derived from the first and second branchial arches in cases of HPE, supporting the view that the overall spectrum of facial anomalies reflects the severity and

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly Syndrome

Prominent Features

Causation Gene/Locus

Acalvaria-HPE-facial dysmorphism48

Absent frontal, parietal, squamous, temporal, and occipital bones above cranial fossa; short neck; hypertelorism; downslanting palpebrae; mild proptosis; oblique lateral facial cleft; abnormal auricles; no cephalic dysraphism

Unknown

Agnathia-tetrameliaholoprosencephaly49

Severe micro/tetramelia, cardiovascular anomalies, imperforate anus, cystic dysplastic kidney. Single case

Unknown (202650)

Aicardi50

Varied CNS pathology, typically agenesis of corpus callosum and heterotopias; hemivertebrae; pathognomonic chorioretinal lacunae; bilateral asynchronous hypsarrhythmia

XLD male lethal (304050) Xp22

Aqueductal-stenosis51

Single patient with cebocephaly and aqueductal stenosis; two maternal half-sibs with hydrocephalus. Chance concurrence, occasional manifestation of gene, or different gene/allele?

XLR (307000?) L1CAM?, Xq28?

Beemer-Langer: short ribbed polydactyly52

Lethal short rib dwarfism; hydrops, flat face, epicanthus, midline cleft lip, stenotic ear canals, short neck, nuchal edema, omphalocele, small penis, fused labioscrotal folds, minimal bowing femora and marked of radius and ulna; case reported with holoprosencephaly and Dandy-Walker cyst

AR (269860) 17q21?, 17q23?

Brachial amelia-cleft lip/ palate53

Large for gestational age, marked macrocephaly, right coloboma, small fixed left pupil, bilateral cleft lip, hydrocephalus, absent basal ganglia, ‘‘fused’’ cerebral hemispheres; single case

Unknown

Brancho-oto-facial-CNS54

Bilateral cleft fistulae, holoprosencephaly, encephalocele, microphthalmia, heart defect, facial anomalies; single case

Unknown

BRESHECK55

Microhydrocephaly with fused thalami, growth failure, mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR or XLR

Camptodactyly-whistling face56

Severe developmental delay, polyhydramnios, hypotonia, cleft palate (4/8), whistling face (8/8), early lethal, microscopic brain and muscle calcification, camptodactyly; case with holoprosencephaly and vermis hypoplasia

AR

Caudal regressionholoprosencephaly57

A heterogeneous spectrum of imperforate anus, sacral agenesis, sirenomelia reported associated with holoprosencephaly; see also Maternal diabetes

Chromosomal (63%), sporadic

Cerebro-oculo-nasal58

Macrobrachycephaly, craniosynostosis, low-set ears, anophthalmia, midline nasal groove, nasal skin appendages, single maxillary central incisor, agenesis of the corpus callosum, hydrocephalus, frontal encephalocele, evidence of holoprosencephaly weak

Unknown

CHARGE59

Choanal atresia, congenital heart defects, growth failure, mental retardation, hypoplastic genitalia, deafness, external ear anomalies; over half with CNS anomalies including holoprosencephaly/arhinencephaly, absent corpus callosum, septal agenesis, migrational defects

AD (214800), CHD7, 8q12.1

Chromosome abnormality60–63

Trisomy 13, 18, 20, 21, 22 X; mosaic trisomy 8, 15; duplication 3p, 6q, 11q, 14(pterq24), 22q; deletion (1)(q42/q43-qter), 2p21, (7)(pter-q32), 5q, 7(q34-qter); 11q, 13q, 14q, 18p, 21(q22.3), (22)(pter-q11), X(p11) mosaic; dup 5q del 5p; dup 5q, 9p, 11q, 13q; unbalanced t(6;18); iso 18p; ring 6, 21; triploidy. Phenotype variable depending on the chromosome imbalance.

Chromosome imbalance

Diabetes insipidus-colobomaholoprosencephaly64

Alobar holoprosencephaly, pituitary present, diabetes insipidus of unknown cause, unilateral coloboma; single case

Unknown

Ectopia cordis-embryonal neoplasms61

Complex cardiac anomalies, neuroblastoma, germ cell tumor of the ovary, cleft lip (alobar HPE)

Unknown

Familial isolated14,65

‘‘Non-syndromic’’ HPE with spectrum from normal facies to cyclopia, variation may be marked within families; lateral cleft lip suggested as microform in one kindred

AR (236100) HPE1, 21q22.3 HPE2 SIX3, 2p21 HPE3 SHH, 7q26 HPE4 TGIF, 18p HPE5 ZIC2, 13q32 HPE6, 2q37 HPE7 PTCH, 9q22.3 GLI2, 2q14 TDGF1, 3p23-p21 FAST1, 8q24.3

Holoprosencephaly þ/ Arhinencephaly

(continued)

531

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Microcephaly, narrow palpebrae, smooth philtrum, thin upper lip; CNS anomalies include agenesis of the corpus callosum, cavum septum pellucidum, ventriculomegaly, hypoplasia of inferior olivary eminences, small brain stem, migrational abnormalities; holoprosencephaly an occasional finding with severe abuse Unproven association; 35-week-old infant with malformed ears, microphthalmia, diaphragmatic hernia, costo-vertebral, and severe brain malformations. Immunohistochemical evidence of influenza virus antigens in the brain

In utero exposure

Genoa: holoprosencephalycraniosynostosis68

Semilobar holoprosencephaly, craniosynostosis, facial asymmetry, hypotelorism, upslanting palpebrae, nonspecific retinal pigmentation, hypoplastic terminal phalanges, cone-shaped epiphyses, slender long bones, slightly small vertebral bodies

AR? (601370)

Grote: octodactyly-cardiac anomalies69

Microphthalmia, downslanting palpebrae, median facial agenesis, microstomia, low-set and posteriorly rotated ears, tetramelic octodactyly, absent tibia, complex cardiovascular anomaly, renal hypoplasia, gut malrotation

AR? Consanguinity

Hartsfield: ectrodactyly-cleft face70

Proportional IUGR, abnormal hair pattern, cranial asymmetry, closed metopic and coronal sutures, supraorbital skull defects, hypertelorism, microphthalmia, low rotated ears, asymmetric digital absence in hands and feet (lobar HPE)

Unknown

Holoprosencephaly-DandyWalker71

Several case reports of holoprosencephaly and concurrent Dandy-Walker cyst; two in association with interstitial del 13q

Unknown, del 13q

Holoprosencephaly-endocrine dysgenesis72

Premaxillary agenesis, micropenis, absence of pituitary tissue, variable adrenal hypoplasia, hypoinsulinism; one sib with posterior ventricular cyst; may be an underdiagnosed association

AR (236100)

Holoprosencephaly-fetal hypokinesia73

Extreme IUGR and microcephaly by second trimester, sloped forehead; micrognathia; short neck; flexed elbows, thumbs, hips; extended fingers, knees; severe brain disorganization may include cerebellum, brain stem, and cellular architecture. One case with possible aprosencephaly

XLR (306990)

Holoprosencephalyhypothalamic hamartoma74

Probably heterogeneous and overlapping Pallister-Hall; hypothalamic hamartoblastoma, frontonasal dysplasia, nasal probosci, microphthalmia, megalocornea, corneal clouding, cleft palate, cardiac anomalies, absent cribriform plate, agenesis of corpus callosum, arhinencephaly to lobar holoprosencephaly

Unknown

Holoprosencephaly-NTDnerve palsy-deafness75

Three sibs, one with cyclopia, one with meningomyelocele, one hypoteloric with deafness, branchial tag, and abducens palsy. Others have reported these types of findings in relatives.

AR?

Holoprosencephaly-transverse limb defect76

Flat nasal bridge, bifid nasal tip, prominent philtral pillars, high and narrow palate, nuchal thickening, four limb terminal transverse defects, small penis, alobar holoprosencephaly, heterotopic neurons; similar to brachial amelia syndrome

Unknown

Hydantoin, prenatal77

Mild developmental delay, short nose with broad base, telecanthus, ptosis, short neck, wide mouth, developmental delay, distal digital hypoplasia. One case with holoprosencephaly may be chance concurrence.

In utero exposure

Lambotte: microcephaly-facial anomalies78

IUGR; lethal; telecanthus/hypertelorism, large pinnae, hooked nose, narrow mouth, severe mental retardation; variable anterior chamber and cardiac anomalies and polydactyly; cryptic t(2;4)(q37.1;p16.2)

Partial trisomy 2q, monosomy 4p

Lip synechia-imperforate anus79

Lobar HPE in a patient with soft tissue bands between upper and lower lips, absent external ears, cleft palate, camptodactyly of second finger, diastematomyelia, tricuspic atresia

Unknown

Majewski variant chondrodysplasia80

Micromelic lethal dwarfism, tibias especially short, narrow chest with short and horizontal ribs, flat vertebrae, hypoplastic pelvis, pre- and postaxial polydactyly hands, hexadactyly feet, short rounded long bones, visceral anomalies. Single case with cebocephaly.

AR (263520)

Martin: midline clefting skeletal anomalies81

Mental retardation, microcephaly, hypotelorism, downslanting palpebrae, high cleft palate, cleft lip, partial/complete premaxilla agenesis; nose variably flat and deviated, large or small; talipes equinovarus; vertebral fusions; scoliosis; sacral agenesis (variable with incomplete penetrance)

AD (157170) Considered to be HPE2 SIX3, 2p21

Maternal diabetes82

Higher rate of NTDs, cardiac defects (specifically transposition), sacral agenesis, proximal focal femoral deficiency; HPE a rare complication

In utero exposure

Maternal phenylketonuria83

IUGR, microcephaly, developmental delay, seizures, epicanthus, long and poorly modelled philtrum, anteverted nares, heart malformation

Poor control of maternal PKU

66

Fetal alcohol

Fetal influenza66

In utero infection

(continued)

532

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Spectrum of CNS anomalies; occipital encephalocele, HPE, hypoplastic cerebellum, micro/polygyria; microphthalmia, polydactyly, cystic kidneys and liver, hypoplastic genitalia, cleft palate

AR (249000) 8q24, 11q13, 17q22-q23

Meckel-like-Donnai85

Lobar holoprosencephaly, cebocephaly, encephalocele, post-axial polydactyly, renal cortical cysts, bilobed lungs, hypoplastic cerebellum; consanguinity

Unknown

Meckel-like-Fried86

Microcephaly, occipital meningoencephalocele, short neck, thumb hypoplasia/ absence, abnormal bones in forearm, unilateral 2-3 finger syndactyly, complex heart anomaly, hemiuterus, kidney normal (lobar HPE)

Unknown

Median cleft face-other anomalies87

Median cleft of nose þ/ lip and palate notched alae, nasal tip may be present in some, hypertelorism, cranium bifidum, widow’s peak. Cases reported with holoprosencephaly and with absent corpus callosum and arhinencephaly.

Unknown

Pallister-Hall88

Bathrocephaly, large fontanel, hypothalamic hamartoblastoma, hypopituitarism, auricular anomalies, multiple frenulas, natal teeth, asymmetric limb shortness, polydactyly, syndactyly; larynx, lung, heart, vertebral, and anal malformations

AD (146510) GLI3, 7p13

Pseudotrisomy 1389

HPE with postaxial hand hexadactyly, heart defects, normal kidneys, normal chromosomes; all sporadic cases

AR? (264480)

Seller: cerebellar hypoplasiafacial dysmorphism90

Varied intrafamilial spectrum; high and receding forehead, low-set ears, hypertelorism/hypotelorism, absent external nares, thick and overhanging upper lip, small jaw, cardiac defects, dilatated ileum, cerebellar hypoplasia

AR

Severe Nager-like acrofacial dysostosis91

Very small and malformed pinnae, eyelid colobomas, micrognathia, lateral oral clefts, cleft lip, short forearms with absent thumbs, lower limb phocomelia. Case with single nostril, left cryptophthalmos, absent mandible, finger-like arms, and HPE.

Unknown (154400)

Short rib-polydactyly, Martinez-Frias type92

Pre- and postaxial polydactyly, syndactyly, cleft lip, abnormal genitalia; hydrocephalus; holoprosencephaly; relationship to other SRP syndromes unclear

AR

Smith-Lemli-Opitz93

Postnatal growth failure, mental retardation, narrow forehead, ptosis, epicanthus, broad anteverted nasal tip, broad alveolar ridges, micrognathia. Severe end of spectrum has more marked genital and internal anomalies, and postaxial polydactyly.

AR (270400) DHCR7, 11q12-q13

Steinfeld: absent thumb-short forearm94

Family had consistent thumb and variable other upper limb reduction anomalies; sibs had dysplastic kidney, absent gall bladder, congenital heart defect. HPE in propositus chance or part of syndrome?

Uncertain (184705)

Trilobar holoprosencephalylimb defects95

Lobar HPE, right accessory frontal lobe containing an encephalomeningocele that protruded frontally; hypertelorism, median facial cleft; finger and toe anomalies

Unknown

Turner: XLMR-macrocephaly96

Moderate X-linked mental retardation, macrocephaly in males and some carrier females; holoprosencephaly a possible expression of the gene in males

XLD Xp21-q21

Velo-cardio-facial97

Developmental delay, long narrow face, receding chin, prominent nose with wide and prominent bridge, narrow nasal tip and hypoplastic alae, thin hands, short stature, cardiac anomalies (ventricular septal defect, tetralogy of Fallot, right-sided aorta), microcephaly (HPE rare)

Del 22q11 (192430)

Zlotogora-Dagan: thumb anomalies98

IUGR, growth and developmental delay, aplastic or malpositioned thumb, amenorrhea, azoospermia, some with skin hyperpigmentation, occasionally other anomalies, including case with holoprosencephaly

Uncertain

Acrofacial dysostosis, Rodriguez type99

Severe and lethal acrofacial dysostosis, prominent nasal bridge, severe micrognathia, microtia, severe pre- and milder postaxial limb reduction, atrial and ventricular septal defects, shoulder girdle and pelvis hypoplasia

AR

Anosmia-alopecia-deafness100

Protruding ears, microtia, atresia of the otic canal, conductive deafness, total or partial alopecia, dental caries, small jaw, retardation, congenital heart defect, some cases of anosmia

AD (147770)

Anosmia-hypogonadotropic hypogonadism101

Variable expression of the two major hypogonadotropic components of the syndrome; some evidence of increased clefting, diabetes, and perhaps renal anomalies in patients and relatives. Most families interpreted as AR but some have distant partially affected relatives (see text).

XLR (308700) KAL1, Xp22.3 AD (147950) KAL2, FGFR1, 8p11.2-p11.1 AR (244200)

Anosmia-hypogonadismbrachytelephalangy102

Square forehead, hypertelorism, small nose, thin upper lip, flat philtrum, bifid scrotum, depigmented skin spots in adolescence, short stature, short broad toes.

AD or XLD (113480)

Meckel-Gruber

84

Arhinencephaly

(continued)

533

Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Anosmia-ichthyosishypogonadism103

Signs of hypogonadotropic hypogonadism with small penis, undescended small testes, developmental delay, decreased ACTH reserve, hypoplastic kidney. No data on brain structure.

XLR, possibly contiguous gene syndrome

Anosmia-radiohumeral synostosis61

Pierre Robin anomaly, anosmia, radiohumeral synostosis. CNS pathology unknown.

Unknown

Baller-Gerold: craniosynostosisradial aplasia104

Craniosynostosis; small and malformed ears; variable radial ray hypo/aplasia, carpal and metacarpal defects, shortness and curvature of ulna; brain abnormalities include hypoplasia of the olfactory bulbs and tracts

AR (218600)

Campomelic dysplasia105

Wide fontanels/sutures, hypertelorism, flat nasal bridge, small mouth/jaw, cleft palate, bowed femora/tibias, broad distal phalanges, small chest, 11 ribs, hypoplastic scapulae, wide spaced ischia and vertical ilia, sex reversal

AD (114290) SOX9, 17q24.3-q25.1

Campomelia-cystic renal dysplasia106

Four limb shortness and campomelia; dysplastic kidneys, pancreas, and liver; polysplenia; cervical lymphocele; short gut; cleft palate; vertebral anomalies; may be associated with polysplenia and heterotaxia

AR (211890)

Carpenter-Hunter: micromeliapolysyndactyly107

Severe short-limbed dwarfism, encephalocele, marked hypertelorism, microphthalmia, absent external nares, cleft palate, micrognathia, narrow chest, cardiac malformation, cystic dysplasia of the kidneys and pancreas, post-axial polydactyly of hands and feet, duplicated tibia, hydrocephalus, pachygyria

Unknown

Chromosome abnormality61

Duplication 1q, 6p, 6q, 16q; isochromosome 12p; 49,XXXXY

Chromosome imbalance

Cloverleaf skull-polydactyly108

Low-set ears, small and downturned mouth, duplicate thumb, small fifth fingers, limited knee extension, micropenis, bifid scrotum, bilobed lungs, polymicrogyria, hypoplastic frontal lobes

Unknown

Craniosynostosis-bifid thumbmicropenis109

Craniosynostosis, clover-leaf skull, low-set ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, bifid thumbs, small 5th finger, limited extension at the knees, bilobed lungs, polymicrogyria, hypoplastic frontal lobes, Chiari malformation

Unknown

DiGeorge association110

Variable spectrum of absent parathyroids and thymus, cardiac defects of left and right fourth branchial arch origin, persistent truncus arteriosis, hypertelorism, micrognathia, other visceral anomalies

Heterogeneity most sporadic some AD, some del 22q11,10p13, 17p13 (188400) AR?

DK-phocomelia with thrombocytopenia111

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs, thrombocytopenia/reduced megakaryocytes, renal agenesis to milder defects, vaginal atresia, other variable brain anomalies

Case with del(13q) (223340)

Fitch: diaphragmatic herniacardiac anomalies112

Triangular face, hirsute forehead, low nasal bridge, absent 5th finger nails, nail hypoplasia, absent left hemidiaphragm, communicating hydrocephalus, absent corpus callosum, olfactory bulbs and tracts; consanguinity

AR?

Fryns: acral-cornealdiaphragmatic113

Coarse and hirsute face, abnormal pinnae, corneal clouding, broad and flat nasal bridge, large nose, short upper lip, cleft lip/palate, small jaw, distal phalangeal and nail hypoplasia, diaphragmatic defects, gut malrotation and/or atresia; CNS malformations include agenesis of the corpus callosum and heterotopias

AR (229850) 1q?, 6q?

Goldenhar114

Varying asymmetry of lower face, mandible hypoplasia, microtia, preauricular pits and tags, macrostomia, cervical spine and cardiac anomalies; most patients have no CNS signs or anomalies, but variety including arhinencephaly reported. Some with Townes-Brock spectrum have SALL1 mutations.

Sporadic, occasional AD (164210) 14q32

Holmes: brain malformationfetal hypokinesia115

Polyhydramnios and fetal hypokinesia in pregnancy, wide cranial sutures, telecanthus, narrow palpebrae, micrognathia. One brother with absent corpus callosum and other with arhinencephaly; spectrum of holoprosencephaly-fetal hypokinesia.73

XLR?

Hypoplastic right heart116

One of a cluster of 14 infants with right-sided heart anomalies had arhinencephaly; 10 were microcephalic; other anomalies included cleft palate, micrognathia, and low-set ears

Unknown

Hypothalamic hamartomamicrophthalmia-radial ray117

Hypothalamic hamartoma, microphthalmia, ectopic retinal pigment layer, flat nose, absent/hypoplastic thumb, gut malrotation, small stomach, asplenia, abnormal genitalia; related to microgastria-limb reduction syndrome?

Unknown

Ivemark: asplenia/ polysplenia118

Complex cardiac defects, poly/asplenia abnormal pulmonary and/or abdominal situs; cases reported with agenesis of the corpus callosum, Dandy-Walker cyst, absence of the anterior pituitary and olfactory tracts

AR (208530) AD and sporadic 12q13, 6q21-q24 (continued)

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Table 15-4. Syndromes with holoprosencephaly/arhinencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

170

Kallmann

Hypogonadotropic hypogonadism, anomsmia, some cases with additional somatic findings; KAL1 on Xp is anosmin; KAL2 (AD) on 8p is loss of function of FGFR1

XLSD (308700) KAL1, Xp22.3 AD (147950) FGFR1, 8p11.2 AR (244200)

Lateral proboscis-cleft lip/palate119

Unilateral absent nose with blind-ending proboscis and ipsilateral arhinencephaly; cleft lip/palate occur; may have oblique facial cleft with proboscis external to eye

Unknown

Leptomeningeal angiomatosiscleft lip120

Mild hydrops, small and posteriorly rotated ears, overfolded helices, cleft lip/palate, hypoplastic left heart, leptomeningeal angiomatosis, absent septum pellucidum, absent olfactory tracts, hypoplastic corpus callosum. Single case.

Unknown

Melnick-Needles121

Small facial bones, prominent eyes, small chest, thin ribs, short arms and distal phalanges, males severely affected and stillborn; case reported with arhinencephaly, ocular dysplasia, skull hypoplasia

XLD (309350) FLNA, Xq28

Microgastria-upper limb reduction122

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia and porencephalic cyst

Unknown (156810)

Mohr-Majewski: oro-facialdigital type IV123

Severe abnormalities of epiglottis, tongue, and larynx; cystic kidneys, gut malrotations, hepatic fibrosis, arhinencephaly, neuronal migrational defects in patient within gamut of OFD II and short rib-polydactyly II

AR (258860)

Ptosis-coloboma-mental retardation124

Arhinencephaly, prominent nose, hypertelorism, microphthalmia, aniridia, retinal dysplasia, persistent primary vitreous, cleft palate, omphalocele, accessory spleen; cousin with some signs

AR/XLR

Rubinstein-Taybi125

Mental retardation, short stature, downslanting palpebrae, hypoplastic maxilla, narrow palate, beaked nose with extended septum, abnormal pinnae, broad angulated thumbs and halluces; arhinencephaly appears an uncommon occurrence

AD (180847) CREB binding protein, 16p13.3

Varadi: oro-facial-digitallike126

Pre- and postnatal growth failure, duplex hallux, bifid third metacarpal, cleft lip/ palate, lingual nodule, renal hypoplasia, cryptorchidism, absent cerebellar vermis, absent olfactory bulbs and tracts

AR (277170)

Winter-Wigglesworth127

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres; microscopic renal changes

Unknown

Wollcot-Rallison: epiphyseal dysplasia-diabetes128

Spondyloepiphyseal dysplasia, onset of diabetes mellitus in early infancy, shortened middle and distal phalanges, cone-shaped epiphyses of the proximal phalanges, small irregular carpal centres with ivory epiphyses; autopsied case showed endocardial fibroelastosis, laryngeal stenosis, hypoplastic pancreas

AR (226980)

X-linked laterality sequence129

Variable situs inversus of viscera and heart; congenital heart anomalies, polysplenia, asplenia, sacral/anal malformation. One of eight studied had arrhinencephaly, and one a meningomyelocele. Also autosomal dominant and recessive forms.

XLR (306955) ZIC3, Xq26.2 AD (601086), AR (605376) EBAF, 1q42.1 CFC1. Chr 2 CRELD1, 3p25.3 ACVR2B, 3p22-p21.3 NKX2-5, 5q34

Chromosomal130

Hypertelorism and ectrodactyly in a child with a de novo, apparently balanced translocation

t(2;4)(q14.2;q35)

Ectrodactyly-cleft lip/palate131

Bilateral cleft lip/palate, hypertelorism, microtia. Reported as a case of Hartsfield syndrome,70 but latter cases stated to have lobar HPE.

Unknown

Midline Inter-hemispheric Variant

scope of interference with the facial neural crest derivatives. With the exception of the two siblings reported by Pauli et al.,30 who likely both had an unbalanced 46,XX,der(18)(6;18) karyotype, all cases of agnathia have been sporadic, and it has yet to be included in the spectrum of HPE of known etiology. The majority of patients with HPE have some facial dysmorphia that suggests the diagnosis and leads to appropriate neuroimaging studies. In those with a normal face or nonspecific

signs, developmental delay and/or seizures lead to further investigation. Neuroimaging with MRI or good quality CT (slices  5 mm) will demonstrate the single ventricle (holosphere) and allow delineation of the severity of the HPE. The arterial pattern in arhinencephaly is normal, whereas in HPE the circle of Willis is incomplete with the anterior component replaced by uni- or bilateral branches from the internal corotids.31 Expected angiographic findings have been summarized by Fitz.27 Routine skull

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Fig. 15-10. The pathologic subtypes of alobar holoprosencephaly.

radiographs may demonstrate hypotelorism, absent nasal septum and ethmoid sinuses, and a small sella turcica.27 In alobar HPE no midline fissure separates the cerebral hemispheres, and there is no evidence of temporal or occipital horns; the third ventricle is absent, although it may be represented by a midline groove in the fused thalami. Brain weight is in the range of 100 g, but microcephaly is less common than in the less severe forms of HPE, probably because of a frequent accompanying hydrocephalus.7 A small case study has suggested a correlation between the size of the middle cerebral peduncle and the presence or absence of the cortico-ponto-spinal tract (CPST) with the severity of HPE; the CPST is absent in the alobar form.32 The specific radiologic appearance is further modified by the relative development of the frontal lobe (Fig. 15-10). In the pancake form (the most severe) the dorsal ventricular surface consists of a thin membrane and generally a dorsal cyst (vide infra). With further growth of the brain, the fused thalami are larger and the more developed brain partially covers the dorsal cyst, giving rise to the ‘‘cup’’ variant (Figs. 15-10 and 15-11). In the ball variety there is no dorsal cyst, and the prosencephalon is covered by cortex. The subarachnoid space may be very large (Fig. 15-10).27 In semilobar HPE a partial interhemispheric fissure separates the posterior cerebral hemispheres, and temporal horns have developed. However, the inferior monoventricle adjacent to the fused thalami in the alobar form may give the impression of temporal Fig. 15-11. Cup-type alobar holoprosencephaly.

horns; thus, accurate distinction between semilobar and alobar forms is based on other findings. These include a rudimentary third ventricle, the beginning of sagittal separation as evidenced by a downward indentation of the dorsal roof, separate occipital horns, and variably developed posterior fissure and falx.27 The cerebral cortex is continuous across the midline below the interhemispheric fissure.8 Lobar HPE is most likely to be misdiagnosed or missed because the interhemispheric fissure can be deep and virtually complete. Shallowness anteriorly may be detectable, and there is an area, which may be small, of visible continuity of the frontal cortex at the extreme rostral/ventral region.8,27 The lateral ventricles are closely apposed and have a narrow appearance. When adequately visualized in a coronal view, the fused anterior horns have somewhat squared borders and a flat roof. In some cases there may be a well-developed corpus callosum contiguous with a small posterior portion of normally divided cerebral hemispheres, but most of the antero-posterior axis continues to show continuity of the cerebral cortex across the midline with absence of the corpus callosum.8 The septum pellucidum is absent. Abnormalities of gyral, sulcal, and basal ganglia appear to show broad correlation with the severity of HPE. Cortical thickness appears to be normal across the spectrum of HPE.33 Gyral pattern and sulcal depth are normal in most patients with lobar and semilobar HPE; but with increasing severity (alobar) there is an increasing prevalence of shallow sulci, often associated with subcortical heterotopias, and abnormal gyral patterning.8,33 With increasing severity the Sylvian fissure becomes displaced in an antero-medial direction and is absent in the most severe cases.33 There is a decreasing gradient of gyral and cytoarchitectural abnormality in an antero-medial to postero-lateral direction.8,9 There is a consensus that primary defects of radial cell migration are uncommon, and it has been suggested that the more commonly observed anomalies of cortical organization are secondary to injury or result from abnormal cortical neuronal connections.8 Judas et al.34 found a normal six-layered neocortex in a patient with semilobar HPE due to 18pbut subtle changes in the cytoarchitecture were seen. The most striking change was an increased cell-body size and total basal dendritic length in the layer III pyramidal neurons. Modern neuroimaging is adding to our understanding of the involvement of the deep gray nuclei in HPE.8,35 It appears that the hypothalmus is always, and the caudate nucleus almost always, non-cleaved. There is a descending prevalence of non-cleavage from thalami, to lentiform, to caudate nuclei.35 Although there is a general correlation between the extent of nuclear fusion and the severity of HPE, there are notable exceptions, with cases of alobar and semilobar HPE showing essentially normal thalamic and lentiform nuclei.35 In alobar and semilobar HPE, the posterior supratentorial cerebrum is usually replaced by a large fluid-filled midline dorsal sac/cyst (Figs. 15-12 to 15-14).8,9 These prosencephalic cysts arise from, and lie behind, the holosphere and are continuous with its horse-shoe shaped, dorsal lip. They contain CSF, have a thin transparent membrane, abut the cerebellum and the parieto-occipital area of the cranial cavity, connect directly to the midline ventricular system, and may protrude through the anterior fontanel. Dorsal cysts vary in their specific pathology and in the spectrum of associated cerebral anomalies. There is some agreement that the membranous covering of the dorsal cyst represents the posterior roof of the holosphere,8 but its direct cause remains a source of conjecture. Simon et al.36 found a strong correlation between the occurrence of a dorsal cyst and the

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Fig. 15-12. Inferior view of a brain with holoprosencephaly (HC) in an infant with trisomy 13. The cerebellar hemispheres (C) and the brain stem (B) are well developed. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

presence and extent of thalamic non-cleavage. They speculated that the uncleaved thalamus blocked exit of CSF from the third ventricle, resulting in cystic expansion of the posterior holosphere. Sarnat and Flores-Sarnat9 posited that the supraspinal recess reFig. 15-13. Gross pathologic view of alobar holoprosencephaly. The dorsal sac has been opened. (Courtesy of Dr. C. Jime´nez, Department of Pathology, Children’s Hospital of Eastern Ontario.)

537

presents the path of least resistance to expansion, and is the sight of origin of the cysts. They suggest that the uncleaved thalamus contributes through reducing the volume of the third ventricle. Yokota et al.37 suggest that two additional types of dorsal cysts should be distinguished. An interhemispheric dorsal cyst arises from the third ventricle and extends between the hemispheres, displacing, rather than replacing, cerebral tissue. The wall is considered to derive from the diencephalic roof, and common associated findings include a complete or partial absent corpus callosum and falx and a midline parietal encephalocele. These primary interhemispheric cysts are distinguished from secondary interhemispheric cysts by the defective falx.37 Cases with associated absent olfactory bulb and tract have been used to argue that this lesion is part of the holoprosencephaly spectrum. However, the cerebellar tentorium is present, and the complete interhemispheric fissure and the course of the pericallosal artery indicate normal hemispheric separation.37,38 The second cystic lesion they discuss is congenital midline porencephaly, which is characterized by congenital hydrocephalus, a midline scalp defect or encephalocele, and a symmetric defect of the midline posterior cerebral mantle and the midline septae. There is no evidence of midline fusion of telencephalic or diencephalic structures or absence of the olfactory system, and the cyst walls contain neural remnants. Several authors have noted that the neuroimage of a dorsal cyst, behind a semi or lobar HPE, is reminiscent of an ‘‘arrowhead’’ and may be a useful diagnostic sign. Absence of the corpus callosum (ACC) with an interhemispheric cyst must be distinguished from HPE with the dorsal cyst lying behind the holosphere. The ‘‘bat wing’’ appearance of the ventricles on coronal view and their widely separated and parallel orientation on axial view, together with the presence of the falx and complete interhemispheric fissure, allows the differentiation to be made. Cohen21 has suggested that isolated ACC can be considered as part of the HPE spectrum when it occurs in syndromes that do include HPE. However, even within a single syndrome the specific embryopathology of the ACC could differ between cases with isolated ACC and those with HPE-associated ACC. Pituitary dysfunction is common in HPE but, although true absence does occur, careful histopathologic study will reveal presence of the gland in most cases.21 Simple absence of the septum pellucidum shows more normal ventricular borders, and hydranencephaly is distinguished by the presence of dysplastic brain remnants and the falx.27 The MRI and CT appearance of the middle hemispheric variant of HPE is distinctive.5 By definition it is the mid-portion of the cerebral hemispheres that is continuous across the midline, and in over 85% the Sylvian fissures also connect over the vertex. Furthermore, the hypothalamus and lentiform nuclei are always separated by a third ventricle, and the cerebral ventricles almost always separate the caudate nuclei. Dorsal cysts, associated with thalamic noncleavage, occur in about one-fourth of cases, and hypotelorism is not characteristic. Although abnormal maturation of white matter can be seen in up to half of the cases of standard HPE, there is evidence that it does not occur in the middle hemispheric variant.39 HPE has often been detected by routine and targeted prenatal ultrasound (PUS), although there continues to be difficulty in both specifying that the malformation is HPE, and in assigning the sub-type of HPE. Bullen et al.40 reported a retrospective study of 68 patients with HPE born between 1985 and 1998 and reported to a congenital malformation registry from among a population that had routine PUS available. The detection rate for HPE was 37/45 (88%) of alobar, 12/18 (58%) of semilobar, 1/3 of lobar, and 3/8 of an unclassified group. The detection rate of 71%

538

Neuromuscular Systems

Fig. 15-14. Superior view and coronal section of the holoprosencephalic brain of the infant shown in Fig. 15-12. A. In the superior view, the hemispheres are completely fused on the surface anteriorly (A), but a shallow midline (arrows) can be seen posteriorly. B. In the coronal section, a single ventricle (V) is shown beneath the midline groove (arrows). (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

for the entire study period improved to 86% for the years 1992 to 1998. However, in only 30 of the 45 PUS-detected cases was a specific diagnosis of HPE made; other diagnoses included ventriculomegaly (5), brain cysts (4), microcephaly (2), encephalocele (2), and other non-CNS anomalies (2). As expected, associated craniofacial and non-craniofacial malformations and chromosome studies were important aides to diagnosis. Detection rates as high as 100% have been reported for alobar HPE in more recent and selected populations.41 Alobar HPE has been subject to firsttrimester diagnosis, and transvaginal and/or 3-D PUS have been useful to better define the CNS and craniofacial pathology.42–44 Prenatal MRI may not be as useful for the clarification of large and complex lesions such as HPE.45 In alobar and semilobar HPE, the diagnosis is made through demonstration of a single sickle-shaped ventricle. In the axial plane, the cortex is crescent shaped without evidence of fissure or midline structures, and posteriorly the protruding fused thalami can usually be visualized.41 The presence of a dorsal sac may aid the differential diagnosis, although visualization of its connection to the ventricle in some cases requires a meticulous search. In hydrocephalus the separation of the ventricles is demonstrable, and hydranencephaly can be excluded if the crescent-shaped frontal cortex can be demonstrated. A careful search for the facial features, such as hypotelorism, cyclopia, a single nostril, and midline cleft, are essential parts of any assessment for HPE. Pilu et al.46 have proposed that the fused and rudimentary fornices are seen as a single fascicle within the third ventricle and are specific for lobar HPE. Congenital midline porencephaly has also been detected by PUS.47 Given the current lack of specificity of PUS, it is important that appropriate post-termination or postnatal examinations and

diagnostic tests are performed in order to detect or confirm HPE and any associated syndrome or etiology. HPE with or without characteristic facial changes can occur as an isolated malformation or as part of a broad range of chromosomal, single gene, and unknown genesis syndromes (Table 15-4). Leech and Shuman6 proposed that there is a spectrum of midline defects ranging from aprosencephaly, which may have an HPE face (see Section 15.3), through typical HPE, to commissural plate agenesis, septo-optic dysplasia, agenesis of the septum pellucidum, and absent corpus callosum. The hypothesis drew on the fact that several of these anomalies are simple epiphenomena in the presence of HPE. However, Cohen13 stressed that the spectrum of brain defects tends to be specific and limited for each known genesis syndrome and that overemphasis of the concept of a continuum may be misleading when counseling families. Examples include the broad range from alobar HPE to isolated arhinencephaly seen in trisomy 13 and the contrasting narrow range of arhinencephaly seen in Kallmann syndrome. The point is further made by comparing the different patterns of associated malformations in isolated ACC with HPE when ACC is an epiphenomenon.28 It is for this reason that Table 15-4 continues to separate syndromes that may have HPE and/or arhinencephaly from those that have only been reported with arhinencephaly. Well-delineated syndromes where there has been a single reported case with HPE have been excluded. Distribution and Etiology

Estimates of the prevalence of HPE can be influenced by sample size, sources and timing of ascertainment, rates of autopsy, the inclusion or exclusion of cases with chromosome anomalies and of pregnancy terminations or losses, and whether isolated arhinencephaly

Brain

is included. However, recent population-based reports of birth prevalence have been fairly constant, ranging from 0.48/10,000 to 0.88/10,000.40,132–134 Inclusion of fetal losses and stillbirths has obtained rates in the range of 1.2/10,000.40,133 The prevalence of HPE is much higher early in pregnancy, and Matsunga and Shiota reported a prevalence of 40/10,000 in early induced abortions.135 Calculation of the contribution of chromosome abnormality to the prevalence of HPE is compromised by the fact that such cases, notably trisomy 13, more often have craniofacial and other malformations, and this makes both ascertainment and karyotyping more likely. Indeed major epidemiologic studies have deliberately used craniofacial signs associated with HPE and trisomy 13 as aids to ascertainemnt.40,132 There has yet to be an epidemiologic study in which all cases of HPE have been karyotyped. Similarly, non-chromosomal syndromes may be over-represented because their associated malformations bias their ascertainment. With those caveats in mind, 63/82 (77%) of the cases reported by Olsen et al.132 were karyotyped, of which 15/63 (24%) were abnormal and 8/15 (53%) were trisomy 13. The comparable figures reported by Bullen et al.40 were 53/68 (78%), 20/53 (38%), and 15/20 (75%); and by Croen et al.133 were 92/121 (76%), 43/92 (46%), and 38/43 (88%). The latter authors considered that the additional seven cases, which were not karyotyped, had clinically recognizable trisomy 13. As would be expected, the studies that included fetal losses and/or stillbirths report a higher proportion of chromosome abnormality and trisomy 13. It is probable that a study limited to early fetal loss would show an even higher contribution from chromosome abnormality. Trisomy 13 is by far the most important chromosome abnormality in terms of its frequency of occurrence and its high rate and broad spectrum of HPE anomalies. Taylor136 estimated that 70% of cases of trisomy 13 have some expression of HPE. In contrast, HPE is an infrequent finding in several of the abnormal karyotypes listed in Table 15-4, and many have a narrower HPE spectrum; indeed several have thus far only been reported with arhinencephaly.13,61 The non-random association of specific cytogenetic abnormalities with HPE has suggested at least 12 loci on 11 chromosomes may contribute to HPE.137 These data have played an important role in the discovery of several non-syndromic HPE genes (Table 15-4). Of the numerous syndromes listed in Table 15-4, most are individually rare or express HPE in a minority of cases. Thus nonchromosomal syndromes appear to account for a relatively small proportion of HPE. Such syndromes were recognized in 4/68 (5.9%) of the series reported by Bullen et al.,40 3/82 (3.7%) reported by Olsen et al.,132 and 18/121 (14.9%) ascertained by Croen et al.133 A somewhat higher rate of syndromic and familial isolated-HPE may be reported from genetic centers, perhaps because of a greater expertise in syndrome diagnosis and more opportunity to fully explore family history; some bias of ascertainment may also be in play.138 Thus, a significant proportion of cases of HPE is unexplained, and progress toward identifying specific etiologies is frustrated by the relatively low background frequency of the malformation and its etiologic diversity. In 1989 Cohen13 listed a number of potential human teratogens that were supported by anecdotal data and required further study. He concluded that maternal diabetes was the only proven environmental cause of HPE in humans. Indeed, maternal diabetes has been the most consistently identified risk factor, occurring in 10/273 cases from population-based studies.40,132,133 Martinez-Frias et al.139 obtained an odds ratio (OR) for HPE of

539

3.27 (95% CI 1.29–7.77), and Croen et al.140 of 10.2 (95% CI 1.9– 39.4), for infants born to diabetic mothers. Several cases of HPE/arhinencephaly have been reported following alcohol abuse during pregnancy, and animal experiments indicate that alcohol can produce the HPE spectrum and other malformation associations.141 An OR of 2.0 (95% CI 0.9– 4.5) for alcohol exposure reported by Croen et al.140 did not quite attain significance, but it did appear to have an additive effect upon cigarette smoking; OR smoking alone was 4.1 (95% CI 1.4– 12.0), and for smoking and alcohol was 5.4 (95% CI 1.9–20.0). HPE can result from experimental exposure to retinoic acid in animals,141 and a human case of HPE associated with excess in utero exposure has also been reported.142 The case-control study by Matsunaga and Shiota135 showed no effects of maternal or paternal ages, parity, acute or chronic maternal illnesses, or menstrual irregularities on HPE. They suggested a borderline significant increase in the mean number of prior abortions, but this requires further study, especially in light of the number of statistical tests applied. The mean maternal and paternal ages recorded by Bullen et al.40 did not differ from the general population, but Olsen et al.132 reported an approximate two-fold greater prevalence in mothers under 18 years of age. An excess of females with HPE has been reported from a number of studies,16,61,132,133,140 and, at least in part, this may result from a greater survival of female infants with trisomy 13.133 The absence of a sex difference in the study by Bullen et al.,40 which included fetal loss, is consistent with this interpretation. Unfortunately there was no information as to the sex ratio of the abortuses studied by Matsunaga and Shiota135 and, hence, their study does not shed light on this question. Roach et al.16 found a significant increase in matrilineal dizygotic twinning in their families. There is perhaps some evidence of a slight excess of twins, discordant for the anomaly, among cases with HPE,40,132 but the finding is inconsistent.133 Croen et al.140 noted a significantly increased OR for children born to Mexican and non–U.S.-born mothers. However, their excess risk to Hispanic-white mothers was not seen in the New York data of Bullen et al.,40 perhaps reflecting a different origin for the Hispanic groups. Other variables showing increased but not quite significant ORs included early age at menarche, medication use for upper respiratory tract infections, and use of aspirin.140 Roach et al.16 reported that of their 32 families, 12 had mental illness and 16 had mental retardation among near relatives. They considered this to be an extremely high rate, although the relatives did not display characteristics consistent with mild expression of the dominant or recessive forms of HPE. Unfortunately, the denominator of the number of individuals counted was not provided, and there was no control group. The latter is of particular importance in light of the poverty status of 30 of the 32 families. It is similarly difficult to assess the possible relationship of neural tube defects to HPE. The spectrum of the ‘‘holoprosencephalic’’ face is seen in association with anencephaly, and affected siblings concurrent for these two anomalies have been reported.13 Similarly, more distant relatives have been reported to have neural tube defects, but these are common malformations and there are as yet no data to show if the rate among relatives is greater than expected by chance. On the other hand, some syndromes, as well as human and animal teratogens, have a spectrum of reported anomalies that include both HPE and neural tube defects. Until such time as all genes causing non-syndromic HPE are isolated and can be tested on a population-based sample, it will

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remain difficult to gauge the contribution of single genes to this disorder. Mutations in the genes presently known account for a relatively small fraction of cases (Table 15-4, vide infra). Roach et al.16 found two recurrences among 35 siblings, a rate of 6%. However, many of their patients were not karyotyped, and those who were, as well as a number of familial cases reported in the literature, were studied in the prebanding era. Recurrent derivative chromosome anomalies remain a possibility in some cases. Bullen et al.40 identified 5 (7.4%) familial cases among their 68 population-based index cases. Starting with an initial series of 258 cases, Odent et al.138 found 97 cases of non-syndromic, nonchromosomal HPE distributed in 79 families. From a segregation analysis they concluded that transmission fit an autosomal dominant model with 82% penetrance for the major HPE phenotype. The proportion of sporadic cases was estimated at 68%, and a recurrence risk of 13% was calculated for sporadic, isolated HPE. The embryologic disturbance that results in HPE occurs early, and the strong association between midline facial malformations and HPE suggests an intimate embryologic relationship between the developing prosencephalon and the neural crest cells that populate the frontonasal process. The neural plate appears by the third week post conception; by the time it begins to fuse at 22 days, the forebrain has two subdivisions and bilateral optic sulci.132,143 As opposed to the midbrain and hindbrain, which are induced by the notochord, forebrain induction is dependent on the prechordal plate and mesoderm. The inducing tissues express sonic hedgehog (SHH), a gene that is subsequently turned on in the CNS floorplate. Current evidence favors a primary defect in the induction and/ or patterning of the rostral neural tube by the prechordal mesoendoderm as the underlying cause of HPE.11,144 Non-random structural cytogenetic abnormalities provided the initial clues as to the potential location of genes that could be involved in these developmental processes, and SHH, at 7q36, was the first gene to be implicated in the pathogenesis of non-syndromic HPE.22 Forebrain expression of SHH is initially restricted to the tuberal and mamillary hypothalamic primordia, and later to a region of the rostrobasal telencephalon, termed the lamina terminalis. It is within the lamina terminalis that the commissural plate forms.11 The key role of the Shh pathway has been confirmed in animal models. Shh / mice have perinatal lethal HPE and cyclopia; in contrast, ectopic expression of Shh leads to ectopic development of the previously mentioned hypothalamic primordia.8 Shh activation of its target genes is suppressed by Gli3-R, and further evidence of the importance of Shh signaling is that the double knockout (Shh /, Gli3-R /) mouse is rescued from HPE.145 The causative role in humans has been confirmed by the demonstration that two HPEassociated SHH mutations decrease in vivo SHH activity in the CNS, and that they fail to induce ventrally expressed genes, and to repress dorsally expressed genes.146 There is evidence that the bone morphogenetic proteins (BMPs) play a role in dorsal patterning of the brain, and that their expression can induce or repress genes normally expressed in the dorsal forebrain.8 Golden et al.147 showed that introducing recombinant BMP4- or BMP5-soaked beads into chick forebrain caused HPE, cyclopia, and loss of ventral midline structures. Markers of dorsal gene expression were present, but those for ventral gene expression were lost. The loss of the basal telencephalon was shown to be due to excess cell death, a finding compatible with the overall decrease in brain size seen in severe HPE spectrum anomalies. This experiment was also important in demonstrating that HPE can be induced at a time when the neural tube has closed.

Mapping and candidate gene approaches have lead to the discovery of causative mutations in other genes in the SHH signaling pathway, as well as in other pathways that may not interact directly with SHH signaling. To date these include PTCH and GLI2 (sonic hedgehog signaling), TDGF1, FAST1, and TGIF (Nodal/ TGF-b signaling), SIX3, and ZIC2 (a dorsally expressed gene).65,148,149 Other genes implicated in mice include Smoothened (Smo) in the Shh-signaling pathway150 and the homeobox genes Nkx2.1151 and Vax1.152 An interesting sidebar to the SHH story is that patients with Smith-Lemli-Opitz syndrome (Table 15-4) have low cholesterol levels due to their defect in 7-dehydrocholesterol reductase, and about 5% of them have HPE. Inhibitors of cholesterol synthesis can also cause HPE.153 SHH signaling may be directly impaired because SHH requires a cholesterol-related processing to attain its functional state.145 Additionally, hypocholesterolemia may act further down the pathway on PTCH, or on caveolin- containing, cholesterol-rich vesicles themselves, to interfere with the intracellular movement of SMO,145 which is a key step in signaling.65 Notwithstanding progress in finding single genes related to the pathogenesis of HPE, surveys of large numbers of patients have found a relatively low rate of mutations.154,155 The four genes available for clinical testing may account for up to 37% to 48% of families showing autosomal dominant inheritance, and less than 5% of sporadic non-syndromal cases.156 Testing of all currently known genes has only found mutations in 15–20% of cases.65 Although there may be a single predominant major gene yet to be discovered, this seems unlikely, and thus there remain questions as to the cause of most sporadic cases of HPE. Also unexplained is the dramatic variation in the expression of HPE, which is seen61 even in families with a known mutation.22 This has lead Ming and Muenke65 to propose that in most instances the occurrence of HPE in humans requires a double hit, either genetically, or genetically and environmentally. They point out that Shh þ/ mice (unlike Shh /) are unaffected by HPE, and they provide three examples of affected children who were heterozygous for mutations at two different HPE loci (biallelic inheritance); parents who were available were heterozygous and unaffected. Indeed there is the potential that a combination of environmental factors (e.g., alcohol, retinoids, low cholesterol) and polymorphisms at multiple HPE loci, each resulting in subtle variation in timing and gradient of gene signaling, might combine to cause sporadic HPE. Concurrent face and brain malformations in HPE point to maldevelopment of a shared precursor or inducer. For example, malformations of the HPE spectrum have been produced in a number of experimental systems by interference with the prechordal mesoderm and/or gastrulation.142,158 Variation in severity suggests differing magnitude or timing of an insult, or of fetal susceptibility. Discordant monozygotic twins would indicate that the insult may be local and quite random. Cases of HPE showing lack of correlation between the face and the brain, either where the face is normal and the brain abnormal or the brain is normal and the face abnormal, suggest that at times the pathogenic process may be specific, and probably later in time than when concurrent effects are induced. Sulik and Johnston10 showed that an insult during gastrulation results in a narrow forebrain and the HPE spectrum. By varying the timing and intensity of alcohol exposure during gastrulation, they produced the entire gamut of malformations, from virtual aprosencephaly through HPE, to the typical prenatal alcohol syndrome. Notable was the production of agnathia/HPE, pointing to damage to the early mesoderm.

Brain

These above data can support variability of timing as a cause for variations in HPE. However, Sarnat-Flores and Sranat9 have proposed that the degree of midface hypoplasia that presents in association with HPE is due to a rostrocaudal gradient in the genetic defect. They note that others19 have shown such a gradient in the rate of non-cleavage, with 96% non-cleavage of the caudate, 67% of the thalamus, and 27% of the midbrain. Failed separation of the inferior and superior colliculi, hypoplasia of the periaqueductal gray matter, and aqueductal stenosis/atresia evidence midbrain non-cleavage. Furthermore, there is a greater dorsal than ventral non-cleavage. Siebert159 implicated the degree of integrity of the ethmoid bone with respect to the occurrence of the ‘‘holoprosencephalic’’ face. The ethmoid derives from the cartilagenous mesethmoid, which is the major component of the nasal capsule and which would be expected to be deficient in proportion to the degree of neural crest cell abnormality. There is not consensus as to whether the middle interhemispheric variant (MIH) is truly part of the HPE specrum.21 However, there is genetic evidence that there are at least some common pathogenic factors. ZIC2, which acts in both closure of the neural tube and differentiation of the dorsal midline to form the roof plate, has been found to play a role in one of 16 cases with MIH.161 MIH has also been described in five fetuses with 13q-, a deletion that includes the ZIC2 locus.162 The primary involvement of a dorsal acting gene would account for the general lack of ventral midline CNS involvement in MIH. Prognosis, Treatment, and Prevention

As would be expected for any severe CNS malformation, HPE carries a high mortality rate and poor prognosis for development in those who survive. However, not all patients die, and some individuals show meaningful development. It is therefore paramount that parents be provided with as accurate information as possible about what can be expected. Data from more recent population-based studies are more likely to reflect the impact of current prenatal diagnosis and perinatal practice. Of the 68 cases reported by Bullen et al.,40 four were lost spontaneously at <24 weeks gestation, 38 pregnancies were terminated following prenatal diagnosis, two were stillborn, and 24 were born alive. Eight of the liveborn infants died within 24 hours, and 14 (58%) within a month; 29% (35% of the euploid) survived to 1 year. Survival rates are affected by the severity of the HPE, the presence of a cytogenetic or syndrome diagnosis, and the occurrence of associated lethal anomalies. Among their 78 liveborn cases, Olsen et al.132 recorded an overall mortality of 32% within 48 hours and of 38.5% within a week. The 48-hour mortality rate for syndromic (including chromosomal) cases was 57%, and the 1week survival was 50% for alobar HPE. At 1 year, 54% of patients with isolated, 14% of those with syndromic, and 25% of those with non-syndromic HPE with multiple associated defects were alive. Of the 121 Californian cases reported by Croen et al.,133 80% of the chromosomal and 32% of the euploid cases died within 1 week, and 2% and 30%, respectively, were alive at 1 year. All euploid patients with cyclopia or ethmocephaly died within a week, whereas 57% of those with less severe facial anomalies were alive at 1 year. Thus, in both of the latter studies the severity of the facial anomalies in the euploid cases allowed some prediction of survival. The cause of death in children with HPE who do not have an associated lethal malformation is not always clear, but may often relate to brainstem dysfunction, manifest as unstable cardiac and respiratory rates, and thermolability. Barr and Cohen163 stress that prolonged episodes of respiratory and cardiac instability are ominous, and parents should

541

be forewarned as to their potential consequence. Recurrent infections, to which the infants often respond poorly, and which may be exacerbated by dehydration due to diabetes insipidus, may also cause death. Although uncommon, survival beyond childhood does occur with alobar HPE and becomes more common as the severity of the HPE diminishes. Additional non-facial malformations are the rule in patients with a chromosome abnormality. Up to 90% of patients with euploid HPE have facial anomalies; 60% involve the eyes and nose, and 33% involve the lips and palate.40 In general, the severity of the facial anomalies does correlate with the severity of the HPE, but there are important exceptions. Plawner et al.7 had three patients with alobar HPE and a normal face, and this pattern may run true in families.20 The euploid group has a 70% incidence of additional non-facial anomalies, which include the skeletal, renal, and cardiovascular systems as well as the gut and lung.28,40 There are a number of medical problems common to children who survive with HPE, and Plawner et al.7 have looked for correlations between their rate and severity and the degree of HPE and involvement of the deep gray nuclei. They reviewed 68 patients, 13 with alobar, 43 with semilobar, and 12 with lobar HPE, whose respective mean ages at the time of study were 0.86, 3.8, and 5.8 years. Where appropriate, the evaluations were limited to the 46 children who were over 1 year of age. Seizures occurred in 33/68 (49%) of cases, and their presence did not correlate with the type of HPE. However, the seizures were judged difficult to control in 17/33 (52%), which did correlate with the severity of the HPE and the presence of cortical malformations. Barr and Cohen,163 whose study was limited to alobar HPE, state that the frequency and intensity of seizures may vary over time, and that they often respond to a standard medical approach, although several medications, alone or in combination, may have to be tried in order to gain control. Diabetes insipidus, treatable with replacement antidiuretic hormone, is common in HPE, affecting 49/68 (72%) of the patients in one series,7 and additional pituitary anomalies including panhypopituitarism can occur. Plawner et al.7 did not find a good correlation between the presence of an endocrine disturbance and the appearance of the pituitary as assessed by neuroimaging; there was some correlation with the severity of the HPE, and a good correlation with the degree of hypothalamic non-cleavage. However, Sarnat-Flores and Sarnat9 do not accept that the endocrinopathies are explicable solely on the basis of hypothalamic non-cleavage and have hypothesized that down-regulation of the OTP homeobox gene, or an interrelated downstream gene, causes a lack of differentiation and/or functional maturity of the magnocellular neurons of the hypothalamus. Temperature instability, unrelated to infection and ranging from 368C to 38.68C, is common and occurred in 22/68 (32%) cases studied by Plawner et al.,7 of which six were judged to be severe. Again they noted a correlation with the degree of hypothalamic non-cleavage. The presence of hydrocephalus is strongly correlated with the severity of the HPE and the presence of a dorsal cyst; the latter two are of course strongly interrelated. In the series by Plawner et al.,7 CSF shunts were required in 62% of patients with alobar, 7% of those with semilobar, and 9% of those with lobar HPE. Dorsal cysts were found respectively in 11/12, 12/43, and 1/11 cases; shunts were needed in 9/23 patients with, and only in 2/41 without, a dorsal cyst. Hercig et al.164 reported a 28-year-old unemployed women, who had been in a common-law relationship for 6 years, and who developed a delusional psychosis. The psychosis, but not her poor short-term memory, responded to antipsychotic medication, and

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a MRI showed lobar holoprosencephaly. The authors posited a causal relationship. Serious developmental delay is the rule in HPE, and its severity shows a general correlation with the degree of HPE. In their review of survivors with alobar HPE, Barr and Cohen163 speak of some infants being able to bat objects, occasionally being able to bring objects to the midline, and the absence of any expressive language. Hearing is usually normal, and the authors state that the children may develop specific sounds for some needs, respond consistently to certain sounds and tones, and, if vision is normal, recognize familiar faces. Plawner et al.7 did not observe sitting in any of their patients with alobar HPE, a minority of those with semilobar HPE had succeeded, and about half with lobar HPE could walk independently or with assistance. The relative ages of the groups should be kept in mind. Use of the upper limbs in patients with alobar HPE was limited to reaching and batting objects, whereas 4/30 patients with semilobar and half of those with lobar HPE had normal or only mild upper limb dysfunction. Development of language was limited to vowel sounds in patients with alobar HPE, while two of those patients with semilobar and two with lobar HPE had multi-word sentences or better. There was a high inverse correlation between development of language and the degree of non-cleavage of the caudate, lentiform, and thalamic nuclei. Plawner et al.7 developed a composite motor scale (CMS), composite clinical severity scale (CCSS), and deep gray nuclear scale (DGS). The CMS for alobar and semilobar HPE did not differ but both were significantly greater than that for lobar HPE. The CCSS was greater for alobar than for semilobar, which was greater than that for lobar HPE, and there was a strong correlation between the CCSS and DGS. The authors proposed that the latter might provide additional predictive clinical/developmental information as compared with the simple measure of HPE severity. The cases reported by Hercig et al.,164 Shanks and Wilson,165 and Moulinger et al.166 serve to emphasize the degree of normalcy that can occur in lobar HPE, and there is likely a bias toward the ascertainment of severe cases. Feeding difficulties are common and often marked, especially at the severe end of the HPE spectrum. They include poor suck and swallowing, gagging, choking, vomiting with its risk of aspiration, airswallowing, and colic, and may be exacerbated by constipation.163 Gastrostomy may be the logical solution in some cases. Postnatal growth failure is frequent. Behavior may cycle between calm and irritable without apparent reason, and does not always respond to the usual approaches. Barr and Cohen163 suggest that continual background noise (e.g., radio) may help and may also restore a normal sleep pattern, which can itself be extremely disturbed. There is no treatment for HPE, and aggressive intervention is not indicated in light of the poor prognosis for both survival and development. In children who do survive, consideration should be given to treatment of non–life-threatening malformations to increase the benefits of routine care. Persing167 discussed some of the ethical issues surrounding surgical treatment of patients with HPE. He argued for a high benefit-to-risk ratio, such as cleft lip/ palate repair, which would aid management and also reduce social isolation of the patient and family. Cleft repair will not correct a feeding difficulty that has a central cause.163 In experienced hands the risks of surgery should not be significantly different from that in the general population. With the possible exception of improved management of diabetic pregnancies, there is no means of primary prevention of HPE. Greater use of routine prenatal ultrasound screening means that a significant majority of cases of HPE can be detected in utero, early

enough to provide parents with the option of terminating the pregnancy.49 However, some couples when presented with this unexpected information elect to continue the pregnancy. RedlingerGross et al.168 have discussed this decision-making process and stress the need of the parents for informational, emotional, and general support from their family, friends, and health care professionals. The increasing recognition of individual syndromes and the genes responsible for both syndromic and isolated HPE means that there is a growing potential for prenatal diagnosis in high-risk families, both through application of ultrasound for the detection of HPE and the syndrome-associated malformations, and through specific mutation analysis. Direct mutation analysis is available clinically for four of the genes causing isolated HPE,156 and preimplantation diagnosis has been applied in a case of HPE due to a SHH mutation.169 All affected infants (or fetuses), not only those who appear to have trisomy 13, should be karyotyped. This is not simply to document the cause of the HPE and to enable more precise counsel regarding its risk of recurrence, but because young couples who give birth to a child with standard trisomy have a nonspecific (about 1%) risk of recurrent trisomy. Specific chromosome findings in an affected patient may of course lead to further family studies and, in the case of a familial rearrangement, identification of a higher recurrence risk and the potential for prenatal karyotyping. High-resolution studies are indicated in cases in which the clinical syndrome diagnosis is not apparent. The potential risk for autosomal recessive and autosomal dominant forms of HPE, and with it the importance of assessing close relatives for microforms such as absent or single maxillary central incisors, hypotelorism, anosmia, and endocrine dysfunction, has been discussed previously. Any such relative should be counseled as to potential risk. The counseling of individuals found to have these ‘‘microforms’’ in the absence of a family history is more problematic; they are probably at low risk, but offering prenatal ultrasound would be prudent.

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543 40. Bullen PJ, Rankin JM, Robson SC: Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England. Am J Obstet Gynecol 184:1256, 2001. 41. Lai TH, Chang CH, Yu CH, et al.: Prenatal diagnosis of alobar holoprosencephaly by two-dimensional and three-dimensional ultrasound. Prenat Diagn 20:400, 2000. 42. Hsu TY, Chang SY, Ou CY, et al.: First trimester diagnosis of holoprosencephaly and cyclopia with triploidy by transvaginal threedimensional ultrasonography. Eur J Obstet Gynecol Reprod Biol 96:235, 2001. 43. Blass HG, Eik-Nes SH, Vaino T, et al.: Alobar holoprosencephaly at 9 weeks gestational age visualized by two- and three-dimensional ultrasound. Ultrasound Obstet Gynecol 15:62, 2000. 44. Stagiannis KD, Sepulveda W, Bower S: Early prenatal diagnosis of holoprosencephaly: the value of transvaginal ultrasonography. Eur J Obstet Gynecol Reprod Biol 61:175, 1995. 45. Vimercati A, Greco P, Vera L, et al.: The diagnostic role of ‘‘in utero’’ magnetic resonance imaging. J Prenat Med 27:303, 1999. 46. Pilu G, Ambrosetto P, Sandri F, et al.: Intraventricular fused fornices: a specific sign of fetal lobar holoprosencephaly. Ultrasound Obstet Gynecol 4:65, 1994. 47. Vintzileos AM, Hovick TJ, Escoto DT: Congenital midline porencephaly: prenatal sonographic findings and review of the literature. Am J Perinatol 4:125, 1987. 48. Sperber GH, Honore´ LH, Johnson ES: Acalvaria, holoprosencephaly, and facial dysmorphism syndrome. J Craniofac Genet Dev Biol (Suppl) 2:319, 1986. 49. Ades LC, Sillence DO: Agnathia-holoprosencephaly with tetramelia (case report). Clin Dysmorphol 1:182, 1992. 50. Menezes AV, MacGregor DL, Buncic JR: Aicardi syndrome: natural history and possible predictors of severity. Pediatr Neurol 11:313, 1994. 51. Lambert JC, Ferrari M, Donzeau M, et al.: Association d’une hydrocephalie he´re´ditaire et d’une holoprosencephalie. Arch Fr Pediatr 40:397, 1983. 52. Yang SS, Roth JA, Langer LO Jr: Short rib syndrome, Beemer-Langer type with polydactyly: a multiple congenital anomalies syndrome. Am J Med Genet 39:243, 1991. 53. Thomas M, Donnai D: Bilateral brachial amelia with facial clefts and holoprosencephaly. Clin Dysmorphol 3:266, 1994. 54. Hing AV, Torack R, Dowton SB: A lethal syndrome resembling branchio-oculo-facial syndrome. Clin Genet 41:74, 1992. 55. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/ BRESHECK). Am J Med Genet 68:386, 1997. 56. Stoll C, Benoit F, Peter MO, et al.: Familial association of camptodactyly, mental retardation, whistling face and Pierre Robin sequence. Clin Dysmorphol 8:247, 1999. 57. Martinez-Frias ML, Bermejo E, Garcia A, et al.: Holoprosencephaly associated with caudal dysgenesis: a clinical-epidemiological analysis. Am J Med Genet 53:46, 1994. 58. Ercal D, Say B: Cerebro-oculo-nasal syndrome: another case and review of the literature. Clin Dysmorphol 7:139, 1998. 59. Lin AE, Siebert JR, Graham JM Jr: Central nervous system malformations in the CHARGE association. Am J Med Genet 37:304, 1990. 60. Norman M, McGillivary B, Kalousek D, et al.: Holoprosencephaly: defects of the mesobasal prosencephalon. In: Congenital Malformations of the Brain. Pathological, Embryological, Clinical, Radiological and Genetic Aspects. Norman MG, McGillivray BC, Kalousek DK, et al., eds. Oxford University Press, New York, 1995, p 187. 61. Cohen MM: Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and syndromology. Teratology 40:211, 1989. 62. Lurie IW, Ilyina HG, Podleschuk LV, et al.: Chromosome 7 abnormalities in parents of children with holoprosencephaly and hydronephrosis. Am J Med Genet 35:286, 1990. 63. Estabrooks LL, Rao KW, Donahue RP, et al.: Holoprosencephaly in an infant with a minute deletion of chromosome 21 (q22.3). Am J Med Genet 36:306, 1990.

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64. Van Gool S, de Zegher F, de Vries LS, et al.: Alobar holoprosencephaly, diabetes insipidus and coloboma without craniofacial abnormalities: a case report. Eur J Pediatr 149:621, 1990. 65. Ming JE, Muenke M: Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Med Genet 71: 1017, 2002. 66. Bonnemann C, Meinecke P: Holoprosencephaly as a possible embryonic alcohol effect: another observation . Am J Med Genet 37:431, 1990. 67. Conover PT, Roessmann U: Malformational complex in an infant with intrauterine influenza viral infection. Arch Path Lab Med 114:535, 1990. 68. Camera G, Lituania M, Cohen MM Jr: Holoprosencephaly and primary craniosynostosis: the Genoa syndrome. Am J Med Genet 47:1161, 1993. 69. Grote W, Rehder H, Weisner D, et al.: Prenatal diagnosis of a probable hereditary syndrome with holoprosencephaly, hydrocephaly, octodactyly, and cardiac malformations. Eur J Pediatr 143:155, 1984. 70. Hartsfield JK, Bixler D, De Myer WE: Hypertelorism associated with holoprosencephaly and ectrodactyly. J Clin Dysmorphol 2:27, 1984. 71. Kurokawa Y, Tsuchita H, Sohma T, et al.: Holoprosencephaly with Dandy-Walker cyst: rare coexistence of two major malformations. Child Nerv Syst 6:51, 1990. 72. Begleiter ML, Harris DJ: Holoprosencephaly and endocrine dysgenesis in brothers. Am J Med Genet 7:315, 1980. 73. Hockey A, Crowhurst J, Cullity G: Microcephaly, holoprosencephaly, hypokinesia-a second report of a new syndrome. Prenat Diagn 8:683, 1988. 74. Iafolla K, Fratkin JD, Spiegel PK, et al.: Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (PallisterHall syndrome). Am J Med Genet 33:489, 1989. 75. Burck U, Held KR, Kitschke HJ: Occurrence of cyclopia, myelomeningocele, deafness, and abducens paralysis in siblings. Am J Med Genet 11:443, 1982. 76. Slavotinek A, Stahlschmidt J, Moore L: Transverse limb defects, holoprosencephaly and neuronal heterotopia - a new syndrome? Clin Dysmorphol 6:365, 1997. 77. Kotzot D, Weigl J, Huk W, et al.: Hydantoin syndrome with holoprosencephaly: a possible rare teratogenic effect. Teratology 48:15, 1993. 78. Verloes A, Dodinval P, Beco L, et al.: Lambotte syndrome: microcephaly, holoprosencephaly, intrauterine growth retardation, facial anomalies, and early lethality-a new sublethal multiple retardation syndrome in four sibs. Am J Med Genet 37:119, 1990. 79. Rowlatt U, Pruzansky S: Premaxillary agenesis, ocular hypotelorism, holoprosencephaly, and extracranial anomalies in an infant with a normal karyogram. Cleft Palate J 17:197, 1980. 80. Prudlo J, Stoltenburg-Didinger G, Jimenez E, et al.: Central nervous system alterations in a case of short-rib polydactyly syndrome, Majewski type. Dev Med Child Neurol 35:158, 1993. 81. Martin AO, Perrin JCS, Muir WA, et al.: An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly. Clin Genet 12:65, 1977. 82. Barr M, Hanson JW, Currey K, et al.: Holoprosencephaly in infants of diabetic mothers. J Pediatr 102:565, 1983. 83. Keller K, McCune H, Williams C, et al.: Lobar holoprosencephaly in an infant born to a mother with classic phenylketonuria. Am J Med Genet 95:187, 2000. 84. Lurie IW, Prytkov AN, Meldere LV: Meckel syndrome in different populations. Am J Med Genet 18:661, 1984. 85. Meinecke P: Holoprosencephaly, polydactyly, and lethal outcome— another observation. Proc Greenwood Genet Center 8:78, 1989. 86. Fried K: A Meckel-like syndrome? Clin Genet 5:46, 1974. 87. Bomelburg T, Lenz W, Eusterbrock T: Median cleft face syndrome in association with hydrocephalus, agenesis of the corpus callosum, holoprosencephaly and choanal atresia. Eur J Pediatr 146:301, 1987. 88. Hall JG, Pallister PD, Clarren SK: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly-a new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47, 1980. 89. Moerman P, Fryns JP: Holoprosencephaly and postaxial polydactyly: another observation. J Med Genet 25:501, 1988.

90. Seller MJ, Pal K, Moscoso G, et al.: Cerebellar hypoplasia, facial dysmorphism and internal abnormalities: a new recessive syndrome? Clin Dysmorphol 7:41, 1998. 91. Christianson AL, Kruger H, Dini L: Atypical acrofacial dysostosis syndrome. Am J Med Genet 51:32, 1994. 92. Martinez-Frias ML, Bermejo E, Urioste M, et al.: Short rib-polydactyly syndrome (SRPS) with anencephaly and other central nervous system anomalies: a new type of SRPS or a more severe expression of a known SRPS entity? Am J Med Genet 47:782, 1993. 93. Kelley RI: RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am J Hum Genet 63:322, 1998. 94. Nothen MM, Knopfle G, Fodisch H-J, et al.: Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet 46:467, 1993. 95. Mazal PR, Schuhfried G, Budka H: Trilobar holoprosencephaly (‘‘triprosencephaly’’) a unique type of cerebral malformation. Acta Neuropathol (Berl) 89:567, 1995. 96. Turner G, Gedeon A, Mulley J: X-linked mental retardation with heterozygous expression and macrocephaly: pericentromeric gene localization. Am J Med Genet 51:575, 1994. 97. Meinecke P, Beemer FA, Schinzel A, et al.: The velo-cardio-facial (Shprintzen) syndrome. Eur J Pediatr 145:539, 1986. 98. Zlotogora J, Dagan J, Ganen A, et al.: A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism. J Med Genet 34:813, 1997. 99. Wessels MW, Den Hollander NS, Cohen-Overbeek TE, et al.: Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez. Am J Med Genet 113:97, 2002. 100. Johnson VP, McMillin JM, Aceto T Jr, et al.: A newly recognized neuroectodermal syndrome of familial alopecia, anosmia, deafness, and hypogonadism. Am J Med Genet 15:497, 1983. 101. White BJ, Rogol AD, Brown KS, et al.: The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am J Med Genet 15:417, 1983. 102. Hunter AGW, Feldman W, Miller J: Characteristic craniofacial appearance and brachytelephalangy in a mother and son with Kallmann syndrome in the son. Am J Med Genet 24:527, 1986. 103. Perrin JCS, Idemoto JY, Sotos JF, et al.: X-linked syndrome of congenital ichthyosis, hypogonadism, mental retardation and anosmia. Birth Defects Orig Artic Ser XII(5):267, 1976. 104. Nwokoro NA, Jaffe R, Barmada M: Baller-Gerold syndrome: a postmortem examination. Am J Med Genet 47:1233, 1993. 105. Hall BD, Spranger JW: Campomelic dysplasia. Am J Dis Child 134:285, 1980. 106. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 107. Carpenter BF, Hunter AGW: Micromelia, polysyndactyly, multiple malformations, and fragile bones in a stillborn child. J Med Genet 19:311, 1982. 108. Cohen MM Jr: The Child with Multiple Birth Defects. Raven Press, New York, 1982, p 78. 109. Cohen MM Jr: Craniosynostosis: Diagnosis, Evaluation, and Management. Raven Press, New York, 1986. 110. Conley ME, Beckwith JM, Mancer JFK, et al.: The spectrum of Di George syndrome. J Pediatr 94:883, 1979. 111. Bamforth JS, Lin CC: DK-phocomelia phenotype (von Voss-Cherstvoy syndrome) caused by somatic mosaicism for del(13q). Am J Med Genet 73:408, 1997. 112. Fitch N, Sorolovitz H, Robitaille Y, et al.: Absent left hemidiaphragm, arhinencephaly, and cardiac malformations. J Med Genet 15:399, 1978. 113. Fryns JP: Fryns syndrome: a variable MCA syndrome with diaphragmatic defects, coarse face, and distal limb hypoplasia. J Med Genet 24:271, 1987. 114. Wilson GN: Cranial defects in the Goldenhar syndrome. Am J Med Genet 14:435, 1983. 115. Holmes LB, Schoene WC, Benacerraf BR: New syndrome: brain malformation, growth retardation, hypokinesia and polyhydramnios in two brothers. Clin Dysmorphol 6:13, 1997. 116. Baetz-Greenwalt B, Ratliff NB, Moodie DS: Hypoplastic right-sided heart complex: a cluster of cases with associated congenital birth defects. A new syndrome? J Pediatr 103:399, 1983.

Brain 117. Verloes A, Narcy F, Fallet-Bianco C: Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and mu¨llerian regression: further delineation of a new syndrome? Clin Dysmorphol 4:33, 1995. 118. Sultan Z, Gnanaratnam J, Sharief N: Isolated aplasia of the anterior pituitary gland with unusual associations. Clin Dysmorphol 5:347, 1996. 119. Antoniades K, Baraister M: Proboscis lateralis: a case report. Teratology 40:193, 1989. 120. Hurst JA, Hallam LA, Hockey KA: Leptomeningeal angiomatosis, absent olfactory tracts, hypoplasia of the cerebellar vermis, cleft lip and palate and congenital heart disease in a stillborn infant. Clin Dysmorphol 1:168, 1992. 121. Barr M, Cohen MM Jr: The kidney-skull connection: is selective or general hypotension a teratogenetic mechanism? Proc Greenwood Genet Center 10:61, 1991. 122. Meinecke P, Bonnemann CG, Laas R: Microgastria-hypoplastic upper limb association: a severe expression including microphthalmia, single nostril and arhinencephaly. Clin Dysmorphol 1:43, 1992. 123. Ades LC, Clapton WK, Morphett A, et al.: Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation in a fetus of consanguineous parents: a new multiple malformation syndrome, or a severe form of oral-facial-digital syndrome type IV? Am J Med Genet 49:211, 1994. 124. Le Marec B, Odent S, Urvoy M: A new syndrome with ptosis, coloboma and mental retardation. Genet Couns 3:119, 1992. 125. Kimura H, Ito Y, Koda Y, et al.: Rubinstein-Taybi Syndrome with thymic hypoplasia. Am J Med Genet 46:293, 1993. 126. Mattei J-F, Ayme S: Syndrome of polydactyly, cleft lip, lingual hamartomas, renal hypoplasia, hearing loss and psychomotor retardation: variant of the Mohr syndrome or a new syndrome? J Med Genet 20:433, 1983. 127. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. 128. Stewart FJ, Carson DJ, Thomas PS, et al.: Wolcott-Rallison syndrome associated with congenital malformations and a mosaic deletion 15q11-12. Clin Genet 49:152, 1996. 129. Mathias RS, Lacro RV, Jones KL: X-Iinked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. 130. Corona-Rivera A, Corona-Rivera JR, Bobadilla-Morales L, et al.: Holoprosencephaly, hypertelorism, and ectrodactyly in a boy with an apparently balanced de novo t(2;4)(q14.2;q35). Am J Med Genet 90:423, 2000. 131. Imaizumi K, Ishii T, Masuno M, et al.: Association of holoprosencephaly, ectrodactyly, cleft lip/palate and hypertelorism: a possible third case. Clin Dysmorphol 7:213, 1998. 132. Olsen CL, Hughes JP, Youngblood LG, et al.: Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York state, 1984–1989. Am J Med Genet 73:217, 1997. 133. Croen LA, Shaw GM, Lammer EJ: Holoprosencephaly: epidemiologic and clinical characteristics of a Californian population. Am J Med Genet 64:465, 1996. 134. Urioste M, Valcarcel MA, Gomez I, et al.: Holoprosencephaly and trisomy 21 in a child born to a nondiabetic mother. Am J Med Genet 30:925, 1988. 135. Matsunaga E, Shiota K: Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology 16:261, 1977. 136. Taylor AI: Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Med Genet 5:227,1968. 137. Roessler E, Muenke M: Holoprosencephaly: a paradigm for the complex genetics of brain development. J Inherit Metab Dis 21:481, 1998. 138. Odent S, Le Marec B, Munnich A, et al: Segregation analysis in nonsyndromic holoprosencephaly. Am J Med Genet 77:139, 1998. 139. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet 78:140, 1998.

545 140. Croen LA, Shaw GM, Lammer EJ: Risk factors for cytogenetically normal holoprosencephaly in California: a population-based casecontrol study. Am J Med Genet 90:320, 2000. 141. Sulik KK, Cook CS, Webster WS: Teratogens and craniofacial malformations: relationship to cell death. Development (Suppl) 103:213, 1988. 142. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid and embryopathy. N Engl J Med 313:837, 1985. 143. O’Rahilly R, Muller F: Human Embryology and Teratology. WileyLiss, New York, 1992, p 3. 144. Siebert J, Cohen MM Jr, Sulik K, et al.: Holoprosencephaly. An Overview and Atlas of Cases. Wiley-Liss, New York, 1990. 145. Roessler E, Muenke M: How a Hedgehog might see holoprosencephaly. Hum Mol Genet 12 (Supp 1):R15, 2003. 146. Schell-Apacik C, Rivero M, Knepper JL, et al.: SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet 113:170, 2003. 147. Golden JA, Bracilovic A, McFadden KA, et al.: Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly. Proc Nat Acad Sci USA 96:2439, 1999. 148. Melhuish TA, Wotton D: The interaction of the carboxyl terminusbinding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF. J Biol Chem 275:39762, 2000. 149. Ming JE, Kaupas ME, Roessler E, et al.: Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 110:297, 2002. 150. Zang XM, Ramalho-Santos M, McMahon AP: Smoothened mutants reveal redundant roles for shh and ihh signaling including regulation of l/r asymmetry by the mouse node. Cell 105:781, 2001. 151. Sussel L, Marion O, Kimura S, et al.: Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular specification within the basal telencephalon: evidence for transformation of the pallium into the striatum. Development 126:3359, 1999. 152. Hallonet M, Hollemann T, Pieler T, et al.: Vax1, a novel homeoboxcontaining gene, directs development of the basal forebrain and visual system. Genes Dev 13:3106, 1999. 153. Cooper MK, Porter JA, Young KE, et al.: Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280:1603, 1998. 154. Aguilella C, Dubourg C, Attia-Sobol J, et al.: Molecular screening of the TGIF gene in holoprosencephaly. Hum Genet 112:131, 2003. 155. Nanni L, Croen LA, Lammer EJ, et al.: Holoprosencephaly: molecular study of a California population. Am J Med Genet 90:315, 2000. 156. Muenke M, Gropman A: Holoprosencephaly overview. In: GeneReviews: Genetic Diseases Online Reviews at GeneTests-GeneClinics [database online]. Copyright University of Washington, Seattle. Available at http:// www.geneclinics.org, 2003. 157. Chiang C, Litingtung Y, Lee E, et al.: Cyclopia and defective axis patterning in mice lacking sonic hedgehog gene function. Nature 383: 407, 1996. 158. Lieuw Kie Song SH, Been W: Median facio-cerebral anomalies in chick embryos resulting from local destruction on the anterior-most parts of the early neural plate and neural crest. Acta Morphol Neerl Scand 18:231,1980. 159. Siebert JR: The ethmoid bone: implications for normal and abnormal facial development. J Craniofac Genet Dev Biol 1:381, 1981. 160. Braddock SR, Grafe MR, Jones KL: Development of olfactory nerve: its relationship to the craniofacies. Teratology 51:252, 1995. 161. Brown LY, Odent S, David V, et al.: Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet 10:791, 2001. 162. Marcorelles P, Loget P, Fallet-Bianco, et al.: Unusual variant of holoprosencephaly in monosomy 13q. Pediatr Dev Pathol 5:170, 2002. 163. Barr M Jr, Cohen MM Jr: Holoprosencephaly survival and performance. Am J Med Genet 89:116, 1999. 164. Hercig D, Bau A, Resnek L: Psychosis associated with lobar holoprosencephaly. Can J Psychiatry 39:449, 1994. 165. Shanks DE, Wilson WG: Lobar holoprosencephaly presenting as spastic diplegia. Dev Med Child Neurol 30:378, 1988. 166. Moulignier A, Fenelon G, Aubin ML, et al.: Holoprosencephalie lobaire associe´e a des he´te´rotopies de substance grise. Rev Neurol 146:51, 1990.

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167. Persing JA: Craniofacial surgery and the ethics of decision-making. Cleft Palate Craniofac J 39:357, 2002. 168. Redlinger-Grosse K, Bernhardt BA, Berg K, et al.: The decision to continue: the experiences and needs of parents who receive the prenatal diagnosis of holoprosencephaly. Am J Med Genet 112:369, 2002. 169. Verlinsky Y, Rechitsky S, Verlinsky O, et al.: Preimplantation diagnosis for sonic hedgehog mutation causing familial holoprosencephaly. N Eng J Med 348:1449, 2003. 170. Parr JH: Midline cerebral defects and Kallmann’s syndrome. J R Soc Med 81:355, 1988.

15.5 Malformations of Cortical Development: Disorders of Neuronal and Glial Formation, Migration, and Maturation; Lissencephaly, Pachygyria, Polymicrogyria, Heterotopias, Ectopias, and Cortical Dysplasias Malformations of cortical development are any significant disturbance to the embryogenesis of the cellular architectonics of the six-layered cerebral cortex, which will result in a quite predictable alteration in the gross morphologic appearance of the brain. Careful neuroimaging and attention to clinical-pathologic correlation has led to a greater ability to make the reverse prediction, and in some situations, to suggest the gene that is most likely to have been involved. However, it remains true that the same gross pathology can result from markedly different underlying histopathology. Furthermore, several morphologic, and therefore cellular architectonic, abnormalities can coexist within the same brain. Distinct and recognizable patterns of cellular disturbance may result from diverse genetic and environmental causes. Specific recognition of extrinsic etiologies may be hampered because the brain is incapable of mounting a glial scarring response during the first and second trimesters of pregnancy. A general understanding of the normal pattern of the origin and migration of the neurons and glia is helpful when considering cortical malformations. The reader is referred to the original referenced papers for a more complete discussion of cortical development than is provided in this brief overview. Morphogenesis of the cerebral cortex can be divided into the three distinct, but overlapping, stages of neurogenesis, migration, and organization. Neurons develop from about 40 to 125 days gestation in subependymal proliferative zones that are present along the entire maturing neural tube.1 There are peaks of neuronal production between 8 to10 weeks and at 12 to 14 weeks, with a maximum at 13 weeks.1 In this ventricular zone (VZ), cells in the deeper regions prepare for mitosis and migrate toward the luminal surface, where they divide.2 The daughter cells move to the more superficial VZ, and the process continues back and forth until the cells cease to divide, and migrate to their ultimate cortical positions as neuroblasts and glioblasts, which are initially indistinguishable.2 In some regions a subventricular zone develops in which cells divide, and later migrate, without initially moving to the ventricular lumen.2,3 Some 30% to 50% of young neurons may undergo programmed cell death. A decrease in cell proliferation, excessive cell death, or an alteration in determination of cellular fate at this stage will have a profound impact upon cortical morphogenesis. Mutations in the transcription factor EMX2 have been found in a few cases of open-lipped schizencephaly (see Section 15.11).4 Emx2 is normally produced at the VZ, and mice lacking Emx2 fail to produce radial glial cells (RGC) and lose the ability to produce reelin, thus preventing the next stage of cortical development, which is neuronal migration.5

Cell migration begins by 7 weeks gestation, shortly after neuroblast histiogenesis begins, and continues to about 25 weeks gestation, although the exact endpoint is unknown. At the outset, the cerebrum is limited to the VZ and a narrow marginal zone (MZ) between it and the pia.3 Studies in mice, in which migration occurs between E11 and E18, show that the initial wave of cells that moves toward the pial surface forms a ‘‘preplate’’ neuronal layer.6 A second wave of cells at E13, which forms the cortical plate, splits the preplate into the superficial marginal (plexiform) layer and the subplate, through which all subsequent migrating cells must pass. The marginal zone produces an early synaptic network, mainly of Cajal-Retzius (CR)–like neurons and contains a transient subpial granular cell layer.7,8 The origin of these initial cells remains under study, 7,8 but they are known to secrete reelin, which plays a critical role in cell migration and cortical lamination (vide infra). The subplate neurons are thought to play a role in the early patterning of the internal capsule and commissural fibers of the hippocampus.8 Migration to the cortical plate occurs either by nuclear translocation, which is glial independent, or by locomotion, which requires the presence of specialized radial glial cells (RGC). RCG arise from the VZ before the neuroblasts, and bipolar and monopolar forms produce a radial array of processes, resulting in an intermediate zone (IZ), along which the neuroblasts maintain an intimate contact as they migrate. Bergmann glial cells are the monopolar equivalent in the cerebellum. Radial cells in the superficial ventricular zone (SVZ) or the IZ maintain contact through their descending processes with the basal processes of cells in the VZ.3 RGC remain mitotically active and give rise to further generations of RGC. Important features of the RGC architecture are: 1) they are gathered into bundles as they cross the IZ, and 2) these fascicles become split in a stepwise fashion across the cortical plate until they are ultimately single fibers. The migrating neuroblasts appear to contact multiple RGC fibers as they move up the fascicle; but, as they reach their cortical destination, they move between and separate the fascicle fibers and thus may play a role in controlling the destination of future neuroblasts.3 The initial migrating neurons need only travel a relatively short distance, which permits their own cellular processes to extend to the final destination, and migration can occur by the smooth and continuous process of nuclear translocation to that site.6 As distances become greater, migration becomes dependent upon the integrity of, and interaction with, the RGC. There is evidence that neurons can leave the RGC as they approach their destined lamina and complete the journey by nuclear translocation. Locomotion along the RCG is an intermittent process requiring production of a ‘‘leading process’’ to which the remainder of the cell catches up. The mature cortex consists of six layers (Fig. 15-15): the superficial, relatively acellular, marginal layer (I) and five cellular neuronal layers (II-VI), which are formed embryologically in order from deepest to most superficial but which are named in reverse order from outside in. Cortical lamination is apparent by 23 to 25 weeks gestation, and the outermost layers, II and III, have reached the cortical plate by 26 weeks gestation.1 Layers II and III contain small to medium-sized pyramidal cells; layer IV, stellate cells; layer V, large pyramidal cells; and layer VI, polymorphic cells.3 After the cells reach their destination, there is some orthogonal migration, and growth continues with the development and organization of dendrites, axons, and glial cells. In addition to this predominant radial migration, there is evidence of non-radial migration of cells from the medial ganglionic eminence, and that

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orders according to their presumed pathogenic pathway with subdivision according to clinical and/or genetic detail, and potential but as yet undescribed categories, is attractive and to some extent followed in this section: 1. abnormal neuronal and glial proliferation, 2. abnormal neuronal migration, and 3. abnormal cortical organization. These groups provide a useful framework for thinking about these disorders. However, as emphasized by the authors, our understanding of the detail of underlying pathogenesis is limited, and major shifts are to be expected between major categories and subgroups. As an example, schizencephaly is listed under ‘‘cortical disorganization,’’ whereas the Emx2 mouse model would suggest some cases result from decreased proliferation of RGC. 15.5.1 Lissencephaly

Fig. 15-15. Section through cortex showing the normal six-layered appearance. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Lissencephaly is a generalized failure of the normal pattern of cortical neuronal migration resulting in a smooth cerebral cortex with absent gyral formation (agyria). Some authors prefer the term agyria/pachygyria to lissencephaly because agyria of the entire cortex is relatively uncommon. Lissencephaly is used in this section because the term has become firmly associated with welldefined subtypes of generalized neuronal migration disorders, in several cases due to mutations in known genes. Children with a birth OFC < 3 SD and a lissencephalic brain are classified as having microcephaly with simplified gyral pattern (MSG). Originally called microlissencephaly and classified by Barkovich et al.10 under ‘‘abnormal neuronal and glial proliferation,’’ this condition is discussed in Section 15.1. In fact, our present knowledge does not provide a biologic basis on which to define this demarcation. Diagnosis

these cells are an important source of GABA-staining cortical neurons.9 Cells in the cerebellum migrate from germinal zones over the surface, thus forming the external granular cell layer; they then move inward to form the internal granular cell layer. Over a dozen genes in man, mouse, and other animal models are now known to play a role in migration, and there is little doubt that more will be discovered.4 Specific human genes that have been associated with defined clinical-pathological cortical malformations will be included in the discussion of those conditions that follow. Animal models have also been instructive. For example, mouse studies have shown that Reln (reeler mouse), Dab1 (scrambler and yotari mice), Vldlr (very low density lipoprotein receptor), and ApoER2 (Apolipoprotein E receptor 2) are all part of the same signaling pathway, which when disrupted causes a failure of splitting of the preplate, with the cortical layers remaining below this level and in an inverted order.6 The cells responsible for splitting of the subplate normally arrive at E13 by nuclear translocation, and the histopathology observed with these mutations differs from that seen in other signaling pathways that more closely relate to locomotion and/or the RGC. As our knowledge of the pathogenesis of cortical malformations increases, there is need for a nosology that takes us beyond the purely descriptive. The clinician requires an approach that logically connects the clinical and neuroimaging presentation of the patient with the growing array of DNA diagnostic tests that are becoming available. It is reasonable to assume that genes and teratogens that act at a particular time and on a specific process will have a similar effect upon the histopathology and thus the gross pathology of the cortex. Thus, the effort by Barkovich et al.10 to group these dis-

Lissencephaly may be suspected on the basis of neonatal behavior, appearance, and the presence of commonly associated malformations. Neonates usually present with moderate microcephaly, poor responsiveness and feeding, hypotonia, and often early-onset seizures. Confirmation is readily provided by neuroimaging, which demonstrates a smooth, thick cortex with smooth subsurface lines and an early fetal pattern of the ventricular system resembling colpocephaly (see Section 15.9). With lack of development and operculization, the sylvian fissure is replaced by a fossa and results in a ‘‘figure 8’’ appearance of the brain (Fig. 15-16). Dobyns et al.11 used the specific microscopic pathologic findings to define subtypes of lissencephaly and have further subdivided the classic form (type I) according to the degree of gyral abnormality12 and cerebellar involvement.13 The gyral gradations are grade 1 (diffuse agyria), grade 2 (diffuse agyria with a few shallow sulci over the frontal or occipital pole), grade 3 (mixed agyria and pachygyria), grade 4 (pachygyria only), grade 5 (pachygyria with subcortical band heterotopia (SBH), and grade 6 (SBH only). The classification appears to have validity in that there is good correlation between specific subtypes and certain syndromes and/or specific genes. Classic (type I) lissencephaly is characterized by a smooth neocortex, which may spare the hippocampus and the temporal and limbic cortex (Fig. 15-17). The head circumference at birth usually lies between 1 SD and 2 SD, falling to about 2 SD as the child grows, but microcephaly does not occur in a significant proportion of cases. A majority of children will have treatmentresistant seizures, and both spastic quadriparesis and hypotonia with increased tendon reflexes are common. Although patients with isolated classic lissencephaly have been considered to be

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Fig. 15-16. CT image of a patient with Miller-Dieker syndrome showing the characteristic ‘‘figure 8’’ appearance of lissencephaly. (Courtesy of Dr. W.B. Dobyns, Indiana University School of Medicine, Indianapolis, and Dr. A.E. Chudley, Children’s Hospital, Winnipeg)

normal in appearance, minor facial dysmorphia are not uncommon, and they have been shown to have a similar facial pattern profile to patients with Miller-Dieker syndrome (Fig. 15-18).14 There is hypoplasia of the corticospinal tract and lateral rhombic lip derivatives. When the cerebellum is involved the hypoplasia is maximal in the midline, affecting the vermis, sometimes including mild hypoplasia of the hemispheres, but folia are maintained.13 This midline cerebellar involvement is considered characteristic of classic lissencephaly by Ross et al., and

Fig. 15-17. Gross lissencephaly brain specimen showing smooth cortical surface with shallow sylvian fissure. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Fig. 15-18. Photograph of patient showing the typical facial appearance of Miller-Dieker syndrome. (Courtesy of Dr. A.E. Chudley, Children’s Hospital, Winnipeg.)

is classified as type LCHa in their discussion of lissencephaly with cerebellar involvement (LCH).13 The overall cortical thickness is increased with more gray matter and less white (Fig. 15-19). This increase varies from moderate levels of 5–10 mm to more marked values of 10–20 mm depending upon the particular syndrome/ gene involved. The MRI detection of a thin cortical band with a high T2-weighted signal may be helpful in distinguishing classic lissencephaly. This band represents a partially myelinated layer with reduced cell numbers, which lies beneath the true cortex.15 Microscopically the cortex consists of four, rather than the normal six, layers (Fig. 15-20): an outer, abnormally wide molecular layer; a relatively thin superficial layer of neurons oriented perpendicular to the surface; a plexus of myelinated fibers horizontal to the cortex and containing few nerve cells; and a thick, poorly organized, deep cellular layer joining the thin layer of white matter and representing neurons that failed to migrate. The third layer may not be apparent in the very young, and the fourth layer may become subdivided by myelinated fibers in older children.16 The four cortical layers do not blend into normal adjacent cortex and are thus distinguished from the findings in true polymicrogyria. The combination of gross cerebral and cerebellar pathology, and histopathologic differences, can be combined to better define subtypes of classic lissencephaly, and these in turn show useful clinical-genotype correlation (Table 15-5). In a preliminary study,

Brain

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Fig. 15-19. Lateral gross view and parahorizontal section from a fetus at 34 weeks gestation with lissencephaly and dilatation of the posterior lateral ventricles (V). The surface of the cerebral cortex is smooth (arrows). Other findings include heterotopic foci of gray matter and septum cavum pellucidi defect. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Viot et al.298 have proposed that lissencephaly due to mutations in DCX (vide infra) result in a roughly ordered ‘‘six-layered’’ cortex. Cobblestone (type II) lissencephaly is thought to represent the migration of neurons beyond the cortical plate and marginal zone, through a disrupted pial-glial limitans, and into the leptomeninges. This results in a pitted, verrucous (cobblestone) layer over the surface of the cortex (Fig. 15-21). This type of lissencephaly does not occur as an isolated malformation, but rather is accompanied by additional abnormalities of the brain, eyes, and muscles in specific syndromes (Fig. 15-22; Table 15-5). The clinical and pathologic severity varies with the specific syndrome, and most cases have been associated with Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), or Fukuyama congenital muscular dystrophy (FCMD), which are listed in descending order of severity. In its most severe expression, the cerebrum is void of gyri except for a shallow sylvian fissure. A few patients may have some areas of abortive gyri with shallow, distorted fissures. The cortex is relatively thickened (7–10 mm), and the third and lateral ventricles are grossly dilated. Obstructive hydrocephalus due to gliovascular and mesodermal overgrowth can usually be demonstrated. Hydrocephalus may obscure the characteristic smooth surface of lissencephaly in neuroimaging sections (Fig. 15-22), and diagnosis depends on recognition of the smooth subsurface lines. Associated neuropathologic findings may include a small, dysplastic cerebellum with a simple foliar pattern, absent posterior vermis, and hypoplastic anterior vermis. The cerebellar cortex is usually thickened but may be absent in small areas. Olfactory elements may be absent or hypoplastic, and the optic pathway (in association with malformations of the eye) is often hypoplastic.

The cerebral hemispheres, notably the frontal areas, may be fused by a gliosis; the septum pellucidum is absent and the corpus callosum absent or hypoplastic. The claustrum is absent, and most deep nuclei are present but small. A variety of brain stem structures may be affected, largely related to lack of their usual cortical and cerebellar connections.17 Dandy-Walker cysts or posterior cephaloceles may occur. The cerebral white matter has a spongy edematous appearance, and subependymal cavitations have been observed. Microscopic examination shows clear differences from type I.17 The cortex lacks normal lamination, and two broad laminations may be recognized.9 An outer band is broken into pockets of cells and acellular zones by ingrowing gliovascular bundles that show extensive proliferation near the surface and in the subarachnoid space (Fig. 15-23). Glial fibrous bands may interrupt the gray matter. Cell columns are sparse and disoriented, as are neurons that have reduced axons. Oligodendrocytes and myelin are reduced. A deeper layer of disorganized neurons may represent the original cortical plate.9 Neuronal heterotopias are present in the deeper cortex and white matter. Adjacent areas of pachygyria and polymicrogyria show similar pathology but with greater acellular areas and are thus distinct from classic pachygyria and polymicrogyria. The pathologic cortical findings in Neu-Laxova syndrome, although not unique to that syndrome (Table 15-5), have been referred to as type III lissencephaly.18 Findings vary somewhat but are characterized by virtual agyria and by a granular-appearing cortex. The corpus callosum is generally absent, the cerebellum very hypoplastic; olfactory and optic tracts, quadrigemina, basal ganglia, and thalami are hypoplastic or absent. Identifiable nuclei tend to show immature forms. The third and fourth ventricles

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Fig. 15-20. Section from cortex of a patient with Norman-Roberts type lissencephaly showing three to four layers. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

may have an open roof; the cortex is thin, and there is poor gray matter/white matter distinction. In most studied cases there are six cortical layers with many immature neurons, and glial elements are seen in the periventricular area. Within the same case, the small cerebellum may consist of two to four layers. Immature neurons are found in the white matter, especially the wall of the fourth ventricle. Patients whose pathologic findings in the brain are less clearly defined have been described and are included in Table 15-5. Etiology and Distribution

Lissencephaly is the endpoint of causally heterogeneous abnormalities of neuronal migration (Table 15-5). Details of the embryology of neuronal migration have been published by Sidman and Rakic58 and summarized in a number of recent reviews4,6,9,59 (see also Fig. 15-24). The discovery of a number of genes in which mutations cause lissencephaly is leading to a greater understanding of the gene interactions and processes that are required for neurons to migrate along the RGC and to successfully settle at their appropriate lamina. In classic (type I) lissencephaly, early layering of the cerebral cortex and relative preservation of the cerebellum and specific areas affected are compatible with arrest of development at 11 to 13 weeks gestation and with primary involvement of the pallial and rhombic lip pathways (Fig. 15-24). In what Dobyns et al.11 have called the cerebrocerebellar lissencephaly variant of type I (Table 15-5), changes are most compatible with disrupted development at 8 to 9 weeks gestation; the cerebellar pathway is also

involved and results in extreme cerebellar hypoplasia. In some patients, the absence of cortical layering suggests an earlier occurrence of developmental arrest than in those who have a fourlayered cortex.11,21 Haploinsufficiency of LIS1 was the first gene to be identified as causing classic lissencephaly.60 It is deleted in all patients with Miller-Dieker syndrome and accounts for 40% of isolated classic lissencephaly. The gene product, a non-catalytic alpha subunit of intracellular 1b isoform platelet activating factor acetylhydrolase (PAFAH1b1), is widely distributed from early fetal to adult life in the brain and spinal cord.61 More recently, patients with a milder lissencephaly phenotype have been found to have missense mutations in LIS1, raising the potential for under-ascertainment of patients with milder migrational defects caused by mutations in this gene.62 From a series of patients it has been noted that those with LIS1 deletions or null mutations in the coded coil domain (exons 2–5) had a grade 2–3 cortical severity; those with null mutations more distally generally were grade 3–4, whereas missense mutations, with the exception of those involving a critical amino acid, were even less severe.12 Studies of null and hypomorphic conditional knockout mice6,9 have shown that Lis1/ is a trophoblast stage lethal, and that cortical disruption in heterozygotes is Lis1 dose dependent. The primary embryopathology is a slowing of cell migration. In mild Lis1 deficiency, the cortical lamination proceeds in its normal inside-out direction but the layers are indistinct; more severe reduction of Lis1 results in failed subplate splitting and a complete loss of lamination.63 PAFAH is an inactivator of platelet activating factor (PAF), and it is not clear whether or not LIS1, in its role as a subunit of PAFAH, has a direct effect upon neuronal migration, but altered signal transduction could act upon the neuronal cytoskeleton. The current consensus is that the critical role of LIS1 is its microtubule-associated regulation of dynein activity. This system is highly conserved from yeast, to flies and mammals. Work with NudF (aspergillus nidulans equivalent of LIS1) has shown that it interacts with a tyrosine kinase (NudC) and a cytoplasmic dynein (NudA), with additional involvement of NudE (mouse Nudel), which binds to NudF and the dynein light chain.64,65 Findings are similar in drosophila and mammals. LIS1, dynein, and the dynein-regulatory complex localize to the VZ and cortical plate, and play a key role in microtubular organization in the cell periphery.4 Disruption might well affect production or function of the leading process or ‘‘catch up’’ of the cell body, thus impairing locomotion during RGC-related neuronal migration. The LIS1-dynein complex may also have a direct effect on cell division and nuclear translocation. LIS1 is localized to the kinetocores and the mitotic spindle, and varying LIS1 levels can cause in vitro disruption of mitosis.66 Diminished cell number, and delayed production of cells and altered interkinetic nuclear migration, which would both alter the timing of migration, would be expected to disrupt normal cortical lamination. The gene 14-3-3e (YWHAE) lies 40kb telomeric of LIS1 on 17p13.3, and its concurrent deletion in patients with MillerDieker syndrome appears to account for the greater severity of lissencephaly (grade 1) in that syndrome, as compared to patients with deletions restricted to LIS1 (grades 2–3).67 The gene product of 14-3-3e binds to and prevents the dephosphorylation of CDK5/ p35 phosphorylated NUDEL, and is necessary for localization of NUDEL, and for the functioning of the dynein complex.22 Mice deficient in 14-3-3e have brain pathology equivalent to heterozygous Lis1 deficient mice, whereas compound heterozygotes for Lis1 and 14-3-3e are more severely affected.22

Table 15-5. Syndromes with lissencephaly Syndrome

Prominent Features

Causation Gene/Locus

Microlissencephaly-cardiacspinal urogenital19

Severe growth and developmental delay, quadriparesis, roving eye movements, early death, ventricular septal defect, distal arthrogryposis, urethral valves, hypospadias; consanguinity

AR/XLR?

Microcephaly-simplified gyri20

Severe congenital microcephaly, early onset seizures, normal tone to mild spasticity, simplified gyral pattern on neuronal imaging

AR (603802) Not linked to 17p, 8p22

Barth: cerebro-cerebellar I21

No extracranial anomalies, very small brain, extreme neopallial and cerebellar hypoplasia, failure of mesencephalic flexure, absence of rhombic lip and cortico-spinal structures

Probable AR

Miller-Dieker22,23

Microcephaly usually of postnatal onset, prominent occiput, bitemporal narrowing; low, rotated ears, upturned nares, long, thin upper lip, micrognathia, postnatal growth failure, genital and heart anomalies, absent corpus callosum, calcification between lateral ventricles, profound mental retardation (Figs. 15-16 and 15-18)

(247200) del 17p13.3; may be sub-microscopic LIS1, 14-3-3e

Norman-Roberts24

Microcephaly, small forehead, wide-set eyes, micrognathia, flat nasal bridge, chordee, clinodactyly 5th finger, high number of whorls on finger-tips, low brain:total weight ratio; some consider this is LCHb and due to RELN mutations but unproven

AR (257320) RELN, 7q22?

Isolated lissencephalygeneral23,25

Extracranial anomalies other than deformations rare: agenesis of the corpus callosum less common than in Miller-Dieker; when present, calcifications are scattered and may be periventricular; ~75–80% associated with known genes

Heterogeneity AD/XLR/AR

Isolated lissencephaly-LIS1 associated12,26

Cortex 10–20 mm, posterior ! anterior gradient, cell sparse zones in agyric areas, midline cerebellar involvement, grades 2–4 severity; deletions (40%) and point mutations

AD (607432) LIS1, 17p13.3

Isolated lissencephaly-DCX associated12,13,27

Cortex 10–20 mm, anterior ! posterior gradient, cell sparse zones in agyric areas, SBH in female heterozygotes, grade of severity variable but 3 uncommon

XLD (300121) DCX, Xq22.3q23

Isolated lissencephaly-RELN associated (LCHb)12,86

Cortex 5–10 mm, anterior ! posterior gradient, no cell sparse zones in agyric areas, abnormal hippocampus, cerebellar hypoplasia

AR (605140) RELN, 7q22

Isolated lissencephaly-14-3-3e associated12,22

Posterior ! anterior gradient, grade 1 severity when deleted with LIS1

AD/biallelic, 17p13.3

Lissencephalyhypomyelinating neuropathy29

Arthrogryposis, severe developmental delay, microcephaly, axonal neuropathy with hypomyelination. Single case

Unknown

X-linked-abnormal genitalia (XLAG)12,30

Cortex 5–10 mm, posterior ! anterior gradient, no cell sparse zones in agyric areas, deficient small cortical granular cells, immature white matter, poorly demarcated basal ganglia that may have small cysts, agenesis corpus callosum (includes 50% of females), neonatal onset of seizures, hypothalamic dysfunction, ambiguous male genitalia

XLR (300382, 300215) ARX, Xp22.13

Microlissencephaly

Classic (Type I) Lissencephaly

Cobblestone (Type II) Lissencephaly

Cobblestone lissencephalynormal eyes and brain31

Moderate to severe developmental delay, mild axial hypotonia and lower limb spasticity, Dandy-Walker, ventriculomegaly, brain stem hypoplasia, normal eye examination including ERG, normal CK

AR

Cobblestone lissencephalyretinal atrophy32

Profound mental retardation, abnormal cerebellum, severe myopia; sectors of retina of varied thickness with gliosis and disordered layers, gliotic optic nerve; normal muscle; eye pathology considered distinctive

Unknown

Dobyns: cephalocele-retinal elevation11

Large fontanels, cephalocele, mild microcephaly, abnormal ears, myopia, peripheral retinal elevation, low nasal bridge, epicanthus, ptosis, small jaw; one case

Unknown

Dobyns: facio-oculo-aural33

Microcephaly, mild trigonocephaly, short nose and jaw, flat philtrum, low-set ears with absent crura and antihelix, microcornea, ectopic pupils, choroidal coloboma, finger contractures, absent corpus callosum

Unknown

Fukuyama: cerebro-oculomuscular4,34,35

Less severe than Walker-Warburg, developmental delay, small areas of agyria, pachygyria/ polymicrogyria microscopically as in type II lissencephaly, mild cerebellar foliation defects, minor or absent eye defects, progressive facial and limb muscular dystrophy and contractures, raised CK; founder mutation in Japanese

AR (253800) Fukutin, FCMM, 9q31-q33

Muscle-eye-brain4,36

Early onset severe hypotonia, delayed development, frontal pachygyria, occiput less severe, agenesis of the corpus callosum, hypoplasia of the pons and cerebellar vermis, white matter abnormalities patchy or absent, mild hydrocephalus, nystagmus, anterior chamber defects, glaucoma, myopia, preretinal glial membrane, ERG abnormal after age 1 year, cataracts, myopathy with elevated CK levels; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

(continued)

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Table 15-5. Syndromes with lissencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Seidahmed: congenital muscular dystrophy37

Profound prenatal and postnatal hypotonia, generalized joint contractures, biopsy evidence of muscular dystrophy, lack of ocular involvement differentiates from cerebrooculo-muscular and Fukuyama congenital muscular dystrophy, probable cerebellar hypoplasia, type II lissencephaly with a cobblestone appearance

AR

Walker-Warburg (HARDþ/E)4,17,38

Diffuse agyria, cobblestone appearance may be obscured by hydrocephalus, abnormal white matter, laminar heterotopia below cortex, absent septum pellucidum, severe midline to lateral cerebellar hypoplasia, brain stem hypoplasia, Dandy-Walker malformation, cephalocele, retinal dysplasia/nonattachment; microphthalmia, cataract, corneal opacity, hyaloid vessels, retinal corneal opacity, abnormal face; myopathic skeletal muscle with variable size and splitting of fibres with endomysial fibrosis

AR (236670) POMT1, 9q34.1

Neu-Laxova18

Sloping forehead, hypertelorism, abnormal ears, extreme microcephaly, absent corpus callosum, flexion contractures, syndactyly, phalangeal hypoplasia, subcutaneous edema, ichthyosis, hypoplastic genitalia, pulmonary hypoplasia

AR (256520)

Stippled epiphyses-loose skin-lissencephaly type III39

Microcephaly, arthrogryposis, craniofacial edema with onset in utero; stippled cervical vertebrae, feet and sacrum; short metacarpals and distal phalanges, agenesis of corpus callosum, agyria, hypoplastic brain stem, diffuse severe neuronal loss

AR

3-hydroxyisobutyric acid40

Poor neonatal behavior, triangular face, short and sloping forehead, narrow bitemporal distance, shallow supraorbital ridges, epicanthus, micrognathia, adducted thumbs, clinodactyly of toes 4 and 5, intracerebral calcification, cerebellar hypoplasia, agenesis of the corpus callosum, lissencephaly, pachygyria

AR (236795)

Abnormal lymph nodes-Tcell deficiency41

Early onset of infections, rheumatoid symptoms, postnatal growth failure, hypertonia, dysmature lymph nodes, hypodontia, micrognathia

Unknown

Cerebro-cerebellar II11

Similar to that reported by Barth et al.,9,12 but without four-layered cortex

Unknown

Choi: subarachnoid neuronal ectopia42

Early lethal, recurrent apnea, posteriorly rotated ears, prominent supraorbital ridges, high palate, smooth brain, including cerebellum, massive ectopic neurons and glial cells in the subarachnoid space; single case

Unknown

Craniotelencephalic dysplasia43

Craniosynostosis, frontal bone protrusion, encephalocele, microphthalmia, hydrocephalus, absent corpus callosum, grade 2 lissencephaly, incomplete lamination, no mature neuronal organization, cerebellar heterotopias

Probably AR (218670)

Dental anomaliespolyarthritis44

Hypodontia, polyarthritis, flared ribs, T-cell dysfunction, probably type I lissencephaly; one case

Unknown

Fontaine: craniosynostosislimb defects45

IUGR, craniosynostosis, wormian bones, broad forehead, downslanting palpebrae, overfolded helix, disorganised posterior hair patterning, especially at the back, small hands, hypoplastic distal phalanges, hypoplastic abdominal muscles, small genitalia, patchy lipodystrophy, ventricular septal defects, lissencephaly; single case

Unknown

Goldenhar46

Variable asymmetric and hypoplastic lower face, microtia, preauricular tags and pits, macrostomia, upper vertebral anomalies, epibulbar dermoids, variety of CNS defects in low frequency

Sporadic: occasionally AD (164210), 14q32

Kozlowski-Tsuruta: cortical hyperostosis47

Stillborn, hydrops, hypoplastic lungs with incomplete lobation, bone cortical thickening most marked in long bones and ribs, narrow proximal metacarpals and metatarsals, vertebral coronal clefts, may have had lissencephaly

Unknown

Lissencephaly-cleft palatecerebellar hypoplasia48

IUGR, cleft palate, ventriculomegaly, long thumbs and halluces, absent distal digital creases, variable brain stem involvement, absent corpus callosum, absent cerebellum, thick and disorganized cortex, no cortical lamination, severe cerebellar hypoplasia, LCHc of Ross et al.13

Uncertain

Majoor-Krakauer: Seckel like49

IUGR, extreme micrognathia, dysplastic low-rotated ears, beak-like nose, prominent eyes, absent gyral pattern and abnormal neuronal migration, not further described

AR

Micro50

Severe mental retardation, microcephaly, prominent ears, beaked nose with a prominent root, microcornea, cataracts, optic nerve atrophy, retinal dystrophy, small pupils, posterior synechiae, hypertrichosis, agenesis of the corpus callosum, one of three patients stated to have lissencephaly

AR (600118) RAB3GAP, 2q21.3

Type III Lissencephaly

Undefined Lissencephaly

(continued)

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Brain

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Table 15-5. Syndromes with lissencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Osteogenesis imperfectamicrocephaly-cataracts

Type II osteogenesis imperfecta, IUGR, hypertelorism, cataracts, cardiac anomaly, ambiguous genitalia, single umbilical artery, marked microcephaly, ‘‘smooth cortex without convolutions,’’ cerebellum hypoplastic; one family of three siblings

Probably AR (259410)

Pena-Shokier I: fetal hypokinesia52,53

Restriction at major joints, camptodactyly, decreased dermal ridges and digital flexion creases, IUGR, micrognathia, abnormal pinnae, small mouth, pulmonary hypoplasia, cryptorchidism, polyhydramnios

Heterogenous, many AR (208150)

Prenatal alcohol54

Growth deficiency, short palpebral fissures, midface hypoplasia, joint restriction, abnormal dermatoglyphics, developmental delay, brain heterotopias, ectopias, and, in the most severe cases, lissencephaly

In utero alcohol exposure

Prenatal cytomegalovirus24

Microcephaly, retinopathy, deafness, periventricular calcification. Severe cases have lissencephaly with no differentiation of cortex, unmyelinated parenchyma, and central nuclei, large leptomeningeal vessels, astroglial scarring, disorganized cortex, heterotopias, and cell loss

In utero infection exposure

Prenatal isoreinoin55

Neural crestopathy with craniofacial and cardiac anomalies. Some patients have areas of pachygyria or agyria with histology most like type I lissencephaly

In utero exposure

Prenatal valproic acid56

High and narrow forehead, infraorbital skin creases, telecanthus, short nose, midface hypoplasia, cardiac malformations. Neural tube defects are the most common CNS lesion, but abnormal corpus callosum, colpocephaly, and lissencephaly have been reported.

In utero exposure

Sedaghatian: lethal metaphyseal dysplasia57

Mild rhizomelia of the arms, narrow chest, mild platyspondyly, lacy iliac crests, severe metaphyseal dysplasia, relatively few reports, one with lissencephaly

AR (250220)

Winter: osteodysplastic primordial dwarfism86

IUGR, sloped forehead, prominent occiput, alopecia, low-rotated abnormal ears, largebeaked nose, disproportionate short limbs, redundant skin, joint dislocations and limited extension, platyspondyly, delayed ossification of vertebrae, short long bones, broad metaphyses, hypoplastic vermis, absent corpus callosum, few gyri, loss of cortical layers

Unknown

Doublecortin (DCX) was the second major isolated lissencephaly gene to be found, and it accounts for about 35% of cases.27,68 Most mutations are missense and cause classic lissencephaly in hemizygous males and subcortical band (sometimes called laminar) heterotopia (SBH) in heterozygous females (Fig. 15-25). Females have a normal laminar cortex, except for somewhat shallow sulci, and a bilateral, symmetrical band of gray matter within the central white matter. The relative thickness of the band shows some correlation with clinical severity, which can range from normal intelligence to significant mental retardation with

Fig. 15-21. External surface of the brain from a patient with type II lissencephaly showing smooth verrucous surface. (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

seizures. Random X-inactivation accounts for the mixed population of normal cells migrating to the cortical plate, and the abnormal cells that fail to migrate and form the SBH. The severity of lissencephaly in the male is quite variable (grades 1–4), and in general, males with grade 1 lissencephaly have symptomatic heterozygous female relatives with thick SBH, whereas those with grade 4 lissencephaly have female relatives with SBH limited to the

Fig. 15-22. Coronal CT image from a patient with WalkerWarburg syndrome illustrating how hydrocephalus obscures the brain surface. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

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Neuromuscular Systems

Fig. 15-23. Section of cortex from a patient with cobblestone lissencephaly taken through a verrucous area showing lack of lamination and having a polymicrogyric appearance with vertically descending blood vessels (arrows). (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Fig. 15-24. Summary of the embryologic milestones relevant to the occurrence of lissencephaly.

frontal region and/or thin bands and a more favorable outcome.12 MRI changes may be subtle and discontinuous in some cases.69 Normal carrier women have been seen with mutations that cause only frontal SBH in males.70 Somatic mosaicism appears relatively common in both sexes, again resulting in a milder phenotype. Thus, a high index of suspicion may be necessary when considering mutation in this gene. DCX is a mammalian gene that has two tandem conserved repeats (doublecortin domains) that bind to a- and g-tubulin, but

not directly to microtubules per se.6,12 Expression is exclusive to the fetal brain, and in vitro and mouse brain extract it acts in concert with LIS1 to maintain stability of microtubular polymerization.6 Thus, it may be related to the LIS1 pathway. Clinicalgenotype correlation shows that truncating mutations in exons 1–7 cause severe disease, while those in exon 9 are milder; missense mutations cluster in the doublecortin domains of exons 4–6.12 Mutations in RELN have been reported in a small number of patients with LCHb,13,28 which some consider to include the

Brain

Fig. 15-25. T1-weighted MRI, axial sequence, supraventricular region. Note the simplified gyral pattern with several large gyri (left anterior, bilateral occipital). The posterior hemispheres show an extensive bilateral subcortical band of heterotopic gray matter. Anteriorly the pachygyric cortex shows increased thickness of the gray matter layer. The left hemisphere is on the reader’s right. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario)

Norman-Roberts phenotype. These patients have a moderately increased cortical thickness of 5–10 mm, with an anterior-toposterior gradient of severity, involvement of the hippocampus, and a cerebellum with virtually no folia. RELN is a 388 kd protein with 8 EGF repeats that is secreted into the extracellular matrix by the CR cells of the preplate, MZ, cerebellar EGL, and hippocampal pioneer cells.4 RELN was initially cloned as Reln, the gene responsible for the mouse reeler phenotype, which shows failed preplate splitting and a poorly laminated inverted cortex. Further work with the scrambler and yotari mice that have different mutations in Dab1 (disabled), and a double null knockout for Vldlr and ApoER2, all of which share a phenotype similar to reeler, have demonstrated the relationships of this signaling pathway.4,6,12 RELN acts as an extracellular ligand for Vldlr and ApoER2, thereby directing tyrosine phosphorylation of Dab1, which binds on the cytoplasmic side of the cell membrane. Reeler mice and double null homozygotes for Vldlr and ApoER2 have elevated levels of Dab1, and knock-in mice with absent Dab1 tyrosine phosphorylation sites have a reeler phenotype,71 thus proving the key role of this phosphorylation pathway. Dab1 is known to interact with a number of other mouse proteins (Abl, Enah, fax, prospero) that have been implicated in neuronal migration and neurite outgrowth.6 The fact that Dab1, Vldlr, and ApoER2 are secreted by

555

the radially migrating neurons and that RELN is secreted by the CR cells of the MZ suggests that a RELN gradient may play a role in radial migration. Reln also binds to other signaling components such as a3b1-integrin and the cadherin related neuronal receptor family, possibly suggesting a role in determining when neurons detach from the RGC.6 Kitamura et al.30 have demonstrated that mutations in ARX (aristaless-related homeobox) cause abnormal forebrain and testicular development in mice and the X-lissencephaly abnormal genitalia (XLAG) syndrome in humans. This condition represents the first clear example of human lissencephaly that primarily affects the tangential migration of interneurons from the medial ganglionic eminence (MGE). The lissencephaly in this syndrome is characterized by a moderately increased cortical thickness, a posterior-to-anterior gradient of severity, a normally oriented 3-layered cortex with immature white matter, absent corpus callosum, basal ganglion cysts, and a deficiency of small granular neurons in the cerebral cortex.12,30 Males with XLAG have null or non-conservative missense mutations, whereas heterozygous females may have a normal phenotype with absent corpus callosum or suffer variable mental retardation and seizures. Other types of ARX mutations are responsible for a broad syndromic spectrum with poor genotype phenotype correlation, including X-linked infantile spasms, non-syndromic XLMR, Partington syndrome, hydranencephaly, and/or agenesis of the corpus callosum with abnormal genitalia.12,72 The mouse model of XLAG shows decreased proliferation throughout the VZ, normal radial neuronal migration, and severely disturbed migration from the MGE to the cortical intermediate zone. Interestingly, neurons from the MGE show normal migration to the cortical subventricular zone.30 Normally, intercortical neurons are scattered throughout the cortical plate, but in Arx mutant mice, those cells that do migrate are restricted to the subplate; GABAergic interneurons that are normally found in layer V are scattered in the cortical plate of mutant mice. Thus, there is disruption of a two-stage migrational process; step one from the MGE to the intermediate zone, and step two from there to the appropriate cortical lamina. As already discussed, cobblestone (type II) lissencephaly appears to be due to migration of neurons and glial cells beyond the cortical plate and a disrupted glia-limitans. It is largely associated with WWS, MEB, and FCMD (Table 15-5), which show varying severity of brain and muscle disease, with or without eye involvement. All three syndromes share a common pathogenesis involving defective glycosylation of a-dystroglycan (a-DG). Dystrophin at the inner cell surface binds with the transmembrane b-subunit of dystroglycan, which binds to extracellular a-DG.73 The latter then binds other proteins such as laminin, agrin, and neurexin, also engaging integrins and perlecan in the incorporation of laminin into larger clusters that are important to the integrity of the glia-limitans. Dystroglycan binding requires that glycosyltransferases add sugar moieties to both the a and b subunits.73 Michelle et al.74 demonstrated reduced glycosylation of aDG in MEB and FCMD, as well as in the naturally occurring myodystrophy (myd) mouse, which has similar brain pathology. a-DG, but not b-DG, was absent from muscle biopsies in both diseases, and in the mouse, which also had a disrupted glia-limitans. Moore et al.75 created a conditional knockout mouse, with absent aDG limited to neurons and glial cells. The mouse demonstrated brain changes compatible with cobblestone lissencephaly, but, as expected, had normal muscle. The MEB gene, O-mannosyl-b-1,2N-acetylglucosaminyltransferase (POMGnT1), which was isolated

556

Neuromuscular Systems

by Yoshida et al.,76 adds an N-acetylglucosamine residue to a protein O-linked mannnose.38 The FCMD gene, Fukutin, was found by Kobayashi et al.77 The disease is rare outside of Japan, where a significant majority of cases are attributable to an ancient insertion of a retrotransposon in the 30-untranslated region. Recently, Beltran-Valero de Bernabe´ et al.,38 using a candidate gene approach with homozygous mapping in consanguineous families, have shown that WWS is due to a deficiency of O-mannosyltransferase (POMT1). This enzyme catalyzes the first step in O-mannosylglycan synthesis, a process limited to the brain, peripheral nerves, and muscle, perhaps accounting for the greater severity of WWS, as compared to MEB and FCMD. The current consensus is that abnormal glycosylation of a-DG causes impaired stability of the basement membrane and dystrophin complex causing muscular dystrophy, and that diminished binding and clustering of laminin causes a defective glia-limitans. Abnormal glycosylation may act through other pathways, including dysfunction of neuromuscular junctions and synapses. Other potential causes for cobblestone lissencephaly are suggested by the production of similar brain pathology in a presenilin-1 deficient mouse model.78 Presenilin-1 is transiently expressed in leptomeningeal fibroblasts, and its role in the maintenance of CR cells was illustrated by the loss of the majority of cells in the MZ, including most of the CR cells. Type III lissencephaly (Neu-Laxova) is suggestive of inadequate migration of neurons, with incomplete maturation and differentiation corresponding to arrested development at 12 to 16 weeks gestation; but responsible genes have yet to be discovered.18 There do not appear to have been any systematic determinations of the incidence of lissencephaly. Although research groups may assemble reasonable numbers of cases for study, true lissencephaly appears to be uncommon. Prognosis, Treatment, and Prevention

The outlook for all children with lissencephaly is extremely grave, more so for those with the identifiable syndromes. An occasional patient with isolated lissencephaly may sit or roll, and a rare patient with mild, mixed agyria and pachygyria will walk.79 The majority of patients show no significant development beyond the 3- to 5-month level.23 The neonate is hypotonic and feeds poorly; feeding may improve, but development of spasticity in type I may compromise both feeding and respiration. Seizures begin shortly after birth in most patients and frequently are, or evolve into, infantile spasms. While the overwhelming majority of patients, regardless of the type of lissencephaly, will die before age 2 years, parents should be informed that occasionally there will be survival to late childhood. Leventer et al.87 estimate survival to age 10 years for lissencephaly due to mutations in DCX. As discussed, certain mutations may give rise to milder cortical changes and be compatible with a significantly better prognosis, but such children do not have lissencephaly per se. The same is true of SBH. The severe underlying malformations of the brain are not amenable to treatment, but normal supportive care is appropriate to facilitate comfort and nursing requirements. Seizures should be controlled, significant progressive hydrocephalus shunted, and, if feeding proves difficult, a gastrostomy tube should be considered. Aspiration and respiratory disease are the most common terminal events. The fact that the normal fetal brain is lissencephalic in the first half of the second trimester, and that many children with lissencephaly are born with an OFC that falls within the normal range, means that early recognition of isolated lissencephaly during

standard prenatal ultrasound is unlikely. Early microcephaly or associated cerebellar hypoplasia may be detected in some cases, although generally this has occurred in the late second or early third trimester.21,80 With improved prenatal imaging and greater attention to the subtle details of normal evolution of cortical sulcation, earlier diagnosis may prove possible.81 Toward that end, Abe et al.82 have studied and classified normal fetal gyral and sulcal development from 18 to 39 weeks gestation. In syndromic lissencephaly (Table 15-5), brain malformations or anomalies in other systems may allow for earlier prenatal detection of fetal anomaly. Prenatal diagnosis of Walker-Warburg syndrome is possible through recognition of associated hydrocephalus, absent corpus callosum, posterior fossa cysts, clefting, and even retinal detachment.83,84 Thus, except for the chance recognition of abnormalities on a routine ultrasound, prevention is based on the recognition of specific etiologies, provision of appropriate genetic counseling, cytogenetic and molecular diagnostics, and prenatal diagnosis for specific syndromes. Careful pregnancy and family histories should be obtained. All patients with Miller-Dieker syndrome will be found to have either a cytogenetically visible or submicroscopic deletion of 17p13.3, and appropriate counsel will depend on parental karyotypes. Patients without visible deletions should be studied with appropriate molecular probes.85 In the absence of a parental chromosome rearrangement, most families of patients with this syndrome have a low recurrence risk. Attention to the details of clinical and pathological examination, as well as neuroimaging studies, will allow the most appropriate choice of cytogenetic and/or DNA diagnostic testing. Current knowledge is such that abnormalities in known genes account for a significant majority of affected children, both those with non-syndromic classical and with syndrome-associated cobblestone lissencephaly. Thus, a majority of families should be able to benefit from this knowledge as they consider having additional children. The relatively high frequency of somatic mosaicism in DCX should be kept in mind. The presence of marked cerebellar involvement in association with classic lissencephaly probably raises a greater concern for autosomal recessive inheritance. The possibility of a contiguous gene syndrome should be considered in cases of syndromic classic lissencephaly, especially if the clinical and neuroimaging pattern is suggestive of any of the known genes. In cases where marked microcephaly has been present at birth, it is reasonable to screen for microcephaly with prenatal ultrasound in subsequent pregnancies, but with the understanding that the onset of microcephaly may occur relatively late in gestation. 15.5.2 Pachygyria Definition

Pachygyria is an area of cerebral cortex that shows a reduced number of gyri, which are unusually broad and in which the cortical mantle is abnormally thick (Figs. 15-26, 15-27). The affected cortex is generally four layered and is similar to, but reflects a slightly later embryologic timing than, agyria. The subdivision and nomenclature of the neuronal layers differ slightly between authors and are summarized in Fig. 15-28. The molecular or marginal layer is normal. The outer or cellular layer consists of large, medium, and small neurons and of polymorphic cells that have reached their normal location but that occur in reduced quantity in the cortex.2,87 Many of the neurons have abnormal orientation of their apical dendrites, and other

Brain

557

Fig. 15-26. T1-weighted MRI, coronal sequence, parieto-occipital region. The left panel shows a normal brain. The right panel is an image from a mentally handicapped individual with severe congenital microcephaly. Note the enlarged lateral ventricles, the thin cerebral mantle, and the simplified gyral pattern. There are abnormally broad gyri in the parasagittal convexity and virtual absence of gyri in the cortex apposed to the tentorium cerebelli. Cortical gray matter thickness is relatively normal. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

Fig. 15-27. Macrogyria (black lines) in a fetus at 33 weeks gestation with asphyxiating thoracic dystrophy. C, cerebellum; BS, brain stem; A, anterior; P, posterior. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

disoriented organization.88 It is less defined and marked than in classic lissencephaly, and the differences in Fig. 15-28, therefore, are more a question of timing and severity with respect to this third layer. The inner or thick cell layer consists of neurons, poorly arranged in broad radial columns, whose migration has been arrested. The subcortical white matter is thinned and may contain heterotopias. Diagnosis

Disorders of neuronal migration and cortical layering can be found under diverse circumstances, either alone or in combination with each other or with additional intracranial and extracranial

malformations, including those of the cerebellum and brain stem. The first edition of this book, and several other volumes and reviews, considered pachygyria and polymicrogyria together, primarily because they were so often reported in the same patient and were therefore thought to represent a spectrum of abnormality. They are now treated separately because there are differences in the histopathology, as well as a growing consensus that, unless MRI slices of < 4 mm or other neuroimaging adaptations such as curvilinear reconstruction are used, the fusion of the molecular layer over the sulci in polymicrogyria can be misinterpreted as pachygyria.4,89 Furthermore, genes thus far discovered to cause cortical malformations generally cause agyria/pachygyria or polymicrogyria, but not both. There may be exceptions.90 Cortical malformation with pachygyria is a continuum from agyria/pachygyria (lissencephaly) to focal areas of pachygyria. Indeed, grade 4 lissencephaly, as defined by Dobyns et al.,12 is generalized pachygyria. Unilateral involvement, except in the context of hemimegalencephaly, appears to be uncommon. Focal involvement has been divided into bilateral posterior and bilateral parietal by Barkovich et al.,10 to which frontoparietal could logically be added. Although the severity of clinical presentation can be expected to vary with the degree of cortical involvement, pachygyria is a severe cortical malformation. Patients are likely to present with some combination of severe developmental delay, failure to thrive, variable anomalies of tone, pyramidal signs, seizures, microcephaly or hydrocephalus, and EEG changes. Caraballo et al.91 have suggested that a combination of developmental delay, motor deficits, and seizures, together with a posterior interictal polyspikewave paroxysms and diffuse ictal 10-11Hz EEG changes, may be suggestive of bilateral posterior agyria/pachygyria. Liang et al.92 have stated that evoked potential and EEG may provide some useful correlation with the clinical severity of CNS dysfunction. It is apparently unusual for pachygyria to be an incidental finding at autopsy.1

Fig. 15-28. Variations in terminology of layers.

558

Neuromuscular Systems

With MRI the abnormal gyration is readily visible, and the gray–white matter ratio is reversed. On T2-weighted MRI images, a high intensity circumferential band, believed to represent the cell-sparse layer, may be seen.87 The brain stem may appear small because of underdeveloped spinocerebellar tracts. Distribution and Etiology

There are no systematic studies of the prevalence of either syndromic or isolated pachygyria. It is only with the development of modern neuroimaging methods that in vivo diagnosis has become possible, and even recently there may be failure to distinguish some cases of polymicrogyria from pachygyria. Autopsy series clearly select cases at the severe end of the spectrum, and unfortunately, they have also often failed to distinguish the different types of cortical malformation.93,94 However, it seems probable that the rates of significant pachygyria would be even lower among patients with milder delay or less intractable seizures. More restricted and less severe anomalies might occur in patients with focal neurologic disturbances. With the exception of cases representing the mild spectrum of genetic lissencephaly, the etiology of pachygyria remains largely unexplained. Migrational disorders are common to a number of peroxisomal disorders, non-ketotic hyperglycinaemia, and glutaric acidemia type II (Table 15-6). A common pathway might be energy production systems on which the actively developing brain is dependent. A prominent hypothesis was that a hypoxic/hypoperfusion episode, about the time the cells in layers V and VI had completed their migration, led to laminar necrosis and the cell sparse layer. This layer was thought to inhibit neuronal migration to the cortical plate. However, cortical freezing experiments, which mimic production of this layer, do not prevent the later transmigration of neurons, so that it is necessary to postulate more direct damage to the neurons or RGC in human pachygyria.95 Cells whose processes are trapped in the cell sparse zone may undergo degeneration. The architectonic changes in classic lissencephaly and in pachygyria differ only in degree, and within the same brain lissencephaly can be seen at the extremes of arterial supply, whereas pachygyria is seen in the more proximal areas. Thus, hypoperfusion/hypoxia remains a viable hypothesis for some cases of pachygyria. The timing of the teratogenic insult is considered to be the fourth month. Abnormal development and thickness of the cortex presumably inhibits normal gyral formation. Twin studies and cross-correlation comparisons between twins and non-twins have shown that while the heritability of brain size is high (94%), gyral patterning is predominantly non-genetic.144 Familial recurrence of focal pachygyria appears to be uncommon, suggesting that a genetic etiology is infrequent. However, pachygyria is seen in a number of the lissencephaly syndromes included in Table 15-5, and the possibility of milder mutations or polymorphisms of the lissencephaly genes, perhaps only acting in the face of an environmental stress, and/or on cells at arterial watersheds, remains a consideration. In their study of factors associated with malformations of cortical development, Montenegro grouped patients with agyria/pachygyria and heterotopia together and found a history of prenatal events in 42% compared with 5% of controls.96 They also noted a 32% family history of seizures and a 32% family history of neurologic impairment, which likely was due in part to some of the recognized genetic lissencephaly syndromes. Somatic mosaicism affecting a limited area of the VZ or MGE is also possible, although without any supportive evidence to date. Table 15-6 lists a number of syndromes and case reports with

pachygyria. Many include other CNS lesions, including polymicrogyria, and were described without benefit of modern neuroimaging. Thus, some of the syndromes listed may not actually demonstrate pachygyria, but until there is experience with further cases that have been subject to adequate imaging, no distinction can be made. It is also clear that in some cases pachygyria and polymicrogyria do occur together and represent the expression of a single etiology with varied timing, degree of exposure, and/or location in the brain resulting in the differing pathology. Some such cases appear to be genetic.90,140 Prognosis, Treatment, and Prevention

Notwithstanding a bias toward selection of cases with neurologic signs and symptoms, it is rare that pachygyria is an unexpected finding at autopsy. This finding is consistent with the significant disruption of normal CNS development and function. Golgi studies have shown that neurons that have reached their normal destination have abnormal orientation and interconnections.3,88,216 In general, neurologic development is profoundly delayed, and intractable seizures and microcephaly are common. Initial hypotonia often evolves into hypertonia. Titlebaum et al.217 studied 23 children with pachygyria-like changes on CT or MRI. The malformations were isolated in seven cases, syndromic in nine, and due to infection in seven. Patients were divided into unilateral diffuse and bilateral nondiffuse and had been ascertained through investigation of seizures and developmental delay. Eighteen had developmental quotients (DQ) of 20 and failed to obtain any milestones. Three patients had DQs between 50 and 70 and were ambulatory and communicative, and in two of these the lesion was nondiffuse and nonsyndromic. One had unilateral megalencephaly. Eight of 10 with nondiffuse pachygyria had frontotemporal predominance. In the study by Montenegro et al.,96 all of the patients with pachygyria/agyria were retarded, and this contrasted dramatically with their patient groups with focal cortical dysplasia and those with polymicrogyria in which retardation was the exception (vide infra). Developmental delay with or without seizures appear as constant features of the pachygyriaassociated syndromes in Table 15-6. Treatment is supportive in such patients and includes attempts to control seizures and thus facilitate care. Prevention must be directed at primary causes. Cytomegalovirus infection, and in endemic areas, toxoplasmosis, may contribute a proportion of cases, and prevention and/or recognition of maternal gestational infection would represent an important preventive measure. Recognition and appropriate counseling in the case of specific syndromes is also important. Some have no significant recurrence risks; others do and may be subject to prenatal diagnosis because of known specific biochemical anomalies or associated malformations (Table 15-6). The challenge of prenatal diagnosis of gyral abnormalities has been discussed in the section on lissencephaly. 15.5.3 Polymicrogyria Definition

Polymicrogyria (PMG) are areas of the cerebral cortex characterized by an excessive number of gyri that are small and may give the appearance of a wrinkled walnut (Figs. 15-29, 15-30). The depth of the sulci is variable, and fusion of the molecular layer between the gyri may result in a glandular or, paradoxically, smooth appearance.2,87 The cortex is abnormally thick, but the reversal of the grayto-white ratio is not as marked as in pachygyria.

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias Syndrome

Prominent Features

Causation Gene/Locus

Acrofacial dysostosisintermediate severity97

Malar, maxillary, and mandibular hypoplasia; downslanting palpebrae, absent eyelashes; lateral and typical facial clefts; macrostomia; abnormal ears; mesomelic dysostosis; congenital heart; hydrocephaly, polymicrogyria

Unknown

Adams-Olivercortical dysplasia98,99

Cutis aplasia congenita of the scalp, terminal limb reduction defects, short digits, hypoplastic nails, may have constriction rings; case with unilateral cortical dysplasia and sibs with polymicrogyria

AD (100300) AR?

Ades: campomeliapolydactyly-dysplastic kidney100

Cleft epiglottis and tongue, dysplastic larynx, coloboma, cystic dysplastic kidneys, periportal hepatic fibrosis, mesomelia, absent corpus callosum, abnormal gyri

Unknown

Agonadism-CNS anomalies101

Agonadism with urogenital sinus and 46,XY karyotype, severe mental retardation, absent corpus callosum, cerebellar agenesis, pachygyria. Single case

Unknown

Agyria-pachygyria-absent corpus callosum102

Normencephaly, hypertonia, apnea, neonatal death, absent corpus callosum, cortical dysplasia–probably agyria/pachygyria

AR

Aicardi103

Pathognomonic retinal lacunae, absent corpus callosum, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, heterotopias, colpocephaly, hypoplastic cerebellar vermis

XLD, male lethal (304050) Xp22

Alcohol, prenatal104

Short stature, microcephaly, short palpebral fissures, hypoplasticphiltrum, thin vermillion border, mental impairment Macrocephaly, microophthalmia, bilateral cleft lip/palate, myoclonic seizures, hypotonia, posterior midline cyst, frontal polymicrogyria, absence of the corpus callosum. Single case; could be part of the oculocerebrocutaneous spectrum.

In utero exposure

Apert106

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS includes corpus callosum (5/113), limbic system, microgyria, polymicrogyria, heterotopia, ventriculomegaly

AD (101200) FGFR2, 10q25.3-q26

Arena: XLMR-spasticity-iron in basal ganglia107

Mental retardation, severe spastic paraplegia, hypoplasia of white matter with poor myelination, macrogyria, cerebellar hypoplasia, possible iron deposits in the basal ganglia

XLR Xq22-q25

Autosomal dominant microcephaly-pachygyria108

Mildly retarded woman with moderate microcephaly, small cerebellum, and mild pachygyria; child with severe microcephaly, horizontal scalp folds, small cerebellum and brain stem, pachygyria greatest over frontal and parietal area

AD

Baller-Gerold: craniosynostosis-radial ray109

Craniosynostosis; variable radial ray, carpal and metacarpal hypoplasia/aplasia; small anomalous ears, hypertelorism, epicanthus, prominent nasal bridge; anal abnormalities; thin corpus callosum, crowded and small gyri, abnormal hippocampi, hypothalamic heterotopias

AR (218600)

Baraitser-Winter: iris coloboma-pachygyria110

Mental retardation, short stature, ptosis, iris colobomata, hypertelorism, marked epicanthus inversus, flat nasal bridge, pachygyria; two cases with similar inversion 2p12;q14

AR, microdeletion? 2p12-q14

Bohring-Opitz111

Trigonocephaly, microcephaly, prominent eyes, broad nasal bridge, micrognathia, cleft lip/palate, flexion deformities at elbows and wrists, postnatal growth failure; small brain stem, reduced white matter, focal nodular heterotopia

AR (605039)

Bo¨rjeson-ForssmanLehmann112

Central obesity, narrow palpebrae, large ears, short stature, moderate to severe retardation, kyphosis, short neck, post-pubertal hypogonadism

XLR (301900) PHF6, Xq26.3

Carnitine palmitoyltransferase II deficiency113

Neonatal lethal, hypoglycemia, hepatic decompensation, cardiomyopathy, cystic renal dysplasia; CNS degeneration with gliosis, neuronal migrational defects

AR (600649) CPT2, 1p32

Carpenter-Hunter: micromelia-polysyndactyly114

Severe short-limbed dwarfism, encephalocele, marked hypertelorism, microphthalmia, absent external nares, cleft palate, micrognathia, narrow chest, cardiac malformation, cystic dysplasia of the kidneys and pancreas, post-axial polydactyly of hands and feet, duplicated tibia, hydrocephalus, pachygyria

Unknown

Cataracts-contracturescortical dysplasia115

Postnatal growth and developmental failure, prominent supraorbital ridge, cataracts, large joint contractures, osteoporosis, cavum septum pellucidum, right temporal arachnoid cyst, cerebellar atrophy, multiple foci of cortical dysplasia in frontal and parietal lobes

AR

Cerebellar hypoplasialymphedema116

Mental retardation, hypotonia, ataxia, clonic/tonic seizures, pale fundi and poor VEP, variable duodenal atresia, cerebellar hemisphere and vermis hypoplasia, poor cerebral white matter, abnormal neuronal migration, pachygyria

AR (600514) RELN, 7q22

Cerebral calcificationleukodystrophy117

Microcephaly and cerebellar hypoplasia variable, seizures, cerebral calcification is most marked in the periventricular area, generalized delay in myelination. Case with microphthalmia. Case reported with pachygyria was the offspring of first cousins.

AR

Anophthalmia-cranial cystscleft lip/palate105

Unknown

(continued)

559

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cerebro-oculo-faciallymphatic118

Acrobrachycephaly, trigonocephaly, thick hair, hypertelorism, ptosis, bushy and arched eyebrows, broad nasal bridge and tip, epicanthus, macrostomia, broad and webbed neck, abnormal nipples, contractures, short and wide hands, frontal agyria/pachygyria

Unknown

Cerebro-oculo-hepato-renal (Arima)119

Leber congenital amaurosis, telecanthus, blepharoptosis, polycystic kidneys and renal failure, hepatic fibrosis, hypotonia, mental retardation, aplasia inferior vermis, micropolygyria of dentate and pachygyria inferior olivary nuclei

AR

Chromosomal120

A number of karyotypic anomalies are listed as associated with cortical malformations but such malformations are often not mentioned in reviews of recurrent cytogenetic anomalies, and neuroimaging studies are lacking. See reference for specifics.

Chromosome deletion/ duplication

Coad: agenesis of cortical tracts121

Cortical spinal tract aplasia due to cortical migration or proliferation defect, hypertelorism, flat nose, micrognathia, arthrogryposis, cortical thumbs, hypospadias

Unknown

Congenital alopecia-seizuresmental retardation122

Microcephaly, congenital alopecia, neonatal seizures, profound mental and growth retardation, spastic quadriparesis; microgyria over frontal, parietal and occiput with pachygyria in temporal and orbitofrontal regions; reduced neurons, mostly in 3rd and 4th layers

AR (203600)

Congenital extraocular muscle fibrosis-brain anomalies123

Mother and two children with congenital extraocular muscle fibrosis, unilateral hypoplasia of body and tail of caudate with ipsilateral ventriculomegaly; children had bilateral cortical dysplasia

AD (135700) CFEOM1?, 12p11.2-q12

Cortical dysplasia-anterior horn arthrogryposis124

Bilateral symmetrical cortical dysplasia maximal in the sylvian region, infolded cortex, abnormal gyri, seizures, lower limb contractures, short right leg with muscle atrophy

Unknown

Cranio-carpo-tarsal dystrophy125

Usually normal intelligence, deep-set eyes, small nose; puckered, H-shaped, and small mouth; long philtrum, camptodactyly with ulnar deviation; reported with delayed myelination, dysplastic corpus callosum, agenesis of inferior vermis, cortical dysplasia

AD (193700)

Craniofacial dysostosis-limbomphalocele126

Frontal bossing, severe hypertelorism, thin and small mouth, philtral skin tag, lower lid colobomas, hypoplastic nasal alae, cleft palate, asymmetric limb anomalies, syndactyly, short sternum, omphalocele, internal anomalies, ‘‘polygyria’’

Unknown

Craniosynostosis-bifid thumb-micropenis127

Craniosynostosis, low-set and posteriorly rotated ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, flat nasal bridge, bifid thumbs, limited extension at the knees, small 5th finger, bilobed lungs, small penis with bifid scrotum, polymicrogyria, hypoplastic frontal lobes, arhinencephaly, cerebellar herniation, hydrocephalus

Unknown

Cutis marmoratamacrocephaly295

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous hemangiomas of the skin, and developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects. Case with cortical dysplasia.

Unknown (602501)

Cutis verticus gyrata-Lennox Gastaux128

Developmental delay, early onset of seizures, most characteristically tonic and akinetic; EEG slow with irregular spike and wave complexes, usually at less than 3 cps. Case with polymicrogyria reported.

Unknown

Cytomegalovirus infection, prenatal129

In symptomatic cases: microcephaly, deafness, chorioretinitis, intracranial calcification, mental retardation, paraventricular cysts, pachygyria, polymicrogyria, cerebellar hypoplasia

In utero infection

Desmosterolosis130

IUGR, downslanting palpebral fissures, low nasal bridge, thick alveolar ridges, gingival nodules, congenital heart defect, ambiguous genitalia. Case with macrocephaly and another with microcephaly, ‘‘immature gyral pattern,’’ cholesterol biosynthesis.

AR (602398) Sterol-delta 24-reductase, 1p33-p33.1

Diffuse cortical dysplasiafamilial131

Generalized tonic/clonic and atonic seizures; pachygyria, with underlying cell-sparse zone, over the parietal area with less involvement over the temporal and occipital regions; sparing of the perisylvian region of the temporal lobe

AR/XLR

Diffuse pachygyria-cerebellar hypoplasia132

Diffuse broad gyri and severe hypoplasia of cerebellar vermis and hemispheres but with normal birth OFC, which remained normal in 3 of 4 cases; severe developmental delay, seizures, early hypotonia, truncal ataxia, action tremor; non-dysmorphic

AR

Disorganization-like133

Various malformations, generally affecting the craniofacial area and limbs, in association with aberrant digits/skin tags thought to resemble the mouse mutation. Case with periventricular heterotopias.

Unknown (223200)

Duchenne muscular dystrophy134

Mean IQ is reduced compared with those of sibs. Initial report of pachygyria and heterotopias not confirmed in recent studies, which have revealed abnormal dendritic arborization

XLR (310200) dystrophin, Xp21.2 (continued)

560

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Ehlers Danlos

Heterogeneous connective tissue disorder with hyperelasticity/friability most apparent in skin and joints; CNS not limited to a specific type and include cortical dysplasia, heterotopias, bilateral perisylvian polymicrogyria

Most AD

Ellis: microcephaly-heartrenal136

IUGR, severe microcephaly, small ears, pre-auricular pits, short palpebral fissures, hypoplastic alae, cleft palate, redundant neck skin folds, varied congenital heart defects, lung segmentation defects, unilateral renal agenesis, high lethality. One sib had small brain with reduced gyri, malformed cortical areas; other hydrancephaly-like.

AR (601355)

Encephalocele-radial anomalies137

Esophageal atresia, abnormal lung lobulation, congenital heart, radial ray defects, visceral anomalies, partial absent corpus callosum, hypoplastic cerebellum, encephalocele, ‘‘cortical microgyria’’

Fetal akinesia (PenaShokeir)138

IUGR, depressed nose, micrognathia, ankylosis, camptodactyly, pulmonary hypoplasia, variable CNS pathology, polymicrogyria with four-layered and unlayered cortex, heterotopias

Heterogeneity some AR (208150)

FG syndrome139

Megalencephaly, mental retardation, hypotonia, contractures, congenital heart defects, anal anomalies, constipation, pyloric stenosis, hypertelorism, short palpebrae, epicanthus, high palate, mouth breathing, absent corpus callosum, pachygyria, heterotopias of nerves 7 and 8

XLR (305450) Xq12-q21.3

Focal occipital neuronal migration defect140

Profound mental retardation, seizures, polymicrogyria/pachygyria/agyria limited to the occipital region; male siblings from an isolate

Uncertain

Frontal pachygyriaautosomal recessive141

Non-dysmorphic, mental retardation, mild seizures, pyramidal and cerebellar signs, shallow sulci mostly anterior to the sylvian fissures, pachygyria in the frontal lobes, less abnormality in the occipital area

AR

Fryns142

Coarse face, hypertelorism, anteverted nares, eye anomalies, macrostomia; genital, renal, gut, and cardiac anomalies; diaphragmatic hernia; high lethality; absent corpus callosum, cerebellar heterotopia and hypoplasia, gyral anomalies

AR (229850)

Fuhrmann143

Dislocated hips, angulated femora, absent/hypoplastic fibulas, hypoplastic fingers and nails, metacarpal and metatarsal coalescence and hypoplasias; cortical dysplasia in one of six cases

AR (228930)

Galloway-Mowat: abnormal gyri-glomerulopathy145

Floppy ears, minor dysmorphia, increased/decreased tone, lethal nephrosis onset from birth to age 2 years, variable pathology with pachygyria, polymicrogyria, marginal glioneuronal heterotopias

AR (251300)

Genitopatellar146

Coarse face, prominent nasal root and bulbous tip, micrognathia, high palate, soft skin, flexion contractures, dislocated/absent patellae, variable skeletal changes. Case with absent corpus callosum and periventricular neuronal heterotopias.

AR (606170)

Glutaric aciduria type 2147

Macrocephaly early sign, cryptorchidism, hypospadias; most show initial normal health and development; signs can include respiratory distress, hypoketotic hypoglycemia, sweaty-foot odor, seizures, dystonic cerebral palsy; aliphatic mono- and dicarboxylic acids, sarcosine, glycine conjugates in blood and urine; abnormal electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-dehydrogenase)

AR (231680) multiple acyl-CoA dehydrogenase defects; ETFA, 15q23-q25 ETFB, 19q13.3 ETFDH, 4q32qter

Goldberg-Shprintzen148

Microcephaly, short stature, developmental delay, hypertelorism, submucous cleft palate; diminished white matter, hypo/partial absence corpus callosum, pachygyria, cerebellar hypoplasia

AR (235730) SMADIP1, 2q22

Hayashi: leprechaunismlike149

Megalencephaly, hydrocephaly, unusual appearance, severe growth failure, hypoglycemia, no hyperinsulinemia, cardiac defect, decreased cortical neuronal density, fronto-parietal dysplasia. Single case

Unknown

Heptacarpo-octatarsodactyly-plus150

Lethal, hypertelorism, hydrocephalus, ependymal cysts, ‘‘polygyria,’’ cleft lip/palate, macroglossia, abnormal lung lobulation, complex heart malformation, genitourinary anomalies, complex polydactylies all four limbs

Unknown

Holmes: brain malformationfetal hypokinesia151

Polyhydramnios, fetal hypokinesia, wide cranial sutures, telecanthus, narrow palpebrae, micrognathia. One sib had agenesis of the corpus callosum, slightly broad gyri, focal cerebellar disorganisation; other sib had arhinencephaly, hypoplastic gyri, regions of persistent external cerebral granular layer

Uncertain

Hypochondroplasia297

Disproportionate short stature; milder but clinical and radiologic resemblance to achondroplasia; case report with inadequate white/gray differentiation and abnormal gyri in temporal lobe

AD (146000) FGFR3, 4p16

135

(continued)

561

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Irregular congenital hypopigmented streaks follow lines of Blashko; may be otherwise asymptomatic or have skeletal, eye, or brain anomalies; cortical dysplasia, brain atrophy, increased Virchow-Robin spaces

Chromosome mosaicism (300337)

Hypothalamic hamartomamicrophthalmia-radial ray153

Hypothalamic hamartoma, microphthalmia, ectopic retinal pigment layer, flat nose, absent/hypoplastic thumb, gut malrotation, small stomach, asplenia, abnormal genitalia. Case with agenesis of the corpus callosum, meningeal dysplasia, abnormal gyral pattern

Unknown

Joint contractures-renalfacies154

Brachycephaly, large fontanel, upswept anterior hair, short palpebrae, flat face, thin nares, cystic pinnae, camptodactyly, small kidneys with dysplastic foci, pachygyria with atypical histology

Uncertain

Kabuki155

Developmental delay, long palpebrae with ectropion of outer 3rd lower lid, arched eyebrows, broad nasal tip, large ear lobes, cardiac defects, brachydactyly, prominent finger-tip pads; reported with polymicrogyria

AD (147920)

Larson-like-brain dysplasia156

Severe mental retardation, tetraplegia, intractable partial seizures, laryngotracheomalacia, multiple joint dislocations, bilateral perisylvian cortical dysplasia with zonal heterotopia of pyramidal and granule neurons in molecular layer, brain protrusion in subarachnoid space

Unknown

Lurie: cerebro-renal-digital157

Microcephaly, short and webbed neck, renal dysplasia, polysplenia, microgyria (family ‘‘L’’ in report)

AR (200995)

Linear nevus sebaceous158

Papular/verrucous lesions with atrophic scars over craniofacial area, pigment changes, ipsilateral brain anomalies, hemimegalencephaly, pachygyria heterotopias, porencephalies, mental retardation, seizures

Unknown (163200)

Majewski: short ribpolydactyly159

Lethal short ribbed micromesomelic dwarfism, short tibiae, pre- and postaxial polydactyly, median cleft lip, genital anomalies, hypoplastic epiglottis and larynx, glomerular cysts, tortuous cerebral vessels, cerebellar vermis hypoplasia, posterior fossa arachnoid cysts, agenesis or hypoplasia of the corpus callosum, pachygyria, neuronal heterotopia

AR (263520)

Marshall-Smith160

Accelerated linear and skeletal growth with prenatal onset, poor weight gain, dolichocephaly, prominent eyes, anteverted nose, broad proximal and middle phalanges, narrow distal phalanges, respiratory problems often lethal, absent corpus callosum, pachygyria inferior vermis hypoplasia, pachygyria

Unknown (602535)

McPherson-Clemens: cleft lip/palate-heart161

Lethal, nuchal cysts, short neck, flat face, hypertelorism, upslanting palpebrae, cleft lip/ palate, bilobed tongue, complex hypoplastic heart defects, abnormal lung segmentation, wide spaced nipples, small penis, short hands and feet, deep set nails, organomegaly, crowded cerebral gyri, abnormal hypocampi; subependymal, cerebellar cortical, and leptomeningeal glial heterotopias

AR (601165)

Meckel-Gruber162

Meningoencephalocele; renal cystic dysplasia; congenital hepatic fibrosis; postaxial polydactyly; eye, heart, genital, and other CNS anomalies, including polymicrogyria, heterotopias, and neuroepithelial rosettes

AR (249000) 8q24 11q13 17q22-q23

Megalencephaly-mega corpus callosum163

Mental retardation, no motor development, prominent forehead, low nasal bridge, large eyes; MRI evidence of megalencephaly, a broad corpus callosum, ‘‘enlarged’’ white matter, focal increased thickness of thick gray matter, pachygyric appearance, wide sylvian fissures

Unknown

Microcephaly-intracranial calcification164

IUGR, postnatal growth failure, hepatomegaly, corneal opacities, bile duct hypoplasia, disorganized cortex, small calcified basal ganglia, pachygyria, polymicrogyria; may be allelic with Aicardi-Goutieres and Cree encephalitis

AR (251290)

Mohr-Majewski: oro-facialdigital type IV165

Severe abnormalities of epiglottis, tongue, and larynx; cystic kidneys, gut malrotations, hepatic fibrosis, arhinencephaly, neuronal migrational defects in patient within gamut of OFD II and short rib-polydactyly II

AR (258860)

Muenke: craniosynostosis297

Coronal synostosis, variable radiographic changes include thimble-like middle phalanges, coned epiphyses, carpal and tarsal fusions, brachydactyly, sensorineural deafness

AD (602849) FGFR3, 4p16

Multiple peroxisomal oxidative deficiency166

Clinical presentation like Zellweger cerebro-hepato-renal syndrome (pseudo-Zellweger), but abundant peroxisomes, normal DHAP-AT, high pipecolic acid, and very long chain fatty acids. Gliosis most marked in cerebellum, which contained heterotopias; heterogeneity, peroxisomal b-ketothiolase or bifunctional enzyme defect

AR (261510) 3p22-p23

Nephrotic syndromeinfantile spasms167

Developmental delay, early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits, floppy ears, hiatal hernia, flexion contractures; areas of polymicrogyria, agyria, and pachygyria

AR (251300)

Hypomelanosis of Ito

152

(continued)

562

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Non-ketotic hyperglycinemia168

Acute metabolic disease presentation; abnormal mitochondrial glycine cleavage; hypotonia, lethargy, abnormal cry, jaundice, coma, elevated urine and plasma glycine; CNS includes absent corpus callosum, pachygyria

AR (605899) GSCP, 3p21.2-p21.1 GSCT, 9p22 GSCH, 16q24

Occidental congenital muscular dystrophy169

Congenital severe hypotonia muscle weakness with elevated CPK, intelligence normal or with mild delay, variation in fiber size, leukodystrophy that may show postnatal onset, polymicrogyria in some cases who may show seizures, merosin deficiency in some patients

AR (156225) 6q22-q23

Orofacial-digital type I170

Variable mental retardation, sparse and dry hair, excess oral frenula, oral hamartomas, clefting, absent lateral incisors, brachydactyly, polysyndactyly, polycystic kidneys; CNS variable, absent corpus callosum, Dandy-Walker, pachygyria

XLD, male lethal (311200) CXORF5, Xp22.3-p22.2

Pachygyria-hypogenitalism171

Microcephaly, developmental and growth delay, sloping forehead, undescended testis, pachygyria. Hypogenitalism is a non-specific finding with many severe brain anomalies).

AR/XLR?

Pachygyria-agenesis corpus callosum-X-linked172

Microcephaly, lethal in males, severe developmental delay, early onset seizures, agenesis of the corpus callosum, microphallus, neuronal migration defect; less severely retarded male did not have neuroimaging; band heterotopia a possibility

XLD (600102)

PAX6-related eye-brain anomalies173

Microcephaly, anophthalmia, small nares, large pinnae, absent corpus callosum, focal polymicrogyria; compound heterozygote for PAX6 mutations; unilateral polymicrogyria and absent pineal in heterozygotes

AR (106210) PAX6, 11p13

Periventricular nodular heterotopia-autosomal recessive174

Typical periventricular nodular heterotopia, seizures, developmental delay, consanguinity and family history compatible with autosomal recessive inheritance, exclusion of linkage to FLNA and FLNB

AR (608097) ARFGEF2, 20q11.21-q13.2

Periventricular nodular heterotopia-ectodermal dysplasia175

Two cases, one with normal intelligence and bilateral, diffuse periventricular heterotopias, and ectodermal changes limited to hair; second with developmental delay, joint laxity, ataxia, single nodular heterotopia, dental and hair changes, face dysmorphia

Unknown

Periventricular nodular heterotopia-frontonasal176

Mild mental retardation, frontal bossing, low-set ears, prominent glabella, broad nasal root, hypertelorism, epicanthus, high palate þ/ cleft, variable hypoplastic genitalia, bilateral periventricular nodular heterotopia, cortical dysplasia, ventriculomegaly, cerebellar vermis hypoplasia

Unknown, XLR?

Periventricular nodular heterotopia-multiple pterygium177

Microcephaly, mental retardation, seizures, micro-retrognathia, downslanting palpebrae, cleft palate, poor tongue movement, inwardly rotated thumbs, multiple joint pterygia diagnosed at 4.5 years. Single case.

Unknown

Periventricular nodular heterotopia-rhizomelia178

Short stature, short humeri, dysplastic mitral valve, abnormal pinnae, sparse temporal hair, deep paranasal creases, short nose, long philtrum, thin upper lip, brachydactyly, penoscrotal hypospadias, delayed ossification centers

Unknown

Periventricular nodular heterotopia-syndactylycerebellar hypoplasia179

Severe mental retardation, seizures, syndactyly; variable cataracts, hypospadias, areas of cortical dysplasia

XLR

Periventricular nodular heterotopia-unusual appearance180

Three sisters with developmental delay, resistant seizures, upslanting palpebrae, low nasal bridge, long feet with sandal-gap, low T4, urinary tract anomalies, intestinal polyps

AR? (mother unaffected)

Peters anomalymicrocephaly-intestinal atresia181

Developmental delay, Peters anomaly, multiple intestinal atresias in distribution of superior mesenteric artery, extensive migrational defects, parasylvian clefts not reaching the ventricles

Unknown, possible vascular basis

Polyasplenia-caudal deficiency-absent corpus callosum182

Laterality associated defects, imperforate anus, renal anomalies, lumbosacral agenesis, lower limb anomalies; cases reported with meningocele, hydrocephalus; one case with absent corpus callosum and white matter neuronal heterotopias and abnormal cortical architecture

AR?

Polymicrogyria-bilateral frontal183

Polymicrogyria from frontal poles to precentral gyrus and inferiorly to frontal operculum, mild to moderate mental retardation, motor and language delay, spastic quadriparesis or double hemiparesis; consanguinity in 2 of 13 cases

Unknown

Polymicrogyria-bilateral frontoparietal184

Frontoparietal region most involved with PMG, moderate to greater developmental delay, seizures, dysconjugate eye movement, pyramidal and cerebellar signs, ventriculomegaly, white matter changes

AR (606854) 16q12-q21 (continued)

563

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Polymicrogyria-bilateral perisylvian185

Mild to moderate mental retardation, seizures are often difficult to control, pseudobulbar palsy, variable diplegia of the facial, pharyngeal, tongue and masticatory muscles; slight dysarthria to lack of speech; in some families females are significantly affected

Variable, many sporadic (300388) Xq28

Polymicrogyria-sagittalparieto-occipital186

Usually diagnosed in older individuals after onset of seizures; motor signs are absent; cognitive involvement absent or mild

Unknown

Polymicrogyriadermatomyositisinclusions187

Developmental delay, spasticity, cerebellar dysfunction, dermatomyositis, polymicrogyria, paracrystalline inclusions in muscle

AR

Polymicrogyriahydrocephaluscraniosynostosis188

Craniosynostosis, scaphocephaly, severe mental retardation, early lethal, low-set ears, eyebrow hypoplasia, short nose, long philtrum, small mouth, small genitalia. Single case.

Unknown

Polymicrogyriaturribrachycephaly189

Microbrachycephaly, turricephaly, blepharophimosis, midface hypoplasia, prognathism, cryptorchidism, camptodactyly, adducted thumbs

AR?

Potter190

In utero renal insufficiency (agenesis/dysplasia), leading to oligohydramnios, lung, hypoplasia, facial and appendicular deformations. Frontal/occipital vertical neuronal columns, abnormal gyri, cerebellar heterotopias.

Heterogeneous

Prenatal methylmercury191

Minimata disease; severe neurologic impairment with hypertonicity; combination of broad, flat, and simple gyri, and narrow gyri with shallow sulci; heterotopias in white matter, cerebellum; marginal glio-neuronal heterotopias; neuronal anomalies

In utero exposure

Progressive hemifacial atrophy192

Onset in childhood/adolescence of unilateral facial pigmentation, bone and soft tissue atrophy, midline facial groove, trigeminal neuralgia, contralateral Jacksonian seizures; possibly a subset of patients with cortical dysgenesis

Unknown (141310)

Proteus193

Marked and asymmetric overgrowth can lead to a range of complications; skin includes shagreen patches, linear verrucous epidermal nevi, intradermal nevi, lipomas, hemangiomas, patchy dermal hypoplasia, hyperplastic and pebbly plantar overgrowth; frequent ocular problems; CNS abnormalities uncommon, partial absent corpus callosum, lissencephaly, hydrocephalus

Uncertain (176920) Some PTEN, 1q11-q25, mutations claimed but cases questioned296

Sakoda: anophthalmiacortical dysgenesis194

Anophthalmia, cleft lip/palate, short stature, hemivertebrae, basal encephalocele, absent corpus callosum, cerebral dysgenesis. Single case.

Unknown

Samsom: mitochondrial encephalopathy195

Prenatal microcephaly, calcification of frontal lateral ventricles and cerebral hemispheres, partial callosal dysgenesis, polymicrogyria, neuronal heterotopia, severe neonatal metabolic acidosis, abnormalities of complex I and IV, deficient pyruvate dehydrogenase complex in muscle and liver

Unknown

Severe periventricular hyperplasia196

Severe microcephaly, early seizures, lethal; one of the three cases had sloped forehead, hypotelorism, microphthalmia, absent thumbs, micropenis; extremely disorganized neuronal migration causing obliteration of the ventricles; basal ganglia a central mass of nodules

Unknown

Shanske: Seckel-like197

IUGR; severe mental retardation, microcephaly, and short stature; receding forehead, downslanting palpebrae, large beaked nose, retrognathia, dislocated radial head; one family with three children with agenesis of the corpus callosum, cortical dysgenesis, dorsal cerebral cyst, pachygyria

AR (210600)

Smith-Lemli-Opitz198

IUGR, microcephaly, postnatal growth failure, bifrontal narrowness, epicanthus, anteverted nares, prominent alveolar ridges, abnormal genitalia, dermatoglyphic whorls, polydactyly, frontal lobes particularly affected by pachygyria

AR (270400) DHCR7, 11q12-q13

Spinal muscular atrophypachygyria199

Clinical presentation as Werdnig-Hoffmann disease, seizures, variable arthrogryposis; pathology of anterior horn cell disease and pachygyria

Unknown

Spondylocostal dysostosispolymicrogyria200

Severe spondylocostal dysostosis, sacral agenesis, anal atresia, cystic kidneys, variable preaxial polydactyly and cartilage containing skin tags; fetus reported with bicornuate uterus and polymicrogyria

Unknown

Tectocerebellar dysraphiaoccipital encephalocele201

VSD, small mandible, cleft palate, CNS anomalies include posterior encephalocele, absent corpus callosum, hydrocephaly, cerebellar vermis agenesis, heterotopias

Unknown

Thanatophoric-dysplasia202

Neonatal lethal (occasional longer survival), short ribbed, micromelic dwarfism, excess skin folds, achondroplasia-like face, undermineralized spine with ‘‘H’’ or ‘‘U’’-shaped vertebrae on AP, curved femur, metaphyseal changes; polymicrogyria, leptomeningeal, and periventricular neuronal heterotopias

AD (187600) FGFR3, 4p16

(continued)

564

Brain

565

Table 15-6. Syndromes with pachygyria, polymicrogyria, heterotopias, and ectopias (continued) Syndrome

Prominent Features

Causation Gene/Locus

Tuberous sclerosis

Depigmented macules and hair patches, shagreen patches, fibroangiomas in butterfly distribution, periungual fibromas, phakomas of retina, heterotopias, multiple focal cerebral tubers with absent laminar and columnar organization, and abnormal cellular orientation

AD (191100) TSC1, hamartin, 9q34 TSC2, tuberin, 16p13.3 12q14

Typus Edinburgensis204

Macrocephaly, hirsute, frontal bossing, nasal obstruction, ‘‘small eyes,’’ carp mouth, postnatal growth failure, profound mental retardation, lethal, polymicrogyria, ectopias

t(1;2)(q42.3;q37.1)

Velo-cardio-facial205

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart; especially conotruncal defects; several reports with pachygyria and/or polygyria

AD (192430) del 22q11 del 10p

Weaver206

Prenatal onset of accelerated linear and skeletal growth, delay, hoarse voice, flat occiput, hypertelorism, large ears, long philtrum, camptodactyly, large joint limitation, loose skin, cerebral atrophy with occasional abnormal vessels, pachygyria (one case)

XLR or AR? (277590)

Wiedemann: microcephalyshort thumbs207

Microcephaly, mental retardation, short stature, large anterior fontanel, craniosynostosis, low-set ears, small and fleshy hands and feet, stubby and broad thumbs and halluces, hyperconvex and hypoplastic finger- and toenails, ventriculoseptal defect, frontal brain atrophy, dilatation of basal cisternae, pachy/agyria

XLD/AD?

WiedemannRautenstrauch208

IUGR, postnatal growth failure, prominent head-to-face ratio, progeroid appearance, sparse hair, prominent veins, lipoatrophy, natal teeth, caudal fat pad, initial skeletal signs clear, cerebral sudanophilic demyelinization, polymicrogyria

AR (264090)

Winter: pachygyria-joint contractures-unusual face209

Brachycephaly, large fontanel, small and cystic ear pinnae, flat face and nose, slender nares, hypertelorism, camptodactyly, talipes equinovarus, anomalous superior vena cava, hypoplastic lungs, small kidneys, hypogenitalism; simple and broad cerebral convolutions, pachygyria, polymicrogyria

Uncertain

Winter-Wigglesworth210

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres; microscopic renal changes

Unknown

XLR-corpus callosum dysgenesis211

Microcephaly, wide anterior fontanel, frontal bossing, telecanthus, broad nasal root, downturned mouth, short broad hands, brachydactyly; absent corpus callosum, interhemispheric cyst, cortical gyral dysplasia

XLR (304100)

Yokochi: athetosis-deafnesspachygyria212

Microcephaly, short stature, mental retardation athetosis, sensorineural deafness, areas of frontal, temporal, and parietal pachygyria. Case report.

Unknown

Zellweger: cerebro-hepatorenal213,214

Hypotonia, postnatal growth failure, large fontanels, high forehead, flat face, excess nuchal skin, hepatic and renal dysgenesis, contractures, hypomyelination, pachygyria (especially inferior olive), polymicrogyria, heterotopias merge with layers V and VI and affect mostly late migrating cells, germinolytic cysts

AR (214100) PEX1, 7q21-q22 PEX2, 8q21.1 PEX3, 6q23-q24 PEX5, 12p13.3 PEX6, 6p Others: 1p22-p21, 1q22, 2p15

Zollino: hypogenitalismpolymicrogyria215

Severe hypotonia, metopic ridge, upslanting palpebrae, megalocornea, epicanthus, smooth philtrum, macrostomia, club feet, agenesis of the corpus callosum, polymicrogyria; female less severely affected than three males

Unbalanced chromosomal translocation

203

Two basic types have been described: a classic four-layered form and one with absence of lamination, which is considered to have an earlier origin.1 In four-layered PMG, the outer marginal cell layer is sharply demarcated from the outer, laminar, cellular layer, which is the equivalent of the fusion of layers II, III, and IV in the normal cortex.2,87 Next to this layer is a cell-sparse layer that represents the equivalent of normal layer V, followed by an inner cellular layer. The subcortical white matter is reduced in thickness. True polymicrogyria thus occurs at a time when neuronal migration is virtually complete. Ferrer and Catala218 used Golgi staining to demonstrate that neurons that had migrated had reached their proper destination. In four cases with associated nodular neuronal heterotopias, the heterotopias and layers II and III of the cortex contained small- to-medium sized nonpyramidal neurons and multipolar neurons with axon plexi,

typical of later migrating cells of the outer cortical layers. Variant forms of polymicrogyria with somewhat atypical histopathology can occur after migration is complete.219 Diagnosis

PMG is a condition whose clinical importance, spectrum of signs, and diagnosis has markedly increased with the advent of MRI techniques (Fig. 15-31). It has been noted that fusion of the molecular layer over the shallow sulci can give a misleading impression of pachygyria. Techniques such as curvilinear reconstruction,89 and other methods that allow for partition size as low as 1.5 mm and the reconstruction of images along chosen planes,183 will allow detection of the increased number and deceased sized gyri. Typically there is a mild diminution of white matter myelination and increased subarachnoid space. CT scans are compromised by the

566

Neuromuscular Systems

Fig. 15-29. Gross brain specimen showing localized area of polymicrogyria. (Courtesy of the Department of Laboratory Medicine and Pathology, Children’s Hospital of Eastern Ontario.)

adjacent skull bones,87 and there are several reports in which it has failed to diagnose PMG accurately.183,220 The presenting clinical signs are highly dependent upon the area and the location affected by the PMG, as well as the presence or absence of associated intracranial malformations. PMG often accompanies schizencephalic clefts and porencephaly, most typically in the distribution of the middle cerebral artery, although the anterior and posterior distributions may be involved.221 Even when the porencephaly is unilateral, involvement with PMG is usually bilateral.1 It has become apparent over the past several years that bilateral PMG occurs in several well-defined patterns, not necessarily related to vascular watersheds, and that these patterns define clinical, and in some cases genetic, entities. These bilateral distributions include parasagittal parieto-occipital,186 perisylvian,185 sylvian and parieto-occipital,222 frontal,183 and fronto-parietal.184

Fig. 15-30. Lateral view of the brain from a term newborn infant showing polymicrogyria, Arnold-Chiari malformation. Dissection revealed internal hydrocephalus and agenesis of the inferior olivary nuclei. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Fig. 15-31. FLAIR (fluid-attenuated inversion recovery) MRI axial sequence, supraventricular region, with abnormal upward extension of the sylvian fissures, both broadly open rather than closed. Note the increased thickness of the perisylvian cortex with multiple small sulci, as well as nodular irregularity of the underlying gray-white junction. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

Defined by Kuzniesky et al.185 in a group of 31 patients, congenital bilateral perisylvian PMG (CBPP) is the most distinctive PMG syndrome. When involved with PMG, the sylvian fissure appears more vertical and extends more posteriorly.183 The initial cohort was characterized by mild-to-moderate mental retardation, seizures, pseudobulbar palsy, feeding difficulties, and by varying severity of diplegia of the facial, pharyngeal, tongue, and masticatory muscles. Expressive language difficulties ranged from slight dysarthria to lack of speech. Seizures occurred in 25 of the patients and covered a range of types, although partial were infrequent, and were often difficult to control. The adult syndrome of pseudobulbar palsy, facio-pharyngeal-glossal-masticatory diplegia, is the Foix-Chavany-Marie complex and reflects bilateral anterior operculum damage or maldevelopment. It is thought that the pediatric equivalent described by Worster-Drought likely had an equivalent cortical malformation.89 As more cases of CBPP have been reported, the overall prevalence of reported neurologic signs has fallen and additional anomalies have been noted.223,224 The most typical neurologic sign appears to be difficulty with protrusion and lateral movement of the tongue and/or dysarthria.89,223 Arthrogryposis, micrognathia, pectus excavatum, and esophageal atresia have been noted.224 Miller et al.225 reported three patients with CBPP who presented with unilateral hemiplegia, although in one case the diagnosis of CBPP was not certain. Bingham et al.226 used a quantitative MRI approach to assess

Brain

the size of the sylvian fissure and found it to be enlarged in a group of children with diverse etiologies for their developmental delay, seizures, and marked feeding problems. Noting the similarity of the clinical presentation to that in children with CBPP, they questioned whether underdevelopment of the operculum they had shown might share a common pathogenesis with CBPP. Although the presentation of several other PMG topographies may be characteristic, they are not specific and overlap with the signs and symptoms of other CNS pathology. The patients with bilateral frontal PMG reported by Guerrini et al.183 ranged in age from 10 months to 32 years and presented with mostly mild, but in some cases moderate, mental retardation, delayed motor and language milestones, and either spastic quadriparesis or double hemiparesis. Seizures were seen in less than half the patients, but many were young at the time of assessment. Chromosome 16q12q21-linked frontoparietal PMG is typified by moderate or greater mental retardation, epilepsy, dysconjugate gaze, and pyramidal and cerebellar signs.184 Parieto-occipital PMG is usually diagnosed in older patients during evaluation onset of seizures. Motor signs are absent, and any cognitive involvement is likely to be mild.186 In addition to these relatively circumscribed bilateral presentations, PMG may be more generalized and accompany other CNS anomalies, thus presenting with severe to profound mental retardation, additional severe CNS deficits, and seizures. In contrast, localized expression of PMG has been noted in otherwise normal individuals with specific learning deficits such as dyslexia and dysphasia, 227,228 and in benign epilepsy with centrotemporal spikes.229 An excess of small gyri is frequently described in ArnoldChiari type II and has been quantified by McLendon et al.230 However, although true four-layered polymicrogyria has been demonstrated in a significant portion of cases, in others the underlying neurohistology has been entirely normal, and the term polygyria has been suggested for this condition.230 Distribution and Etiology

Major areas of polymicrogyria are probably uncommon, although no systematic prevalence data are available. It is possible that small, localized areas of PMG may be more prevalent among patients with more minor types of cerebral dysfunction, but this will remain a question until systematic and sensitive MRI studies have been carried out on well-defined cohorts of patients. The frequent occurrence of PMG at the edge of what are considered clastic lesions, and its association with infections such as cytomegalovirus (CMV) and toxoplasmosis, suggest a disruptive basis for PMG. That a common denominator could be hypoperfusion is supported by the watershed distribution of many cases. Evrard et al.231 have summarized causes of hypoxia and/or perfusion failure, and they have included fetal and maternal origin. The brain is considered susceptible to insults causing PMG throughout virtually the entire period of cell migration, and perhaps beyond.1,183 Typical polymicrogyria has been well documented prior to 20 weeks gestation.1 Unlayered PMG is considered to reflect an earlier insult than the classic four-layered type but both may be seen in contiguous areas of the same brain.95 The concurrence could reflect a sustained or recurrent insult or perhaps a gamut of severity from a single event. Cases with associated subependymal or subcortical heterotopias clearly predate completion of cell migration. The gross polygyric appearance is considered to arise from an exaggeration of the normal differential rate of growth between the inner and outer cortical layers.2 Susuki and Choi232 were able to produce pathology very similar to human four-layered PMG with

567

cryogenic injury to the neonatal rat cortex. Recovery of pial-glial integrity was found to be critical in determining whether migrating neurons were likely to reach their normal positions. Montenegro et al.96 compared the rates of positive family history and prenatal events in three groups of patients with malformations of cortical development (MCD) with each other and with controls: 1) focal cortical dysplasia, 2) heterotopia/pachygyria/agyria, and 3) PMG/schizencephaly. Prenatal events were reported in 37% of patients with MCD and 5% of controls. Family history and prenatal events were not increased in group 1. A positive family history of neurologic impairment was noted in 32% of patients in group 2 and 39% of those in group 3. Five of the 14 positive family histories in the PMG/schizencephaly group were of a first-degree relative with CBPP. Prenatal events were reported in 42% of groups 2 and 3, and six of 15 such events in the PMG/schizencephaly group were failed attempted abortions. In a similar vein, Toti et al.233 compared cortical architecture in 32 fetuses suffering spontaneous abortion due to ascending chorioamnionitis with eight induced abortions as controls. They found that 25 (78%) cases, but none of the controls, showed one or more of three types of cortical pathology. In 19 of the cases, although the glia-limitans was intact, the molecular layer was broken by granular cell neurons, resulting in an undulating cortex with many small and irregular gyri projecting in various directions. The inner cell layers were less involved. Eight of the cases (8/18 < 20 weeks gestation) showed premature folding of the brain surface, fusion of the molecular layer, and the presence of small blood vessels. The granular cell layers appeared normal. Finally, in eight cases there was loss of granular cells, a thin cortex or laminar cell depletion, and/or necrosis that often just involved the middle cell layers. In two cases there were visible cortical microhemorrhages; generally the meninges were hypervascular. In all cases the gross morphology was normal, and they hypothesized that these changes could evolve into PMG in surviving infants. Among infectious causes CMV has been particularly associated with PMG, and Norman et al.1 have emphasized the importance of considering the temporal relationship of the detection of CMV infection and its attribution as a cause for PMG. Their studies of fetal brains infected with CMV from 17 to 40 weeks gestation showed marked variation in pathology dependent upon the timing and duration of the infection. Two hydropic fetuses had cerebral infarcts with PMG located around the infarct margins. Based on evidence from their cases, the authors concluded that CMV mediated migrational defects could arise from one or more of the following: direct viral-induced neuronal or glial cell death, loss of cells in the VZ, loss of glial-pial border integrity, and vascular insults due to either local vasculitis or systemic hypotension. The overwhelming majority of cases of PMG are sporadic, and this includes forms that do sometimes show clear evidence of a single gene cause. Only two of the 31 patients with CBPP reported by Kuzniesky et al.185 had a positive family history. One family had an affected set of male monozygotic twins; the finding in the other family was compatible with X-linked inheritance. A multicenter study of familial CBPP found that 10 families fit with X-linked inheritance, one family fit best with autosomal dominant with reduced penetrance, and one family was likely autosomal recessive with pseudodominance related to consanguinity. Among X-linked families there was marked intra- and interfamilial variability. In some families, only males were symptomatic, while in other families females showed variable manifestation of CBPP. Villard et al.234 have shown linkage to Xq28.

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Neuromuscular Systems

As discussed, autosomal recessive bilateral frontoparietal polymicrogyria has been linked to 16q12-q21. Although the parents of 2 of the 13 patients with bilateral frontal PMG were cousins, there were no instances of recurrent PMG in those families. There are other reports of recurrent PMG in siblings, some in concert with pachygyria (see Section 15.5.2). Also, PMG has been reported in a number of known and unknown genesis syndromes summarized in Table 15-6. However, at this time virtually nothing is known beyond the specific Xq28 and 16q12-q21 linkages about the genes involved in PMG. A small minority of cases of schizencephaly-associated PMG is caused by mutations in the EMX2 homeotic gene on 10q26.4 No EMX2 mutations have been found in patients with CBPP or parieto-occipital PMG (discussed in ref 183). Unilateral PMG was found in 1 of 24 patients with known mutations in PAX6.173 The patient was one of three who had Cterminal extending mutations, and the mother who carried the same mutation was thought to also have an area of PMG. There is evidence that a gross appearance of polymicrogyria, in the absence of a typical four-layered cortex, can occur with insults at or around 24 weeks gestation. Such cases may show a greater macrophage and glial response than found in cases arising earlier in gestation. An often quoted example is that of the mother poisoned by carbon monoxide at 24 weeks gestation.95 Ferrer216 reported detailed anatomic and Golgi studies of a case of unlayered PMG associated with bilateral porencephaly. The thickness of the cortex varied, as did the histopathology, which did not show abrupt transformation to the normal zones. Partially preserved gyri were separated by narrow sulci, and there was a gradient of severity away from the porencephalies. Although the neurons were randomly orientated the general distribution of types approached normal in the better preserved areas. Transformed RGC and some heterotopias were noted; the Golgi studies resembled those produced by freezing the cortex surface of rats at a time when neuronal migration is about complete.3,216 Ferrer216 pointed out that the blood supply to the cortex during months 5 and 6 is via the right-angled penetration of spiral artery branches of superficial cortical vessels, which have poor anastomotic connections as compared with the superficial meningeal network. Infarction would lead to variable damage in those arterial territories. Subsequent cortical growth toward the damaged areas would result in fusion of the molecular layer with central glial-mesodermic scarring. Neuronal organization at the borders of scarred areas would be impaired due to the prior vascular compromise. Prognosis, Treatment, and Prevention

It is evident from the previous discussion that the prognosis for patients with PMG is highly dependent on the presence or absence of accompanying anomalies such as porencephaly, and on the extent and specific topography of the lesion. Generalized PMG is usually accompanied by other CNS malformations. There will continue to be a bias toward the assessment with suitable MRI of patients with significant mental retardation and/or neurologic signs. Therefore, it is important to keep in mind that later onset seizures may be the presenting sign of patients with parietooccipital PMG,186 and that developmental delays can be mild in CBPP and in bilateral frontal PMG, in which motor signs may predominate.183 Kuker et al.224 have suggested that the association of CBPP and esophageal atresia may predict a poor developmental outcome. Of the 36 patients in the PMG/schizencephaly group studied by Montenegro et al.,96 32 were listed as having normal intelligence. All four stated to have some degree of retardation had associated schizencephaly. The prognosis for patients whose

polymicrogyria is limited to small areas can be quite favorable, and the condition is less likely to be diagnosed. For example, polymicrogyria localized to the left posterior superior temporal gyrus has been reported in some patients with dyslexia.227 Treatment would appear to be limited to providing control of seizures and developmental support for learning and motor difficulties that may arise. Surgical options are limited to perhaps cases of associated heterotopia that can be clearly shown to be the focus for refractory seizures. Options for prevention appear limited to the recognition of syndromes with known recurrence risks. In some syndromes associated malformations might be detectable by ultrasound, or a genetic or biochemical test can be applied (Table 15-6). In suitable families with either CBPP or bilateral frontoparietal PMG, there may be the option of applying linkage studies to Xq28 or 16q12q21. Methods to reduce maternal complications during pregnancy, including CMV and toxoplasmosis, may also reduce the population prevalence of PMG. Changes that proved to be polymicrogyria have been detected by 24 weeks gestation using fetal MRI.299 15.5.4 Heterotopias Definition

Heterotopias are collections of neurons that have arrested at an abnormal position along or beyond their normal path of neuronal migration (Fig. 15-32). Heterotopias can be further subcategorized according to whether they are generalized or focal, and as to their location as subependymal, subcortical, or beyond the cortical plate and into the molecular and leptomeningeal space.10 The latter are also referred to as ectopias and leptomeningeal heterotopias, but the term most often used today is marginal glioneuronal heterotopia. Subcortical band heterotopia has been discussed under lissencephaly. Norman et al.1 stress that numbers of single heterotopic (ectopic) neurons can be found scattered in the subcortical white matter of most brains, regardless of maturity, and that extensive experience is required to judge whether their numbers are excessive. There is some consensus that a cluster of
12 neurons describes a microscopic heterotopia.235 Fig. 15-32. Axial cross section of brain showing periventricular nodular heterotopias (arrows). (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

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Diagnosis

With development of modern neuroimaging techniques, most notably MRI, the diagnosis of heterotopia is no longer a primarily post mortem diagnosis, and its clinical importance as a cause of seizures and/or developmental delay has become apparent. Lesions range from 0.5 to 3 cm.220 The predominant location may correlate with a specific syndrome. For example, in some situations the arrest is predominantly between the ventricular zone and the external sagittal stratum (ESS); whereas in classic lissencephaly and WalkerWarburg syndrome, the halt is between the ESS and the cortical plate in the corona radiata.3 Use of narrow MRI slices (< 3 mm) with appropriate weighting to distinguish gray from white matter is important,87 and separation of the gray matter heterotopia from surrounding white matter is facilitated as CNS myelination progresses and matures. Barkovich 236 has described the MRI morphology of subcortical heterotopias, which may present as multiple nodules, curvilinear bands of cortex always extending into the white matter in at least two points, or a combination of the two with the nodules lying deep to the more peripheral curvilinear areas. The curvilinear bands may contain apparent blood vessels and/or CSF-containing spaces. Heterotopias are the most prevalent of the cerebral dysplasias.237 Seizures, which are often refractory, are the more common presentation in all types of heterotopia and may be accompanied by developmental delay. Clearly there is a bias toward ascertainment of symptomatic cases, and heterotopias can be an incidental finding at autopsy.1 Furthermore, heterotopias can be associated with other cortical anomalies, which may account for some of the symptomatology.88,238 Of five patients studied by Spalice et al.,239 the two who were not developmentally delayed were the same two who lacked associated cortical anomalies. Associated cortical anomalies may be subtle and not apparent on MRI. Borgatti et al.240 described a 17-year-old boy with a single periventricular nodular heterotopia near the right ventricular occipital horn and seizures, in whom neuropsychological testing showed abnormalities of frontal associative function. The EEG showed bilateral slow waves, and a single photon PET scan increased tracer uptake over the frontal area, providing evidence of a cortical disturbance beyond that suggested by the heterotopia. That neuronal heterotopias are highly associated with seizures, and the fact that neurons that do not make interconnections

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are subject to apoptosis, suggest that interneuronal connections must occur and that they likely extend beyond the individual heterotopia. In one study, the typical periventricular heterotopias contained both neuronal and glial cells.88 There were small and medium pyramidal cells, polymorphic neurons, small stellate neurons, and rare neurons with opposed double dendrite arbors. The neurons showed a random orientation and a reduced number of dendritic spines. The changes were similar to those reported with radiation damage by x-ray, Zellweger syndrome, and neurons transplanted into young rat brains.88 Extrinsic axons were noted. Hannan et al.240 examined nodular heterotopias from four patients with diverse clinical presentations and differing associated CNS anomalies. With a combination of standard histology and carbocyanide dye tracing, they observed that few of the surrounding fibers penetrated the nodules and that projections from the nodules were uncommon. In one case they were able to show a connection between adjacent nodules. They were able to show numerous cells expressing calretinin and neuropeptide Y, an expression pattern typical of GABAergic interneurons. However, the intranodular neurons were less complex than normal cortical neurons. Importantly, the overlying cortex showed evidence of a generalized migrational defect in the form of clusters of calretinin-positive cells. In an immunohistochemical study of neurosurgically removed heterotopias, decreased expression of the a-subunit of Ca2/ calmodulin dependent kinase II and its active phosphorylation form was observed.237 In severe cases with associated anomalies of cortical lamination, there were also reduced N-methyl-d-aspartate receptor units. The authors hypothesized that these changes might play a role in increased excitability and the seizures associated with heterotopia. Nodular heterotopias appear to be the most commonly diagnosed form of heterotopia, and their most frequent location is along the subependymal region of the posterior lateral ventricles. They may occur singly or as multiples, at times creating a diffuse row extending around the ventricular surface. They may also occur lateral to the basal ganglia and thalamus.1 X-linked dominant bilateral periventricular nodular heterotopia (BPNH) (Fig. 15-33) is of particular note because of its genetic implications, and because filamin 1 (FLN1) has been identified as the gene affected (vide infra).242 The X-linked nature of the condition was identified because of an excess of females

Fig. 15-33. T1-weighted MRI, coronal sequence, parieto-occipital region. The two panels are adjacent MRI sections. Note the extensive nodules of gray matter in the walls of both lateral ventricles. The apparent intraventricular mass in the left ventricle of the left panel is the posterior termination of the thalamic pulvinar nucleus, the plane of section being slightly offcenter (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

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with BPNH, the occurrence of families with female-to-female transmission, and an increase of male pregnancy wastage in those families. Affected women are generally of normal to borderline low intelligence and present with seizures of multiple types. Variability is considered in part due to random X-inactivation, with lethality in the hemizygous male. In one family a liveborn male, who carried the affected haplotype, died of severe systemic bleeding at day 3.242 The bone marrow showed an arrest of myeloid and erythroid differentiation, suggesting that coagulation abnormalities may account for the loss of affected males. The MRI is characterized by bilateral, rounded, homogeneous, periventricular masses with a signal intensity characteristic of gray matter.243 There may be mild hypoplasia of the corpus callosum and cerebellar vermis, the latter resulting in an enlarged cisterna magna. The nodular pathology varies from groups of neurons with apparently random size and orientation, to an organization reminiscent of cortical lamination.244 In an autopsied case reported by Kakita et al.,245 which had a proven FLN1 mutation, the authors were able to show bundles of neuronal fibers extending into the neighboring white matter, between adjacent heterotopias, and into the cerebral cortex. The cortical cytoarchitecture was abnormal, with the normally columnar neuronal pattern distorted around abnormal blood vessels that ran closely packed and parallel across the cortical layers. Women with XL-BPNH, and an affected male with an Xq28 duplication, appear to have an excess of non-CNS anomalies, which include premature stroke, patent ductus arteriosis, minor finger anomalies, and perhaps disturbance of gut motility.242 Further genotype-phenotype correlations will be of interest. For the most part, marginal glioneuronal heterotopias (MGNH) have remained a pathologic diagnosis (Fig. 15-34), although large or extensive lesions may possibly be visible with careful MRI examination of the superficial cortex. They are commonly associated with other major malformations and often go unreported. They are more commonly found in infra- than supratentorial locations and appear of major importance in the fetal alcohol syndrome.3,231 Infratentorial

Fig. 15-34. Leptomeningeal neuroglial heterotopia. The leptomeningeal space is completely obliterated by a dense fibrillary tissue containing astrocytic and neuronal cells of various sizes. The superficial cortex underneath shows reactive gliosis and aberrant neurons in the molecular layer. The pia mater is absent. (Courtesy of Dr. Jean Michaud, Department of Laboratory Medicine and Pathology, Children’s Hospital of Eastern Ontario.)

MGNH usually do not contain neurons and are usually located beside the brain stem.1 MGNH of the cerebral cortex frequently do contain neurons, and their extent is extremely variable, ranging from a single chance lesion to a sheet covering the cortex as in cobblestone lissencephaly. Where present, the MGNH often give the sulcus a shallow appearance. And when an individual lesion can be identified, it has a visible stalk-like connection to the molecular layer.246 Two unusual types of neuronal heterotopia are mentioned here, although they do not meet the strict definition of a heterotopia. There have been a number of reports of apparent heterotopic neuronal tissue on the scalp with no detectable connection to the intracranial cavity. Neuronal and glial elements have been shown clearly in at least one instance.247 Similar situations may arise intracranially.248 The origin is unclear but could represent pinched off neuroectoderm that continued to develop, or a cephalocele in which the original connection was lost. The second type is an unusual situation, termed by some accessory brain, wherein there is an intracranial mass or partially organized brain with neurons, astrocytes, ependyma, and choroid plexus.249 One proposed origin is as an extra telencephalic vesicle developing at the time of cerebral cleavage. Distribution and Etiology

The population prevalence of heterotopias is unknown, although they are considered the most common type of cerebral dysgenesis. Small lesions are very likely to be overlooked or not recorded at autopsy, and ascertainment during life is highly dependent on their being symptomatic and the appropriate neuroimaging studies being performed. These anomalies are not infrequent in brains that have other structural anomalies such as Arnold-Chiari malformation or porencephaly. In one series, subependymal heterotopias were detected by MRI in 3 of 6 patients undergoing surgery for encephalocele and in 4 of 8 with encephalocele who came to autopsy.250 Soto Ares et al.238 found 10 cases of subependymal and 11 cases of focal or diffuse subcortical heterotopias among 22 patients selected because of seizures and

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developmental delay. In two of the patients with focal subcortical heterotopia, they were unable to determine any clinical-radiologic correalation. In a series of 133 consecutive surgical specimens from patients with extra temporal lobe epilepsy, Frater et al.251 identified 59 (44%) with neuronal heterotopia. This is similar to the study by Hardiman et al.,252 who found heterotopias in 42% and neuronal clustering in 28% of resected brain specimens from patients with focal epilepsy and whose EEG demonstrated the focal origin. Leventer et al.253 reviewed their series of 109 patients in whom a malformation of cortical development (MCD) had been identified, and heterotopic gray matter (19%) was the most common lesion, followed by cortical tubers (17%). They noted that pediatric patients with MCD had a significant rate of associated non-CNS anomalies (19%), and heterotopias are listed as accompanying a number of syndromes in Table 15-6. Lower rates of neuronal heterotopias (3.3%) were found in a study of institutionalized mentally retarded patients,93 perhaps reflecting a milder clinical impact in most cases of heterotopia. The most important development in understanding the etiology of neuronal heterotopias has been the discovery, through classic linkage, the study of a male with a duplication Xq28,254 and the candidate gene approach, that mutations in filamin 1 (FLN1) were responsible for XL-BPNH. Filamin 1 is expressed at high levels in the developing brain, and it is a member of a family of actinbinding proteins that reorganize actin in response to cell-cell signaling.243 As such, it is thought to play a role in cell motility. Its additional involvement in blood vessel formation and coagulation might further explain some of the non–CNS malformations that have been observed in the syndrome, and perhaps also the male lethality through defective coagulation.243 Sheen et al.,255 using SSCP, found FLN1 mutations in five of six families with a pedigree characteristic of XL-BPNH, and in 6 of 31 females with sporadic subependymal neuronal heterotopia (SNH). All six of the positive sporadic cases had an MRI characteristic of XL-BPNH, whereas no mutations were found among the six women whose MRI was atypical. They also found mutations in 2 of 24 males with sporadic SNH. Mutations in FLN1 that cause BPNH are all loss of function; and in all the familial and four of the female sporadic cases, the changes were either nonsense mutations near the N-terminus or splice site mutations that predict an unstable mRNA and truncated protein. The mutations in two of the sporadic female cases and the two male patients were predicted to produce less detrimental changes in gene function. One of the males had a typical MRI, while the second had only a few nodules; both were clinically mildly affected. Thus, FLN1 plays an important role in SNH, particularly in those patients with a positive family history and/or a typical MRI. Although somatic mosaicism has not been demonstrated for this gene, it remains possible that relatively local somatic changes in FLN1, DCX, or any of the other genes involved in migration could give rise to some paucinodular cases of neuronal heterotopia. There is some evidence that a subset of cases of BPNH may be due to autosomal recessive inheritance (Table 15-6).174 Battaglia et al.256 noted that their patients with BPNH tended to have a positive family history of seizures, were more likely to be female, to have structural anomalies in the posterior fossa, and to have multiple seizure types (FLN1 studies were not available) than patients with unilateral SNH. The later tended to have drugresistant focal seizures that had a visual or auditory onset. Of interest was that the unilateral heterotopias were paratrigonal in location, a watershed area, suggesting the possibility of vascular compromise as an etiology.

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It is to be expected that the study of single gene human syndromes may reveal relatively specific findings. For example, in Zellweger syndrome the parasylvian gyri are smaller, and the upper central gyri are larger, than normal. While the six-layered cortex is maintained, heterotopias including all neuronal classes are found throughout the cortex and subcortical white matter. The horizontal lamination becomes partly inverted, and the layers are uneven due to different levels of migration along adjacent radial glial fascicles. The observations suggest disordered migration over a prolonged period of time and are consistent with the metabolic basis for this condition.3,231 The etiology of MGNH appears to be nonspecific and related to compromise of the integrity of the glia-limitans. The glia-limitans is formed by gestational age 6 to 7 weeks by the apposition of the ends of the RGC to the basal lamina of the pial surface. Below is the molecular layer, whose maturation may be an important boundary to cell migration.257 In areas of superficial scarring, the neurons appear freed from their usual constraints and continue their migration into the molecular and pial layers. The underlying cortex may show abnormalities not seen in adjacent cortex that lacks heterotopia. Such findings are typical of the rat cortex–freezing experiments, as well as of alcohol embryopathy.3 Astrocyte transformation of the RGC as a response to injury may be the pathway that frees the neurons from normal constraints. MGNH are common in the Dreher-Shaker short tail mouse, in which disproportion in growth between CNS and skull entraps the growing brain, resulting in a variety of lesions, including damage to the superficial cortex, with scarring.3 Ligon et al.258 observed MGHN, equivalent to those seen in humans, in Emx2 / mice. The heterotopias were detected as early as day 13.5, which is during early neuronal migration and preplate formation. They also provided evidence of over expression of Wnt1 in the roof-plate organizer region and dorsal telencephalon, and that Emx2 acts normally as a Wnt1 repressor. Prognosis, Treatment, and Prevention

It seems likely that heterotopias per se, even when quite extensive, are unlikely to be associated with developmental delay or neurologic deficits. However, heterotopias are commonly associated with other CNS lesions, including developmental anomalies of the overlying cortex that can be invisible to MRI, which can be responsible for significant clinical signs. The two patients with periventricular heterotopias reported by Spalice et al.239 who were of normal intelligence had no associated CNS or non-CNS lesions. The remaining three patients were developmentally delayed and had other CNS lesions such as areas of pachygyria and/or extracranial anomalies that included bifid thumbs, cardiomyopathy, and metatarsal agenesis. Heterotopias are associated with seizures, which may be resistant to medical treatment, thus leading to consideration of surgery. Jan259 reported a pair of female monozygotic twins who presented because of megalencephaly and were found to have BPNH. At age 6 years, they were seizure free and showed normal development. Andermann89 has stressed the point that the epileptogenic abnormalities may be distant from the heterotopia and that it may remain unclear as to whether the seizures result from the heterotopia or overlying cortical dysplasia. Invasive cortical recording may be required to determine the site of the epileptogenic focus. Failure to do so may result in surgery that is ineffectual. Hardiman et al.252 showed a significant excess of heterotopias and abnormal neuronal clustering in patients selected for surgical treatment of intractable temporal lobe epilepsy of demonstrable focal origin. The presence of severe heterotopias and/or clustering in the surgical specimen was significantly correlated with a

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favorable response to operative management. This provides strong evidence in support of a causative role for the heterotopias in the etiology of the seizures. Steams et al.260 reported a favorable response to callosectomy in a patient with intractable atonic seizures associated with diffuse bilateral heterotopias. Prevention of heterotopias is limited to recognition of families with XL-BPNH and other metabolic or syndromic conditions. The offer of genetic counseling, and where appropriate, prenatal diagnosis should be made. Onyeje et al.261 reported prenatal ultrasound detection of a subcortical heterotopia at 23 weeks gestation. However, the situation was unusual in that the heterotopia had caused a midline shift with compression of the cerebral ventricle, hydrocephalus, and hydrops fetalis. Importantly, there was no evidence of invasion of the surrounding tissue. Postnatal MRI and autopsy confirmed the diagnosis. Bargallo et al.262 made the diagnosis of BPNH at 29 weeks gestation through a combination of ultrasound and fetal MRI. They emphasize the difficulty posed to ultrasound diagnosis by the normally large germinal matrix. An enlarged cisterna magna may draw attention to the presence of underlying CNS pathology. MRI of the mother revealed typical BPNH, which emphasizes the importance of studying the mother, who may be completely asymptomatic, in order to detect XL-BPNH. 15.5.5 Focal Cortical Dysplasia Definition

Focal cortical dysplasia is a localized malformation of cortical development that is intracortical. Gross malformations of cortical development including agyria/pachygyria, polymicrogyria, and macroscopic heterotopias are excluded. Focal cortical dysplasias (FCD) can be further subdivided according to their specific histology, but to date there is no classification that has had extensive use of a significant period of time to establish its clinical validity and relevance. This section follows the suggested classification of Palmini and Luders, which derived from a workshop on the terminology and classification of cortical dysplasias.235 A slight modification is that a group of very mild cortical dysplasias is referred to herein as type 0 simply to give them a place in the nomenclature. The subtypes are defined by the presence of architectural abnormalities (dyslamination) and the presence or absence of one or more of immature and/or giant cells or dysmorphic neurons with or without balloon cells. Immature neurons are homogeneous, round or oval cells with a large nucleus and sparse cytoplasm. Giant neurons may be found throughout layers II to VI and have a normal pyramidal shape, but are larger than normal neurons of layer V. Dysmorphic neurons can be increased in size and have an abnormal shape, orientation, and cytoskeleton. There is clumping of Nissl substance, and special immunostaining shows an excess of cytoplasmic neurofilaments.235 Balloon cells can be multinucleated; the nuclei are eccentric, the cytoplasm eosinophilic, and the cell membrane thin. They are usually large and can be massive. Vimentin staining is relatively specific for these cells.263 Taylor type FCD is sometimes used to describe FCD with balloon cells, but the initial patients reported by Taylor et al.264 included patients with dysmorphic neurons both with and without balloon cells. The suggested classification of FCD is outlined in Figure 15-35. Diagnosis

Most diagnoses of FCD are made in the context of medically refractory seizures, and these lesions clearly have a high epileptogenic

Type 0—Mildest forms of malformations of cortical development 0A: Abnormality confined or adjacent to cortical layer I i) neurons present in the molecular layer ii) persistent subpial granular layer iii) small area(s) of marginal glioneuronal heterotopia 0B: Malformation outside of layer I i) small clusters (
12) of heterotopic white matter neurons ii) dysgenesis of hippocampal formation Type I—Architectural dyslamination with no abnormal cellular elements IA: Architectural dyslamintion alone IB: As per IA with immature and/or giant neurons Type II—Architectural dyslamination with abnormal neurons IIA: Architectural dyslamination plus dysmorphic neurons þ/ immature neurons or giant cells IIB: As per IIA plus balloon cells (most severe form of FCD)

Fig. 15-35. Classification and definition of focal cortical dysplasias.235

potential. Typically they present as partial seizures, often accompanied by motor and secondary generalized seizures. Status epilepticus is common in the history. The EEG shows a high frequency of continuous spiking or other types of highly epileptogenic patterns.265 Electrocorticography can be used to better define the bounds of the lesion and tends to show generous amounts of interictal, semi-rhythmic epileptogenic activity over the FCD. Especially in the more severe type II dysplasias, this activity can be virtually continuous.266 The EEG/electrocortical pattern differs from that seen in cerebral tumors, which are in the differential diagnosis for the clinical presentation. The epileptoform activity is intrinsic to the FCD and does not arise from the surrounding normal tissue, as is the case for tumors.267 Dysplasia may be accompanied by gray matter thickening and a homogeneous hyperintensive signal in the subcortical white matter that extends in a tapering pattern to the lateral ventricles; frontal lobe is more likely to be a dysplasia and temporal lobe a neoplasm.268 Factors that influence the clinical presentation of FCD include the subtype of pathology, the location, and the extent of the lesion. Type 0 lesions are very unlikely to be detected by neuroimaging, and thus far there appear to be few data as to whether they can be suspected with diagnostic techniques such as singlephoton emission computed tomography (SPECT) or PET. Very often they are discovered after the fact in a patient with a neurologic or behavioral complaint, and the causative role remains unproven. However, a positive role has been suggested for some cases of epilepsy, developmental delay, autism, and schizophrenia.235 Type I FCD has been found as the only pathology in patients who have had successful surgical treatment for their epilepsy, and clearly it is clinically important in some patients.269 What is not known is the frequency of asymptomatic type I and type II FCD, although type II is pathologically more abnormal and is more likely to be detected on neuroimaging. The extent of FCD can range from a few Type 0 heterotopic neurons in the mesiotemporal area that are of questionable significance, to type II FCD of an entire hemicortex (Fig. 15-36). The whole cortex can be involved without causing enlargement,89 but usually there is an associated hemimegalencephaly with macrogyria, enlarged lateral ventricles, poor gray–white demarcation, a dyslaminated architecture, usually with a wide distribution of dysmorphic neurons, heterotopic subcortical groups of neurons,

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Fig. 15-36. T1-weighted MRI, coronal sequence, fronto-central region, from a young boy with congenital left spastic hemiparesis and epilepsy. The left hemisphere is normal in appearance, whereas the right shows an abnormal gyral pattern in the entire convexity area, including an abnormally configured sylvian fissure. The right lateral ventricle is enlarged. (Courtesy of Dr. Peter Humphreys, Division of Neurology, Children’s Hospital of Eastern Ontario.)

and often multinucleated giant cells in the molecular layer.270 Of interest is an association of FCD with dysplastic tumors including gangliogliomas, dysembryoplastic neuroepithelial tumors, and xanthoastrocytomas.271 Surrounding the tumors an area of dyslamination with dysmorphic neurons and associated subcortical heterotopias may be seen. Patients usually present under the age of 20 years with refractory seizures, and the MRI is characterized by poorly defined borders to the mass, lack of edema, and absence of a mass effect.89 Similar findings, together with calcification, which is unusual in FCD, have been reported in association with a hamartoma.272 FCD may be accompanied by skin changes that are usually ipsilateral and confined to the head and neck; most commonly multiple hemangiomas or linear nevus, and are associated with several syndromes including neurofibromatosis, hypomelanosis of Ito, and tuberous sclerosis (Table 15-6). The later is of particular note because its pathology is highly associated with balloon cells and the MRI findings of transmantle dysplasia (TD) (vide infra). Of importance and interest has been the relative sensitivity of neuroimaging techniques in detecting the presence of FCD. MRI may give a normal result in the presence of FCD, and detection rates are higher for type II lesions.273 Signs suggestive of FCD can include focal cortical thickening, abnormal gyral and sulcal contours, a blurred cortical–subcortical transition with abnormal signal intensity in subcortical white matter, and an increased signal intensity in T2-weighted, proton density, or fluid-attenuated inversion recovery (FLAIR) studies.273,274,275 Bronen et al.276 noted a prominent CSF space overlying an area of loss of cortical volume (dimple) in 29 of 71 (41%) of cases of FCD. In about half of patients this sign was more apparent than other MRI signs, and it

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was particularly prominent (22/25) in lesions with a primarily architectural pathology. The MRI can show TD, which was first described by Barkovich et al.,277 in a group of 18 patients who presented with seizures or a neurologic deficit under the age of 20 years. The findings consist of an abnormal signal extending radially and inward from the cortex to the superiolateral wall of the lateral ventricle. The associated pathology is that of type IIB FCD with astrogliosis, and the lesion is associated with, but is not unique to, tuberous sclerosis.278 Barkovich and Peacock279 described a type of sublobar dysplasia, which they considered to be a distinct cortical malformation. The report concerned five patients who were of normal intelligence and had no focal neurologic deficit in whom a local area of cortical dysplasia, not specific to any lobe, was separated from the cortex by a deep infolding of the cortex. In all patients, the dysplastic cortex was thickened with an abnormal sulcal depth and pattern, and the ipsilateral lateral ventricle was abnormal. Thinning to absence of the corpus callosum and hypoplastic cerebellar vermis were common associated findings. One patient who was ascertained because of a calvarial defect was seizure free at 13 years. The other four presented with seizures, but only two had evidence of persistent partial epilepsy. Chan et al.274 performed high-resolution T2-weighted fast multiplanar inversion-recovery MR (FMPIR) on 42 patients with suspected neocortical seizures, and in 10 they predicted the presence of FCD. In three cases the only MRI finding was localized blurring of the gray–white border, and in two patients this was only detectable with FMPIR. The diagnosis of FCD was confirmed in all seven patients in whom surgery was performed. Although adequate cerebral tissue was available for study, the study does not inform with respect to the negative predictive value of FMPIR. Scalp EEG was able to localize the lesion in five of the eight surgically treated patients, and PET was correct in three of three patients in whom it was applied. Kim et al.273 reported a blinded, retrospective comparison of the detection of FCD by MRI versus [18F] fluorodeoyglucose PET (FDGPET) in a consecutive series of 19 patients with surgically proven FCD. The MRI studies included a series of T1- and T2weighted studies in the axial, sagittal, and coronal planes, as well as 3D-spoiled gradient studies with 1.6-mm sections. The surgical specimens were subdivided into grade I (4), grade II (4), which would seem to fall into type I, and grade III (11), which appears to correspond with type II FCD. MRI detected 10 of 19 (53%) of FCD lesions, of which 9 were grade III. The anomalies noted were broad gyri (6), thick cortex (6), abnormal sulcal contour (6), indistinct gray–white junction (8) and increased white matter signal (9). PET was positive in 15/17 (83%) cases in which it was performed, including seven of the eight grade I and II, and nine of the ten grade III FCD. The size of the lesion as estimated by PET did not correlate with the grade; in 65% of cases detected by both methods, the malformation was judged by PET to cover a wider area. The authors noted that their detection rate by MRI was lower than for some prior reports. This could relate to case selection. Surface coil MRI with 3D acquisition may be more sensitive,280 especially with the addition of curvilinear reformatting.281 More comparative studies using a standardized classification system are required. Study of the uptake of specific ligands may add to the information provided by PET. There remains much to learn about the cell types and their behavior in FCD, and the reasons behind the high epileptogenicity of these developmental malformations. There is evidence of an increase in excitatory neurotransmitters in FCD, and a decrease in intra- and perilesional inhibition.89 An increase in excitatory and

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decrease in GABAergic neurons have been noted.282 When compared with normal cortex, type I and II FCD cortex both show an increased cellularity in lamina I, but only in type I was the population of Cajal-Retzius cells (CR) significantly increased.283 Jansky et al.284 performed functional MRI (fMRI) on a cross section of MCD and noted activity in response to simple tasks in all polymicrogyria, schizencephaly or mild FCD. However, activity was detected in less than half of heterotopias or type II FCD. Focal EEG slowing and focal neurologic signs correlated with lack of fMRI response. In vitro electrophysiologic patch-clamp studies also appear to confirm that there is some validity in separating the different histopathologic types of FCD. Cepeda et al.285 showed that immature pyramidal and dysmorphic pyramidal neurons did not show significant abnormality compared with normal; whereas what were likely balloon cells showed evidence that they did not receive synaptic inputs. What appeared to be giant cells produced abnormal currents and influxes under testing conditions. Distribution and Etiology

There are no data as to what proportion of the different types of FCD are symptomatic and, combined with the fact that FCD will not be noted during most post-mortem studies, this means that there is no meaningful estimate of their prevalence in the general population. FCD has been reported in between 6% to 23% of most surgical epilepsy series.273,290 Prayson and Eastes271 found 52 cases among 360 (14%) lobectomy specimens from patients with epilepsy. The patients ranged in age from 3 months to 47 years, and there was no significant sex difference. The temporal lobe was most commonly affected (34), followed by the frontal (18), with a few patients each having occipital, parietal, or multiple lobe involvement. Of note, 13 (25%) of their patients had an associated tumor (ganglioglioma, 8; dysembryoblastic neuroepithelial, 3; low-grade astrocytoma, 2), and 4 (13%) had tuberous sclerosis. These data do not show whether the lobar distribution, and rates of associated tumors and other syndromes, are representative of FCD in general or, more likely, are biased toward cases most likely to be symptomatic. At this time, very little is known about the pathogenesis of FCD. Inherited and perinatal factors appear unlikely to play a significant role.96 Whatever the mechanism, it is clear that the population of cells involved can be very small and lead to circumscribed involvement, or large, as in cases of hemimegalencephaly. There is some evidence that the subtypes of FCD vary in their cell types and gene expression. As mentioned there is an excess of CR cells in FCD IA that is not seen in type IIB.283 Cotter et al.286 looked at a number of proteins in the Notch/Wnt signaling pathway and found differences in the expression of several between FCD balloon cells and FCD giant neurons. For example, balloon cells had absent Notch-1 and elevated APC, whereas giant neurons had elevated Notch-1 and normal APC. This pathway is important in neuronal and glial determination, and one could speculate as to whether perturbations in the likes of the APC gene might play a role in the association with dysplastic tumors. Barkovich et al.277 speculate that transmantle dysplasia (TD) is due to a primary stem cell defect and include the lesion in their classification (I-B-3-iv) as a ‘‘malformation due to abnormal neuronal and glial proliferation.’’10 The association of TD and balloon cells with tuberous sclerosis led Becker et al.287 to compare the rates of sequence changes in certain exons of the TSC1 and TSC2 genes in 48 cases of type II FCD and 200 control samples. They found amino acid altering sequence changes in 2.3% of exons 5 and 35% of exons 17 in the type IIB FCD compared with 0% and 1%, respectively, in

the controls. The comparable figures for silent base-pair changes in exons 14 and 22 were 37.8% and 45% for the FCD and 15% and 23.8% for controls. Loss of heterozygosity for TSC1 was noted in 11 FCD samples. In contrast, TSC2 exhibited only silent base-pair substitutions at the same frequency as controls. Therefore, TSC1 may have a role in the pathogenesis of type IIB FCD. Using trinucleotide repeat number (TNR) variations at the X-linked androgen receptor locus, Hua and Crino288 showed random X-inactivation in both heterotopic neurons and balloon cells. In contrast, closely apposed normal neurons showed 70– 80% homology for TNR, which led the authors to conclude that the FCD cells arose in post-mitotic neurons, or from a population of progenitor cells. Growing interest in the nature and origin of FCD will undoubtedly lead to significant changes in understanding over the next several years. Prognosis, Treatment, and Prevention

The clinical presentation of FCD is predominantly that of epilepsy, which is often medically refractory. Prognosis is therefore primarily a question of severity, frequency, and the successful management of seizures. FCD may also be more frequent in patients with posttraumatic seizures, suggesting that these developmental lesions provide a focus of susceptibility to further damage. Mental retardation is uncommon, affecting only 1 of 21 patients with FCD discussed by Montenegro et al.96; but, focal neurologic signs may occur in extensive and diffuse lesions, and mild developmental problems may be more common. Klein et al. compared verbal and performance IQ between a group of 15 children with developmental mass lesions (glial-neuronal hamartomas, 8; dysembryoplastic neuroepithelial tumor, 4; ganglioneuroma, 4) and 39 children with FCD that was divided into mild, moderate, and severe.289 Performance IQ scores in those with mass lesions were in the low–normal range and were significantly higher than for children with FCD, whose mean scores tended to fall in the borderline range. Likewise, those in the former group who had right-sided lesions had clearly normal mean verbal scores, whereas those with right-sided FCD were significantly lower and in the low–normal range. Interestingly, there was no significant difference in verbal scores for left-sided lesions, with scores tending to be at the borderline level; and there was no correlation with IQ and the histologic scoring of the FCD pathology. Subsample sizes were small and the assessments were not all standardized, but the work points out the need for more study of development in individuals with FCD. The primary approach to intractable seizures associated with FCD is operative and, therefore, most information related to outcome derives from surgical series. Factors that might be expected to influence outcome include the location, extent, and histology of the lesion. It does appear that type I has a less severe presentation of seizures than does type II FCD.235,290 Although most clinically recognized FCD is extratemporal, type I may be more likely temporal.290 However, the impact of type on surgical outcome remains unclear, perhaps confounded by other variables such as actual location, variations in histopathologic classification, and chance due to small subtype numbers in the different series. Palmini and Luders235 state that when found retrospectively at surgery, type I FCD has a better prognosis, whereas Kloss et al.291 found no correlation between type and outcome, and Tassi et al.290 obtained better outcomes in patients with type IIB FCD. Partial surgical lobectomy has proved to benefit a significant proportion of patients. In one series of 68 cases, 60% were judged to have good results, with 50% seizure free at 2 years and 7%

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unchanged.291 Age at surgery had no impact and the outcomes were similar in patients followed to 3 years. Tassi et al.290 provided outcomes for seizure control for 40 of 52 patients 1 year post surgery. Forty two percent of patients with type I, two of four with type IIA, and 9 of 12 with type IIB FCD were seizure free at 1 year. The seemingly better outcomes for patients with type IIB lesions is not necessarily attributable to the histopathologic differences and might reflect the small sample numbers, or perhaps the location and size of the lesions. For example, 66% of the type I were temporal as compared with 13% of the type IIB FCD. Vigliano et al.278 reported successful suppression of seizures in three of four patients with tuberous sclerosis associated transmantle dysplasia. The authors cautioned that seizures might be anticipated to return because of other associated tuberous sclerosis pathology. Factors to be considered in surgical outcome include location in the perirolandic cortex235 and the fact that the FCD may extend beyond the borders of the lesion as visualized by neuroimaging. Seizures may continue to originate from surrounding FCD following removal of a dysplastic tumor. Studies such as PET, electrocorticography, and deep cortical recording may serve to better define the extent of the lesion. Raymond et al.292 reported that FCD was seen in 15% of their series of patients with hippocampal sclerosis. Ho et al.293 carried out comparative volumetric studies of the amygdala (AM) and hippocampal formation (HF) in a series of 30 patients with type IIB FCD of the temporal lobe. They noted decreased AM volume in 18 and HF volume in 26 of the patients. In contrast with patients who had isolated hippocampal sclerosis (i.e., not associated with FCD), there was a very high rate of bilateral involvement. The authors favor secondary damage from recurrent FCD-driven seizures as a cause for the AM and HF atrophy because the temporal lobe cortex, AM, and HF derive from different germinal matrices. They cautioned that these atrophic areas could become independent epileptogenic foci and compromise results of FCD surgery. Further cautions arise from the fMRI studies that have been discussed, which show activity in type I lesions and a significant minority of type II FCD.284 Preul et al.294 carried out extensive neuroimaging, electrophysiologic and functional studies on a 16-year-old boy with a large fronto-parietal nodular heterotopia that had overlying areas of cortical dysplasia. They were able to show compensatory cortical reorganization, and that the heterotopia and dysplastic cortex retained some motor and sensory function. Therefore, there is concern that removal of such areas at surgery could lead to functional loss. To date there does not appear to be any approach to the primary prevention of FCD. References (Malformations of Cortical Development) 1. Norman M, McGillivray BC, Kalousek DK, et al.: Neuronal migration disorders and cortical dysplasias. In: Congenital Malformations of the Brain. Pathological, Embryological, Clinical, Radiological and Genetic Aspects. Norman MG, McGillvray BL, Kalousek DK, et al., eds. Oxford University Press, New York, 1995, p 223. 2. Volpe JJ: Normal and abnormal human brain development. Clin Perinatol 4:3, 1977. 3. Caviness VS, Mission I-P Jr, Gadisseux I-F: Abnormal neuronal patterns and disorders of neocortical development. In: From Neuron to Reading: Toward a Neurobiology of Dyslexia. AM Galaburda, ed. MIT Press, Cambridge, MA, 1990, p 406. 4. Ross ME, Walsh CA: Human brain malformations and their lessons from neuronal migration. Ann Rev Neurosci 24:1041, 2001. 5. Mallamaci A, Mercurio S, Muzio L, et al.: The lack of Emx2 causes impairment of Reelin signaling and defects of neuronal migration in the developing cerebral cortex. J Neurosci 20:1109, 2000.

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228. Cohen M, Campbell R, Yaghmai F: Neuropathological abnormalities in developmental dysphasia. Ann Neurol 25:567, 1989. 229. Gelisse P, Corda D, Raybaud C, et al.: Abnormal neuroimaging in patients with benign epilepsy with centrotemporal spikes. Epilepsia 44:372, 2003. 230. McLendon RE, Crain BJ, Oakes WJ, et al.: Cerebral polygyria in the Chiari type II (Arnold-Chiari) malformations. Clin Neuropathol 4:200, 1985. 231. Evrard P, de Saint-Georges P, Kadhim HJ, et al.: Pathology of prenatal encephalopathies. In: Child Neurology and Developmental Disabilities. Paul H Brooks, Baltimore, 1989, p 153. 232. Suzuki M, Choi BH: Repair and reconstruction of the cortical plate following closed cryogenic injury to the neonatal rat cerebrum. Acta Neuropathol (Berl) 82:93, 1991. 233. Toti P, De Felice C, Palmeri ML, et al.: Inflammatory pathogenesis of cortical polymicrogyria: an autopsy study. Pediatr Res 44:291, 1998. 234. Villard L, Nguyen K, Cardoso C, et al.: A locus for perisylvian polymicrogyria maps to Xq28. Am J Hum Genet 70:1003, 2002. 235. Palmini A, Luders HO: Classification issues in malformations caused by abnormalities of cortical development. Neurosurg Clin N Am 13:1, 2002. 236. Barkovich AJ: Morphologic characteristics of subcortical heterotopia: MR imaging study. AJNR Am J Neuroradiol 21:290, 2000. 237. Battaglia G, Pagliardini S, Ferrario A, et al.: AlphaCaMKII and NMDAreceptor subunit expression in epileptogenic cortex from human periventricular nodular heterotopia. Epilepsia 43 (Suppl 5):209, 2002. 238. Soto Ares G, Hamon-Kerautret M, Houlette C, et al.: Unusual MRI findings in grey matter heterotopia. Neuroradiology 40:81, 1998. 239. Spalice A, Taddeucci G, Perla FM, et al.: Periventricular nodular heterotopia: report of a pediatric series. J Child Neurol 17:300, 2002. 240. Borgatti R, Zucca C, Piccinellli P, et al.: Unilateral periventricular nodular heterotopia associated with diffuse areas of cerebral functional abnormalities. J Child Neurol 15:622, 2000. 241. Hannan AJ, Servotte S, Katsnelson A, et al.: Characterization of nodular heterotopia in children. Brain 122:219, 1999. 242. Fox JW, Lamperti ED, Eksioglu YZ, et al.: Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 21:1315, 1999. 243. Leventer RJ, Mills PL, Dobyns WB: X-linked malformations of cortical development. Am J Med Genet 97:213, 2000. 244. Harding BN: Gray matter heterotopia. In: Dysplasia of Cerebral Cortex and Epilepsy. Guerrini R, Andermann F, Canapicchi R, et al., eds. Lippincott-Raven, Philadelphia, 1996, p 81. 245. Kakita A, Hayashi S, Moro F, et al.: Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation: widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex. Acta Neuropath (Berl) 104:649, 2002. 246. Dambska M, Wisniewski KE, Sher IH: Marginal glioneuronal heterotopias in nine cases with and without cortical abnormalities. J Child Neurol 1:149, 1986. 247. Van Geertruyden JP, Fourez TJ, Hansen P, et al.: Heterotopic brain tissue in the scalp. Br J Plastic Surg 48:352, 1995. 248. Nishio S, Mizuno J, Barrow DL, et al.: Intracranial extracerebral glioneuronal heterotopia. Child Nerv Syst 4:246, 1988. 249. Harris CP, Townsend JJ, Klatt EC: Accessory brains (extracerebral heterotopias): unusual prenatal intracranial mass lesions. J Child Neurol 9:386, 1994. 250. Roelens FA, Barth PG, van der Harten JJ: Subependymal heterotopia in patients with encephalocele. Eur J Neurol 3:59, 1999. 251. Frater JL, Prayson RA, Morris HH III, et al.: Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections. Arch Pathol Lab Med 124:545, 2000. 252. Hardiman O, Burke T, Phillips J, et al.: Microdysgenesis in resected temporal neocortex: incidence and clinical significance in focal epilepsy. Neurology 38:1041, 1988. 253. Leventer RJ, Phelan EM, Coleman LT, et al.: Clinical and imaging features of cortical malformations in childhood. Neurology 53:715, 1999. 254. Fink JM, Dobyns WB, Guerrini R, et al.: Identification of a duplication of Xq28 associated with bilateral periventricular nodular heterotopia. Am J Med Genet 61:379, 1997.

255. Sheen VL, Dixon PH, Fox JW, et al.: Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet 10:1775, 2001. 256. Battaglia G, Granata T, Farina L, et al.: Periventricular nodular heterotopia: epileptogenic findings. Epilepsia 38:1173, 1997. 257. Choi BH: Developmental events during the early stages of cerebral cortical neurogenesis in man: a correlative, light, electronmicroscopic, immunohistochemical and Golgi study. Acta Neuropathol (Berl) 75: 441, 1988. 258. Ligon KL, Echelard Y, Assimacopoulos S, et al.: Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia. Development 130:2275, 2003. 259. Jan MMS: Outcome of bilateral periventricular nodular heterotopia in monozygous twins with megalencephaly. Dev Med Child Neurol 41:486, 1999. 260. Steams M, Wolf AL, Barry E, et al.: Corpus callosectomy for refractory seizures in a patient with cortical heterotopia: case report. Neurosurgery 25:633, 1989. 261. Onyeije CI, Sherer DM, Jarosz CJ, et al.: Prenatal sonographic findings associated with sporadic subcortical nodular heterotopia. Obstet Gynecol 91:799, 1998. 262. Bargallo N, Puerto B, De Juan C, et al.: Hereditary subependymal heterotopia associated with mega cisterna magna: antenatal diagnosis with magnetic resonance imaging. Ultrasound Obstet Gynecol 20:86, 2002. 263. Spreafico R, Pasquier B, Minotti L, et al.: Immumocytochemical investigation of dysplastic human tissue from epileptic patients. Epilepsy Res 32:34, 1998. 264. Taylor DC, Falconer MA, Bruton CJ, et al.: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:369, 1979. 265. Gambardella A, Palmini A, Andermann F, et al.: Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol 98:243, 1996. 266. Morioka T, Nishio S, Ishibashi H, et al.: Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electroencephalography. Epilepsy Res 33:177, 1999. 267. Palmini A, Gambardella A, Andermann F, et al.: Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 37:476, 1995. 268. Bronen RA, Vives KP, Kim JH, et al.: Focal cortical dysplasia of Taylor, balloon cell subtype: MR differentiation from low-grade tumors. AJNR Am J Neuroradiol 18:1141, 1997. 269. Keene DL, Jimenez CC, Ventureyra E: Cortical microdysplasia and surgical outcome in refractory epilepsy of childhood. Pediatr Neurosurg 29:69, 1998. 270. Adamsbaum C, Robain O, Cohen PA, et al.: Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol 28:583, 1998. 271. Prayson RA, Estes ML: Cortical dysplasia: a histopathological study of 52 cases of partial lobectomy in patients with epilepsy. Hum Pathol 26:493, 1995. 272. Maehara T, Arai N, Shimizu H, et al.: Cortical dysplasia with ossification. Epilepsia 41:1489, 2000. 273. Kim SW, Na DG, Byun HS, et al.: Focal cortical dysplasia: comparison of MRI and FDGPET. J Comp Assit Tomog 24:296, 2000. 274. Kirchhof K, Harting I, Bast T, et al.: Focal dysplasias: neurological findings and differential diagnosis. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 175:1056, 2003. 275. Chan S, Chin SS, Nordli DR, et al.: Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the nonballoon cell subtype. Ann Neurol 44:749, 1998. 276. Bronen RA, Spencer DD, Fulbright RK: Cerebrospinal fluid cleft with cortical dimple: MR imaging marker for focal cortical dysgenesis. Radiology 214:657, 2000. 277. Barkovich AJ, Kuzniecky RI, Bollen AW, et al.: Focal transmantle dysplasia: a specific malformation of cortical development. Neurology 49:1148, 1997.

Brain 278. Vigliano P, Canavese C, Bobba B, et al.: Transmantle dysplasia in tuberous sclerosis: clinical features and surgical outcome in four children. J Child Neurol 17:752, 2002. 279. Barkovich AJ, Peacock W: Sublobar dysplasia. A new malformation of cortical development. Neurology 50:1383, 1998. 280. Lee BC, Hatfield G, Park TS, et al.: MR imaging surface display of the cerebral cortex in children. Pediatr Radiol 27:199, 1997. 281. Bastos AC, Comeau RM, Andermann F, et al.: Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three dimensional magnetic resonance imaging. Ann Neurol 46:88, 1999. 282. Spreafico R, Battaglia G, Arcelli P, et al.: Cortical dysplasia. An immunological study of three patients. Neurology 50:27, 1998. 283. Garbelli R, Frassoni C, Ferrario A, et al.: Cajal-Retzius cell density as a marker of type of focal cortical dysplasia. Neuroreport 12:2767, 2001. 284. Jansky J, Ebner A, Kruse B, et al.: Functional organization of the brain with malformations of cortical development. Ann Neurol 53:759, 2003. 285. Cepeda C, Hurst RS, Flores-Hernandez J, et al.: Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia. J Neurosci Res 72:472, 2003. 286. Cotter D, Honavar M, Lovestone S, et al.: Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex. Acta Neuropathol (Berl) 98:465, 1999. 287. Becker AJ, Urbach H, Scheffler B, et al.: Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann Neurol 52:29, 2002. 288. Hua Y, Crino PB: Single cell lineage analysis in human focal cortical dysplasia. Cereb Cortex 13:693, 2003. 289. Klein B, Levin BE, Duchowny MS, et al.: Cognitive outcome with epilepsy and malformations of cortical development. Neurology 55:230, 2000. 290. Tassi L, Colombo N, Garbelli R, et al.: Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 125:1719, 2002. 291. Kloss S, Pieper T, Pannek H, et al.: Epilepsy in children with focal cortical dysplasia (FCD): results of long-term seizure outcome. Neuropediatr 33:21, 2002. 292. Raymond AA, Fish DR, Stevens JM, et al.: Association of hippocampal sclerosis with cortical dysgenesis in patients with epilepsy. Neurology 44:1841, 1994. 293. Ho SS, Kuzniecky RI, Gilliam F, et al.: Temporal lobe developmental malformations and epilepsy. Neurology 50:748, 1998. 294. Preul MC, Leblanc R, Cendes F, et al.: Function and organization in dysgenic cortex. Case report. J Neurosurg 87:113, 1997. 295. Giuliano F, David A, Edery P, et al.: Macrocephaly-cutis marmorata telangiectasia congenita: seven cases including two with unusual cerebral manifestations. Am J Med Genet 126A:99, 2003. 296. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003. 297. Grosso S, Farnetani MA, Beradi R, et al.: Medial temporal lobe dysgenesis in Muenke syndrome and hypochondroplasia. Am J Med Genet 120A:88, 2003. 298. Viot G, Sonigo P, Simon I, et al.: Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different. Am J Med Genet 126A:123, 2004. 299. Righini A, Zirpoli S, Mrakic F, et al.: Early prenatal MR imaging diagnosis of polymicrogyria. AJNR Am J Neuroradiol 25:343, 2004.

15.6 Agenesis of the Corpus Callosum Definition

Agenesis of the corpus callosum is complete or partial failure of the callosal commissural fibers to cross the midline and form the major neopallial connection (the corpus callosum) between the

581

two cerebral hemispheres (Figs. 15-37, 15-38). In current literature the term callosal dysgenesis is most often used to describe partial callosal agenesis, but hypogenesis may also be found. The definition is restricted to primary developmental failure and excludes secondary atrophy, destruction, and simple hypoplasia.

Fig. 15-37. Sagittal MRI scan showing absence of the corpus callosum and anterior (white area) lipoma. (Courtesy of Dr. S. Grahovac, Ottawa General Hospital.)

Fig. 15-38. Sagittal MRI scan showing partial absence of the corpus callosum, along with aqueductal stenosis and compensated hydrocephalus. (Courtesy of Dr. S. Grahovac, Ottawa General Hospital.)

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Neuromuscular Systems

Diagnosis

There is a remarkable heterogeneity in absent corpus callosum (ACC) in terms of both its broad etiologic origins and in its association with other CNS and non-CNS anomalies. It has only been within the past decade that the importance of separating these broad nosological groups has been emphasized, so to better enable the unraveling of the complex underlying pathogeneses. As recapitulated by Dobyns,1 there are four general types of ACC: two primary and two secondary. In the first primary subgroup, the axons develop and move toward the midline but are unable to cross. This results in pathognomonic, aberrant, longitudinal bundles of Probst that run along the medial ventricular walls and lateral to the fornices. In the second primary subtype of ACC, the commissural axons or their cell bodies fail to form and therefore never approach the midline. This pattern is typical of some forms of lissencephaly (see Section 15-5) and is seen in Walker-Warburg and several other syndromes. Among the secondary forms of ACC are those associated with major malformations of the forebrain, such as frontal encephaloceles or holoprosencephaly (Section 15-4), and cases in which there is a secondary atrophy leading to marked thinning or even absence of areas of the corpus callosum. Often it is not possible to distinguish a corpus callosum that is thin because of a primary hypoplasia where axons did not arrive in sufficient numbers from an instance in which there was excess apoptosis or another secondary cause for axonal loss. This section is limited to the first subgroup of primary ACC. Intracerebral cysts may accompany ACC, and there is consensus that the types of cysts and their associated clinical and pathological findings may reflect differing underlying pathogenesis. The classification of cysts associated with ACC suggested by Barkovich et al.2 has attained general acceptance, with the understanding that some changes are inevitable as knowledge increases. Type 1 cysts are connected to the ventricular system and have three subtypes. In type 1a, communicating hydrocephalus is the only neocortical abnormality accompanying the ACC and interhemispheric cyst. In type 1b, the egress of CSF to the aqueduct of Sylvius is blocked, most often by fusion of the thalami. The authors provide a compelling argument as to why this should not be considered a form fruste of holoprosencephaly. Microcephaly and hypoplasia of a cerebral hemisphere characterize type 1c. Type 2 cysts do not connect with the ventricular system, and in type 2a there are no other associated CNS findings. In type 2b, the falx is absent and there are subependymal heterotopias and polymicrogyria. Type 2c is defined by subcortical heterotopia; and in type 2d the cyst is of the arachnoid type. Recently, Da´vila-Gutie´rrez3 has suggested an all-inclusive classification that first separates isolated ACC (category 1) from that with associated anomalies (category 2). The latter is then subdivided into the following: 2.1, with other brain anomalies; 2.2, with cysts and incorporating the subtypes of Barkovich et al.2; 2.3 with neuropathy; 2.4, associated with inherited metabolic diseases; 2.5, posited to be due to toxins; 2.6, with a callosal lipoma; and 2.7, with less frequent malformations. If this classification is used one needs to be mindful that some of the categories could include both primary and secondary ACC and their different subtypes. There is a consensus that the presenting signs in individuals with ACC are due to concurrent brain abnormalities and that isolated ACC is essentially asymptomatic. This conclusion is supported by the fact that clinically normal persons have been

found to have ACC at routine autopsy. Furthermore, modern imaging has led to the inter vivo diagnosis of increasing numbers of individuals with normal intelligence in whom it is necessary to test for functions and learning that are dependent on specific inter-cerebral callosal connections in order to detect functional deficiencies due to ACC (vide infra). The spectrum of clinical signs observed and the age at diagnosis are correlated with, and highly dependent on, the ascertainment of the population studied and the clinical threshold at which diagnostic procedures are applied. A common, albeit nonspecific, associated facial appearance is hypertelorism with a broad nose and nasal tip. Diagnosis in the neonatal period may derive from the presence of macrocephaly (notably in types 1a, 1b, 2a, and 2b of Barkovich et al.2), seizures, or craniofacial dysmorphism. Microcephaly may also be seen and is typical of type 2c. The diagnosis in infancy usually follows investigation of developmental delay, seizures, macrocephaly, or microcephaly. Other neurologic signs are frequent, and in a follow-up study of 14 prenatally and 61 postnatally diagnosed cases, 40.6% had poor coordination, 36.2% were spastic, 14.5% had quadriparesis, and 11.6% hemiparesis.4 Postnatal growth failure occurred in 15.9%, 2.9% had increased intracranial pressure, and 5.8% were asymptomatic. Older children may present with learning disability. Infantile spasms are well represented among the seizures, accounting for 7 of 40 cases in one series,5 and being characteristic of some syndromes such as Aicardi (Table 15-7). The clinical spectrum of ACC that ranges from an isolated and asymptomatic malformation to one accompanied by severe mental retardation with associated CNS and other malformations presents a special problem when the diagnosis is suspected on the basis of prenatal ultrasound. Given the benign clinical course of many patients with isolated ACC, most neurologic signs that are observed in patients are attributed to associated CNS anomalies. Symptomatic patients who do not have associated visible brain malformations are assumed to have disturbances that remain undetected with current neuroimaging techniques. A diverse array of malformations of the CNS may accompany ACC. Jeret et al.6 summarized 705 reported and personally studied cases and found that 23% had associated hydrocephalus; 15%, microcephaly; 23%, heterotopias/polymicrogyria; 6%, microgyria; 2.4%, pachygyria; 3%, lissencephaly; and 3%, arhinencephaly. Twenty-three percent had associated cysts, either interhemispheric, porencephalic, Dandy-Walker, or arachnoid. Tumors, including lipoma, papilloma, and meningioma, were present in 7% of cases. Arnold-Chiari type II malformation, neural tube defects, and various cerebellar anomalies have also been noted. Structural anomalies of the eye were common and included retinal lacunae (Aicardi syndrome), colobomas, microphthalmia, and cataracts. A wide array of dysmorphic facial features was also reported, with hypertelorism in 20% of patients being the single most common feature. In a recent series, 44% of patients had an accompanying CNS defect, 29.3% had craniofacial and skeletal signs, 13.3% had cardiorespiratory anomalies, 8% had gastrointestinal defects, and 2.7% had renal malformations.4 Franco et al.7 found undescended testes in 23% of 22 boys with ACC and hypothesized hypothalamic insufficiency as a cause. They also noted renal and ureteral anomalies respectively in 18% and 15% of their 33 patients. The comparable rates for the 18 patients who underwent urinary tract imaging were 33% and 27%. Obviously there is a bias toward dysmorphic and/or symptomatic patients in this type of series. Symptomatic patients who do not have associated visible brain malformations are assumed to have

Table 15-7. Syndromes with absent corpus callosum Syndromes

Prominent Features

Causation Gene/Locus

3-hydroxyisobutyric acid

Poor neonatal behavior, triangular face, short and sloping forehead, narrow bitemporal distance, shallow supraorbital ridges, epicanthus, micrognathia, adducted thumbs, clinodactyly of toes 4 and 5, intracerebral calcification, cerebellar hypoplasia, agenesis of the corpus callosum, lissencephaly, pachygyria

AR (236795)

Acrocallosal27

Broad high forehead, large fontanel, hypoplastic alae, short neck, macrocephaly, pre and/ or postaxial polydactyly of hands and feet of a variable degree, mental retardation

AR (200900) 12p13.3-p11.2

Acrofacial dysostosis-type Rodriguez28

Severe acrofacial dysostosis, congenital heart defects, absent lung lobation, small kidneys; variable limb anomalies include short limbs, absent fibulae, oligodactyly; hypoplastic scapulae; hydrocephalus, agenesis of the corpus callosum

AR (201170)

Acromesomelic frontonasal dysplasia29

Epibulbar dermoid, cleft nose, notched alae, midline cleft lip/palate, renal anomalies, preand post-axial polydactyly, delayed development; CNS includes absent corpus callosum, Dandy-Walker, hydrocephalus, encephalocele

Unknown

Ades: campomeliapolydactyly-dysplastic kidney30

Cleft epiglottis and tongue, dysplastic larynx, coloboma, cystic dysplastic kidneys, periportal hepatic fibrosis, mesomelia, absent corpus callosum, abnormal gyri

Unknown

Agenesis corpus callosumobesity camptodactyly31

Postnatal growth and developmental delay, android truncal obesity, hypertelorism, upslanting palpebrae, long hands with thin fingers, finger 5 camptodactyly, ventricular septal defect, abnormal venous return

Unknown

Agenesis corpus callosumpyloric stenosisHirschsprung32

Hypertelorism, depressed nasal bridge, hypertrophic pyloric stenosis, callosal agenesis; part of the SMADIP1 Hirschsprung-midline spectrum?

Unknown

Agonadism-CNS anomalies33

Agonadism with urogenital sinus and 46,XY karyotype, severe mental retardation, absent corpus callosum, cerebellar agenesis, pachygyria. Single case.

Unknown

Agyria-pachygyria-absent corpus callosum-AR34

Normancephaly, hypertonia, apnea, neonatal death, absent corpus callosum, cortical dysplasia—probably agyria/pachygyria

AR

Aicardi35

Chorioretinal lacunae, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, periventricular nodules, colpocephaly, hypoplastic cerebellar vermis

XLD, male lethal (304050), Xp22

Alcohol, prenatal36

IUGR, mild microcephaly, short palpebral fissures, malar hypoplasia, short nose, hypoplastic philtrum, thin upper lip, micrognathia, hypoplastic distal phalanges, tremorous movement, developmental delay

In utero exposure

Andermann: neuropathycallosal agenesis37

Psychomotor delay, progressive flaccid quadriparesis, ptosis, strabismus, brachycephaly, hypoplastic maxilla, anterior horn cell disease, neuronal heterotopias

AR (218000) SLC12A6, 15q13-q14

Anophthalmia-cranial cystscleft lip/palate38

Macrocephaly, microphthalmia, bilateral cleft lip/palate, myoclonic seizures, hypotonia, posterior midline cyst, frontal polymicrogyria, absence of the corpus callosum. Single case; could be part of the oculocerebrocutaneous spectrum

Unknown

Anophthalmia-heminasal aplasia-CNS anomalies39

Postnatal growth and developmental delay, prominent forehead, anophthalmia, heminasal hypo/aplasia, preauricular skin tags, abnormal pinnae, atypical clefts

Unknown

Apert40

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS includes corpus callosum (5/113), limbic system, microgyria, polymicrogyria, heterotopia, ventriculomegaly

AD (101200) FGFR2, 10q25.3-q26

Basal cell nevus41

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomata, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 9q22.3 PTCH2, 1p32

Ben Ari: trigonocephalycallosal agenesis42

Moderate developmental delay, trigonocephaly, upslanting palpebrae, posteriorly rotated ears, high palate, cubitus valgus, anterior placement of anus, double left collecting system

Unknown

Beta-hydroxyisobutyryl Co A deacylase43

Facial dysmorphia, vertebral anomalies, hemangiomas, severe hypotonia, tetralogy of Fallot, agenesis of cingulate gyrus and corpus callosum; increased urinary cysteine and cysteamine, beta-hydroxyisobutyryl CoA deacylase deficiency

AR (250620)

Blepharophimosis-joint contractures-Dandy Walker cyst44

Short stature, low-set ears, preauricular pits, ptosis, blepharophimosis, epicanthus inversus, multiple joint contractures, kyphoscoliosis, CNS includes absence of the corpus callosum, ventriculomegaly, Dandy-Walker cyst

Unknown

Brooks: XLMR-unusual facegrowth failure45

Severe mental retardation, spasticity, triangular face, bifrontal narrowing, low-set and cupped ears, malar flatness, short and downslanting palpebrae, deep-set eyes, bulbous or beaked nose, tented upper lip, mild knee and elbow contractures, ventriculomegaly; partial agenesis of the corpus callosum in one case

XLR

Brumback: microcephaly46

Microcephaly from birth, normal development at 1 year, craniofacial disproportion, sloping forehead, maintained primitive reflexes, delayed dentition

Unknown

26

(continued)

583

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Buntinx: ocular anomaliespolydactyly47

Mental retardation, blepharophimosis, iris coloboma, upslanting palpebrae, short nose, narrow auditory canals, mixed hearing loss, postaxial polydactyly of hands, hydroureter, large fontanel

AR

Cao: Microcephaly48

Microcephaly from birth, infantile spasms, spastic quadriparesis, severe mental retardation, 1 of 3 cases had retinopathy, aqueduct stenosis (McKusick questions if same as Andermann: neuropathy-callosal agenesis.37)

AR

Carpenter: acrocephalopolysyndactyly type IIchromosome49

Established acrocephalopolysyndactyly syndrome; case with de novo reciprocal translocation 46,XX,t(1;18)(p31;q11) with preaxial polysyndactyly, craniosynostosis and partial agenesis of the corpus callosum

Uncertain

Castro-Gago: optic atrophyheterotopias-callosal agenesis50

Severe mental retardation, hypotonia, optic atrophy, dilated unreactive pupils, agenesis of the corpus callosum, gray matter heterotopias, brain atrophy

Unknown

Cerebral lactic acidosis51

Microcephaly, severe developmental delay, postnatal growth failure, initial hypotonia, spasticity, blindness, metabolic disturbance confined to CNS; CNS anomalies include absent pyramids and corpus callosum, heterotopia of the inferior olive, marginal glialneuronal heterotopia. Clinical features include mutations in E1-alpha subunit of the pyruvate dehydrogenase complex.

XLR (312170) PDH, Xp22.1

Cerebro-facio-thoracicdysplasia52

Mental retardation, macro/brachycephaly, hypertelorism synophrys, bifid and synostosed ribs, narrow chest, elevated scapulas, hemivertebrae, short neck

AR (213980)

Cerebro-oculo-facialskeletal53

Microcephaly, cataracts, joint contractures, early death or severe postnatal growth and developmental failure, severely sloped forehead, prominent nose, cataract, microophthalmia, micrognathia; heterogeneity, some in Cockayne spectrum; CNS include mild cortical neural loss, ventriculomegaly, delayed myelination, abnormal myelinization, gliosis, cerebellar degeneration, partial callosal agenesis

AR (214150)

Cerebro-oculo-nasal54

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears. The other girl had a single maxillary central incisor; case reported with agenesis of the corpus callosum; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst.

Unknown

Cerebro-oculo-skeletalrenal55

Optic atrophy, absence of retinal vessels, seizures, growth and developmental delay, elongated clavicles, cupped ribs, mild platyspondyly, rhizomelia, schizencephaly, nephritis/nephrosis

Unknown

Cerebro-renal-digital56

Microcephaly, pterygium colli, cystic renal dysplasia, polysplenia, postaxial polydactyly, stillborn (family G)

AR

CHARGE57

Association of coloboma, heart malformation, choanal atresia, growth and/or mental retardation, ear anomalies and/or deafness. Absent corpus callosum (4/47), arrhinecephaly (2/47), septal agenesis (2/47), vermian agenesis (1/47), meningomyelocele (1/47).

AD (214800) CHD7, 8q12.1 small minority del22q11

Chlorpyrifos, prenatal58

Profound mental retardation, growth retardation, defects involving eyes, ears, palate, teeth, heart, genitalia; abnormal choroid plexus, septum pellucidum, and callosal agenesis; similar to findings in animals

In utero exposure

Chondrodysplasia-callosal agenesis-thrombocytopenia59

Rhizomelia, hypertension, thrombocytopenia, flat nasal root, anteverted nasal tip, wide metaphyses, platyspondyly, deficient dorsal ossification centers of vertebrae, agenesis of the corpus callosum, severe hydrocephalus

Unknown (166990)

Chromosomal aberrations 1,60

Agenesis of the corpus callosum has been reported with about 30 different chromosomal aberrations, and findings vary with the specific imbalance. Most common are trisomy 13, 18, 11q, and mosaic problems.

Chromosomal imbalance

Cleft lip/palate-ectrodactyly61

Half sibs through mother: female had clefting, atrial septal defect, oligodactyly of both feet and hands; male had clefting, syndactyly, ectrodactyly, dysplastic ears (Same as EEC syndrome?)

Unknown

Cocaine, prenatal exposure62

Debatable if recognizable facial appearance, limb reduction, genitourinary anomalies; CNS has included porencephaly, septo-optic dysplasia, schizencephaly, midline cysts, and callosal agenesis

In utero exposure

Coffin-Siris63

Postnatal growth failure; lax joints; coarse face; sparse hair; hypoplastic or absent nails; especially 5th digits; hypertrichosis of body; severe mental retardation

Uncertain (135900) (continued)

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Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Coffin-Lowry

Mental retardation, prominent forehead and supraorbital ridges, downslanting palpebrae, hypertelorism, low nasal bridge with thick septum, small and anteverted nares, full and patulous lips, everted lower lip; soft, hyperextensible, and tapering fingers; non-specific radiographic changes, progressive kyphoscoliosis; three cases reported with ACC

XLD (303600) RDS6KA3

Congenital bowingcamptodactyly-callosal agenesis64

IUGR, bowing of long bones, proximal shortness, camptodactyly, talipes equinovarus, neonatal death, wide metaphyses, increased trabeculation and cortical thickness on concave side, mild platyspondyly

Unknown

Corpus callosum agenesis, isolated65

Uncommonly ACC occurs as a familial condition without associated anomalies. Individuals may be asymptomatic or have various neurologic/developmental problems

AR, XLR, AD (217990, 304100)

Crane: skeletal dysostosisclefting66

Facial dysmorphia, cleft lip/palate, abnormal and low-set ears, hypoplastic alae, absent vertebrae C1-C6 and clavicles, soft tissue syndactyly

AR

Craniofacial dyssynostosis67

Variable developmental delay, premature fusion of the lambdoid and posterior sagittal sutures, dolichocephaly, protuberant forehead; one each of seven original patients had congenital heart defect, agenesis of the corpus callosum, and hydrocephalus (same as craniotelencephalic dysplasia?)

AR (218350) heterogeneity?

Craniotelencephalic dysplasia68

Protruding frontal bone with encephalocele, craniosynostosis, small eyes, absent olfactory nerves, grade 2 lissencephaly, cerebellar heterotopias

Probable AR (218670)

Curatolo: white matter hypoplasia-callosal agenesis70

Severe mental retardation, growth failure, downslanting palpebrae, broad nasal root, hypertelorism, synophrys, long eyebrows, micrognathia, severe diffuse cerebral white matter hypoplasia, agenesis/hypoplasia of the corpus callosum, partial agenesis of cerebellar vermis

Uncertain

Curry-Jones: craniosynostosispolysyndactyly71

Craniosynostosis, asymmetric face, low nasal bridge, anteverted nares, hypertelorism, narrow palpebrae, scarring of eyelids, variable preaxial polysyndactyly of hands and feet, linear hypopigmented streaking of the skin, gut obstruction, intestinal myofibromata

Unknown (601707)

DaSilva: mental retardationmicrocephaly72

Severe retardation, postnatal growth failure, preauricular skin tag, nasal skin tag, camptodactyly, club feet, increased tone, pulmonary infections, lethal

AR (217990)

Dwarfism-microcephaly73

Hydrocephalus, sloping forehead, deformity at base of skull, short limbs, postnatal growth failure, short and cupped ribs, lethal

AR

Delleman: oculocerebrocutaneous74

Psychomotor delay, eye anomalies, orbital cysts, skin tags and defects, calvarial defects, vertebral, rib, hand/foot anomalies, porencephalic cysts

Unknown (164180)

Desmosterolosis75

IUGR, downslanting palpebral fissures, low nasal bridge, thick alveolar ridges, gingival nodules, congenital heart defect, ambiguous genitalia, case with macrocephaly and another with microcephaly, ‘‘immature gyral pattern,’’ cholesterol biosynthesis

AR (602398) Sterol-delta 24-reductase, 1p33-p33.1

Diaphragmatic herniahypertelorism-deafness76

High birth weight, large fontanel, marked hypertelorism, myopia, variable coloboma, short nose, posteriorly rotated ears, sensorineural deafness, diaphragmatic hernia, gut malrotation

AR (222448)

Diaphragmatic herniapulmonary hypoplasiahydrocephalus77

Right diaphragmatic defect, pulmonary aplasia or hypoplasia, borderline developmental delay, atrial septal defect, aqueduct stenosis, ventriculomegaly

AR

DK-phocomelia with thrombocytopenia78

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs, thrombocytopenia/reduced mega-karyocytes, renal agenesis to milder defects, vaginal atresia, other variable brain anomalies

Unknown (223340) Case with del(13q)

Dobyns: facio-oculo-aural79

Microcephaly, mild trigonocephaly, short nose and jaw, flat philtrum, low-set ears with absent crura and antihelix, microcornea, ectopic pupils, choroidal coloboma, finger contractures, absent corpus callosum

Unknown

Ectodermal dysplasiahypothyroidism80

Relative macrocephaly, large fontanel, hypertelorism, downslanting palpebrae, abnormal ear shape, severe mental retardation, ectopic thyroid remnant

Unknown Uncertain (225040)

Ectrodactyly-diaphragmatic hernia-heart defect81

Bilateral split hands and feet, left diaphragmatic hernia, ventricular septal defect, agenesis of the corpus callosum

Unknown

Edwards: microphthalmia82

Microcephaly, Dandy-Walker cyst, cerebellar vermis hypoplasia, choanal atresia, and other defects in a child whose mother and grandmother had Hallerman-Strieff- like face, aniridia cataract (see PAX6)

AD PAX6

Ehlers-Danlos83

Heterogeneous connective tissue disorder with hyperelasticity/friability most apparent in skin and joints; CNS not limited to a specific type and include cortical dysplasia, heterotopias, bilateral perisylvian polymicrogyria

AD heterogeneity several genes known

257

(continued)

585

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Encephalocele-radial anomalies84

Esophageal atresia, abnormal lung lobulation, congenital heart defect, lung anomalies, radial ray defects, anterior anus, hypoplastic spleen, tracheoesophageal fistula, renal agenesis, partial callosal agenesis, hypoplastic cerebellum, encephalocele, ‘‘cortical microgyria’’

Unknown

Endothelial dystrophy-band keratopathy85

Bilateral corneal clouding, thin and degenerate corneal epithelium, spherical aggregates in Bowman’s membrane with target appearance on EM, abnormal collagen in pre-Decemet’s membrane area

Unknown

Femoral deficiency-facial86

Short anteverted nose, long philtrum, thin upper lip, micrognathia, cleft palate, proximal focal femoral deficiency, preaxial toe polydactyly, reported CNS anomalies include agenesis posterior corpus callosum, brain atrophy, absent septum pellucidum, dilatated lateral ventricles, heterotopias

Associated with maternal diabetes

FG87

Mental retardation, hypotonia, constipation, anal anomalies, broad forehead, cowlick, ‘‘hypotonic facies,’’ often postnatal growth failure and death

XLR (305450) Xq12-q21.3 Multiple loci probable

Fine88

Asymmetric skull with lateral bulging, cleft palate, asymmetric eyes, cataract OD, glaucoma OS, small and abnormal ears, small mouth and mandible, small genitalia, aqueduct stenosis. Single case.

Unknown

Focal dermal hypoplasia89

Skin pigment anomalies, telangiectasias, focal skin atrophy with protruding lipomatous nodules, enamel and dental hypoplasia, perianal and perioral angiofibromata, nail dystrophy hand and foot syndactyly, ocular malformations

XLD, male lethal (305600)

Francois: callosal agenesiscoloboma-vermis hypoplasia90

Marked hypertelorism, downslanting palpebrae, complete eye colobomas, bifid uvula, short neck, diastasis recti, small thumbs, hypoplastic genitalia, microgyria, ventriculomegaly, hypoplastic cerebellar vermis

Unknown

Frontonasal dysplasia91

Spectrum of midcraniofacial anomalies, hypertelorism, cranium bifidum, broad nasal root, bifid tip, cleft nose and/or upper lip; mental retardation correlates with severity of extracranial findings; CNS anomalies uncommon

Most sporadic; some AD (136760)

Frontonasal dysplasiaacromelia33

Craniofacial appearance as described for frontonasal dysplasia,91 short neck, short limbs, preaxial- and/or postaxial polydactyly of all limbs, short humerus and ulna, DandyWalker cyst. Single case.

Unknown

Frontonasal dysplasiacoloboma-Temple type93

Moderate developmental delay, hypertelorism, broad nasal root, nose bifid or with median groove, notched alae, cleft lip/palate, eye coloboma, microphthalmia; part of frontonasal spectrum?

Unknown

Frontonasal dysplasiamacrobleparon-retardation94

Developmental delay, coronal synostosis, prominent forehead, hypertelorism, macroblepharon, ectropion, notched eyelids, high-arched eyebrows, broad and bifid nose, clefting, macrostomia, abnormal pinnae, hand anomalies, callosal hypo/agenesis

Unknown

Fryns: acral-diaphragmatic hernia95

Hydramnios, coarse face, facial hirsutism, cloudy corneae, large nose with broad flat bridge, short upper lip, micrognathia, cleft lip/ palate, abnormal pinnae, hypoplastic distal phalanges and nails, diaphragmatic defects, gut anomalies, cardiac defects, bicornuate uterus; CNS anomalies include agenesis of the corpus callosum, arhinencephaly, heterotopias

AR (229850)

Fullana: caudal deficiencyasplenia96

IUGR, marked caudal regression, hypoplastic pelvis, imperforate/stenotic anus, myelomeningocele, laterality anomalies with asplenia, complex cardiac anomalies. Variant of X-linked laterality syndrome?85

AR or XLR

G97

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males

AD (145410) 22q11.2 XLR (300000) Xp22

Genitopatellar98

Coarse face, prominent nasal root and bulbous tip, micrognathia, high palate, soft skin, flexion contractures, dislocated/absent patellae, variable skeletal changes. Case with absent corpus callosum and periventricular neuronal heterotopias

AR (606170)

Glass: ear anomalies-limb reduction100

Cleft palate, stenotic auditory meati, preauricular tags, helical folding; one sib with upper limb deficiencies, other with callosal agenesis and porencephaly

AR

Goldberg-Shprintzen99

Microcephaly, short stature, developmental delay, hypertelorism, submucous cleft palate; diminished white matter, hypo/partial absence corpus callosum, pachygyria, cerebellar hypoplasia

AR (235730) SMADIP1, 2q22 (continued)

586

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Goldblatt: genitopatellar

Hypoplastic/absent patella, contractures of major joints, short stature, cupped ears, flat nasal bridge, midface hypoplasia, micrognathia, crossed renal ectopia, scrotal hypoplasia; 4 of 7 cases with absent corpus callosum

Unknown (606170)

Goldenhar104

Variable asymmetric lower face, especially mandible hypoplasia, microtia, preauricular tags and pits, macrostomia, vertebral anomalies, epibulbar dermoids, variety of CNS defects in low frequency

Sporadic; some AD (164210) 14q32

Greig cephalopolysyndactyly101

Variable postaxial hand and preaxial toe polysyndactyly, telecanthus, hypertelorism, low and wide nasal root

AD (175700) GLI3, 7p13

Grubben: short-dentaleczema105

Pre- and postnatal growth and developmental delay, hypotonia; small, widely spaced or missing teeth, eczematous skin rash; small, puffy hands and feet with tapering digits; partial agenesis of the corpus callosum or ventriculomegaly; selective IgG2 subclass deficiency a possible marker

AR (233810)

Halal-Silver: de Lange-like106

Postnatal growth and developmental delay, microcephaly, low anterior hairline, long eye lashes, depressed nasal bridge, long philtrum, thin upper lip, micrognathia, severe metatarsus adductus

AD

Hendricks: deafness-callosal agenesis-arachnoid cyst107

Normal intelligence, sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, hydrocephalus

AR

Hersh: mirror hands and feetbrain anomalies108

Sagittal synostosis, flat nasal bridge, bulbous nasal tip, hypoplastic alae, hamartomatous enlargement of parotid glands, stenotic ear canals, pelvic kidneys, ventricular septal defects, fusion and platyspondyly of cervical vertebrae, hydrocephalus, callosal agenesis

Unknown

Holmes: brain malformationfetal hypokinesia109

Polyhydramnios, fetal hypokinesia, wide cranial sutures, telecanthus, narrow palpebrae, micrognathia. One sib with agenesis of the corpus callosum, slightly broad gyri, focal cerebellar disorganization; other sib had arhinencephaly, hypoplastic gyri, regions of persistent external cerebral granular layer

Uncertain

Hydrolethalus110

Aqueductal stenosis/hydrocephalus, preaxial and/or postaxial polydactyly hands, cleft lip/ palate, anomalies of pulmonary and cardiovascular systems

AD (236680) 11q23-q25

Hypothalamic hamartomagelastic epilepsy-precocious puberty111

Well established association reported in association with Dandy-Walker cyst, heterotopias, and callosal agenesis

Unknown

Hypothalamic hamartomamicrophthalmia-radial ray112

Hypothalamic hamartoma, microphthalmia, ectopic retinal pigment layer, flat nose, absent/hypoplastic thumb, gut malrotation, small stomach, asplenia, abnormal genitalia. Case with agenesis of the corpus callosum, meningeal dysplasia, abnormal gyral pattern

Unknown

Influenza, prenatal113

Possible rare complication of maternal infection; microphthalmia, malformed pinnae, diaphragmatic hernia, costovertebral defects; ependymal damage, aqueduct forking, hydrocephalus, heterotopias; agenesis of the corpus callosum, cerebellum, pontine and inferior olivary neurons, optic and olfactory nerves; immunohistochemical evidence of influenza virus antigens in brain

Unproven association

Iris dysplasiahypertelorism114

Mesodermal dysgenesis of the iris, telecanthus, hypertelorism, hypotonia, lax joints, sensorineural hearing loss, short stature; callosal agenesis unproven

AD (147590)

Ivemark: asplenia/ polysplenia-situs anomalies115

Polysplenia/asplenia, complex cardiac malformations are usually defects of situs, pulmonary or abdominal situs anomalies; CNS uncommon and include agenesis of the corpus callosum and Dandy-Walker cyst

Unknown AD/AR (208530) 12q13, 6q21–q23

Ives: microcephalymicromelia116

IUGR, perinatal death, fused elbows, forearm shortened with single long bone, two to four digits on hands

AR (251230)

Jonas: pontine hypoplasiacallosal agenesis117

Macrocephaly, frontal bossing, deep-set eyes, short palpebrae, Duane retraction anomaly, hydronephrosis, patent ductus arteriosus, agenesis of corpus callosum, hypoplastic pons; mild, focal, subcortical white matter changes; communicating hydrocephalus

AR

Joubert: cerebellar vermis aplasia plus118

Developmental delay, episodic alternating hyperpnoea and apnea, abnormal ocular movements, coloboma, hypo/aplasia of cerebellar vermis; groups have been separated on basis of retinal dystrophy and renal disease; callosal agenesis uncommon

AR (213300) NPHP1, 2q13 AHI1, 6q23.2-q23.3 9q34.3

Kallmann119

Hypogonadotropic hypogonadism, anosmia, some cases with additional somatic findings; KAL1 on Xp is anosmia; KAL2 (AD) on 8p is loss of function of FGFR1

XLSD (308700) KAL1, Xp22.3 AD (147950) FGFR1, 8p11.2-p11.1 AR (244200)

103

(continued)

587

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Kivlin: anterior chambershort stature120

Variable developmental delay, prominent forehead, round face, telecanthus, sclerocornea, short nose, long philtrum, cupid-bow mouth, variable segment limb shortness, variable hyperextensibility, congenital heart and renal abnormalities, hypospadias. Case report with callosal agenesis.

AR (261540)

Kozlowski-Ouvrier: callosal agenesis-osseous changes121

Mental retardation, wormian bones, thin ribs, abnormal clavicles, small iliae, metaphyseal irregularity, hypoplastic distal phalanges, delayed bone age

Unknown

Leigh122

Early onset encephalomyelopathy, gray matter involvement similar to Wernicke, elevated lactate, pyruvate, urine thiamine triphosphate inhibitor; absence of corpus callosum correlates with severe pyruvate decarboxylase deficiency; multiple nuclear and mitochondrial loci in oxidative phosphorylation pathway

AR (256000) 2q33, 5p15, 5q11.1, 9q34, 11q13, 19p13

Leprechaunism123

Flat nasal bridge, flared nostrils, thick lips, large and low-set ears, breast and genital hyperplasia, hirsutism, postnatal growth failure, lack of response to insulin

AR (246200) INSR, 19p13

L’Hermitte: oxycephaly retardation124

Macrocephaly, oxycephaly with open sutures, high palate, flat face, shallow orbits, porencephaly, absent inferior vermis

AR

Lin-Gettig: craniosynostosiscallosal agenesiscamptodactyly125

Severe mental retardation, metopic/sagittal craniosynostosis, small low-set ears, nasal and external ear stenosis, small palpebrae, epicanthus, small nose, genital hypoplasia, camptodactyly

Uncertain (218649)

Linear sebaceous nevus126

Papular/verrucous lesions with atrophic scars over craniofacial area, pigment changes, ipsilateral brain anomalies, hemimegalencephaly, pachygyria heterotopias, porencephalies, mental retardation, seizures

Unknown (163200)

Lissencephaly-cleft palatecerebellar hypoplasia127

IUGR, cleft palate, ventriculomegaly, long thumbs and halluces, absent digital distal creases, variable brain stem involvement, absent corpus callosum, absent cerebellum, thick and disorganized cortex, no cortical lamination, severe cerebellar hypoplasia

Uncertain

Lujan: marfanoid128

Tall stature, long narrow face, high palate, small jaws, double row of teeth, variable mental retardation, hyperextensible joints and pectus, atrial septal defect, macrocephaly

XLR (309520)

Lurie-Kletsky: callosal agenesis-diaphragmatic defect129

Fetal hydrops, microcephaly, scalp defect, short palpebrae, posterior diaphragmatic defect, agenesis of corpus callosum, ventriculomegaly

Unknown

Majewski: short ribpolydactyly130

Lethal short ribbed micromesomelic dwarfism, short tibiae, pre- and postaxial polydactyly, median cleft lip, genital anomalies, hypoplastic epiglottis and larynx, glomerular cysts, tortuous cerebral vessels, cerebellar vermis hypoplasia, posterior fossa arachnoid cysts, agenesis or hypoplasia of the corpus callosum, pachygyria, neuronal heterotopia

AR (263520)

Marshall-Smith131

Increased birth length and bone age, postnatal growth failure, dolichocephaly, prominent forehead and eyes, choanal atresia, epiglottis anomaly, occasional absence of corpus callosum, pachygyria, hypoplasia inferior vermis

Unknown

MASA69,132

Mental retardation, adducted thumbs, shuffling gait with aphasia or speech delay. May have agenesis of corpus callosum, hydrocephalus due to agenesis of aqueduct of Sylvius. Same gene as X-linked hydrocephalus, X-linked paraplegia type I

XLR (309250) L1CAM, Xq28

Meckel-Gruber133

Cystic dysplastic kidneys, postaxial polydactyly, hydrocephalus, occipital encephalocele, microphthalmia, genital anomalies

AR (249000) 11q13, 17q21-q23, 8q

Micro134

Severe mental retardation, microcephaly, prominent ears, beaked nose with a prominent root, microcornea, cataracts, optic nerve atrophy, retinal dystrophy, small pupils, posterior synechiae, hypertrichosis, agenesis of the corpus callosum, one of three patients stated to have lissencephaly

AR (600118) RAB3GAP, 2q21.3

Microgastria-upper limb reduction135

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia and porencephalic cyst

Unknown (156810)

Microphthalmia-linear skin defects136

Lethal in males; linear, erythematous skin defects; variable microphthalmia, anterior chamber defects, sclerocornea; short stature; congenital heart defects; CNS include hydrocephalus, colpocephaly, cavum septum pellucidum, variable corpus callosum defect

del Xp22.31 (309801) Xp22.31, male lethality due to loss of holocytochrome ctype synthase

Moerman137

Appearance similar to achondrogenesis, cleft palate, dysplastic kidneys, cardiac anomaly, tetramicromelia, spondylocostal dysostosis, Dandy-Walker cyst

Unknown (continued)

588

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Morning gloryanomalysphenoidal encephalocele138

Characteristic optic nerve, hypertelorism, microphthalmia, other eye anomalies, midline cleft, pituitary/hypothalamic dysfunction, hydrocephalus, absent corpus callosum, sphenoidal encephalocele

Unknown

Mowat-Wilson: Hirschsprung-microcephalyretardation139,140

Microcephaly, large nose, prominent ears, deep-set and large eyes, infero-nasal coloboma, short philtrum, developmental delay, CT evidence of defective neuronal migration; several cases with callosal agenesis

AD ZFHX1B, SMADIP1, 22q22

Muller: cerebral malformationhypertrichosis141

Hypertelorism, telecanthus, microphthalmos, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Muscle-eye-brain142

Early onset severe hypotonia, delayed development, frontal pachygyria, occiput less severe, agenesis of the corpus callosum, hypoplasia of the pons and cerebellar vermis, white matter abnormalities patchy or absent, mild hydrocephalus, nystagmus, anterior chamber defects, glaucoma, myopia, preretinal glial membrane, ERG abnormal after age 1 year, cataracts, myopathy with elevated CK levels; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

Mutchinik143

Microcephaly, hydrocephalus, growth and developmental delay, high forehead, ptosis, downslanting palpebrae, prominent nose, high nasal bridge, protruding ears; 1 of 8 cases with ACC

AR

Nasopharyngeal teratoma144

Massive macrocephaly, broad and triangular flat face, hypertelorism, nasopharangeal hairy polyp through cleft palate, diaphragmatic hernia, Dandy-Walker cyst, cavum septum pellucidum and vergi

Unknown

Necrotizing myopathycataract-cardiomyopathy145

Microcephaly, profound developmental delay, axial hypotonia, extensor plantar reflexes, early onset diarrhea and vomiting, cataracts, cardiomyopathy, raised CK, excess muscle glycogen, necrotizing myopathy, absent corpus callosum, few and swollen cortical axons, no pyramidal tracts

AR (225740)

Neonatal progeroid-callosal agenesis146

IUGR, postnatal growth failure, progeroid appearance, wide fontanels, frontal bossing, prominent scalp veins, entropion, beaked nose, small mouth, lipodystrophy, camptodactyly, hypoplasia lower limb muscles

AR

Neu-Laxova147

IUGR, edema, ichthyosis genital hypoplasia, microcephaly, slanted forehead, flat nose, hypoplastic fingers, syndactyly, lissencephaly

AR (256520)

Neuroepithelial cysts-absent corpus callosum148

Interhemispheric cysts of glioependymal type, absent corpus callosum, neocortical microgyria, abnormal foramen magnum, nodular heterotopias, cerebellar hypoplasia

Unknown

Neurofibromatosis149

Cafe´-au-lait spots, neurofibromas, Lisch nodules, occasional plexiform neuromas, diverse complications of tumors

AD (162200) NF1, 17q11.2

Nezelof: arthrogryposis-renal and hepatic disease150

Joint contractures, muscle atrophy, proximal thumbs, obstructive jaundice, variable liver histology, renal tubular degeneration and/or nephrocalcinosis, reported with microcephaly, corpus callosum anomalies

AR (208085)

Nijmegen breakage151

Growth and variable intellectual impairment, sloping forehead, prominent mid-face and long nose, large and abnormal pinnae, upslanting palpebrae, cafe´-au-lait spots, immunodeficiency, chromosome breakage and rearrangements of 7/14

AR (251260) NBS1, 8q21

Non-ketotic hyperglycinaemia152

Acute metabolic disease presentation; abnormal mitochondrial glycine cleavage; hypotonia, lethargy, abnormal cry, jaundice, coma, elevated urine and plasma glycine; CNS include absent corpus callosum, pachygyria

AR (605899) GCSP, 9p22 GCST, 3p21.2-p21.1 GCSH, 16q24

Oberklaid-Danks: Opitz C-like153

IUGR, postnatal growth failure and death, prominent metopic suture, hirsute forehead with forehead/glabellar hemangioma, synophrys, exophthalmos, hypertelorism, cleft lip/ palate, multiple joint contractures, flexion deformity at wrist, camptodactyly, DandyWalker cyst (1 case), agenesis of the corpus callosum

AR

Oculo-auricular-frontalnasal154

IUGR, microtia, preauricular tags, bifid nose, epibulbar dermoids, cleft lip/palate, midface hypoplasia, renal anomalies

Unknown

Oculo-pituitary155

In one of three families with features similar to septo-optic dysplasia, the patient had ACC but cousin with hypopituitarism did not

Unknown

Ohdo156

Retardation, blepharophimosis, mild microphthalmia, ptosis, hypoplastic teeth, variety of congenital heart defects, cryptorchidism, one report of agenesis of the corpus callosum

AR (249620)

Opitz C-trigonocephaly157

Mental retardation, trigonocephaly, wide alveolar ridges, wide oral frenula, short neck, polydactyly, visceral anomalies. Brain defects include absent corpus callosum, cerebellar vermis agenesis, Dandy-Walker

AR (211750)

(continued)

589

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Oral-facial-digital type I

Midline cleft/notched upper lip, multiple oral frenulae, lobulated tongue with hamartomas, asymmetric brachysyndactyly, variety of other anomalies (including CNS)

XLD, male lethal (311200) CXORF5, Xp22.3-p22.2

Oral-facial-digital type II159

Short stature, hypertelorism, low nasal bridge, broad and bifid nasal tip, hypertrophied oral frenula, cleft and lobulate tongue, cleft palate; brachysyndactyly, preaxial and postaxial polydactyly of hands; preaxial foot polydactyly; usually normal intelligence; CNS includes porencephaly, hydrocephaly, callosal agenesis

AR (252100)

Oral-facial-digital-type Chung160

Hypertelorism, flat nasal bridge, lingual nodule, micrognathia, four-limb postaxial hexadactyly, oromotor dysfunction, Dandy-Walker cyst, hypothalamic hamartoma. Single case

Unknown

Orstavik: aplasia cutisretinal-brain161

Aplasia cutis on scalp and abdomen, broad bulbous nose, small chin, long philtrum, hypoplasia to absence of fingers with the nails attached to metacarpals, ventricular dilatation and cerebral atrophy, variable thalamic calcification; male had agenesis of the corpus callosum

AR

Osteodysplastic primordial dwarfism162

Type I and II and Taybi-Lindes are equivalent. Marked IUGR, prominent nose, micrognathia, sloped forehead, alopecia, dry skin, contractures, early death, variety of skeletal changes

AR (210710)

Osteosclerosis-brain anomalies163

Generalized osteosclerosis, wide metaphyses, wide sutures, large anterior fontanel, downslanting palpebrae, depressed nasal bridge, micrognathia, large posterior fossa cyst, cerebellar hypoplasia, agenesis of the corpus callosum, large interhemispheric cyst, hydrocephalus

AR

Pachygyria-agenesis corpus callosum-X-linked164

Microcephaly, lethal in males, severe developmental delay, early-onset seizures, agenesis of the corpus callosum, microphallus, neuronal migration defect; less severely retarded male did not have neuroimaging; band heterotopia a possibility

XLD (600102)

Pai: corpus callosum lipomafacial polyps165

Median cleft upper lip, facial cutaneous polyps, nasal polyps, normal intelligence; all cases male; associated with corpus callosum lipoma

Unknown

Pallister-Hall166

Low ears, broad nasal bridge, buccal frenula, cleft palate, nail dysplasia, postaxial polydactyly, syndactyly, renal anomalies, imperforate anus. CNS includes hypothalamic hamartoblastoma, arhinencephaly, hydrocephaly, absent corpus callosum, encephalocele, Dandy-Walker, polymicrogyria, heterotopia

AD (146510) GLI3, 7p13

Pallister W167

Mental retardation, seizures, mild spasticity, tremors, high forehead, hypertelorism, frontal cowlick, downslanting palpebrae, strabismus, flat and broad nasal bridge with blunt tip, submucous cleft palate, median cleft of upper lip, absent upper central incisors, cubitus valgus, subluxation of proximal radio-ulnar joints, camptodactyly, clinodactyly; females similar face but not retarded

XLR (311450)

PAX6-related eye-brain anomalies168

Microcephaly, anophthalmia, small nares, large pinnae, absent corpus callosum, focal polymicrogyria; compound heterozygote for PAX6 mutations; unilateral polymicrogyria and absent pineal in heterozygotes

AR (106210) 11p13

Perlman: overgrowth169

Macrosomia, low-set ears, deep-set eyes, small nose, full upper and everted lower lip, serrated alveolar margins, nephromegaly, renal hamartoma/dysplasia, Wilms, islet of Langerhan hyperplasia, hypoglycemia, cryptorchidisim

AR (267000)

Peters anomaly-callosal agenesis-brain calcification170

Peters anomaly, frontal bossing, hypertelorism/telecanthus, malar hypoplasia, bulbous nose, long philtrum, conotruncal heart defect, agenesis of the corpus callosum, intracerebral calcification

Unknown

Phylloid hypomelanosis171

Hypopigmentation distributed in round or oval lesions, large and asymmetrical patches like begonia leaves, and pear-shaped or oblong macules; in 5 of 6 cases there was mosaicism or a translocation of chromosome 13

Chromosome imbalance

Polyasplenia-caudal deficiency-absent corpus callosum172

Laterality associated defects, imperforate anus, renal anomalies, lumbosacral agenesis, lower limb anomalies; cases reported with meningocele, hydrocephalus; one case with absent corpus callosum and white matter, neuronal heterotopias, and abnormal cortical architecture

Uncertain

Proteus173

Marked and asymmetric overgrowth can lead to a range of complications; skin includes shagreen patches, linear verrucous epidermal nevi, intradermal nevi, lipomas, hemangiomas, patchy dermal hypoplasia, hyperplastic and pebbly plantar overgrowth; frequent ocular problems; CNS abnormalities uncommon, partial absent corpus callosum, lissencephaly, hydrocephalus

AD?(176920) Some PTEN, 1q11-q25, mutations claimed but cases questioned258

Proud: XLMR-seizurescallosal agenesis174

Microcephaly, severe mental retardation, seizures, spasticity, coarse face, nystagmus, joint contractures, tapering fingers, porencephaly, agenesis of the corpus callosum, conservative substitution in homeodomain

XLD (300004) ARX, Xp22.13

158

(continued)

590

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Pseudo-TORCH

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; similar to, and may be allelic with, Aicardi-Goutieres and Cree encephalitis; Bedouin family reported with callosal agenesis

AR (251290)

Pyruvate dehydrogenase complex deficiency176

IUGR, perinatal presentation of severe lactic acidosis, and/or poor feeding, hypotonia and lethargy, profound mental retardation, seizures, spasticity, microcephaly, narrow forehead, frontal bossing, wide nasal bridge, long philtrum, blindness; CNS can include cerebral atrophy, callosal agenesis, absent medullary pyramids, abnormal/ectopic inferior olives

XLR/AR (208800) PDH E1 subunit, Xp22.1 11p13

Rubinstein-Taybi177

Short stature, mental retardation, downslanting palpebrae, beaked nose with septum below alae, radially deviated broad thumbs, broad toes

AD (268600) CBD, 16p13

Sakoda-anophthalmiacortical dysgenesis178

Anophthalmia, cleft lip/palate, short stature, hemivertebrae, basal encephalocele, absent corpus callosum, cerebral dysgenesis. Single case.

Unknown

Say: cloverleaf skull-skeletal anomalies179

Short wide clavicles, winged scapulas, prominent costochondral junctions, polysyndactyly of hands and feet, abnormal ulna/radius

Unknown

Schinzel-Giedion: hypertrichosis-midface retraction180

Tall and prominent forehead, hirsute, severe temporal narrowness, full cheeks, groove under eyes, choanal atresia, fleshy earlobes, narrow and deep-set nails, variable post-axial polydactyly, hypospadias, hydronephrosis/hydroureter, congenital heart defects, radiographic anomalies, ventriculomegaly, intraventricular bands, subependymal pseudocysts, leukomalacia

AR (269150)

Seckel181

Severe IUGR, proportionate growth failure, severe mental retardation, receding forehead and chin, downslanting palpebrae, prominent curved nose, dislocated radial head

AR (210600) ATR, 3q22.1-q24, SCKL2, 18p11.31-q11.2

Shanske: Seckel-like182

IUGR; severe mental retardation, microcephaly, and short stature; receding forehead, downslanting palpebrae, large beaked nose, retrognathia, dislocated radial head. One family with three children with agenesis of the corpus callosum, cortical dysgenesis, dorsal cerebral cyst, pachygyria

AR (210600)

Shapira: hyperhydrosishypothermia183

Periodic hypothermia, hyperhydrosis. One report of sibs with recurrent apnea, hypertonia, disturbed respiratory rhythm, white matter spongiosis, Purkinje cell loss

Most sporadic; AR (217990)

Siber: microphthalmia184

Microphthalmia, corneal opacities, hypospadias, one sib had more extensive brain anomalies noted at autopsy

XLR (309800)

Skeletal dysplasia-cloverleaf skull185

Lethal chondrodysplasia with short limbs and hands, cloverleaf skull, narrow chest, lowset ears, large anterior fontanel, hypertelorism, microphthalmia, ventricular septal defect, ambiguous genitalia

AR

Slee: hydrocephalus-growth failure-digital186

Lethal, severe polyventricular hydrocephalus, patent aqueduct of Sylvius, cleft palate, overlapping of the fingers; CNS defects variable and include partial/complete callosal agenesis, hypoplastic mid- and hindbrain, cerebellar agenesis

Uncertain

Smith: Hypopituitarism187

Multiple pituitary hormone deficiency, may be accompanied by retardation (Same as oculo-pituitary?50)

Unknown

Smith-Lemli-Opitz188

IUGR; postnatal growth failure; narrow frontal area, microcephaly; anteverted nares; female external genitalia with 46,XY karyotype; cleft palate; anomalies of eye, heart, and lung, pachygyria

AR (268670) DHCR7, 11q12-q13

Sotos like-macular degeneration189

Macrocephaly, developmental delay, tall stature, prominent forehead, downslanting palpebrae, juvenile atrophic macular degeneration with cone dysfunction, abnormal cavity above the 3rd ventricle, very small lateral ventricles, callosal agenesis

Unknown

Sternal clefts-telangiectasiashemangiomas190

Capillary/cavernous hemangiomas of face and upper trunk, patches of atrophic skin, midline abdominal raphe from sternal cleft to umbilicus. Case reported with microcephaly, microphthalmia, ectopia cordis, diffuse hemangiomatosis, callosal agenesis.

Unknown (140850)

Stippled epiphyses-loose skin-lissencephaly type III191

Microcephaly; arthrogryposis; craniofacial edema with onset in utero; stippled cervical vertebrae, feet, and sacrum; short metacarpals and distal phalanges; agenesis of corpus callosum, agyria, hypoplastic brain stem, diffuse severe neuronal loss

AR

Stippled humeral epiphysesiris colobomata192

Developmental delay, brachycephaly, small nose and anteverted nares, low-set ears, midface hypoplasia, iris coloboma, stippled proximal humeral epiphyses, dysplastic distal phalanges, hepatic fibrosis, deep palmar creases, toenail hypoplasia, partial absence of the corpus callosum, small cerebellar vermis

AR (215105)

Stoll: cerebellar hypoplasiaspastic paraplegia193

Mental retardation, spastic paraplegia, hypoplasia of the cerebellar hemispheres, partial agenesis of cerebellar vermis, agenesis of the corpus callosum

AR (220200)

175

(continued)

591

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

Tectocerebellar dysraphiaoccipital encephalocele194

VSD, small mandible, cleft palate; CNS anomalies include posterior encephalocele, absent corpus callosum, hydrocephaly, cerebellar vermis agenesis, heterotopias

Unknown

Temtamy: callosal agenesiscolobomas-retardation195

Macrodolichocephaly, low-set and simple ears, narrow face, hypertelorism, complete colobomas, beaked nose, micrognathia, dental anomalies, dilated aorta, mild brachydactyly of digits 2-5 of hands and feet

AR

Thakker-Donnai196

IUGR, Klippel-Feil, long and downslanting palpebrae, hypertelorism, short nose with blunt tip, small downturned mouth, vertebral anomalies, short esophagus, diaphragmatic hernia, congenital heart defect. One sib with hydrocephalus, the other with callosal agenesis.

AR (227255)

Thanatophoric dysplasia197

Short ribs, micromelia; usually lethal during neonatal period, few with longer survival; achondroplasia-like face, extra skin folds on limbs, ‘‘U’’- or ‘‘H’’-shaped flat vertebrae, ‘‘telephone receiver’’-shaped femora, metaphyseal flare of long bones, short and broad tubular bones

AD (187600) FGFR3, 4p16.3

Thrombocytopenia-Robin sequence198

Mental retardation, pre- and postnatal growth failure, Robin sequence, telecanthus, downslanting palpebrae, short and broad tipped nose, enamel hypoplasia, camptodactyly, cerebellar vermis hypoplasia

Unknown

Toriello-Carey199

Short palpebral fissures, telecanthus, Robin sequence, small nose, abnormal auricles, excess nuchal skin, larynx anomaly, hypospadias, brachydactyly, microcephaly, mental retardation

AR (217980)

Trigonocephalypolysyndactyly-callosal agenesis200

Trigonocephaly, four-limb preaxial polysyndactyly, partial agenesis of corpus callosum. Single case.

Unknown

Tuberous sclerosis201

Depigmented macules and hair patches, shagreen patches, fibroangiomas in butterfly distribution, periungual fibromas, phakomas of retina, heterotopias, multiple focal cerebral tubers with absent laminar and columnar organization, and abnormal cellular orientation

AD (191100) TSC1, hamartin, 9q34 TSC2, tuberin, 16p13.3, 12q14

Van Biervliet: thoracic dystrophy202

IUGR, multiple joint contractures, narrow thorax, small mouth and mandible, appear older than age, developmental delay

AR

Van Maldergem: blepharonaso-facial203

Moderate to severe mental retardation, small and malformed ears, telecanthus, epicanthus, broad and flat nose, wide mouth, camptodactyly, clinodactyly , mild skin syndactyly. Case with ataxia, hypotonia enlarged lateral ventricles, reduced white matter, absence of callosal rostrum.

Unknown

Velocardiofacial204

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay; congenital heart, especially conotruncal defects; several reports with pachygyria and/or polygyria

AD (192430) del 22q11 del 10p

Vici: Immunodeficiencycataracts 205

Hair and skin hypopigmentation, combined immunodeficiency, cleft lip/palate, hypertelorism, hypospadias, cerebellar hypoplasia; may be type I Griscelli syndrome due to MYOVA gene256

AR (242840)

Vles: callosal agenesis-spastic quadriplegia206

Severe mental retardation, spasticity, irregular outline to the lateral ventricles

Uncertain

Walker-Warburg207

Cobblestone lissencephaly, retinal dysplasia, microphthalmia, other eye anomalies, Dandy-Walker cyst, progressive hydrocephalus, myopathy, postnatal growth failure, early death

AR (236670) POMT1, 9q34.1

Warfarin, prenatal208

Significant developmental delay, small and grooved nose with depressed bridge, stippled epiphyses, mild nasal hypoplasia, short fingers, other CNS includes microcephaly, Dandy-Walker cyst, cerebral atrophy

In utero exposure ARSE inhibition

Wells: Apert plus209

Facial features of Apert syndrome with microcornea and coloboma, 2-4 finger syndactyly, mild 4-5 toe syndactyly, non-fused posterior ribs, hemivertebrae, platyspondyly, partial callosal agenesis

Unknown

Winter: osteodysplastic primordial dwarfism210

IUGR, sloped forehead, prominent occiput, alopecia, low-rotated abnormal ears, large-beaked nose, disproportionate short limbs, redundant skin, joint dislocations and limited extension, platyspondyly, delayed ossification of vertebrae, short long bones, broad metaphyses, hypoplastic vermis, absent corpus callosum, few gyri, loss of cortical layers

Unknown

Winter-Wigglesworth211

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres, microscopic renal changes

Unknown

(continued)

592

Brain

593

Table 15-7. Syndromes with absent corpus callosum (continued) Syndromes

Prominent Features

Causation Gene/Locus

X-linked corpus callosum dysgenesis212

Microcephaly, wide anterior fontanel, frontal bossing, telecanthus, broad nasal root, downturned mouth, short broad hands, brachydactyly; absent corpus callosum, interhemispheric cyst, cortical gyral dysplasia

XLR (304100)

X-linked lissencephalyabnormal genitalia (XLAG)40,213

Cortex 5–10 mm, posterior ! anterior gradient, no cell sparse zones in agyric areas, deficient small cortical granular cells, immature white matter, poorly demarcated basal ganglia that may have small cysts, agenesis corpus callosum (includes 50% of females), neonatal onset of seizures, hypothalamic dysfunction, ambiguous male genitalia

XLR (300382, 300215) ARX, Xp22.13

Young: macrocephaly214

Relative macrocephaly, prominent forehead, deep-set eyes, developmental delay and hypotonia, cerebellar hypoplasia

AR

Zellweger215

Hypotonia, postnatal growth failure, large fontanels, high forehead, flat face, excess nuchal skin, hepatic and renal dysgenesis, contractures, hypomyelination, pachygyria (especially inferior olive), polymicrogyria, heterotopias merge with layers V and VI and affect mostly late migrating cells, germinolytic cysts

AR (214100) Peroxin1, 7q21-q22 Peroxin2, 8q21.1 Peroxin3, 6q23-q24 Peroxin5, 12p13.3 Peroxin6, 6p Others, 1p22-p21,1q22, 2p15

Zimmer: tetra-amelia216

Polyhydramnios, amelia, severe facial clefting, no nose, ocular anomalies, hydrocephalus, absent ophthalmic and possibly olfactory nerves

XLR (301090)

Zollino: hypogenitalismmicropolygyria217

Severe hypotonia, metopic ridge, upslanting palpebrae, megalocornea, epicanthus, smooth philtrum, macrostomia, club feet, agenesis of the corpus callosum, micropolygyria; female less severely affected than three males

Unbalanced translocation

disturbances that remain undetected with current neuroimaging techniques. There has been a growing interest in the status of the corpus callosum in several less traditional areas. Although hypoplasia of the corpus callosum (HCC) is not the subject of this section, it is of interest that alterations in the shape, angles, and/or thickness of the corpus callosum were seen in 30 of 61 patients with a broad range of genetic syndromes,8 and that similar findings have been noted in a series of 31 treatment naı¨ve schizophrenics.9 Among another series of 140 schizophrenics, two were found to have partial ACC.10 EEGs of patients with ACC may be normal or may show a dysrhythmia, including asynchronous alpha activity.6 This activity reflects the underlying neurologic disturbances and is nonspecific. Central conduction delay on brain stem audiology evoked response and prolonged visual responses may be common in ACC.5 Before the advent of the pneumoencephalogram (PEG), none of the 83 reported cases of ACC had been diagnosed in a living patient The PEG allowed in vivo diagnosis but was an invasive procedure with attendant morbidity and was thus reserved for patients with significant clinical signs. Modern neuroimaging, both prenatally and postnatally, has allowed more liberal investigation, has led to earlier and more frequent diagnosis, and has changed the clinical profile of reported patients. The diagnosis of ACC is based both on the direct demonstration of the absence of this midline structure and on recognition of the characteristic distortion of cerebral architecture. It can be demonstrated by appropriate use of any of the standard neuroimaging procedures (Fig. 15-37). The specific findings are essentially the same regardless of the procedure, although MRI has advantages in distinguishing partial agenesis (Fig. 15-38)11 and in elucidating the presence and characteristics of any associated CNS anomalies.12 In the coronal view, there is a wide separation of the frontal horns and bodies of the lateral ventricles, both of which have sharp angled lateral peaks, giving a ‘‘double horn’’

appearance (Fig. 15-39). A useful sign in distinguishing type 1, primary, from other types of ACC is that, in the former, the callosal fibers persist as an anterior bundle of fibers (of Probst) that causes a concave medial border of the lateral ventricles. In the axial view the lateral ventricles tend to be parallel and more widely separated (Fig. 15-40). In the absence of hydrocephalus, the frontal horns tend to be narrow, whereas the decreased white matter in the occipital region, and the fact that the occipital axons do not form Probst bundles, result in enlarged occipital horns (colpocephaly) and an overall bull’s horns or teardrop appearance (Fig. 15-41).13 Normally, the corpus callosum forms the roof of the 3rd ventricle and, in its absence, the 3rd ventricle tends to ride high between the lateral ventricles. In the axial plane, the dilated and high 3rd ventricle and the combination of the frontal and posterior horns have been likened to a leaping frog.13 Sagittal views can document absence of the corpus callosum and its extent. The cingulate sulcus, which appears to be induced by the corpus callosum, is also absent, and the cingulate gyrus is inverted and has a radial pattern about the roof of the 3rd ventricle (Fig. 15-42). Doppler studies may show abnormal branching of the anterior cerebral artery14 and non-visualization of the pericallosal artery.15 The anterior commissure runs rostral and the hippocampal commissure (HC) infero-caudal to the corpus callosum, and either or both may be present or absent in ACC. When present in ACC, the HC can be mistaken for callosal fibers.14 When the HC is absent, the hippocampus and fornix are hypoplastic and the inferolateral horns of the temporal horns are dilated.14 The timing of prenatal diagnosis of ACC is closely related to its embryogenesis, which is not completed until 20 weeks gestation. Achison and Achison16 carried out a cross sectional ultrasound study of callosal growth in 270 pregnancies, between 16 to 37 weeks gestation, using transabdominal and transcervical ultrasound, as dictated by fetal position. They were able to measure the length, width, and thickness in 258 cases and showed a linear

594

Neuromuscular Systems

Fig. 15-40. Axial CT scan at the level of the lateral ventricles showing parallel ventricles with somewhat convex medial borders. (Courtesy of Department of Radiology, Children’s Hospital of Eastern Ontario.)

Callosal lipomas are associated with at least partial ACC about half the time, but their presence may obscure the ultrasound confirmation of ACC. Bennett et al.18 reviewed the results of routine 16 to 22 week obstetric ultrasound scans that had been performed in 15 fetuses diagnosed with ACC in the 3rd trimester. Ten of the earlier scans were completely normal; two fetuses had extracranial anomalies; and three had CNS malformations, only two of which were suggestive of ACC. Fig. 15-39. Coronal section at the level of the thalamus showing absent corpus callosum (arrows). (Courtesy of Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

relationship of growth to gestational age with maximal growth at 19 to 21 weeks. The corpus callosum was identified as a hypoechogenic structure demarcated by two echogenic lines; on the mid-sagittal view, bound above by the callosal sulcus and the cingulate gyrus and below by the cavae; on the coronal view, the superior border is the echogenic interhemispheric midline, the lateral the frontal horns, and again the cavae below. Growth of the length and width is comparable in males and females, but the corpus callosum is significantly larger in females throughout gestation,17 an interesting observation in light of a consistent excess of male predominance in ACC. The prenatal ultrasound signs that confirm ACC are the same as those observed in the postnatal period, but the required imaging views may be obscured by fetal position, and there is a consensus that the diagnosis is unreliable before 20 weeks gestation. Clues that lead to a suspicion of ACC include ventriculomegaly, a high position of the 3rd ventricle, and failure to visualize the cavum septum pellucidum.14,18 It is notable that mild ventriculomegaly is more typical of ACC than is severe ventriculomegaly.18 ACC occurs in up to 10% of mild19and 3% of overall prenatal ventriculomegaly.20

Fig. 15-41. Axial CT scan at the level of the anterior ventricles showing their separation by an enlarged and rising third ventricle. (Courtesy of Department of Radiology, Children’s Hospital of Eastern Ontario.)

Brain

595

Fig. 15-42. Brain cut sagittally in the midline showing absence of the corpus callosum (arrows) and radial arrangement of the cingulate gyrus. (Courtesy of Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario.)

Good sagittal views, which are necessary to best directly assess the midline structures, may be difficult to obtain, especially if the fetus is in a cephalic position. Vesentin et al.21 were successful in 89% of 126 pregnancies at 19 to 24 week gestation by using the frontal suture, as opposed to the anterior fontanel, to obtain midline views, and transvaginal sonography can be used to advantage, facilitated by having the patient in the lithotomy position with cephalic presentations.22 Wang et al.23 were able to obtain an adequate sagittal view, between 18 and 32 weeks gestation, in only 3.1% of fetuses in the cephalic position when they used standard 2D-ultrasound. However, they were successful in 25/32 (78%) of cases when they applied 3D-sonography with multiplanar reformatting. Although prenatal MRI is not routinely applied, there is growing evidence that the newer equipment, with scan times of 1 second or less, can effectively confirm or rule out ACC, determine its extent, and often confirm the presence of additional CNS anomalies.24,25 Optimal neuroimaging should allow distinction between primary and secondary ACC, as well as their subtypes. ACC is a common component of a number of multiple malformation syndromes and is an occasional finding in a number of others that are summarized in Table 15-7. The rate of chromosomal and non-chromosomal syndromic causes of ACC is highly dependent on ascertainment and what authors include as a syndrome diagnosis. For example, one series included cerebral palsy, dyslexia, and Asperger as syndrome diagnoses. Overall in the series reviewed, it appeared that up to 15% of ACC is associated with a chromosome imbalance, and that about 12% of patients have had a specific syndrome diagnosis. Some series have claimed a known etiology in almost half of cases, but this is not the general experience to date. Single case reports of ACC in common syndromes or diseases such as G6PD deficiency, sickle cell anemia, cystic fibrosis, Noonan syndrome, and arthrogryposis may be coincidental.

malformation, are generally confined to symptomatic individuals. A significant proportion of isolated, and indeed complex, cases will be missed on routine prenatal ultrasound, thus eliminating this possible source of an estimate of prevalence. Reports from routine autopsy series are probably the closest estimates of true prevalence, but rates observed in selected populations are of interest, and a representative sample of these rates is summarized in Table 15-8. Table 15-8. Prevalence of ACC with different methods of ascertainment Rate per 10,000 Source of Ascertainment

0.5

Reference

Routine autopsy series

218

Unselected hospitalized population

219

36

Stillbirths and neonatal autopsies

220

36

Referral to pediatric neurology service

221

70

Large series of pneumoencephalograms

222

101

Consecutive MRI series in neurologically abnormal children

223

157

Consecutive MRI series in patients under 17 years

224

230

Series of mentally retarded children

225

300

Cases of prenatally detected ventriculomegaly

10–30

300–500

1000

Cases among all CNS anomalies detected by prenatal ultrasound Cases of prenatally detected mild ventriculomegaly

20 226

19

Other Small Series of Specific Conditions

Distribution and Etiology

Determination of the true prevalence of ACC is confounded by the fact that isolated cases may be essentially asymptomatic, and neuroimaging studies, which are required to document the

43

Patients with choanal atresia (23)

142

New cases of schizophrenia (140)

731

Patients with hypoplastic left heart (41)

227 10 228

596

Neuromuscular Systems

Almost all series report an excess of males with ACC, and the male-to-female ratio in the papers reviewed for this section was 1.84:1. As mentioned, the male corpus callosum lags behind that of the female in thickness throughout gestation, and Barkovich et al.2 have suggested that the skewed sex ratio may be specific to certain subtypes of ACC. Interestingly, the BALB/cCF mouse model shows a female excess.229 At 6 to 8 weeks gestation, the dorsal rostral portion of the telencephalon, the lamina terminalis, thickens and becomes densely cellular and is called the lamina reuniens of His (LR). A median groove, the sulcus medianus telencephali medii, is formed when the lamina reuniens folds along its dorsal part during week 8. During week 9, proliferation of the LR cells causes the groove to deepen and brings the edges closer, so that they become separated by a single layer of early meninges.230 By week 10, the sulcus is obliterated by fusion, thus forming the massa commissuralis. The latter grows in a dorsal direction over the ensuing 5 to 7 weeks and is the path through which the commissural fibers pass to form the corpus callosum.231 Contrary to some earlier views, this is not a passive pathway that acts simply as a conduit for axonal migration. The neocortical neurons that will ultimately form the corpus callosum derive mainly from cortical layers 2, 3, and 5. En route they must make several directional changes. First they travel ventrally to the intermediate zone, then medially toward the midline and the cingulate gyrus, again vertically to the corticoseptal boundary, medially across the midline, and finally reversing the process in the contralateral hemisphere.102,232 There are several active processes that must occur in and around the midline to allow and guide the passage of the callosal axons. Apoptosis of a midline glial barrier is required, and in a mouse model where this fails to occur, ACC results.3 A glial sling (GS) is formed in the midline across the massa commissuralis of cells derived from the medial wall of the lateral ventricles. An absence or interruption of the GS results in ACC, and the malformation can be rescued by insertion of a glial-coated membrane. The glial cells of the GS do not show the characteristics of mature glial cells.232 In the BALB/c mouse, the development of the GS and subsequently the corpus callosum is interfered with by the development of a midline, fluid-filled gap. A dorsal midline bulge accompanies this gap where corpus collosal axons have approached the midline. Ventrally there is a narrow midline groove that resembles the human sulcus medianus telencephali medii. The abnormal gap is seen in almost all of the BALB/c mice, but its size and impact are variable, thus accounting for the variable spectrum of callosal defects observed. The development of the midline gap is itself a normal developmental step in the formation of the septal cavity, but it appears after formation of the GS and crossing of the callosal axons. Between the lateral margins of the GS and the medial ventricular walls there develops a glial wedge of cells, ventral to the eventual corpus callosum. Dorsal to the future corpus callosum, glial cells form the indusium grissium, which is a thin structure that derives from the cingulate gyrus and runs the length of the corpus callosum.232 Excising or altering the orientation of the glial wedge or indusium grissium will result in ACC. The midline glial cells produce a number of evolutionarily conserved molecules whose expression affects axonal pathfinding across the midline. In Drosophila, the glial cells were shown to secrete Slit, and axons expressing its receptor (Robo) are guided across the midline, whereas those not expressing Robo turn away and form the perforating pathway.233,234 The growing tip of the axon (growth cone) requires a number of intermediate targets along its course, to which it is either attracted or repelled. The major fascicles of axons are proceeded by a vanguard of pioneering axons that appear to show the way for those

following. Evidence using carbocyanine dyes in mice have shown that during initial migration the pioneering axons are only about 200 microns in advance of the main axonal bundles but that this distance increases to 0.5–2.5 mm as the midline is crossed.235 Ablation of the pioneering axons will also result in ACC. Recently it has been shown that neurons from the cingulate gyrus are the first to cross the midline, and that they provide guidance to the neocortical callosal axons. There is also some evidence that some cingulate axons travel laterally and may provide guidance to the cortical axons as they travel to the midline.232 The caudal callosal axons may use the axons of the hippocampal commissure for guidance across the midline.102 The first fibers to cross the midline are the anterior and hippocampal commissures, which link older parts of the brain. The former can be recognized growing medially as early as 6 weeks and to cross by 54 days gestation.3 The corpus callosum forms in a rostral to caudal sequence, with the earliest fibers or the rostrum crossing at 74 days, followed by the genu and body, with the splenium and adult morphology present by 115 days.3 Richards et al.102 argue that the most caudal, hippocampal dependent, callosal axons may cross at or near the same time as the most rostral components. As the cerebral hemispheres grow in a caudal direction, there is parallel anteroposterior elongation of the corpus callosum, forming the body and splenium. From this point further development of the corpus callosum consists of enlargement, and it reflects the rapidly expanding cerebral hemispheres.231 Disturbances beyond 18–20 weeks would be expected to show hypoplasia or secondary destruction. The latter is distinguishable by absence of the bundle of Probst and is suspected in cases where an anterior or middle component of the corpus callosum is absent in the presence of normal posterior components. Relatively little is known about the pathogenesis of type 1, primary ACC, in humans. Early theories have included vascular and infectious disruption as causes, but Barkovich and Norman236 have questioned the assumption that ACC reflects an insult occurring at the time the corpus callosum is developing. After studying the known embryologic timing of specific cerebral malformations found in association with ACC, they proposed that damage to the sulcus medianus telencephali medii prior to formation of the corpus callosum was more compatible with the timing of the associated malformations. Disruption later in gestation may still account for cases of ACC that do not fit the embryologic timetable, as well as for callosal hypoplasia. Other suggested etiologies have included failure of closure of the anterior neuropore causing absence of the lamina terminalis, and dilatation of the roof of the 3rd ventricle, secondary to hydrocephalus, causing interference with the midline.4 ACC is etiologically heterogeneous. Infectious agents, prenatal alcohol exposure, and maternal diabetes have been implicated in case reports, while a variety of vitamin deficiencies and irradiation have been used to produce ACC in animals.237 Anomalies in the corpus callosum, including absence, have been well documented in fetal alcohol syndrome.36 ACC can occur in association with a number of unrelated inborn errors of metabolism. Dobyns238 reported ACC in 6 of 15 patients with nonketotic hyperglycinemia. Abnormal gyral patterns and cerebellar hypoplasia were also noted. ACC has also been present in cases of unspecified lactic acidosis, pyruvate carboxylase and dehydrogenase deficiencies, Zellweger syndrome, histidinemia, Hurler syndrome, mucolipidoses III and IV, and Lowe syndrome (Table 15-7).6,122 Metabolic causes may account for up to 4% of cases.4 A recent review102 listed 34 mouse genes associated with absent and/or reduced size of the corpus callosum. The nature of

Brain

their activities encompassed guidance molecules, transcription factors, extracellular matrix molecules, intracellular signaling/cytoplasmic molecules, and growth factors. The broad spectrum of syndromes and the Mendelian inheritance of isolated ACC reported in humans suggest that many human genes may have an impact on development of the corpus callosum. However, not all the syndromes in Table 15-7 are known to cause type 1, primary ACC, and in relatively few is ACC a high frequency manifestation of the syndrome. Two important human ACC associated genes have thus far been isolated. Neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the I-set of the immunoglobulin super family (IgSF). The first mutations in L1CAM were found in patients with X-linked hydrocephalus due to stenosis of the aqueduct of Sylvius (HSAS), and it has since been associated with a number of X-linked conditions that may express ACC, under the acronym CRASH,69 a term not favored for clinical use (Table 157).69 L1CAM has six immunoglobulin-like and five fibronectin type III–like extracellular domains, a single transmembrane segment, and a short cytoplasmic C-terminus. It is expressed in outgrowing axons and growth cones of post-mitotic cells in the central and peripheral nervous system and plays a role in neuronal-neuronal and neuronalSchwann cell adhesion, myelination, axonal outgrowth and pathfinding, growth cone morphology, and neuronal migration.69 Given its wide range of influences, it is not surprising that L1CAM has many extracellular and intracellular interactions. These include homophilic interaction with other cells, heterophilic involvement with other IgSF proteins, with neurocan and phosphacan, with a number of cis-acting factors such as NCAM, and with a variety of signal transduction pathways.69 Known mutations are spread widely across the gene, and for the most part, the mechanism whereby ACC occurs is not known. The C-terminus of L1CAM is anchored via interaction with ankrin to the actin cytoskeleton, and mutations in mouse ankrinB lead to callosal hypoplasia.232 Missense mutations in the C-terminus of three patients with ACC have been shown to cause diminished L1CAM-ankrin interaction.239 The second important ACC gene to be isolated was SLC12A6 in patients with Andermann syndrome (Table 15-7).240 This autosomal recessive gene shows a founder effect in the Charlevoix and Saguenay-Lac-St-Jean region of Quebec, where the gene has an estimated prevalence of 1 in 23. The primary characteristic of the syndrome is that of an early onset of progressive neuropathy and, contrary to the impression sometimes given in the literature, ACC is not an obligatory feature of the syndrome. In a survey of 64 Quebec patients, 37 (57.8%) had complete ACC, 6 (9.4%) had partial ACC, and in 21 (32.8%) the corpus callosum was intact.241 Indeed, the homozygous mouse knockout model has a neuropathy and behavioral changes but not ACC, thus suggesting a role for other genes and/or environmental factors in modifying the impact of mutations in SLC12A6 on callosal development. SLC12A6 is involved in the KCC3 mediated transport of Kþ and CL. It is as yet unclear how perturbations in ion transport affect axonal migration and result in the type 1, primary ACC, seen in Andermann syndrome. Prognosis, Treatment, and Prevention

The prognosis for patients with ACC is entirely dependent on the presence or absence of accompanying cerebral dysfunction and associated malformations. One might expect that ACC would lead to some failure of normal lateralization of brain function and impairment in tasks that are thought to rely heavily on crossed pathways. However, Ettlinger et al.242 carried out a broad

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battery of tests in patients who had ACC and normal intelligence and concluded that ‘‘the most conspicuous feature of our present results is the lack of impairment found amongst the acallosal patients.’’ In a study specifically directed at language, Jeeves and Temple243 concluded that ‘‘retrieving words in response to rhymes was the only language deficit clearly exhibited by all three acallosals discussed in this paper.’’ As testing becomes more sophisticated and specific, subtle differences in the performance of patients with isolated ACC do become apparent. Evidence from mice suggests the differences may be highly task dependent. Acallosal 129 x BALB/c mice show no deficits in behavior or motor performance on a notched balance, but do have impaired running speed on wheels with differing inter-rung distances.244 Human studies in both acallosal and callosectomy patients have detected deficits in explicit learning of repetitively presented visual sequences that require bimanual, but not those requiring unimanual, keyboard responses245; decreased speed and accuracy of bilateral visual matching246; and ability to localize a moving, binaurally presented sound.247 There is also evidence that acallosal and callosectomy patients may develop compensatory neurologic paths, and that in some cases this is limited to those with ACC. Normal subjects show little difference in reaction time (RT) to crossed and uncrossed visual response tasks (CUD), and little difference when the stimuli are presented unilaterally versus bilaterally. Patients with ACC show significantly larger CUD and improvement with bilateral stimuli, suggesting subcortical neuronal summation.248 This summation is only apparent when the bilateral signals are positive (go/go) and are not seen when one signal is positive (go) and the other negative (no-go) for the set task.249 Acallosal patients may perform better than controls in localizing unilateral auditory stimuli, suggesting a compensation toward the use of unilateral cues.247 The response times of patients with ACC to color and shape discrimination tasks presented in one or other visual field and requiring crossed and uncrossed manual responses were the same as in controls, whereas a callosectomy patient showed increasing errors as the task complexity increased.250 Brown et al.251 studied four patients with ACC, two with partial ACC, and one with a callosectomy. None of the patients showed ipsilateral hemisphere visual evoked responses, thus demonstrating that the posterior corpus callosum is necessary for this interhemispheric transfer. However, acallosal patients, but not the callosectomy patient, were as capable as the controls in comparing bilaterally presented letters, suggesting transfer via the anterior commissure. On the other hand, the patients with complete ACC were unable to perform the matching when presented with complex visual patterns, and those with partial ACC were able to do so. Given that isolated ACC is essentially a benign, asymptomatic malformation, there will be a bias toward ascertainment of patients who have neurologic dysfunction due to an associated malformation. As discussed previously, the presenting signs vary with the age at diagnosis, and one would expect some correlation between the age at which a patient becomes symptomatic and the clinical prognosis. Lacey5 reported that all but 2 of 32 children diagnosed in infancy and who were older than 12 months at follow-up had developmental quotients less than 80. In contrast, of eight children diagnosed at age 4 years or older, three had IQs in the 80s and four others were considered normal. Thus, in contrast to those who develop signs later in life and to those with isolated ACC, neonates and infants who have neurologic signs have a poor prognosis. However, the prognosis is related to the signs and symptoms secondary to the associated malformations and not to the age of the subject per se.4,221

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Earlier studies were based on autopsy diagnoses or the use of relatively invasive diagnostic procedures; the diagnosis was heavily biased toward patients with severe seizure disorders or mental retardation. More recent studies present a more optimistic perspective for patients with ACC. Of 56 patients ascertained through the British Neurological Survey Unit, 3 of 19 pediatric patients were delayed and four had hemiplegia; of the 31 adults, 19 were considered to have some intellectual delay, of which two-thirds were mild.252 Thirty-two of the 56 patients had seizures: 20 generalized, 12 focal, and 4 focal leading to generalized seizures. About one-third of the patients had neuropsychiatric symptoms, but ascertainment was through neuropsychiatric clinics. Shevell221 ascertained 24 cases among 6911 consecutive patients in a neurology clinic. These cases were ascertained prenatally (9), neonatally (6), and later (9), and had high rates of associated complications including microcephaly (8), dysmorphia (12), and seizures (11). Overall, 83% had some developmental delay, and in 71% the delay was moderate to severe. Again, there is the bias of ascertainment through a neurology clinic, and it seems that a prenatally ascertained group, carefully subdivided by the subtype of ACC and carefully followed for associated anomalies and long-term development, will give the best overview of prognosis. In jurisdictions that permit termination of pregnancy beyond 20 weeks gestation, the prediction of neurologic outcome can be the determining factor in the decision whether or not to continue a pregnancy. When termination of the pregnancy is not an option, accurate information concerning prognosis can help parents to prepare for the birth of their child. Current evidence suggests that the timing of the diagnosis of ACC, that is, whether it occurs prenatally, neonatally, or later, is not a determinant of prognosis.4,221 Prognosis is largely dependent on the presence or absence of associated CNS malformation and syndromes. The major difference between prenatal and postnatal diagnosis is the reduced ability to detect the presence of associated anomalies and the inability to carry out functional studies on the fetus. Gupta and Lilford253 reviewed 70 cases of prenatally ascertained ACC reported in the literature prior to 1995. In group 1 were 34 patients considered prenatally to have isolated ACC and followed up after birth. Three cases were found to have additional anomalies postnatally: one with trisomy 8 mosaicism, one who died, and one in whom follow-up was lacking. Of the 31 cases confirmed as isolated, in four the pregnancy was terminated, leaving 27 livebirths, of whom 23 were developmentally normal, two were mildly delayed, and one was severely delayed. The severely delayed patient had fetal alcohol syndrome, and in one patient there was no follow-up. The length of follow-up was from birth to 11 years with a mean of 29 months. In group 2 were patients noted on prenatal ultrasound to have additional anomalies. In 16 of 36 cases the pregnancy was interrupted, and in four there was in utero death. Of the 16 patients who survived, there was no information on five, two were normal, and nine had mental and/or motor delay. There have been a number of follow-up studies on prenatally ascertained cases of ACC. Vergani et al.13 reported a normal outcome in five of seven isolated cases after 6 months to 8 years follow-up, with the two delayed patients having Aicardi syndrome (Table 15-7). Their seven complex cases included lissencephaly (3), trisomy 13, Arnold-Chiari malformation, porencephaly, and pleural effusion in a fetus with a family history of Andermann syndrome (Table 15-7). Of 15 cases reported by Bennett et al.,18 there were three in utero deaths, all with complex associated findings. Six children showed normal development, five had isolated ACC, and one had polydactyly. The two patients with definite

mental retardation had associated anomalies that were detected prenatally (partial trisomy 3, abnormal thalami and Dandy-Walker cyst). In four cases the developmental outcome was not clearly reported. Although an elevated position of the third ventricle and a widened interhemispheric fissure have been estimated to have respective relative risks for a poor outcome of 2.2 (CI 1.4-3) and 2.5 (CI 1.6-3.4),253 the former was seen in all six cases with a normal outcome in this series and is a poor discriminator. The most complete outcome study to date is that of Moutard et al.,254 who have attempted to follow 21 prenatally ascertained patients with apparently isolated ACC. All patients had normal karyotypes and viral studies, and a postnatal examination at 9 to 14 months to rule out any associated anomalies. One patient was lost to follow-up; three (with normal development at 3, 6, and 8 years) were excluded, as the research group did not follow them. Full scale IQ (FSIQ) in those followed to 2 years was 80–89 (3) and 90–109 (13); in those followed to 4 years it was < 80 (1), 80–89 (2), 90–109 (5), and >110 (1); and in those followed to 6 years it was < 80 (1), 80–89 (2), 90–109 (3), and >110 (1). Handedness was the same as in the general population; all but one child had normal manual dexterity; males had equivalent outcomes to females; and the FSIQ at 2 years was not predictive of that at 4 and 6 years. The authors noted that maternal sociocultural factors were a risk factor for lower IQ, that many of the IQs were below 100, and that subtle differences in speech development became apparent with age. Although some have claimed a better prognosis in partial than in complete ACC,4 it was not apparent in this study. Treatment of ACC is essentially that of careful evaluation for associated CNS and other malformations and control of associated signs and symptoms such as hydrocephalus and seizures. Seizure control is not different from that in patients without ACC. Given the importance of associated CNS anomalies in determining the prognosis of ACC, careful consideration should be given to the use of fetal MRI when ACC is suspected on prenatal ultrasound, especially where a decision may be pending about the continuation of the pregnancy. A fetal karyotype should also be considered, especially as not all chromosome abnormalities associated with ACC have a high likelihood of additional malformations that would be noted on ultrasound. A very few cases of ACC may be due to preventable teratogen exposures such as rubella or alcohol. Otherwise, prevention is based on making specific syndrome diagnoses and thus providing appropriate genetic counseling and specific prenatal diagnosis. Although the typical ultrasound signs of ACC are not generally noted until after 20 weeks gestation, the diagnosis is possible between 18 and 20 weeks gestation on a sagittal view. Techniques to obtain these views should be applied in high-risk histories and when other clues, such as ventriculomegaly, are noted. Furthermore, many of the associated CNS malformations that are associated with a poor prognosis may be detected on routine sonography. Indeed, a normal mid-trimester ultrasound is a favorable prognostic indicator in the face of later diagnosed ACC.18 The false-positive diagnosis of ACC has generally been confined to reports prior to 1990, but care must be taken not to misdiagnose fetuses with ACC as having hydrocephalus. Advice on prenatally ascertained cases of ACC should be based on the completeness and sophistication of the imaging studies at hand and the current literature of similar cases. One must be mindful that some of the syndromes most strongly associated with ACC (e.g., Aicardi and Andermann) are not expected to provide specific prenatal clues as to their presence, and that non-CNS malformations can have a significant impact on prognosis.255

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Brain 196. Thakker Y, Donnai D: A new recessive syndrome of unusual facies and multiple structural abnormalities. J Med Genet 28:633, 1991. 197. Wongmongkolrit T, Bush M, Roessmann U: Neuropathologic findings in thanatophoric dysplasia. Arch Pathol 107:132, 1983. 198. Khabbaze Y, Karayalcin G, Paley C, et al.: Thrombocytopenia absent corpus callosum syndrome: third case of a distinct clinical entity. J Pediatr Hematol Oncol 23:469, 2001. 199. Barisic I, Peter B, Mikecin L: Further delineation of the Toriello-Carey syndrome: a case report of two siblings. Am J Med Genet 116A:188, 2003. 200. Fryns JP, Devriendt K, Legius E: Polysyndactyly and trigonocephaly with partial agenesis of corpus callosum: an example of the variable clinical spectrum of the Acrocallosal syndrome? Clin Dysmorphol 6:285, 1997. 201. Barth PG, Stam FC, von der Harten JJ: Tuberous sclerosis and dysplasia of the corpus callosum: case report of their combined occurrence in a newborn. Acta Neuropathol 42:63, 1978. 202. Van Biervliet JP, Hendrickx G, van Ertbruggen I: Intrauterine growth retardation with craniofacial and brain anomalies and arthrogryposis. Acta Paediatr Belg 30:97, 1977. 203. Zampino G, Colosimo C, Balducci F, et al.: Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome. Clin Genet 45:140, 1994. 204. Kraynack NC, Hostoffer RW, Robin NH: Agenesis of the corpus callosum associated with DiGeorge-velocardiofacial syndrome: a case report and review of the literature. J Child Neurol 14:754, 1999. 205. Chiyonobu T, Yoshihara T, Fukushima Y, et al.: Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections. Am J Med Genet 109:61, 2002. 206. Vles JSH, de Die-Smulders C, Van der Hoeven M, et al.: Corpus callosum agenesis in two male infants of a heterozygotic triplet pregnancy. Genet Couns 4:239, 1993. 207. Dobyns WB, Kirkpatrick JB, Hittner HM, et al.: Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly. Am J Med Genet 22:157, 1985. 208. Kaplan LC: Congenital Dandy Walker malformation associated with first trimester warfarin: a case report and literature review. Teratology 32:333, 1985. 209. Wells TR, Falk RE, Senac MO, et al.: Acrocephalospondylosyndactyly— a possible new syndrome: analysis of the vertebral and intervertebral components. Pediatr Pathol 10:117, 1990. 210. Haan EA, Furness ME, Knowles S, et al: Osteodysplastic primordial dwarfism: report of a further case with manifestations similar to those of types I and III. Am J Med Genet 33:224, 1989. 211. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. 212. Kang WM, Huang CC, Lin SJ: X-linked recessive inheritance of dysgenesis of corpus callosum in a Chinese family. Am J Med Genet. 44: 619, 1992. 213. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359, 2002. 214. Young ID, Trounce MI, Fitzsimmons JL, et al.: Agenesis of the corpus callosum and macrocephaly in siblings. Clin Genet 28:225, 1985. 215. Barkovich AJ, Peck WW: MR of Zellweger syndrome. AJNR Am J Neuroradiol 18:1163, 1997. 216. Zimmer EZ, Taub E, Sova Y, et al.: Tetra-amelia with multiple malformations in six male fetuses of one kindred. Eur J Pediatr 144:412, 1985. 217. Zollino M, Colosimo C, Zuffardi O, et al.: Cryptic t(12;12)(q44;p13.3) translocation in a previously described syndrome with polymicrogyria, segregating as an apparently X-linked trait. Am J Med Genet 117A:65, 2003. 218. Myrianthopoulos NC: Epidemiology of central nervous system malformations. In: Congenital Malformations of the Brain and Skull. Part I. Vinken PJ, Bruyn GW, Myrianthopoulos NC, eds. North Holland Biomedical, Amsterdam, 1977, p 139.

603 219. Larsen PD, Osborn AG: Computerized tomographic evaluation of corpus callosum agenesis and associated malformations. J Comput Tomogr 6:225, 1982. 220. Pinar H, Tatevosyants N, Singer DB: Central nervous system malformations in a perinatal/neonatal autopsy series. Pediatr Dev Pathol 1:42, 1998. 221. Shevell MI: Clinical and diagnostic profile of agenesis of the corpus callosum. J Child Neurol 17:896, 2002. 222. Grogono JL: Children with agenesis of the corpus callosum. Dev Med Child Neurol 10:613, 1968. 223. Chako A, Koul R, Sankhla DK: Corpus callosum agenesis. Saudi Med J 22:22, 2001. 224. Bodensteiner J, Schafer GB, Breeding L, et al.: Hypoplasia of the corpus callosum: a study of 445 consecutive MRI scans. J Child Neurol 9:47, 1994. 225. Jeret JS, Serur D, Wisniewski K, et al.: Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatr Neurosci 12:101, 1986. 226. Couture A, Droulle P, Didier F: Les malformations ce´re´brales. In: Echographie du Foetus au Nouveaune´. Couture A, Veyrac C, Baud C, eds. Sauramps Me´dical Editions, Montpellier, 1994, p 267. 227. Rejjal A, Alaiyan S, Coates R, et al.: The prevalence of brain abnormalities in congenital choanal atresis. Neuropediatrics 25:85, 1994. 228. Glauser TA, Rorke LB, Weinberg PM, et al.: Congenital brain anomalies associated with hypoplastic left heart. Pediatrics 85:984, 1990. 229. Manhaes AC, Medina AE, Schmidt SL: Sex differences in the incidence of total callosal agenesis in BALB/cCF mice. Neurosci Lett 325:159, 2002. 230. Sidman RL, Rakic P: Development of the human central nervous system. In: Haymaker W, Adams RD, eds. Histology and Histopathology of the Nervous System. Charles C Thomas, Springfield, IL, 1982, p 42. 231. Rakic P, Yakovlev PI: Development of the corpus callosum and cavum in man. J Comp Neurol 132:45, 1968. 232. Richards LJ: Axonal pathfinding mechanisms at the cortical midline and in the development of the corpus callosum. Braz J Med Biol Res 35:1431, 2002. 233. Shu T, Richards LJ: Cortical axon guidance by the glial wedge during development of the corpus callosum. J Neurosci 21:2749, 2001. 234. Tear G, Harris R, Sutaria, et al.: Commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein. Neuron 16:501, 1996. 235. Ozaki HS, Wahlsten D: Prenatal formation of the normal mouse callosum: a quantitative study with carbocyanine dyes. J Comp Neurol 323:81, 1992. 236. Barkovich AJ, Norman D: Anomalies of the corpus callosum: correlation with further anomalies of the brain. AJR Am J Roentgenol 151: 171, 1988. 237. Andermann E: Agenesis of the corpus callosum. In: Handbook of Clinical Neurology, vol 42, section I: Malformations. PJ Vinken, GW Bruyn, eds. Elsevier, North Holland Biomedical, Amsterdam, 1981, p 6. 238. Dobyns WB: Agenesis of the corpus callosum and gyral malformations are frequent manifestations of non-ketotic hyperglycinemia. Neurology 39:817, 1989. 239. Needham LK, Thelen K, Maness PF: Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions. J Neurosci 21:1490, 2001. 240. Howard H, Mount DB, Rochfort D, et al.: The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 32:384, 2002. 241. Mathieu J, Bedard F, Prevost C, et al.: Motor and sensory neuropathies with or without agenesis of the corpus callosum: a radiological study of 64 cases. Can J Neurol Sci 17:103, 1990. 242. Ettlinger G, Blakemore CB, Milner AD, et al.: Agenesis of the corpus callosum: a further behavioural investigation. Brain 97:225, 1974. 243. Jeeves MA, Temple CM: A further study of language function in callosal agenesis. Brain Lang 32:325, 1987. 244. Schalomon PM, Wahlsten D: Wheel running behavior is impaired by both surgical section and genetic absence of the mouse corpus callosum. Brain Res Bull 57:27, 2002. 245. de Guise E, del Pecse M, Foschi N, et al.: Callosal and cortical contribution to procedural learning. Brain 122:1049, 1999.

604

Neuromuscular Systems

246. Jeeves M, Ludwig T, Moes P, et al.: The stability of compromised interhemispheric processing in callosal dysgenesis and partial commissurotomy. Cortex 37:643, 2001. 247. Lessard N, Lepore F, Villemagne J, et al.: Sound localization in callosal agenesis and early callostomy subjects: brain reorganization and/or compensatory strategies. Brain 125:1039, 2002. 248. Roser M, Corballis MC: Interhemispheric neural summation in the split brain with symmetrical and asymmetrical displays. Neuropsychologia 40:1300, 2002. 249. Roser M, Corballis MC: Interhemispheric neural summation in the split brain: effects of stimulus colour and task. Neuropsychologia 41: 830, 2003. 250. Forster B, Corballis MC: Interhemispheric transfer of colour and shape information in the presence and absence of the corpus callosum. Neuropsychologia 38:32, 2000. 251. Brown WS, Jeeves MA, Dietrich R, et al.: Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and callosal agenesis. Neuropsychologia 37:1165, 1999. 252. Taylor M, David AS: Agenesis of the corpus callosum: a United Kingdom series of 56 cases. J Neurol Neurosurg Psychiatry 64:131, 1998. 253. Gupta JK, Lilford RJ: Assessment and management of fetal agenesis of the corpus callosum. Prenat Diagn 15:301, 1995. 254. Moutard M-L, Kieffer V, Feingold J, et al.: Agenesis of corpus callosum: prenatal diagnosis and prognosis. Childs Nerv Syst 19:471, 2003. 255. Lu WH, Chen CC, Chiu PC, et al.: Isolated complete agenesis of the corpus callosum. Acta Peadiatr Taiwan 44:5, 2003. 256. Bahadoran, Ballotti R, Ortonne J-P: Hypomelanosis, immunity, central nervous system: No more ‘‘and,’’ not the end. Am J Med Genet 116A:334, 2003. 257. Hunter AGW: Coffin-Lowry syndrome: a 20 year follow-up and review of long term outcomes. Am J Med Genet 111:345, 2002. 258. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003.

15.7 Cavum, Cysts, and Absence of the Septum Pellucidum and Cavum Vergae Definition

A cavum is a fluid-filled cavity between the apposed sides of the septum pellucidum and/or vergae. The cavum vergae is more caudally placed and usually is connected to the cavum septum pellucidum. The cava are not connected to the ventricular system and should not be referred to as fifth or sixth ventricles. Cysts are defined usually as symptomatic enlargements of the cavum, but because it is sometimes difficult to show a causal relationship between the cyst and the symptoms, some have suggested a definition based on size and a convex contour of the cyst walls.1 Diagnosis

Most often a cavum is an incidental diagnosis at autopsy or on neuroimaging studies, and the prevalence is inversely related to the age of the patient. It has been reported in 100% of normal infants of less than 36 weeks gestation, and in a third of normal term infants.2 Estimates of prevalence in adults have varied widely from < 1–85%, although rates of up to 5% are probably realistic for the general population.3–6 Distinction between cavum septi pellucidi, cavum vergae, and cavum interpositum, which stems from a separation of the crura of the fornix, is generally clear on CT (Fig. 15-43). In case of doubt, MRI is useful (Fig. 15-44).7 Suggestions have been made for an association between a wide variety of clinical conditions and an increased prevalence of cava septi pellucidi and/or vergae. Examples include boxing,8 schizophrenia,9 developmental delay,7,10,11 dyslexia,12 and non-

Fig. 15-43. Axial CT scan showing midline cavum (arrows) between the lateral ventricles.

syndromic cleft lip with or without cleft palate.13 Children with cava septi pellucidi have been reported to show asymmetry and immaturity on EEGs and the differences are detectable by formal analysis.14 There appears to be some level of acceptance that continued postnatal appearance of a cavum may be a marker for some underlying disturbance of brain development and function. Given the wide and age-dependent variation in the estimated prevalence of cava, any such association studies require properly selected control subjects and should be considered in light of rates obtained in larger population series. In a MRI study of 505 non-psychotic individuals, Alder et al.6 found that anomalies of the septum pellucidum were about three times more common in the 0–9 years age group than across other decades, which did not show a trend in prevalence. Overall they obtained a 4.16% rate of cavum septum pellucidum with or without vergae, and there was no significant difference in prevalence between the sexes. Degreef et al.9 found a cavum septum pellucidum (large in two cases) in 14 of 62 (23%) patients with schizophrenia and in 1 of 46 (2%) of controls, whereas Gewertz et al.15 found a cavum in only 1 of 168 psychotic patients who had a cranial CT. In a study of children with developmental delay, Bodensteiner et al.10 found a cavum septum pellucidum in 3 of 124 (2.4%) of normal controls and 38 of 249 (15.3%) of subjects with developmental delay. A cavum vergae was noted in 20.5% and 19.3% of the respective groups. In their study of adult males with facial clefting, Nopoulous et al.13 noted an inverse relationship between the presence and size of the cavum septum pellucidum and IQ. Kim and Peterson16 noted that the cavum septum pellucidum was significantly smaller in children and adults with Tourette syndrome

Brain

Fig. 15-44. Axial MRI showing midline cavum septi pellucidi (arrows).

than among their control population, and that the prevalence of cavum vergae did not differ between the groups. It is this author’s opinion that additional studies with carefully selected subjects and age-matched normal controls, which include detailed, observer blinded, MRI assessment of adjacent areas of the brain, are required to assess the predictive value of the cavum septum pellucidum with respect to neuropsychiatric morbidity. There is consensus that in any such association the cavum is a marker of disturbed function in the adjacent areas of the brain, such as the limbic system, and that it is not a direct cause of the pathology. Cava are normally present during gestation and can provide important landmarks in the ultrasound assessment of the midline. Interpretation of what is considered to be enlargement of a cava is complicated by consideration of other potential causes of midline cysts, as well as issues surrounding normal variation and the uncertain clinical importance of an enlarged cavum. A careful search for associated CNS and extra-CNS anomalies is important. Sahinoglu et al.17 reported three cases of prenatal diagnosis of a dilated cavum vergae. One fetus had an associated meningomyelocele and ventriculomegaly, one required surgery for intracranial hypertension due to continued expansion of the cavum, and one remained asymptomatic. Cava have been noted in a number of reports of chromosome abnormalities and in a large number of syndromes (Table 15-9). The minimal clinical significance of cava has undoubtedly led to their being overlooked and underreported. The prevalence might be greater in syndromes involving midline defects of the CNS. However, for most syndromes there are inadequate data to determine whether a cavum occurs more often than would be expected in the general population.

605

Most authors consider that a cyst of the septum pellucidum (SPC) or cavum vergae is defined as a symptomatic enlargement of a cavum. This definition works well when severity of the symptoms parallels enlargement of the cyst or when symptoms are reduced/ cured by surgical intervention. However, in some instances, such as intermittent headache, the connection between an expanded cavum and the symptoms is less clear, and this has led some to seek different diagnostic criteria. Sener1 used a definition of the septal walls being
10 mm apart and showing a convex (laterally bowed) profile, but concluded that further studies were required to define diagnostic and interventional criteria for cysts of the septum pellucidum. Signs and symptoms that have been attributed to SPC are both chronic and acute and include changes in behavior, hydrocephalus, autonomic and sensorimotor (which may be asymmetric) dysfunction, intermittent or acute headache, papilledema and other neurophthalmologic signs, emesis, and syncope. Onset can be at any age. Lancon et al.55 were able to find 18 patients with SPC that met their strict diagnostic criteria of symptomatic expansion of an existing cavum in concert with neurologic symptoms, which were demonstrated to be relieved by intervention. The age at presentation ranged from 2 months to 61 years with a mean of 46.3 years and 56% presenting over the age of 34 years. Signs at presentation included headache (61%), behavioral and autonomic (67%; 5 of 6 children), sensorimotor/reflexes (56%), neurophthalmologic (50%), syncope (33%), emesis (33%), and papilledema (33%). These symptoms are non-specific and require that other possible intracranial pathology be excluded by detailed neuroimaging. Lancon et al.55 stress the importance of examining the optic chiasm for evidence of compression, and that MR venography should be considered in the presence of sensorimotor, behavioral or autonomic symptoms, or if anomalies in the size or signal characteristics of the basal ganglia and diencephalon are noted. Not all agree with the latter recommendation.56 A number of mechanisms have been proposed to account for the varied neurologic signs and symptoms associated with SPC55: 1) expansion of the cyst, obstructing the interventricular foramina causing hydrocephalus, and possibly compressing the origins of the internal cerebral veins; 2) distortion of adjacent vascular/venous systems of the deep cerebral veins, the internal capsule, and/or the lateral hypothalamus; 3) compression of cerebral nuclei in and around the hypothalamoseptal triangle; and 4) direct compression of the visual pathways. Intermittent signs are assumed to be due to periodic relief of interventricular foraminal obstruction. A case of cavum septum pellucidi obstructing a ventricular shunt has been reported.57 Absence of the septum pellucidum (ASP) is part of the septooptic dysplasia complex (Table 15-9) and usually is accompanied by other, more severe, CNS malformations, notably those involving the midline and/or ventricular system such as absent corpus callosum, holoprosencephaly, schizencephaly and Chiari II malformations.58 Apparently, longstanding hydrocephalus may lead to loss of the septum pellucidum.59 Newer imaging techniques have led to recognition that ASP can occur in otherwise neuroradiologically and clinically normal individuals60 and to its recognition in a number of syndromes (Table 15-9). The MRI hallmark of ASP is a squared-off and pointing appearance of the interior portions of the frontal horns at the level of the foramina of Monro.60 Etiology and Distribution

The development of the septum pellucidum is closely related to that of the corpus callosum and fornix, which it bridges together. The septum pellucidum is formed by the infolding halves of the neural

Table 15-9. Syndromes with cyst or cavum septum pellucidum or absent septum pellucidum as a feature Syndrome

Prominent Features

Causation Gene/Locus

Apert18

Severe craniofacial synostosis, marked syndactyly; developmental delay is common; CNS includes absent corpus callosum, limbic system, microgyria, polymicrogyria, heterotopia, ventriculomegaly, and high rate of abnormal septum pellucidum that may correlate with IQ

AD (101200) FGFR2, 10q25.3-q26

BRESHECK19

Microhydrocephaly with fused thalami, poor growth and mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR/XLR

Fetal phencyclidine20

Rhombencephalosynapsis, hypoplastic commissural systems, septo-optic dysplasia with absent septum pellucidum, absent posterior lobe of the hypothalamus, moderate hydrocephalus, abnormal pulmonary venous return, spinal segmentation defect. Mother took phencyclidine in first 6 weeks of pregnancy

In utero exposure?

Holzgreve-Wagner-Rehder21

Type II persistent bucopharangeal membrane, postaxial polydactyly, cleft palate, complex cardiac anomalies, renal agenesis, IUGR, absent septum pellucidum

Unknown (236110)

Marinesco-Sjogren22

Mental retardation, congenital cataracts, cerebellar ataxia, muscle wasting with neurogenic atrophy and vacuolar degeneration, distal weakness, ataxia, cerebellar atrophy mostly of vermis, skeletal anomalies including scoliosis, posterior vertebral scalloping, enlargement of intervertebral foramina, short metatarsals and metacarpals. Case report with arachnoid cyst and absent septum pellucidum

AR (248800), some SARA2, 5q31

Neish-Roberts: hypoplastic left heart23

Wide forehead, abnormal pinnae, bifid nasal tip, micrognathia, thin upper lip, hypoplastic left heart, camptodactyly of fingers and toes, non-obstructive hydronephrosis; absent septum pellucidum in one sib

AR

Oculo-encephalo-hepato-renal24

Epicanthus, nystagmus, ptosis, micrognathia, abnormal external genitalia, syndactyly, postaxial polydactyly, cystic renal dysplasia, cerebellar defects, mental retardation, postnatal growth failure, periodic breathing. Case reported with cerebral dysplasia and absent septum pellucidum.

Unknown

Porencephaly-cerebellar hypoplasia-heart defect25

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Porencephaly/schizencephalyseptum pellucidum26

Absent septum pellucidum, porencephaly/schizencephaly, mental retardation, neurologic dysfunction including paraplegia

Unknown-case in utero benzol exposure

Septoopticdysplasia27

Septum pellucidum agenesis, optic nerve hypoplasia, hypothalamic/pituitary dysfunction; variable growth hormone deficiency, diabetes insipidus, trophic hormone deficiencies; seizures and developmental delay common; brain anomalies include agenesis of the corpus callosum, hydrocephalus, cerebral atrophy, porencephaly, schizencephaly. The association may be a component of other syndromes28 or seen occasionally in well-established syndromes.29,30

Heterogeneity (182230) some due to HESX1, 3p21.2-p21.1

Third ventricular obstruction31

Hydrocephalus with dilated lateral ventricles and narrowing of posterior 3rd ventricle, polygyria, choroid plexus atrophy, thin corpus callosum, absent septum pellucidum

Unknown

Velo-cardio-facial32

Long narrow face, retrognathia, prominent nose with hypoplastic lip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay; congenital heart; especially conotruncal defects. High prevalence of septal pellucidum anomalies.

AD (192430) del 22q11, del 10p

Walker-Warburg (HARDþ/E)33

Diffuse agyria, cobblestone appearance may be obscured by hydrocephalus, abnormal white matter, laminar heterotopia below cortex, absent septum pellucidum, severe midline to lateral cerebellar hypoplasia, brain stem hypoplasia, Dandy-Walker malformation, cephalocele, retinal dysplasia/non-attachment; microphthalmia, cataract, corneal opacity, hyaloid vessels, retinal corneal opacity, abnormal face; myopathic skeletal muscle with variable size and splitting of fibres with endomysial fibrosis

AR (236670) POMT1, 9q34.1

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomata, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 9q22.3 PTCH2, 1p32

Syndromes with Absent Septum Pellucidum

Syndromes with Cyst or Cavum Septum Pellucidum

Basal cell nevus34

(continued)

606

Table 15-9. Syndromes with cyst or cavum septum pellucidum or absent septum pellucidum as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Bertini: myoclonic epilepsymacular degeneration35

Hypotonia, congenital ataxia, mental retardation, progressive encephalopathy, recurrent infections, hypoplasia of corpus callosum and cerebellar vermis, septum pellucidum cyst

XLR, Xp22-Xpter

Cataracts-contractures-cortical dysplasia36

Postnatal growth and developmental failure, prominent supraorbital ridge, cataracts, large joint contractures, osteoporosis, cavum septum pellucidum, right temporal arachnoid cyst, cerebellar atrophy, multiple foci of cortical dysplasia in frontal and parietal lobes

AR

Cerebro-facio-thoracicdysplasia37

Mental retardation, macro/brachycephaly, absent corpus callosum, enlarged septum pellucidum, hypertelorism synophrys, bifid and synostosed ribs, narrow chest, elevated scapulas, hemivertebrae, short neck

AR (213980)

Chromosome anomalies38,39

Duplication (1)(q25-qter), (3)(q21-qter), (5)(11.2-q13.3); deletions (3)(pter-p15), (9)(pter-p21), (13)(q22-qter); mosaic trisomy 9, r(22)

Chromosome imbalance

Fetal alcohol40

Microcephaly, narrow palpebrae, smooth philtrum, thin upper lip. CNS anomalies include agenesis of the corpus callosum, cavum septum pellucidum, ventriculomegaly, hypoplasia of inferior olivary eminences, small brain stem, migrational abnormalities; holoprosencephaly an occasional finding with severe abuse.

In utero exposure

Fetal face41

Prominent forehead, wide mouth, small nose, hypertelorism, micropenis, variable mesomelic shortness, vertebral defects, oral clefts. Case with pellucidal cyst.

AD (180700) AR (268310) ROR2, 9q22

G42

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males

AD (145410) 22Q11.2 XLR (300000) MID1, Xp22.3

Growth failureencephalopathy-endocrine43

Postnatal onset microcephaly and growth failure, high bossed forehead, flat occiput, upslanting palpebral fissures, high palate, small pointed chin, cortical atrophy. One sib with septum pellucidum cyst, stereotypic movements

AR

Hall-Riggs: coarse face-skeletal dysplasia44

Progressive meta-epiphyseal disorder with severe retardation, flat nasal bridge, large lips, brachydactyly, short arms (microcephaly may be of postnatal onset)

AR (234250)

Macrocephaly-cavum septum pellucidum45

Macrobrachycephaly, developmental delay, cavum septum pellucidum, and cavum vergae

Uncertain

Microphthalmia-linear skin defects46

May have other CNS anomalies including septum pellucidum cyst, absent corpus callosum, colpocephaly, and hydrocephaly; microphthalmia, sclerocornea, linear dermal aplasia usually of the head and neck

XLD, male lethal (209801) del Xp22.3

Morning glory47

Indented and funnel-shaped optic disc with surrounding retinal pigment abnormality. Cases with enlarged optic disc and cavum vergae.

Unknown

Muller: cerebral malformation-hypertrichosis48

Hypertelorism, telecanthus, microphthalmos, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Nasopharyngeal teratoma49

Massive macrocephaly, broad and triangular flat face, hypertelorism, nasopharyngeal hairy polyp through cleft palate, diaphragmatic hernia, DandyWalker cyst, cavum septum pellucidum and vergae

Unknown

Neurofibromatosis 150

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudarthrosis, and diverse complications of tumors; two of five cases with large deletions had cavae

AD (162200) NF1, 17q11.2

Pseudo-TORCH51

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; similar to, and may be allelic with, Aicardi-Goutieres and Cree encephalitis; reported with pellucidal cysts

AR (251290)

Thrombocytopenia-absent radius52

Congenital thrombocytopenia, absent radius with preservation of thumbs, variable additional anomalies. Case with cerebellar hypoplasia, callosal hypoplasia, cavum septum pellucidum

AR (274000)

Sotos: cerebral gigantism53

Early overgrowth with large hands and feet, prominent and high forehead, downslanting palpebrae, long and prominent chin, high palate, somatomedian initially high and falls during first year, variable developmental delay

AD (117550) NSD1, 5q35

Weaver54

High broad forehead, broad nasal root, telecanthus, micrognathia, large ears, accelerated growth and bone age, hypotonia, camptodactyly, prominent finger pads

AR/AD (277590) Heterogeneity Some with NSD1, 5q35, mutations

607

608

Neuromuscular Systems

tube and is present by the third month of gestation.61 The cavum is apparent once the corpus callosum bridges the midline, and the septum pellucidum is usually, but not always, absent in agenesis of the corpus callosum. The cavum normally begins to close in a caudal to rostral sequence by 6 months gestation. A number of theories have been proposed for the origins of the cava. These include a stretching of the rapidly growing lamina terminalis, failure of fusion of the apposing halves of the neural tube, or a secondary cavitation at a site of hemispheric fusion due to cell death as fibers of the corpus callosum bridge the midline.61 Whatever the etiology, most cava probably are simple variations of normal development. Indeed Liss and Mervis62 demonstrated histologically three variations in development of the septum pellucidum: 1) a single midline membrane (50%); 2) two separate apposed membranes (25%); and 3) the two membranes separated by a space (25%). In some cases septal fenestrations were present. There is good evidence that at least some cava are acquired following head trauma. A cavum septum pellucidum has been noted in 18% of boxers.58 Borgdanoff and Natter63 found a cavum septum pellucidum in 5 of 80 (6.25%) of pediatric and 14 of 1914 (0.73%) of adult cranial CT examinations. Nine of the 14 adults were male, and of these, five had been boxers and one had suffered two significant episodes of head trauma as an adolescent. Nishimoto et al.64 observed the gradual post-traumatic development of a cavum septum pellucidum and vergae over a 33-month period in a 29-year-old woman and provided evidence for unidirectional flow of CSF from the 3rd ventricle to the posterior cavum vergae. A case involving a 26-month-old boy who developed progressive hydrocephalus and a cavum septum pellucidum and vergae secondary to venous sinus occlusion is interesting, as there was resolution of the complications with relief of the occlusion. The authors posit that venous hypertension, secondary to the occlusion, disrupted normal resorption of fluid by a pressure gradient involving septal capillaries and veins.65 It has also been suggested that cava may persist as a result of perinatal brain insult, such as meningitis.3 It is not known whether there is a relationship between the underlying developmental anatomy, as described by Liss and Mervis,62 and the propensity to acquire a cavum. The reason why a cavum should expand and become symptomatic is not known. As discussed by Lancon et al.,55 formation of a congenital cyst requires production of fluid that lacks an egress from the cavity, and it seems most likely that it would arise when the septal membranes are unfused and separated. The cyst fluid closely resembles CSF; the caval lining is the same as that of the ventricles62 and has been shown to be capable of secreting fluid.66 Given that some membranes have fenestrations, it is likely that some potential cysts decompress naturally, while others will rupture under tension, through a weakness, or with trauma, and thus self correct. Although there is consensus that hydrocephalus occurs secondary to obstruction by the expanding SPC, the case described previously, and three children in whom hydrocephalus preceded development of the SPC and did not resolve with drainage of the cysts, suggest that this is not always the case.67 True colloid cysts are occasionally seen in the septum pellucidum, but their neuroepithelial lining suggests an origin from cell nests of the invaginating diencephalic roof.68 A symptomatic endodermal cyst of the septum pellucidum has also been successfully treated.69 A set of monozygotic twins concordant for cysts has been reported.70 Absence of the septum pellucidum is estimated to occur with a frequency of 2 to 3 per 100,000,58 but this may well be an underestimate as most cases to date have been ascertained because of their association with other more significant CNS malformations. The etiology and pathogenesis of isolated ASP are unknown.

Prognosis, Treatment, and Prevention

The common cava is by definition asymptomatic, and, although a variety of neurologic complaints have been attributed to their presence, they do not respond to drainage of the cavum. The cavum likely represents a chance finding in the patient who is investigated for an unrelated problem, although it may prove to be a marker for some forms of developmental pathology or acquired trauma. True symptomatic cystic enlargement of a cava, which can result in hydrocephalus, increased intracranial pressure, and a wide spectrum of neurologic symptoms, is uncommon and will usually respond well to procedures that lead to drainage of the cyst. Treatment approaches have included cystoperitoneal, ventriculoperitoneal, cysto-ventriculo-subarachnoid, and cystoventricular shunting, and simple fenestration of the cysts. Externalized shunts run a higher risk of complications such as infection, are not always successful, and could result in an unnecessary continued peritoneal drainage of CSF in a patient without a primary hydrocephalus.56 The current consensus is to use a stereotactic, endoscopic approach to introduce a communication between the cyst and the ventricular system. This may be accomplished with insertion of a cyst-to-lateral-ventricle drain56,71 or by fenestration of the cyst.72,73 Extirpation of a cyst is rarely necessary. The prognosis for selectively and appropriately treated SPC is very good, and some cysts may be ‘‘cured’’ by spontaneous rupture.55,74 Of the 18 patients reviewed by Lancon et al.,55 four resolved spontaneously or at pneumoencephalogram, 10 were treated by craniotomy and fenestration of the cyst to the lateral ventricle, two by percutaneous fenestration, and two by cystoperitoneal shunt. Three recurrences in the craniotomy group were successfully treated by other approaches. At follow-up, 15 patients were asymptomatic, two were improved, and one had stabilized. The ASP by itself is of no significance and is not treatable. However, when found, it is necessary to look carefully for signs of an associated syndrome, notably septo-optic dysplasia, and to rule out additional CNS anomalies. References (Cavum Septum Pellucidum and Vergae) 1. Sener RN: Cysts of the septum pellucidum. Comput Med Imaging Graph 19:357, 1995. 2. Mott SH, Bodensteiner JB, Allan WC: The cavum septi pellucidi in term and preterm newborn infants. J Child Neurol 7:35, 1992. 3. Shaw GM, Alford EC Jr: Cava septi pellucidi et vergae: their normal and pathological states. Brain 92:213, 1969. 4. Garza-Mercado R: Giant cysts of the septum pellucidum. J Neurosurg 55:646, 1981. 5. Aldur MM, Gurcan F, Basar R, et al.: Frequency of septum pellucidum anomalies in non-psychotic population: a magnetic imaging study. Surg Radiol Anat 21:119, 1999. 6. Borgdanoff B, Natter HM: Incidence of cavum septum pellucidum in adults: A sign of boxer’s encephalopathy. Neurology 39:991, 1989. 7. Miller ME, Kido D, Homer F: Cavum vergae: association with neurologic abnormality and diagnosis by magnetic resonance imaging. Arch Neurol 43:821, 1986. 8. Casson IR, Seigal O, Sham, et al.: Brain damage in modern boxers. JAMA 251:2663, 1984. 9. Galarza M, Merlo AB, Ingratta A, et al.: Cavum septum pellucidum and its increased prevalence in schizophrenia: a neuroembryological classification. J Neuropsychiatry Clin Neurosci 16:41, 2004. 10. Bodensteiner JB, Schaefer GB, Craft JM: Cavum septi pellucidi and cavum vergae in normal and developmentally delayed populations. J Child Neurol 13:120, 1998. 11. Soto-Ares G, Joyes B, Lemaitre MP, et al.: MRI in children with mental retardation. Pediatr Radiol 33:334, 2003.

Brain 12. Lampl Y, Barak Y, Gilad R, et al.: Familial dyslexia associated with cavum vergae. Clin Neurol Neurosurg 99:142, 1997. 13. Nopoulos P, Berg S, VanDemark D, et al.: Increased incidence of a midline brain anomaly in patients with nonsyndromic clefts of the lip and/or palate. J Neuroimaging 11:418, 2001. 14. Kacinski M, Kubik A, Augustyn G, et al.: Quantitative analysis of bioelectric activity of both brain hemispheres in children with a cavum septum pellucidum. Przegl Lek 60 (Suppl 1):15, 2003. 15. Gewirtz G, Squires-Wheeler E, Sharif Z, et al.: Results of computerized tomography during first admission for psychosis. Br J Psychiatry 164:789, 1994. 16. Kim KJ, Peterson BS: Cavum septi pellucidi in Tourette syndrome. Biol Psychiatry 54:76, 2003. 17. Sahinoglu Z, Uludogan M, Delikara MN: Prenatal sonographic diagnosis of dilated cavum vergae. J Clin Ultrasound 330:378, 2002. 18. Renier D, Arnaud E, Cinalli G, et al.: Prognostic mental du syndrome d’Apert. Arch Pediatr 3:752, 1996. 19. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate and kidney dysplasia/hypoplasia (BRESEK/BRESHECK). Am J Med Genet 68:386, 1997. 20. Michaud J, Misrahi EM, Urich H: Agenesis of the vermis with fusion of the cerebellar hemispheres, septo-optic dysplasia and associated anomalies. Acta Neuropath 56:161, 1982. 21. Legius E, Moerman PH, Fryns JP, et al.: Holzgreve-Wagner-Rehder syndrome: Potter sequence associated with persistent buccopharyngeal membrane. A second observation. Am J Med Genet 31:269, 1988. 22. Williams TE, Buchhalter JR, Sussman MD: Cerebellar dysplasia and unilateral cataract in Marinesco-Sjogren syndrome. Pediatr Neurol 14:158, 1996. 23. Neish AS, Roberts DJ: Hypoplastic left heart, nephromegaly, and distinctive facies in two siblings. Am J Hum Genet 50:153A, 1992. 24. Ehara H, Tamaoki Y, Eda I: A case in the spectrum of the oculoencephalo-hepato-renal syndrome. Pediatr Neurol 21:757, 1999. 25. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 26. Hosley MA, Abroms IF, Ragland RL: Schizencephaly: case report of familial incidence. Pediatr Neurol 8:148, 1992. 27. Burke JP, O’Keefe M, Bowell R: Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol 75:236, 1991. 28. Hayashi M, Sakamoto K, Kurata K, et al.: Septo-optic dysplasia with cerebellar hypoplasia in Cornelia de Lange syndrome. Acta Neuropathol 92:625, 1996. 29. Pagon RA, Stephan MJ: Septo-optic dysplasia with digital anomalies. J Pediatr 105:966, 1984. 30. Gieron-Korthals MA, Helal A, Martinez CR: Expanding spectrum of cocaine induced central nervous system malformations (Case report). Brain Dev 16:253, 1994. 31. Chow CW, McKelvie PA, Anderson RM, et al.: Autosomal recessive hydrocephalus with third ventricle obstruction. Am J Med Genet 35: 310, 1990. 32. van Amelsvoort T, Daly E, Robertson D, et al.: Structural brain anomalies associated with deletion at chromosome 22q11: quantitative neuroimaging study of adults with velo-cardio-facial syndrome. Br J Psychiatry 178:412, 2001. 33. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al.: Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 71:1033, 2002. 34. Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine 66:98, 1987. 35. des Portes V, Marchiani V, Bertini E, et al.: X-linked neurodegenerative syndrome with congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration, linked to Xp22.33-pter. Am J Med Genet 64:69, 1996. 36. Shotelersuk V, Desudchit T, Suwanwela N: Postnatal growth failure, microcephaly, mental retardation, cataracts, large joint contractures,

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46.

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59. 60. 61. 62.

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63. Bogdanoff B, Natter HM: Incidence of cavum septum pellucidum in adults: a sign of boxer’s encephalopathy. Neurology 39:991, 1989. 64. Nishimoto H, Wada T, Kuroda K, et al.: A case of the development of cavum vergae after head trauma. No Shinkei Geka 31:297, 2003. 65. Sencer A, Sencer S, Turantan I, et al.: Cerebrospinal fluid dynamics of the cava septi pellucidi and vergae. Case report. J Neurosurg 94:127, 2001. 66. Lancon JA, Haines DE, Lewis AI, et al.: Endoscopic treatment of symptomatic septum pellucidum cysts: with some preliminary observations on the ultrastructure of the cyst wall: two technical case reports. Neurosurgery 45:1251, 1999. 67. Wester K, Krakenes J, Moen G: Expanding cava septi pellucidi and cava vergae in children: report of three cases. Neurosurgery 37:134, 1995. 68. Ciric I, Zivin I: Neuroepithelial cysts of the septum pellucidum. J Neurosurg 43:69, 1975. 69. Mishra GP, Sharma RR, Musa MM, et al.: Endodermal cyst of the septum pellucidum and pregnancy: a case report. Surg Neurol 53:583, 2000. 70. Craig WM, Miller RH, Holman CB: Cysts of the septum pellucidi. Interesting case reports. Proc Staff Meet Mayo Clinic 28:330, 1953. 71. Wester K, Pedersen PH, Larsen JL, et al.: Dynamic aspects of expanding cava septi pellucidi et vergae. Acta Neurochir (Wien) 104:147, 1990. 72. Jackowski A, Kulshresta M, Sgouros S: Laser-assisted flexible endoscopic fenestration of giant cyst of the septum pellucidum. Br J Neurosurg 9:527, 1995. 73. Donati P, Sardo L, Sanzo M: Giant cyst of the cavum septi pellucidi, cavum vergae and veli interpositi. Minim Invasive Neurosurg 46:177, 2003. 74. Kocer N, Kantarci F, Mihmalli I, et al.: Spontaneous regression of a cyst of the cavum septi pellucidi. Neuroradiology 42:360, 2000.

Table 15-10. Classification of hydrocephalus A. Hypersecretion 1. Choroid plexus papillomas—hydrocephalus of ventricles and basal cisterns B. Mechanical obstruction 1. At foramen of Monro a. Neoplasia b. Ventriculitis c. Ventricular hemorrhage d. Primary aplasia of foramen* 2. At the 3rd ventricle a. Stenosis* b. Neoplasia either by direct invasion or compression c. Obstruction by congenital cysts i. Choroid plexus{ ii. Neuroepithelial 3. At the aqueduct (the most common site of obstruction) a. ‘‘Congenital’’ stenosis/atresia, including membranous* b. ‘‘Acquired’’ stenosis/atresia (post necrosis, meningitis, hemorrhage) c. Direct occlusion by vascular malformation d. External compression i. Arteriovenous malformation—vein of Galen ii. Cysts in cisterna ambiens: arachnoid,{ glioependymal{

15.8 Hydrocephalus

4. At the cerebellar foramen a. Without caudal displacement of the cerebellum i. Neoplasia

Definition

ii. Dandy-Walker malformation{

Hydrocephalus is an increase in the volume of the intracranial cerebrospinal fluid (CSF)–containing space relative to that of the cerebral parenchyma and may result from both primary atrophy of cerebral parenchyma and fluid production that exceeds resorption and any compensatory mechanisms. The latter is the subject of this section and usually results in an increased pressure hydrocephalus, although normal, and even low-pressure hydrocephalus can occur. The former produces hydrocephalus ex vacuo, which may be complicated by a secondary pressure hydrocephalus, but is not covered in this section. A distinction should also be made from hydranencephaly (Section 15.10), in which only remnants of the cortex remain and the rest is replaced by fluidfilled sacs lined by leptomeninges, and from porencephaly (Section 15.11), in which the parenchyma contains one or more fluid-filled cavities that may result from either a primary abnormality of development or a secondary enclastic process. This section is concerned with congenital malformations that lead to hydrocephalus; several malformations that are often associated with hydrocephalus are covered in their own sections. However, Table 15-10 provides a general classification, as modified from Friede,l in order to provide an overall context. Those types considered in more detail in this section are noted.

iii. Retrocerebellar arachnoid cyst{

Diagnosis

In brains of lower animals and that of the early embryo, there is no connection between the CSF and meningeal spaces, and circulation is via the brain parenchyma. As the brain develops and thickens, this mechanism no longer suffices, and CSF circulation is dependent on the development and integrity of the cerebral foramina, subarachnoid space, and resorptive processes. In the

iv. Infratentorial subdural hematoma b. With caudal displacement of the cerebellum i. Acute cerebellar tonsillar herniation ii. Arnold-Chiari malformation(s){ 5. At the level of the subarachnoid space a. Non-canalization as a primary anomaly (speculative) b. Acquired fibrotic obstruction (most common cause) i. Organized fibropurulent exudate ii. Organized subarachnoid hemorrhage iii. Organized necrotic debris or protein exudates iv. Abnormal storage such as mucopolysaccharidoses c. Abnormalities of arachnoid granulations/villi i. Congenital absence of granulations* ii. Acute hemorrhagic block (speculative) C. Functionally impaired CSF resorption 1. Altered CSF colloid osmotic pressure (no firm evidence) 2. Increased venous pressure (perhaps on transient basis) 3. Large arteriovenous shunts (scattered case reports) D. Hydrocephalus associated with bony dysplasia* *Discussed in this section. {

Discussed in sections 15.13–15.14.

Brain

normal brain there is a marked excess of resorptive capacity over normal levels of CSF production,2 and an increased production of CSF is matched by a concomitant increased resorption.3 There is also some evidence of a fall in CSF production with increasing pressure, although production continues in the face of high pressures.1,4 The production of CSF is under stimulatory sympathetic and inhibitory cholinergic enervation, and several other CSF compounds and their receptors also play a controlling role.5 The traditional view that there is a continuous flow of CSF from the choroid plexus to the arachnoid (pachionian) granulations, and that hydrocephalus results from an excess of CSF production over resorption, has been recently challenged by a review of the extant literature,6 clinical experience,7 and newer neuroimaging and experimental approaches.7–9 Johnson and Papaiconomou7 suggest that the extracranial lymphatic system may play a far greater role in CSF absorption than was previously credited. Protein tracers injected into brain interstitial space or ventricles exit the cranium via perineural extensions of the subarachnoid space and appear in spinal lymph nodes and lymphatic vessels. The cribiform plate and nasal mucosa may be important components of this pathway.7 Greitz et al.9 have examined the possibility that CSF is reabsorbed into the venous system of the brain. Flow-sensitive MR methods have shown that what was interpreted as the bulk flow of CSF in standard radionuclide cisternography is due to pulsatile mixing of the tracer, combined with its dilution by the egress of new CSF at the foramina of Lushka and Magendie.8 Notwithstanding the relative impermeability of the blood–brain interface, there is evidence that there is no such brain–blood barrier,9 and indeed that there is an active transport involved at that interface.10 Cardiac systole causes cerebral arterial expansion, compression of cerebral veins, and an increased sinus flow, thus forcing CSF into the spinal cord. The latter is reversed during diastole, again tending to collapse the cerebral veins. It has been hypothesized that pressure on the venous outlets causes inflation of the veins, leading to less resistance and increased flow, and that compression of the pachionian granules into the veins may cause them to act as valves, again aiding venous circulation.9 Thus, these investigators propose a return to the original views of the early 1900s that hydrocephalus is an essentially vascular process, which Greitz et al.9 propose to group as primary and secondary hemodynamic disturbances. They call the former, which presents as communicating hydrocephalus, restricted arterial pulsation type, and it arises from any cause of reduced arterial pulsations, such as diminished arterial compliance, and decreased compliance of the arachnoid space (e.g., arachnoiditis, Chiari malformations). Intracranial pressure is normal to slightly increased with intermittent high pressure waves. Expansion of the ventricles is considered due to a rise in the normal ventricular to subarachnoid gradient, which is transmitted into the brain parenchyma. Secondary or venous congestion hydrocephalus is the typical obstructive, high-pressure hydrocephalus. In this case there is an excess of CSF production over resorption because of a block to outflow (e.g., aqueductal stenosis, tumor mass); the resulting mass effect of the expanding ventricles compresses the cortical veins, raising intracranial blood volume, and thus pressure. This hemodynamic concept of hydrocephalus provides a basis for understanding cases of hydrocephalus that occur with extracranial lesions, such as a tumor compressing the superior vena cava.11 Notwithstanding the varied causes and mechanisms of hydrocephalus, its diagnosis rests on recognition of the signs and symptoms of increased intracranial pressure, and/or decreased cerebral blood volume and flow, which vary with the age of the patient and the severity of involvement.

611

Increased use of routine and high-risk obstetric ultrasound has meant that increasing numbers of fetuses are being diagnosed as having ventriculomegaly; both bilateral and unilateral. The prenatal diagnosis of unilateral ventriculomegaly requires that both cerebral hemispheres be well visualized as both acoustic noise in the cortex proximal to the transducer and some reverberation artifacts in the distal hemisphere may lead to a false-positive diagnosis.12 Although the fetal cranial sutures are open, in the presence of hydrocephalus, significant ventricular enlargement and parenchymal compromise may occur before there is evidence of an abnormal increase in biparietal diameter. Thus, the diagnosis of fetal hydrocephalus rests on intracranial measurements, including comparison of the lateral ventricle to hemisphere ratio (LV/H) with nomograms,13 a search for separation of the choroid plexus from the ventricular wall (dangling choroid), and direct measurement of the ventricular diameters. A lateral ventricular atria diameter of >10 to 15 mm (from 15 to 35 weeks) and/or a choroid separation of >3 and  8 mm is an accepted definition of mild ventriculomegaly.14 It must be emphasized that mild to moderate in utero ventriculomegaly is often non-progressive and ultimately will not require treatment. Providing genetic counseling to couples whose fetus has been found to have mild ventriculomegaly is fraught with uncertainty (vide infra). Mention should be made of what some term as benign external hydrocephalus in which the postnatal presentation is with macrocephaly, a squared forehead, symmetrical enlargement of the frontal horns, and enlarged subarachnoid spaces over the anterior part of the cerebral hemispheres.15 It is interesting that the prenatal presentation of this condition is with mild and asymmetric posterior ventriculomegaly, a normal biparietal diameter, with either contralateral, ipsilateral, or bilateral posterior enlargement of the subarachnoid spaces.15 The condition is most often idiopathic but it may accompany skeletal dysplasia, intraventricular hemorrhage, and storage disorders. Most, but not all, cases of hydrocephalus that occur because of a congenital malformation will present by childhood, during which time the sutures and cranium remain elastic and subject to expansion. Thus, the most important signs of untreated hydrocephalus in the infant and child are those of macrocrania and, more importantly, an occipitofrontal circumference (OFC) that upwardly crosses centiles. Raised intracranial pressure in the adult occurs in an enclosed space with relatively little capacity to accommodate changes in pressure, and the classic presentation is that of headache, vomiting, and papilledema. More unusual presentations, including endocrine disturbance and secondary amenorrhea, may occur.16 The presentation of hydrocephalus in childhood is extremely varied. Almost one-half may be asymptomatic, but a large proportion will have some combination of irritability, headache, and vomiting.17 More subtle presentation with mild developmental delay, personality change, unsteady gait, seizures, or endocrine dysfunction may occur in the older child.18 The most important clinical signs include increasing head circumference, a tense fontanel, widened sutures that may be visible on routine skull radiographs, distended scalp veins and sparse hair, loss of upward gaze, and a retracted or rigid neck (Fig. 15-45).17 As the cranium expands it often assumes a characteristic shape, with prominent frontal and rounded parietal regions. Normally, when in the sitting position, an infant’s anterior fontanel is sunken and pulsates. With increasing pressure, it begins to bulge and lose its pulsation. Again, a more gradual presentation with a disinterested dull affect, increased deep tendon reflexes, especially in the lower limbs, and papilledema and other neurologic signs may occur.19

612

Neuromuscular Systems

Fig. 15-45. Facial view of a 5-month-old infant with a large head secondary to hydrocephaly. The infant had a number of other malformations as well, and chromosome analysis showed mosaicism for trisomy 9. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

A number of neuro-ophthalmologic signs, including abducens, trochlear, and occasionally oculomotor palsies, amblyopia due to long-standing papilledema, and optic atrophy, as well as loss of upward gaze, the ‘‘setting sun’’ sign, may be seen.20 The setting sun sign is characterized by downward displacement of the eyes with exposure of the sclera. Some have argued that this is due to the effect of increased intracranial pressure on the orbital roofs while others have argued that it is due to direct pressure on the quadrigeminal plate.4 Corbett20 reviewed the chronology of this dorsal midbrain syndrome, which is seen most characteristically with aqueduct stenosis and aneurysm of the vein of Galen. It begins with dissociation between the pupillary response during accommodation and its response to light, followed by lid retraction and paresis of upward gaze, the ‘‘setting sun’’ sign. He concurs with the view that aqueductal dilation leads to an increase in periaqueductal pressure, which in turn decreases local cerebral blood flow and causes fiber dysfunction. Thus, actual fiber stretching would not be required. It bears emphasizing that almost one-half of the children with clinical signs of hydrocephalus are asymptomatic and, more importantly, that up to 15% of children with symptoms will have no clinical signs of increased intracranial pressure. This has led Kirkpatrick et al.17 to advocate a high index of suspicion for hydrocephalus and to advocate early use of direct measurement of intracranial pressure. This view is supported by unusual case presentations, for example, a child whose only signs were the sudden onset of episodic torticollis and screaming, and who required long-term intracranial pressure monitoring to demonstrate the increased intracranial pressure.21 Routine skull radiographs may show relative macrocrania, splayed sutures, changes in the position of the torcular, thinning of the calvarium and supraorbital ridges, flattening of the cranial base, and, in long-standing cases, digital impressions (Fig. 15-46).

Fig. 15-46. Lateral radiograph of infant with hydrocephalus showing macrocranium, widened sutures, and large fontanel.

Neuroimaging techniques, including ultrasonography in the young infant, radionuclide flow studies, CT (Fig. 15-47), and MRI, will readily establish the diagnosis and generally detail the site of the abnormality. Specific neuroimaging findings will Fig. 15-47. Axial cranial CT scan showing enlarged lateral and third ventricles in a patient with aqueductal stenosis.

Brain

usually allow distinction between true hydrocephalus and hydrocephalus ex vacuo. In the former the temporal horns are dilated relative to the bodies of the lateral ventricles, and there is dilation of the anterior and posterior recesses of the 3rd ventricle and a short mamillopontine distance.22,23 Finally, there is a decreased ventricular angle and increased frontal horn radius, as opposed to an increased ventricular angle and decreased frontal horn radius seen in the latter.22 If the question remains unclear, a number of invasive studies may provide further information.22 The importance of distinguishing between severe (or ‘‘maximum’’) hydrocephalus and hydranencephaly is discussed in the section on hydranencephaly (Section 15.10). Venkataramana et al.24 reported that brain stem auditory evoked responses were abnormal in up to 95% of untreated children with hydrocephalus. Total absence of response was more common in communicating hydrocephalus. The formation of cerebral gyri allows an enlarging cortex to be contained within a confined space. Early hydrocephalus that expands the cranium provides a larger cavity to accommodate the growing brain and may be associated with numerous irregular convolutions (Fig. 15-48). This ‘‘polymicrogyria’’ does not show the microscopic pathology of true polymicrogyria, and indeed thinning of the cortex to as little as 2 cm can occur, at least initially, without significant loss of cortical parenchyma. Specific malformations, as listed in Table 15-10 as causing hydrocephalus, and which are not covered in other sections of the chapter, are now considered in more detail. 15.8.1 Aplasia of the Foramen of Monro

Friede1 questioned whether true aplasia occurs, but several putative cases have been reported. Involvement is of the lateral

613

ventricles and, when only one foramen is involved, will present the uncommon picture of unilateral hydrocephalus and herniation across the midline. Several cases have been diagnosed in utero, and all have presented early.25–27 Obstruction at this level may be characteristic of the Chudley-McCullough syndrome (Table 15-11). 15.8.2 Stenosis of the Third Ventricle

In this uncommon condition, obstruction at the level of the third ventricle leads to dilation of the lateral ventricles, while the third ventricle remains narrow. Obstruction at this level can occur on a genetic basis and may represent a spectrum of stenosis involving the third ventricle and/or aqueduct and/or fourth ventricle.28 15.8.3 Congenital Aqueduct Stenosis/Atresia

This is the most common lesion causing congenital hydrocephalus and may occur alone or as a component of a number of syndromes (Table 15-11). There continues to be significant confusion concerning the descriptive pathologic anatomy, uncertainty as to the underlying pathogenic mechanisms, and even questions as to whether aqueductal stenosis is a primary cause of, or rather is secondary to, hydrocephalus.29 Thus, although the concept of distinguishing stenosis due to malformation from that secondary to acquired obstruction may be helpful intellectually, in most cases the differentiation cannot be made. The aqueduct is the narrowest portion of the CSF spaces, and the adult shape, which is not significantly different from that of the newborn, results from gradual narrowing due to growth of the surrounding tissue. The embryology is summarized in several sources.1,4 The normal aqueduct is characterized by marked

Fig. 15-48. Left: Medial view of the right cerebral hemisphere with dilation of the lateral ventricle (LV) due to aqueductal stenosis. M, midbrain; A, anterior. Right: Coronal section from the cerebral hemispheres from a 5-month-old infant with severe dilation of the cerebral ventricles (V) and marked atrophy of the cerebral cortex. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

Table 15-11. Syndromes with hydrocephalus as a feature Syndrome

Prominent Features

Causation Gene/Locus

Variable expression, Dandy-Walker, cerebellar hypoplasia, cleft palate, congenital heart defect, rigidly extended fingers lacking flexion creases

AD (147800)

Achondroplasia47

Rhizomelic short stature, low nasal bridge, prominent forehead, trident hand, short cranial base, small foramen magnum, narrowed lumbar interpeduncular distance, short tubular bones; megalencephaly may relate to mild undetected hydrocephalus

AD (100800) FGFR3, 4p16.3

Acrania48

Absent calvarial bones; brain anomalies include absent pituitary, hydrocephalus, holoprosencephaly, cerebellar hypoplasia; often misinterpreted prenatally as encephalocele; cleft lip/palate, congenital heart defects, omphalocele, and NTD often concurrent

Unkown

Acrofacial dysostosisintermediate severity49

Malar, maxillary, and mandibular hypoplasia; downslanting palpebrae, absent eyelashes; lateral and typical facial clefts; macrostomia; abnormal ears; mesomelic dysostosis; congenital heart; hydrocephaly, polymicrogyria

Unknown

Acrofacial dysostosis-type Rodriguez50

Severe acrofacial dysostosis, congenital heart defects, absent lung lobation, small kidneys; variable limb anomalies include short limbs, absent fibulae, oligodactyly; hypoplastic scapulae; hydrocephalus, agenesis of the corpus callosum

AR (201170)

Acromesomelic frontonasal dsplasia51

Epibulbar dermoid, cleft nose, notched alae, midline cleft lip/palate, renal anomalies, pre- and post-axial polydactyly, delayed development; CNS includes absent corpus callosum, Dandy-Walker, hydrocephalus, encephalocele

Unknown

Albinism-eye defectshydrocephalus52

Developmental delay, trigonocephaly, oculocutaneous albinism, megalocornea, retinal coloboma, congenital hydrocephalus

Unknown

al-Gazali: anterior segmentskeletal anomalies53

IUGR, large and clouded cornea, downslanting palpebrae, cleft lip, small mouth, contractures at large joints, talipes equinovarus, congenital heart defect, osteopenia, long ulnas and fibulas, bowed radius; 1 of 4 had hydrocephalus

AR

al-Gazali: webbed neck-face dysmorphia54

Growth and developmental delay, short webbed neck, low-set ears, downslanting palpebrae, arched eyebrows, hypoplastic supraorbital ridges, large nose, pectus carinatum/excavatum, cardiac septal defects, 5th finger clinodactyly; 1 of 4 had hydrocephaly

AR

Amelo-cerebrohypohydrotic55

Can show normal early development, variable regression, and seizures; can have ataxia, amelogenesis imperfecta, broad thumbs, and great toes; CNS includes hypoplasia of cerebellar vermis and dilation of the lateral ventricles

AR (226750)

Aminopterin-like56

Cranial ossification defect, upswept frontal hair, hypertelorism, prominent nasal root, low and rotated ears, digital defects, variable delay (obstruction at 3rd ventricle)

Possible AR

Aminopterin, prenatal57

Parietal/frontal bone defects, brachycephaly, widow’s peak, upswept hair, narrow palpebrae, prominent long nose, short stature, anomalies of palate, ears, distal limbs, digits

Prenatal drug exposure

Amniocentesis trauma58

Few reports have appeared of fetal damage following 2nd-trimester amniocentesis. This case of hydrocephalus and subarachnoid cyst followed non-ultrasound guided testing.

Physical trauma

Amniotic bands59

Disruptions may involve craniofacies, trunk, or limb, and clefts often do not follow the normal plains of embryologic fusion. Cases have been described with internal anomalies, including of the brain with aqueduct dysgenesis

Disruption (217100)

Aniridia-renal anomalies60

Partial aniridia, glaucoma, hypertelorism, hypotonia, mental retardation, frontal bossing, short stature, renal anomalies. Similar to that described by de Hauwere et al.113

AR (206750)

Anophthalmia-cleft lip/ palate61

Cutis aplasia, macrocephaly, hypopituitarism, hydrocephalus with ‘‘grape-cluster’’ ventricular system

Anophthalmia-nasal proboscis62

Macrocephaly, hydrocephalus, craniosynostosis, anophthalmia, and proboscis-like nose; 1 of 2 unrelated girls had frontal encephalocele

Unknown (605627)

Anterior chamberhydrocephalus-heart defect63

Peters anomaly, persistent hyaloid artery, unilateral absent lens, obstructed aqueduct of Sylvius, enlargement of the lateral and 4th ventricles, cerebellar, pontine, and medullary atrophy, porencephaly, tricuspid valve dilation, atrial septal defect, lethal

Unknown

Antley-Bixler296

Brachycephaly, craniosynostosis, large fontanelle, midface hypoplasia, proptosis, choanal atresia/stenosis, radioulnar stenosis, femoral bowing, less frequent internal anomalies, hydrocephaly in 17%, case with AC-I

AR (207410) POR, 7q11.2

Aase-Smith

46

(continued)

614

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Apple peel atresia-ocular anomalies-microcephaly64

Marked microcephaly, developmental delay, variable eye anomalies include anterior chamber and microphthalmia, apple peel jejunal atresia; postnatal growth failure and hydrocephalus

AR (243605)

Aqueductal stenosisautosomal dominant65

Mild hydrocephalus in mother and two sons; no mutation in L1CAM

AD

Aqueductal stenosisautosomal recessive66

Inherited aqueductal stenosis is usually X-linked recessive but is sometimes inherited as an autosomal recessive trait.

AR (236600) 6q25-6qter

Aqueduct stenosis-basilar impression67

Clinically different from typical XLR aqueductal stenosis in that onset was in adulthood and associated with basilar impression.

XLR? (307000?)

Atelosteogenesis type III68

Broad forehead, hypertelorism, flat nasal bridge, cleft palate, bowed and rhizomelic limbs, absent or hypoplastic fibulae, multiple joint dislocations, platyspondyly, scoliosis, coronal and sagittal vertebral clefts and segmentation defects, short humeri with distal tapering; abnormal size, ossification and morphology of phalanges; 50% neonatal mortality due to respiratory and feeding problems, and hydrocephalus

AD (108721) FLNB, 3p14.3

Axenfield-Riegerleptomeningeal calcification69

Mild mental retardation, short stature, Axenfeld-Rieger eye anomaly, leptomeningeal calcification, non-obstructive hydrocephalus; one sib each with epilepsy, sensorineural deafness, significant recurrent bilateral iridocyclitis

AR

Axial mesodermal dysplasia70

A spectrum of distal vertebral, lower limb, urogenital, and usually anal stenosis/ atresia; case patient also had epibulbar dermoid, pre-auricular tags, heart defect, webbed neck, and hydrocephalus

Unknown

Barnicoat: ‘‘overgrowth’’polysyndactyly71

Birth weight and OFC >97%, coarse appearance, flat nasal bridge, short neck, large shoulder cavernous hemangioma, slender long bones, four limb bilateral postaxial polydactyly, 3-4 zygodactyly of hands

Unknown

Basal cell nevus72

Prominent supraorbital ridges, heavy eyebrows, broad nasal root, hypertelorism, long mandible, pouting lower lip, basal cell carcinomata, jaw cysts, rib anomalies, palmoplantar pits, calcified falx

AD (109400) PTCH, 9q22.3 PTCH2, 1p32

Beemer: dense bones73

Dense bones, ambiguous genitalia, bulbous nose with broad root and bridge, cardiac lesions, minor face dysmorphia, communicating hydrocephalus

AR (209970)

Bellini: epimetaphyseal dysplasia-mental retardation74

Moderate mental retardation, disproportionate short stature, knee contractures with wedge-shaped epiphyses, primarily lower limb metaphyseal dysplasia, platyspondyly; one brother with sparse hair, hydrocephalus

AR/XLR

Bijlsma: aqueductal stenosis75

Cleft palate, hypoplastic mandible, long fingers, club feet, finger contractures, myopia, narrow palpebrae. Father with camptodactyly, mother with cleft lip

Unknown

Bone fragility-proptosis76

Postnatal compression fractures, demineralization and diaphyseal fractures, orbital synostosis, frontal bossing, growth failure, enamel hypoplasia

Unknown

BRESHECK77

Microhydrocephaly with fused thalami, growth and mental retardation, alopecia, scaling skin, Hirschsprung, cleft palate, renal anomalies, microphthalmia

AR/XLR

Brooks: XLMR-distinctive face78

Triangular face, bifrontal narrowing, cupped and low-set ears, malar flattening, deep-set eyes, short palpebrae, epicanthus inversus, bulbous/beaked nose, short and flat philtrum, mild joint contractures at knees/elbows, spasticity, variable nystagmus/mild optic atrophy, enlarged ventricles; one case partial agenesis corpus callosum

XLR

Campomelia-ankyloglossia79

Multiple rib fractures, tongue adhesions to palate, cleft palate, micrognathia, severe angulation of long bones, digital contractures.

Unknown

Campomelic dysplasia80

Macrocephaly, micrognathia, flat nasal bridge, cleft palate, laryngomalacia, bowed femur and tibia, narrow chest, cardiac and renal defects common, ambiguous genitalia in most males; characteristic radiographic changes; hydrocephalus in ~10%

AD (114290) SOX9, 17q24q-25

Cardiac fibromahydrocephalus-cleft lip/ palate81

Myocardial fibromas causing death, cleft lip/palate, cyst of the olfactory lobe, mild communicating hydrocephalus, thin corpus callosum

Unknown

Cardio-facial-cutaneous82

Facial appearance resembles Noonan syndrome; sparse, friable, curly hair; bitemporal narrowness; dry and hyperkeratotic skin; frequent ptosis, strabismus and nystagmus; pulmonary stenosis most common congenital heart defect

Uncertain (115150)

(continued)

615

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Carpenter-Hunter: micromelia-polysyndactyly83

Severe short-limbed dwarfism, encephalocele, marked hypertelorism, microphthalmia, absent external nares, cleft palate, micrognathia, narrow chest, cardiac malformation, cystic dysplasia of the kidneys and pancreas, post-axial polydactyly of hands and feet, duplicated tibia, hydrocephalus, pachygyria

Unknown

Cataract-ossified pinnae84

Short stature, downslanting palpebrae, palate mass, large ears, deafness, distal wasting/contractures radiographic lucencies, severe mental retardation

Unknown

Caudal appendage-short terminal phalanges85

Monozygous twin with ‘‘tail,’’ short stature, short terminal phalanges, mixed deafness, developmental delay, initial normal OFC, arrested hydrocephalus, then microcephaly

Unknown

Centromere instabilityimmunodeficiency86

Facial dysmorphia, skin and respiratory infections, hypogammaglobulinemia, decreased T cells, chromosome centromeric instability, multiradial formation

AR (242860) Some DNMB3B, 20q11.2

Cephalothoracic lipodystrophy-deafness87

Barraquer-Simons-type cephalothoracic lipodystrophy in a woman with deafness and hydrocephalus

Unknown

Cerebellar hypoplasia-brain stem calcification88

Sib fetuses with cerebellar aplasia, dilated ventricles, aqueductal stenosis in one, necrosis and calcification in the brain stem and cortex, cortex contained foamy macrophages and prominent vascularity

AR

Cerebroarthrodigital89

Extreme IUGR, microcephaly or hydrocephaly, severe arthromyodysplasia, budlike digits with hypoplastic to absent nails, long bone shortness, sacral vertebral anomalies, little active range of motion, postnatal growth failure

Unknown

Cerebro-oculo-nasal90

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears. The other girl had a single maxillary central incisor, case reported with agenesis of the corpus callosum; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst

Unknown

Chondrodysplasia-callosal agenesis-thrombocytopenia91

Rhizomelia, hypertension, thrombocytopenia, flat nasal root, anteverted nasal tip, wide metaphyses, platyspondyly, deficient dorsal ossification centers of vertebrae, agenesis of the corpus callosum, severe hydrocephalus

Unknown (166990)

Chromosome aberrations92,93

Reported in a wide range of deletions and duplications (over 50 in ref 93), generally with associated malformations, developmental delay, and dysmorphic features

Chromosome imbalance

Chromosome 14 maternal disomy94

Macrocephaly, short to tall stature, obesity common, normal or impaired intelligence, communicating hydrocephalus that may resolve, premature puberty, small testes, hyperextensible joints

Maternal disomy

Chudley-McCullough: hydrocephalus-deafness95

Normal intellect, non-dysmorphic, obstruction at foramen of Monro, severe bilateral sensorineural hearing loss; recent reports with ACC suggest it is same as Hendriks syndrome137

AR (604213)

Ciliary akinesia/ dyskinesia96,97

Abnormal function of cilia cause respiratory infection, bronchiectasis, and sperm dysfunction; mental retardation and hydrocephalus (ependymal cell dysfunction) run in some families; Kartagener syndrome has associated abnormalities of laterality

AR (242650), DNAH5, 5p15-p14 DNAH11, der 7 DNAI1, 9p21-p13 CILD2, 19q13.3-qter

Clefting-corneal opacity98

Growth and developmental delay, cleft lip/palate, hypertelorism, colobomas, optic atrophy, spasticity, cardiac murmur, overlapping fingers and toes (aqueduct stenosis)

AR

Coffin-Lowry99

Mental retardation, prominent forehead and supraorbital ridges, downslanting palpebrae, hypertelorism, low nasal bridge with thick septum, small and anteverted nares, full and patulous lips, everted lower lip; soft, hyperextensible, and tapering fingers; non-specific radiographic changes, progressive kyphoscoliosis; true hydrocephalus uncommon

XLD (303600) RDS6KA3, Xp22.2

Craniofacial conodysplasia100

Macrocephaly, frontal bossing, flat nasal bridge, telecanthus, midface hypoplasia, prognathism, acrodysostosis, hypertonia, short proximal phalanges of thumbs and middle phalanges of 2nd and 5th fingers, stenotic foramen magnum, spinal cord atrophy

AD

Craniofacial dyssynostosis101

Variable developmental delay, premature fusion of the lambdoid and posterior sagittal sutures, dolichocephaly, protuberant forehead; one each of seven original patients had congenital heart defect, agenesis of the corpus callosum, and hydrocephalus (same as craniotelencephalic dysplasia?)

AR (218350)

(continued)

616

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Craniomicromelia

IUGR, short limbs, absent coronal sutures, short palpebrae, pinched nose, hypoplastic alae, microstomia, cleft palate, large fontanels, absent 2nd finger phalanges, occipital protrusion containing cerebellum

AR (602558)

Craniosynostosis-bifid thumb-micropenis103

Craniosynostosis, low-set and posteriorly rotated ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, flat nasal bridge, bifid thumbs, limited extension at the knees, small 5th finger, bi-lobed lungs, small penis with bifid scrotum, polymicrogyria, hypoplastic frontal lobes, arhinencephaly, cerebellar herniation, hydrocephalus

Unknown

Craniosynostosis-choanal atresia-dysphagia104

Normal intelligence, exophthalmos, choanal atresia, severe swallowing difficulties, gastroesophageal reflux, ventriculomegaly; one case ankylosis of temporomandibular joint and maxillomandibular synechiae, other cleft soft palate

AR

Craniotelencephalic dysplasia

See Craniofacial dyssynostosis102

Crouzon106

Craniofacial dysostosis due to suture synostosis, exophthalmos, prominent and beaked nose, prognathism maxillary hypoplasia (communicating hydrocephaly of unknown cause)

AD (123500) FGFR2, 10q26

Cutis marmoratamacrocephaly107

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous hemangiomas of the skin, developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects; hydrocephalus reported

Unknown (602501)

Cytomegalovirus-prenatal infection108

Asymptomatic to severe CNS changes. May include IUGR, microcephaly, intracranial calcification, hydrocephaly, chorioretinal changes, deafness

Prenatal infection

Czeizel: omphalocele-cleft palate109

Omphalocele, cleft palate/uvula, uterus bicornis; one of three femal sibs had hydrocephalus

AR (258320)

Daish: tall stature-joint hypermobility110

Tall stature, kyphoscoliosis, floppy mitral valve, joint hypermobility, susceptible to luxation

Uncertain (236660)

Da Silva: mental retardationmicrocephaly111

Severe retardation, postnatal growth failure, preauricular skin tag, camptodactyly nasal skin tag, club feet, increased tone, pulmonary infections, lethal

AR (217990)

DeHauwere: iris dysplasia112

Mesodermal iris dysplasia telecanthus/hypertelorism, psychomotor delay, short stature, hypotonia ventricular and cisternal enlargement, possible agenesis of the corpus callosum

AD or SLD

Devi: endocardial fibroelastosis-cataracts113

Congenital cataracts, endocardial fibroelastosis (lethal), postnatal communicating hydrocephalus; two unrelated males

Unknown (600559)

Diaphragmatic herniapulmonary hypoplasiahydrocephalus114

Right diaphragmatic defect, pulmonary aplasia or hypoplasia, borderline developmental delay, atrial septal defect, aqueduct stenosis, ventriculomegaly

AR

Disseminated hemagiomatosis115

Congenital multiple hemangiomas of skin and viscera, and sometimes fundi, brain stem, cerebellum, and cortex; complications include larger cavernous hemangiomas causing high-output cardiac failure and/or thrombocytopenia, subglottic hemangiomas, and obstruction by intracranial capillary hemangiomas causing hydrocephalus

Unknown (106070)

Dwarfism-microcephalyhydrocephaly116

Sloping forehead with marked microcephaly, no developmental progress, short and cupped ribs, mildly flat vertebrae, post mortem hydrocephalus; one sib with absent corpus callosum

AR

Dysmorphic facies-sex discrepancy117

Low-set ears, hypertelorism, flat nose, microretrognathia, female external genitalia, no uterus or vagina, testicular tissue in gonads, vas deferens present, 46,XX karyotype

Unknown

El-Khazen: lethal osteopetrosis118

Prenatal-onset increased bone density, brittle bones, hydrocephalus, marked gliosis of cortex and white matter, extensive neuronal loss, axonal swellings, some calcifications, hypoplastic cerebellum

AR (259720)

Enamel hypoplasia-cataractsaquedate stenosis119

Normal intelligence, anterior and posterior subcapsular lenticular opacities with radial spoke opacities in the lens cortex, enamel hypoplasia, anterior overbite, aqueduct stenosis noted on neuroimaging

Unknown (600907)

Epidermal nevus120

Nevus unius lateris, icthyosis hystrix, acanthosis nigricans, nevus sebaceous, hemangiomas, hemihypertrophy, pigment changes

Unknown (163200)

Fine: ocular anomalies-cleft palate-asymmetry121

Asymmetry of skull and body, cataract, glaucoma, low-set and abnormal pinnae, small mouth and mandible, hypoplastic genitalia, absent corpus callosum (aqueductal stenosis)

Unknown

102

(continued)

617

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Wide sutures, small eyes, abnormal external ears, flat nose, cleft palate, syndactyly hands/feet, abnormal pubic rami, laryngeal stenosis, absent/dysplastic kidneys, genital anomalies, abnormal gyri

AR (219000) FRAS1, 4q21

Fried: XLMR-spastic diplegia123

Mental retardation, spastic diplegia; congenital or possibly postnatal regression with loss of muscle tone wasting; ventricular dilation, calcification of the basal ganglia

XLR Xp22

Fukuyama: cerebro-oculomuscular124

Less severe than Walker-Warburg, developmental delay, small areas of agyria, pachgyria/polymicrogyria microscopically as in type II lissencephaly, mild cerebellar foliation defects, minor or absent eye defects, progressive facial and limb muscular dystrophy and contractures, raised CK; founder mutation in Japanese

AR (253800) Fukutin, FCMM, 9q31-q33

Game: hydrocephalusabnormal lungs125

Growth retardation, hypoplastic and/or hypersegmented lungs, intestinal malrotation, omphalocele, bowed tibiae and hypoplastic/absent fibula, rocker-bottom or clubbed feet

AR (236640)

Gaucher-like disease126

Neurologic deterioration, supranuclear gaze palsy, hydrocephalus, aortic stenosis, mitral valve calcification

AR (231005) acid b-maltase, D409Hm

Gibson: absent radiusanogenital anomalies127

Hydrocephalus, absent radial rays, hypospadias; report of fetus; maternal uncle reported with medially deviated and short forearms, imperforate anus; this is within spectrum of X-linked VATER with hydrocephalus

XLR (312190)

Goldblatt: spondylocostal metaphyseal dysplasia128

Very short limbs, macrocephaly due to hydrocephalus, narrow thorax, left cystic dysplastic kidney, short digits, metaphyseal cupping of long bones, phalanges and metacarpals of hands, platyspondyly with anterior beaking, short ribs, cupped costochondral junctions, squared scapulae and iliac wings, lambdoid and posterior sagittal synostosis

Unknown

Goldenhar129

Variable asymmetric lower face, with mandibular hypoplasia, microtia, preauricular tags and pits, epibulbar dermoids, macrostomia, upper vertebral anomalies; variety of CNS defects in low frequency

Sporadic, occasionally AD (164210)

Greig: cephalopolysyndactyly130

Macrocephaly, high forehead, frontal bossing, hypertelorism, broad nasal base, postaxial and/or preaxial polydactyly of hands, broad thumbs, hallux often duplicated, 1-3 toe syndactyly with occasional post-axial polydactyly, possible agenesis of the corpus callosum, and a few cases with mild communicating hydrocephalus

AD (175700) GLI3, 7p13

Haar-Dyken: athetotic hemiplegia131

Congenital, unilateral, hypertonic, hemiparesis, later onset athetoid posturing, dysarthria, contralateral cerebral atrophy; case with mild communicating hydrocephalus, aqueduct stenosis, macrocephaly

AD

Habel: microstomiahydrocephalus132

Frontal bossing, hirsutism, nasal obstruction (apparent), microphthalmia, carp mouth, low-set ears, profound mental retardation, postnatal growth failure, micropolygyria, early death

t(1;2)(q42.3;q37.1)

Hajdu-Cheney133

Coarse face, short neck, hirsutism, lax joints, acro-osteolysis, bathrocephaly, vertebral anomalies, normal intelligence; CNS anomalies include hydrocephalus (7/49) and syringomyelia

AD (102500)

Hayashi: leprechaunismlike134

Megalencephaly, hydrocephaly, unusual appearance, severe growth failure, hypoglycemia, no hyperinsulinemia, cardiac defect, decreased cortical neuronal density, fronto-parietal dysplasia. Single case

Unknown

Hemihypertrophyhemimegalencephalypolydactyly135

Hemimegalencephaly, cutis marmorata, hemihypertrophy of face and limbs, 3-4 syndactyly and post-axial polydactyly of hands, polydactyly of left foot with 2-3 toe syndactyly, wide-sandal gap. Single case

Unknown

Hendriks: deafness-callosal agenesis-arachnoid cyst136

Normal intelligence, sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, hydrocephalus

AR

Heptacarpo-octatarsodactyly137

Cleft lip/palate, hypertelorism, macroglossia, horseshoe kidney, congenital heart defect, micropenis, internal hydrocephalus, ependymal cysts

Unknown

Hersh: mirror hands and feet-brain anomalies138

Sagittal synostosis, flat nasal bridge, bulbous nasal tip, hypoplastic alae, hamartomatous enlargement of parotid glands, stenotic ear canals, pelvic kidneys, ventricular septal defects, fusion and platyspondyly of cervical vertebrae, hydrocephalus, callosal agenesis

Unknown (135750?)

Hydrocephalus-angiopathyhypercholesterolemia139

Normal initial development, acute hydrocephalus in infancy, neurologic deterioration, seizures, high lipoprotein(a) and cholesterol; perivascular calcifications in Sylvian fissure, brain stem, cisterna magna; subpial gliosis and other changes

Unknown

Fraser: cryptophthalmos

122

(continued)

618

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Hydrocephalus-cataractmicrophthalmos140

Hydrocephalus, congenital cataract, microphthalmia; possible Walker-Warburg variant

Unknown

Hydrancephalic hydrocephalus-proliferative vasculopathy141

Late 2nd trimester hydramnios, multiple upper and lower limb major joint contractures, maximum hydrocephalus, with vascular glomeruloids, cytoplasmic inclusions, calcified necrotic foci in cortex

AR (225790) some due to mitochondrial dysfunction

Hydrocephalus-Sprengel shoulder-skeletal142

Mild mental retardation or psychosis, arachnoid or cerebellar cysts, hydrocephalus, abnormal white matter, Sprengel shoulder anomaly, brachydactyly of variable type

AD (600991)

Hydrolethalus143

Cleft lip/palate, small tongue and mandible, abnormal nose and ears, malformed respiratory tract, genitourinary and heart anomalies, polydactyly, stillbirth/ neonatal death

AR (236680) 11q23-q25

Hypoglossia-hypodactyly144

Normal intelligence, small jaw, intraoral band from palate to floor of mouth, variable limb reduction from absent digits to distal limb, association with bilateral facial and abducens nerve palsies; some may have followed early CVS; case with aqueduct stenosis, hydrocephalus, and histologic brain stem changes

Possibly vascular (103300)

Ichthyosis-biliary atresia145

Ichthyosis congenita, biliary atresia, neonatal death of brother from umbilical hemorrhage; sister with hydrocephalus

AR (242400)

Influenza, prenatal146

Possible rare complication of maternal infection; microphthalmia, malformed pinnae, diaphragmatic hernia, costovertebral defects; ependymal damage, aqueduct forking, hydrocephalus, heterotopias; agenesis of the corpus callosum, cerebellum, pontine and inferior olivary neurons, optic and olfactory nerves; immunohistochemical evidence of influenza virus antigens in brain

Unproven association

Jeune: thoracic dysplasia147

Hypoplastic rib cage with short ribs, ‘‘trident’’ pelvis, postaxial polydactyly, short stature, dental anomalies, renal microcysts and failure, mild dilation of lateral ventricles

AR (208500) 15q13

Jonas: pontine hypoplasiacallosal agenesis148

Macrocephaly, frontal bossing, deep-set eyes, short palpebrae, Duane retraction anomaly, hydronephrosis, patent ductus arteriosus, agenesis of corpus callosum, hypoplastic pons; mild, focal, subcortical white matter changes; communicating hydrocephalus

AR

Kabuki149

Mental retardation, short stature, prominent ear lobes, everted lateral 1/3 of the lower lid, long palpebrae, broad nasal tip, cleft/high-arched palate, short 5th finger, fetal finger pads, cardiac and renal anomalies, variety of minor anomalies; case with hydrocephalus

Uncertain (147920)

Kartagener

See Ciliary akinesia/dysgenesis96

Kraues-Kivlin: Peters plus150

Central corneal leukoma with abnormal posterior stroma and Descemet membrane, iris synechia, unusual facies, disproportionate short limbs; digital cardiac and renal anomalies; case with communicating hydrocephalus

AR (261540)

Larsen151

Normal intelligence, prominent forehead, flat face, low nasal bridge, hypertelorism, dislocation at large joints, varus or valgus foot deformities, long tapering fingers

AD (150250) LAR1, 3p21.1-p14.1 AR (245600)

Ligneous conjunctivitis152

Palpebral pseudomembranes become nodular masses of amorphous, hyalinized ground substance; mucous membranes of mouth, tongue, nasopharynx, tracheobronchial tree, and the female genital tract may be involved; minority have obstructive hydrocephalus

AR (217090) Plasminogen 1 deficiency, 6q26

Lockwood: short-arthritislipodystrophy153

Late childhood growth failure, broad nasal bridge, cupped optic discs, mild generalized lipodystrophy, osteoporosis, short pelvis, bilateral coxa valga, mild platyspondyly, short metacarpals, degenerative arthritis of hips and knees, arrested hydrocephalus

Unknown

Lurie-Kletsky: callosal agenesis-diaphragmatic defect154

Fetal hydrops, microcephaly, scalp defect, short palpebrae, posterior diaphragmatic defect, agenesis of corpus callosum, ventriculomegaly

Unknown

Marshall-Smith155

Accelerated linear and skeletal growth with prenatal onset, poor weight gain, dolichocephaly, prominent eyes, anteverted nose, broad proximal and middle phalanges, narrow distal phalanges, respiratory problems often lethal, absent corpus callosum, hypoplasia inferior vermis, pachygyria

Unknown (602535)

MASA (X-linked hydrocephaly spectrum)156

Mental retardation, adducted thumbs, shuffling gait with aphasia or speech delay, agenesis of corpus callosum, spastic paraplegia, hydrocephalus. Same gene as X-linked hydrocephalus, X-linked paraplegia type 1

XLR (303350) L1CAM, Xq28 (continued)

619

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Metatropic dwarfism-lethal variant157

Normal face, expanded joints, cleft soft palate, cataracts, wide metaphyses, short and narrow diaphyses, intrauterine fractures, unossified epiphyses, normal vertebrae

AR (250600)

Microgastria-upper limb reduction158

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia, porencephalic cyst, hydrocephalus

Unknown (156810)

Microphthalmia-linear skin defects159

May have other CNS anomalies including septum pellucidum cyst, ACC, colpocephaly and hydrocephaly; microphthalmia, sclerocornea, linear dermal aplasia usually of the head and neck

XLD male lethal (309801) del Xp22.3

Mizoguchi: hydrocephalustrigonocephaly160

Communicating hydrocephalus, trigonocephaly, spastic gait in 3rd decade, dementia starting in 5th decade

AD

Morning glory-sphenoidal encephalocele161

Characteristic optic nerve, hypertelorism, microphthalmia, other eye anomalies, midline cleft, pituitary/hypothalamic dysfunction, hydrocephalus, absent corpus callosum, sphenoidal encephalocele

Unknown

MULIBREY nanism162

Muscle hypotonia, liver enlargement, brain defects including large ventricles, and cysternae, eyes with yellow pigmentation of retina. Growth failure, triangular face, pericardial constriction, long shallow sella turcica, fibrous dysplasia of bones

AR (253250) TRIM37, 17q22-q23

Muscle wasting-cataractscalcified pinnae163

Severe mental retardation, calcification pinnae, posterior polar cataracts, progressive muscle wasting (mostly of hands) and joint contractures, cystic areas in head of humeri and upper femora

Unknown (259050)

Mutchinick164

Microcephaly, hydrocephalus, growth and developmental delay, high forehead, ptosis, downslanting palpebrae, prominent nose, high nasal bridge, protruding ears; 1 of 8 cases with ACC

AR

Nephropathyventriculomegaly165

Protein losing nephropathy with grossly elevated MSAFP levels; nephrin mutations excluded, mild ventriculomegaly and echogenic kidneys on prenatal ultrasound

AR

Nephrosis-neuronal migrational defect166

Mental retardation, aqueduct stenosis, periventricular neuronal heterotopias, spastic tetraplegia, seizures, proliferative glomerulonephritis, periodic hypertension

Uncertain

Neurocutaneous melanosis167

Classical and variant forms of cutaneous pigmented nevi and leptomeningeal melanosis with malignant change, intracranial anomalies and cysts, arachnoid villi infiltration in some cases

Unknown

Neurofibromatosis168

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudoarthrosis, and diverse complications of tumors; macrocephaly is common

AD (162200) NF1, 17q11.2

Noonan169

Variable mental retardation and short stature, ptosis, downslanting palpebrae, low/abnormal ears, short/webbed neck, pectus malformation, pulmonary valve stenosis/dysplasia; hydrocephalus in about 5%

AD (163950) PTPN11, 12q24.1

Ochoa-urofacial170

Hydronephrosis, hydroureter, intravesicular ureteral stenosis, urethral valve stenosis; crying or smiling causes a lateral displacement of the mouth, nasal flattening, deepening of the nasolabial sulcus; case with aqueduct stenosis

AR (236730) 10q23-q24

Oculocerebrocutaneous171

Orbital cysts, microphthalmia, lid coloboma, skin defects, skeletal anomalies, agenesis of the corpus callosum, multiple cysts of brain

Unknown (164180)

Ohdo: tetra-amelia; ectodermal dysplasia172

Tetra-amelia, upslanting palpebrae, absent scalp hair and eyebrows, absent lacrimal puncti, prominent nose, large and downturned mouth, bilateral preauricular pits, ventriculomegaly, increased subarachnoid space

AR (273390)

Oral-facial-digital type I173

Midline cleft/notched upper lip, multiple oral frenulae, lobulated tongue with hamartomas, asymmetric brachysyndactyly; CNS includes hydrocephaly, porencephaly, cerebellar vermis hypoplasia, Dandy-Walker cysts, neuronal migration defects, and agenesis of the corpus callosum

XLD (311200), male lethal CXORF5, Xp22.3-p22.2

Oral-facial-digital type II174

Short stature, hypertelorism, low nasal bridge, broad and bifid nasal tip, hypertrophied oral frenula, cleft and lobulate tongue, cleft palate; brachysyndactyly, pre- and post-axial polydactyly of hands; pre-axial foot polydactyly; usually normal intelligence; CNS includes porencephaly, hydrocephaly, callosal agenesis

AR (252100)

Oral-facial-digital type Gabrielli175

Severe developmental delay, low-set ears, preauricular pits, hypertelorism, blepharophimosis, bulbous nose, multiple oral frenula, long philtrum, split upper lip, micrognathia, cleft palate, bilateral postaxial polydactyly of hands and feet, fusion of posterior arches of C2 and C3 and of atlas to occiput, clefts of cervical and thoracic vertebrae, hypoplastic odontoid, dilated lateral ventricles

Unknown

(continued)

620

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Orstavik: aplasia cutisretinal-brain176

Aplasia cutis on scalp and abdomen, broad bulbous nose, small chin, long philtrum, hypoplasia to absence of fingers with the nails attached to metacarpals, ventricular dilation and cerebral atrophy, variable thalamic calcification; male had agenesis of the corpus callosum

AR

Osteogenesis imperfecta, lethal type177

Prenatal onset hydrocephalus may be due to either fractures at foramen magnum or sub-arachnoid haemorrhage (may reflect severe type II osteogenesis imperfecta).

Most AD (166210) COL1A1, 7q22.1 COL1A2, 17q21.31-q22

Osteogenesis imperfectaretinopathy-mental retardation178

Postnatal growth and developmental retardation, blue sclera, optic atrophy, retinopathy, fractures, wormian bones, large fontanel, seizures, congenital heart defect

AR

Osteoglophonic dwarfism179

Multiple metaphyseal lucencies, craniosynostosis, flat-beaked vertebrae, marked growth failure, delayed dentition, hypertelorism, abnormal face, obstructive hydrocephalus

AD (166250)

Oto-palato-digital II180

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia; case reported with cerebellar hypoplasia and hydrocephalus

XLR (304120) FLNA, Xq28

Palmer-Pagon: hydrocephalus-low umbilicus181

Mild facial signs with short and bulbous nose, wide palpebrae, low position of umbilicus, congenital heart defect, mild speech delay, ventricular dilation

Unknown

Pena-Shokier without IUGR182

Small and immobile mouth, low and angulated ears, choanal atresia, pterygia, camptodactyly; macrocephaly; posterior fossa cyst and hydrocephalus in one case

XLR or AR

Polyasplenia-caudal deficiency-absent corpus callosum183

Laterality associated defects, imperforate anus, renal anomalies, lumbosacral agenesis, lower limb anomalies; cases reported with meningocele, hydrocephalus; one case with absent corpus callosum and white matter neuronal heterotopias and abnormal cortical architecture

Uncertain

Polymicrogyriahydrocephaluscraniosynostosis184

Craniosynostosis, scaphocephaly, severe mental retardation, lethal early; low-set ears, eyebrow hypoplasia, short nose, long philtrum, small mouth, small genitalia. Single case

Unknown

Porencephaly-cerebellar hypoplasia-heart defect185

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Port-wine nevi-mega cisterna magna186

Glabellar port-wine stain, mega cisterna magna; 2 of 5 affected persons had congenital communicating hydrocephalus, agenesis of posterior vermis

AD

Proliferative vasculopathyhydranen/hydrocephaly187

Ventriculomegaly/hydranencephaly; proliferative blood vessels in spinal cord, brain stem, retina, and cerebral mantle; decreased number of primitive neuroectodermal cells, maturing neurons and glia; no gyral pattern; hypoplastic muscles, joint contractures, pterygia; possibly a destructive vascular process; cerebro-oculo-muscular spectrum?

AR (225790)

Proteus188

Marked and asymmetric overgrowth can lead to a range of complications; shagreen patches, linear verrucous epidermal nevi, intradermal nevi, lipomas, hemangiomas, patchy dermal hypoplasia, hyperplastic and pebbly plantar overgrowth; frequent ocular problems; CNS abnormalities uncommon, partial absent corpus callosum, lissencephaly, hydrocephalus

Uncertain (176920) Some PTEN, 1q11-q25, mutations claimed, but cases questioned296

Pseudomarfanism189

Ectopia lentis arachnodactyly, mild osteopetrosis, hypertelorism, high palate, malocclusion, communicating hydrocephalus

AD

Reuss: cystic kidneysventiculomegaly190

Polyhydramnios elevated amniotic fluid a-fetoprotein level, normal-sized dense kidneys with corticomedullary and medullary cysts with amorphous eosinophilic material, unexplained ventriculomegaly

AR (219730)

Rhombencephalosynapsis191

Facial signs can include marked low-set ears, hypertelorism, strabismus, long philtrum; CNS includes absent incisuria cerebelli posterior, velum medullare anterius, and nuclei fastigii; fusion dentate nuclei and cerebellar hemispheres; survivors show neurologic signs including ataxia, dysarthria, and mental retardation

Unknown

Riccardi: Dandy-Walker malformation192

Hydrocephalus, cerebellar agenesis, Dandy-Walker malformation; maternal greatgreat uncle with hydrocephalus

Unknown

Rogers: anophthalmia tracheoesophageal fistula193

Prominent forehead, open fontanel, bilateral anophthalmia, high palate, glandular hypospadias, tracheoesophageal fistula, arrested hydrocephalus. Single case.

Unknown (continued)

621

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Complete absence of upper and lower limbs, severe pulmonary hypoplasia; one case with cleft lip and hydrocephalus; see also Zimmer tetra-amelia

AR (273395)

Sagittal synostosis-DandyWalker195

Developmental delay, sagittal synostosis, Dandy-Walker malformation, hydrocephalus

AD (123155)

Schinzel-Giedion: hirsutismmidface retraction196

High cranium, midface retraction, choanal atresia, cardiac and renal anomalies, hirsutism, sclerosis of skull base, wormian bones, mental retardation, subependymal pseudocysts, intraventricular bands

AR (269150)

Sengers: obesityhypogenitalism197

Mental retardation, short stature, obesity, hypogenitalism

XLR

Sensorineural deafnesshypospadias-digit synostosis198

Mental retardation, truncal obesity, small kidneys, sensorineural deafness, hypospadias, synostosis of the 4th and 5th metacarpals and metatarsals, high rate of digital arches, dilated ventricles, mildly underdeveloped occipital lobes and cerebellum

Unknown

Shprintzen-Goldberg: arachnodactylycraniosynostosis199

Mental retardation, hypotonia, craniosynostosis, low-set ears, exophthalmos, maxillary and mandibular hypoplasia, prominent lateral palatine ridges, abdominal hernias, arachnodactyly, camptodactyly; significant overlap with Melnick-Needles and spectrum of syndrome uncertain; possible case with cloverleaf skull, hydrocephaly, and hypoplastic corpus callosum

AD (182212), some FBN1, 15q21.1

Siber: microphthalmia200

Microphthalmia, corneal opacities, hypospadias; one sib had more extensive brain anomalies noted at autopsy

XLR (309800)

Slee: hydrocephalus-growth failure-digital201

Severe polyventricular hydrocephalus, patent aqueduct of Sylvius, cleft palate, overlapping fingers; CNS variable and includes partial/complete callosal agenesis, hypoplastic mid- and hindbrain, cerebellar agenesis; lethal

Uncertain

Split foot-congenital hearthydrocephalus202

Developmental delay, depressed and broad nasal bridge, downslanting palpebrae, low-set ears, torticollis, left foot ectrodactyly, secundum atrial septal defect, thin corpus callosum, dilated 3rd and lateral ventricles

Unknown

Temtamy: callosal agenesiscolobomas-retardation203

Macrodolichocephaly, low-set and simple ears, narrow face, hypertelorism, complete colobomas, beaked nose, micrognathia, dental anomalies, dilated aorta, mild brachydactyly of digits 2-5 of hands and feet, dilated lateral and 4th ventricles and slightly dilated sulci

AR

Tetralogy of Fallot-unusual facies-hydrocephalus204

Developmental delay, midface hypoplasia, short palpebrae, cyanotic heart disease, variable hypertelorism and hydrocephalus

AR

Thakker-Donnai205

IUGR, Klippel-Feil, long and downslanting palpebrae, hypertelorism, short nose with blunt tip, small downturned mouth, vertebral anomalies, short esophagus, diaphragmatic hernia, congenital heart defect; one sib with hydrocephalus, the other with callosal agenesis

AR (227255)

Third ventricular obstruction206

Hydrocephalus with dilated lateral ventricles and narrowing of posterior 3rd ventricle, polygyria, choroid plexus atrophy, thin corpus callosum, absent septum pellucidum

Unknown

Thrombocytopeniaalloimmune207

Equivalent of rhesus disease; involves platelet antigens (usually HPA1a); hydrocephalus secondary to thrombocytopenia mediated, in utero, intracerebral hemorrhage; recurrence risk of >80%

Immune sensitization

Tibial aplasia-ectrodactyly208

Pregnancy complicated by early twin resorption, left forearm hypoplasia, absent thumb, syndactyly, bilateral lower limb hypoplasia, idiopathic hydrocephalus. Single case

Twin vascular interaction possible

Tibial aplasia-polysyndactylyimperforate anus209

Imperforate anus, femoral hypoplasia, unilateral tibial aplasia, ipsilateral pre-axial polysyndactyly, vertebral and rib anomalies, ventriculomegaly

Unknown

Tibial hypoplasiapolydactyly-retrocerebellar cyst210

Tibial aplasia/hypoplasia, cleft lip, postaxial polydactyly of hands, pre- or postaxial polydactyly of feet, short radii, colonic malrotation, diaphragmatic agenesis, ventriculomegaly (one sib), retrocerebellar arachnoid cyst (two sibs)

AR (601027)

Tranebjaerg: XLMR-ataxiaapraxia211

Mental retardation, ataxia, apraxia, club feet, seizures, dilation of cerebral ventricles

XLR

Trigonocephaly212

Patients presented with isolated metopic fusion and communicating hydrocephalus, hypothesized to be due to developmental anomaly of cortical veins; onset of spastic gait in 3rd decade

AD

Tollner: polydactyly-visceral anomalies213

Hypertelorism, bilateral cleft lip/palate, macroglossia, hepatosplenomegaly, accessory lobe of right lung, horseshoe kidney, complex congenital heart defect, heptadactyly of hands, pre-axial polysyndactyly of feet, micropenis, hydrocephalus, ependymal cysts, polygyria, leptomeningeal fibrosis. Single case.

Unknown

Rosenak: tetra-amelia

194

(continued)

622

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Short palpebral fissures, telecanthus, Robin sequence, small nose, abnormal auricles, excess nuchal skin, larynx anomaly, hypospadias, brachydactyly, microcephaly, mental retardation

AR (217980)

Toxoplasmosis215

IUGR, developmental delay, hydrocephalus, microcephaly, intracranial calcifications, choreoretinitis, hearing loss

Prenatal infection

VATER, VACTERL216

Typical association of vertebral, anal, cardiac, tracheoesophageal, renal and limb (radial) anomalies; increasingly noted with aqueductal stenosis

Sporadic some XLR (192350)

Van Biervliet: thoracic dystrophy217

IUGR, multiple joint contractures, narrow thorax, small mouth and mandible, appear older than age, developmental delay, aqueduct stenosis

AR

Varicella, fetal218

Risk about 2% with maternal infection at 13–20 weeks; mild mental retardation, eye defects, skin scarring distributed over dermatomes, limb hypoplasia; most reported brain lesions seem clastic but hydrocephalus reported

In utero infection

Ventriculo-radial-renal219

Progressive prenatal hydrocephalus, absent radial rays, horseshoe kidney/crossed renal ectopia; elevated amniotic fluid g-glutamyltranspeptidase, total protein

AR (602200)

Vitamin A, prenatal220

Spontaneous abortion, microtia, microophthalmia, anophthalmia, congenital heart, limb reduction defects, thymic hypoplasia, jaw hypoplasia, hydrocephalus

In utero exposure

Waaler: costovertebral dysplasia221

Sprengel anomaly, kyphoscoliosis, rib anomaly and minor vertebral changes, hypertelorism, enamel hypoplasia, prominent mandible, communicating hydrocephalus

AD (143250)

Walker-Warburg (HARDþ/E)222

Diffuse agyria, cobblestone appearance may be obscured by hydrocephalus, abnormal white matter, laminar heterotopia below cortex, absent septum pellucidum, severe midline > lateral cerebellar hypoplasia, brain stem hypoplasia, Dandy-Walker malformation, cephalocele, retinal dysplasia/non-attachment; microphthalmia, cataract, corneal opacity, hyaloid vessels, retinal corneal opacity, abnormal face; myopathic skeletal muscle with variable size and splitting of fibers with endomysial fibrosis

AR (236670) POMT1, 9q34.1

Wallace: dwarfism-midline cleft223

Short-limbed dwarfism, short ribs, midline cleft lip/palate, pulmonary hypoplasia, disrupted endochondrial ossification, aqueductal stenosis

AR?

Weaver: craniosynostosis224

Coronal and lambdoid fusion, cranial bone defects, hypertelorism, clefting, arthrogryposis, growth and developmental delay, esophageal reflux and apnea

Unknown

Winter: IUGRhydrocephalus-skeletal225

Severe IUGR, rhizomelia, small face and ears, blue sclerae, beaked and pinched nose, small hands, zygodactyly of 4th and 5th toes, bifid 5th left toenail, small penis, retarded bone age; radiologic changes including metaphyseal flaring, platyspondyly, pelvic anomalies, wormian bones; enlarged 3rd and lateral ventricles, small 4th ventricle, normal aqueduct, probable cerebellar vermis dysgenesis/agenesis

Unknown, AR?

Winter: thoracic dysplasia226

Short ribs, mild rhizomelia, pelvis of newborn was not trident. Could be same as Jeune asphyxiating thoracic dysplasia

AR (273730)

Winter-Wigglesworth227

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, severe hydrocephalus, poorly formed hemispheres; microscopic renal changes

Unknown

X-linked laterality defect228

Variable visceral situs inversus, complex congenital heart disease, splenic malformations; CNS less common and includes arhinencephaly, hydrocephalus, meningomyelocele, cerebellar hypoplasia

XLR (304750) ZIC3, Xq24-q27

XLMR-corpus callosum dysgenesis229

Microcephaly, wide anterior fontanel, frontal bossing, telecanthus, broad nasal root, downturned mouth, short broad hands, brachydactyly; absent corpus callosum, interhemispheric cyst, cortical gyral dysplasia

XLR (304100)

X-linked myotubular myopathy230

Congenital lethal myopathy with hypotrophic muscle fibers, central nuclei and surrounding clear area lacking myofibrils; several cases with communicating hydrocephalus

XLR (310400) Myotubukarin, Xq28

Zaglul-Odita: multiple hernia231

Moderate mental retardation, hypotonia, low-set ears, downslanting palpebrae, hypotelorism, mild ptosis, anteverted nares, retrognathia, high-arched palate; herniae of diaphragm, stomach, lungs, inguinal region; bladder diverticulae; hydrocephalus and mild cerebellar atrophy

Unknown

Toriello-Carey

214

(continued)

623

624

Neuromuscular Systems

Table 15-11. Syndromes with hydrocephalus as a feature (continued) Syndrome

Prominent Features

Causation Gene/Locus

Zimmer: tetra-amelia

Polyhydramnios, amelia, severe facial clefting, no nose, ocular anomalies, hydrocephalus, absent ophthalmic and possible olfactory nerves

XLR (301090)

Zolotukhina: nasal proboscismultiple anomalies233

Low-set ears, hypertelorism, downslanting and short palpebrae, micophthalmia, blind-ending proboscis, cleft alveolus, ectrodactyly/polydactyly, band-like sacral protrusion, cerebral atrophy probable hydrocephalus

Unknown

232

variation in shape and histology along its length: triangular at the rostral opening, round to oval under the superior colliculi, ‘‘U’’shaped below the posterior colliculi, and forming a deep midline slit in the floor throughout the caudal portion. The walls may fuse at their dorsal margin at various points along this slit, thus forming a small ventral channel, seen in some cross sections, below the main passage. This normal phenomenon has been misinterpreted as pathologic aqueductal forking when associated with aqueductal stenosis.1 Attempts have been made, on the basis of histopathology, to distinguish atresia/stenosis due to malformation from blockage that is acquired (mainly postinflammatory). The appearance of the former was considered to be represented by lack of any evident channel or by multiple small irregular channels, whereas in the latter the original outline of the lumen was represented by residual nests of ependyma, and the canal was filled by gliosis. However, Drachman and Richardson30 reported a patient in whom the two types of pathology were noted at different levels of the aqueduct. Evidence from animal experimentation also shows clearly that infectious agents can produce aqueductal occlusion without producing gliosis.31 Thus, histopathology does not truly aid in the differentiation of the causes of aqueductal stenosis. Perez-Figares et al.5 have proposed that primary abnormalities in the subcommissural organ, which secretes glycoproteins that aggregate along the floor of the aqueduct, 4th ventricle, and central canal as Reissner’s membrane, may cause aqueductal stenosis. There is some consensus that 0.15 cm2 represents the lower limit of normal for lumen area, but both normal-sized ventricles with smaller areas and ventriculomegaly in the presence of apparently larger areas have been reported.1,29 Perhaps the length of stenosis plays a role in this regard. The age of onset and severity of congenital aqueductal stenosis are extremely variable. In general, the signs and symptoms are as described previously. However, the ‘‘bobble-head’’ doll phenomenon, which consists of to-and-fro head movement at 2–3 hz, is considered characteristic of 3rd ventriculomegaly due to obstruction at the level of the aqueduct. Although this sign has been considered due to pressure on the dorsal medial nucleus of the thalamus, Coker32 has argued that it results from interference with the red nucleus. Standard diagnostic techniques will demonstrate obstruction at the level of the aqueduct with ventriculomegaly involving the third and lateral ventricles (Fig. 15-47). The specific findings with MRI, including those of a membranous obstruction, have been described.33 Narrowing of the aqueduct is directly visible in its position ventral to the tectum, the appearance of which varies with the level of the stenosis. With stenosis at the level of the intercollicular sulcus, the tectum is often thinned. Stenosis at the level of the superior colliculi causes lateral compression of the tectum due to dilated temporal lobes and foreshortening due to downward compression from the dilated suprapineal recess of the 3rd ventricle. Uncommonly, the obstruction may consist of a thin web of loose fibroglial tissue with or without ependymal rests.34 The age

of onset in these patients is generally older than in the total group with aqueductal stenosis, and complaints often relate to disturbances of gait and changes in levels of consciousness and behavior. Presentation at age 12 years with bobble-head movement has been reported.35 The membrane always occurs in the caudal portion of the aqueduct and, with appropriate imaging techniques, can be seen to bulge into the 4th ventricle. The histopathology is not distinctive, and this may simply represent the minimal end of the spectrum of aqueductal stenosis. Recognition remains important, as simple fenestration may be sufficient treatment.34 In light of the known occurrence of aqueductal stenosis in neurofibromatosis, it is interesting that three of four patients with membranous stenosis reported by Turnbull and Drake34 had cafe´-au-lait spots. That aqueductal stenosis could be genetic was first recognized by Bickers and Adams36 in 1949, and a number of reviews have been published since.28,37 Most families have shown an X-linked pattern of inheritance,38 although several families compatible with autosomal recessive inheritance have been reported (Table 15-11).39 Our understanding of the X-linked form (XLH) has expanded rapidly since the discovery that it was due to mutations in L1, a member of the Ig superclass of cell adhesion molecules. The gene has a number of roles including axonin-1 binding affecting neurite growth, ankrin binding in the function of the cytoskeleton, and a kinase-related influence on intracellular secondary messangers.40 It is now clear that mutations in L1CAM can result in the various components of X-linked hydrocephalyMASA spectrum (Table 15-11). Aqueductal stenosis is not always present, even in those with hydrocephalus, and there does appear to be some genotype–phenotype correlation. The most severe expression, associated with marked hydrocephalus and a high prenatal and postnatal mortality, is seen in patients with nonsense mutations in the extracellular domain, which disrupts all functions of the gene. Missense mutations in the extracellular domain, followed by all types of intracellular domain mutations, cause respectively less severe effects, and it has been suggested that the hydrocephalus in such cases my be ex vacuo due to diminished white matter.40 The estimated birth prevalence of XLH is 1/30,000,41 and to date there is no evidence of genetic heterogeneity. The mental retardation that accompanies L1CAM mutations is not influenced by early shunting, is present even in the absence of hydrocephalus, and therefore must have a more intrinsic cause. There are no absolute criteria that distinguish the sporadic genetic case from those with other etiologies. The presence of adducted thumbs, due to abnormalities of the extensors and abductors of the thumb, affect about 25% of XLH cases and can be a useful sign. However, caution is required because adducted thumbs can be seen in severe hydrocephalus on the basis of the bipyramidal syndrome.28,37 Although new mutations are considered to be rare, most are private, and mutation screening in the absence of an X-linked family history or tissue from an affected male is problematic.41

Brain

15.8.4 Deficient Arachnoid Granulations

Arachnoid granulations are not visible at birth, but may be seen with a hand lens by age 6 months and with the naked eye by 18 months. Patients present with signs of communicating hydrocephalus, and the diagnosis requires pathologic confirmation.1,42 The condition appears to be extremely rare, although some degree of underascertainment seems likely. The fact that any granulations that are found in these patients are dysplastic supports a developmental rather than an acquired cause. Deficient granulations can readily explain hydrocephalus if they are the site of major CSF absorption. Under the hemodynamic model, the absence of their valve effect would lead to increased venous collapse, and hence an increased resistance to flow. 15.8.5 Associated with Skeletal Dysplasias

The nature of hydrocephalus associated with skeletal dysplasias has been controversial. Achondroplasia is certainly the most studied example, and it was long considered that the mild to moderate dilation observed in most cases was self-limited and perhaps due to hypoplasia of the base of the skull with compression at the level of the foramen magnum. However, although it has been increasingly recognized that the small foramen magnum may compromise the cord and medulla and contribute to the increased mortality in achondroplasia and some other chondrodystrophies, its surgical relief does not alter the ventricular dilation. Although a few patients with achondroplasia have obstructive hydrocephalus, the overwhelming majority have a communicating type.43 Radioisotope cisternography shows evidence of failure of CSF absorption at the level of the sagittal sinus, and, together with evidence of abnormally wide sulci (which become normal with relief of the hydrocephalus), support a hydrodynamic etiology of hydrocephalus due to elevated sinus venous pressure.43,44 The level of venous obstruction appears to be at the point of exit from the skull and may be ultimately selfcorrecting, as the skull base grows and anastomotic venous channels develop. One can speculate that similar venous obstruction could be responsible for hydrocephalus in related chondrodystrophies and conditions causing osteosclerosis.45 Syndromes in which hydrocephalus or ventriculomegaly can be attributed to other CNS malformations, such as holoprosencephaly, Dandy-Walker cyst, Chiari malformation and other intracranial cysts, are treated in their respective sections. Many syndrome descriptions refer to varying degrees of ‘‘ventriculomegaly,’’ often in the face of microcephaly (which can be accompanied by hydrocephalus), and representing ex vacuo/atrophic hydrocephalus. An attempt has been made to exclude such syndromes from Table 15-11, but it is certain that some of the conditions that have been included will lack true hydrocephalus, and some may have been mistakenly excluded. Distribution and Etiology

As discussed by De Lange,4 the prevalence of hydrocephalus is reported to range from 0.1 to 3.5 per 1000, and such figures can only be interpreted in the context of how the data were obtained and what types of cases were included. Rates for spina bifida are known to show geographic, ethnic, and temporal variation, and hydrocephalus associated with spina bifida should therefore always be reported separately. Other factors aside from true biologic population variation, which may contribute to differing rates, may include whether a survey relies on registry reporting or active case ascertainment, whether all births or only live births are in-

625

cluded, and whether the survey is limited to specific age groups. There was some temporal decline in the prevalence of congenital hydrocephalus from 1940 to 1960 that may reflect the parallel decline in the rates of neural tube defects. Stein et al.234 found some evidence of an association with lower socioeconomic status, a higher rate among Puerto Ricans, but a similar rate in blacks and whites, and no association with age or parity. Rates for isolated congenital hydrocephalus cluster in the range of 0.5–0.8 per 1000.4 In a low-risk population, mild prenatal ventriculomegaly occurs at a rate of about 1.48 per 1000 births.235 Unilateral prenatal ventriculomegaly is detected in about 1 in 1400 pregnancies (0.07%), and in two-thirds of cases it is an isolated finding.236 The etiology of hydrocephalus is varied and to a large extent outlined in Table 15-10. Again, the prevalence of each specific type of hydrocephalus and the different causative factors will be influenced by many of the same variables mentioned previously. For example, the perivascular granulomas caused by prenatal toxoplasmosis infection may obliterate the aqueduct. Martinovic et al.237 provided evidence that 15 of 38 infants in Belgrade who had congenital hydrocephalus had contracted toxoplasmosis in utero. Rates of seropositivity in women vary from about 33% in New York City and London to 85% in Paris. Hagberg et al.238 used a modified optimality concept to study factors of history that might play a role in the etiology of hydrocephalus. In this approach, details normally available from the prenatal, perinatal, and postnatal medical records are simply assigned a dichotomous optimal or nonoptimal scoring. In a manner similar to numerical taxonomy, which is perhaps more familiar to dysmorphologists, there is no preconceived weighting of an item’s importance. The authors carried out a case control study of 128 term and 50 preterm children of whom they considered 73 had definite prenatal, 33 definite perinatal, and 72 undefined onset of their hydrocephalus. This compares with previous reports that term infants have 70% prenatal, 25% perinatal, and 5% postnatal, and preterm infants 40%, 60%, and 4%, respectively, causes for their hydrocephalus. Patients in the prenatal group showed significantly higher odds ratios than did the perinatal or control groups for prenatal nonoptimal factors. These included problems in prior pregnancies, recurrent abortion, twinning, and reduced pregnancy interval. Conversely, the perinatal group had increased odds ratios for perinatal factors. The profile of those children with unknown cause was similar to those of term children with a prenatal cause. The rates of the broad categories of congenital hydrocephalus are similar in different surveys, although the exact etiology is usually unknown. Table 15-12 compares data from the studies of Burton239 and of Renier et al.240 Causes of prenatal onset unilateral hydrocephalus include atresia or obstruction of the foramen of Monro, gliosis secondary to inflammation, an association with hemihypertrophy, and it is seen occasionally with absent corpus callosum, but most cases Table 15-12. Proportions of hydrocephaly by various causes Burton75

Renier et al.76

Cause

No.

Percent

No.

Percent

Aqueductal

42

Communicating

39

38.9

88

42.9

36.1

77

Dandy-Walker

37.6

10

9.3

26

Other anatomic

12.7

17

15.7

14

6.8

626

Neuromuscular Systems

remain idiopathic.12 Most cases in adults have an acquired cause but some may represent chance discovery of an asymptomatic unilateral hydrocephalus of prenatal onset. The proportion of aqueductal stenosis that has a genetic basis is difficult to determine, and initial estimates of 2% were not based on firm data. Renier et al.240 considered 6/42 and Burton239 4/88 cases had family histories compatible with X-linked inheritance. Current estimates are that L1CAM mutations account for about 5% of all non-syndromic congenital hydrocephalus.41 The spectrum of the L1CAM-associated X-linked hydrocephaly–MASA gamut accommodates previously reported X-linked families with partial midline fusions and absent corpus callosum.37 Landrieu et al.29 cited animal experiments that demonstrate, in both mutant and virally infected mice, that initial communicating hydrocephalus can lead to aqueductal stenosis. They describe an affected patient (from an extensive family) with X-linked aqueductal stenosis who had a minimal aqueductal measurement of 0.33 cm2. When considering the genetic contribution to aqueductal stenosis, it should be remembered that many X-linked cases are stillborn and that autosomal recessive cases have been reported. There are several non-X-linked animal models of hydrocephalus, notably in rats (H-Tx) and mice, and progress in discovering and understanding the genes in these other species may come to shed light on the etiology in humans. Mice homozygous for mutations in the forkhead/winged helix (Mf1) gene have skeletal and eye anomalies and hydrocephalus associated with abnormal differentiation of arachnoid cells.241 Heterozygous mice, and humans with mutations in the equivalent gene (FOXC1/FREAC3 on 6p25), have Axenfeld-Rieger malformation (iridogoniodysgenesis type 1),242 and testing of human syndromes (Table 15-11) with resemblance to the Mf1 / mouse would be of interest. Other mouse models include Otx2 þ/ (human OTX2 on 14q21-q22) where the pups present with severe lethal hydrocephalus and edematous periventricular white matter243; Tal2 / (human TAL2 on 9q31) in which there is dysgenesis of the midbrain tectum and apparent obstruction of the foramen of Monro244; and Hy3 mice homozygous for mutations in Hydin, which is limited in its expression in the brain to the ciliated lining of the ventricles.245 The latter model appears to underlie developmental anomalies of the subcommissural organ with aqueductal stenosis.5,246 Mice homozygous for a disruption of the nuclear factor 1-A gene (Nfia) (human NFIA on 1p31.3-p31.2) usually die within 2 weeks of birth with absent corpus callosum and early signs of hydrocephalus.247 The few Nfia -/- survivors have an almost normal life span, callosal agenesis, neurologic and fertility deficits, and severe communicating hydrocephalus. Prognosis, Treatment, and Prevention

In discussing the prognosis and treatment of patients with hydrocephalus it is important to consider the age at diagnosis, the type of treatment, the etiology, and whether there are associated intracranial or extracranial malformations. An important group of patients are those in whom the diagnosis is made by prenatal ultrasound done on a routine basis or because of family history or a gestational problem. Not atypical is the report from one center that 38% of its referrals for prenatal assessment were for fetal ventriculomegaly.15 Recent years have seen several reviews of fetal ventriculomegaly (FV) in which the authors have provided guidelines for proper prenatal assessment, stressed variables that can have an impact on prognosis, and compiled summaries of reported series so as to have better information available for expectant parents.14,235,248,249 First and foremost it is critical that the ventricular system is assessed accurately and completely using appropriate landmarks and tech-

nique.235 The echogenic characteristics of the ventricular walls may provide some information as to the underlying etiology, and thus the prognosis. For example, increased echogenicity suggests intraventricular hemorrhage, whereas a thick and irregular appearance that is accompanied by mild atrial dilation can suggest a neuronal migrational defect.249 Studies suggest that measurement of ventricular size can be reliable and reproducible. Mean measurements have ranged from 5.6 to 7.4 mm,14 and generally have shown little variation across gestation from 15 to 35 weeks. Different surveys have found that 10 mm represents anywhere from 2.5 to
4 SD above the mean, but there is consensus that it is a reasonable cut-off for defining FV. Although the mean diameter in males has ranged from 0.1 to 0.6 mm above that in females, and many studies have noted an excess of males with mild FV, the use of a higher figure (e.g., 12 mm) for males has not met with general acceptance.14 The upper limit for the diameter of the 3rd ventricle is 3.5 mm by ultrasound and 4 mm with MRI, and the respective values for the 4th ventricle are 4.8 mm and 7 mm, respectively.249 Mild FV, as defined earlier as >10 to 15 mm, is generally considered to have a better prognosis than that exceeding 15 mm, and it is certainly more common and has attracted most of the attention in recent reports. Therefore, it is interesting to note that in their review Kelly et al.235 found a mean of 40% of cases of FV had an associated malformation, and that the rate was 43% if the summary was limited to those with mild FV. Furthermore, the rate of associated chromosomal anomalies has not always differed between the two groups.250 Perhaps the most important variable in estimating prognosis is whether the FV is isolated or whether it is associated with other CNS and/or extracranial malformations, which will sometimes define a syndrome. Given that fetal imaging is unable to detect all associated anomalies, it can only be said that the fetus has sonographically isolated ventriculomegaly (SIV). A review of studies on the accuracy of the detection of additional anomalies in the face of FV found that 12.8% of fetuses with SIV had another malformation that was detected at follow-up or after birth.14 However, the rates of non-detection vary greatly between individual studies (e.g., 0/27251 to 10/14252). Notwithstanding the small study sizes, the differences seem unlikely to be solely due to chance, and variables that could affect the rate of non-detection would be important to consider when counseling families. There is some evidence that fetuses with minimal ventriculomegaly (<12 mm) are less likely to have associated anomalies and will do better.248,251,253 Critical is the actual gestational age at the time the FV is detected. Several significant CNS malformations are not subject to reliable sonographic diagnosis below 20 weeks gestation. Of the 10 undetected anomalies in the study of Greco et al.,252 there were five with absence of the corpus callosum, one with lissencephaly, and one with heterotopias. Given the greater difficulty in detecting associated CNS malformations in earlier gestations, there seems little to justify attempting to diagnose FV by transvaginal ultrasonography at between 14 to 18 weeks, except where there is a high recurrence risk of a known syndrome.254 Studies also vary widely in the proportion of fetuses subject to amniocentesis for karyotyping, and in the proportion studied for fetal infections such as toxoplasmosis, cytomegalovirus, and parvovirus B19. Variation in the frequency of associated chromosome anomalies can reasonably be attributed to the small sample size in most studies. In summarizing the literature, Kelly et al.235 concluded that 9% of 491 fetuses with mild FV had a chromosome anomaly and that the rate fell to 4% if cases with

Brain

other malformations were excluded. This is comparable to the 14/ 324 (4.3%) reported by Wax et al.14 The use of ancillary fetal MRI can also affect the status of a fetus with SIV but has been used in relatively few series to date. In one such study the addition of MRI provided additional information in 32.8% of 51 cases and provided a diagnosis in 21.3%.255 A further potential variable is the natural history of the ventriculomegaly. A summary to date of mild FV suggests that about 29% will resolve, 57% remain stable, and 14% progress. The prognosis of the first group is not guaranteed to be normal; it has been suggested to be superior,253,256 although some have argued that some of such cases do not merit the diagnosis of FV.257 Those fetuses in which the ventriculomegaly progresses, both isolated and in association with additional anomalies, appear to have a worse prognosis,256 and the data from Pilu et al.248 suggest females with FV may be at greater risk for a poor developmental outcome. Finally, in addition to the caveats outlined previously, outcome data are variably compromised by underlying case heterogeneity, notably whether or not patients with meningomyeloceles have been excluded, a generally limited period of follow-up, and lack of constant and formal developmental evaluations.249 However, Wax et al.14 found favorable outcomes in 168/199 (84.4%) of cases that had normal chromosomes, and Kelly et al.235 estimated an overall 90% favorable outcome. Where delay does occur in SIV with normal chromosomes it is most often in the mild range. By contrast to SIV, Wax et al.14 noted that 20/108 (18.5%) of fetuses with additional ultrasound anomalies had a chromosome abnormality and that 18/ 40 (45%) had developmental delay. Clearly there is a dichotomy based on the presence or absence of associated anomalies. However, some circumspection is necessary until more long-term information is available for children who had SIV. For example a small study of five children with mild FV, followed at the ages of 4 to 9 years, found one with ADHD, one with autism, and two with learning disablity.258 Another small controlled study of 22 pairs of children at a mean postnatal age of about 22 months found that children who had FV were at significantly increased risk of developmental delay.259 Guidelines for the management of FV include a detailed pregnancy and family history, an ultrasound search for intracranial and extracranial anomalies including the soft signs of aneuploidy and/or evidence of an NTD, serial ultrasounds to continue the search for anomalies and to follow the course of the FV, screening for teratogenic infections, consideration of fetal karyotyping, and fetal MRI. A search for potential causes of fetal intracranial hemorrhage has been suggested by some235 but has a relatively low yield and perhaps can be reserved for cases where the ultrasound is suggestive of a bleed. It has been suggested that unilateral, prenatal ventriculomegaly may have a generally better prognosis than its bilateral counterpart, and that it should be considered separately. Wax et al.14 summarized cases from the literature and none of 47 had a significant anomaly detected postnatally; 1 of 30 had a chromosome anomaly; and 3 of 51 were developmentally delayed. A review of 55 cases from the recent literature12,26,27,236 is perhaps not quite as optimistic. At least five cases underwent spontaneous resolution; a further 32 were considered normal at follow-up; 18 had a variety of associated findings and/or developmental delay. Included in the latter patients were three with atresia of the foramen of Monro, four with a syndrome, two with prenatal intracranial bleeds, four with associated intracranial developmental pathology, one with toxoplasmosis, and four with idiopathic neurologic impairment. Two patients had died and three pregnancies were terminated. The lack of any associated anomalies and a stable or resolving ventriculomegaly was highly associated with a good outcome, with the converse suggestive of a

627

poor prognosis. Thus, management requires a careful ultrasound and/or MRI search for associated CNS or non-CNS anomalies and continued monitoring during pregnancy and after delivery. Not all patients will require intervention.12 Overall the developmental outlook for children with congenital hydrocephalus is poor, and fetuses in which the diagnosis of hydrocephalus is made before 32 weeks gestation do worse than those in whom the diagnosis is made later in pregnancy. This suggests that there could be a role for the in utero shunting of early progressive hydrocephalus. In addition some animal studies have suggested some benefit from in utero shunting. Studies of human fetuses and animal experimentation have shown hydrocephalusrelated changes in brain histology, including impaired myelinization and neuronal migration, axonal damage and degeneration, neuronal loss, decreased synapses, and gliosis.260 In a rat model, Del Bigio261 and co-workers have shown white matter injury due to elevated calcium and activation of proteolytic calpains. Blood flow is seen to increase with shunting and normalization of pressure; but while there was some recovery of myelinization and lamination, there was only partial recovery of synapses and neuronal size. Experimental studies have also shown early initial changes in cellular membrane lipids, followed by decreased levels of intracellular metabolites, thus resulting in cellular swelling and loss of osmolytes and neurotransmitters.262 The outcomes from initial attempts to install in utero shunts in humans have been disappointing, but at least in part this might be attributable to the inclusion of patients with additional CNS pathology. A voluntary international registry was established, and it formulated guidelines for the selection of patients for in utero placements of shunts. Patients with additional CNS anomalies were to be excluded.260 Forty-one patients were reported to the registry, and they had a mean gestational age at diagnosis of 25 þ/ 2.7 weeks and at treatment of 27 þ/ 2.6 weeks.263 Twenty-two percent were later found to have undetected associated CNS malformations that included holoprosencephaly, Dandy-Walker cyst, porencephaly, and Arnold-Chiari malformation. Of the 83% who survived surgery and were born alive, 53% had serious and 12% mild to moderate handicap. Although survival was somewhat improved, normal development was limited to patients with isolated aqueductal stenosis, a group that has faired at least as well in historical samples. Thus, fetal shunt procedures were largely abandoned in the late 1980s when reviews showed either no improvement or worse outcome in fetuses which were treated prenatally as compared to those treated postnatally.260,263 However, von Koch et al.260 have pointed out that with improved fetal MRI imaging to detect associated CNS malformations, and advances in cytogenetic and molecular prenatal diagnosis, it may be time to reevaluate the role of surgical intervention in a selected subpopulation of fetuses with early progressive hydrocephalus. They argue that the worse prognosis in fetal as compared with neonatal and pediatric diagnosed cases reflects in utero damage that is irreversible by the time of postnatal surgery. Although the argument is quite compelling, it is possible that the earlier onset in the fetal cases is in itself a marker for a more severe underlying CNS pathology, which has an inherently poorer prognosis and will be unaltered by fetal intervention. The answer will only come from a properly designed randomized comparison of intervention with non-intervention. Early induction of labor in the face of advancing hydrocephalus is a balance between the risks of prematurity and the hope that earlier shunting will prevent further brain damage, which would be irreversible at term. There is some consensus to

628

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deliver at about 32 weeks or beyond, depending on lung maturity and clinical aspects surrounding the hydrocephalus. Of children with congenital hydrocephalus unassociated with spina bifida, about 24% are stillborn and 17% die as neonates.234 Eighty-four percent of the 108 children reported by Renier et al.240 were treated at less than 3 months and were followed from 1 to 10 years. Of the 75 1iving at the time of study, 28% had an IQ >80, and in 50% it was < 60. The OFC, ventricular size, and age at surgery were not prognostic of outcome; lack of associated malformations, shunt infections and failures, a developmental quotient of >80 at 6 months, and aqueductal stenosis not due to an X-linked gene or to toxoplasmosis predicted a good outcome. Aqueductal stenosis had an 80% survival to age 10 years and almost one-half had a normal IQ compared with 60% and 20%, respectively, for communicating hydrocephalus. Shunt infections in the perinatal period are often due to gram-negative organisms and can be extremely damaging. Renier et al.240 reported that only 5% of neonates with infected shunts had a normal IQ at the mean follow-up of 7 years, and that half had died by the age of 10 years. In a survey of 1450 cases treated for hydrocephalus, Mori et al.22 confirmed a poor outcome (IQ < 50) was more common in congenital cases, and that associated CNS malformations, seizures, and an increased OFC at birth were predictors of a poor outcome. Fernell et al.264 studied 47 patients in whom hydrocephalus was present at birth from among a group of 202 children with infantile hydrocephalus. Patients with spina bifida were excluded. Thirteen were not shunted, five because it was not required and eight, all of whom died, because of the severity of their problems. Eight of the 34 who were shunted died. Of those over age 2 years, 27% had cerebral palsy, 55% had seizures, and 45% had delayed development, most with an IQ < 50. Only 11 had no major dysfunction. The presence of additional malformations was again a poor prognostic sign. Donders et al.265 reviewed previous studies regarding the importance of early medical variables as predictors of long-term outcome. Problems with earlier studies included variable and often ill-defined sample selection, lack of definition of outcome measures, variation in the medical parameters included in the studies, and inadequate statistical evaluation. The authors reported a multivariate analysis of a mixed group of 48 patients treated before age 1 year and who were between 5.6 and 8.6 years at follow-up. They found that neonatal and infancy problems, most commonly anoxia (and/or early seizures) and ocular defects, were highly predictive of a performance and verbal IQ of < 71. A lacunar skull deformity was associated with a low verbal score. As discussed, the expanding cranium can allow for significant ventricular enlargement and cortical thinning without any actual loss of parenchyma. However, very high-grade ventriculomegaly with cortical thinning and poor response to shunting has been associated with a poor prognosis.264 Young et al.266 used pneumoencephalography to estimate mantle thickness at the time of assessing IQ in 147 patients aged 3 to 20 years. Forty-two of 59 children with isolated hydrocephalus, mostly aqueductal stenosis, had an IQ >80, and 41 had a cerebral mantle of >2.8 cm. Above 2.8 cm there was no correlation with IQ. Ten of those with an IQ < 80 and a mantel < 2.8 cm were treated either late or inadequately. The thickness of the cerebral mantle at the time of diagnosis and the time of the study were both related to early treatment. All patients who were treated before 6 months had a mantle of >2.8 cm, although seven had an IQ < 80. The authors argued that early shunting improved prognosis. Although the case is not proven in that other factors influencing early detection and

presentation could apply, it would appear reasonable to advocate early recognition and treatment of isolated hydrocephalus. However, whereas 41/48 children with isolated hydrocephalus were considered normal, only one-half of 39 children with spina bifida and a mantle of >2.8 cm had an IQ >80. Previous studies of untreated survivors have shown no correlation with mantle thickness and IQ. There are also reports of patients with a normal IQ and mantle thickness of 0.5 cm at the time of treatment.267 Pediatric patients with treated isolated hydrocephalus may show a pattern of motor dysfunction, notably of gait, cognitive problems, especially in non-verbal performance,268 and hypothalamic disturbance resulting in growth failure and short stature. Specific difficulties in coordination, mathematics, and reading269 could result in difficulties with social integration and consequent maladaptive behavior. Difficulties with visuospatial processing and memory have also been described.268 However, Hommet et al.,268 in a study that included eight adults with isolated aqueductal stenosis, found no discrepancy between verbal and non-verbal performance or verbal versus visuospatial memory, and no abnormalities on the Vineland Adaptive Behavioral Scale. Overall, those patients with aqueductal stenosis outperformed those with spina bifida. That shunting can have an immediate benefit was shown in an older population by Czepko et al.270 who performed neuropsychological testing before and 4 to 8 months after shunt placement. Of the 45 treated patients, 81.4% showed improved functioning, 7% were unchanged, and 11.6% declined. Poor prognostic signs included cerebral atrophy and symptomatology that had been present for more than a year. Castro-Gago et al.271 have suggested that measurement of CSF oxypurine values can be used to select patients who require shunting and to follow the status of those who have been shunted. Values of CSF xanthine, hypoxanthine, and total oxypurine were significantly elevated over those in normal controls and in children with self-compensated hydrocephalus. The elevated values returned to normal with treatment and were considered to reflect tissue and cellular hypoxia. A discussion of the indication for specific placements and types of shunts is beyond the scope of this discussion; the reader is referred to standard neurosurgical references. Ventriculoperitoneal and cystoperitoneal shunts have been the standard method of CSF diversion for over 40 years, but while they can be highly effective, they are also plagued by a long list of potential complications, some of which are rather common. Among the difficulties that can arise, which include slit 3rd ventricle, craniosynostosis, lumbar canal stenosis, subdural hematomas, sylvian aqueduct syndrome, chronic tonsilar herniation, non-resorptive peritoneal ascites, trapped 4th ventricle, and renal and/or cardiac failure with ventriculoatrial shunts,272 infection and various types of shunt failure are the most important. Newer techniques of manufacture have reduced material failures, but shunt obstruction and migration still occur. Development of anti-siphon valves to prevent transmission of negative pressure from the pleural space may allow the safer use of ventriculopleural drainage when other approaches may be precluded by complications such as peritoneal adhesions, peritonitis, or persistent ascites.273 However, shunt obstruction is an ongoing risk to patients; in a series of 1564 children followed by Vinchon et al.274 for a mean of 10.7 years, they observed that 70.7% required at least one revision. They found that children whose shunt failure was detected and repaired while they were asymptomatic showed a lower rate of shunt infection and recurrent shunt failure than those children whose shunt replacement occurred after they became symptomatic.

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The rate of shunt infection has varied from < 1–30%, and a rate of about 10% has been treated as acceptable.275 About 90% of infections occur in the first 6 months after surgery,276 many in the first 2 months, and infection introduced at the time of surgery is believed to be the main source. Several centers have shown a reduction in rates of infection in parallel with changes in type of shunt and surgical protocols.275-277 Staphlococcus epidermidis is the causative agent in most cases, but Caboulives et al.276 completed a meta-analysis with the conclusion that there were inadequate data on which to base a recommendation for or against prophylactic antibiotics. A prospective randomized trial of a standard shunt versus an antibiotic impregnated shunt (AIS) had infection in 10/60 of the controls and 3/50 of the AIS group.278 All the control group infections, but none of those in the AIS group, were with S. epidermidis. Complications and infections are much more common in preterm and term neonates than in older children. For example, Bruinsma et al.279 had a 46.4% rate of infection in 28 patients who were < 37 weeks gestation at the time of surgery, as compared to 19.6% in those under 6 months at the time of surgery. A not infrequent complication of shunting is the development of shunt dependence, the requirement for a shunt even after the initial cause for the hydrocephalus has been resolved. As discussed earlier, the cerebral veins are thought to play an important role in the regulation of cerebral blood flow and in CSF dynamics. One hypothesis for shunt dependence is that chronic drainage by the shunt leads to persistent venous dilation, and that the venous role is subverted and hard to regain, even after the shunt is removed.9 Initial work with programmable valves, which can be used to reduce venous drainage and increase intraventricular pressure, suggest that this approach may allow a greater proportion of shunts to be removed.280 Close monitoring is required with this approach. Historically, several other approaches to the relief of hydrocephalus, such as aqueductal stenting and 3rd ventriculostomy, have been attempted and largely abandoned because of the surgical complexity and high associated morbidity. However, the development of fiberoptic endoscopy opened up the option of 3rd ventriculostomy, in which a stoma is created in the floor of the 3rd ventricle, allowing the CSF to drain into the subarachnoid space of the interpeduncular cistern. Initial enthusiasm has been tempered somewhat by the reality of complications and failures.272 However, in carefully selected patients it has significant advantages and may be the treatment of choice. Brockmeyer et al.281 attempted 98 ventriculostomy procedures on 97 patients, of which 26 were abandoned because of the anatomy found at surgery, inability to perform the cisterotomy, or bleeding. Of the 71 patients who had a completed procedure, 49% were successful, either in avoiding a shunt or in allowing a shunt to be removed. Although the numbers were small, the greatest rate of success was with aqueductal stenosis, posterior fossa and tectal plate tumors, and the slit ventricle syndrome. A prior history of having a shunt was the only factor significantly associated with failure. Greitz et al.9 suggest that chronic ventricular dilation causes compression of the subarachnoid space and restricted arterial pulsation, thus converting an obstructive hydrocephalus into a communicating hydrocephalus, which is not aided by the 3rd ventriculostomy. Cinalli272 has emphasized the importance of accurately diagnosing aqueductal stenosis, so as to diminish failure rates. Whereas some authors have suggested radiologic criteria that would exclude certain patients from ventriculostomy, he has argued that those criteria change with insertion of the endoscope and removal of a

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small amount of CSF, and that a decision as to whether or not to proceed to ventriculostomy can be made at the time of surgery. The decrease in ventricular size is less, and slower to occur, with ventriculostomy than with a shunt,272 and continuous intracranial monitoring has been suggested as an effective way to follow these patients in the postoperative period and to deal with the intracranial hypertension that can occur.282 To date there is no randomized controlled trial of ventriculostomy versus shunting. Retrospective studies do not show significant differences in mortality, neurologic or endocrine dysfunction, behavior or social status.272 Data from series suggest that 80% of patients with isolated aqueductal stenosis treated by 3rd ventriculostomy have an IQ of over 80.283 Failures occur with the procedure, including sealing of the stoma, but in selected cases may be  25% at 6 years.272 Cinalli272 disagrees with those who state that age  1 year is a factor in treatment failure. The slit ventricle syndrome is an uncommon complication of treatment that merits brief mention because it may go unrecognized and have serious consequences. Following successful shunting, the ventricles assume a normal or even reduced size. A small number of patients present, usually 3 to 5 years after their first early shunt, with chronic or intermittent headache, nausea and vomiting, and occasionally loss of consciousness in the absence of ventriculomegaly. This slit ventricle syndrome was believed to be due to periodic shunt blockage resulting from the narrowly apposed ventricular walls, but the true situation is likely more complex and may relate to changes in intracranial CSF space and compliance, secondary to chronic CSF drainage.284 The underlying problem may be an excess drainage of CSF, and Greitz et al.9 believe that this causes a reduction of systolic expulsion of CSF through the foramen magnum with a corresponding reduction in diastolic venous counter pressure, thus creating a communicating hydrocephalus. Epstein et al.285 reported 20 cases from among 2000 patients. In 6 of the 20, ventricular size was normal when asymptomatic, but moderately increased while symptomatic, thus documenting intermittent shunt malfunction. They stressed the importance of doing diagnostic studies while the patient is symptomatic. The remaining 14 children had a relatively small calvarium and elevated CSF pressure in the face of normal shunt function. They hypothesized that initial shunting led to collapse of the skull and fusion of the sutures, and those patients benefited from craniectomies. There has been moderate success in treating slit ventricle by ventriculostomy.281 To a large extent prevention of hydrocephalus awaits increased knowledge and understanding of its many prenatal, perinatal, and postnatal causes, including infections and trauma. Ultimately, public health measures aimed at preventing prenatal infection and at improving prenatal and obstetric care can be expected to have their impact. Hydrocephalus associated with perinatal hemorrhage has a generally poor prognosis and is an important complication of prematurity. Several preventive and therapeutic approaches have been attempted including streptokinase, urokinase, plasminogen activator, steroids, hyaluronidase, and selective venous dilators.260 Meta-analysis has shown no benefit, and an increased need for ventilator support, with phenobarbitone,286 and no evidence to date of benefit from intraventricular streptokinase.287 A phase 1 trial of drainage, irrigation with artificial CSF, and prior intravenous plasminogen activator has shown a downward trend in mortality, and single and multiple disabilities.288 Alloimmune thrombocytopenia affects about 0.01% of pregnancies, and about 10–20% of those will suffer either a prenatal or perinatal intracranial bleed that may lead to hydrocephalus. Maternal treatment with high-dose immunoglobulin and/or corticosteroids may significantly reduce this risk.289

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Appropriate counseling and advice regarding prenatal diagnosis should be provided to the family at risk for recurrence of a specific syndrome. In the absence of a specific syndrome, including proven X-linked hydrocephalus, empiric recurrence risk data must be applied. However, even in the absence of a syndrome diagnosis, it is important to distinguish isolated hydrocephalus from that associated with other CNS malformations. The 205 patients reported by Burton239 had 353 siblings, of whom 5 were also affected. This included 4 males of 123 siblings of male index cases with aqueductal stenosis who also had other matrilineal male-affected relatives. This provided a 6% risk to siblings, and a 12% risk to male siblings, of males with aqueductal stenosis. There was one recurrence among 154 siblings of patients with communicating hydrocephalus, 0/54 with Dandy-Walker malformation, and 0/22 in the ‘‘other’’ category. Howard et al.290 provide a 4.5% recurrence risk for a male sibling and 2% for a female sibling of a male propositus with aqueductal stenosis, and a 1% risk for all siblings of a female propositus. Varadi et al.291 followed 261 pregnancies of 362 couples who had been referred because of a personal or family history of a child with hydrocephalus. They considered children with neural tube defects, other associated malformations, and no associated anomalies as distinct groups. Parents of one previous child with isolated hydrocephalus experienced a 5/89 (5.6%) recurrence rate. In two instances, both propositus and sibling were male. Hydrocephalus was not broken down into communicating versus aqueductal. The higher recurrence rates are likely due in part to the prenatal/ prospective nature of the study, and may also reflect relatively small numbers. Haverkamp et al.292 recently proposed a genetic etiology for 13 of 35 (37%) of their cases of aqueductal stenosis. However, they included both members of two sibling sets in the total (11/33 more appropriate), assumed that all four cases of VACTERL syndrome with hydrocephalus were mendelian, and included a case of Krabbe disease, as well as four cases of ‘‘phenotypic abnormalities not classified’’ in the genetic total. A cautious approach is needed if using these types of data in genetic counseling. Summarizing data to date, male siblings of a male propositus with aqueductal stenosis have a 12% risk, female siblings a 6% risk, and the siblings of a female propositus a 2% risk for hydrocephalus.292 Adams et al.293 addressed and summarized the question as to whether relatives of propositi who have isolated hydrocephalus are at greater risk for neural tube defects. They found that in 74 families in which there were 159 siblings, three (1.83%) had hydrocephalus and one (0.63%) had spina bifida. Seven of 846 first cousins had spina bifida, one anencephaly, and three isolated hydrocephalus. Thus, there was no increased incidence of neural tube defects over that expected in the general Northern Ireland population. Other studies have suggested an increased risk, and differences may reflect endemic versus nonendemic neural tube defects and the possibility of unrecognized neural tube defects in the index patients with hydrocephalus. Journel et al.294 examined the question from the opposite perspective and studied the rate of hydrocephalus among the relatives of propositi with neural tube defects. Three of 691 siblings had hydrocephalus, whereas rates of 1/460 and 1/430 were found in uncles and cousins, respectively. This was considered to be somewhat increased over expected, but unfortunately there were no control groups or local data on the frequency of hydrocephalus. Finally, a cautious approach to the prospective prenatal ultrasound diagnosis of hydrocephalus is emphasized. As discussed

in some detail, a fetus with a mild ventriculomegaly may not have true and/or progressive hydrocephalus and has a generally good prognosis. Second, ventriculomegaly may become apparent after the usual 20-week window for prenatal diagnosis. Friedman et al.295 reported two patients with X-linked aqueductal stenosis who had normal studies at 17–18 weeks, ventriculomegaly by 22 weeks, and an increased biparietal diameter by 30 weeks. References (Hydrocephalus) 1. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 203. 2. Bell, WO: Cerebrospinal fluid reabsorption. Concepts Pediatr Neurosurg 10:214, 1990. 3. Mortensen OA, Weed LH: Absorption of isotonic fluids from subarachnoid space. Am J Physiol l08:458, 1934. 4. De Lange SA: Progressive hydrocephalus. In: Handbook of Clinical Neurology. Congenital Malformations of the Brain and Skull, Part I. PJ Vinkin, GW Bruyn, eds. North Holland Publishing, Amsterdam, 1977, p 525. 5. Perez-Figares JM, Jimenez AJ, Rodriguez EM: Subcommissural organ, cerebrospinal fluid circulation, and hydrocephalus. Microsc Res Tech 52:591, 2001. 6. Mawera G, Asala SA: The function of arachnoid villi/granulations revisited. Cent Afr J Med 42:281, 1996. 7. Johnston M, Papaiconomou C: Cerebrospinal fluid transport: a lymphatic perpspective. News Physiol Sci 17:227, 2002. 8. Greitz D, Hannerz J: A proposed model of cerebrospinal fluid circulation; observations with radionuclide cisternography. AJNR Am J Neuroradiol 17:431, 1996. 9. Greitz D, Greitz T, Hindmarsh T: A new view on the CSF-circulation with the potential for pharmacological treatment of childhood hydrocephalus. Acta Pediatr 86:125, 1997. 10. Reed DJ, Woodbury DM: Kinetics of iodide, sucrose, inulin, and radio-iodinated serum albumin in the central nervous system and cerebrospinal fluid of the rat. J Physiol 169:816, 1963. 11. Kollar CD, Johnston IH, Sholler GF: Communicating hydrocephalus secondary to a cardiac tumour compressing the superior vena cava. Child Nerv Syst 17:117, 2001. 12. Sherer DM, Allen TA, Ghezzi F: Prenatal diagnosis of moderate unilateral hydrocephalus subsequently not requiring neonatal decompression. Am J Perinatol 12:50, 1995. 13. Johnson ML, Dunne MG, Mack, LA, et al.: Evaluation of fetal intracranial anatomy by static and real time ultrasound. J Clin Ultrasound 8:311, 1980. 14. Wax J, Bookman L, Cartin A, et al.: Mild fetal ventriculomegaly: diagnosis, clinical associations, and outcomes. Obstet Gynecol Surv 58: 407, 2003. 15. Girard NJ, Raybaud CA: Ventriculomegaly and pericerebral CSF collection in the fetus: early stage of benign external hydrocephalus? Child Nerv System 17:239, 2001. 16. Lowry DW, Lowry DL, Berga SL, et al.: Secondary amenorrhea due to hydrocephalus treated with endoscopic ventriculostomy. Case report. J Neurosurg 85:1148, 1996. 17. Kirkpatrick M, Engleman H, Minns RA: Symptoms and signs of progressive hydrocephalus. Arch Dis Child 64:124, 1989. 18. Di Rocco C, Caldarelli M, Ceddia A: ‘‘Occult’’ hydrocephalus in children. Child Nerv Syst 5:71, 1989. 19. Bromberger P, James HE, Saunders B, et al.: Sudden infant apnea and insidious hydrocephalus. Child Nerv Syst 4:241, 1988. 20. Corbett JJ: Neuro-ophthalmologic complications of hydrocephalus and shunting procedures. Semin Neurol 6:111, 1986. 21. Bech RA, Juhler M: Unusual manifestations of disturbed CSF dynamics in hydrocephalic chidren. Child Nerv Syst 16:446, 2000. 22. Mori K, Shimada J, Kurisaka M, et al.: Classification of hydrocephalus and outcome of treatment. Brain Dev 17:338, 1995. 23. Barkovich AJ, Edwards MSB: Applications of neuroimaging in hydrocephalus. Pediatr Neurosurg 18:65, 1992.

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631 51. Verloes A, Gillerot Y, Walczak E, et al.: Acromelic frontonasal ‘‘dysplasia’’: further delineation of a subtype with brain malformation and polydactyly (Toriello syndrome). Am J Med Genet 42:180, 1992. 52. Dube P, Der Kaloustian VM, Demczuk S, et al.: A new association of congenital hydrocephalus, albinism, megalocornea, and retinal coloboma in a syndromic child: a clinical and genetic study. Ophthalmic Genet 21:211, 2000. 53. al-Gazali LI, Bakir M, Sadaghatian MR, et al.: Anterior segment anomalies of the eye associated with multiple skeletal abnormalities and early lethality: confirmation of an autosomal recessive syndrome. Clin Dysmorphol 8:87, 1999. 54. al-Gazali LI, Aziz SAA, Salem F: A syndrome of short stature, mental retardation, facial dysmorphism, short webbed neck, skin changes and congenital heart disease. Clin Dysmorphol 5:321, 1996. 55. Musumeci SA, Elia M, Ferri R, et al.: A further family with epilepsy, dementia and yellow teeth: the Kohlschutter syndrome. Brain Dev 17: 133, 1995. 56. Fraser FC, Anderson RA, Mulvihill JI, et al.: An aminopterin-like syndrome without aminopterin (ASSAS). Clin Genet 32:28, 1987. 57. Reich EW, Cox RP, Decker MH, et al.: Recognition in adult patients of malformations induced by folic-acid antagonists. Birth Defects Orig Artic Ser XIV(6B):139,1978. 58. Chong SKF, Levitt GA, Lawson J, et al: Subarachnoid cyst with hydrocephalus-a complication of mid-trimester amniocentesis. Prenat Diagn 9:677, 1989. 59. Baker DW, Vinters HV: Hydrocephalus with cerebral aqueductal dysgenesis and craniofacial anomalies. Acta Neuropathol 63:170, 1984. 60. Sommer A, Rathbun MA, Battles ML: A syndrome of partial aniridia, unilateral renal agenesis, and mild psychomotor retardation in siblings. J Pediatr 85:870, 1974. 61. Leichtman LG, Wood B, Rohn R: Anophthalmia, cleft lip/palate, facial anomalies, and CNS anomalies and hypothalamic disorder in a newborn: a midline developmental field defect. Am J Med Genet 50:39, 1994. 62. Richeri-Costa A, Guin-Almeida ML: Mental retardation, structural anomalies of the central nervous system, anophthalmia and abnormal nares: A new MCA/MR syndrome of unknown cause. Am J Med Genet 47:702, 1993. 63. Gunderson CA, Stone R, Peiffer R, et al.: Corneal coloboma, aphakia and retinal neovascularization with anterior segment dysgenesis (Peters’ anomaly). Ophthalmologia 210:361, 1996. 64. Slee J, Goldblatt J: Further evidence for a syndrome of ‘‘apple peel’’ intestinal atresia, ocular anomalies and microcephaly. Clin Genet 50:260, 1996. 65. Verhagen WIM, Bartels RHAM, Fransen E, et al.: Familial congenital hydrocephalus and aqueduct stenosis with probably autosomal dominant inheritance and variable expression. J Neurol Sci 158:101, 1998. 66. Zlotogora J, Sagi M, Cohen T: Familial hydrocephalus of prenatal onset. Am J Med Genet 49:202, 1994. 67. Sajid MH, Copple PJ: Familial aqueduct stenosis and basilar impression. Neurology 18:260, 1968. 68. Stern HJ, Graham J Jr, Lachman RS, et al.: Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet 36:183, 1990. 69. Moog U, Bleeker-Wagemakers EM, Crobach P, et al.: Sibs with AxenfeldRieger anomaly, hydrocephalus, and leptomeningeal calcifications: A new autosomal recessive syndrome? Am J Med Genet 78:263, 1998. 70. Russell LJ, Weaver DD, Bull MJ: The axial mesodermal dysplasia spectrum. Pediatrics 67:176, 1981. 71. Barnicoat AJ, Salman M, Chitty L, et al.: A distinctive overgrowth syndrome with polysyndactyly. Clin Dysmorphol 5:339, 1996. 72. Lo Muzio L, Nocini PF, Savoia A, et al.: Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 55:34, 1999. 73. Beemer FA, Ertbruggen IV: Peculiar facial appearance, hydrocephalus, double-outlet right ventricle, genital anomalies and dense bones with lethal outcome. Am J Med Genet 19:391, 1984. 74. Bellini F, Chiumello G, Rimoldi R, et al.: Wedge-shaped epiphyses of the knees in two siblings: a new recessive rare dysplasia? Helv Paediatr Acta 39:365, 1984.

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a previously unrecognized autosomal recessive disorder? Clin Dysmorphol 5:313, 1996. Winter RM, Campbell S, Wigglesworth JS, et al.: A previously undescribed syndrome of thoracic dysplasia and communicating hydrocephalus in two sibs, one diagnosed prenatally by ultrasound. J Med Genet 24:204, 1987. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. Mathias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. Kang WM, Huang CC, Lin SJ: X-linked recessive inheritance of dysgenesis of corpus callosum in a Chinese family. Am J Med Genet. 44:619, 1992. Joseph M, Shashidhar P, Kenton R, et al.: X-linked myotubular myopathy: clinical observations in ten additional cases. Am J Med Genet 59:168, 1995. Zaglul HF, Odita JC: Multiple herniae: a defect in the celomic mesoderm? Am J Med Genet 57:537, 1995. Zimmer EZ, Taub E, Sova Y, et al.: Tetra-amelia with multiple malformations in six male fetuses of one kindred. Eur J Pediatr 144:412, 1985. Zolotukhina T, Kuznetov M, Lurie I, et al.: Unusual complex of congenital malformations. Am J Med Genet 46:728, 1993. Stein SC, Feldman JG, Stewart A, et al.: The epidemiology of congenital hydrocephalus: a study in Brooklyn, N.Y. 1958–1976. Child Brain 8:253, 1981. Kelly EN, Allen VM, Seaward AG, et al.: Mild ventriculomegaly in the fetus, natural history, associated findings and outcome of isolated mild ventriculomegaly: a literature review. Prenat Diagn 21:697, 2001. Kinzler WL, Smulian JC, McLean DA, et al.: Outcome of prenatally diagnosed mild unilateral cerebral ventriculomegaly. J Ultrasound Med 20:179, 2001. Martinovic J, Sibalic D, Djordjovic M, et al.: Frequency of toxoplasmosis in the appearance of congenital hydrocephalus. J Neurosurg 56:830, 1982. Hagberg C, Femell E, von Wendt: Epidemiology of infantile hydrocephalus in Sweden: reduced optimality in prepartum, partum and postpartum conditions. A case control study. Neuropediatrics 19:16, 1988. Burton BK: Recurrence risks for congenital hydrocephalus. Clin Genet 16:47, 1979. Renier D, Sainte-Rose C, Pierre-Kahn A, et al.: Prenatal hydrocephalus: outcome and prognosis. Child Nerv Syst 4:213, 1988. Kume T, Deng KY, Winfrey V, et al.: The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 93:985, 1998. Hong HK, Lass JH, Chakravarti A: Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix/forkhead transcription factor gene. Hum Mol Genet 8:625, 1999. Makiyama Y, Shoji S, Mizusawa H: Hydrocephalus in the Otx þ/– mutant mouse. Exp Neurol 148:215, 1997. Bucher K, Sofroniew MV, Pannell R, et al.: The T cell oncogene Tal2 is necessary for normal development of the mouse brain. Dev Biol 227:533, 2000. Davy BE, Robinson ML: Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum Mol Genet 12:1163, 2003. Wagner C, Batiz LF, Rodriguez S, et al.: Cellular mechanisms involved in the stenosis and obliteration of the cerebral aqueduct of hyh mutant mice developing congenital hydrocephalus. J Neuropathol Exp Neurol 62:1019, 2003. das Neves L, Duchala CS, Tolentino-Silva F, et al.: Disruption of the murine nuclear factor I-A (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc Natl Acad Sci USA 96:11946, 1999. Pilu G, Falco P, Gabrielli S, et al.: The clinical significance of fetal isolated cerebral borderline ventriculomegaly: report of 31 cases and review of the literature. Ultrasound Obstet Gynecol 14:320, 1999.

635 249. Garel C, Luton D, Oury J-F, et al.: Ventricular dilatations. Child Nerv Syst 19:517, 2003. 250. Graham E, Duhl A, Ural S, et al.: The degree of antenatal ventriculomegaly is related to pediatric neurological morbidity. J Matern Fetal Med 10:258, 2001. 251. Bromley B, Frigoletto FD, Benacerraf B: Mild fetal lateral cerebral ventriculomegaly: clinical course and outcome. Am J Obstet Gynecol 164:863, 1991. 252. Greco P, Vimercati A, De Cosmo L, et al.: Mild ventriculomegaly as a counselling challenge. Fetal Diagn Ther 16:398, 2001. 253. Mercier A, Eurin D, Mercier PY, et al.: Isolated mild fetal cerebral ventriculomegaly: a retrospective analysis of 26 cases. Prenat Diagn 21:589, 2001. 254. Monteagudo A, Timor-Trisch IE, Moomjy M: In utero detection of ventriculomegaly during the second and third trimesters by transvaginal sonography. Ultrasound Obstet Gynecol 4:193, 1994. 255. Launay S, Robert Y, Valat AS, et al.: IRM ce´re´brale foetale et ventriculome´galie. J Radiol 83:723, 2002. 256. Bannister CM, Russel SA, Rimmer S, et al.: Pre-natal ventriculomegaly and hydrocephalus. Neurol Res 22:37, 2000. 257. Greco P, Vimercati A, Selvaggi L: Isolated mild fetal cerebral ventriculomegaly. Prenat Diagn 22:158, 2002. 258. Gilmore JH, van Tol JJ, Lewis Streicher H, et al.: Outcome in children with fetal mild ventriculomegaly: a case series. Schizophr Res 48:219, 2001. 259. Bloom SL, Bloom DD, Dellanebbia C, et al.: The developmental outcome of children with antenatal mild isolated ventriculomegaly. Obstet Gynecol 90:93, 1997 260. Von Koch CS, Gupta N, Sutton LN, et al.: In utero surgery for hydrocephalus. Child Nerv Syst 19:574, 2003. 261. Del Bigio MR: Future directions for therapy of childhood hydrocephalus: a view from the laboratory. Pediatr Neurosurg 34:172, 2001. 262. Jones HC, Harris NG, Rocca JR, et al.: Progressive changes in cortical metabolites at three stages of infantile hydrocephalus studied by in vitro NMR spectroscopy. J Neurotrauma 14:587, 1997. 263. Pinckert TL, Golbus MS: Fetal surgery. Clin Perinatol 15:943, 1988. 264. Fernell E, Uvebrant P, von Wendt L: Overt hydrocephalus at birthorigin and outcome. Child Nerv Syst 3:350, 1987. 265. Donders J, Canady AI, Rourke BP: Psychometric intelligence after infantile hydrocephalus: a critical review and reinterpretation. Child Nerv Syst 6:148, 1990. 266. Young HF, Nulsen FE, Weiss MH, et al.: The relationship of intelligence and cerebral mantle in treated infantile hydrocephalus. Pediatrics 52:38, 1973. 267. Macnab GH: Hydrocephalus in infancy. In: Surgical Progress, vol 2. ER Carling, JP Ross, eds. Butterworths, London, 1961, p 98. 268. Hommet C, Billard C, Gillet P, et al.: Neuropsychologic and adaptive functioning in adolescents and young adults shunted for congenital hydrocephalus. J Child Neurol 14:144, 1999. 269. Harmadek MCS, Rourke BP: Principal identifying features of the syndrome of nonverbal learning disabilities in children. J Learning Disab 27:144, 1994. 270. Czepko R, Danilewicz B, Orlowiejska, et al.: The influence of shunt surgery on the improvement of cognitive disorders in hydrocephalic patients. (Abstract) Przegl Lek 56:489, 1999. 271. Castro-Gago M, Rodriguez IN, Rodriguez-Nufiez A, et al.: Therapeutic criteria in hydrocephalic children. Child Nerv Syst 5:361, 1989. 272. Cinalli G: Alternatives to shunting. Child Nerv Syst 15:718, 1999. 273. Torres Lanzas J, Rı´os Zambudio A, Martı´nez Lage JF, et al.: Tratamiento de la hidrocefalia mediante la derivacio´n ventriculopleural Arch Bronconeumol 38:511, 2002. 274. Vinchon M, Fichen A, Delestret I, et al.: Shunt revision for asymptomatic failure: surgical and clinical results. Neurosurgery 52:347, 2003. 275. Mottolese C, Grando J, Convert J, et al.: Zero rate of shunt infection in the first postoperative year in children—dream or reality? Child Nerv Syst 16:210, 2000. 276. Camboulives J, Meyrieux V, Le´na G: Infections des de´rivations du liquide ce´phalorachidien chez l’enfant: pre´vention et traitment. Ann Fr Anesth Re´anim 21:84, 2002.

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277. Choux M, Genitori L, Lang D, et al.: Shunt implantation: reducing the incidence of shunt infection. J Neurosurg 77:875, 1992. 278. Govender ST, Nathoo N, van Dellen JR: Evaluation of an antibioticimpregnated shunt system for the treatment of hydrocephalus. J Neurosurg 99:831, 2003. 279. Bruinsma N, Stobberingh EE, Herpers MJ, et al.: Subcutaneous ventricular catheter reservoir and ventriculoperitoneal drain-related infections in preterm infants and young children. Clin Microbiol Infect 6:202, 2000. 280. Takahashi Y: Withdrawal of shunt systems—clinical use of the programmable shunt system and its effect on hydrocephalus in children. Child Nerv Syst 17:472, 2001. 281. Brockmeyer D, Abtin K, Carey L, et al.: Endoscopic third ventriculostomy: an outcome analysis. Pediatr Neurosurg 28:236, 1998. 282. Belloti A, Rapana A, Iaccarino C, et al.: Intracranial pressure monitoring after endoscopic third ventriculostomy: an effective method to manage the ‘adaptation period’. Clin Neurol Neurosurg 103:223, 2001. 283. Sainte-Rose C, Chumas P: Endoscopic third ventriculostomy: Techn Neurosurg 1:176, 1996. 284. Bruce DA, Weprin B: The slit ventricle syndrome. Neurosurg Clin N Am 12:709, 2001. 285. Epstein F, Lapras C, Wisoff JH: ‘‘Slit ventricle syndrome’’: etiology and treatment. Pediatr Neurosci 14:5, 1988. 286. Whitelaw A: Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants. Cochrane Database Syst Rev CD001691, 2001. 287. Whitelaw A: Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database Syst Rev CD000498, 2000. 288. Whitelaw A, Pople I, Cherian S, et al.: Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy. Pediatrics 111:759, 2003. 289. Sharif U, Kuban K: Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol 16: 838, 2001. 290. Howard FM, Till K, Carter CO: A family study of hydrocephalus resulting from aqueduct stenosis. J Med Genet 18:252, 1981. 291. Va´radi V, To´th A, To¨ro¨k O: Heterogeneity and recurrence risk for congenital hydrocephalus (ventriculomegaly): a prospective study. Am J Med Genet 29:305, 1988. 292. Haverkamp F, Wo¨lfle J, Aretz M, et al.: Congenital hydrocephalus internus and aqueductal stenosis: aetiology and implications for genetic counselling. Eur J Pediatr 158:474, 1999.

Fig. 15-49. Sagittal ultrasound section typical of colpocephaly, taken at 6 days of age in an infant diagnosed prenatally as hydrocephalic. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario, Ottawa.)

293. Adams C, Johnson WP, Nevin NC: Family study of congenital hydrocephalus. Dev Med Child Neurol 24:493, 1982. 294. Joumel H, Parent P, Roussey M, et al.: ‘‘Isolated’’ hydrocephalus in families of spina bifida and anencephaly: a coincidence? Neuropediatrics 20:220, 1989. 295. Friedman, JM, Santos-Ramos R: Natural history of X-linked aqueductal stenosis in the second and third trimester of pregnancy. Am J Obstet Gynecol 150:104, 1984. 296. Cohen MM, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003.

15.9 Colpocephaly Definition

Colpocephaly is an enlargement of the occipital horns of the ventricular system due to an underdevelopment of the white matter in the posterior cerebrum. The appearance is of an apparent hydrocephalus of the occipital horns, while the frontal portions are relatively normal (Figs. 15-49, 15-50). Diagnosis

There are no specific extracranial or surface clues to the presence of colpocephaly. The condition is a marker of disturbed brain development that may have a variety of clinical presentations and associated intracranial and extracranial anomalies. The condition is usually recognized when a cranial neuroimaging technique is applied to the diagnosis of a patient with developmental delay, seizures, or related neurologic problems. Colpocephaly is a marker of underlying maldevelopment of the brain, and the clinical presentation will be influenced by the underlying pathology. Bodensteiner and Gay1 have stressed the importance of separating colpocephaly from hydrocephalus ex vacuo of the posterior horns. Their patient had a stomy perinatal course, and the CT was interpreted as showing colpocephaly. Later MRI demonstrated acquired cystic changes in the white matter of the posterior centrum semiovale that were responsible for the enlarged posterior horns

Brain

637

those had colpocephaly.11 Table 15-13 lists several syndromes that have been associated with colpocephaly. It does not include the many syndromes with absent corpus callosum and/or malformations of cortical development that are included in their own section and which might be expected to sometimes show colpocephaly. Etiology and Distribution

Fig. 15-50. Axial CT scan at 1 week of age showing narrow anterior ventricle and dilated occipital horns characteristic of colpocephaly. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

and the appearance of colpocephaly. They emphasized that colpocephaly is most often associated with normal reflexes, hypotonia, moderate to severe developmental delay, and other CNS anomalies. Hydrocephalus ex vacuo is acquired and is more likely to be seen with an at risk medical history, spasticity, and more variability in intellect. However, there is significant clinical overlap, and movement abnormalities with choreoathetosis or spasticity may also be seen in colpocephaly, and reliable distinction requires careful neuroimaging. Examples of the milder clinical spectrum of colpocephaly include affected monozygotic twins with above-normal intelligence and brief tonic seizures,2 and a 30-year-old, intellectually normal man with a structurally normal cortex and a right temporal lobe focus of complex-partial seizures.3 Visual impairment, including abnormal fixation, nystagmus, and/or optic atrophy, is a common associated finding. Bittar et al.4 used functional MRI in a patient with normal visual acuity and visual fields, and showed major reorganization of the visual cortex and reduced activation foci in the occipital lobes. Partial or complete absence of the corpus callosum is the most commonly associated intracerebral malformation, and it is logical to assume that in these cases the colpocephaly and the callosal agenesis both reflect a primary abnormality of neuronal development. In one series of 23 patients with callosal abnormalities varying from hypoplasia to complete agenesis, 16 had colpocephaly.5 Porencephaly and hydrocephaly are also reported,6,7 and the ventricular system often has the appearance of colpocephaly in lissencephaly. The diagnosis of colpocephaly has been made in patients with a wide array of conditions, including neurofibromatosis, Pierre Robin anomaly, Tourette syndrome, Leigh disease, schizophrenia, and a variety of seizure disorders.6,8–10 MR imaging in a series of 23 patients with caudal spinal dysraphism showed that seven had an absence of the posterior third of the corpus callosum and that six of

Although with greater application of neuroimaging numbers are increasing, relatively few cases of colpocephaly have been reported since its original description as ‘‘vesiculocephaly’’ by Bendas in 1940.26 The term colpocephaly was coined by Yakovlev and Wadsworth7 who reported further on the first patient of Benda. They noted that the cortical gray matter was two to three times normal thickness and that the thin, poorly myelinated white matter contained heterotopic islands of gray matter. Benda’s second patient had a history and pathologic findings compatible with a perinatal encephalopathy and hydrocephalus ex vacuo. Given the broad range of clinical presentation and associated findings in colpocephaly, it is likely that many cases are undiagnosed or simply unreported. The 1988 paper of Noorani et al.,6 which described 14 cases among a review of 3411 consecutive cranial CT scans, doubled the cases reported to that time. Initially, the lateral ventricles are the simple outpouching of the telencephalon. With forward growth of the temporal lobes they then form a ‘‘U’’ shape; the occipital projection rapidly follows. At first this system is relatively large but becomes reduced in size following development of the foramina, and with ventricular and related interhemispheric growth. It is considered that an insult to the developing brain, at a variable time between the first and fourth months, leads to a reduction in white matter development in the region of the posterior pole. Hence, there is a failure of reduction in the size of the occipital horns and maintenance of the fetal appearance.6,27 Clearly colpocephaly is a nonspecific response to a variety of etiologic insults, including metabolic (Leigh), chromosomal (mosaic 8), and multifactorial (meningomyelocele). Maternal diabetes, valproic acid, and alcoholism have been reported as possible causative teratogens.8,11,27,28 Chen at al.29 reported a case of vanishing twin in a monochorionic-diamnionic pregnancy in which the surviving cotwin was noted by 28 weeks gestation to be microcephalic. A postnatal MRI revealed dysgenesis of the posterior corpus callosum, a thin occipital cortex, and colpocephaly. It has been proposed that early loss of a co-twin can cause major abnormalities of the CNS.30 The surviving monozygotic twins reported by Tanaka et al.31 are interesting in that one expressed incontinentia pigmenti and the other had colpocephaly but no skin disease. Familial recurrence of colpocephaly is infrequently reported but could occur on the basis of a syndrome with a significant recurrence risk and reasonable frequency of associated colpocephaly. For example, the two brothers with posterior agyria-pachygyria reported by Ferrie et al.32 both had colpocephaly. Nigro et al.2 argue that the concurrence of colpocephaly in monozygotic twins is evidence for a genetic cause in some cases. Prognosis, Treatment, and Prevention

The ages of patients who have been reported range from 1 week to 30 years, and the prognosis for survival and intellectual development undoubtedly reflects the impact of any associated condition and the severity of the concurrent maldevelopment of the brain. The patient with colpocephaly and mosaic trisomy 8 reported by Herskowitz et al.8 showed only mild developmental delay. There is a spectrum of increasingly significant signs, and several patients have been severely retarded, with seizures, abnormalities of tone, and visual impairment.

Table 15-13. Syndromes with colpocephaly Syndrome

Prominent Features

Causation Gene/Locus

Chudley-McCullough: hydrocephalus-deafness12

Normal intellect, non-dysmorphic, obstruction at foramen of Monro, severe bilateral sensorineural hearing loss; 8/8 with colpocephaly, recent reports with ACC suggest it is same as Hendriks syndrome (Table 15-11137)

AR (604213)

Colpocephaly-recurrent13

Male and female maternal half sibs; girl had unilateral micophthalmia with coloboma, male had mild developmental delay and seizures

Uncertain

Congenital fibrosis extrocular muscles14

Dysfunction of cranial nerves III and IV, or the muscles served by those nerves; CNS infrequent and includes cerebellar vermis hypoplasia, callosal agenesis, pachygyria, hydranencephaly, colpocephaly

AR (135700) (602078) ARIX, 11q13.3-q13.4 AD (607034) KIF21AI, 12p11.2-q12 AD (600638) 16q24.2-q24.3

Cutis verticus gyrata-mental retardation15

Severe mental retardation, microcephaly, vertical furrows on scalp, seizures, optic atrophy, thick calvarium; case with atrophic occipito-parietal cortex, hypoplastic splenium, colpocephaly

Unknown (219300)

Femoral deficiency-facial16

Short anteverted nose, long philtrum, thin upper lip, micrognathia, cleft palate, proximal focal femoral deficiency, pre-axial toe polydactyly; CNS includes agenesis posterior corpus callosum, brain atrophy, absent septum pellucidum, dilated lateral ventricles, heterotopias, colpocephaly

Associated with maternal diabetes (134780)

Grubben: short-dentaleczema17

Pre- and postnatal growth and developmental delay, hypotonia; small, widely spaced or missing teeth, eczematous skin rash; small, puffy hands and feet with tapering digits; partial agenesis of the corpus callosum or ventriculomegaly; selective IgG2 subclass deficiency a possible marker

AR (233810)

Hemimegalencephaly18

Isolated and syndromic forms show abnormal gyration, displacement of the occipital lobe across the midline, ventriculomegaly or colpocephaly

Unknown, heterogeneous

Linear nevus sebaceous19

Papular/verrucous lesions with atrophic scars over craniofacial area, pigment changes, ipsilateral brain anomalies; case report with left megalencephaly, lissencephaly, schizencephaly, excess and heterotopic gray matter and colpocephaly

Unknown (163200)

Marden-Walker20

Motor delay, blepharophimosis, low-set and malformed ears, cleft palate, micrognathia, renal microcysts/cystic dysplasia, arachnodactyly, camptodactyly, joint contractures, congenital heart defect; case with brain stem and cerebellar hypoplasia, callosal agenesis, colpocephaly; likely heterogeneous

AR (248700)

Microphthalmia-linear skin defects21

Male lethal; linear, erythematous skin defects; variable microphthalmia, anterior chamber defects, sclerocornea; short stature; congenital heart defects, CNS includes hydrocephalus, colpocephaly, cavum septum pellucidum, variable corpus callosum defect

del Xp22.31 (309801) male lethality due to loss of holocytochrome c-type synthase

Mosaic trisomy 88

Scaphocephaly, prominent forehead, broad nose, small mandible, contractures of digits, scoliosis, rib and vertebral anomalies, deep creases on soles, mental deficiency

Chromosome imbalance

Muscle-eye-brain22

Early severe hypotonia, delayed development, anterior chamber defects, glaucoma, preretinal glial membrane, ERG becomes abnormal, cataracts, myopathy, predominant frontal pachygyria, agenesis of corpus callosum, hypoplasia of pons and cerebellar vermis, white matter abnormalities patchy or absent, sibs with colpocephaly; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

Nijmegen breakage23

Growth and variable intellectual impairment, sloping forehead, prominent mid-face and long nose, large and abnormal pinnae, upslanting palpebrae, cafe´-au-lait spots, immunodeficiency, chromosome breakage and rearrangements of 7/14; 4/10 cases had posterior callosal agenesis and colpocephaly

AR (251260) NBS1, 8q21

Peroxisome-deficient disorders24,25

Includes Zellweger and isolated peroxisomal b-oxidation defects; developmental delay, hypotonia, hepatic and visual dysfunction, multifoca spikes on EEG; thick cortex with colpocephaly, some with partial callosal agenesis

AR (214100) PEX1, 7q21-q22 PEX2, 8q21.1 PEX3, 6q23-q24 PEX5, 12p13.3 PEX6, 6p Others, 1p22-p21, 1q22, 2p15

638

Brain

Treatment is generally supportive and should be appropriate for the management of the specific associated problems of the patient. Concurrent hydrocephalus may occasionally require treatment.8 There is no primary prevention, other than the recognition of specific syndromes with established recurrence risks. The abnormality may be detected during routine prenatal ultrasound but is likely to be diagnosed as hydrocephalus, as was the case with the patient whose cranial CT scan is shown in Figure 15-50. The investigations outlined for evaluation of fetal ventriculomegaly (Section 15.8) would appear to be appropriate in this situation. Levine et al.33 provided evidence that fetal MRI is superior to ultrasound in detecting subtle differences in the proportions of the ventricles. References (Colpocephaly) 1. Bodensteiner J, Gay CT: Colpocephaly: pitfalls in the diagnosis of a pathologic entity utilizing neuroimaging techniques. J Child Neurol 5:166, 1990. 2. Nigro MA, Wishnow R, Maher L: Colpocephaly in identical twins. Brain Dev 13:187, 1991. 3. Wunderlich G, Schlaug G, Jancke L, et al.: Adult-onset complex partial seizures as the presenting sign in colpocephaly: MRI and PET correlates. J Neuroimaging 6:192, 1996. 4. Bittar RG, Ptito A, Dumoulin SA, et al.: Reorganization of the visual cortex in callosal agenesis and colpocephaly. J Clin Neursci 7:13, 2000. 5. Utsunomiya H, Ogasawara T, Hayashi T, et al.: Dysgenesis of the corpus callosum and associated telencephalic anomalies: MRI. Neuroradiology 39:302, 1997. 6. Noorani PA, Bodenstiener JB, Barnes PD: Colpocephaly: frequency and associated findings. J Child Neurol 3:100, 1988. 7. Yakovlev PI, Wadsworth RC: Schizencephaly: a study of the congenital clefts in the cerebral mantle: II. Clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol 5:169, 1946. 8. Herskowitz J, Rosman P, Wheeler CB: Colpocephaly: clinical, radiologic, and pathogenetic aspects. Neurology 35:1594, 1985. 9. Shaenboen MJ, Nigro MA, Martocci RJ: Colpocephaly and Gilles de la Tourette’s syndrome. Arch Neurol 41:1023, 1984. 10. Pe´rez Castrillo´n JL, Duen˜as Laita A, Ruiz Mambrilla M, et al.: Ausencia del cuerpo calloso, colpocefalia y esquizofrenia. Rev Neurol 33:995, 2001. 11. Kawamura T, Nisho S, Morioka T, et al.: Callosal anomalies in patients with spinal dysraphism: correlation of clinical and neuroimaging features with hemispheric abnormalities. Neurol Res 24:463, 2002. 12. Ostergaard E, Pedersen VF, Skriver EB, et al.: Brothers with ChudleyMcCullough syndrome: sensorineural deafness, agenesis of the corpus callosum, and other structural brain abnormalities. Am J Med Genet 124A:74, 2004. 13. Cerullo A, Marini C, Cevoli S, et al.: Colpocephaly in two siblings: further evidence of a genetic transmission. Dev Med Child Neurol 42:280, 2000. 14. Pieh C, Goebel HH, Engle EC, et al.: Congenital fibrosis syndrome associated with central nervous system abnormalities. Graefes Arch Clin Exp Ophthalmol 241:546, 2003. 15. Farah S, Farag T, Sabry MA, et al.: Cutis verticis gyrata-mental deficiency syndrome: report of a case with unusual neuroradiological findings. Clin Dysmorphol 7:131, 1998. 16. Leal E, Macias-Gomez N, Rodriguez L, et al.: Femoral-facial syndrome with malformations in the central nervous system. Clin Imaging 27:23, 2003. 17. Ainsworth SB, Baraitser M, Mueller RF, et al.: Selective IgG2 subclass deficiency - a marker for the syndrome of pre/postnatal growth retardation, developmental delay, hypotrophy of distal extremities, dental anomalies and eczema. Clin Dysmorphol 6:139, 1997. 18. Flores-Sarnat L: Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 17:373, 2002. 19. Hager BC, Dyme IZ, Guertin SR, et al.: Linear nevus sebaceous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 7:45, 1991. 20. Garcı´a-Alix A, Blanco D, Caban˜as F, et al.: Early neurological manifestations and brain anomalies in Marden-Walker syndrome. Am J Med Genet 44:41, 1992.

639 21. Paulger BR, Kraus EW, Pulitzer DR, et al.: Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck. Pediatr Dermatol 14:26, 1997. 22. Zervos A, Hunt KE, Tong HQ, et al.: Clinical, genetic and histopathological findings in two siblings with muscle-eye-brain disease. Eur J Ophthalmol 12:253, 2002. 23. Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J, et al.: Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology 42:43, 2000. 24. Suzuki Y, Shimozawa N, Takahashi Y, et al.: Peroxisomal disorders: clinical aspects. Ann NY Acad Sci 804:442, 1996. 25. Nakai A, Shigematsu Y, Nishida K, et al.: MRI findings of Zellweger syndrome. Pediatr Neurol 13:346, 1995. 26. Benda CE: Microcephaly. Am J Psychiatr 97:1135, 1940. 27. Garg BP: Colpocephaly an error of morphogenesis? Arch Neurol 39:243, 1982. 28. Bermejo E, Garcia-Alix A, Martinez S, et al.: Brain anomalies in infants exposed to valproic acid (VPA) monotherapy during the first trimester of gestation. Proc Greenwood Genet Center 10:115, 1991. 29. Chen C-P, Lin S-P, Chiu N-C: Microcephaly with dysgenesis of corpus callosum and colpocephaly in the survivor after the first-trimester death of a monochorionic co-twin. Prenat Diagn 22:633, 2002. 30. Sebire N, Taylor M, Fisk NM: Consequences of in utero death in a twin pregnancy. Lancet 356:1108, 2000. 31. Tanaka K, Kambe N, Fujita M, et al.: Incontinentia pigmenti in identical twins with separate skin and neurological disorders. Acta Derm Venereol 70:267, 1990. 32. Ferrie CD, Jackson GD, Giannakodimos S, et al.: Posterior agyriapachygyria with polymicrogyria: evidence for an inherited neuronal migration disorder. Neurology 45:150, 1995. 33. Levine D, Trop I, Mehta TS, et al.: MR imaging appearance of fetal cerebral ventricular morphology. Radiology 223:652, 2002.

15.10 Hydranencephaly Definition

Hydranencephaly is a condition in which the cerebral hemispheres are virtually absent and have been replaced by fluid-filled sacs, lined by leptomeninges, and contained within a normal skull and brain compartment. Cortical remnants are generally confined to the temporal lobe and the tentorial parts of the occipital lobes.1 Typically the brain stem and cerebellum are normal; the falx is usually present but may be partially or completely absent. Among the basal ganglia, the thalamus and corpus striatum are usually normal. Hydranencephaly is an encephaloclastic abnormality and must be distinguished from maximal hydrocephalus (Section 15.8), which results from an excess of cerebrospinal fluid production over absorption, and from developmental porencephaly (schizencephaly) (Section 15.11), in which clefts or cavities within the cerebral cortex result from a primary abnormality of neurocellular development. The relationship between hydranencephaly and congenital encephaloclastic porencephaly and multicystic encephalomalacia (MCE) (Section 15.11) is essentially one of timing and degree of involvement. Diagnosis

The neonate with hydranencephaly is usually macrocephalic, with frequent seizures, irritability, and hyperreflexia. Elevated intracranial pressure and an expanding head circumference can occur. In the absence of hypothalamic involvement the infant will often survive and show relatively normal behavior until profound developmental delay becomes apparent in the early months.1,2 Hakamada et al.3 have suggested that observation of body movements during sleep may aid the diagnosis. They observed periodic alteration between active and

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quiet sleep and reported that muscle activity, ocular movement, and respiration rates were similar to those in control neonates. However, generalized body movement showed a bilateral synchrony rather than the normal asymmetric pattern. In addition, there was significant increase in symmetric synchronized contraction of two or four limbs and a decrease in brief, isolated movement of a single limb. It is important to distinguish early between hydranencephaly and ‘‘maximal hydrocephalus,’’ because the latter carries a significantly better prognosis and requires ventricular shunt therapy. Transillumination of the skull (Fig.15-51) may occur in both conditions (less commonly in hydrocephalus), but bright light shining out through the pupils appears unique to hydranencephaly. In severe hydrocephalus, in contrast to hydranencephaly, neuroimaging shows maximal preservation of cortex in the frontal region, and the cerebral vascular architecture is normal, albeit attenuated.4 An indentation at the site of division of the frontal lobes may be seen, and, with shunting, the cortical mantle may sometimes show improvement with time.2 Electrophysiological studies, specifically the EEG and various evoked responses, may aid in making the distinction. Patients with maximal hydrocephalus show cortical EEG activity and normal visual and auditory evoked potentials. The EEG in hydranencephaly has been described as flat, but it can show low isoelectric waves in bipolar derivation, with a similar referential derivation from most electrodes.5 Some cases may show independent, irregular spikes and slow waves, reflecting underlying cortical remnants.5 Studies in a child with hydranencephaly and seizures of the Lennox-Gastaut syndrome (LGS)– type showed that the electroencephalographic signatures of the apneic and tonic seizures were similar to children with idiopathic LGS.6 The quantitative disturbances in duration and latency, and the number of sleep cycles, were also similar to the other LGS patients but the patient lacked vertex waves and had abnormal sleep spindles.

Visual, auditory, and somatosensory evoked potentials (SSEP) confirm the absence of cortical response and the preservation of brain stem function.4,7–9 Auditory evoked potentials show an absent middle latency response, and somatic evoked potentials show absent cortical response.7 Kaga et al.10 obtained auditory brain stem responses and wave patterns compatible with age, and reaction to loud noise on behavioral auditory testing that they attributed to brain stem auditory motor reflexes. Tayama et al.9 performed short latency SSEP on two affected children and confirmed absent cortical responses and preservation of brain stem responses. They were also able to correlate an absent No wave in one child with absence of the thalamus. MRI is well suited to showing absence of cortical, and preservation of midbrain and hindbrain, structures.7 Two-dimensional color Doppler has been used successfully to demonstrate absence of the secondary and tertiary branches of the internal carotid arteries in order to distinguish hydranencephaly from maximal hydrocephalus.11 Hydranencephaly is considered by most authors to be the extreme of the enclastic form of porencephaly, and one would not therefore expect this malformation to be a component of many syndromes. Indeed the pathologic findings of ‘‘syndromic’’ hydranencephaly often show variation from the typical isolated cases (Table 15-14). The majority of patients have an abnormal ophthalmologic examination, and findings include microphthalmia, strabismus, nystagmus, chorioretinitis, small retinal vessels, optic nerve hypoplasia, and incomplete cleavage of the anterior chamber.4 Unilateral hydranencephaly, with characteristic clinical, physical, neuroradiologic, and neurophysiologic findings confined to one hemisphere, is occasionally seen and may carry a surprisingly good prognosis (Figs. 15-52, 15-53).28 These patients present with hemiparesis, are less likely to have seizures, and may develop hydrocephalus due to aqueductal stenosis. Etiology and Distribution

Fig. 15-51. Transillumination of an infant with hydranencephaly.

That hydranencephaly usually occurs within a normal cranial cavity is strong evidence that it is the result of an enclastic process rather than a primary malformation. A number of clinical observations and experimental studies support this hypothesis. Prevalent today is the theory that hydranencephaly derives from compromise of carotid artery supply, which provides an explanation for the relative sparing of the inferior temporal and occipital regions. Carotid occlusion using paraffin balls in puppies and ligation of the carotid arteries and jugular veins in monkeys produce massive liquefaction necrosis of the brain and a condition equivalent to hydranencephaly.29,30 Unilateral ligation causes unilateral involvement. However, in contrast to typical hydranencephaly this experimental model has been associated with a degree of cranial collapse and microcephaly and more closely resembles the patients reported by Moore et al.,31 one of whom did, however, have classic hydranencephaly. Other differences from the experimental model include preservation of the lenticulostriatum and patency of the carotid vessels in patients with hydranencephaly.1,32 This may relate to involvement of more distal carotid tributaries in many cases of spontaneous hydranencephaly,11,33 or perhaps to a matter of timing. More recently an ovine model, in which the internal carotid arteries were ligated at day 100 (human weeks 26–27), has produced hydranencephaly, but with evidence of cerebellar involvement.34 There is clinical evidence in support of a vascular disruptive pathogenesis. Hydranencephaly has been reported in surviving monozygotic twins.35–37 It has been hypothesized that fetus to fetus transfer of thromboplastins from the dead twin results in cerebral infarction in the surviving twin. An alternative, and perhaps now

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Table 15-14. Syndromes with hydranencephaly as a feature Syndrome

Prominent Features

Causation Gene/Locus

Agnathia malformation complex12

An association of holoprosencephaly and agnathia is well established; a fetus had agnathia, hydranencephaly, bilobed lungs, situs inversus, polysplenia, duodenal atresia, and a cystic dilation of the oropharynx

Unknown (202650) 6pter-6p24 18pter-18p11

Cerebro-oculo-genital13

Microphthalmia, corneal opacity, severe developmental delay, small phallus, hypospadias, marked microcephaly or hydranencephaly, absent corpus callosum

XLR (309800)

Craniosynostosishumeroradial-aplastic thumbs14

IUGR, marked microcephaly, ridged sutures, prominent eyes with short palpebrae, micrognathia, elbow and knee flexion contractures, absent thumbs, bilateral humeroradial synostosis, hydranencephaly

Unknown

Deletion (13)(q22)15

Transposition of the penis and scrotum, anal atresia, syndactyly of toes 2-3, hypoplasia of optic nerve

Chromosome imbalance

Familial hydranencephaly16

Small for gestational age, microcephaly, microphthalmia, multiple joint contractures, wide-spaced first and second toes, absent olfactory and optic nerves, cerebellum only a remnant

AR

Herpes, prenatal17

About 5% of neonatal herpes is acquired in utero; variable clinical spectrum may include cutaneous, ocular, and CNS lesions; about 1⁄2 have an encephalitis that can cause microcephaly or hydranencephaly

Prenatal infection with herpes virus

Hydranencephalyhydrocephalusmitochondrial18

May represent maximal hydrocephalus; abnormal muscle biopsy included ragged red fibers, abnormal mitochondria; low levels of complexes III and IV enzymes; some evidence of glomeruloid vessels (see ref. 23)

AR?

Hydranencephalyhypoplastic thumbs19

Collapsed skull vault, absent left and proximal right thumb, campto/ clinodactyly of 5th finger, talipes equinovarus, reported as hydranencephaly but closer to aprosencephaly and XK-aprosencephaly spectrum

Unknown

Mbakop: lethal multiple pterygium20

Hydramnios, cystic hygroma, fetal edema, cervicoaxillary pterygia, joint contractures, camptodactyly, cleft lip/palate, abnormal placenta. One case

Unknown (253290)

Microhydranencephaly21

Microhydranencephaly, severe growth and developmental delay, sloping forehead, exophthalmia, micrognathia, spastic quadriplegia, joint contractures, athetosis, respiratory and skin infections

AR (605013) 16p13.3-12.1

PEHO-like22

Progressive encephalopathy, edema, hypsarrhythmia, optic atrophy by age 2 years; hypotonia, hyperreflexia, infantile spasms after 2 weeks; narrow forehead, puffy cheeks; mild supratentoral atrophy and no cerebellar atrophy differ from PEHO. One case hydranencephaly

AR (260565)

Proliferative vasculopathyhydranen/hydrocephaly23

Ventriculomegaly/hydranencephaly; proliferative glomeruloid blood vessels in spinal cord, brain stem, retina, and cerebral mantle; decreased number of primitive neuroectodermal cells, maturing neurons and glia; no gyral pattern; hypoplastic muscles, joint contractures, pterygia; possibly a destructive vascular process; cerebro-oculo-muscular spectrum? (see ref. 18)

AR (225790)

Renal adysplasia24

Renal remnants with primitive tubules and concentric fibrous tissue, 2-3 toe syndactyly, no normal cortical layering in cortical remnant, abnormal multinucleated neurons; sib had ‘‘rudimentary brain at base of skull.’’ Similar case had multicystic dysplastic kidneys

AR (236500)

Trisomy 1325

Scalp defect, holoprosencephaly spectrum (including facies), postaxial polydactyly hands/feet, overlapping fingers, various internal malformations

Chromosome imbalance

Valproate, prenatal26

Brachycephaly, high forehead, prominent eyes, crease of skin below eye, thin and long upper lip, prominent lower lip, long philtrum, metopic ridge, lumbosacral NTD. Case with partial hydranencephaly

In utero exposure

X-linked-abnormal genitalia (XLAG)27

Lissencephaly with posterior-to-anterior gradient, neonatal onset of seizures, hypothalamic dysfuction, ambiguous male genitalia (see Table 15-5); termination mutations in exons 1 to 4 can cause hydranencephaly

XLR (300382, 300215) ARX, Xp22.13

more favored, mechanism is that of an acute hemorrhage from the surviving twin into the dead twin at the time of fetal death, resulting in an acute hypoperfusion/hypoxic insult.37,38 Case reports do associate hypoxia with anomalies along the hydranencephaly spectrum.39,40 Hemorrhagic states such as familial factor XIII deficiency have also been associated with hydranencephaly.41 There are a number of cases where the evolution of the typical picture of

hydranencephaly has been followed on prenatal sonography.1,37,42 In the case of a prenatal intracranial bleed, the echogenic hemorrhage gradually gives way over a period of weeks to anechoic cranial contents that match CSF, and the head size usually increases.1,42 Although most such cases relate to the late second and early third trimester, Tang43 observed abnormal cranial and intracranial findings starting at 11 weeks gestation.

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Neuromuscular Systems

Fig. 15-52. Superior and lateral views of an infant brain with hemihydranencephaly. Histology showed a thin layer of glial tissue lining the inner surface of the hydranencephalic membrane (arrows). A, anterior; P, posterior; LC, left cerebral hemisphere; E, right ear. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Fig. 15-53. Axial and coronal MRI scans of a 3-year-old girl with hemihydranencephaly. She had hemiparesis and unilateral facial paresis. She sat alone at 12 months and walked at 31 months. (Courtesy of Dr. R. C. M. Hennekam, Institute for Human Genetics and Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam.)

Brain

There are also cases that suggest localized vascular anomalies may cause hydranencephaly. Stevenson et al.44 reported a patient with hydranencephaly and multiple vascular anomalies that included extensive port wine stains, nevus flammeus, abnormal retinal vessels, and absent internal carotid artery blood flow. Absent right middle cerebral artery with a right hemihydranencephaly,33 and multicystic encephalomalacia (MCE) in association with intraluminal webs of the right common carotid and left subclavian arteries,45 have been reported. Reduced maternal age (MA), which has been associated with other malformations thought to have a vascular basis, has been noted in hydranencephaly. Lubinsky et al.46 found that a MA of < 20 years was five times, and a MA of < 18 years was ten times more frequent in mothers of infants with hydranencephaly than in the general population. An odds ratio of 56 (95% CI; 7.41–427) for maternal smoking in mothers of infants with hydranencephaly compared with mothers of children with other CNS anomalies, and of 179 (95% CI; 18.6–1719) compared with mothers in the general population has been reported.47 Prenatal infections, including toxoplasmosis, herpes simplex, and cytomegalovirus (CMV), have also been associated with hydranencephaly.48–50 A case of prenatal CMV infection with hydranencephaly reported by Kubo et al.50 raises the possibility of a vascular mechanism in prenatal infection. Their patient had narrow carotids and an atheromatous plaque between the right brachiocephalic and left common carotid artery. Experience with natural and experimental animal systems raises the potential that a viral cause of hydranencephaly may be more common than is generally believed. However, it is of note that the viral animal models tend to show cerebellar hypoplasia or agenesis. Administration of live parvovirus vaccine to a pregnant cat resulted in three dead and two living kittens that both had hydranencephaly and cerebellar hypo/aplasia.51 Natural and vaccine-related transplacental transmission of bovine-virus diarrhea virus (BVDV) resulted in 33 neurologically damaged cattle of which 25 had cerebellar hypoplasia in association with one or more of hydranencephaly, obstructive hydrocephalus, porencephaly, or microcephaly.52 The hydranencephalic cases lacked any ependymal lining to the cerebral sac, which contained glial fibrillary acid-protein– positive cells and a dense layer of immunoreactive cell processes. There were small areas of heterotopias. Viral pathogenesis also seems likely as the cause of a 6-month outbreak in Miyazaki, Japan that affected 62 calves, of which 47 had cerebellar hypoplasia and hydranencephaly, eight had isolated hydranencephaly, and seven had ventriculomegaly.53 Inflammatory/reactive changes, heterotopias, loss of lamination, and neuronal degeneration were observed. Hydranencephaly and cerebellar hypoplasia have also been produced by Aino virus infections in chick embryos,54 and it is of note that while viral antigen is detectable early in the infection, it is not found at 13 days, perhaps reflecting the loss of Aino virus–susceptible cells. Finally, there is an interesting and unique report of hydranencephaly in association with a congenital rhabdoid tumor.55 This neoplastic hydranencephaly is distinguished by the highly proteinaceous content within the sac, unlike the CSF characteristics seen in standard hydranencephaly. Thus, hydranencephaly appears to represent the endpoint of massive brain necrosis, which may have different causes, several of which operate through the common mechanism of vascular/oxygenation compromise. Dixon25 states the prevalence of hydranencephaly to be between 1/4000 and 1/10,000 births. Prognosis, Treatment, and Prevention

The outlook for children with complete hydranencephaly is universally poor, although diagnosis may be delayed for several months

643

because of relatively appropriate early behavior. As time passes profound delay, deafness, blindness, and spastic quadriparesis become apparent. There is no primary treatment, and active medical intervention is not indicated. Almost one-half of infants with hydranencephaly die within 1 month, and less than 15% survive 1 year.25 However, long-term survival, up to 20 years, does occur56 and medical and surgical complications can be seen. Patients who do survive do not display meaningful development, have cortical blindness, spastic tetraplegia seizures, and dysphagia. Autonomic57 and hypothalamic dysfunction and chronic hypernatremia have been reported.58,59 Kobayashi et al.59 demonstrated in their patient, who had hypothalamic dysplasia, that the hypernatremia was due to both a disturbed thirst center and abnormal secretion of ADH. In a study of three affected children, Hashimoto et al.60 showed preservation of an active sleep cycle, but with decreased quiet, and increased indeterminate, sleep. The sleep-circadian rhythm was disturbed, and in the two patients who underwent endocrine testing, abnormal cortisol peaks were seen and one child lacked an increase in growth hormone secretion with sleep. Abnormalities were also noted in the establishment and maintenance of the normal circadian rhythm of body temperature. Although it is unlikely that patients with hydranencephaly perceive their situation,61 some long-term survivors do orient to sound, and may react differently to different individuals and to pleasant versus painful stimuli.56 Increased intracranial pressure may complicate hydranencephaly and require treatment because of increasing head size and/or the potential for discomfort. Standard shunt procedures in hydranencephaly have a high rate of complications including blockage, infection and, because of a lack of the sealing effect of normal surrounding cortex, a tendency to leak fluid along the shunt track.58 Wellons et al.58 compared the outcome in 13 patients, nine of whom had undergone standard shunt procedures and four of whom had a choroid plexectomy (removal of the choroid plexus). The latter procedure had been attempted for the treatment of hydrocephalus in the early 20th century, and largely abandoned because of morbidity, mortality, and the development of shunt systems. Seven of the nine patients who received a shunt had complications, six shunts required revision, five on multiple occasions. These patients required an average of two operations, 1.5 readmissions, and 43.5 hospital days for neurosurgical reasons. In contrast, none of the four plexectomy patients had a surgical complication, none required a repeat operation or readmission, and they had fewer day-clinic visits and follow-up neuroimaging tests than the shunt cohort. Care is required at surgery to prevent inward collapse of the hydranencephalic sac.58 As was mention previously, the outlook for patients with hemihydranencephaly is substantially better, although all have a contralateral hemiparesis, which can involve the face mildly.33 Four of five patients who underwent psychomotor assessment had mild to moderate delay, and the one patient with severe mental retardation had multiple congenital anomalies including a median cleft lip and anophthalmia.28 There is evidence for what has been called neuronal plasticity in that patients with both right and left hydranencephaly have developed speech,28 and Porro et al.33 reported a 12-year-old girl with an IQ of 60 whose right visual hemifields had expanded above the middle line. She had an amblyopic left eye that did not respond to patching but photopic visual evoked potentials were the same from both eyes. In addition, she had developed a torticollis, left-sided head tilt, and rotation of the eyes, presumably to aid her visual fixation. Although most patients do not develop hydrocephalus, shunting is indicated when there is danger of compromise to the uninvolved side.

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There is no primary method of preventing hydranencephaly. Familial cases are rare and, as discussed, tend to show anatomic variation from the usual case. Such families should be offered prenatal monitoring by ultrasound. Most cases of hydranencephaly that have been detected by routine prenatal ultrasound have been during the second half of pregnancy,1,37,42,62 although some cases may begin in the first trimester.43 The location of any remaining cortex may help to distinguish hydranencephaly from hydrocephaly, but in light of the difficulty in distinguishing these abnormalities, a cautious approach to intervention is indicated. MRI and/or color Doppler ultrasound may aid in the specific diagnosis.11,63

References (Hydranencephaly) 1. Greene MF, Benacerraf B, Crawford JM: Hydranencephaly: US appearance during in utero evolution. Radiology 156:779, 1985. 2. Sutton LN, Bruce DA, Schut L: Hydranencephaly versus maximal hydrocephalus: an important clinical distinction. Neurosurgery 6:35, 1980. 3. Hakamada S, Watanabe K, Hara K, et al.: Hydranencephaly: sleep and movement characteristics. Brain Dev 4:45, 1982. 4. Herman DC, Bartley GB, Bullock JD: Ophthalmic findings of hydrancephaly. J Pediatr Ophthalmol Strabismus 25:106, 1988. 5. Iinuma K, Handa I, Kojima A, et al.: Hydranencephaly and maximal hydrocephalus: usefulness of electrophysiological studies for their differentiation. J Child Neurol 4:114, 1989. 6. Velasco M, Velasco F, Gardea G, et al.: Polygraphic characterization of the sleep-epilepsy patterns in a hydranencephalic child with severe generalized seizures of the Lennox-Gastaut syndrome. Arch Med Res 28:297, 1997. 7. Hanigan WC, Aldrich WM: MRI and evoked potentials in a child with hydranencephaly. Pediatr Neurol 4:185, 1988. 8. Yuge T, Kaga K: Brain functions of an infant with hydranencephaly revealed by auditory evoked potentials. Int J Pediatr Otorhinolaryngol 45:91, 1998. 9. Tayama M, Hashimoto T, Mori K, et al.: Electrophysiological study on hydranencephaly. Brain Dev 14:185, 1992. 10. Kaga K, Yasui T, Yuge T: Auditory behaviors and auditory brainstem responses of infants with hypogenesis of cerebral ventricles. Acta Otolaryngol 122:16, 2002. 11. Doi H, Tatsuno M, Mizushima H, et al.: The use of two-dimensional Doppler sonography (color Doppler) in the diagnosis of hydranencephaly. Child Nerv Syst 6:456, 1990. 12. Persutte WH, Yeasting RA, Kurczynski TW, et al.: Agnathia malformation complex associated with a cystic distension of the oral cavity and hydranencephaly. J Cranio Gen Dev Bio 10:391, 1990. 13. Siber M: X-linked recessive microcephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 14. Samson G, Gardner JC: Craniosynostosis, microcephaly, hydrancephaly, humero-radial synostosis, and thumb aplasia: a new syndrome? Am J Med Genet 61:174, 1996. 15. Gershoni-Baruch R, Zekaria D: Deletion (13)(q22) with multiple congenital anomalies, hydranencephaly and penoscrotal transposition. Clin Dysmorphol 5:289, 1996. 16. Najafzadeh TM, Reinisch L, Dumars KW: Etiologic heterogeneity in hydranencephaly. Birth Defects Orig Artic Ser XVIII(3B):229, 1982. 17. Parish WR: Intrauterine herpes simplex virus infection: hydranencephaly and a nonvesicular rash in an infant. Int J Dermatol 28:397, 1989. 18. Castro-Gago M, Pintos-Martı´nez E, Forteza-Vila J, et al.: Congenital hydranencephalic-hydrocephalic syndrome with proliferative vasculopathy: a possible relation with mitochondrial dysfunction. J Child Neurol 16:858, 2001. 19. Norman AM, Donnai D: Hypoplastic thumbs and hydranencephaly: a new syndrome? Clin Dysmorphol 1:121, 1992. 20. Mbakop A, Cox IN, Stormann C, et al.: Lethal multiple pterygium syndrome: report of a new case with hydranencephaly. Am J Med Genet 25:575, 1986.

21. Kavaslar GN, Onengut S, Derman O, et al.: The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1. Am J Hum Genet 66:1705, 2000. 22. Goizet C, Espil-Taris C, Husson M, et al.: A patient with hydranencephaly and PEHO-like dysmorphic features. Ann Genet 46:25, 2003. 23. Laurichesse-Delmas H, Beaufre`re AM, Martin A, et al.: First trimester features of Fowler syndrome (hydrocephaly-hydranencephaly proliferative vasculopathy). Ultrasound Obstet Gynecol 20:612, 2002. 24. Gschwendtner A, Mairinger T, Soelder E, et al.: Hydranencephaly with renal dysgenesis: a coincidental finding? Gynecol Obstet Invest 44:206, 1997. 25. Dixon A: Hydranencephaly. Radiography 54:12, 1988. 26. Barrera MN, Campos MR, Ribed MLS: Partial hydranencephaly in a child coincidental with intrauterine exposure to sodium valproate. Neuropediatrics 25:334, 1994. 27. Kato M, Das S, Petras K, et al.: Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23:147, 2004. 28. Greco F, Finocchiaro M, Pavone P, et al.: Hemihydranencephaly: case report and literature review. J Child Neurol 16:218, 2001. 29. Becker H: Uber Himgefassausschaltungen. II. Intrakranielle Gefassverschlusse. Uber experimentalle Hydranencephalie (Blasenhim). Dtsch Z Nervenheilkd 161:446, 1949. 30. Myers RE: Brain pathology following fetal vascular occlusion: an experimental study. Invest Ophthalmol 8:41, 1969. 31. Moore CA, Weaver DD, Bull MJ: The fetal brain disruption sequence. J Pediatr 116:383, 1990. 32. Freide RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 109. 33. Porro G, Wittebol-Post D, de Graff M, et al.: Development of visual function in hemihydranencephaly. Dev Med Child Neurol 40:563, 1998. 34. Wintour EM, Lewitt M, McFarlane A, et al.: Experimental hydranencephaly in the ovine fetus. Acta Neuropathol (Berl) 91:537, 1996. 35. Hoyme HE, Higginbottom MC, Jones KL: Vascular etiology of disruptive structural defects in monozygotic twins. Pediatrics 67:228, 1981. 36. David TJ: Vascular basis for malformations in a twin. Arch Dis Child 60:166, 1985. 37. Hahn JS, Lewis AJ, Barnes P: Hydranencephaly owing to twin-twin transfusion: serial fetal ultrasonography and magnetic resonance imaging findings. J Child Neurol 18:367, 2003. 38. Sebire N, Taylor M, Fisk NM: Consequences of in-utero death in twin pregnancy. Lancet 356:1108, 2000. 39. Iannetti P, Galletti F, Emanuelli O, et al.: Severe outcome of brain perfusion failure: a pre-hydrancephalic state? Brain Dev 13:447, 1991. 40. Ferna`ndez F, Pe`rez-Higuerez A, Herna`ndez R: Hydranencephaly after maternal butane-gas intoxication during pregnancy. Dev Med Child Neurol 28:355, 1986. 41. Takada K, Shiota M, Ando M, et al.: Porencephaly and hydranencephaly: a neuropathological study of four autopsy cases. Brain Dev 11:51, 1989. 42. Edmundson SR, Hallak M, Carpenter RJ Jr, et al.: Evolution of hydranencephaly following intracerebral hemorrhage. Obstet Gynecol 79:870, 1992. 43. Lam YH, Tang MH: Serial sonographic features of a fetus with hydranencephaly from 11 weeks to term. Ultrasound Obstet Gynecol 16:77, 2000. 44. Stevenson DA, Hart BL, Clericuzio CL: Hydranencephaly in an infant with vascular malformations. Am J Med Genet 104:295, 2001. 45. Sandelbach KM, Gujrati M, Husain AN: Web-like malformation of the carotid artery and multicystic encephalomalacia. Pediatr Pathol 12:701, 1992. 46. Lubinsky MS, Adkins W, Kaveggia EG: Decreased maternal age with hydranencephaly. Am J Med Genet 69:232, 1997. 47. To WW, Tang MH: The association between maternal smoking and fetal hydranencephaly. J Obstet Gynaecol Res 25:39, 1999. 48. Plantaz D, Joannard A, Pasquier B, et al.: Hydranence´phalie et toxoplasmose conge´nitale. A propos de quatre observations. Pediatrie 42:161, 1987.

Brain 49. Christie JD, Rakusan TA, Martinez MS, et al.: Hydranencephaly caused by congenital infection with herpes simplex virus. Pediatr Infect Dis 5:473, 1986. 50. Kubo S, Kishino T, Satake N, et al.: A neonatal case of hydranencephaly caused by atheromatous plaque obstruction of aortic arch: possible association with a congenital cytomegalovirus infection? J Perinatol 14:483, 1994. 51. Sharp NJ, Davis BJ, Guy JS, et al.: Hydranencephaly and cerebellar hypoplasia in two kittens attributed to intrauterine parvovirus infection. J Comp Pathol 121:39, 1999. 52. Hewicker-Trautwein M, Liess B, Trautwein G: Brain lesions following transplacental infection with bovine-virus diarrhea virus. Zentralbl Veterinarmed B 42:65, 1995. 53. Tateyama S, Yamaguchi R, Uchida K, et al.: An outbreak of congenital hydranencephaly and cerebellar hypoplasia among calves in South Kyushu, Japan: a pathological study. Res Vet Sci 49:127, 1990. 54. Kitano Y, Ohzono H, Yasuda N, et al.: Hydranencephaly, cerebellar hypoplasia, and myopathy in chick embryos infected with aino virus. Vet Pathol 33:672, 1996. 55. Velasco ME, Brown JA, Kini J, et al.: Primary congenital rhabdoid tumor of the brain with neoplastic hydranencephaly. Child Nerv Syst 9:185, 1993. 56. Covington C, Taylor H, Gill C, et al.: Prolonged survival in hydranencephaly: a case report. Tenn Med 96:423, 2003. 57. Appenzeller O, Snyder R, Kornfeld M: Autonomic failure in hydranencephaly. J Neurol Neurosurg Psychiatry 33:532, 1970. 58. Wellons JC III, Tubbs RS, Leveque J-CA, et al.: Choroid plexectomy reduces neurosurgical interventions in patients with hydranencephaly. Pediatr Neurosurg 36:148, 2002. 59. Endo H, Kobayashi S, Nakamigawa, et al.: Endocrinological analysis of chronic hypernatremia in two cases of hydranencephaly. No To Hattatsu 22:3, 1990. 60. Hashimoto T, Fukuda K, Endo S, et al.: Circadian rhythm in patients with hydranencephaly. J Child Neurol 7:188, 1992. 61. Morgan H: Hydranencephalic children and the ability to suffer. J Clin Ethics 1:325, 1990. 62. Hadi HA, Mashini IS, Devoe LD, et al.: Ultrasonographic prenatal diagnosis of hydranencephaly: a case report. J Reprod Med 31:254, 1986. 63. Vila-Coro AA, Dominquez R: Intrauterine diagnosis of hydranencephaly by magnetic resonance. Magnetic Res Imag 7:105, 1989.

15.11 Porencephaly Definition

The term porencephaly was first used by Heschl1 to include any cavity or cleft of the cerebral cortex. He described a variety of lesions, some of which communicated with both the ventricular and the subarachnoid systems, others that only connected with the ventricles, and some that were enclosed within the cortex. These abnormalities are clinically, pathologically, and etiologically diverse. Most authors recognize two major subgroups, based on both pathologic findings and etiologic hypotheses: type 1 or encephaloclastic porencephaly (EP), and type 2 or developmental porencephaly (DP), with the latter being subdivided into schizencephaly and simple porencephaly (SP). There has been a proliferation of confusing terminology in the literature, and this, along with the nosology used in this section, is shown in Figure 15-54. What has been called congenital midline porencephaly is considered to be a variant of the dorsal cyst seen in holoprosencephaly (Section 15.4 ).2 Encephaloclastic porencephaly is presumed to arise from secondary cortical destruction in an otherwise normal brain, whereas the developmental porencephalies are thought to be due to defective embryogenesis. Schizencephaly is generally accepted as a disorder of

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Fig. 15-54. The terminology used in this section is underlined and in standard script. Type 1 (for encephaloclastic) and type 2 (for developmental) are in common use today. Terms in small italics have been used but should be abandoned.

formation of the germinal matrix or migration of neuroblasts. Thus, it might seem logical to place schizencephaly in the section on malformations of cortical development (Section 15.5), especially as it occurs commonly in association with cortical dysplasia, gyral anomalies, and heterotopias. However, there is a tradition of treating these abnormalities under the heading of porencephaly and, perhaps more important, there is evidence that sometimes these pathological and histological distinctions are more a matter of timing and severity than fundamental differences in underlying etiology. Several examples illustrate this latter point. Cerebral hemorrhage is a welldocumented cause of EP, but schizencephaly has been reported after in utero exposure to warfarin,3 and as a consequence of alloimmune thrombocytopenia with intracranial bleeding prior to 20 weeks, as compared to bleeding after 26 weeks in the equivalent cases with EP.4 Debus et al.5 have provided very suggestive evidence of an association between inherited thrombophilia variants and EP. Therefore, it is of interest that an inherited thrombophilia variant was found in three of four members of a family with incomplete penetrance of an autosomal dominant form of SP.6 Maternal abdominal trauma is thought to result in malformations through hemorrhage or hypoperfusion, and a case of EP with limb reduction defects following serious maternal abdominal trauma has been reported.7 Schizencephaly with limb reduction has also been reported (Table 15-15). In utero cytomegalovirus (CMV) infection has been associated with hydranencephaly and EP, probably as a result of a vasculitis, and schizencephaly has also been reported following CMV infection,8 including a case with a coexisting area of encephalomalacia.9 Schizencephaly has also been reported after probable twin-twin transfusion associated with a genetic amniocentesis.10 In a report of 10 pregnancies with CNS anomalies associated with in utero exposure to vasoactive drugs (predominantly cocaine),11 there was one child with hydranencephaly, three with typical EP, two with schizencephaly, one with a severe SP, one with cortical infarcts, and two with absent corpus callosum and colpocephaly, thus covering the whole spectrum of porencephaly and beyond. Finally, some of the most provocative findings are those of Marin-Padilla et al.12 who reported on the evolution of typical encephaloclastic lesions in the postnatal shaken-baby syndrome. By 6 months of age, the cortex had developed microgyria, abnormal lamination, and cortical dysplasia; changes that might readily be attributed to early prenatal damage. If the possibility of shared etiology is kept in mind it remains reasonable to consider the major groups and subgroups of porencephaly separately because they do tend to differ in their clinical

Table 15-15. Syndromes with porencephaly/schizencephaly Syndrome

Prominent Features

Causation Gene/Locus

Anophthalmiahypopituitarism-renal60

Micro/anophthalmia, cleft lip/palate, absent pituitary, nephronopthisis, delayed development, reduced cerebral white matter, multiple small porencephalic cysts; father had large head

Unknown

Anterior chamberhydrocephalus-heart defect61

Peters anomaly, persistent hyaloid artery, unilateral absent lens, obstructed aqueduct of Sylvius, enlargement of the lateral and 4th ventricles, cerebellar, pontine, and medullary atrophy, porencephaly, tricuspid valve dilation, atrial septal defect, lethal

Unknown

Beckwith-Wiedemann62

Usually prenatal onset overgrowth, macroglossia, omphalocele, visceromegaly, ear creases/pits at the front or back of the lobes or helices, nevus flammeus, midfacial hypoplasia; association with embryonal malignancies; hemihypertrophy a risk factor for malignancy; case report with schizencephaly

AD (130650) imprinting and gene dosage effects 11p15.5

Cerebro-oculo-skeletalrenal63

Optic atrophy, absence of retinal vessels, seizures, growth and developmental delay, elongated clavicles, cupped ribs, mild platyspondyly, rhizomelia, schizencephaly, nephritis/nephrosis

Unknown

Cocaine, prenatal exposure64

Debatable if recognizable facial appearance, limb reduction, genitourinary anomalies; CNS has included porencephaly, septo-optic dysplasia, schizencephaly, midline cysts, and callosal agenesis

In utero exposure

DK-phocomelia65

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs; case with bilateral upper limb amelia, right parieto-occipital porencephalic cyst, severely retarded, gingival hyperplasia

Unknown (223340)

Encephalocraniocutaneous lipomatosis66

Unilateral cerebral anomalies include hemiatrophy and defective operculization of insula, ipsilateral protuberant soft scalp masses with overlying alopecia, papular skin lesions on face and eyes, pterygium-like scleral lesions that may lead to scarring, and progressive intracranial calcifications associated with vascular malformations; a few cases with porencephaly

Unknown (176920)

Linear nevus sebaceous67,68

Various skin lesions include nevus unius lateris, icthyosis histrix, acanthosis nigricans, nevus sebaceous of Jadasshon; cortical atrophy, intracranial aneurysms; various neurologic sequelae in 50% of patients; brain tumor in 2/64; cases with porencephaly/schizencephaly

Unknown (163200)

Generalized fibromatosiscutis marmorata69

Fibrous nodules of various organs may compromise vital organs. Only one case with associated cutis marmorata telangiectasia, hemiatrophy, porencephaly

Unknown, some familial (228550)

Glass: ear anomalies-limb reduction70

Findings variable: macrocephaly, over-folded helices, preauricular tags, external meatal stenosis, narrow palpebrae, cleft palate, agenesis of the corpus callosum, multilocular porencephaly; sister lacked brain abnormalities, had absent right arm, absent proximal left humerus, humero-radio-ulnar synostosis

AR

Hypocalvaria-heartcamptomelia71

IUGR, microcephaly, wide sutures, areas of absent calvarial bones, prominent eyes, low-set and anomalous pinnae, anteverted nares, bowing greatest in tibia, bilateral cleft-like cysts in front of anterior horns

Uncertain

L’Hermitte: oxycephaly72

Oxycephaly with open sutures, absent frontal sinuses, flat face, shallow orbits, absence of the corpus callosum, hypoplastic vermis

AR

Merlob: morning gloryporencephaly73

Macrodolichocephaly, long palpebrae, epicanthus, absent eye movements, central retinal colobomas, anteverted nares, tented lips, high palate, hydronephrosis, unilateral porencephaly and atrophy, parasagittal arachnoid cyst.

Unknown

Microgastria-upper limb reduction74

Microgastria, variable upper limb defects, asplenia/splenogonadal fusion; case reports in association with iris coloboma, orbital cyst, fused thalami, arhinencephaly, agenesis of corpus callosum, several internal anomalies, hypothalamic hamartoma; anophthalmia, porencephalic cyst, and hydrocephalus

Unknown (156810)

Nephrotic syndromeinfantile spasms-GallowayMowat75

Developmental delay, early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits, areas of microgyria, cortical layer fusion. Single incompletely documented case with ‘‘diffuse encephalomalacia’’

AR (251300)

Neurocutaneous melanosis76

Classical and variant forms of cutaneous pigmented nevi and leptomeningeal melanosis with malignant change, intracranial anomalies and cysts, arachnoid villi infiltration in some. Report of a case with porencephaly

Unknown (249400)

Oculocerebrocutaneous77

Orbital cysts, microphthalmia, lid coloboma, periorbital skin appendages, areas of skin hypoplasia/aplasia, skeletal anomalies, agenesis of the corpus callosum, multiple brain cysts of undetermined type

Unknown (164180)

Oral-facial-digital type I78

Midline cleft/notched upper lip, multiple oral frenulae, lobulated tongue with hamartomas, asymmetric brachysyndactyly; CNS includes hydrocephaly, porencephaly, cerebellar vermis hypoplasia, Dandy-Walker cysts, neuronal migration defects, and agenesis of the corpus callosum

XLD (311200) male lethal CXORF5, Xp22.3-p22.2 (continued)

646

Brain

647

Table 15-15. Syndromes with porencephaly/schizencephaly (continued) Syndrome

Prominent Features

Causation Gene/Locus

Oral-facial-digital type II

Short stature, hypertelorism, low nasal bridge, broad and bifid nasal tip, hypertropied oral frenula, cleft and lobulate tongue, cleft palate; brachysyndactyly, preaxial and postaxial polydactyly of hands; preaxial foot polydactyly; usually normal intelligence; CNS includes porencephaly, hydrocephaly, callosal agenesis

AR (252100)

Porencephaly-cerebellar hypoplasia-heart defect80

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Porencephaly/ schizencephaly-septum pellucidum81

Absent septum pellucidum, porencephaly/schizencephaly, mental retardation, neurologic dysfunction including paraplegia; this is basically a developmental association (see text)

Unknown, case in utero benzol exposure

Porphyria-acute intermittent, homozygote82

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) porphobilinogen deaminase, 11q23.3

Progressive hemifacial microsomia-tumors83

Progressive postnatal hemifacial atrophy with ipsilateral cerebral calcification, mild learning difficulties, orbital neuroma, oral odontogenous fibroma, lower limb cartilaginous hamartomas, porencephaly; same as encephalocraniocutaneous lipomatosis?

Unknown

Proud: XLMR-seizurescallosal agenesis84

Microcephaly, severe mental retardation, seizures, spasticity, coarse face, nystagmus, joint contractures, tapering fingers, porencephaly, agenesis of the corpus callosum; conservative substitution in homeodomain

XLD (300004) ARX, Xp22.13

Pycnodysostosis85

Osteosclerosis, short stature, open fontanels, wide cranial sutures, wormian bones, prominent nose, dental anomalies, abnormal clavicles, acro-osteolysis, fractures, variable mental retardation

AR (265800) cathepsin K, 1q21

Schizencephalyectrodactyly86

Two unrelated children with unilateral schizencephaly associated with an ipsilateral ectrodactyly in one, and a contralateral lobster claw deformity in the other

Unknown

Septo-optic dysplasia87

Septum pellucidum agenesis, optic nerve hypoplasia, hypothalamic/pituitary dysfunction; variable growth hormone deficiency, diabetes insipidus, trophic hormone deficiencies; seizures and developmental delay common; brain anomalies include agenesis of the corpus callosum, hydrocephalus, cerebral atrophy, porencephaly, schizencephaly. May be a component of other syndromes or occur occasionally in established syndromes (see this text and Section 15.7).

Heterogeneity (182230) some due to HESX1, 3p21.2-p21.1

Triophthalmia-facial clefting88

Dolichocephaly, cleft lip/palate, asymmetric face, micrognathia, ventricular septal defect; dilated ventricles, brain atrophy and ‘‘porencephaly’’

Unknown

Triple-X89

Tall stature, disproportionately long limbs, lowered mean OFC, mean IQ 85-90; commonly poor coordination, delayed motor milestones, poor verbal learning and expressive language. Case with right closed-lip schizencephaly, arachnoid cyst, abnormal left gyri.

Chromosome imbalance

Vitamin A embryopathy90

Microtia/anotia, asymmetric second arch anomalies, flat nose, hypertelorism, micrognathia, limb and heart defects. CNS includes hydrocephalus, microcephaly, porencephaly, focal agyria, heterotopias, vermis hypoplasia, Dandy-Walker

In utero exposure

79

presentation, management, and prognosis. Also some etiologies may be limited to a specific type of porencephaly. 15.11.1 Encephaloclastic Porencephaly Definition

Congenital encephaloclastic porencephaly is a cavity in the brain resulting from destruction of normal tissue. It may be single or multiple and may be self-contained within the cerebral hemisphere or connect with the lateral ventricles and/or subarachnoid space. As such it forms part of the spectrum of hydranencephaly (Section 15.10). Congenital EP usually originates from a hemorrhage anterior to the subependymal germinal matrix at 24 to 32 weeks gestation, which tends to show centripetal growth with relative sparing of the medial structures.13 The in utero sonographic evolution of several cases of EP, often with earlier documented normal ultrasounds, has been reported. The initial hemorrhage appears as a hyperechoic area,

and over a period of up to several weeks it presents an anechoic center with an echogenic border, eventually developing anechoic properties characteristic of CSF. Angiography, and presumably in utero color-Doppler ultrasound, typically shows normal preexisting blood vessels crossing the cavity. With maturation the cavity is lined by gliosis, and the degree of glial scarring varies with the timing of the insult. Unlike the situation with DP, clefts are not lined by gray matter, and MRI can be useful in clarifying this detail. There is often asymmetric dilation of the lateral ventricles with a midline shift.13 Etiology and Distribution

The major causes of EP relate to hemorrhage/infarction, infection, and trauma, and it is likely that the latter two have an underlying vascular hypoxic basis. The distribution of EP is often seen to fall within the distribution of a specific cerebral artery, of which the middle cerebral is the most common.14 Debus et al.5 reported that 13 of 24 infants and children with EP had a single, and three others had two, inherited risk factors for thrombophilia. Two children

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Neuromuscular Systems

with microcephaly, cerebral atrophy, cerebral cystic lesions, and factor V Leiden mutations were reported by Voudris et al.15 Several additional cases have been reported with alloimmune thrombocytopenia,4,8 and it is generally accepted that hemorrhage is the mechanism of damage with warfarin exposure.3 Prenatal sonography has documented the development of EP following in utero CMV infection7,16 and herpes zoster infection at 25 weeks gestation.17 Cases have also been reported following penetration of the skull by an amniocentesis needle,18 and after early (9 weeks) chorionic villus sampling (CVS).19 It is of note that early CVS has also been related to limb reduction defects, and that the combination of limb reduction and EP has followed maternal abdominal trauma.7 Cases segregating with COL4A1 mutations have been reported in mice and humans.112 There are no good estimates of the incidence of EP. Porencephaly was noted in 2.5% of pediatric autopsies with known CNS anomalies, of which 2.2% were considered to be DP.20 Congenital cases appear to be uncommon, and the prevalence will be higher if peri- and postnatally acquired cases are included. Premature infants (24–32 weeks) are clearly susceptible to major intracranial bleeding, which may be observed to evolve, both by neuroimaging and pathological examination, into a full thickness necrosis of the cerebral cortex.21 Another picture typical for EP can be seen following postnatal head trauma,22 including the shaken baby syndrome.12 Initial concerns that perinatal chest physiotherapy in very premature infants might cause EP appear to have been unfounded.23 Prognosis, Treatment, and Prevention

The outcome for children with EP will largely depend on the timing, extent, and location of the lesion, and may range from asymptomatic, to later-onset seizures, to motor and/or variable intellectual disability and medication-resistant seizures. Seizures can be an important complication, and in some cases originate directly from the EP and are often of the Lennox-Gastaux type. A good response to ‘‘decapping’’ a large cyst has been reported, and in a series of 37 children with relatively smaller lesions, 62% became seizure free after fenestration of the cyst into the lateral ventricle.24 In addition, it appears that there is an over 30% associated occurrence of mesial temporal sclerosis with EP. Ho et al.14 reported 14 patients with EP and seizures; 12 had congenital hemiparesis, and the MRI showed the porencephaly to be in the distribution of the middle cerebral artery in eight, the posterior in three, the internal carotid in one, and multiple arteries in three. Thirteen had demonstrable hippocampal, and 10 amygdalar atrophy, and the seizures showed a temporal origin in nine. Two patients were surgically treated and became seizure free. Burneo et al.25 reported 24 patients with EP and seizures. In nine patients the seizures were drug resistant, and in six of these there was an extratemporal porencephaly with a temporal sclerosis and focus of the seizures. Five patients had surgical removal of the temporal focus and were seizure free at an average follow-up of 47 months. In five of the six cases, the temporal sclerosis was ipsilateral to the porencephaly, and the authors hypothesized a common ischemic pathogenic event. For the contralateral lesion they raise the possibility of diaschisis, where an insult at one site causes changes at a distant contralateral region of the brain. Prevention of EP would largely depend on removing the causes of brain hemorrhage/ischemia, infections, and trauma. Specific treatment of alloimmune thrombocytopenia can reduce the risk of fetal intracerebral hemorrhage26; amniocentesis should be performed under direct ultrasound guidance, and CVS should not be performed below 11 weeks gestation. The risk of EP in the fetus of a mother carrying a single inherited risk factor for thrombophilia is clearly low, and there is no indication for the treatment of such

women in pregnancy. However, a woman with two such risk factors, who already had an affected child would present difficult management choices, for which there are no informing data. 15.11.2 Developmental Porencephaly

15.11.2.1 Schizencephaly Definition

The term schizencephaly was first used by Yakovlev and Wadsworth27 to refer to clefts found in the region of the primary fissures and is characterized by an infolding of the cerebral cortex into the cleft and continuity of a pia-ependymal seam. The lesion can be bilateral or unilateral, and contralateral gyral anomalies or heterotopias often accompany the latter (Figs. 15-55 and 15-56). Yakovlev and Wadsworth27 subdivided schizencephaly according to whether the sides of the clefts are closely apposed or lie completely open and allow the ventricles to connect to the subarachnoid space (Fig. 15-57). Today the former, which usually lacks hydrocephalus, is called closed-lip, and the latter, in which hydrocephalus is the norm, is called open-lip schizencephaly. This distinction has no pathogenic basis, indeed 12 of 15 patients with bilateral schizencephaly reported by Denis et al.28 had one open and one closed cleft, but it is useful as a measure of severity. In utero progression from closed to open-lip has been observed.29 Diagnosis

The clefts most often involve the parasylvian fissure and region of the central sulcus. Patients typically present with developmental delay, asymmetric muscle tone, seizures, and hemiparesis or quadriparesis. Patients with the closed-lip form more often present with motor delay and hemiparesis; those with the open-lip type more often present with hydrocephalus and seizures.30 The seizures may be of a variety of types, including tonic-clonic, partial motor, sensory, and infantile spasms.31 Mental retardation is variable but is usually toward the Fig. 15-55. Axial CT scan showing bilateral schizencephaly with the margins of the cleft closely apposed on the right. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario, Ottawa.)

Brain

Fig. 15-56. Axial MRI scan of a 26-year-old woman who presented with hemiparesis and onset of seizures, showing unilateral left-sided cleft and contralateral gyral anomalies. (Courtesy of Dr. S. Grahovac, Ottawa Hospital, Ottawa.)

Fig. 15-57. Axial CT scan showing bilateral schizencephaly and wide separation of the cleft margins. (Courtesy of Dr. C. Greenberg, Winnipeg.)

649

severe end of the spectrum in individuals with bilateral openlip schizencephaly,28,30 and microcephaly is a poor prognostic sign.32 Motor deficits are more common with frontal than non-frontal lesions.33 Patients with large clefts may show increased transillumination over the affected area, but this is a nonspecific finding, and the diagnosis is confirmed with appropriate imaging techniques. It is the continuity of the cerebral gray matter into and along the walls of the cleft and of the pia-ependymal connection that provides the distinctive findings on neuroimaging (Fig. 15-56). Although angiography has been superceded by noninvasive approaches, it does show a characteristic incurving of the cortical vessels at the border of the cleft and their continuity with the subependymal veins, as well as reticular masses of small vessels in the areas of accompanying microgyria.34 Sonographic diagnosis of open-lip schizencephaly is made by demonstrating dilated ventricles that connect directly with the subarachnoid space, and in closed lip by detecting a funnel-shaped, cortically lined, indentation of the cortex.29,35 The diagnosis is not always apparent on prenatal sonography and is more likely to be perceived as hydrocephalus, with or without visualization of the associated cortical abnormalities. For example, Denis et al.36 reported three cases where ultrasound detected ventriculomegaly and cortical anomalies, but where prenatal fast MRI images were required to make the diagnosis of schizencephaly. The specific neuroimaging findings will vary with the size and precise location of the cleft(s). Typically, the cleft is seen to arise vertically from the area of the midsylvian fissure and may be presylvian or suprasylvian; the length and orientation of the fissure may be altered.31 The cleft itself extends through the entire cortical mantle and is lined by cortex of normal density, but often increased thickness.32 There may be a triangular indentation (dimple) at the ventricular end of the cleft, with gray matter extending a short distance along the ventricle. Choroid plexus may extend into larger open-lip clefts. MRI appears to be the procedure of choice to best define the cleft and its associated anomalies. There have been several reports where CT has either failed to detect or has imprecisely defined schizencephaly.28,33,37 Pathologic examination of the cleft demonstrates the piaependymal lining along the seam, and true micropolygyria and heterotopias, both at the site and often at more distant locations. Functional imaging with positron emission tomography and single photon emission CT have shown that the gray matter lining the cleft has equivalent perfusion and glucose metabolism to that of normal cortex.38 Absence of the septum pellucidum occurs in association with schizencephaly often enough that the finding of either of these lesions should trigger a search for the second.31,37,39,40 Some have argued that this is a distinct neuropathological syndrome,37,39,40 but there is nothing distinctive about the clinical, etiologic, or pathologic nature of schizencephaly with or without absence of the septum pellucidum. This author agrees with Osborn41 that the single name schizencephaly should be used whether or not the septum pellucidum is present. Furthermore, there is evidence that the difference simply reflects the site and timing of the initial embryologic insult. Raybaud et al.42 hypothesized that the septum pellucidum is part of a medial medullary velum that represents the frontal lobe, and that the psalterium corresponds to the parietooccipital, and the fimbria to the temporal, lobes. They found that in all cases where the septum pellucidum was absent, the clefts were in the frontal lobe; whereas if the septum pellucidum was present, the clefts were occipital, parietal, or temporal. In three

650

Neuromuscular Systems

central clefts there were overlapping findings, but in these cases the actual lobar location of the cleft could not be determined. These results support a segmental organization of septal and cortical development and indicate that the presence or absence of the septum pellucidum depends on the precise location of the developmental disturbance. Kuban et al.43 highlighted that schizencephaly may be present in septo-optic dysplasia (SOD), which includes absent septum pellucidum, optic nerve hypoplasia, and pituitary hypofunction. They argued, from a review of the literature, that either optic nerve hypoplasia or absence of the septum pellucidum alone is also associated with neuroendocrine dysfunction, and they proposed that this represented a spectrum of neurodevelopment malformations. The concept of a spectrum is further supported by reports of patients with SOD and polymicrogyria.44,45 Etiology and Distribution

The facts that the clefts in schizencephaly are lined by cortex, there is continuity between the ependyma and pia, a dimple of the ventricle is often seen at the point of entry, blood vessels are often seen extending between the cortical surfaces, and associated brain anomalies such as absence of the septum pellucidum, heterotopias, and microgyria are present, argue strongly for a developmental rather than a destructive basis for schizencephaly.32 The timing and nature of the underlying insult remain matters for debate. Yakovlev and Wadsworth27 argued for an origin during the first 2 months of gestation, while Dekaban,46 noting the common location in the distribution of the middle cerebral circulation, has argued in favor of a somewhat later vascular basis. The frequent bilateral involvement, including microgyria, supports a timing before division of the cerebral hemispheres, and this is further supported by the strong association with optic nerve hypoplasia and absence of the septum pellucidum that relate to development of the lamina terminalis.43 The ultimate gross pathologic lesion can be explained as the result of a local failure of neuroblast migration from the germinal matrix. The pia and ependyma become apposed at this site of failure and cause the surrounding, normally developing cortex, as well as the ventricular wall, to be drawn into the cleft, producing both the cortical lining and the ventricular dimple characteristic of schizencephaly. Arachnoid cysts have been reported a number of times in association with schizencephaly. Sener47 reported two patients with large schizencephalic clefts and large temporal arachnoid cysts, and argued that the cyst originated from splitting of the leptomeninges caused by the cortical infolding into the cleft. However, the report of monozygotic twins, one with unilateral schizencephaly and the other with a temporal arachnoid cyst,48 and a patient with schizencephaly and dilated subarachnoid space whose brother had a typical arachnoid cyst,28 rather favor a shared, and possibly familial, underlying pathogenesis. The distinction between open-lip and closed-lip schizencephaly may reflect the size of the initial lesion rather than be a consequence of obstructive hydrocephalus, because many patients with open-lip schizencephaly are microcephalic.32 The discovery that mutations in EMX2, a homeobox gene specifically expressed in proliferating cells of the ventricular zone and considered to play an important roll in the proliferation and possible migration of neuroblasts, are present in a substantial portion of cases of sporadic schizencephaly49,50 supports an early origin involving cells of the germinal matrix as a cause for this disorder. In the two small series reported to date, sequence changes have been reported in 13 of 18 patients. While there is an early suggestion of some

genotype-phenotype correlation, the pathogenicity of some of the mutations is uncertain at this time, and more information is required before the true importance of this gene can be assessed. However, the fact that not all cases studied have had mutations in EMX2, together with evidence from certain case reports, suggests that other etiologies, and perhaps later timing, may also come into play. Hamsters infected with Kilham strain mumps virus during the time of neuronal migration show antigen on neuroepithelial cells in the ventricular zone and in vimentin immunoreactive radial glial fibres.51 There is pathologic evidence of hemorrhage, neuronal necrosis, and a picture compatible with schizencephaly, which raises the potential of a direct viral cause for schizencephaly. Examples of schizencephaly associated with alloimmune thrombocytopenia,4 fetal bradycardia following genetic amniocentesis in a twin pregnancy,10 and in utero exposure to vasoactive drugs11,52 have already been mentioned. One of those patients reported by Souchet52 had occlusion of the right middle cerebral artery, which the author speculated might have recanalized in the other two cases; middle cerebral artery stenosis was also noted in the CMV-associated cases of Tonas-Vila et al.9 Landrieu and Lacroix53 reported a 3-month-old girl with bilateral schizencephalic clefts lined by microgyric cortex without evidence of arrested neuronal migration. Distant areas had subependymal heterotopias, and there was evidence of later cortical ischemic events and atypical vessels in the cleft, a hemorrhage from which led to her death. Thus, there is substantive support for a vascular origin for some cases of schizencephaly, and for the suggestion by Landrieu and Lacroix53 that a malacic process, at a time when the entire cortical mantle can be destroyed (< 20 weeks), can cause this malformation. Chromosome imbalance is not a significant cause of schizencephaly. A number of familial cases of non-syndromic schizencephaly, typified by the families reported by Haverkamp et al.,54 Ueda et al.,55 Hillberger et al.,56 Robinson,57 and the brothers with identical EMX2 mutations reported by Granata et al.,58 have all involved affected siblings with normal parents. All the familial cases have been bilateral, although the severity has varied, and both males and females have been affected. Senol et al.59 did report a pair of dizygotic twins with absent septum pellucidum in which one member had bilateral closed-lip schizencephaly and the other had unilateral cortical dysplasia in the same area as the sibling’s cleft. On the surface the pattern is most suggestive of autosomal recessive inheritance. However, the mutation reported in the two brothers reported by Granata et al.58 was not found in either parent. The likely explanation is that of germline mosaicism and this, together with the relatively high rate of EMX2 mutations in sporadic schizencephaly,49,50 raises the question as to whether these ‘‘autosomal recessive’’ families are in fact further examples of germline mosaicism for heterozygous genetic lethal mutations. Alternatively, some sibling recurrences of milder schizencephaly could be expected to occur due to non-penetrance of less severe mutations in a carrier parent. Four patients with mild unilateral sporadic schizencephaly have been found to have the same synonymous C ! A substitution at position 7 in EMX2 (not seen in 1500 controls), and in one case the unaffected mother, carried the same muation.50 The true incidence of schizencephaly is unknown. There does not appear to be any significant difference in sex ratio. Considering that patients are selected for neuroimaging study because of suspicion of an intracranial lesion, it must be a rare malformation. Rates of 1 in 625 and 1 in 1650 have been reported from large series of consecutive CT examinations.31,32 Table 15-15

Brain

lists a number of syndromes in which porencephaly has been reported, but the specific type has not always been made clear. Prognosis, Treatment, and Prevention

The prognosis in schizencephaly is correlated with the extent and type of the malformation, and can be affected by the presence and medical responsiveness of any accompanying seizure disorder. Packard et al.30 reported 12 cases of bilateral and 17 unilateral openlip, and 6 cases of bilateral and 12 unilateral closed-lip schizencephaly. The majority of clefts were anterior. Among the total group, 57% had seizures and a third of these were medically unresponsive. Fifty-one percent were severely, 32% moderately, and 17% mildly or not at all mentally retarded. Patients with a closed-lip malformation were more likely to show mild to moderate delay than were those with open-lip schizencephaly (78% vs. 31%), as were those with unilateral as compared to those with bilateral involvement (62% vs. 28%). Normal language development was noted in 48% of those with a unilateral cleft compared with only 6% of those with bilateral clefts, and children who had a single lobe involved made up 88% of those with mild, and 58% of those with moderate delay. Eleven of 12 patients with bilateral, open-lip schizencephaly had severe mental retardation. Denis et al.28 reported 15 patients with bilateral and 15 patients with unilateral schizencephaly. Mental retardation was noted in 57% of the cases. Of the unilateral cases, 53% had presented by 1 year of age with asymmetric muscle tone (8), seizures (2), developmental delay (2), locomotor delay (2), and nystagmus (1). Twelve of the 15 children had a mild hemiparesis, which was contralateral in 11, and one had no motor deficiency. Intelligence was considered normal in 10, although seven exhibited language delay. Seven children had seizures, with a mean age of onset of 4 years, and although there were a variety of seizure types, most children expressed a single form, and only one case was refractory to drug treatment. Of the bilateral cases, 47% were diagnosed by 1 year of age with the presenting signs including developmental delay and asymmetric tone (5), language abnormality (1), and microcephaly (1). Nine patients had tetraparesis, and five had hemiparesis; 12 were considered to have mental retardation and all showed language delay, with four exhibiting a bucco-lingual apraxia equivalent to that seen in bilateral perisylvian cortical malformation (Section 15.5). Only four of the 15 had a seizure disorder and all were drug responsive. Similar results were obtained in the smaller series reported by Granata et al.,91 and it can be concluded that patients with bilateral, open-lip defects have the poorest developmental and motor prognosis, while those with unilateral, closed schizencephaly have the most favorable outlook, and may indeed show very little impact.31,32,92 In contrast, the occurrence of seizures does not correlate as well with the type of lesion,8,28,91 although they may be determined by the presence of associated areas of cortical dysplasia. There is no specific treatment for schizencephaly. If the site of origin of medically resistant seizures can be localized, patients may benefit from surgery, which may involve dysplasia in the wall of the cleft itself,93 or a more distant focus, such as the temporal lobe.94 Other complications that may respond to intervention include hydrocephalus, which may be associated with a mass effect and midline shift in unilateral cases. Alexander et al.95 described two patients with schizencephaly and a schizoaffective disorder, and Relan et al.96added another with bipolar affective disorder. At this time there are insufficient data by which to determine whether these cases represent chance concurrence or an increased risk for psychosis in schizencephaly.

651

As is the case in hemihydranencephaly, there is evidence that the unaffected cortex may undergo some functional compensatory reorganization (plasticity), notably in the case of unilateral disease,97–99 although Denis et al.28 discuss the concern that such reorganization, in order to preserve one function, may compromise other specific functions through a crowding effect. There are no direct preventive measures, although the steps mentioned under EP might be expected to have some small impact. Testing for mutations in EMX2 should be considered especially in typical cases where no other etiology is apparent. If a mutation is found, prenatal diagnosis should be offered in subsequent pregnancies, even if parental evaluations are negative because of the, as yet undefined, risk of germline mosaicism. In the absence of a mutation or additional cases in the family, patients can be counseled that the recurrence risk is low. Targeted prenatal ultrasound may be provided in subsequent pregnancies, with the understanding that all cases will not be detected, and that other neuroimaging approaches, such as fetal MRI, may be required in order to clarify suspicious signs. 15.11.2.2 Simple Porencephaly Definition

Simple porencephalies appear as unilateral or bilateral outpouchings or diverticuli of the lateral ventricle(s). These lesions are lined by ependyma and are to be distinguished from encephaloclastic or destructive lesions that develop after the adult brain shape has been achieved. Again, it should be kept in mind that at least in some cases it may be the gestational timing and not the underlying pathogenesis that differs between the two, and that the distinction is often not clear from the available neuroimaging in clinical reports. Also, as already discussed, it is not certain that schizencephaly is fundamentally different from what is herein called simple porencephaly.100 However, differences in clinical presentation, prognosis, and treatment make the distinction useful. Diagnosis

Most infants are symptomatic shortly after birth, and, with increased use of noninvasive neuroradiographic techniques, the diagnosis is usually made before age 1 year. Presenting signs include delayed growth and development, spastic paresis, hypotonia, seizures that are often infantile spasms, and macrocephaly or microcephaly.101,102 The presentation of unilateral lesions may be more distinctive because of contralateral hemiparesis and ipsilateral cranial bulging. Porencephaly is a diagnostic consideration in any child with unexplained hemiparesis.103 Transillumination of the skull is positive in the presence of large cysts and shows good correlation with their location. Routine skull radiographs may show local bulging and thinning on the side of unilateral cysts and a shift in the attachment of the falx.101,102 The EEG is frequently abnormal and may show local changes over the site of the cysts.102 CT or MRI readily shows the cyst and its communication to the lateral ventricles, which may show hydrocephalus.100 In unilateral cases there is frequently a marked thinning of the cortex over the lesion and a shift toward the contralateral normal side that becomes compressed. The porencephaly usually involves more than one lobe. The frequency of associated extracranial malformations does not appear increased above normal, but associated cerebral pathology such as heterotopias, microgyria, and absence of the corpus callosum or septum pellucidum are not uncommon and

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help to distinguish this malformation from later in utero acquired encephaloclastic lesions, which may on occasion communicate with the ventricles.101,102,104,105 Blood vessels crossing the cyst and ipsilateral atrophy both suggest the latter etiology, but in some cases the distinction may be difficult. Simple porencephaly is not a common component of syndromes (Table 15-15). Although absence of the septum pellucidum occurs with SP, it is more characteristic of schizencephaly. Etiology and Distribution

The pathogenesis of this form of porencephaly remains a matter of debate, with the weight of evidence favoring a disturbance in vascular supply leading to the cerebral dysgenesis. The nature of associated malformations would place the event before 12 weeks gestation. Several studies have found an apparent association between porencephaly and adoption and/or fostering or unwed mothers.102,106 There is currently no evidence as to whether this may represent an effect of reduced maternal age, poor prenatal care, attempted abortion, in utero drug exposure, or some unexplained bias of ascertainment. The majority of cases of SP have been sporadic, but there have been several reports of familial occurrence.6,107–110 These families are generally characterized by a pattern consistent with autosomal dominant inheritance with variable expression and lack of penetrance, and are clinically indistinguishable from sporadic cases. The reported neuroimaging findings are compatible with both simple and encephaloclastic porencephaly. None of these dominant families have displayed schizencephaly, none have yet been reported with EMX2 mutations and, as discussed previously, it is possible that inherited thrombophilic variants may play a role in some cases.6 A careful family history is always indicated, and to date neuroimaging studies have not detected asymptomatic obligate carriers.6,108 The cases reported by Smit et al.111 with apparent autosomal dominant inheritance of porencephalies within the white matter that bordered on a normal cortical ribbon may be different. The authors interpreted areas of hypodensity in the remaining periventricular white matter as evidence of a possible disease of myelinization. Simple developmental porencephaly is far less common than both the prenatal and perinatal encephaloclastic types and has been estimated to have a prevalence of 1 in 9000.111 The true rates as revealed by modern neuroimaging techniques may be higher. Prognosis, Treatment, and Prevention

Simple porencephaly in general presents with early neurologic signs and carries a poor prognosis. However, the degree of impairment reflects the variability in the size and location(s) of the lesion and any associated cerebral pathology. It is thus quite variable, with some patients showing only mild to borderline impairment.101,102 Of major importance is the fact that a significant proportion of patients with unilateral lesions have evidence of compression of the cerebral mantle next to the porencephaly, an increasing size of the cyst over time, and a shift of the midline toward the contralateral normal side. Such patients may show progression of their impairment. In some cases shunting, which allows collapse of the cyst, is followed by an increased thickness of the cerebral mantle neighboring the cyst, a return of the midline, and an improvement in neurologic signs.103 Any ipsilateral cranial bulge returns to normal, and ultimately the side can become relatively microcephalic. Tardieu et al.101 have advocated shunting of children under age 2 years who have, in the absence of concurrent significant cerebral lesions, a large cyst, macrocephaly, marked motor signs, and developmental delay. They speculate that

early treatment might have prevented some of the neurologic impairment seen in their patients. Older and/or microcephalic patients should be followed closely for evidence of progression of clinical signs. Patients who have had appropriate studies do not show evidence of impaired CSF circulation, and the hydrocephalus is of a normal pressure type, perhaps reflecting the effect of the increased ventricular surface area due to the porencephaly. The underlying cause of SP has not been determined. Prevention is therefore limited to recognition of genetic cases, the true incidence of which is unknown, and to the provision of appropriate counseling. The majority, if not all, of familial cases of simple porencephaly have shown dominant inheritance, and the affected parent is by necessity mildly affected. Therefore, it is reasonable to have a high index of suspicion when deciding whether to investigate a parent or sibling of an affected individual. References (Porencephaly) 1. Heschl R: Gehimdefekt und Hydrocephalus. Prager Vierteljahrsch Prakt Heilkunde 61:59, 1859. 2. Vintzileos AM, Hovick TJ, Escoto DT, et al.: Congenital midline porencephaly: prenatal sonographic findings and a review of the literature. Am J Perinatol 4:125, 1987. 3. Pati S, Helmbrecht GD: Congenital schizencephaly associated with inutero warfarin exposure. Reprod Toxicol 8:115, 1994. 4. Dale ST, Coleman LT: Neonatal alloimmune thrombocytopenia: antenatal and postnatal imaging findings in the pediatric brain. AJNR Am J Neuroradiol 23:1457, 2002. 5. Debus O, Koch HG, Kurlemann G, et al.: Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child Fetal Neonatal Ed 78:F121, 1998. 6. Vilain C, Van Regemortar N, Verloes A, et al.: Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Am J Med Genet 112:198, 2002. 7. Viljoen DL: Porencephaly and transverse limb defects following severe maternal trauma in early pregnancy. Clin Dysmorphol 4:75, 1995. 8. LiangJS,LeeWT,PengSS,etal.:Schizencephaly:correlationbetweenclinical and neuroimaging features. Acta Paediatr Taiwan 43:208, 2002. 9. Tomas-Vila M, Garcia-Tamarit P, Garcia-Colino A, et al.: Schizencephaly associated with congenital cytomegalovirus infection. Rev Neurol 31:952, 2000. 10. Sherer DM, Salafia CM: Midtrimester amniocentesis of a twin gestation complicated by immediate severe fetal bradycardia with subsequent associated fetal anomalies. Am J Perinatol 13:347, 1996. 11. Dominguez R, Vila-Coro AA, Slopis JM, et al.: Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 145:688, 1991. 12. Marin-Padilla M, Parisi JE, Armstrong DL, et al.: Shaken infant syndrome: developmental neuropathology, progressive cortical dysplasia, and epilepsy. Acta Neurol (Berl) 103:321, 2001. 13. Eller KM, Kuller JA: Fetal porencephaly: a review of etiology, diagnosis, and prognosis. Obstet Gynecol Surv 50:684, 1995. 14. Ho SS, Kuzniecky RI, Gilliam F, et al.: Congenital porencephaly and hippocampal sclerosis. Clinical features and epileptic spectrum. Neurology 49:1382, 1997. 15. Voudris KA, Skardoutsou A, Vagiakou EA: Congenital microcephaly in two infants with the factor V Leiden mutation. J Child Neurol 17:905, 2002. 16. Moinuddin A, McKinstry RC, Martin KA, et al.: Intracranial hemorrhage progressing to porencephaly as a result of congenitally acquired cytomegalovirus infection—an illustrative report. Prenat Diagn 23:797, 2003. 17. Ong C-L, Daniel ML: Antenatal diagnosis of a porencephalic cyst in congenital varicella-zoster virus infection. Pediatr Radiol 28:94, 1998. 18. Eller KM, Kuller JA: Porencephaly secondary to fetal trauma during amniocentesis. Obstet Gynecol 85:865, 1995. 19. Sharma AK, Phadke SR: CVS and porencephaly. Prenat Diagn 13:1077, 1993.

Brain 20. Gross H, Simanyi M: Porencephaly. In: Handbook of Clinical Neurology. Vinken PJ, Bruyn GW, eds. Elsevier/North Holland Biomedical Press, Amsterdam, 1977, p 479. 21. Cross JH, Harrison CJ, Preston PR, et al.: Postnatal encephaloclastic porencephaly—a new lesion? Arch Dis Child 67:307, 1992. 22. Yang DN, Townsend JC, Ilsen PF, et al.: Traumatic porencephalic cyst of the brain. J Am Optom Assoc 68:519, 1997. 23. Knight DB, Bevan JE, Harding JE, et al.: Chest physiotherapy and porencephalic brain lesions in very preterm infants. J Paediatr Child Health 37:554, 2001. 24. Koch CA: How should patients with porencephaly and generalized seizures such as West syndrome be treated? Brain Dev 21:566, 1999. 25. Burneo JG, Faught E, Knowlton RC, et al.: Temporal lobectomy in congenital porencephaly associated with hippocampal sclerosis. Arch Neurol 60:830, 2003. 26. Sharif U, Kuban K: Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol 16:838, 2001. 27. Yakovlev PI, Wadsworth RC: Schizencephalies: a study of the congenital clefts in the cerebral mantle. I. Clefts with fused lips. J Neuropathol Exp Med 5:116, 1946. 28. Denis D, Chateil J-F, Brun M, et al.: Schizencephaly: clinical and imaging features in 30 infantile cases. Brain Dev 22:475, 2000. 29. Klingensmith WC III, Cioffi-Raggan DT: Schizencephaly: diagnosis and progression in utero. Radiology 159:617, 1986. 30. Packard AM, Miller VS, Delgado MR: Schizencephaly: correlations of clinical and radiologic features. Neurology 48:1427, 1997. 31. Miller GM, Stears JC, Guggenheim MA, et al.: Schizencephaly: a clinical CT study. Neurology 34:997, 1984. 32. Bird CR, Gilles FH: Type I Schizencephaly: CT and neuropathologic findings. AJNR Am J Neuroradiol 8:451, 1987. 33. Barkovich AJ, Norman D: MR imaging of schizencephaly. AJR Am J Roentgenol 150:1391, 1988. 34. Braun JP, Toumade A: Porencephaly. J Neuroradiol 9:161, 1982. 35. Di Pietro MA, Brody BA, Kuban K, et al.: Schizencephaly: rare cerebral malformation demonstrated by sonography. AJNR Am J Neuroradiol 5:196, 1984. 36. Denis D, Maugney-Laulom B, Carles D, et al.: Prenatal diagnosis of schizencephaly by fetal magnetic resonance imaging. Fetal Diagn Ther 16:354, 2001. 37. Menezes L, Aicardi J, Goutieres F: Absence of the septum pellucidum with porencephalia: a neuroradiologic syndrome with variable clinical expression. Arch Neurol 45:542, 1988. 38. Morioka T, Nishio S, Sasaki M, et al.: Functional imaging in schizencephaly using [18F]fluro-2-deoxy-D-glucose positron emission tomography (FDGPET) and single photon emission computed tomography with technetium99m-hexamethyl-propyleneamine oxime (HMPAO-SPECT). Neurosurg Rev 22:99, 1999. 39. Shimozawa N, Ohno K, Takashima S, et al.: The syndrome of the absence of a septum pellucidum with porencephaly. Brain Dev 8:632, 1986. 40. Aicardi J, Goutieres F: The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 12:319, 1981. 41. Osborne RE: Schizencephaly: the true name for the syndrome of absence of the septum pellucidum with porenecephalies. Clin Neuropathol 10:107, 1991. 42. Raybaud C, Girard N, Levrier O, et al.: Schizencephaly: correlation between the lobar topography of the cleft(s) and absence of the septum pellucidum. Child Nerv Syst 17:217, 2001. 43. Kuban KCK, Teele RL, Wallman J: Septo-optic-dysplasia schizencephaly. Pediatr Radiol 19:145, 1989. 44. Siejka S, Strefling AM, Urich H: Absence of septum pellucidum and polymicrogyria: a form fruste of the porencephalic syndrome. Clin Neuropathol 8:174, 1989. 45. Miller SP, Shevell MI, Patenaude Y, et al.: Septo-optic dysplasia plus: a spectrum of malformations of cortical development. Neurology 54: 1701, 2000.

653 46. Dekaban A: Large defects in cerebral hemispheres associated with cortical dysgenesis. J Neuropathol Exp Neurol 24:512, 1965. 47. Sener RN: Coexistence of schizencephaly and middle cranial fossa arachnoid cyst: a report of two patients. Eur Radiol 7:409, 1997. 48. Briellmann RS, Jackson GD, Torn-Broers Y, et al.: Twins with different temporal lobe malformations: schizencephaly and arachnoid cyst. Neuropediatrics 29:284, 1998. 49. Capra V, De Marco P, Moroni A, et al.: Schizencephaly: surgical features and new molecular genetic results. Eur J Pediatr Surg 6(Supp 1):27, 1996. 50. Faiella A, Brunelli S, Granata, et al.: A number of schizencephaly patients including two brothers are heterozygous for germline mutations in the homeobox gene EMX2. Eur J Hum Genet 5:186, 1997. 51. Takano T, Takikita S, Shimada M: Experimental schizencephaly induced by Kilham strain of mumps virus: pathogenesis of cleft formation. Neuroreport 10:3149, 1999. 52. Suchet IB: Schizencephaly: antenatal and postnatal assessment with color-flow Doppler imaging. Can Assoc Radiol J 45:193, 2000. 53. Landrieu P, Lacroix C: Schizencephaly, consequence of a developmental vasculopathy? A clinicopathological report. Clin Neuropathol 13:192, 1994. 54. Haverkamp F, Zerres K, Ostertun B, et al.: Familial schizencephaly: further deliniation of a rare disorder. J Med Genet 32:242, 1995. 55. Ueda M, Kamiya T, Ohyama M, et al.: Two siblings with familial schizencephaly—report of a family and review in relation to clinical features and neuroradiological findings. Rinsho Shinkeigaku 36:774, 1996. 56. Hillberger AC, Willis JK, Bouldin E, et al.: Familial schizencephaly. Brain Dev 15:234, 1993. 57. Robinson RO: Familial schizencephaly. Dev Med child Neurol 33:1010, 1991. 58. Granata T, Farina L, Faiella A, et al.: Familial schizencephaly associated with EMX2 mutation. Neurology 48:1403, 1997. 59. Senol U, Karaali K, Aktekin B, et al.: Dizygotic twins with schizencephaly and focal cortical dysplasia. AJNR Am J Neuroradiol 21:1520, 2000. 60. Rauchman M, Hoffman WH, Hanna J, et al.: Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure. Am J Med Genet 104:31, 2001. 61. Gunderson CA, Stone R, Peiffer R, et al.: Corneal coloboma, aphakia and retinal neovascularization with anterior segment dysgenesis (Peters’ anomaly). Ophthalmologia 210:361, 1996. 62. Worth LL, Slopis JM, Herzog CE: Congenital hepatoblastoma and schizencephaly in an infant with Beckwith-Wiedemann syndrome. Med Pediatr Oncol 33:591, 1999. 63. Silengo MC, Lerone M, Pelizza A, et al.: A new syndrome with cerebrooculo-skeletal-renal involvement. Pediatr Radiol 20:612, 1990. 64. Gieron-Korthals MA, Helal A, Martinez CR: Expanding spectrum of cocaine induced central nervous system malformations (Case report). Brain Dev 16:253, 1994. 65. Urioste M, Paisan L, Martinez-Frias ML: DK-phocomelia syndrome in a child with a long follow-up. Am J Med Genet 52:269, 1994. 66. Fishman MA: Encephalocraniocutaneous lipomatosis. J Child Neurol 2:186, 1987. 67. Baker RS, Ross PA, Baumann RJ: Neurologic complications of the epidermal nevus syndrome. Arch Neurol 44:227, 1987. 68. Hager BC, Dyme IZ, Guertin SR, et al.: Linear nevus sebaceous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 7:45, 1991. 69. Spraker MK, Stack C, Esterly NB: Congenital generalized fibromatosis: a review of the literature and a report of a case associated with porencephaly, hemiatrophy, and cutis marmorata telangiectasia congenita. J Am Acad Dermatol 10:365, 1981. 70. Glass IA, Walford-Moore J, Chapman S, et al.: Ear anomalies, clefting and limb reduction defects: a new autosomal recessive condition? Clin Dysmorphol 3:150, 1994. 71. al-Gazali LI, Bakalinova D, Aziz, S, et al.: Hypocalvaria associated with intrauterine growth retardation, facial dysmorphism, congenital heart disease and camptomelia. Clin Dysmorphol 8:129, 1999.

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72. L ’Hermitte MMS, Ajuriaguerra J de, Trotot RP: Oxycephalie avec age´nesie de la commissure calleuse et du vermis inferieur. Rev Neurol (Paris) 76:146, 1944. 73. Merlob P, Horev G, Kremer I, et al.: Morning Glory fundus anomaly, coloboma of the optic nerve, porencephaly and hydronephrosis in a newborn infant: MCPH entity. Clin Dysmorphol 4:313, 1995. 74. al-Gazali LI, Bakir M, Dawodu A, et al.: Recurrence of the severe form of microgastria-limb reduction defect in a consanguineous family. Clin Dysmorph 8:253, 1999. 75. Hou JW, Wang TR: Galloway-Mowat syndrome in Taiwan. Am J Med Genet 58:245, 1995. 76. Martinez-Granero MA, Pascual-Castroviejo I, Roche Herroer MC, et al.: Melanosis neurocuta´nea y nevus melanocı´tico conge´nito: presentacio´n de 6 casos. Neurologia 12:287, 1997. 77. Giorgi PL, Gabrielli O, Catassi C, et al.: Oculo-cerebro cutaneous syndrome: description of a new case. Eur J Pediatr 148:325, 1989. 78. Odent S, Le Marec B, Toutain A, et al.: Central nervous system malformations and early end-stage renal disease in Oro-facio-digital syndrome type 1: a review. Am J Med Genet 75:389, 1998. 79. Balci S, Guler G, Kale G, et al.: Mohr syndrome in two sisters: prenatal diagnosis in a 22-week-old fetus with post-mortem findings in both. Prenat Diagn 19:827, 1999. 80. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 81. Hosley MA, Abroms IF, Ragland RL: Schizencephaly: case report of familial incidence. Pediatr Neurol 8:148, 1992. 82. Beukeveld GJJ, Wolthers BG, Nordman, et al.: A retrospective study of a patient with homozygous form of acute intermittent porphyria. J Inherit Metab Dis 13:673, 1990. 83. Derex L, Isnard H, Revol M: Progressive facial hemiatrophy with multiple benign tumors and hamartomas. Neuropediatrics 26:306, 1995. 84. Kato M, Das S, Petras K, et al.: Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23:147, 2004. 85. Figueiredo J, Reis A, Vaz R, et al.: Porencephalic cyst in pycnodysostosis. J Med Genet 26:782, 1989. 86. Humbertclaude V, Pedespan JM, Azaı¨s M, et al.: Schizence´phalie et malformation du membre supe´rieur. Arch Pediatr 3:357, 1996. 87. Burke JP, O’Keefe M, Bowell R: Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol 75:236, 1991. 88. Tayel SM, Sabry MA, Kader NA, et al.: Triophthalmia and facial clefting: a case report. J Med Genet 35:875, 1998. 89. Ehara H, Eda I: Schizencephaly in triple-X syndrome. Pediatr Int 43:296, 2001. 90. De Wals P: Surveillance of retinoic acid embryopathy. Teratology 40:274, 1989. 91. Granata T, Battaglia G, D’Incerti L, et al.: Schizencephaly: neuroradiologic and epileptologic findings. Epilepsia 37:1185, 1996. 92. Cho WH, Seidenwurm D, Barkovich AJ: Adult-onset neurologic dysfunction associated with cortical malformations. AJNR Am J Neuroradiol 20:1037, 1999. 93. Maehara T, Shimizu H, Nakayama H, et al.: Surgical treatment of epilepsy from schizencephaly with fused lips. Surg Neurol 48:507, 1997. 94. Landy HJ, Ramsay RE, Ajmone-Marsan C, et al.: Temporal lobectomy for seizures associated with unilateral schizencephaly. Surg Neurol 37:477, 1992. 95. Alexander RC, Patkar AA, Lapointe JS, et al.: Schizencephaly associated with psychosis. J Neurol Neurosurg Psychiatry 63:373, 1997. 96. Relan P, Chaturvedi SK, Shetty B: Schizencephaly associated with bipolar affective disorder. Neurol India 50:194, 2002. 97. Lee HK, Kim JS, Hwang YM, et al.: Location of motor cortex in schizencephaly. AJNR Am J Neuroradiol 20:163, 1999. 98. Takajo I, Ohi T, Shiomi K, et al.: A case with symptomatic epilepsy and mirror movements due to unilateral schizencephaly. No To Shinkei 52:617, 2000. 99. Vandermeeren Y, De Volder A, Bastings E, et al.: Functional relevance of abnormal fMRI activation after unilateral schizencephaly. Neuroreport 13:1821, 2002.

100. Friede RL: Developmental Neuropathology. Springer—Verlag, New York, 1975, p 1055. 101. Tardieu M, Evrard P, Lyon G: Progressive expanding congenital porencephalies: a treatable cause of progressive encephalopathy. Pediatrics 68: 198, 1981. 102. Nixon GW, Johns RE, Myers GO: Congenital porencephaly. Pediatrics 54:198, 1981. 103. Claeys V, Deonna T, Chrzanowski R: Congenital hemiparesis: the spectrum of lesions. A clinical and computerized tomographic study of 37 cases. Helv Paediatr Acta 38:439, 1983. 104. Suarez JC, Sfaello ZM, Albarenque M, et al.: Porencephalic congenital cysts with hydrocephalus. Child Brain 11:77, 1984. 105. Kolawole TM, Patel PJ, Mahdi AH: Porencephaly: computed tomography (CT) scan findings. Comput Radiol 11:53, 1987. 106. Barth PO, Gerver J, Mahdi AH: Porencephaly and schizencephaly in adopted infants: frequency ascertainment in a risk group. Clin Neurol Neurosurg 89:17, 1987. 107. Berg RA, Aleck KA, Kaplan AM: Familial porencephaly. Arch Neurol 40:567, 1983. 108. Zonana J, Adomato BJ, Glass ST, et al.: Familial porencephaly and congenital hemiplegia. J Pediatr 109:671, 1986. 109. Haar L, Dyken P: Hereditary nonprogressive athetotic hemiplegia: a new syndrome. Neurology 27:849, 1977. 110. Sensi A, Cerruti S, Calzorari E, et al.: Familial porencephaly. Clin Genet 38:396, 1990. 111. Smit LME, Barth PG, Valk J, et al.: Familial porencephalic white matter disease in two generations. Brain Dev 6:54, 1984. 112. Gould DB, Phalan FC, Breedveld GJ, et al.: Mutations in COL4A1 cause perinatal cerebral hemorrhage and porencephaly. Science 308: 1167, 2005.

15.12 Cerebellar Anomalies Definition

Cerebellar abnormalities include agenesis/hypoplasia of all or individual parts, dysplasias that may be focal or diffuse, disruptions of normal embryologic processes, and atrophy of a normally formed(ing) cerebellum. Advances in the molecular biology and embryology of the cerebellum, together with a quantum leap in the ability to visualize its abnormalities with MRI and renewed evidence of the role of the cerebellum in higher cognitive functions and language, have kindled a remarkable upsurge of interest in this organ. Unfortunately, at this time there is not a standard use of terminology or an agreed-upon classification of anomalies that meets the needs of all. Much of the new data are from the field of neuroimaging, but often there is a paucity of clinical and/ or pathologic information to match with the radiologic findings. Agenesis or hypoplasia is the absence of all or part of the cerebellum, which can be isolated or accompany anomalies of other parts of the brain. At neuroimaging, the defining features of hypoplasia are a small vermis and/or hemispheres with small fissures that are of normal width compared to the folia.1,2 In agenesis, there is absence of specific lobules and fissures of the vermis and/or hemispheres. Strictly, dysplasia refers to a disorganization of cells within the cerebellum, and it may be focal or diffuse within the cerebellum and in the latter case is usually associated with a generalized brain dysplasia. However, in the nosology of cerebellar abnormalities, dysplasia has been used at neuroimaging to denote a cerebellum with disorganized/abnormal vermian and/or hemispheric folia, with the assumption that the alterations in the folia reflect underlying disturbances in cell migration and cortical layering. Although there is evidence that the pattern of folia is reproducibly initiated and

Brain

determined by the arrival of migrating neurons,3,4 it is not clear that all MRI-defined folial anomalies are true dysplasias. Furthermore, dysplasia has been stated to accompany ‘‘most if not all’’ cases of partial cerebellar agenesis.2 Some prefer the term dysgenesis for such radiologic anomalies.5 Atrophy represents loss of cerebellar tissue that was present in the cerebellar vermis and/or hemispheres, which is represented on gross examination and at neuroimaging as a reduction in tissue mass and a concomitant increase in fissure width relative to that of the folia. The vermis may take on a ‘‘fern leaf’’ appearance on MRI.2 In practice, it is not always clear whether an apparent atrophy is simply a degenerative condition or whether the atrophy is superimposed on a developmental abnormality.1,6 The cerebellum presents a particular challenge because its development continues well into the second year of life. The one point of agreement with respect to the classification of cerebellar abnormalities is that there is no agreed-upon classification.1,2,5,7,8 As mentioned, the radiologic classifications1,2 have some current disadvantages, and clinicians continue to favor a more anatomic and embryologic approach.7,8 Still others have come from the direction of the clinical presentation of a non-progressive ataxia and emphasize key clinical points. Patients whose cerebellar abnormalities fit different categories of classification may have the same clinical presentation, and the actual malformation may differ between siblings. Patients with no visible cerebellar anomaly may have the identical presentation to those with a visible malformation and, again, there can be discordance within a siblingship.9,10 The approach taken for purposes of this chapter is outlined in Table 15-16 and follows a predominantly anatomic/embryologic approach.

655

Table 15-16. Classification of cerebellar anomalies used in this section A. Vermis and paravermian hemispheric anomalies (mainly paleocerebellum) 1. Dandy-Walker malformation (Section 15.13) 2. Tectocerebellar dysraphia (also Chapter 16) 3. Rhombencephalosynapsis 4. Molar tooth sign complex 5. Isolated vermis hypoplasia/aplasia/dysplasia - syndrome associated (Table 15-17) B. Hemispheres with or without vermis involved (mainly neocerebellar) 1. Complete cerebellar agenesis 2. Unilateral cerebellar agenesis/hypoplasia 3. True cerebellar dysplasia a. with generalized equivalent supratentorial pathology (e.g., lissencephaly, congenital muscular dystrophy; Section 15.5) b. focal to cerebellum—local heterotopia/abnormal cortex layering - hypertrophy 4. Cerebellar hypoplasia/aplasia/dysplasia a. Type I - syndromic (Table 15-17) b. Type II - granule cell aplasia and related - metabolic disorders - syndromic (Table 15-17) C. Pontocerebellar

Diagnosis

1. Pontine agenesis

Except for syndromes with a defined pattern of associated anomalies, or certain cerebellar syndromes like Joubert syndrome that have a diagnostic handle such as hyperpnea, the clinical presentation of young children with cerebellar anomalies is non-specific, and the diagnosis requires a high index of suspicion. The classic signs of ataxia or dysequilibrium do not appear until completion of postnatal cerebellar maturation and the integration of higher cerebellar functions.9 Early infancy is characterized by hypotonia and delayed motor milestones, with extended periods of cruising and delayed walking. The initial hypotonia and common orofacial dysfunction often leads to a tented, open-mouthed appearance and drooling. Refractive errors, strabismus, and other ocular anomalies are common.10 The mean age at walking in the mixed series of patients reported by Esscher et al.10 was 25 months, with 11.5% walking before 18 months, and 14% walking after 7 years or not at all. The patients with idiopathic, pure non-progressive cerebellar ataxia reported by Steinlin9 sat between 2 to 3 years and walked between 3 to 7 years of age. Once walking does occur it tends to be broad-based, clumsy, and ataxic, and with time fine motor problems become apparent. Speech is affected both by dysarthria and cognitive delays, which may affect speech disproportionately. In the series of Esscher at al.,10 25 (32%) of patients had an IQ of < 50 and 28% fell between 50 and 75. Of 31 children in normal school, 14 required help with language. Only 22% were considered completely cognitively normal, and 88% had language delay. Twelve lacked any speech. The IQ of the patients discussed by Steinlin9 ranged from 20 to 90, and one-third had seizures, which were a negative correlate with IQ. In some cases, intellectual delay can be ascribed to an associated supratentorial anomaly, but such cases are the exception and there is a growing consensus that the cerebellum has a, yet to

2. Pontocerebellar hypoplasia (PCH1, 2 and 3) Italicized headings or subheadings are considered in this section.

be fully defined, role in normal cognitive development.11–13 This role may include behavior such as expression of aggression and habituation, anticipatory planning, mental imagery, language processing, abstract thought, and word and pattern recognition.11 Connections to the cerebellum, via the pons, from the cerebral associative and paralimbic areas are well established. The diagnosis and understanding of these pure non-progressive cerebellar ataxias are further complicated by the lack of pathologic data in most cases, and the fact that neuroimaging has frequently been unable to document a cerebellar anomaly. A cerebellar abnormality was demonstrated in half the patients studied by Steinlin,9 who stated that MRI did not detect malformations missed by CT but that it did add useful information in several cases. No data were provided as to the quality of the imaging, and there was an instance of discordance within an affected sibling pair for the presence of a detectable malformation. Neuroimaging failed to detect cerebellar pathology in 43 of 70 (61%) of cases studied by Esscher et al.,10 but only 46 patients had an MRI and in a significant proportion of cases the studies were suboptimal (i.e., adequate or less). MRI did detect two cases considered normal with CT and added useful data to other cases. Notwithstanding less than excellent imaging in some instances, it is likely that the cerebellar ataxia and other clinical signs are related to changes in the cerebellum at the microscopic level. That the clinical spectrum does relate to changes in the cerebellum is suggested by a correlation between the degree of cerebellar involvement and clinical severity.9 Changes in the anterior vermis appear to produce mild signs and

656

Neuromuscular Systems

symptoms; changes in the whole vermis and hemispheres are found with the most severe cerebellar signs. The likelihood that MRI will diagnose a posterior fossa anomaly, either prenatally or postnatally, will vary with the quality of the study, which is often dependent on the patient. The sonographic prenatal diagnosis of posterior fossa anomalies is biased toward the more readily visible cystic lesions. Prenatal diagnosis, primarily as it relates to MRI, has been reviewed by Adamsbaun et al.14 Developmental landmarks include a closed, triangular fourth ventricle covered by the cerebellar vermis by 15 weeks, a vermis length of 15 mm at 28 weeks and 20 mm at 30 weeks, the appearance of the primary fissure by 30 weeks, and greater size of the posterior lobe than the anterior lobe. They also suggest four questions to be addressed with a prenatal posterior fossa scan: 1) whether and where are there any abnormal fluid collections, 2) whether the volume of the posterior fossa is normal, and if it is increased whether this relates to increased fluid pressure, 3) whether or not the fourth ventricle is open and has a membrane, and 4) whether the cerebellar peduncles, vermis, and hemispheres appear normal. This same group has also outlined the planes, cuts, weighting, and appearance to be noted in the postnatal MRI assessment of the posterior fossa, including the component parts of the cerebellum.2 15.12.1 Tectocerebellar Dysraphia

Tectocerebellar dysraphia (TCD) was first described in the literature by Padget and Lindenberg15 as ‘‘inverse cerebellum with occipital encephalocele,’’ and it was Friede, in 1978, who coined the term tectocerebellar dysraphia.16 TCD consists of hypoplasia/aplasia of the vermis, with a marked dorsal deformation of the tectum toward an occipital encephalocele, which contains hypoplastic cerebellar cortex, with traction of the brain stem causing kinking, and positioning of the hypoplastic cerebellum ventrolateral to the brain stem. Associated findings can include subependymal heterotopias, thalamic fusion, hydromyelia, callosal agenesis, absent septum pellucidum, and arhinencephaly.17 The origin of TCD has been hypothesized to result from herniation of the mesencephalon, prior to the appearance of the cerebellum, into an occipital encephalocele.18 There is a significant associated mortality, and surviving children are often microcephalic and require shunting.7 Developmental delay is expected but may not always be severe. 15.12.2 Rhombencephalosynapsis

In rhombencephalosynapsis (RES) the cerebellar vermis is absent, or severely hypoplastic, the hemispheres are fused across the midline, and there is variable underdevelopment of the cerebellar peduncles and quadrigeminal plate. Fusion of the cerebellar peduncles and inferior colliculi give the fourth ventricles a typical ‘‘keyhole’’ appearance.19 The roof nuclei are absent and the dentate nuclei are fused or apposed;1,19 the posterior fossa is small.7 A partial form has been described.245 The typical presentation is with hypotonia and delayed motor milestones. Other neurologic signs have included optokinetic nystagmus,20 clumsiness, drop attacks, and side-to-side head nodding.18 The latter may be the same as the 1–2 Hertz head stereotypy noted by Hottinger-Blanc et al.20 in eight patients with cerebellar anomalies, one of whom had RES. Intellectual and psychological development appears to vary from the normal range to severe impairment, but the latter may sometimes be due to associated supratentorial anomalies, which may include absent septum

pellucidum, cerebral dysplasia, callosal agenesis, and hydrocephalus.1,21 RES is considered rare, and in 2002 Niesen7 was only able to find 20 cases in the literature. However, in that same year, Patel and Barkovich1 reported eight cases among 70 patients with MRI-detected cerebellar malformations; two patients were added by Demaerel et al.18; and there were two single case reports.20,21 Odemis et al. reported a case with pretibial hemangiomas.22 The etiology is unknown; one pregnancy each was reported with in utero exposure to phencyclidine19 and ethosuxamide.18 To date there does not appear to have been a familial recurrence of RES, but the cerebellar vermis defect rat (cvd), which may be a model of this malformation, shows autosomal recessive inheritance.23 The cvd rat has an overall reduction in the size of the cerebellum, not typical of RES, and appears to be due to abnormal migration of external granule cells to a perivascular position, perhaps secondary to abnormal Purkinje cell location, resulting in dysplastic lamination and cell positioning within the cerebellar cortex.23 15.12.3 Molar Tooth Sign Complex

First described in 1997, the molar tooth sign, or MTS (Fig. 15-58), is an appearance on axial view through the isthmus that results from marked hypoplasia/dysplasia of the cerebellar vermis, an unusually profound interpeduncular fossa, and straight and thickened superior cerebellar peduncles.24 Additional findings commonly include a bent or kinked appearance of the vermis on mid-sagittal view, enlargement of the fourth ventricle, whose margin has an umbrella shape, and less often an excess of fluid in the posterior fossa.25 The archetypical disease associated with the MTS is Joubert syndrome, which was first described in 1969 (Table 15-17) and presents with an unusual pattern of alternating hyperpnea and apnea in the newborn period. The breathing pattern usually improves in surviving children, but most suffer moderate developmental delay, ataxia, and may develop seizures and other

Fig. 15-58. Axial view at isthmus showing molar tooth sign (arrow).

Table 15-17. Syndromes with cerebellar hypoplasia Syndrome

Prominent Features

Causation Gene/Locus

3-a hydroxyisobutyric acid

Poor neonatal behavior, triangular face, short and sloping forehead, narrow bitemporal distance, shallow supraorbital ridges, epicanthus, micrognathia, adducted thumbs, clinodactyly of toes 4-5, intracerebral calcification, cerebellar hypoplasia, agenesis of the corpus callosum, lissencephaly, pachygyria

AR (236795)

Acrania67

Absent calvarial bones; CNS includes absent pituitary, hydrocephalus, holoprosencephaly, cerebellar hypoplasia; often misinterpreted prenatally as encephalocele; cleft lip/palate, congenital heart defects, omphalocele, and NTD often concurrent

Unknown

Acrocephalopolysyndactylytype II68

Craniosynostosis, developmental delay is variable, high forehead, midfacial hypoplasia, ptosis, epicanthic folds, anteverted nares, brachysyndactyly of hands, radial deviated thumb, pre-axial polydactyly of feet, hypoplasia of middle phalanges; case with cerebral atrophy and marked cerebellar vermis ‘‘atrophy’’

AR (201000)

Adenylosuccinase deficiency69

Mental retardation, autistic features, muscle wasting, cerebellar hypoplasia; accumulation of succinyladenosine and succinylaminoimidazole

AR (103050) ADSL, 22q13.1

Agonadism-CNS anomalies70

Agonadism with urogenital sinus and 46,XY karyotype, severe mental retardation, absent corpus callosum, cerebellar agenesis, pachygyria. Single case.

Unknown

Aicardi71

Chorioretinal lacunae, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, periventricular nodules, colpocephaly, hypoplastic cerebellar vermis

XLD (304050) male lethal Xp22

Alcohol, prenatal72

IUGR, microcephaly, psychomotor delay, flat midface, short palpebrae, micrognathia, minor cardiac and vertebral anomalies, various CNS anomalies; cerebellar hemisphere hypoplasia, hypoplastic/malformed vermis

Prenatal alcohol exposure

Amelo-cerebrohypohydrotic73

Can show normal early development, variable regression, and seizures; can have ataxia, amelogenesis imperfecta; cases with broad thumbs and great toes; CNS includes hypoplasia of cerebellar vermis and dilation of the lateral ventricles

AR (226750)

Anterior chamber cleavagecerebellar hypoplasia74

Postnatal microcephaly, dense hair, broad nose with low bridge, wide cupid-bow mouth, shield chest, tracheostenosis, congenital hypothyroidism, cerebellar hypoplasia, anterior chamber eye anomalies

Unknown (601427)

Anterior chamber-cleft lip/ palate-skeletal75

IUGR, anterior chamber abnormalities, clouded cornea, cleft lip and palate, congenital heart disease, radio-ulnar synostosis, bowed forearms and fibulas, arachnodactyly, variable dislocation of interphalangeal joints, fractures, sclerosis of skull base. One case with hypoplastic inferior cerebellar vermis.

AR

Anterior chamberhydrocephalus-heart defect76

Peters anomaly, persistent hyaloid artery, unilateral absent lens, obstructed aqueduct of Sylvius, enlargement of the lateral and 4th ventricles; cerebellar, pontine, and medullary atrophy; porencephaly, tricuspid valve dilation, atrial septal defect, lethal

Unknown

Arena: XLMR-spastic paraplegia77

Severe spastic paraplegia; lower limbs greater than upper; macrogyria, poor myelination, white matter hypoplasia, cerebellar hypoplasia, possible iron deposits in basal ganglia

XLR Xq22-q25

Arima: cerebro-oculohepato-renal78

Telecanthus, ptosis, flat nasal bridge, large mouth, aplasia of the cerebellar vermis, micropolygyria of dentate nuclei, pachygyria of inferior olivary nuclei, anomalous pyramidal tracts, Leber’s amaurosis, nephronophthisis, hepatic fibrosis (see also ref. 26,143,167)

AR (608091)

Arthrogryposis-craniofacialeye anomalies79

Normal intelligence, congenital contractures of small and large joints, pulmonary hypoplasia, nonspecific muscle changes, some denervation, minor skeletal anomalies, abnormal retinal vessels, mild vermis hypoplasia

Unknown

Avegno: mental retardationface dysmorphia80

Severe psychomotor and postnatal growth delay, short stature, microcephaly, cerebral dysgenesis, cerebellar hypoplasia, hypotonia and late hypertonia, marked hypertelorism, downslanting palpebrae, supernumerary teeth, hypospadias, cryptorchidism, overlapping fingers, rocker-bottom feet

AR, product of incest

Bardet-Biedl81

Developmental delay, retinal dystrophy, obesity, variable post-axial polydactyly, hypogenitalism, renal anomalies; reported with cerebellar hypoplasia

AR (209900) BBS1, 11q13 BBS2, 16q21 BBS3, ARL6, 3p13-p12 BBS4, 15q22.3-q23 BBS5, 2q31 BBS6, 20p12 BBS7, 4q27 BBS8, 14q32.1

66

(continued)

657

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Barth: cerebro-cerebellar

Very small brain, extreme neopallial and cerebellar hypoplasia, failure of mesencephalic flexure, absence of rhombic lip and corticospinal structures, type I lissencephaly (one form with type II lissencephaly)

Probable AR

Bertini: myoclonic epilepsymacular degeneration83

Hypotonia, congenital ataxia, mental retardation, progressive encephalopathy, recurrent infections, hypoplasia of corpus callosum and cerebellar vermis, septum pellucidum cyst

XLR Xp22-Xpter

Branchio-oculo-facial84

Variable mental retardation and short stature, ear pits, colobomas, hemangiomatous orbital cysts, hypertrophy of philtral pillars (pseudocleft), lip pits, broad and asymmetric nose with broad tip, lacrimal duct stenosis, sinus or linear skin lesion behind the ear, premature gray hair. A case with agenesis of the cerebellar vermis.

AD (113620)

Congenital disorders of glycosylation85

Dysmorphic signs can include abnormal fat distribution and inverted nipples; various subtypes with postnatal growth failure, psychomotor delay, retinopathy, renal cysts/ tubulopathy; cerebellar hypoplasia most likely in type I

AR (212065) CDIa PMM2, 14q21 CDIb PMI, 16p13

Cerebellar hypoplasia-brain stem calcification86

Sib fetuses with cerebellar aplasia, dilated ventricles, aqueductal stenosis in one, necrosis and calcification in the brain stem and cortex, cortex contained foamy macrophages and prominent vascularity

AR

Cerebellar hypoplasiaendosteal sclerosis87

Developmental delay, oligodontia, small teeth, congenital hip dislocation, sclerosis of long bones and vertebrae, stenosis of medullary space

AR (213002)

Cerebellar hypoplasiahemangioma-coarctation of aorta88

Two unrelated cases with cavernous facial hemangioma, ipsilateral cerebellar hypoplasia with abnormal internal ganglia, coarctation of the aorta

Unknown

Cerebellar hypoplasialymphedema89

Mental retardation, hypotonia, ataxia, clonic/tonic seizures, pale fundi and poor VEP, variable duodenal atresia, cerebellar hemisphere and vermis hypoplasia, poor cerebral white matter, abnormal neuronal migration, pachygyria

AR (600514) RELN, 7q22

Cerebellar hypoplasia-short stature90

Nonprogressive congenital ataxia, truncal ataxia, dysarthria, hypotonia, hyperreflexia, short stature, hypoplasia of cerebellar hemispheres and vermis

AR 9q34-9qter

Cerebellar hypoplasia-short stature, type Kvistad91

Postnatal onset of growth failure between 12 and 18 months, normal intelligence, mild to moderate cerebellar signs, mild spasticity; cerebellum on CT include normal, mostly vermis ‘‘atrophy,’’ one slight hemispheric change

AR

Cerebello-trigeminal-dermal dysplasia92

Parietal alopecia, midface hypoplasia, clouded cornea, low and rotated ears, facial anesthesia, developmental delay, ataxia, fusion of pons and vermis, absent 4th ventricle, hypoplastic cerebellar hemispheres

AR (601853)

Cerebro-oculo-muscular93

Initial hypotonia, infancy-onset cataract, retardation, ataxia, myopathic changes with cavuolar degeneration, cerebellar hypoplasia or atrophy; resembles Marinesco-Sjo¨gren (248810)

AR

Cerebro-oculo-nasal94

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears, single maxillary central incisor; reported with agenesis of the corpus callosum, hypoplastic vermis; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst

Unknown (605627)

Cerebro-renal-digitalPiantanida95

Mental retardation, cerebellar vermis agenesis, polydactyly, unusual appearance. Two sibs, one with cystic dysplastic kidney, other a meningocele

AR?

CHARGE96

Choanal atresia, congenital heart defects, growth failure, mental retardation, hypoplastic genitalia, deafness, external ear anomalies; over half with CNS including holoprosencephaly/arhinencephaly, absent corpus callosum, septal agenesis, migrational defects

Most sporadic, AD (214800) CHD7, 8q12

Chondrodysplasia-pseudohermaphroditism97

IUGR, growth retardation, hypoplastic irides, optic disc colobomas, micromelia, narrow chest, hypoplastic scapulae, trapezoid vertebrae, short hand bones. One case a 46,XY female with cerebellar hypoplasia

AR? (600092)

Chondrodysplasia punctatairis coloboma98

Developmental delay, brachycephaly, low-set ears, small nose, anteverted nares, midface hypoplasia, iris coloboma, stippled proximal humeral epiphyses, dysplastic distal phalanges, hepatic fibrosis. Case with partial callosal agenesis, small cerebellar vermis, mild enlargement of anterior horns

AR (215105)

Chromosomal aberrations99,100

Includes trisomy 13, 18, 21; duplications (1)(q25-qter), (2)(pter-p13), (3)(pter-p21), (3)(q21-qter), (4)(p15-pter), (5)(p11-p13.2), (5)(p15.1), (6)(q21-qter), (7)(p11-p12), (7)(pter-p11), (9)(q32-qter), (9p), (13)(q14-qter) (20)(q13.1-qter), der(22) from t(11q;22q); deletions of (4)(pter-p16.1), (9)(pter-p21), (11)q23.3), (14)(q22-q23), (17)(q25-qter)

Chromosome imbalance

82

(continued)

658

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

COACH: cerebello-oculorenal101,102

Developmental delay, molar tooth sign, coloboma; variable occurrence of nephronophthisis, hepatic fibrosis, Dandy-Walker cyst/encephalocele

AR (216360)

Coats disease-hair and nail defects103

Abnormal retinal vessels lead to exudate and detachment, sparse wispy hair, mild finger zygodactyly, dysplastic or deep-set nails; calcification of cerebrum, cerebellum, and basal ganglia; seizures, normal development. Case with marked cerebellar atrophy, but no calcification.

AR

Colobomatous microphthalmia-cerebellar hypoplasia104

Microcephalic at birth, microphthalmia, iris coloboma, cataracts, optic nerve hypoplasia, high palate, cerebellar hypoplasia. Single case, parental consanguinity.

Uncertain

Congenital fibrosis extraocular muscles105

Dysfunction of cranial nerves III and IV, or the muscles served by those nerves; CNS anomalies are occasional findings and include cerebellar vermis hypoplasia, callosal agenesis, pachygyria, hydranencephaly, colpocephaly

AR (135700), (602078) ARIX, 11q13.3-q13.4 AD (607034) KIF21A, 12p11.2-q12 AD (600638) 16q24.2-q24.3

Craniofacial-congenital hypothyroidism-cerebellar hypoplasia106

Postnatal growth and developmental failure, large and anteverted ears, brachycephaly, strabismus, small nose and mouth, pectus carinatum, severe hypoplasia of right cerebellar hemisphere and vermis, brain stem hypoplasia

Unknown

Congenital muscular dystrophy-vermis agenesis107

Congenital myopathy, mild calf hypertrophy, cerebellar ataxia, dysarthria, cerebellar vermis agenesis; several similar reports may or may not reflect the same condition

Uncertain

Congenital mydriasis108

Congenital fixed and dilated pupils; all cases to date are female; patient with developmental delay had enlarged 4th ventricle, a degree of cerebellar vermis hypoplasia

AD (159420)

Crome: cataractsnephropathy109

Congenital cataracts, growth failure, renal tubular necrosis, seizures, lack of development, spongiform changes in gray and white matter, lack of myelination, lack of Purjinke cells. Degenerative disorder?

AR (218900)

Curatolo: white matter hypoplasia-callosal agenesis110

Severe mental retardation, growth failure, downslanting palpebrae, broad nasal root, hypertelorism, synophrys, long eyebrows, micrognathia, severe diffuse cerebral white matter hypoplasia, agenesis/hypoplasia of the corpus callosum, partial agenesis of cerebellar vermis

Uncertain

Cutis aplasia-pulmonic stenosis-vermis aplasia111

Midline scalp defect, valvular pulmonary stenosis, cerebellar hypoplasia with vermis agenesis

Unknown

Cytomegalovirus infection, prenatal112

Microcephaly, intracranial calcification, choreoretinopathy, deafness, mental retardation, general and often asymmetric hemisphere changes, vermis hypoplasia, gliosis (similar to animal models)

Prenatal infection

D-CHRAMPS113

Postnatal growth failure, microcephaly, sparse scalp hair, absent eyebrows, triangular face, developmental delay, hypergonadotrophic hypogonadism, absent pubic and axillary hair, retinitis pigmentosa, pancerebellar hypoplasia

Unknown

Deafness-hypospadiassynostosis114

Developmental delay, sensorineural deafness, anteverted ears, small nose with blunt tip, long chin, fused 4th and 5th metacarpals, mild hypoplasia of occipital lobes and cerebellum

Unknown

De Lange115

IUGR, mental retardation, synophrys, short nose, anteverted nares, prominent philtrum, thin upper lip with downward ‘‘V’’ at midpoint, proximal thumbs, ulnar ray defects, several cases with cerebellar hypoplasia

AD (122470) NIBPL, 5p13.1

Dyskeratosis congenita116

Unusual case of autosomal recessive form with severe microcephaly, mental retardation, and cerebellar hypoplasia, in addition to usual nail dystrophy, mucosal and skin pigment changes, and bone marrow failure

AR (224230)

Dystonia-cataractencephalopathy117

Normal head circumference becomes microcephalic, progressive neurologic deterioration, extrapyramidal signs, cataracts, partial agenesis of vermis, ventricular dilation, loss of central white matter, elevated methylmalonic aciduria but not at usual pathological levels

AR

Egger-Joubert-Boltshauser118

Joubert syndrome with typical hyperpnea, apnea, associated with polydactyly, fleshy nodules under tongue. Dandy-Walker in one sib, and cerebellar hypoplasia in other.

AR (213300) variant

Exomphalos-short limbsmacrogonadism119

Nuchal web, low-set ears, hypertelorism, macrostomia, anteverted nares, long philtrum, micrognathia, wide and irregular metaphyses, coronal cleft vertebrae, thin ribs, adrenal cytomegaly; hypoplastic Leydig cells, ovarian stroma cells and Langherans cells, renal microcysts, microgyria, cerebellar hypoplasia

AR

(continued)

659

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Facial hemangiomacerebrovascular anomalies120

Strawberry nevus, ipsilateral optic atrophy, stenotic and aneurysmal cerebral vascular anomalies, hypoplasia of cerebellar hemisphere

Unknown

Fernhoff; abnormal facies121

IUGR; microcephaly, growth failure, small facies, low-set ears, narrow palpebrae, micrognathia, cleft palate, camptodactyly, absent granular cell layer

Unknown

Fetal phencyclidine19

Rhombencephalosynapsis, hypoplastic commissural systems, septo-optic dysplasia, absent septum pellucidum, absent posterior lobe of hypothalamus, fused cerebellar hemispheres, absent vermis, moderate hydrocephalus, abnormal pulmonary venous return, spinal segmentation defect; mother took phencyclidine in first 6 weeks

In utero exposure

Fragile-X mental retardation122

Tend to be macrocephalic, long face, large and/or prominent ears, prominent jaw, postpubertal macroorchidism, hyperextensible joints, hyperactivity, autistic-like behavior, seizures, decreased cerebellar posterior vermis size, occasional frank cerebellar hypoplasia

XLR (309550) FMR1, Xq27.3

Frontonasal dysplasia123

Occult frontal cranium bifidum, widow’s peak, hypertelorism/telecanthus, broadtipped or bifid nose, cleft mid-lip/palate. One patient with coloboma, small penis, absent corpus callosum, microgyria, hypoplastic cerebellar vermis.

Unknown

Frontonasal dysplasia-like124

Large fontanel, hypertelorism, wide nasal tip with midline groove, notched upper lip, high/cleft palate, short neck, cryptorchidism, pre/postaxial polydactyly of hands and feet, short limbs

Unknown

Fryns: acral-diaphragmatic hernia125

Hydramnios, coarse face, facial hirsutism, cloudy corneae, large nose with broad flat bridge, short upper lip, micrognathia, cleft lip/palate, abnormal pinnae, hypoplastic distal phalanges and nails, diaphragmatic defects, gut anomalies, cardiac defects, bicornuate uterus; CNS includes callosal agenesis, arhinencephaly, heterotopias; probable case with cerebellar hypoplasia

AR (229850)

G126

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males

AD (145410) 22q11.2 XLR (300000) Xp22

Gentile: vermis hypoplasialiver fibrosis127,128

Developmental delay, ataxia, no hyperpnea, ocular motor apraxia/amaurosis, hepatic fibrosis, no colobomas, no retinal dysplasia, vermis hypoplasia with ‘‘molar tooth sign’’(see also ref. 26,143)

AR

Gillespie: aniridia-ataxia129

Partial aniridia, ptosis, mild mental retardation, pulmonic stenosis (one case), cerebellar hypoplasia (most marked of vermis)

AR (206700)

Glutaric aciduria type 2130

Macrocephaly, absent cerebellar vermis, cryptorchidism, hypospadias; usually normal early health and development; signs can include respiratory distress, hypoketotic hypoglycaemia, sweaty-foot odor, seizures, dystonic cerebral palsy; aliphatic monoand dicarboxylic acids, sarcosine, glycine conjugates in blood and urine; abnormal electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETFdehydrogenase)

AR (331680) ETF-dehydrogenase, ETFDH, 4q32-qter ETFA, 15q23-25 ETFB, 19q13.3 15q23-25, 19q13.3 4q32-qter

Goldberg-Shprintzen131

Microcephaly, short stature, developmental delay, hypertelorism, submucous cleft palate; diminished white matter, hypo/partial absence of corpus callosum, pachygyria, cerebellar hypoplasia

AR (235730) SMADIP1 2q22

Herrick: multisystem atrophy132

Microcephalic at birth, low forehead, contractures, hypertonia, death, severe cortical atrophy (‘‘walnut brain’’), cerebellum disproportionately small vestige. Combination of hypoplasia and atrophy?

AR

Hingorani: hypothalamic hamartoma-polydactyly133

Hypothalamic hamartoma, preaxial polydactyly of toes, midline cleft lip, oral frenula, notched tongue, short long bones; dilated 4th ventricle, absent inferior vermis; overlap with several syndromes including Pallister-Hall

Unknown

Histidinemia134

Single report of patient with callosal dysgenesis and cerebellar hypoplasia, clinical picture of Joubert syndrome and congenital ocular fibrosis. Association with histidinemia likely fortuitous.

AR (235800) Histidase, 12q22-q23

Holoprosencephaly-fetal hypokinesia135

Extreme IUGR and microcephaly by 2nd trimester, sloped forehead; micrognathia; short neck; flexed elbows, thumbs, hips; extended fingers, knees; severe brain disorganization may include rudimentary cerebellum and brain stem, and cellular architecture

XLR (306990)

Horizontal gaze palsy-scoliosis-brain stem hypoplasia136

Horizontal gaze palsy, progressive scoliosis, significant developmental delay in two of three affected sibs, brain stem hypoplasia likely affecting abducens nucleus and caudal longitudinal fascicle

AR 11q23 (continued)

660

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Hoyeraal-Hreidarsson

Microcephaly, congenital thrombocytopenia, pancytopenia in year 2, postnatal growth failure, immunodeficiency, cerebellar hypoplasia most marked of the vermis; probable heterogeneity

XLR (600545) DKC1, Xq28

Hutterite dysequilibrium138

Moderate to profound mental retardation, nonprogressive truncal ataxia, mild dysmetria; variable short stature, microcephaly, seizures; absent inferior hemispheres and inferior vermis, granular cell ‘‘aplasia’’

AR (224050)

Hydrocephalus-VATERlike139

Bilateral radial aplasia, anal atresia, hypospadias, incomplete lung lobation, hypoplastic adrenals, horseshoe kidneys, accessory spleens, hydrocephalus, hypoplastic cerebellum; three males from consanguineous relationship

AR/XLR? (276950)

Isotretinoin, prenatal140

Microtia, anotia, narrow and sloped forehead, U-shaped cleft palate, conotruncal malformations, microcephaly, hydrocephalus, absent corpus callosum

Prenatal retinoic acid exposure

Jespers: midline defectsHirschsprung141

Excessive nuchal skin, low-set ears, hirsute forehead, unusual eyebrows, hypertelorism, broad nasal bridge, anteverted nares, flat philtrum, micrognathia, cleft palate, heart defect; hypoplastic larynx, vocal cords, and trachea; omphalocele, cryptorchidism, metatarsus adductus, hypoplastic nails, hypoplastic corpus callosum, cerebellar hypoplasia, subcortical atrophy

AR ?

Joubert: cerebello-oculo-renal 1142

Severe developmental delay, aggressivity, hyperactivity, prominent forehead, high and round eyebrows, anteverted nares, open mouth, ocular motor apraxia, rhythmic tongue protrusion, hyperpnea/apnea, molar tooth sign, superior vermis hypoplasia/ aplasia; CORS1 is used by some for patient without renal or eye changes

AR (213300) NPHP1, 2q13 AHI1, 6q23.2-q23.3 9q34.3

Joubert: cerebello-oculo-renal 226,143

As per type 1, CORS2 has addition of cystic renal dysplasia/agenesis and retinal dysplasia/coloboma; significant additional clinical and genetic heterogeneity (see also ref. 78,101,127,167,224)

AR (608091) 11p12-q13.3 Heterogenity

KID (keratitis-ichthyosisdeafness)144

General or patchy ichthyosiform, hyperkeratosis, palmoplantar hyperkeratosis, keratosis impairing vision, nerve deafness, hypoplasia middle and lower cerebellar hemispheres and tonsils

AR (242150)

Leber amaurosis, congenital145

Severe early visual impairment, progressive disc pallor and arteriolar attenuation, polycystic kidneys, variable CNS anomalies, normal to impaired intellect, vermis hypoplasia (see discussion of Joubert syndrome)

AR (204100) Multiple loci: GUCY2D, RPE65, CRX, AIPL1, etc.

Leptomeningeal angiomatosis-cleft lip146

Mild hydrops, small and posteriorly rotated ears, overfolded helices, cleft lip/palate, hypoplastic left heart, leptomeningeal angiomatosis, absent septum pellucidum and olfactory tracts, hypoplastic corpus callosum and inferior vermis. Single case

Unknown

Lethal mesomelic dwarfism147

V-shaped upper lip, micrognathia, cysts of tongue, webbed neck, dislocated femur and radius, four-finger creases; cardiac, lung, renal abnormalities

AR (268670)

Lethal osteopetrosis148

In utero hyperdense bones, fractures, macrocephaly, hydrocephaly, skin edema, absent osteoclasts, loss of neurons, gliosis, ischemia leading to arrest of brain development

AR (259720)

L’Hermitte: oxycephalyretardation149

Macrocephaly, oxycephaly with open sutures, high palate, flat facies, shallow orbits, porencephaly, absent inferior vermis

AR

Lissencephaly-cleft palatecerebellar hypoplasia150

IUGR, cleft palate, ventriculomegaly, long thumbs and halluces, absent distal digital creases, variable brain stem involvement, absent corpus callosum, absent cerebellum, thick and disorganized cortex, no cortical lamination, severe cerebellar hypoplasia

AR?

Majewski: short ribpolydactyly151

Micromelia, hydrops, median cleft, hypoplastic epiglottis, renal anomalies, ambiguous genitalia, hypoplastic cerebellar vermis, pachygyria

AR (263520)

Marden-Walker152

Motor delay, blepharophimosis, low-set and malformed ears, cleft palate, micrognathia, renal microcysts/cystic dysplasia, arachnodactyly, camptodactyly, joint contractures, congenital heart defect; case with brain stem and cerebellar hypoplasia, callosal agenesis, colpocephaly; likely heterogeneous

AR (248700)

Marinesco-Sjogren153

Mental retardation, congenital cataracts, cerebellar ataxia, muscle wasting with neurogenic atrophy and vacuolar degeneration, distal weakness, skeletal anomalies including scoliosis, posterior vertebral scalloping, enlargement of intervertebral foramina, short metatarsals and metacarpals; cerebellar atrophy mostly of vermis; cerebellar dysplasia reported

AR (248800) 5q31

Marshall-Smith154

Initial increased length with postnatal growth failure, dolichocephaly, prominent forehead and eyes, anteverted nares, micrognathia, larygeal anomalies, accelerated bone age, broad proximal and middle phalanges, reported with absent corpus callosum and cerebellar hypoplasia

Unknown (602535)

137

(continued)

661

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Posterior encephalocele, cystic dysplastic kidneys, postaxial polydactyly, cleft palate, microphthalmia, genital anomalies, cerebellar agenesis or hypoplasia

AR (249000) Multiple loci: 8q, 11q13, 17q22-q23

Me´garbane´: joint dislocationabnormal skin156

Microcephaly, delayed growth, severe retardation, ptosis, prominent and low-set ears, beaked nose, joint laxity, dislocations, delayed bone age, abnormal blood vessels in skin; consanguinity, mild vermis hypoplasia

AR or XLR

Melorheostosis-cerebellar hypoplasia157

Bone changes in femoral and humeral diaphyses, pelvis, and lower spine; optic atrophy; hearing loss, mental retardation; small cerebellar hemispheres

AR? (155950) Consanguinity

Microcephalyaminoaciduria158

Postnatal growth failure, marked psychomotor delay, hyperreflexia, optic atrophy, myoclonus becoming opisthotonus, mild aminoaciduria, elevated CSF a-amino nitrogen

XLR (311400)

Microcephaly-cerebral calcificationmicrophthalmia159

Progressive microcephaly, periventricular, basal ganglia and cerebellar calcification, seizures, cataracts, hypermetropia, large ears, laxity at smaller joints; inferior vermis and cerebellar hemisphere hypoplasia

AR

Microcephaly-flexion contractures-ichthyosis160

Progressive microcephaly and postnatal growth failure, sloping forehead, prominent nose, posteriorly rotated ears, limitation at major and small joints, mild lamellar ichthyosis, generalized skin edema, hypertonia, cerebellar hypoplasia, brain atrophy

Uncertain

Mo¨bius161

Usually bilateral sixth and seventh nerve palsy, although other cranial nuclei may be involved; minority with mental retardation, associated hypoglossia, and/or hypodactyly; minor facial anomalies. One case with unilateral cerebellar hypoplasia.

Vascular disruption AD (157900) Multiple loci: 3q21-q22, 10q21.3-q22.1, 13q12.2-q13

Mubashir: situs inversusmental retardation162

Profound mental retardation, growth failure, small head, situs inversus totalis, long face, hypertelorism, ptosis, anteverted nares, long philtrum, large mouth, tented upper lip, goiter, brachydactyly, short 4th and 5th metacarpals, tetraparesis, contractures at ankles, talipes equinovarus; cerebellar/brain stem migration disorder with featureless cerebellar cortex, no folia or vermis

Unknown

Muller: cerebral malformationhypertrichosis163

Hypertelorism, telecanthus, microphthalmos, small and low-set ears, hypertrichosis, camptodactyly, overlapping fingers, absent swallowing and suck; variable CNS in sibs including macrocephaly, absent corpus callosum, septum pellucidum cyst, cerebellar hypoplasia

AR (213820)

Multiple hernia164

Moderate mental retardation, hypotonia, low-set ears, downslanting palpebrae, hypotelorism, ptosis, anteverted nares, retrognathia, high-arched palate; hernias included diaphragmatic, hiatal, lung, and inguinal; bladder diverticulae; hydrocephalus, ‘‘cerebellar atrophy’’

Unknown

Multiple pterygium syndrome-lethal165

IUGR, polyhydramnios, multiple joint contractures, joint pterygia, pulmonary hypoplasia, edema, cystic hygromas, hypertelorism, downslanting palpebrae, cleft palate. Case with cerebellar and pontine hypoplasia

AR (253290)

Muscle-eye-brain166

Early severe hypotonia, delayed development, anterior chamber defects, glaucoma, preretinal glial membrane, ERG becomes abnormal, cataracts, myopathy, predominant frontal pachygyria, agenesis of corpus callosum, hypoplasia of pons and cerebellar vermis, white matter abnormalities patchy or absent, sibs with colpocephaly; common in Finland

AR (253280) POMGnT1, 1p32-p34.1

Nephronophthisis-molar tooth sign26,167

Nephronophthisis, variable ocular motor apraxia, normal eyes; a minority of patients with deletions/mutations of this gene have cerebellar hypoplasia (see Joubert)

AR (607100) NPHP1, 2q13

Neonatal diabetes mellituscerebellar168

Severe IUGR, microcephaly, low-set and dysplastic pinnae, beaked nose, poor subcutaneous fat, joint stiffness, talipes equinovarus, cerebellar aplasia/hypoplasia

AR (609069) PTFIA, 10p13-p12.1

Nephrotic syndromeinfantile spasms-GallowayMowat169

Developmental delay, early nephrotic signs due to focal glomerulosclerosis that may show IgM, IgG, and/or C3 deposits, areas of microgyria, cortical layer fusion. Cases reported with cerebellar atrophy/hypoplasia

AR (251300)

Neu-Laxova170

Sloped forehead, flat nose, abnormal auricles, finger hypoplasia, finger and toe syndactyly, severe microcephaly, IUGR, subcutaneous edema, genital hypoplasia, cerebellar vermis hypoplasia, external granular cell layer hypoplasia

AR (256520)

Neuroepithelial cysts-corpus callosum171

Interhemispheric cysts of glio-ependymal type, absent corpus callosum, neocortical microgyria, abnormal foramen magnum, nodular heterotopias, cerebellar hypoplasia

Unknown

Nievergelt: mesomelic dysplasia172

Severe mesomelia, elbows broad and restricted, talipes ulna/ radius, radioulnar synostosis, rhombdoid shaped tibia and fibula, relatively normal hands. Case with cataracts and agenesis of cerebellar vermis.

AD (163400)

Meckel-Gruber

155

(continued)

662

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Nonketotic hyperglycinemia173

Early-onset myoclonic seizures, progressive encephalopathy, profound mental retardation, absent corpus callosum, gyral anomalies, high mortality

AR (238300) GCSP, 3p21.2-21.1 GCST, 9p22 GCSH, 16q24

Ocular motor apraxianeurologic deficit174

Impaired horizontal voluntary saccadic eye movement in association with jerky head movement; variable absence of fast phase horizontal optokinetic nystagmus, verbal apraxia, dysarthria, ataxia, developmental delay; cases with vermis aplasia; also part of cerebello-oculo-renal

Unknown, AR (257550) 2q13

Oculo-renal-cerebellar175

Progressive mental retardation, spastic diplegia, glomerulopathy, retinopathy, absence of cerebellar granular layer

AR (257970)

Olivopontoneocerebellar hypoplasia-dysmorphia176

Like trisomy 18 with prominent occiput, overlapping fingers, rocker-bottom feet; neurologic signs of spasticity, extra-pyramidal dyskinesia, absent voluntary motor responses, marked pontocerebellar hypoplasia, progressive cerebral atrophy (PCH2)

AR (277470)

Organoid nevus177

Linear nevus sebaceous reported in one girl who was retarded and had mild cataract, cerebellar agenesis with superior vermis remnant

Unknown (165630)

Orofaciodigital-type III178

Lobulated tongue, supernumerary teeth, postaxial polydactyly, metronome eye movements, cleft palate, choanal atresia, cerebellar hypoplasia. Case with Dandy-Walker cyst

AR (258850)

Osteosclerosis-brain anomalies179

Generalized osteosclerosis, wide metaphyses, wide sutures, large anterior fontanel, downslanting palpebrae, depressed nasal bridge, micrognathia, large posterior fossa cyst, cerebellar hypoplasia, agenesis of the corpus callosum, large interhemispheric cyst, hydrocephalus

AR

Osteosclerosis-meningeal abnormalities180

Narrow face, prominent eyes, mandibular and maxillary hypoplasia, osteosclerosis mainly of skull and spine, wide thoracic and lumbar dorsal sac and subarachnoid, hypoplastic vermis with smooth rostral surface

AD (130720)

Oto-palato-digital II181

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia. Case with cerebellar hypoplasia and hydrocephalus

XLR (304120) FLNA, Xq28

PAX6-related eye-brain anomalies182

Compound heterozygote for PAX6 mutations had microcephaly, anophthalmia, small nares, large pinnae, absent corpus callosum, focal polymicrogyria, hypoplastic pons and cerebellum; heterozygotes had unilateral polymicrogyria and absent pineal

AR (106210) 11p13

Pena-Shokeir phenotype183

IUGR, fetal hypokinesia, polyhydramnios contractures, trismus, retrognathia, hypertelorism, trilobed lungs, hydrocephalus, hypoplastic basal ganglia and cerebellum, lethal

AR (208150)

Periodic alternating nystagmus-microcephaly184

Growth and developmental retardation, congenital periodic alternating nystagmus with decreased visual acuity, prominent ears, cerebellar hypoplasia

Unknown

Periventricular nodular heterotopia-syndactylycerebellar hypoplasia185

Severe mental retardation, seizures, syndactyly; variable cataracts, hypospadias, areas of cortical dysplasia

XLR (300049) possibly FLNA, Xq28

Perrault: deafness-ovarian dysgenesis186

Severe sensorineural hearing loss, ovarian dysgenesis; neurologic signs include variable mental retardation, ataxia, hypotonia, limited extraocular movement; cerebellar hypoplasia noted in one case

AR (233400)

Pfeiffer: oligodactylyabnormal facies187

Absent fibula/ulna, bowed femora, oligodactyly, cleft lip/palate, facial dysmorphia, contractures, Arnold-Chiari type II, absent velum medullare of vermis, focal microgyria, lethal

AR (228930)

Pitt-Hopkins188

Severe developmental delay, voluntary over-breathing, variable microcephaly, prominent nose with wide bridge and flared nares, macrostomia, thick and fleshy lips, finger clubbing, seizures, cerebellar hypoplasia

AR?

Porencephaly-cerebellar hypoplasia-heart defect189

Prominent metopic suture, bilateral epicanthus, high arched palate, absent septum pellucidum, hydrocephalus, bilateral cortical defects, dilated 4th ventricle, absent vermis, cerebellar hypoplasia, probable porencephaly in one sib, congenital heart defects

AR (601322)

Porphyria-acute intermittent, homozygote190

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) homozygote HMBS, 11q23-11qter

Port wine nevus191

Severe port wine nevus, large cisterna magna, communicating hydrocephalus, hypoplasia of posterior vermis

Uncertain (continued)

663

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Pseudo-TORCH

Severe retardation and seizures, extensive and variable deep and superficial supratentorial and basal ganglia calcification, hepatosplenomegaly, petechial rash; may be allelic with Aicardi-Goutieres and Cree encephalitis; 1 of 2 affected brothers had cerebellar hypoplasia

AR (251290)

Refsum, infantile193

Severe psychomotor delay, hypotonia, seizures, retinitis pigmentosa, sensorineural hearing loss, hepatomegaly, similar to but milder than Zellweger, acyl-CoAdihydroxyacetone phosphate acyltransferase deficiency, granular layer hypoplasia

AR (266510) PEX1, 7q21-q22 PEX2, 8q21.1

Retinal coloboma-congenital ataxia194

Bulging fontanels, split sutures, mild hydrocephalus, nystagmus, minor athetosis, hypotonia, abnormal respiration, dilated basal cisterna

AR or XLR

Saldino-Mainzer195

Leber congenital amaurosis, short limbs, small chest, short middle phalanges, coned epiphyses in hands, flat proximal femoral epiphyses, wide femoral neck, sclerotic metaphyses, nephronophthisis; may be same as Senior-Lo¨ken26

AR (266920)

Seller: cerebellar hypoplasiafacial dysmorphism196

Varied intrafamilial spectrum; high and receding forehead, low-set ears, hypertelorism/hypotelorism, absent external nares, thick and overhanging upper lip, small jaw, cardiac defects, dilated ileum, cerebellar hypoplasia

AR

Senior-Lo¨ken: cerebellooculo-renal26

Developmental delay, molar tooth sign, Leber congenital amaurosis, nephronophthisis; variable Dandy-Walker malformation, hepatic fibrosis, coned epiphyses; see also Joubert142

AR (266900)

Siber: microphthalmia197

Microphthalmia, corneal opacities, hypospadias; one sib had callosal agenesis, the second aqueduct stenosis; underdeveloped cerebellum, pons, midbrain, and basal ganglia; absent olfactory, optic, oculomotor nerves, areas of macrogyria

XLR (309800) Xq27-q28

Situs inversus-autosomal recessive198

Midline and lateralization defects including dextrocardia, atrioventricular canal defect, common atrium, lung segmentation defects, polysplenia, hemivertebrae, optic nerve coloboma, chorioretinal atrophy, cleft soft palate, hypoplastic corpus callosum, cerebellar dysgenesis, vermis hypoplasia

AD (601086), AR (605376) EBAF, 1q42.1 CFC1, Chr 2 CRELD1, 3p25.3 ACVR2B, 3p22-p21.3 NKX2-5, 5q34

Slee: hydrocephalus-growth failure-digital199

Severe polyventricular hydrocephalus, patent aqueduct of Sylvius, cleft palate, overlapping fingers; CNS variable and includes partial/complete callosal agenesis, hypoplastic mid- and hindbrain, cerebellar agenesis; lethal

AR/XLR?

Smith-Lemli-Opitz200

Postnatal growth failure, mental retardation, narrow forehead, ptosis, epicanthus, broad anteverted nasal tip, broad alveolar ridges, micrognathia. Severe end of spectrum has more marked genital and internal anomalies, postaxial polydactyly, cerebellar hypoplasia

AR (270400) DHCR7, 11q12-q13

Smith-Magenis201

Short stature, square and broad face, upslanting palpebrae, deep-set eyes, full cheeks, depressed and broad nasal root, marked malar hypoplasia, fleshy and tented upper lip, bulky philtral pillars, characteristic and possibly unique behavior. Two reports with cerebellar anomalies, one with Joubert phenotype

AD (182290) del 17p11.2

Stippled humeral epiphysesiris colobomata202

Developmental delay, brachycephaly, small nose and anteverted nares, low-set ears, midface hypoplasia, iris coloboma, stippled proximal humeral epiphyses, dysplastic distal phalanges, hepatic fibrosis, deep palmar creases, toenail hypoplasia, partial absence of the corpus callosum, small cerebellar vermis

AR (215105)

Stoll: cerebellar hypoplasiaspastic paraplegia203

Mental retardation, spastic paraplegia, hypoplasia of the cerebellar hemispheres, partial agenesis of cerebellar vermis, agenesis of the corpus callosum

AR

Sublobar cortical dysplasia204

Dysplasia of a single hemisphere within a lobe and separated from normal brain, absent or thin corpus callosum, 4 of 5 had hypoplastic cerebellar vermis

Unknown

Syndactyly-cerebellar atrophy-mental retardation205

Developmental delay, axial hypotonia, lower limb hypotonia, lambdoid fusions, large ears, sparse hair, tapered fingers, broad halluces, variable syndactyly

Uncertain

Teebi: Aarskog-like206

Normal intelligence and growth, broad forehead, widow’s peak, hypertelorism, downslanting palpebrae, ptosis, broad nasal bridge, hypoplastic mid-face, long philtrum, thin upper lip, short and broad hands, shawl scrotum. Case with ventricular septal defect, occipital lipoma, hypoplasia of left cerebellar hemisphere

AD (145420)

Thanatophoric dysplasia207

Usually neonatally lethal, short ribbed, micromelic dwarfism, excess skin folds, achondroplasia-like face, H or U-shaped vertebrae on AP, curved femur, metaphyseal changes; cerebellar hypoplasia, inferior vermis aplasia, polymicrogyria, leptomeningeal and periventricular neuronal heterotopias

AD (187600) FGFR3, 4p16

192

(continued)

664

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Thrombocytopenia-absent radius208

Congenital thrombocytopenia, absent radius with preservation of thumbs, variable additional anomalies. Case with cerebellar hypoplasia, callosal hypoplasia, cavum septum pellucidum.

AR (274000)

Thrombocytopenia-Robin sequence209

Mental retardation, pre- and postnatal growth failure, Robin sequence, telecanthus, downslanting palpebrae, short and broad-tipped nose, enamel hypoplasia, camptodactyly, cerebellar vermis hypoplasia

Unknown

Thyrocerebrorenal210

Renal tubular and interstitial nephropathy, thrombocytopenia, thyroid organification defect, late childhood muscle wasting, ataxia, cerebellum with severe demyelination of white matter, neuronal loss

AR (274240)

Trichorrhexis nodosa-lip pits211

Developmental delay, hydrotic ectodermal dysplasia involving hair, nails, and teeth (hypodontia), long narrow face, narrow auditory meati, lip pits, submucous cleft palate, cerebellar hypoplasia

Uncertain

Troost: cerebral calcifications212

Progressive cerebral blindness, tetraplegia, regression; periventricular, ganglial, cerebellar calcification; cerebellar hypoplasia with sparing of paleocerebellum; atrophic granular layer; irregular Purkinje cells

AR

Van Maldergem: blepharonaso-facial213

Moderate to severe mental retardation, small and malformed ears, telecanthus, epicanthus, broad and flat nose, wide mouth, camptodactyly, clinodactyly, mild skin syndactyly. Case with ataxia, hypotonia enlarged lateral ventricles, reduced white matter, absence callosal rostrum, hypoplastic superior vermis and tonsils.

Unknown

Van Staey: facial dysmorphiadeafness214

Developmental delay, overfolded helices, sensorineural deafness, hypertelorism, epicanthus, submucous cleft palate, hydronephrosis, enlarged 4th ventricle, large cisterna magna, and probable vermis hypoplasia

Unknown

Va´radi: OFD-VI215

Severe retardation, postnatal growth failure, median clefts, fatty hamartomas of tongue, pre-axial polydactyly feet, bifid 3rd metacarpal, abnormal cerebellar vermis, high mortality

Uncertain (277170)

Velo-cardio-facial216

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart, microcephaly, hypoplastic pons and vermis lobules VI-VII

AD (192430) del 22q11 del 10p

Vici: immunodeficiencycataracts217

Hair and skin hypopigmentation, combined immunodeficiency, cleft lip/palate, hypertelorism, hypospadias, hypoplastic cerebellar vermis

XLR or AR (242840)

Whistling face-severe form with hearing loss218

Lethal with severe postnatal growth failure, microcephaly, hypertelorism, blepharophimosis, long philtrum, small and puckered mouth, joint stiffness, digital flexion contractures and ulnar deviation, restricted thorax; hypoplastic medulla, pons, midbrain, cerebellar hemispheres and vermis

Unknown

Winter: IUGRhydrocephalus-skeletal219

Severe IUGR, rhizomelia, small face and ears, blue sclerae, beaked and pinched nose, small hands, zygodactyly of toes 4–5, bifid 5th left toenail, small penis, retarded bone age; radiologic changes include metaphyseal flaring, platyspondyly, pelvic anomalies, wormian bones; enlarged 3rd and lateral ventricles, small 4th ventricle, probable cerebellar vermis dysgenesis/agenesis

Unknown, AR?

220

Severe microbrachycephaly, cleft palate, microglossia, patent ductus arteriosus, polymicrogyria, absent corpus callosum, abnormal midbrain and basal ganglia, absent vermis, poorly formed hemispheres; microscopic renal changes

Unknown

X-linked cerebellar hypoplasia-normal intelligence221

Nonprogressive, ataxia, hyperreflexia, dysarthria, nystagmus, absent upward gaze, hypoplasia of cerebellar hemispheres and vermis

XLR Xp11.21-q24

X-linked laterality defect222

Variable visceral situs inversus, complex congenital heart disease, splenic malformations; CNS anomalies less common and include arhinencephaly, hydrocephalus, meningomyelocele, and cerebellar hypoplasia

XLR (304750) ZIC3, Xq24-q27

XLMR-Christianson223

Mild microcephaly, profound mental retardation, no speech, ophthalmoplegia, truncal ataxia, lowered life expectancy, cerebellar and brain stem ‘‘atrophy’’; females may show delay

XLR (300243) Xq24-q27

XLMR-oligophrenin defect32,33

Moderate to severe mental retardation, myoclonic-astatic epilepsy, ataxia, hypogenitalism, fronto-temporal atrophy, lower vermian agenesis, asymmetric cerebellar hypoplasia; 46,XY sisters deleted for oligophrenin and androgen receptor genes expressed syndrome

XLD (300127) OPHN1, Xq12

Yano: cerebello-oculorenal224

Developmental delay, molar tooth sign, Leber congenital amaurosis, renal hypoplasia/ agenesis (see also Joubert ref. 142)

AR (608091)

Winter-Wigglesworth

(continued)

665

666

Neuromuscular Systems

Table 15-17. Syndromes with cerebellar hypoplasia (continued) Syndrome

Prominent Features

Causation Gene/Locus

Young: agenesis of the corpus callosum225

Relative macrocephaly, prominent forehead, deep-set eyes, thin nose, mental retardation, gut malrotation, asymmetric hypoplasia of cerebellar hemisphere

AR (217990)

Young: X-linked congenital ataxia58

Mild to moderate developmental delay, decreased reflexes, trunk and limb ataxia, intention tremor, nystagmus, broad gait, cerebellar hypoplasia

XLR (302500) Xp11.21-q21.3

Yunis-Varon: cleidocranial dysostosis226

Wide anterior fontanelle, sparse scalp hair, short philtrum, narrow palate, micrognathia, thin lips; absent/hypoplastic thumbs, great toes, clavicles; distal toe/ finger aphalangia. Case with hypoplastic vermis

AR (216340)

behavioral problems.8 Oculomotor apraxia is common. Findings at postmortem examination have included vermis dysplasia, cerebellar cortex heterotopias in the white matter, lack of decussation of the pyramidal tracts, dysplasia of the olivary nuclei, and hypoplasia of the fasciculus solitarius and descending trigeminal tract.7 There can be significant interfamilial and intrafamilial variation in the severity of the neurologic signs and CNS changes seen on MRI. From the original report of Joubert syndrome there followed numerous papers describing patients with additional and varied anomalies of the brain, eyes, kidneys, liver, and digits, and this has led to considerable nosological confusion. The common associated anomalies include Leber congenital amaurosis, later onset retinopathies, colobomas, cystic dysplastic kidneys, nephronophthisis, hepatic fibrosis and cysts, and occasional postaxial polydactyly. Satram et al.26 reviewed 100 patients with cerebellar vermis hypoplasia plus additional ocular and/or renal involvement. They excluded cases of pure Joubert syndrome, which has now been linked to 9q34, from the analysis. The authors were able to show that the specific types of associated anomalies ran true within siblingships, and they tentatively identified six MTS syndromes, all but one of which had at least one case reported with demonstrable MTS. These syndromes were Joubert, Arima, Senior-Lo¨ken, COACH, Gentile, and cerebelloretinal-renal agenesis (Table 15-17). The authors also suggested that MTS with nephronophthisis due to NPHP1 mutations be added to the list,27 and questioned the nosological relationship of the 3C and Va´radi (OFD Type VI) syndromes (Table 15-17). Further clarification awaits progress in uncovering the genes for these conditions. Thus far NPHP1 at 2q13 and AHI1 on 6q23.2 have been associated with Joubert syndrome. Of note, the Dandy-Walker malformation, sometimes with the cyst included in an encephalocele, was an occasional component of several of the syndromes.26 Others have simply separated Joubert syndrome as cerebello-oculo-renal syndrome type 1 (CORS1) and grouped the others as CORS2. 15.12.4 Isolated Vermis Aplasia/ Hypoplasia/Dysplasia

In complete vermis aplasia there is either no tissue or a thin remaining membrane. The cerebellar hemispheres may be normal, hypoplastic, or show abnormal convolutions or dysplasia. The dorsal accessory olives are virtually absent, and variable anomalies may be seen in the dentate, inferior olives, ventral accessory olives, and restiform body.28 Parisi and Dobyns8consider that hypoplasia of the vermis is likely underdiagnosed, and often mislabeled as Dandy-Walker variant. Vermian hypoplasia is distinguished from Dandy-Walker malformation by the normal or minimally upwardly rotated position of the vermis relative to the brain stem, the absence of an elevated tentorium and lateral sinuses, and the smaller retrocerebellar collection of fluid that does connect to the fourth ventricle.8,29 Partial agenesis/

hypoplasia generally involves the later developing caudal parts of the cerebellum (Figs. 15-59, 15-60). Again, this is clearly a heterogeneous disorder, which may occur as an isolated CNS anomaly in patients with CNS signs, or as part of a more generalized syndrome (Table 15-17). In a number of syndromes listed, the cerebellar anomaly has not been well described and some may well have been limited to the vermis. Al Shahwan et al.30 described a family with an autosomal recessive, non-progressive cerebellar hypoplasia involving absence of the caudal vermis and hypoplasia of the remaining vermis and paravermian cerebellar hemispheres. The patients exhibited hyperreflexia and positive Babinski signs, along with other typical cerebellar signs. Families with apparent X-linked recessive inheritance have been reported,31 and vermis hypoplasia, specifically with incomplete sulcation of the anterior and posterior vermis with the prominent defects in lobules VI and VII, is seen in the X-linked oligophrenin-1 (OPHN1) form of mental retardation (Table 15-17).32,33 Steinlin9 found reference to seven families in the literature with autosomal dominant, or in some cases perhaps sex-linked dominant, inheritance of a relatively mild, non-progressive cerebellar ataxia with cerebellar vermis hypoplasia. Cognitive impairment was mild with IQ ranging from 70 to 90 and walking prior to age 2 years. There are no available pathologic data. Fig. 15-59. Sagittal MRI scan showing agenesis of the inferior vermis.

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genu of the corpus callosum, pons, and vermis lobules VI–VII has also been reported in Turner syndrome.43 Autism with agenesis of the vermis in association with elevated succinyl purines has been reported in two patients.44 15.12.5 Complete Cerebellar Agenesis

Total agenesis of the cerebellum is exceedingly rare, and Hamilton and Grafe,45 who added two cases of their own in children with multiple associated anomalies, were only able to find two reports in the literature with convincing evidence for a complete lack of the cerebellum. Thus, the majority of the over 50 cases reported as cerebellar agenesis can be shown to have a small cerebellar remnant,46 perhaps representing the flocculus (Fig. 15-61).28 The cerebellar peduncles, olivary nuclei, and pons may be extremely hypoplastic or even absent.28,45 In cases of true agenesis the posterior fossa is small and may be of an abnormal shape; whereas in cases with a cerebellar remnant, it may be of normal size, thus supporting the view that a destructive process may be involved (see Unilateral cerebellar hypoplasia/agenesis). Significant psychomotor delay with severely delayed speech and walking between 4 and 7 years of age is the rule, and gait tends to be clumsy and speech dysathric.46 Glickstein46 has pointed out that there is no evidence to support a claim of normal motor capacity in a man previously reported to have cerebellar agenesis, and that an MRI of the patient’s brain in fact showed a cerebellar remnant. Fig. 15-60. Axial MRI scan showing agenesis of the inferior vermis.

Cortical dysplasia of the hemispheres may accompany vermis hypoplasia.34 Asymptomatic cases of vermis aplasia/hypoplasia may occur, but most patients are recognized because of early psychomotor delay, and typical cerebellar signs.9 Clinically they are not readily distinguishable from patients with more diffuse cerebellar involvement.35 Harris et al.36 described a family with likely autosomal dominantly inherited vermis hypoplasia in which the presentation was with ocular motor apraxia (saccade initiation failure) and mild learning difficulties. In some cases the neurologic picture may be dominated by supratentorial anomalies, and it is certain that mutations in OPHN1 have an effect beyond that in the cerebellum. Parisi and Dobyns8 stress that the neurologic prognosis is generally worse in patients with cerebellar vermis hypoplasia/aplasia than for those with the more obvious Dandy-Walker malformation. This is of great importance when interpreting anomalies of the posterior fossa detected at prenatal sonography, at which time larger cysts with a statistically better prognosis are more likely to be detected, but it can be difficult to distinguish vermis hypoplasia from a true DandyWalker malformation.37 There is continuing interest in the possible association of minor degrees of vermis hypoplasia, often confined to specific lobules, and certain syndromes or neurologic illnesses. Early MRI studies suggested that otherwise normal persons with autism may be found to have hypoplasia of the declive, folium, and tuber of the posterior vermis.38,39 Kaufmann et al.40 confirmed a reduction in the size of vermis lobules VI–VII in idiopathic autism and showed that lobules VI through X were reduced in Down syndrome and fragile-X syndrome. A smaller cerebellum in Down syndrome has also been confirmed between 13 and 26 weeks gestation on prenatal sonography.41 Hypoplasia of vermis lobules VI–VII and the pons has been proffered as a possible explanation for the neurobehavioral profile of velocardiofacial syndrome,42and a reduction in area of the

15.12.6 Unilateral Hemispheric Agenesis/Hypoplasia

The degree of involvement of the cerebellum in unilateral hemispheric agenesis/hypoplasia (UAH) is quite variable. The ipsilateral vermis may or may not be affected, the involved hemisphere may be completely absent, be represented as a remnant, or simply be small, and in some cases the normal side may also be somewhat smaller than normal. Thus, it is likely that this represents a heterogeneous grouping. Secondary changes occur in the contralateral inferior olivary and pontine nuclei, which are normally connected to the affected hemisphere. UAH should be distinguished from crossed cerebellar diaschisis in which the cerebellar hypoplasia is a Fig. 15-61. Axial CT scan at level of the fourth ventricle showing somewhat enlarged basal cisterns and absence of cerebellar structures.

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secondary degeneration that follows atrophy of the contralateral cortex.47 Significant cerebellar asymmetry may be reflected on routine skull radiographs by ipsilateral hypoplastic development of the posterior fossa, thickening of the skull table, and excess petrous pneumatization.48 In the absence of associated CNS pathology, a significant number of cases have been asymptomatic or have exhibited relatively mild cerebellar signs. This speaks for a significant plasticity in the development of the cerebellum, and makes it difficult to ascribe a patient’s clinical signs to the UAH with any certainty. For example, Boltshauser et al.49 described three children, one with complete and two with a small remnant, with UAH. The patients presented, one each, with delayed motor development and contralateral torticollis, hemiplegia, and an ‘‘unusual head nodding,’’ and the authors concluded that it was doubtful that the UAH accounted for their symptoms. In contrast, Goraya et al.50 argued that the hyperekplexia they observed in a 10-year-old girl could logically be attributed to her vermis and right cerebellar UAH. There were three cases of UAH among the 70 patients described by Patel and Barkovich.1 Two were children with developmental delay and one an adult with headaches. Ramaekers et al.51 ascertained 16 cases of UAH among 78 patients with non-Dandy-Walker cerebellar structural anomalies. In eleven cases, the UAH was extensive, and in five it was minor. Although full details were not provided, it would appear that children with significant medical/developmental findings had either associated physical anomalies or medical histories that would account for developmental problems. Of interest were two unrelated males with UAH, microcephaly, severe mental retardation, and ipsilateral choroidal-retinal coloboma. There is some consensus that UAH is often an acquired lesion, and to date there have been no recurrences within a family. Of the seven patients reported by Ramaekers et al.51 with marked UAH but no associated malformations, six had a history of severe prenatal or perinatal hypoxia. Of the five with mild UAH, one had suffered cerebellitis and two had documented cerebellar strokes. The case reported by Robins et al.52 appears to provide concrete evidence of an acquired vascular cause. At an obstetric ultrasound performed because of non-specific abdominal pain at 24 weeks gestation, a 2cm echogenic mass was noted in the right cerebellar hemisphere. By 29 weeks, this was a 5-cm cystic lesion, and a perinatal MRI showed a right UAH. The child showed normal development at 18 months. Fuwa and Kogo53 presented a 51-year-old woman with progressive cerebellar signs and cranial nerve palsies who was shown to have a porencephalic cavity, lined by nonspecific gliosis, suggesting a similar mechanism can occur later in life. 15.12.7 Cerebellar Hypertrophy

Cerebellar hypertrophy is uncommon and not associated with the classic overgrowth syndromes, although it may be seen in hemimegalencephaly.7 The best known cause of cerebellar hypertrophy is the PTEN-associated L’Hermitte-Duclos hamartoma, which is characterized by 1) partial or complete disassociation of the cerebellar cortex from the underlying atrophic/absent white matter, 2) replacement of Purkinje cells, and less so granule cells, by a layer of dysplastic cells that react immunologically as Purkinje cells, 3) replacement of the molecular layer by thick, horizontal and radial nerve fibers, 4) abnormal lamination, even in normal appearing lobules and folia, 5) macrocephaly, and 6) anomalies of the dentate nuceus.54 De Leo´n et al.54 described massive cerebellar hypertrophy due to a lesion that appeared to derive from the inferior vermis, was attached to the hemispheric folia, and consisted of a completely

disorganized mass of poorly differentiated neuroepithelial cells. This may be more of a benign tumor than a true hypertrophy. Schweitzer et al.55 reported two brothers who both had cerebellar hypertrophy and van den Ende-Gupta syndrome. This autosomal recessive syndrome consists of blepharophimosis, a flat and wide nasal bridge but narrow nose, prominent ears with anomalous pinnae, a high or cleft palate, camptodactyly and other contractures that improve over time, arachnodactyly, and other minor skeletal anomalies. MRI showed generalized cerebellar hypertrophy, which was 130% of normal in the one brother in whom measurements were possible. There is no information about the cerebellum in the six other patients reported with this syndrome. The cerebellum has been noted to be enlarged in Williams syndrome, and in a recent study using radiologists blinded to the diagnosis and hypothesis, the radiologists separated out the Williams syndrome patients because of their large cerebellum.56 Finally, in a study that compared normal children, children with idiopathic autism, and children with Down syndrome and fragileX syndrome, with and without autistic features, an enlargement of lobules VI–VII was found (only) in children with fragile-X syndrome and autistic behavior.43 Nothing is known of the histopathology in these syndromes. 15.12.8 Cerebellar Hypoplasia/Aplasia/Dysplasia

Niesen7 has divided cerebellar hypoplasia into type I with normal folia, usually a normal three-layered cortex, and heterotopias, and type II where the fissures are prominent and there is significant cell loss. The former is considered an abnormality of cell migration and differentiation. The latter, which presents the difficulty of separating hypoplasia from atrophy, is viewed as a disorder of cell proliferation. Again, there is nothing distinctive about the clinical presentation, and the two patients with diffuse involvement in the series of 11 patients with non-syndromic cerebellar hypoplasia reported by Shevell and Majnemer35 were not clinically different from those with isolated vermis hypoplasia. Type I hypoplasia is exemplified by trisomy 13 and 18,7 whereas the prototypic type II disorder is granule cell aplasia (GCA), also called granuloprival hypoplasia. GCA is an autosomal recessively inherited cerebellar hypoplasia that presents with a clinical picture typical for a non-progressive cerebellar ataxia.9,57 PascualCastroviejo et al.57 reported 14 cases and reviewed the literature. They believe that cases can be divided into two groups, based on the presence or absence of a normal head circumference, the likelihood of survival, and of language and intellectual skills that allowed them to maintain social contact and learn simple concepts. The histopathology of GCA shows generalized cerebellar hypoplasia with diminished to absent granule cells. The Purkinje cell layer can appear virtually normal, but usually shows reduced cell numbers, heterotopias, and dendritic abnormalities with resultant asteroid bodies and axonal torpedoes (Fig. 15-62).57,58 There may be defective myelination of the cerebellar white matter and cerebral changes consistent with primary microcephaly. Pascual-Castroviejo et al.57 raised the question as to whether this might be a prenatal onset abiotrophy. Genetic heterogeneity of GCA seems likely. Chou et al.59 described three of five male siblings with virtual absence of granule cells in both the fascia dentata of Ammon’s horns of the hippocampus and the cerebellum. In addition to the typical cerebellar signs of GCA, the siblings had intractable seizures and athetoid movements. There was relative preservation of the Purkinje cells, and this condition could be autosomal or X-linked recessive. One form of mild cerebellar hypoplasia with spinal involvement has been linked to 9p12-q12,60

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Fig. 15-62. Silver stain of cerebellar section showing absence of granule cell layer and disoriented Purkinje cells.

and an X-linked form was reported by Young et al. (Table 15-17).61 Pascual-Castroviejo et al.62 described what is probably an autosomal recessive cerebellar hypoplasia that is clinically indistinguishable from GCA, but is characterized by preservation of the granule cell layers, irregular loss of Purkinje cells, mild Bergman gliosis, and globular thickening and deformities of the Purkinje dendrites. Specific diagnosis requires histologic study of the brain. Type II cerebellar hypoplasia may also be seen in the face of metabolic disease, but here again it may be difficult to separate hypoplasia from atrophy. Niesen7 uses congenital disorders of glycosylation as a prime example of type II hypoplasia, whereas Steilin et al.63 consider CDGS to be the most impressive form of atrophy. Those authors list adenylsuccinase deficiency, pyruvate dehydrogenase deficiency, and L-2-hydroxyglutaric acidemia as causing cerebellar hypoplasia, to which can be added cytochrome c oxidase (complex IV) deficiency.64 In reality, the distinction may not be as clear-cut with metabolic diseases likely having both a negative effect on cerebellar development and maturation as well as causing atrophy. 15.12.9 Pontocerebellar Anomalies

Pontine agenesis is exceedingly rare, and Niesen7 was able to find only three cases with adequate documentation. Clinical presentation is with abnormal respiration, increased tone, and absent oculocephalic, corneal, gag, and sucking reflexes. Death is from respiratory failure, and the pons and midbrain are a thin ribbon of tissue, with the cerebellum being small and displaced rostrally. The cause is unknown. The pontocerebellar hypoplasias are not discussed in this chapter because they are progressive abiotrophies. There are three subtypes: one with spinal muscular atrophy (PCH1); one with microcephaly, epilepsy, and chorea (PCH2); and the last similar to PCH2 but without dyskinesia (PCH3), which has been mapped to 7q11-q21.65 Table 15-17 summarizes a number of syndromes in which cerebellar abnormalities have been reported. An effort has been made to identify the specific nature of the cerebellar abnormality, although in some cases it has not been clearly stated, and in most cases pathologic confirmation is not available. Etiology and Distribution

At this time one can do little more than guess the prevalence of cerebellar malformations. Certainly the availability of noninvasive

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CT and MRI has led to an increased awareness and detection of these abnormalities. Still, mild malformations may be hard to detect and require good quality studies,2,5 which are not always possible to obtain, especially where a patient is unable to cooperate.9 The picture is further clouded by the fact that children who have nonprogressive cerebellar ataxia (NPCA) and a detectable cerebellar anomaly do not differ clinically from those with NPCA and no detectable lesion; furthermore, there can be discordance within a siblingship.9,10 Esscher et al.10 found 78 cases of NPCA among a population of 595,688 persons for a prevalence of 0.13/1000. There was no sex difference in prevalence. Fewer cases in earlier years suggest there was some underascertainment. Shevell and Majnemer35 found 11 cases of non-familial, isolated cerebellar hypoplasia (mostly vermian) among 2500 consecutive referrals to a pediatric neurologist. Patel and Brakovich1 gathered 70 cases of cerebellar malformation over 15 years of practice, but the population denominator is not available. However, they had 19 patients with a Dandy-Walker malformation, which has a prevalence as high as 1/5000.8 If one assumes no bias in the referral of cases by type of malformation, then their 12 cases of Joubert syndrome, eight of rhombencephalosynapsis, and six of cerebellar hypoplasia would give rates of 0.13/1000, 0.08/1000, and 0.06/1000, respectively. This is an order of magnitude higher than a survey estimate of the prevalence of Joubert syndrome.227 Of the 78 patients without trapped fourth ventricle, DandyWalker malformation, or Dandy-Walker variant reported by Ramaekers et al.,51 16 had unilateral and 62 bilateral lesions, and of the latter, 15 were primarily vermian, 9 pontocerebellar, and 38 hemispheric. However, 28 of the latter were judged to be progressive and progressive abiotophies were included in the pontocerebellar group. The cerebellum accounts for only 10% of intracranial volume but it contains 50% of neurons in the adult, and until recently knowledge of its development lagged behind that of other parts of the brain. However, recent developments in embryology and molecular biology have added much, and will continue to contribute, to an increased understanding of the pathogenesis of cerebellar abnormalities. The cerebellar origins are defined early in embryogenesis but its maturation continues well into postnatal life and makes it susceptible to malformation, disruption, and dysplasia over a prolonged period. By the week 3 of gestation, the prosencephalon, mesencephalon, and rhombencephalon are apparent, and during the subsequent 2 weeks the neural tube develops the cranial and cervical flexions and the eight transient hindbrain rhombomeres.7 This is followed in the fifth week by the pontine retroflexion, which results in the fourth ventricle and its triangular rhombic roof-plate. Physical evidence of the future cerebellum is present by 5 weeks in the form of the rhombic lips, which develop as a proliferation of cells in the bilateral alar plates at the junction of the roof-plate and neural tube, anterior to the choroid plexus. The bilateral elements come to fuse in the midline. This rhombic lip development is intimately related to the isthmus organizer (IO), a narrowing that originates near the mesencephalic–metencephalic border. It was thought that location of the organizer evidenced both mesencephalic and metencephalic origin of the cerebellum, but more recent work has shown that the isthmus moves rostrally during development to the actual mesencephalic/metencephalic boundary.228,229 An important initial step in defining the rostral limit of the cerebellum and the IO is a reciprocal repression between the expression of Otx2 in the anterior CNS and the posterior CNS expression of Gbx2, with the interface being at the mesencephalic–metencephalic boundary.229,230

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Mutations in these genes have a major effect on the developing CNS and the integrity of the IO.230 The caudal limit of the cerebellum is defined by the rostral limit of Hoxa2 expression, which defines the rh1/rh2 border.231 Mice with mutations in Hoxa2 have enlarged cerebellums, and retinoic acid is important in the function of these genes. Thus, the cerebellum and some pontine neurons derive solely from rhombomere 1. The genes involved in maintaining the integrity of the IO and the pathways emanating from there that control cerebellar development continue to be studied, but do include Wnt1, Fgf8, Pax2/5, En1/2.7,229 Mutations, both natural and knockout, together with transgenic expression studies, result in a variety of midbrain–hindbrain and cerebellar abnormalities, which may vary with strain and/or level of background sensitization.228–230,232 Two sources provide the neurons of the cerebellum. The Purkinje cells, and all other non-granule cells, derive from the subventricular zone in the floor of the fourth ventricle, 233 and the first cells to migrate from this area at about 8 weeks gestation become the deep cerebellar nuclei.233 In the human, from about 9 to 13 weeks, Purkinje cells migrate in the usual radial fashion along the reelin (RELN)-dependent radial fibers of the Bergmann glial cells.1,229 Differentiation and survival of Purkinje cells is dependent on Wnt3 expression.234 Although granule cells are not required during the migration and initial maturation of Purkinje cells, they do play an important interactive role in their final maturation229 and in determining the stop signal for migration.235 The granule cells begin to develop at about 11 weeks and continue their proliferation as external granule cells until about 3 months after birth, with final migration and loss of the external layer ending at about 15 months postnatally.7 The granule cells are unique both in their derivation from a separate germinal matrix in the rhombic lip, and in that they migrate tangentially to form the external granule cell layer before undergoing their final mitosis and migrating inward, between the Purkinje cells, to form the inner granule cell layer. Math-1 has a critical role in granule cell production.7 Additional genes and factors that appear to play a role in the initial migration and differentiation of these cells include nectin, N-methyl-d-aspartate receptor, Zic1/3, and Zipro1.7,229 Markers and genes involved in the development of the internal granule cell layer may include Pax6, Tag1, Tuj1, the Dcc/ netrin pathway, and Unc5h2.229 Maturation of the cerebellum includes the development of connections via mossy fibers from the spinocerebellar pathways, reticulocerebellar nuclei, pontocerebellar nuclei, and others to the deep cerebellar neurons and granule cells. Climbing fibers from the contralateral inferior oliviary nucleus connect directly to Purkinje cells and to deep cerebellar neurons that then connect to Purkinje cells. In turn, the Purkinje cells connect directly and indirectly via superficial basket cells to the parallel fibers (axons) of the granule cells. This process begins by 24 weeks gestation, but the mature Purkinje layer is not formed until 4 to 7 months, and dentritic connections continue to be laid until 20 months postnatally.7,229 At the macroscopic level, the cerebellum develops as three phylogenetically distinct lobes. The first (present in lamprey), the archecerebellum, can be seen by 2 months and consists of the flocculonodular lobe, which is hard to distinguish in humans. The anterior lobe is next to develop and includes the vermis and paravermian hemispheres in front of the primary fissure that appears by 4 months and separates the anterior from the posterior lobe. The initiation of fissuration, at least in part, appears to be related to differential origin and timing of arrival of different groups of Purkinje cells. For example, in the mouse the fissure is a marker for cells generated before and those generated after E15.3

The posterolateral fissure separates the flocculonodular and posterior lobes. The cerebellum can be further subdivided into a series of transverse lobules, labeled I-X, which in turn can be further subdivided into sublobules, each containing a number of folia, which are transversely oriented units with a core of white matter and cover of gray matter. All major fissures and subdivisions are complete in the 120-mm embryo.236 This folial pattern is highly reproducible between individuals.5 In the rat genetic fissura prima malformation, there is a breakdown of the pia, a resultant fusion of the external granule layers from adjacent folia, ectopic cells, and migration of some external granule cells to the adjacent folia.3 This is similar to findings in the Walker-Warburg syndrome in humans. An addition to the understanding of cerebellar development that will undoubtedly have significant functional significance, and perhaps shed light on the specific pattern in both syndromic and isolated cerebellar malformations, is the recognition that the cerebellum is organized in a grid fashion.233 First, expression patterns of Purkinje cell markers and the phenotype of both spontaneous and targeted mutations in mice show a division of the cerebellum into four transverse zones: anterior (AZ), containing lobules I–IV; central (CZ) with lobules VI–VII; posterior (PZ) consisting of lobules VIII– IX; and nodular (NZ) limited to lobule X. Among the better studied markers are zebrin I/II, L7-pcp-lacZ, and Hsp25.233,237 Examples of mouse mutations with localized effects include meander tail that affects the anterior vermis, lurcher that acts at the PZ/CZ boundary, and weaver in which the CZ is absent. In addition to these transverse divisions of the expression patterns of a number of antigens, the vermis and hemispheres are further divided into a series of lateral rostro-caudal stripes.237 The expression patterns within the lateral stripes can differ across different transverse zones. Thus, the cerebellum is divided into a grid-like pattern, which is reflected in, but is not dependent on, the projection pattern of the climbing and mossy fibers. The grid also appears to reflect a functional topography and is reproducible between individuals and shows evolutionary conservation. The weight of evidence favors the origin of this patterning prior to Purkinje migration and in the ventricular zone.233 The growth of the vermis predates that of the hemispheres, and anterior predates posterior. Patients with granular cell aplasia show essentially normal gross cerebellar anatomy and normal numbers of Purkinje cells.238,239 Thus, disturbed embryogenesis from early to late would tend to produce a continuous spectrum ranging from complete aplasia, aplasia of the vermis, posterior vermis aplasia, neocerebellar (hemispheric), and finally cerebellar hypoplasia, many cases of which would represent granular cell aplasia. Not only can we think of cerebellar anomalies in terms of the timing of an insult to the larger lobes or the broad category of cell type involved, but we can begin to think of specific zones, lobules, and cell subpopulations that target to a particular grid location. Despite progress in the embryology, neuroimaging, and syndrome delineation of cerebellar anomalies, the specific etiology of most cases remains obscure. Some discussion, especially of genetic aspects, has been covered in the individual sections on diagnosis. TCD and RES are uncommon, and to date there is not human evidence for a genetic cause. Their origins are early in embryogenesis, and the former may relate to a defect in neural tube closure, and the latter to an early defect in cell migration.23 Many of the genes involved in early cerebellar development have other important roles and, as a result, germ line mutations could be lethal; but this leaves open the possibility of causative local somatic mutations. There is good evidence of a role for vascular disruptions, either thrombosis, hemorrhage, or vasculitis, as a cause for unilateral hemisphere

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agenesis/hypoplasia, and presumably some bilateral cases could have a similar etiology. Some cases have had definite retrograde nuclear atrophy, suggestive of a degenerative rather than a primary malformative process.240 However, bilateral defects could have their origin early in the embryogenesis of the neocerebellum. Perinatal insults appear to be uncommon causes for cerebellar anomalies.10 In contrast, the molar tooth sign malformation appears to be highly associated with Joubert syndrome and its community of related syndromes (Table 15-17). It is therefore predominantly, if not completely, of genetic cause, of which the basis is beginning to be discovered. Although most cases of isolated hypoplasia of the vermis have been sporadic, there are well-documented examples of X-linked recessive,31–33 autosomal recessive,30,241 autosomal dominant,9 and/or X-linked dominant240 inheritance of isolated CVH, and it is a component of a number of syndromes (Table 15-17). Similarly, a broad range of syndromes, including some trisomies, has been reported with cerebellar hypoplasia (Table 15-17). Although individually rare, biochemical genetic diseases are an important consideration in this group63,238 and, notwithstanding the issue of hypoplasia versus atrophy, congenital disorders of glycosylation are of paramount concern. The majority of patients with simple cerebellar hypoplasia who come to autopsy show absence of the cerebellar granular layer, and the abnormality is not always apparent on neuroimaging. The brain is often smaller than normal but with normal architecture. This lesion can be induced by a number of agents, including cytotoxic drugs, radiation, and viral infections, and several animals provide a genetic model.59,238,242 Sibling recurrences are well established in humans, and some variation in clinical presentation raises the possibility of genetic heterogeneity.59 The experimental models show a remarkable regenerative power of the external granular layer, and repeated teratogen exposures are required to produce absence of the granular layer. Granule cell aplasia is a component of Minamata disease.243 Anoxia is more likely to damage Purkinje cells than the granule cells.59 Viruses may act through different mechanisms and produce a different spectrum of anomalies. For example, parvoviruses are cytolytic to dividing and migrating cells and may damage the brain beyond the cerebellum, whereas arenaviruses, acting through an immune-mediated pathogenesis, may be more local to the granule cell layer.59 Prognosis, Treatment, and Prevention

As is clear from the previous discussion, the prognosis for patients with cerebellar hypoplasia shows extreme variation from asymptomatic to severely retarded with early death. However, the typical presentation is of early hypotonia with significant motor delay, with onset of typical cerebellar signs of ataxia and fine motor problems as the cerebellum matures. Although there is undoubtedly an ascertainment bias, a significant proportion of children will have severe developmental problems, although most will be more mildly affected or have normal intelligence with specific learning difficulties.9,10 In the absence of diseases or syndromes known to have a progressive course, this is a static clinical condition, and death in severely retarded children is due to expected causes such as pneumonia. In some cases, but certainly not all, the difference between a benign and a severe course is explained by the presence of associated CNS abnormalities. There is some evidence that patients with isolated absence of the anterior vermian lobule have a milder course than those with a more extensive involvement.9 A symmetrically small brain may accompany granular cell hypoplasia and appears to bode a poor prognosis.59 Although most patients with granular cell aplasia are

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severely retarded and many die at a young age, in some families the impairment may be relatively mild. Intrafamilial variation is less marked than is interfamilial. There is no direct treatment for cerebellar malformations. Appropriate supportive measures, especially in the sphere of motor development and education, should be provided. Patients should be carefully examined to rule out known syndromes, and chromosomal and metabolic testing will be indicated in some cases. Parisi and Dobyns8 stress the importance of recognizing the MTS and point out that the pattern continues to be under-recognized by radiologists. The importance lays both in the genetic implications for recurrence and because of the potential to involve other systems, which requires that the patient receive structured ongoing investigation. The evaluation should include initial assessment of the risk of apnea and swallowing difficulties and a search for ocular and renal disease. Even if the latter search is negative, periodic reevaluation of vision and an annual assessment of renal function are indicated. In the presence of hepatic fibrosis there is the longer-term risk from esophageal varices. In the absence of a specific syndrome diagnosis, genetic counseling will often have to deal with inadequate recurrence risk data. A high proportion of case reports with MTS and a significant number of those with granule cell aplasia show familial recurrence, and in the absence of another clear explanation for GCA families with either of these conditions should be informed of the 25% recurrence risk. A challenge is the heterogeneous group of NPCA. Esscher et al.10 were able to find reports of 65 families with autosomal recessive, 18 with autosomal dominant, and 19 with X-linked recessive inheritance of NPCA in the literature, and estimated that 16% of their cases were genetic. However, the heterogeneity limits the value of these data and fails to address the subgroup of prime concern, those with isolated vermis hypoplasia. If one excludes the cases with associated malformations, known syndromes, and chromosome anomalies from their prenatal group, as well as the three with a perinatal cause, and assumes that the 40 patients with unknown cause had none of the above findings, one is left with 51 cases of isolated NPCA. Of these, three had a dominant pattern of inheritance, leaving 48, of whom four had a sibling recurrence. This is equivalent to the 3 of 36 cases with a sibling recurrence reported by Steinlin.9 The average family size for the two populations is not given, but assuming it is two, and that all cases were recessive and ascertained because of a first affected child, and ignoring issues of ascertainment, then one would expect one-fourth, or 21, affected siblings, whereas seven were observed. This would give an estimate of overall recurrence of 1 in 12. The Oxford Medical Database suggests a recurrence risk of one in eight, but the source for the estimate is not provided. Clearly there is need of further study in this area using optimal imaging and clinicopathologic correlations. Standard measurement of the cerebellum using midtrimester ultrasound has been developed and successfully used in the prenatal diagnosis of posterior fossa anomalies.39,244 Fetal MRI may add helpful information when an anomaly is suspected; but the difficulty in obtaining a specific diagnosis has been emphasized.8 Even with the history of an affected child with a known malformation, one has to keep in mind the variable expression of the posterior fossa anomaly that has been reported for a number of syndromes (Table 15-17). Furthermore, parents must be made aware that recurrence of NPCA, including cases of granule cell aplasia, can occur in the absence of a detectable malformation. References (Cerebellar Abnormalities) 1. Patel S, Barkovich AJ: Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol 23:1074, 2002.

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Brain 149. L’Hermitte MMJ, de Ajuriaguerra J, Trotot RP: Oxycephalie avec age´ne´sie de la commissure calleuse et du vermis inferieur. Rev Neurol 76:146, 1944. 150. Kerner B, Graham Jr JJ, Golden JA, et al.: Familial lissencephaly with cleft palate and severe cerebellar hypoplasia. Am J Med Genet 87:440, 1999. 151. Chen J, Yang SS, Gonzalez E, et al.: Short rib-polydactyly syndrome, Majewski type. Am J Med Genet 7:215, 1980. 152. Garcı´a-Alix A, Blanco D, Caban˜as F, et al.: Early neurological manifestations and brain anomalies in Marden-Walker syndrome. Am J Med Genet 44:41, 1992. 153. Williams TE, Buchhalter JR, Sussman MD: Cerebellar dysplasia and unilateral cataract in Marinesco-Sjogren syndrome. Pediatr Neurol 14:158, 1996. 154. Summers DA, Cooper HA, Butler MG: Marshall-Smith syndrome: case report of a newborn male and review of the literature. Clin Dysmorphol 8:207, 1999. 155. Fraser FC, Lytwyn A: Spectrum of anomalies in the Meckel syndrome, or ‘‘Maybe there is a malformation syndrome with at least a constant anomaly.’’ Am J Med Genet 9:67, 1981. 156. Me´garbane´ A, Ruchoux MM, Loeys B, et al.: Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104:221, 2001. 157. Stoll C, Talon P, Alembik Y, et al.: Hypoplasie ce´re´belleuse conge´nitale avec le´sions osseuses. Ann Pediatr 33:417, 1986. 158. Paine RS: Evaluation of familial biochemically determined mental retardation in children, with special reference to aminoaciduria. N Engl J Med 262:658, 1960. 159. Slee J, Lam G, Walpole I: Syndrome of microcephaly, microphthalmia, cataracts, and intracranial calcification. Am J Med Genet 84:330, 1999. 160. Horn D, Mu¨ller D, Thiele H, et al.: Extreme microcephaly, severe growth and mental retardation, flexion contractures, and ichthyotic skin in two brothers: a new syndrome or mild form of Neu-Laxova syndrome? Clin Dysmorphol 6:323, 1997. 161. Harbord MG, Finn JP, Hall-Craggs MA, et al.: Moebius’ syndrome with unilateral cerebellar hypoplasia. J Med Genet 26:579, 1989. 162. Mubashir MA, Sabry MA, Farah S, et al.: New syndromic entity of situs inversus totalis. Clin Dysmorphol 8:23, 1999. 163. Muller F-M, Barth GM, Menger H, et al.: Cerebral malformation, seizures, hypertrichosis, distinct face, claw hands, and overlapping fingers in sibs of both sexes. Am J Med Genet 47:698, 1993. 164. Zaglul HF, Odita JC: Multiple herniae: a defect in the celomic mesoderm? Am J Med Genet 57:537, 1995. 165. Spearritt DJ, Tannenberg AEG, Payton DJ: Lethal multiple pterygium syndrome: report of a case with neurological anomalies. Am J Med Genet 47:45, 1993. 166. Zervos A, Hunt KE, Tong HQ, et al.: Clinical, genetic and histopathological findings in two siblings with muscle-eye-brain disease. Eur J Ophthalmol 12:253, 2002. 167. Saunier S, Morin G, Calado J, et al.: Large deletions of the NPH1 region in Cogan syndrome (CS) associated with familial juvenile nephronophthisis (NPH). Am J Hum Genet 61:A346, 1997. 168. Hoveyda N, Shield JPH, Garrett C, et al.: Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 36:700, 1999. 169. Shiihara T, Kato M, Kimura T, et al.: Microcephaly, cerebellar atrophy, and focal segmental glomerulosclerosis in two brothers: a possible mild form of Galloway-Mowat syndrome. J Child Neurol 18:147, 2003. 170. Tolmie JL, Mortimer G, Doyle D, et al.: The Neu-Laxova syndrome in female sibs: clinical and pathological features with prenatal diagnosis in the second sib. Am J Med Genet 27:175, 1987. 171. Barth PG, Uylings HBM, Stam FC: Interhemispherical neuroepithelial (glio-ependymal) cysts, associated with agenesis of the corpus callosum and neocortical maldevelopment. Child Brain 11:312, 1984. 172. Tuysuz B, Zeybek C, Zorer G, et al.: Patient with the mesomelic dysplasia, Nievergelt syndrome, and cerebellovermian agenesis and cataracts. Am J Med Genet 109:206, 2002.

675 173. Dobyns WB: Agenesis of the corpus callosum and gyral malformations are frequent manifestations of non-ketotic hyperglycinemia. Neurology 39:817, 1989. 174. Whitsel EA, Castillo M, D’Cruz O: Cerebellar vermis and midbrain dysgenesis in oculomotor apraxia: MR findings. Am J Neuroradiol 16:831, 1995. 175. Hunter AGW, Jurenka S, Thompson D, et al.: Absence of cerebellar granular layer, mental retardation, tapetoretinal degeneration and progressive glomerulopathy: an oculo-renal-cerebellar syndrome. Am J Med Genet 11:383, 1982. 176. Young ID, McKeever PA, Squier MV, et al.: Lethal olivopontoneocerebellar hypoplasia with dysmorphic features in sibs. J Med Genet 29:733, 1992. 177. Wang P-J, Maeda Y, Izumi T, et al.: An association of subtotal cerebellar agenesis with organoid nevus—a possible new variety of neurocutaneous syndrome. Brain Dev 5:503, 1983. 178. Smith RA, Gardner-Medwin D: Orofaciodigital syndrome type III in two sibs. J Med Genet 30:870, 1993. 179. al-Gazali LI, Bakalinova D, Bakir M: Central nervous system malformations, dense bones and facial dysmorphism: a new autosomal recessive syndrome. Clin Dysmorphol 7:123, 1998. 180. Lehman RAN, Stears JC, Wesenberg RL, et al.: Familial osteosclerosis with abnormalities of the nervous system and meninges. J Pediatr 90:49, 1977. 181. Stratton RF, Bluestone DL: Oto-palatal-digital syndrome type II with Xlinked cerebellar hypoplasia/hydrocephalus. Am J Med Genet 41:169, 1991. 182. Mitchel TN, Free SL, Williamson KA, et al.: Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol 53:658, 2003. 183. Erdl R, Schmidtke K, Jakobeit M, et al.: Pena-Shokeir phenotype with major CNS malformations: clinicopathological report of two siblings. Clin Genet 36:127, 1989. 184. Valmaggia C, Gottlab I: Periodic alternating nystagmus in two children with similar, unusual phenotype. Pediatr Neurol 23:432, 2000. 185. Dobyns WB, Guerrini R, Czapansky-Beilman DK, et al.: Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental retardation syndrome. Neurology 49:1042, 1997. 186. Gottschalk ME, Coker SB, Fox LA: Neurologic anomalies of Perrault syndrome. Am J Med Genet 65:274, 1996. 187. Pfeiffer RA, Stoss H, Voight HJ, et al.: Absence of fibula and ulna with oligodactyly, contractures, right-angle bowing of femora, abnormal facial morphology, cleft lip/palate and brain malformation in two sibs: a possibly new lethal syndrome. Am J Med Genet 29:901, 1988. 188. Orrico A, Galli L, Zappella M, et al.: Possible case of Pitt-Hopkins syndrome in sibs. Am J Med Genet 103:157, 2001. 189. Bonnemann CG, Meinecke P: Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 63:428, 1996. 190. Llewellyn DH, Smyth SJ, Elder GH, et al.: Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene. Hum Genet 89:97, 1992. 191. Nova HR: Familial communicating hydrocephalus, posterior cerebellar agenesis, mega cisterna magna, and port wine nevi. J Neurosurg 51:862, 1979. 192. Knoblauch H, Tennstedt C, Brueck W, et al.: Two brothers with findings resembling congenital intrauterine infection—like syndrome (pseudo-TORCH syndrome). Am J Med Genet 120A:261, 2003. 193. Towik A, Torp S, Kase BF, et al.: Infantile Refsum’s disease: a generalized peroxisomal disorder. Case report with postmortem examination. J Neurol Sci 85:39, 1988. 194. Pfeiffer RA, Palm D, Junemann G, et al.: Nosology of congenital nonprogressive cerebellar ataxia. Neuropediatrics 5:91, 1974. 195. Mainzer F, Saldino RM, Ozonoff MB, et al.: Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 49:556, 1970.

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196. Seller MJ, Pal K, Moscoso G, et al.: Cerebellar hypoplasia, facial dysmorphism and internal abnormalities: a new recessive syndrome? Clin Dysmorphol 7:41, 1998. 197. Siber M: X-linked recessive microencephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet 26:453, 1984. 198. Debrus S, Sauer U, Gilgenkrantz S, et al.: Autosomal recessive lateralization and midline defects: blastogenesis recessive 1. Am J Med Genet 68:401, 1997. 199. Slee J, Knowles S, Goldblatt J: Siblings with a syndrome of hydrocephalus with patent aqueduct, growth retardation and associated anomalies. Clin Dysmorphol 8:11, 1999. 200. Kelley RI: RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am J Hum Genet 63:322, 1998. 201. Natacci F, Corrado L, Pierri M, et al.: Patient with large 17p11.2 deletion presenting with Smith-Magenis syndrome and Joubert syndrome phenotype. Am J Med Genet 95:467, 2000. 202. Ciske DJ, Waggoner DJ, Dowton SB: Unique cardiac and cerebral anomalies with chondrodysplasia punctata. Am J Med Genet 75:59, 1998. 203. Stoll C, Huber C, Alembik Y, et al.: Dandy-Walker variant malformation, spastic paraplegia, and mental retardation in two sibs. Am J Med Genet 37:124, 1990. 204. Barkovich AJ, Peacock W: Sublobar dysplasia: a new malformation of cortical development. Neurology 50:1383, 1998. 205. Schorderet DF, Addor M-C, Maeder Ph, et al.: Two brothers with atypical syndactylies, cerebellar atrophy and severe mental retardation. Genet Couns 13:441, 2002. 206. Tsukahara M, Uchida M, Shinohara T: Teebi hypertelorism syndrome: further observations. Am J Med Genet 59:59, 1995. 207. van der Harten HJ, Brons JTJ, Dijkstra PF, et al.: Some variants of lethal neonatal short-limbed platyspondylic dysplasia: a radiological, ultrasonographic, neuropathological, and histopathological study of 22 cases. Clin Dysmorphol 2:1, 1993. 208. MacDonald MR, Schaefer GB, Olney AH, et al.: Hypoplasia of the cerebellar vermis and corpus callosum in thrombocytopenia with absent radius syndrome on MRI studies. Am J Med Genet 50:46, 1994. 209. Khabbaze Y, Karayalcin G, Paley C, et al.: Thrombocytopenia absent corpus callosum syndrome: third case of a distinct clinical entity. J Pediatr Hematol Oncol 23:469, 2001. 210. Cutler EA, Bass J, Romshe CA, et al.: A familial thyrocerebral-renal syndrome: a newly recognized disorder. Birth Defects Orig Artic Ser XIV(6B):265, 1978. 211. Silengo M, Pietragalla A, Jarre L: Trichorrhexis nodosa and lip pits in autosomal dominant ectodermal dysplasia—central nervous system malformation syndrome. Am J Med Genet 71:226, 1997. 212. Troost D, van Rossum A, Pires JV, et al.: Cerebral calcifications and cerebellar hypoplasia in two children: clinical, radiologic and neuropathological studies-a separate neurodevelopmental entity. Neuropediatrics 15:102, 1984. 213. Zampino G, Colosimo C, Balducci F, et al.: Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome. Clin Genet 45:140, 1994. 214. Van Staey M, De Bie S, Craen M, et al.: Craniofacial anomalies, hearing deficit and psychomotor retardation: components in still another undescribed syndrome? Zaragoza, 1st European Meeting of Dysmorphology, 1990, p 85. 215. Doss BJ, Jolly S, Qureshi F, et al.: Neuropathologic findings in a case of OFDS type VI (Va´radi syndrome). Am J Med Genet 77:38, 1998. 216. Eliez S, Schmitt JE, White CD, et al.: A quantitative MRI study of posterior fossa development in velocardiofacial syndrome. Biol Psychiatry 49:540, 2001. 217. Vici CD, Sabetta G, Gambarara M, et al.: Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hyperpigmentation in two brothers. Am J Med Genet 29:1, 1988. 218. Zampino G, Conti G, Balducci F, et al.: Severe form of FreemanSheldon syndrome associated with brain anomalies and hearing loss. Am J Med Genet 62:293, 1996.

219. Winter RM, Shortland D, Collins AL, et al.: Extreme intrauterine growth retardation, hydrocephalus, and aged facial appearance: a previously unrecognized autosomal recessive disorder? Clin Dysmorphol 5:313, 1996. 220. Winter RM, Wigglesworth JS: Unusual association of cerebral and renal abnormalities. Clin Dysmorphol 2:71, 1993. 221. Illarioshkin SN, Tanaka H, Markova ED, et al.: X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. Ann Neurol 40:75, 1996. 222. Mathias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. 223. Christianson AL, Stevenson RE, van der Meyden CH, et al.: X-linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia and cerebellar atrophy in a large South African kindred is localized to Xq24-q27. J Med Genet 36:759, 1999. 224. Yano S, Oda K, Watanabe Y, et al.: Two sib cases of Leber congenital amaurosis with cerebellar vermis hypoplasia and multiple systemic anomalies. Am J Med Genet 78:429, 1998. 225. Young ID, Trounce JQ, Levene MI, et al.: Agenesis of the corpus callosum and macrocephaly in siblings. Clin Genet 28:225, 1985. 226. Ades LC, Morris LL, Richardson M, et al.: Congenital heart malformation in Yunis-Varon syndrome. J Med Genet 30:788, 1993. 227. Flannery DB, Hudson JG: A survey of Joubert syndrome. Proc Greenwood Genet Center 14:130, 1995. 228. Wingate RJT: The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11:82, 2001. 229. Wang VY, Zoghbi HY: Genetic regulation of cerebellar development. Nat Rev Neurosci 2:484, 2001. 230. Wassef M, Joyner AL: Early mesencephalon/metencephalon patterning and development of the cerebellum. Perspect Dev Neurobiol 5:3, 1997. 231. Gavalas A, Davenne M, Lumsden A, et al.: Role of Hoxa-2 in axon pathfinding and rostral hindbrain patterning. Development 124:3693, 1997. 232. Wassef M, Bally-Cuif L, Alvarado-Mallart RM: Regional specification during cerebellar development. Perspect Dev Neurobiol 1:127, 1993. 233. Armstrong CL, Hawkes R: Pattern formation in the cerebellar cortex. Biochem Cell Biol 78:551, 2000. 234. Salinas PC, Fletcher C, Copeland, et al.: Maintenance of Wnt3 expression in Purkinje cells of the mouse cerebellum depends upon interaction with granule cells. Development 120:1277, 1994. 235. Goldowitz D, Hamre KM, Pryzborski SA, et al.: Granule cells and cerebellar boundaries: analysis of Unc5h3 mutant chimeras. J Neurosci 20:4129, 2000. 236. Larsell O: The development of the cerebellum in man in relation to its comparative anatomy. J Comp Neurol 87:85, 1947. 237. Morgan JI, Smeyne RJ: Transgenic approaches to cerebellar development. Perspect Dev Neurobiol 5:33, 1997. 238. Samat HB, Alcala H: Human cerebellar hypoplasia: a syndrome of diverse causes. Arch Neurol 37:300, 1980. 239. Friede RL: Developmental Neuropathology. Springer Verlag, New York, 1975, p 334. 240. Fenichel GM, Phillips JA: Familial aplasia of the cerebellar vermis. Possible X-linked dominant inheritance. Arch Neurol 46:582, 1989. 241. De Haene A: Age´ne´sie partial du vermis du cervelet a` caracte`re familial. Acta Neurol Psychiatry Belg 55:662, 1955. 242. Parrish CR: Pathogenesis of feline panleukopenia virus and canine parvovirus. Baillieres Clin Haematol 8:57, 1995. 243. Nonaka I: Electron microscopy study on granule cells of the cerebellum in experimental congenital Minamata disease. J Electron Microsc 17:86, 1968. 244. Smith PA, Johansson D, Tzannatos C, et al.: Prenatal measurement of the fetal cerebellum and cisterna cerebellomedullaris by ultrasound. Prenat Diagn 6:133, 1986. 245. Demaerel P, Morel C, Lagae L, et al.: Partial rhombencephalosynapsis. AJNR Am J Neuroradial 25:29, 2004.

Brain

15.13 Cystic Malformations 15.13.1 Dandy-Walker and Other Fourth Ventricular Roof Malformations Definitions

The Dandy-Walker malformation (DW) consists of the triad 1) hypoplasia/absence and upward rotation of the vermis; 2) an enlarged posterior fossa with upward displacement of the falx, lateral sinuses, and torcular; and 3) cystic dilation of the fourth ventricle that is in communication with a thin-walled retrocerebellar cyst formed by the roof of the fourth ventricle (Fig.1563). There is wide variation as to specific findings, and cases are seen with mild hypoplasia and little or no upward rotation of the vermis and/or with smaller cysts and a normal-sized posterior fossa.1 Some of these cases probably represent isolated vermis hypoplasia, and others may be mild changes of the DW type.1,2 Hypoplasia of the cerebellar hemispheres is a common accompaniment and to a degree reflects the severity of the vermis hypoplasia.2 The term Dandy-Walker variant has been used for such cases, as well as in isolated atresia of the cerebellar foramina, enlarged cisterna magna, and for cysts that do not communicate with the fourth ventricle. This author agrees that Dandy-Walker variant should not be used as it is imprecise and implies a pathogenetic relationship that is unproven.1,3 As defined by Tortori-Donati et al.,4 mega cisterna magna (MCM) is a clinically silent evagination of the tela choroidea, which remains in contact with the fourth ventricle and the subarachnoid space through normal foramina. Thus, there is no hydrocephalus and any clinical signs would be due to unrelated pathology. There may be expansion into a tentorial defect, and the posterior fossa is often increased in width, the torcular may be upwardly displaced, as in DW, and there may be mild scalloping of the inner occipital table. There is no structural abnormality of the cerebellum. This definition is narrower than that used by Fig. 15-63. Dorsal view of cerebellum showing dilated fourth ventricle, absence of vermis, and thin roof of cyst reflected back.

677

Niesen, who allows that some cases would have hydrocephalus3 and that which Barkovich et al.2 have called type B DW. The cisterna magna may also appear prominent secondary to degenerative changes in the cerebellum. A Blake’s pouch cyst (persistent Blake’s pouch) is an evagination of the tela choroidea into the cisterna magna that may appear similar to MCM, but it is due to absent or poor communication of the fourth ventricle and the subarachnoid spaces because of failure of adequate development of the foramina.4,5 This leads to tetraventricular hydrocephalus, an increased width of the vallecula, and separation of the cerebellar hemispheres. Diagnosis

Early reports stressed the central importance of the signs and symptoms of hydrocephalus to the diagnosis of DW malformation, so much so that it has been considered by many to be an integral part of the malformation.1,6 However, hydrocephalus is not always present in the DW malformation, and it is best considered a frequent secondary complication. Parisi and Dobyns1 propose that an ascertainment bias in neurosurgical series has led to an overestimate of the frequency of concurrent hydrocephalus, and they have noted a significantly lower rate among their patients. The size of the cerebellar cyst does not correlate with the presence, absence, or severity of hydrocephalus. Hirsch et al.7 provided evidence that hydrocephalus is not generally present at birth, but usually develops within the first 3 postnatal months. The authors were able to demonstrate a connection between the cyst and the subarachnoid space, which they hypothesize is often adequate to prevent hydrocephalus in utero but becomes compromised after birth. Most patients ascertained postnatally are diagnosed within the first year of life, but all larger series contain patients diagnosed later, some well into adulthood.6–8 Macrocrania, which often precedes the onset of hydrocephalus and may be partly due to a prominent occiput, is a common presenting sign. The patients treated from 1959 to 1984 and reported by Osenbach and Menezes are typical.9 Of the 37 patients, 70% presented in their first year, 80% by the age 3 years, and four (11%) as adults. Macrocrania with evidence of increased intracranial pressure is the most common presenting sign. The presenting complaints were increasing head size (77%), inability to track visually (younger) or diplopia (older) (30%), headache (24%), emesis (22%), lethargy (8%), and seizures (8%). On neurologic examination, 100% had macrocrania, 91% hydrocephalus, 46% ocular signs, 41% spasticity, 38% developmental delay, 22% ataxia and/or gait disturbance, 19% cranial nerve palsy, and 8% quadriparesis. Ocular signs included upward and lateral gaze palsy, nystagmus, and strabismus. Widened cranial sutures, bulging fontanel, apnea, and hypotonia provide evidence of increased intracranial pressure in young infants, and parietal foramina may also be seen with DW-associated hydrocephalus.10 Although signs of true cerebellar dysfunction and cranial nerve dysfunction are less frequent,7 they may appear if increased intracranial pressure is persistent, notably following ventricular taps or failed shunts.7,8 The patients reported by Golden et al.11 had a significantly older age at presentation. Freeman and Jones12described a man with DW who was diagnosed at age 75 years because of the sudden onset of unilateral sensorineural deafness and periods of vertigo. Three years later he developed cognitive impairment, ataxia, and a gait disturbance. By the definition used here, MCM is a benign and asymptomatic condition, and clinical symptoms should raise the possibility of an associated supratentorial lesion or an associated

678

Neuromuscular Systems

cerebellar pathology or another posterior fossa malformation. Cases of MCM reported with hydrocephalus may represent cases of Blake’s pouch cyst.4 The latter usually presents at a young age with signs and symptoms of increased intracranial pressure and tetraventricular hydrocephalus. In some cases, it appears that drainage of CSF through the foramina of Luschka is adequate, at least initially, and that onset of hydrocephalus may be delayed. This may account for the presentation of two women in their early sixties with headache and recurrent syncopal episodes associated with Blake’s pouch cyst.5 During the initial months of life, transillumination of the posterior fossa may aid diagnosis of a posterior fossa cyst. Hailer et al.13 suggest that the triangular configuration of the fourth ventricle with the apex formed by the torcular, the sides by the lateral attachments of the tentorium, and the base representing the inferior margin of the posterior fossa can help distinguished DW from other posterior fossa cysts, which are oval with more rounded and lobulated borders. Radiographs are generally nonspecific but may demonstrate a higher than normal indent of the transverse sinuses and a thinned occipital bulge (Fig. 15-64). Although CT, MRI and, to a lesser extent, radionucleotide scanning (Figs. 15-65, 15-66, 15-67) have replaced ventriculography, pneumoencephalography, and arteriography in the elucidation of posterior fossa cystic anomalies, challenges continue with respect to the specific diagnosis of these anomalies. The neuroimaging study should include an assessment of posterior fossa size; the presence, location, and size of the falx cerebelli; and whether the cerebellar vermis and hemispheres are aplastic, hypoplastic, compressed, rotated, or atrophic.2 Errors in the diagnosis of DW can be reduced by obtaining good sagittal and axial views at the level of the fourth ventricle. The inferior vermis is most affected in cases with partial agenesis, and the slit between the dysplastic cerebellar hemispheres may be very narrow and parallel to the sagittal plane. Thus, it may appear relatively normal on sagittal CT cuts. This

Fig. 15-64. Lateral skull radiograph in a case of Dandy-Walker cyst showing higher than normal indent of the transverse sinuses and a thinned occipital bulge.

Fig. 15-65. Axial CT scan showing absence of the cerebellum and a posterior fossa cyst.

appearance can occur on MRI with vermis hypoplasia and has been referred to as a pseudo-fourth ventricle.2 This error can be avoided with the use of axial slices, and contrast enhancement can demonstrate the choroid plexus where the cyst wall joins the cerebellar hemispheres. The use of the term Dandy-Walker variant for patients who have a narrow slit between the ventricles and an otherwise typical DW is inappropriate.2 MRI is probably the Fig. 15-66. Radionuclide scan illustrating connection between the ventricular system and posterior fossa cyst.

Brain

Fig. 15-67. Sagittal MRI scan showing Dandy-Walker cyst. Continuity with the fourth ventricle is apparent, and cerebellar remnants are visible. Aqueduct is patent. (Courtesy of Drs. Z. Grahovac and S. Grahovac, Department of Radiology, Ottawa Hospital, Ottawa.)

technique of choice to show the status of the vermis.14 However, the presence or absence of upward rotation of the cerebellar vermis can confound the assessment of vermis aplasia/hypoplasia in the axial plane, and sagittal views must be included. Barkovich et al.2 divided their patients with DW into type A, in which the vermis was absent on axial views at the level of the fourth ventricle, either because of upward rotation and/or hypoplasia/aplasia of the vermis as studied in the sagittal plane, and type B, in which the vermis was present on the axial views and essentially normal on sagittal views. The authors state that the latter group would normally be considered to have MCM, but the definition differs from that used here, and the two groups were not distinguishable on clinical grounds. In almost all reported series, the majority of patients with DW have additional CNS abnormalities that may have a major bearing on prognosis and should therefore be carefully sought.7,8 There is likely to be some bias toward ascertainment of more severe cases, and the rates of associated anomalies are lower among patients who have done well.6,11 With the exception of absent corpus callosum, which they think may be even more common than previously thought, Parisi and Dobyns1 have observed a lower rate of associated CNS anomalies. They consider such anomalies to be more common in isolated vermis hypoplasia, cases of which could be included in some series of DW. Klein et al.15 used detailed prenatal and postnatal MRI to study 26 patients with classic DW. They were able to subdivide their patients into 21 in whom the cerebellum was hypoplastic but demonstrated normal numbers of fissures and lobules and five in whom the vermis was very abnormal and hypoplastic and had zero-to-one fissures. None of the former, but all of the latter, group had an associated CNS abnormality. Extracranial malformations are also common; facial angiomas and cardiovascular and digital anomalies have received particular mention as associated defects. Improved technology and clinical awareness of the importance of the posterior fossa have led to more frequent prenatal sonographic recognition of these malformations. However, accurate diagnosis,

679

especially of cases that do not meet the criteria of classic DW, remains a challenge. For example, in one recent series only 43% of the anomalies in this group were confirmed at autopsy,16 and both false-positive and false-negative cases occur. Some smaller series have reported high levels of diagnostic accuracy,17,18 and the diagnosis of classic DW, with increased size of the posterior fossa, widely splayed hemispheres, and a large vermian defect, can be made with some confidence,19 even with first trimester transvaginal ultrasound.20 However, there are a number of potential pitfalls in the prenatal diagnosis of DW, including the fact that the vermis is structurally incomplete until about 20 weeks gestation,19,21 and that there are the same issues surrounding errors in the visualization of the vermis on axial view because of its potential upward rotation as applies postnatally. In addition, the use of an angled semi-coronal plane can give the false impression of an enlarged cisterna magna and hypoplastic vermis.19,21 Other potential confounding signs can include benign enlargement of the fourth ventricle at 14 to 16 weeks gestation,22 and an entrapped fourth ventricle, which is dilated and herniated into the upper cervical spine.23 Bernard et al.21 provide details as to the appropriate prenatal sonographic evaluation of the transverse cerebellar diameter, the cisterna magna, the vermis, and fourth ventricle. Klein et al.15 have used MRI successfully to provide detailed prenatal information in seven cases of DW, but unfortunately the gestational age at which the studies were performed was not provided. Most larger series of prenatally diagnosed patients have divided cases into DW and DW variant, but the groups do not appear to differ significantly with respect to the frequency of associated CNS and non-CNS malformations or in the rate of abnormal karyotypes. Chang et al.24 reported that 75% of 65 fetuses diagnosed with DW/DWV had an associated malformation and that 45% had an abnormal karyotype, with the latter being somewhat more common in the variant group. Ecker et al.25 reported 50 fetuses with classic DW and 49 with variant DW, which they defined as having a normal-sized posterior fossa and variable hypoplasia of the vermis. The two groups had rates of 86% and 85% of associated anomalies, respectively, similar proportions of CNS to non-CNS anomalies, and similar rates of ventriculomegaly. In this series chromosome abnormalities were slightly more common in the DW (46%) than the variant group (36%). It is likely that these figures overestimate the true frequency of chromosome anomalies because not all cases are karyotyped and there is likely a bias toward testing those with evidence of other anomalies. Consistent with this suggestion is the fact that only 1 of the 21 fetuses with an abnormal karyotype in the series of Ecker et al.25 did not have an additional non-posterior-fossa malformation. That said, the rate of associated malformations and chromosome anomalies in prenatal series appears to be higher than among cases ascertained postnatally, which likely represents a group of fetuses with a high prenatal and perinatal mortality. DW has been noted to occur in a number of syndromes (Table 15-18). In some cases only a single case of DW in association with a syndrome has been included, because, although the concurrence may be a coincidence, underreporting is also possible. In a number of syndromes the cerebellar findings have been noted to vary between siblings, and some syndromes in which the authors have referred to DW variant are included. The pathologic and neuroimaging findings in Joubert syndrome are different from those in DW and are considered elsewhere (Section 15.12). Although Goldenhar syndrome has been tabulated, it should be noted that the initial cases were of agenesis of the vermis with a cerebellocele; one of the cases could be considered

Table 15-18. Syndromes with Dandy-Walker malformation Syndrome

Prominent Features

Causation Gene/Locus

3-CH3-glutoconic aciduria type III26

Postnatal growth and developmental failure, metabolic acidosis, seizures, truncal hypotonia, limb spasticity, basal ganglia defects, deafness, optic atrophy, increased 3-methylglutaconic and 3-methylglutaric aciduria

AR (258501) 19q13.2-q13.3

Aase-Smith27

Prominent forehead, flat nose, cleft palate, joint contractures, tight skin over long fingers, knuckles absent, dermal ridges absent, camptodactyly

AD (147800)

Acromesomelic frontonasal dysplasia28

Epibulbar dermoid, cleft nose, notched alae, midline cleft lip/palate, renal anomalies, pre- and post-axial polydactyly, delayed development, CNS includes absent corpus callosum, Dandy-Walker, hydrocephalus, encephalocele

Unknown

Aicardi29

Corpus callosum agenesis, retinal lacunae, vertebral anomalies, variety of brain malformations including heterotopias, myoclonic seizures

XLD (304050) male lethal

Asphyxiating thoracic dystrophy30

Normal face, small chest, rhizomelia, variable post-axial polydactyly, trident pelvis, short ribs, progressive peri-glomerular fibrosis and/or hepatic cirrhosis. Case report with Dandy-Walker malformation.

AR (208500) 12p11-12p12?

Atkin: oculo-muscular31

Large fontanels, microphthalmia, clouded corneas, abnormal helices, cleft lip, short neck with excess skin, bilateral typical ectrodactyly of hands, hypospadias

Uncertain

Beemer-Langer: short ribbed polydactyly32

Lethal short-rib dwarfism; hydrops, flat face, epicanthus, midline cleft lip, stenotic ear canals, short neck, nuchal edema, omphalocele, small penis, fused labioscrotal folds, minimal bowing femora and marked of radius and ulna. Case reported with holoprosencephaly and Dandy-Walker cyst.

AR (269860)

Blepharophimosis-joint contractures-Dandy Walker cyst33

Short stature, low-set ears, preauricular pits, ptosis, blepharophimosis, epicanthus inversus, multiple joint contractures, kyphoscoliosis, CNS includes absence of the corpus callosum, ventriculomegaly, Dandy-Walker cyst

Unknown

Bowen-Conradi34

IUGR, microdolichocephaly, micrognathia, prominent nose, joint limitation, rocker-bottom feet, lethal

AR (211180)

Buttiens: MRbrachytelephalangy35

Severe to profound mental retardation, hydrocephalus, bushy eyebrows, optic atrophy, macular degeneration, nystagmus, broad nose, short philtrum, spasticity, seizures

AR

Cerebro-oculo-muscular (Walker-Warburg)36

Type II lissencephaly, hypotonia, seizures, posterior cephalocele, abnormalities of retina and anterior chamber, congenital muscular dystrophy

AR (236670)

Cerebro-oculo-nasal37

Macrobrachycephaly, craniosynostosis, anophthalmia, nares separated by a midline groove, nasal skin appendages, low-set ears, single maxillary central incisor; reported with agenesis of the corpus callosum, hypoplastic vermis; other CNS not well documented but may include hydrocephalus, frontal encephalocele, holoprosencephaly, Dandy-Walker cyst

Unknown

Chitayat: macrocephalyfacio-skeletal38

Dolicomacrocephaly, hyperextensible joints, hypertelorism, eccentric pupils, mild to moderate developmental delay, pectus carinatum, kyphoscoliosis, blue sclera

Uncertain

Chondrodysplasia punctatamultiple anomalies39

Aplasia cutis on scalp, large fontanel, hypertelorism, high nasal bridge, clouded corneas, cleft lip/palate, brachydactyly, small nails, punctate calcification at multiple joints, butterfly vertebrae with coronal clefts

Unknown

Chromosome aberrations40–42

Various duplications: 5p, 8p, 8q, 17q; trisomies 9, 13, 18; 49,XXXXX, triploidy; deletion (2)(q13q21), (3)(q25.1-q25.33), (6)(p24-pter), (8)(q21-q22)

Chromosome imbalance

Cobblestone lissencephalynormal eyes and brain43

Moderate to severe developmental delay, mild axial hypotonia and lower limb spasticity, Dandy-Walker, ventriculomegaly, brain stem hypoplasia, normal eye examination including ERG, normal CK

AR

Coffin-Siris44

Postnatal growth failure, lax joints, coarse facies, sparse hair, hypoplastic or absent nails especially of 5th digits, hypertrichosis of body, severe mental retardation

Uncertain (228920) (135900)

Congenital disorders of glycosylation45,46

Dysmorphic signs can include abnormal fat distribution and inverted nipples; various subtypes with postnatal growth failure, psychomotor delay, retinopathy, renal cysts/ tubulopathy; cerebellar anomalies most likely in type I but Dandy-Walker also reported in IId

AR (212065) CDIa PMM2, 14q21 CDIb PMI, 16p13 CDIId, B4GALT1, 9p13

Cranio-cerebello-cardiac (3C)47

Postnatal growth and developmental delay, low-set ears, hypertelorism, downslanting palpebrae, ptosis, prominent nasal bridge, iris or retinal colobomas, cardiac defects, brachydactyly, adducted thumbs, partial syndactyly, gut loss of Ig reported

AR (220210)

Cryptophthalmos48

Frequent eye anomalies, hair on lateral forehead, cupped ears, depressed nasal bridge, cutaneous syndactyly, abnormal external genitalia, laryngeal anomalies, renal agenesis

AR (219000)

Cutic laxa-congenital heart49

Overlap with Cranio-cerebello-cardiac,47 marked cutis laxa, umbilical hernia, hypertrophy of labia majora, atrial septal defect, subaortic ventricular septal defect, absent 12th ribs, poor modeling of long bones, dislocated hips

Unknown

(continued)

680

Table 15-18. Syndromes with Dandy-Walker malformation (continued) Syndrome

Prominent Features

Causation Gene/Locus

Cutis laxaimmunodeficiency50

Macrocrania, normal development, hyperextensible skin hanging in folds, abnormal major artery branching, fluctuating Ig levels and leucopenia

Unknown

Cytomegalovirus51

IUGR, microcephaly, cerebral calcification, deafness, choreoretinitis, mental retardation, thrombocytopenic purpura

Prenatal infection

Dandy-Walker cystcardiovascular anomalies52

Appears to be a probable heterogeneous, greater than chance, association of congenital heart anomalies in individuals with DW malformation

Unknown

Dandy-Walker cyst-isolated53,131

Three sibs with DW malformation; one had glaucoma

Variable, some heterozygous deletion ZIC1/ZIC4, 3q24-q25.33

Dandy-Walker cyst-isolatedX-linked recessive54,55

Family compatible with X-linked uncomplicated DW malformation; another with socalled variant DW

XLR (304340)

Dandy-Walker cystosteopetrosis56

Severe lethal osteopetrosis with bone marrow replacement, macrodolichocephaly, hypertelorism, abnormal eye movements, abnormal metaphyseal modeling, absent corpus callosum

AR

Dandy-Walker cystpolyneuropathy57

Two unrelated males, normal development, chronic polyneuropathy, one with no family history, other had dominant family history of mild polyneuropathy; chance associations?

Unknown

De Lange58

IUGR, postnatal growth failure, microbrachycephaly, synophrys, hirsutism, midline beak upper lip, small anteverted nose, short neck, micromelia, upper limb absence malformations, mental retardation

Possible AD new mutations (122370)

Diabetes, maternal59

Large for dates; postnatal hypoglycemia; increased incidence of cardiac, neural tube, caudal regression, upper limb, and oral anomalies

Disturbed glucose metabolism

DOOR (includes Eronen syndrome)60

Sensorineural deafness, onychodysplasia, onycholysis, mental retardation, seizures, long halluces and thumbs may have triphalangy, remaining digits absent or hypoplastic distal phalanx, ptosis, short wide nose with broad tip and large nares

AR (220500)

Edwards: microphthalmia61

Microcephaly, Dandy-Walker cyst, cerebellar vermis hypoplasia, choanal atresia, and other defects in a child whose mother and grandmother had Hallerman-Strieff-like face, aniridia cataract (see PAX6)

PAX6

Ellis-Van Creveld62

Brachydactyly, postaxial hexadactyly, hypoplastic nails, disproportionate short stature, extra oral frenula, cardiac defect (one case with DW; possibly coincidence due to incest)

AR (225500)

Frontonasal dysplasia63

Broad forehead, cranium bifidum occulta, wide nose with bifid tip, midline cleft (occasionally lateral) hypertelorism, agenesis of the corpus callosum, craniosynostosis

Most sporadic: some AD, AR (136760, 203000)

Fryns64

Polyhydramnios; coarse face; broad and flat nose; large mouth; clouded corneas; brachytelephalangy; anomalies of diaphragm, gut, kidneys; lethal

AR (229850)

G65

Dysphagia, stridor, hypertelorism, prominent forehead, laryngotracheal cleft, tracheoesophageal fistula, hypospadias developmental delay, more severe in males; cerebellar vermis hypoplasia and DW cyst

AD (145410) 22q11.2 XLR (300000) Xp22

Goldenhar66,67

Variable asymmetric lower face, especially mandible hypoplasia, microtia, preauricular tags and pits, macrostomia, upper vertebral anomalies, epibulbar dermoids, variety of CNS defects in low frequency

Sporadic; occasionally AD (164210), 14q32

Griscelli variant68

Silver-gray hair, immature melanosomes, large pigment clusters in hair, recurrent infections, pancytopenia hepatosplenomegaly, abnormal cellular immunity, low Igs; case with DW and hypergammaglobulinemia

AR (214450)

Guschmann: mesomelic campomelia-polydactyly69

Sharp bends in the short middle segments and postaxial polydactyly of all limbs, mildly bowed femurs, flat acetabulae, short ribs, low-set ears, broad face, hypertelorism, disturbed enchondral ossification

AR

Gustavson: blind-deafspasticity70

Generally lethal in 1st year, severe sensorineural hearing loss, large malformed ears, optic atrophy, restricted movement of the large joints, spasticity, seizures. One of six had DW, another cerebellar hypoplasia

XLR Xq26

Holoprosencephaly-DandyWalker71

Several case reports of holoprosencephaly and concurrent DW cyst; two in association with interstitial del 13q

Unknown del 13q

Hydrolethalus72

Hydrocephalus, polydactyly, cleft lip/palate, micrognathia, tracheobronchial and lung anomalies, heart malformations, absent corpus callosum

AR (236680)

Hypothalamic hamartomagelastic epilepsy-precocious puberty73

Well-established association reported with DW cyst, heterotopias and callosal agenesis

Unknown

(continued)

681

Table 15-18. Syndromes with Dandy-Walker malformation (continued) Syndrome

Prominent Features

Causation Gene/Locus

Isotretinoin

Microtia/anotia, narrow and sloped forehead, U-shaped cleft palate, conotruncal cardiac malformations, microcephaly, hydrocephalus, damage to neural crest cells

Prenatal retinoic acid exposure

Ivemark: asplenia/ polysplenia-situs anomalies75

Polysplenia/asplenia, complex cardiac malformations are usually defects of situs, pulmonary or abdominal situs anomalies; CNS uncommon and includes agenesis of the corpus callosum and DW cyst

Unknown AD/AR (208530) 12q13, 6q21-q23

Joint laxity-microcorneaskin76

Macrocephaly, hypotonia, normal intellect, lax joint with dislocations; soft and elastic skin, thin on palms and soles, wrinkled; blue sclera, myopia, talipes equinovarus, later restriction at elbows

AR?

Jones: craniosynostosis77

Coronal and/or sagittal synostosis

AD

Kallmann

Hypogonadotropic hypogonadism; anosmia with some evidence of increased clefting, diabetes, renal anomalies

Most AR (242000); some AD (147950), KAL2, 8p11.2 XLR (308700), KAL1, Xp22.3

Meckel-Gruber80

Posterior encephalocele connecting to 4th ventricle, cystic dysplastic kidneys, cleft palate, microophthalmia, postaxial polydactyly, genital anomalies

AR (249000) Multiple loci

Menkes disease81

Lethargy, poor temperature regulation seizures; facial pallor, hypotonia, full cheeks, cupid bow upper lip; hair becoming depigmented, thin and brittle with pili torti; vascular tortuosity; progressive deterioration, death

XLR (309400) ATP7A, Xq13.3

Moerman: lethal dysplasia82

Appearance similar to achondrogenesis, cleft palate, dysplastic kidneys, cardiac anomalies, tetramicromelia, spondylocostal dysotosis, agenesis of the corpus callosum

Unknown

Mohr (OFD II)83

Broad nasal tip, hypertelorism, lingual nodules, abnormal oral frenula, pre-axial polydactyly, conductive deafness

AR (252100)

Molybdenum cofactor deficiency84

Neonatal onset seizures, developmental delay, coarse, hirsute, hypertonia, hyperreflexia, develop ectopia lentis and urolithiasis; sulfite and other compounds in urine

AR (252150) MOCS1, 6p21.3 MOCS2, 5q11

Mosaic variegated aneuploidy85

Severe microcephaly, frequent eye and renal malformations, variable but usually significant developmental delay, in vitro mosaic trisomy for different chromosomes, premature chromatid separation, endoduplication, high risk of malignancy

AR (257300) BUB1B, 15q15

Nasopharyngeal teratoma86

Massive macrocephaly, broad and triangular flat face, hypertelorism, nasopharyngeal hairy polyp through cleft palate, diaphragmatic hernia, DW cyst, cavum septum pellucidum and vergi

Unknown

Neurocutaneous melanosis87

Classical and variant forms of cutaneous pigmented nevi and leptomeningeal melanosis with malignant change, intracranial anomalies and cysts, arachnoid villi infiltration in some; reports with DW cyst

Unknown (249400)

Oberklaid-Danks: Opitz C-like88

IUGR, postnatal growth failure and death, prominent metopic suture, hirsute forehead with forehead/glabellar hemangioma, synophrys, exophthalmos, hypertelorism, cleft lip/palate, multiple joint contractures, flexion deformity at wrist, camptodactyly, DW cyst (one case), agenesis of the corpus callosum

AR

Oculocerebral hypopigmentation89

Severe developmental delay, spasticity, generalized hypopigmentation, gingival hyperplasia, opacified and vascularized cornea; some cases with cardiac, renal, and CNS anomalies including DW cyst

AR (257800)

Opitz C-trigonocephaly90

Mental retardation, trigonocephaly, wide alveolar ridges, wide oral frenula, short neck, polydactyly, visceral anomalies. Brain defects include absent corpus callosum, cerebellar vermis agenesis, DW.

AR (211750)

Oral-facial-digital type I91

Midline cleft/notched upper lip, multiple oral frenulas, lobulated tongue with hamartomas, asymmetric brachysyndactyly; CNS includes hydrocephalus, porencephaly, cerebellar vermis hypoplasia, DW cysts, neuronal migration defects, agenesis of the corpus callosum

XLD, male lethal (311200) CXORF5, Xp22.3-p22.2

Oral-facial-digital type III92

Lobulated tongue, supernumerary teeth, postaxial polydactyly, metronome eye movements, cleft palate, choanal atresia, cerebellar hypoplasia. Case with DW cyst.

AR (258850)

Oral-facial-digital type VIIIToriello-Lemire93

Intrahemispheric cyst, ventriculomegaly, apnea, optic nerve coloboma, microglossia, tongue hamartoma, cleft soft palate, postaxial polydactyly of hands and feet

Unknown

Oral-facial-digital type IX94

Mild to severe mental retardation, variable microcephaly, multiple frenula, bifid/lobulated tongue, high/cleft palate, broad/bifid hallux, retinal dysplasia/coloboma

AR (258865)

Oral-facial-digital type Chung95

Hypertelorism, flat nasal bridge, lingual nodule, micrognathia, four-limb postaxial hexadactyly, oromotor dysfunction, DW cyst, hypothalamic hamartoma. Single case

Unknown

74

78,79

(continued)

682

Brain

683

Table 15-18. Syndromes with Dandy-Walker malformation (continued) Syndrome

Prominent Features

Causation Gene/Locus

Oral-facial-digital type Hedara-Innes96

Microcephaly, cleft lip/palate, lobular tongue, thick sublingual frenula, absent thumbs, radioulnar synostosis, Y-shaped metacarpal; reported as expanded Juberg-Hayward phenotype (OMIM 216000)

Unknown

Pallister-Hall97

Low ears, broad nasal bridge, buccal frenula, cleft palate, nail dysplasia, postaxial polydactyly, syndactyly, renal anomalies, imperforate anus. CNS includes hypothalamic hamartoblastoma, arhinencephaly, hydrocephaly, absent corpus callosum, encephalocele, DW, polymicrogyria, heterotopia

AD (146510) GLI3, 7p13

Pettigrew: XLMR-basal ganglia disease98

Developmental delay, long narrow face, strabismus, large nose, progressive spasticity/ hyperreflexia, choreoathetosis, contractures, seizures, self abuse

XLR (304340)

PHACE99

Posterior fossa anomalies include DW (81%) and cerebellar hypoplasia, facial and/or subglottic hemangiomas, arterial abnormalities (22%) (include coarctation) and/or intracranial hemangiomas (12%), cardiac, eye defects (31%) (include microphthalmia), suprapubic raphe and sternal cleft

Uncertain, female predominance

Postaxial polydactyly100

Reported with no other anomalies than four-limb postaxial polydactyly

AR (220220)

Posterior fossa anomaliesleukodystrophy101

Macrosomia, developmental delay, prominent forehead, hypertelorism, flat nasal bridge, narrow palate, 4-5 finger clinodactyly, 2-4 toe syndactyly, central hypotonia, absent reflexes lower limbs with distal hypertonia. One sib had vermis aplasia and DW variant, the other a mega cisterna magna.

AR

Renal-hepatic-pancreatic dysplasia102,103

The dysplastic triad as originally reported by Ivemark appears to occur with DW as a distinct syndrome

AR

Rubella, prenatal40

IUGR, microcephaly, cataracts, choreoretinopathy, sensorineural deafness, cardiovascular anomalies, developmental delay, features dependent on gestational timing

Prenatal rubella infection

Rubinstein-Taybi104

Mental retardation, short stature, downslanting palpebral fissures, beaked nose, nasal septum below alae, radially angulated broad thumbs, broad toes

AD (268600)

Ruvalcaba105

IUGR, variable developmental delay, microcephaly, small mouth, thin lips, small and narrow nose, short metacarpals and tarsals. Female maternal cousin with similar signs had DW.

Uncertain (180870)

Smith-Lemli-Opitz106

IUGR, microcephaly, postnatal growth failure, narrow frontal area, cleft palate, anteverted nares, ambiguous genitalia; anomalies of eye, heart, lung. Series of 19 cases, 4 callosal agenesis, 1 arachnoid cyst, 1 DW, 1 holoprosencephaly.

AR (268670) DHCR7, 11q12-q13

Va´radi: OFD-like107

Severe retardation, postnatal growth failure, median clefts, fatty hamartomas of tongue, pre-axial polydactyly feet, bifid 3rd metacarpal, abnormal cerebellar vermis, DW cyst, high mortality

Uncertain (277170)

Walker-Warburg108

Cobblestone lissencephaly, retinal dysplasia, microphthalmia, other eye anomalies, DW cyst, progressive hydrocephalus, myopathy, postnatal growth failure, early death

AR (236670) 9q34.1

Waardenburg type IV109

Hirshsprung disease in association with broad nasal root, white forelock, piebaldism, pale iris, sensorineural deafness

AR (277580)

Warfarin, prenatal110

Three reported patients with DW, none of whom exhibited the chondrodysplasia punctata seen in warfarin exposure

Prenatal warfarin exposure

to represent Meckel-Gruber syndrome.111 Typical DW has since been reported. There have been a number of reports in the literature of DW and occipital encephalocele, where the latter connects directly to the distended fourth ventricle and consists mainly of an extension of the cyst.112 These findings have been reported by Aleksic et al.112 in the Meckel-Gruber syndrome. Those authors consider this to be the same condition that Friede113 has termed the tecto-cerebellar dysplasia type of vermis hypoplasia. Although case 2 of Friede had a demonstrated connection from a meningeal pouch to a somewhat distended fourth ventricle, his patient had several characteristics of Arnold-Chiari malformation. However, the torcular was elevated. One may speculate that early decompression through the encephalocele alters the embryopathy from that of typical DW toward a hypoplastic posterior fossa and a picture more like that of Arnold-Chiari malformation. A perhaps related

situation is the patient with telencephalosynapsis, rhombencephalosynapsis, and DW reported by Sergi et al.114 Distribution and Etiology

The prevalence of DW among livebirths is often quoted as 1/ 25,000 to 1/30,000 livebirths,9 but this probably underestimates the true frequency by an order of magnitude. Hirsch et al.7 summarized a number of studies and concluded that DW comprised 3% of hydrocephalus. Therefore, if hydrocephalus affects 1–1.5% of the population, DW would occur in 1/ 2500 to 1/3500 births. This estimate is close to the 1/5000 cited for Metropolitan Atlanta (cited in Parisi and Dobyns1). In contrast, Ohaegbulam and Afifi115 recorded an incidence of only 1/100,000 livebirths among the offspring of Saudi Arabian military personnel. Some early reports suggested an excess of affected females, but these results are insignificant and inconsistent.

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Suggested pathogenetic mechanisms of DW must account for both the descriptive anatomy and embryology of the cerebellum and the timing of associated malformations. In DW, the cyst membrane, actually the roof of the fourth ventricle, is lined internally by ependyma and externally by pia arachnoid. The origin of the membrane from the brain stem and ventromedial aspect of the lateral lobes is normal. The bulging fourth ventricle separates the cerebellar hemispheres. Although the vermis may be absent, the anterior portion is usually present, and vestigial portions of the inferior vermis may be reflected onto, or dispersed over, the roof of the cyst. The early pathogenic theories do not meet the necessary anatomic and embryologic requirements. Primary failed development or early obstruction of the foramina of Magendie and Luschka, with secondary hydrocephalus and vermis changes, is unlikely because the vermis, and several other organs that are often malformed in individuals with DW, develops prior to the normal opening of the foramina. Furthermore, many cases of DW have been reported with patent foramina, as have patients who had obstructed foramina but lacked DW.9 The suggestion that DW is a form of rachischisis seems hard to reconcile with its primarily cystic nature, and the general presence, even if hypoplastic, of the midline vermis. The fact that all cases do not have hydrocephalus and that, when present, it is often not apparent until several months postnatally is difficult to reconcile with the proposal by Brodal and Hauglie-Hanssen116 that early hydrocephalus bulges the cerebellar plate and stretches the commissures, thus preventing cell migration in the cerebellum. Although the embryopathology of DW, MCM, and Blake’s pouch cyst remain unclear in humans, current hypotheses favor a relatively early disturbance related to the region of the roof of the fourth ventricle. As discussed in Section 15.2, the thin rhomboid roof of the fourth ventricle develops at the pontine flexure and the rhomboid lip develops at the site of its connection of the roof to the neural tube. The roof consists of an inner ependymal layer and an outer pia, which separates from the early meninx. A transverse vascular invagination (plica choroidea) divides the roof into an anterior membranous area (AMA) and a posterior membranous area (PMA) along the plane of the future foramina of Luschka.4 Growth and thickening of the developing cerebellum results in the incorporation of the AMA into the cerebellum with the choroid plexus coming to lie at the caudal margin of the cerebellum. The hy-1 strain of mice, which has an anomaly similar to DW, shows an abnormal persistence, enlargement, and bulging of the AMA. The fourth ventricle is distended, the median cerebellar plate is excessively thin and wide, more so toward the caudal end, and the magnitude of the vermis abnormality is proportional to the distension. Human DW might be related to a disturbance in the sequence of involution of the AMA, due to a disturbance in the alar plates causing a delay and/or hypoplasia of the developing vermis, or to an unusually large or thin AMA. In either case a cystic dilation of the AMA and perhaps later secondary changes would result in DW. This would also account for the low position of the choroid plexus seen in DW.3 DW is etiologically diverse and has been reported in a number of mendelian, teratogenic, and chromosomal syndromes (Table 15-18). Recent work in patients with chromosome 3q2 deletions has implicated heterozygous loss of ZIC1 and ZIC4 as a cause of DW; a mouse model has been developed.131 Inherited inborn errors of metabolism that have been associated with DW include 3-methyl-glutoconic aciduria, autism associated succynil purine excretion, and congenital disorders of glycosylation.26 In some cases the concurrence may be coincidental. Recurrences of non-

syndromic isolated DW within families are uncommon.7 Murray et al.40 have estimated the sibling recurrence risk to be 1 in 98, giving an upper range of 5%. They also point to the association of DW with other multifactorial malformations, which may themselves occur with higher than expected frequency among unaffected siblings of patients with DW. Parisi and Dobyns1 stress the importance in distinguishing cases of isolated vermis hypoplasia, which may have a higher recurrence risk. Tortori-Donati et al.4 hypothesize that MCM and Blake’s pouch cyst derive from anomalous development in the PMA. Concurrent with the changes in the AMA, the primitive meninx splits to form the subarachnoid space of the cisterna magna, which comes to communicate with the fourth ventricle by fenestration of the PMA-derived tela choroidea.4 Blake’s pouch appears as a narrow evagination, which later disappears leaving an opening that will become the foramen of Magendie. The pouch may be present in normal embryos as late as 130 days. MCM, which may account for up to 50% of posterior fossa cysts, is thought to result from evagination of the tela choroidea, perhaps secondary to a delay in formation of the foramen of Magendie. However, an adequate connection through the foramina between the fourth ventricle and the subarachnoid space prevents occurrence of hydrocephalus. The difference in Blake’s pouch cyst would be the lack of this adequate connection, thus obstructing the flow of CSF and resulting in tetraventricular hydrocephalus. Prognosis, Treatment, and Prevention

There is marked variability in outcome for patients affected by DW, and while some have expressed the view that overall prognosis has improved,117 this is not dramatically apparent from reviews of the literature. Hirsch et al.7 summarized series reported to 1984 and found a 27% overall mortality and that only 49% of survivors had an IQ over 80. Parisi and Dobyns1 summarized seven series that included 224 patients reported from 1981 to 1995 and found a 27% mortality. If the group of 23 patients reported by Sawaya and McLaurin,8 in which 71% had an IQ < 83 are excluded, then 47% of the remaining survivors had an IQ >80. The authors pointed out that there appeared to be a bimodal distribution of intelligence with 35% of cases falling below 35 and only 18% between 56 and 79. Some of the variation in outcome can be attributed to associated chromosome abnormalities, syndromes known to include mental retardation and/ or concurrent supratentorial CNS malformations. Indeed studies that distinguish patients who lack additional malformations suggest that they may have a better prognosis. Maria et al.6 found seven of eight such patients diagnosed under age 6 months and five of six diagnosed over age 6 months were in the normal range of mental function; one normal patient died of acute shunt malfunction. In contrast, three of four patients with associated anomalies were severely retarded. Golden et al.11 reported 28 cases, of which 16 had died, all but one of whom had associated CNS and/or significant visceral anomalies. One instance of absent corpus callosum was the only associated anomaly among the 12 survivors, 9 of who were of normal intelligence, although 5 had focal neurologic signs. It is of interest that the survivors were very much older at diagnosis than is typical for reported series, which may simply reflect their relatively benign course. In the absence of other confounding factors, there is some consensus that early and adequate treatment is an important determinant of outcome,9 although there are no data that address this question directly. It remains probable that neurosurgical series have some bias toward ascertainment of symptomatic cases. A minority of reports describe a more protean onset in adults with gradual onset of obstructive hydrocephalus and concomitant brain stem and cerebellar signs.12,118

Brain

The mortality in DW is often related to associated malformations, but causes also have included uncontrolled hydrocephalus, shunt malfunction, and infection. Sudden death is a known but uncommon complication that has generally been ascribed to uncal or tonsilar herniation. However, Elterman et al.119 reported three cases of sudden death in the absence of herniation. They found some pathologic evidence to suggest that the deaths were due to brain stem ischemia. Attempts have been made to correlate specific cerebellar findings with intellectual outcome. Gerszten and Albright120 noted normal intelligence in 45% and normal cerebellar function in 50% of their 20 patients. They found no correlation between the size of the cerebellum relative to that of the posterior fossa and prognosis. Of those with developmental delay, 10% were mild, 15% moderate, and 25% severe. It should be noted that in some cases the cerebellum may show an increase in size following decompression of the cyst. As discussed earlier, Klein et al.15 separated their patients with DW into those with a small but normally structured cerebellum and those with a dysgenic cerebellum. Of the 21 patients in the former group, none had an associated CNS lesion, 15 had hydrocephalus, 43% had another malformation, and 19 showed normal development. Of the two with developmental delay, one had fragile-X syndrome, and the other suffered from perinatal periventricular leucomalacia. All five patients with a structurally abnormal cerebellum had an associated CNS anomaly, most often callosal agenesis, and all were significantly delayed. If confirmed this would suggest that the presence or absence of vermis malformation may be an important variable in predicting outcome. Shunt dependency is the general rule for patients with DW and hydrocephalus.9 Cerebellar dysfunction is present in 16–60% of survivors120 and is expected to be age-related. An association with syringomyelia appears to be uncommon. Cinalli et al.121 found three cases, and added one of their own in whom the lower pole of the cyst became entrapped at C1. Prenatal diagnosis presents greater difficulties in trying to specifically identify the nature of the posterior fossa malformation, and in detecting associated CNS and non-CNS malformations. When good quality MRI is available, it may add additional useful data.15 In addition, there is a paucity of long-term outcome data on well-categorized surviving children. Of seven cases reported by Nyberg et al.,122 six continued to term and all four with associated malformations died. Of the prenatal cases reported by Chang et al.,24 only 24% of 28 fetuses with DW and 20% of 37 with DW variant survived to 1 year of age. Russ et al.52 reported a 55% mortality in continuing pregnancies, and the outcome in survivors ranged from normal to severely retarded. Of 15 fetuses with posterior fossa anomalies (13 with DW) reported by Aletebi and Fung,17 seven had other malformations and 80% of those who survived to the age of 4 years showed delayed development, despite early treatment. In the study of Ecker et al.,25 34/50 pregnancies with DW and 20/49 with DW variant were terminated. Of the remaining 16 fetuses with DW, five died in utero, one exhibited normal and two abnormal postnatal development, and eight were lost to follow-up. Of the 29 continuing DW variant fetuses, three died in utero, seven showed normal and six abnormal postnatal development, and 13 were lost to follow-up. Six of the seven fetuses with a normal outcome had no additional malformation, and the authors concluded that patients with isolated DW variant have the best prognosis. However, they did not have any continuing pregnancies with isolated DW; and since DW and DW variant patients appear to be clinically indistinguishable postnatally, isolated DW might carry an equivalent prognosis. Serlo et al.123 reported normal

685

outcomes at ages 1.5–4.5 years in three prenatally diagnosed patients who had no associated malformations and who were treated at birth by dual shunting. Treatment of DW is essentially control of the hydrocephalus, and a variety of techniques have been applied. Direct posterior fossa craniotomy with excision of the membrane was virtually abandoned because of an extremely high failure rate and significant operative mortality and morbidity. However, Cinalli124 notes that most such procedures were performed in the pre-modern era of surgical and anaesthetic techniques and suggests that the approach may have a role in the treatment of patients who have had multiple, unsuccessful posterior fossa shunts. Indeed Villavincencio et al.125 used this method in six patients who had five or more failed posterior fossa shunts. They experienced no intraoperative complications, and in five of the patients aggressive cyst fenestration relieved the symptoms; the sixth patient required a fourth ventricle shunt. Shunting became the treatment of choice for DW-related hydrocephalus once suitable materials became available. Different shunting procedures, including ventriculoperitoneal (VPS), cystoperitoneal (CPS), and simultaneous ‘‘Y’’ shunting of the lateral and fourth ventricles (VCPS), have their advocates.7,8 Upward herniation of the posterior fossa following lateral ventricular decompression or failure of the fourth ventricle to decompress with use of VPS shunts appear to be uncommon but definite complications. Conversely, chronic transincisural herniation of the cerebellum has been reported in a significant proportion of patients treated with CPS with or without VPS and may correlate with a difficult clinical course.126 Downward herniation of the lateral ventricles may obstruct the aqueduct.124 There are a number of retrospective series that suggest the superiority of VCPS over either type of shunt alone. Some authors advocate imaging or direct visualization at the time of surgery to determine the patency of the aqueduct, and to thereby attempt to determine whether a single or duplex shunt is required.117,127 Osenbach and Menezes9 had eight patients treated by radical fenestration, of which one improved, five were unchanged, and two died. Thirteen were treated with VPS and three were improved, nine were unchanged, and one died. Only four patients were treated by CPS, and two were improved and two unchanged. Finally, of 12 patients treated by VCPS, one was unchanged and 11 were improved. Kumar et al.128 reported the treatment outcomes of 42 patients of which 28 had an initial VPS and eight of them required a subsequent CPS. Of seven who had an initial CPS, six went on to VPS. Cyst fenestration was successful in the three patients in whom it was applied, and of the four treated with VCPS, one required a later repair. However, Y-shaped shunts have about twice the rate of complications that is seen in single shunts. Cedzich et al.129 reported the use of a single tube with multiple perforations that was passed from the lateral ventricle, through the foramen of Monro to the third, and finally into the fourth ventricle giving adequate drainage. Cinalli124 cautions that because of confused terminology and diagnostic errors, data from the pre-MRI era should be considered with caution. He believes that the high frequency of complications related to isolated VPS and CPS is due to the use of low or very-low pressure valves. In reviewing 54 patients treated with medium pressure or flow-regulated valves (33 CPS, 21 VPS), only two developed aqueductal stenosis, and both had undergone prior membrane excision with one developing meningitis and ventriculitis. The same complications are to be expected with the shunt treatment of patients with DW as occur in other causes of hydrocephalus (Section 15.8); therefore, alternative approaches to treatment are being explored. Cinalli124 has had success in some cases using third ventriculostomy (see Section 15.8), thus obviating

686

Neuromuscular Systems

Fig. 15-68. Prenatal sonogram at 14 weeks gestation showing absent cerebellar vermis and posterior fossa cyst.

the need for a shunt. He does stress that in DW there is anatomical distortion, with the brain stem pressed against the clivus, a vertical orientation of the ventricular floor, and a high position of the basilar artery. Thus, skill and expertise are required. Mohanty130 included insertion of an aqueductal stent and performed successful ventriculostomy in two of three patients. Prevention of posterior fossa cysts must be directed at avoidance of suspected teratogens, as well as provision of appropriate diagnostic evaluation and counseling for syndromes. Accurate definition of the malformation is important for prognosis and for future research efforts aimed at better determining etiology, prevention, and recurrence risks. Prenatal testing with ultrasound and/or MRI to look for associated CNS and non-CNS malformations or karyotyping to look for derivative chromosomes are appropriate in specific cases. Given the empiric recurrence risk of between 1% and 5% and the apparent association with other multifactorial anomalies, ultrasound is probably indicated in all pregnancies where parents wish to be informed of possible recurrence. The possibility of variable expression should be kept in mind. The widespread application of routine prenatal ultrasound means that increasing numbers of posterior fossa anomalies will be detected unexpectedly (Fig. 15-68). In such cases, every effort must be made to best define the malformation and to assess the fetus for additional malformations, and the parents should be offered fetal karyotyping. It is reasonable to state, in the presence of a normal karyotype and in the absence of any detected additional malformations, that the outcome can be good. However, unless the diagnosis of MCM can be made with certainty, there remains a risk of other undetected CNS or non-CNS malformations, and the independent possibility of significant developmental problems. It is to be hoped that further studies with improved imaging technologies will enable clinicians to be more specific in their advice to parents.

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687 38. Chitayat D, Moore L, Del Bigio MR, et al.: Familial Dandy-Walker malformation associated with macrocephaly, facial anomalies, developmental delay, and brain stem dysgenesis: prenatal diagnosis and postnatal outcome in brothers. A New Syndrome? Am J Med Genet 52: 406, 1994. 39. Mortier GR, Messiaen L, Espeel M, et al.: Chondrodysplasia punctata with multiple congenital anomalies: a new syndrome? Pediatr Radiol 28:790, 1998. 40. Murray JC, Johnson JA, Bird TD: Dandy-Walker malformation: etiologic heterogeneity and empiric recurrence risks. Clin Genet 28:272, 1985. 41. Myles TD, Burd L, Font G, et al.: Dandy-Walker malformation in a fetus with pentasomy X (49,XXXXX) prenatally diagnosed by fluorescence in situ hybridization technique. Fetal Diagn Ther 10:333, 1995. 42. POSSUM1, Version 5.6. The Murdoch Institute Royal Children’s Hospital, Melbourne, Australia. 43. Dobyns WB, Patton MA, Stratton RF, et al.: Cobblestone lissencephaly with normal eyes and muscle. Neuropediatrics 27:70, 1996. 44. Imai T, Hattori H, Miyazaki M, et al.: Dandy-Walker variant in CoffinSiris syndrome. Am J Med Genet 100:152, 2001. 45. Fiumara A, Barone R, Nigro F, et al.: Familial Dandy-Walker variant in CDG syndrome. Am J Med Genet 63:412, 1996. 46. Peters V, Penzien JM, Reiter G, et al.: Congenital disorder of glycosylation IId (CDG-IId)—a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Neuropediatrics 33:27, 2002. 47. Kosaki K, Curry CJ, Roeder E, et al.: Ritscher-Schinzel (3C) syndrome: Documentation of the phenotype. Am J Med Genet 68:421, 1997. 48. Behrens-Baumann W, Dust G, Rittmeier K, et al.: Okulo-zerebrale Dysplasie: Aplasia nervi optici sowie familiarer Mikr—und Kryptophthalmus. Klin Mbl Augenheilkd 179:90, 1981. 49. Biver A, De Rijcke S, Toppet V, et al.: Congenital cutis laxa with ligamentous laxity and delayed development, Dandy-Walker malformation and minor heart and osseous defects. Clin Genet 45:318, 1994. 50. Litzman J, Buckova H, Ventruba J, et al.: A concurrence of cutis laxa, Dandy-Walker syndrome and immunodeficiency in a girl. Acta Paediatr 92:861, 2003. 51. Ceballos R, Ch’ien U, Whitley RJ, et al.: Cerebellar hypoplasia in an infant with congenital cytomegalovirus infection. Pediatrics 57:155, 1976. 52. Russ PD, Pretorius DH, Johnson MJ: Dandy-Walker syndrome: a review of fifteen cases evaluated by prenatal sonography. Am J Obstet Gynecol 161:401, 1989. 53. Lehman RM: Dandy-Walker syndrome in consecutive siblings: Familial hindbrain malformation. Neurosurgery 8:717, 1981. 54. Cowles T, Furman P, Wilkins I: Prenatal diagnosis of Dandy-Walker malformation in a family displaying X-linked inheritance. Prenat Diagn 13:87, 1993. 55. Wakeling EL, Jolly M, Fisk NM, et al.: X-linked inheritance of DandyWalker variant. Clin Dysmorphol 11:15, 2002. 56. Ben Hamouda H, Sfar MN, Braham R, et al.: Association of severe autosomal recessive osteopetrosis and Dandy-Walker syndrome with agenesis of the corpus callosum. Acta Orthop Belg 67:528, 2001. 57. Riikonen R, Lang H, Kalimo H, et al.: Two cases of Dandy-Walker syndrome and chronic polyneuropathy. Pediatr Neurosci 15:188, 1989. 58. Hart MN, Malamud N, Ellis WG: The Dandy-Walker syndrome. Neurology 22:771, 1981. 59. Bruyere HJ, Viseskul C, Opitz JM, et al.: A fetus with upper limb amelia, ‘‘caudal regression’’ and Dandy-Walker with an insulin dependent diabetic mother. Eur J Pediatr 134:139, 1980. 60. Le Merrer M, David A, Goutieres F, et al.: Digito-reno-cerebral syndrome: confirmation of Eronen syndrome. Clin Genet 42:196, 1992. 61. Glaser T, Jepeal, Edwards JG, et al.: Pax6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7:463, 1994. 62. Christian JC, Dexter RN, Palmer CG, et al.: A family with three recessive traits and homozygosity for a long 9qh þ chromosome segment. Am J Med Genet 6:301, 1980 63. Fontaine G, Walbaum R, Poupard B, et al.: La dysplasie fronto-nasale: a propos de quatre observation. J Genet Hum 31:351, 1983.

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64. Lubinsky M, Severn C, Rapoport JM: Fryns syndrome: a new variable multiple congenital anomaly (MCA) syndrome. Am J Med Genet 14:461, 1983. 65. Guion-Almeida ML, Richieri-Costa A: CNS midline anomalies in the Opitz G/BBB syndrome: report on 12 Brazilian patients. Am J Med Genet 43:918, 1992. 66. Aleksic S, Budzilovich G, Greco MA, et al.: Intracranial lipomas, hydrocephalus and other CNS anomalies in oculoauriculo-vertebral dysplasia (Goldenhar-Gorlin syndrome). Child Brain 11:285, 1984. 67. Pillay K, Mathews LS, Wainwright HC: Facio-auriculo-vertebral sequence in association with DiGeorge sequence, Rokitansky sequence, and DandyWalker malformation: case report. Pediatr Dev Pathol 6:355, 2003. 68. Dinaker C, Lewin S, Kumar KR, et al.: Partial albinism, immunodeficiency, hypergammaglubulinemia and Dandy-Walker cyst—a Griscelli syndrome variant. Indian Pediatr 40:1005, 2003. 69. Guschmann M, Horn D, Entezami M, et al.: Mesomelic campomelia, polydactyly and Dandy-Walker cyst in siblings. Prenat Diagn 21:378, 2001. 70. Gustavson K-H, Anneren G, Malmgren H, et al.: New X-linked syndrome with severe mental retardation, severely impaired vision, severe hearing defect, epileptic seizures, spasticity, restricted joint mobility, and early death. Am J Med Genet 45:654, 1993. 71. Kurokawa Y, Tsuchita H, Sohma T, et al.: Holoprosencephaly with Dandy-Walker cyst: rare coexistence of two major malformations. Child Nerv Syst 6:51, 1990. 72. Anyane-Yeboa K, Collins M, Kupsky W, et al.: Hydrolethalia (Salmonen-Herva-Norio) syndrome: further clinicopathological delineation. Am J Med Genet 26:899, 1987. 73. Gulati S, Gera S, Menon PS, et al.: Hypothalamic hamartoma, gelastic epilepsy, precocious puberty—a diffuse cerebral dysgenesis. Brain Dev 24:784, 2002. 74. Benke PJ: The isotretinoin teratogen syndrome. JAMA 251:3267, 1984. 75. Noack F, Sayk F, Ressel A, et al.: Ivemark syndrome with agenesis of the corpus callosum: a case report with a reveiw of the literature. Prenat Diagn 22:1011, 2002. 76. McKee SA, Barnicoat A, Fryer A, et al.: Joint and skin laxity with DandyWalker malformation and contractures: a distinct recessive syndrome? Clin Dysmorphol 10:177, 2001. 77. Braddock SR, Jones KL, Superneau DW, et al.: Sagittal craniosynostosis, Dandy-Walker malformation, and hydrocephalus: a unique multiple malformation syndrome. Am J Med Genet 47:640, 1993. 78. Parr JH: Midline cerebral defects and Kallmann’s syndrome. J R Soc Med 81:355, 1988. 79. Ueno H, Yamaguchi H, Katakami H, et al.: A case of Kallmann syndrome associated with Dandy-Walker malformation. Exp Clin Endocrinol Diabetes 112:62, 2004. 80. Cincinnati P, Neri ME, Valentini A: Dandy-Walker anomaly in Meckel-Gruber syndrome. Clin Dysmorphol 9:35, 2000. 81. Bekiesinska-Figatowska M, Rokicki D, Walecki J, et al.: Menke’s disease with a Dandy-Walker variant: case report. Neuroradiology 43:948, 2001. 82. Moerman PH, Vandenberghe K, Fryns JP, et al.: A new lethal chondrodysplasia with spondylocostal dysostosis, multiple internal anomalies and DandyWalker cyst. Am J Med Genet 27:175, 1987. 83. Reardon W, Harbord MG, Hall-Craggs MA, et al.: Central nervous system malformations in Mohr’s syndrome. J Med Genet 26:659, 1989. 84. Pintos-Morell G, Naranjo MA, Artigas M, et al.: Molybdenum cofactor deficiency associated with Dandy-Walker malformation. J Inherit Metab Dis 18:86, 1995. 85. Kawame H, Sugio Y, Fuyama Y, et al.: Syndrome of microcephaly, DandyWalker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature. J Hum Genet 44:219, 1999. 86. Aughton DJ, Sloan CT, Milad MP, et al.: Nasopharyngeal teratoma (‘hairy polyp’), Dandy-Walker malformation, diaphragmatic hernia, and other anomalies in a female infant. J Med Genet 27:788, 1990. 87. Berker M, Oruckaptan HH, Oge HK, et al.: Neurocutaneous melanosis associated with Dandy-Walker malformation. Case report and review of the literature. Pediatr Neurosurg 33:270, 2000.

88. Bohring A, Silengo M, Lerone M, et al.: Severe end of Opitz trigonocephaly (C) syndrome or new syndrome? Am J Med Genet 85: 438, 1999. 89. Tezcan I, Demir E, Asan E, et al.: A new case of oculocerebral hypopigmentation syndrome (Cross syndrome) with additional findings. Clin Genet 51:118, 1997. 90. Zampino G, DiRocco C, Butera G, et al.: Opitz C trigonocephaly syndrome and midline brain anomalies. Am J Med Genet 73:484, 1997. 91. Odent S, Le Marec B, Toutain A, et al.: Central nervous system malformations and early end-stage renal disease in Oro-facio-digital syndrome type 1: a review. Am J Med Genet 75:389, 1998. 92. Smith RA, Gardner-Medwin D: Orofaciodigital syndrome type III in two sibs. J Med Genet 30:870, 1993. 93. Toriello HV, Lemire EG: Optic nerve coloboma, Dandy-Walker malformation, microglossia, tongue hamartoma, cleft palate and apneic spells: an existing oral-facial-digital syndrome or a new variant? Clin Dysmorphol 11:19, 2002. 94. Nagai K, Nagao M, Nagao M, et al.: Oral-facial-digital syndrome type IX in a patient with Dandy-Walker malformation. J Med Genet 35:342, 1998. 95. Chung WY, Chung LP: A case of oral-facial-digital syndrome with overlapping manifestations of type V and type VI: a possible new OFD syndrome. Pediatr Radiol 29:268, 1999. 96. Hedera P, Innes JW: Juberg-Hayward syndrome: report of a new patient with severe phenotype and novel clinical features. Am J Med Genet 122A:257, 2003 97. Finnigan DP, Clarren SK, Haas JE, et al.: Extending the Pallister-Hall syndrome to include other central nervous system malformations. Am J Med Genet 40:395, 1991. 98. Pettigrew AL, Jackson LG, Ledbetter DH: New X-linked mental retardation disorder with Dandy-Walker malformation, basal ganglia disease, and seizures. Am J Med Genet 38:200, 1991. 99. Poetke M, Frommeld T, Berlien HP: PHACE syndrome: new views on diagnostic criteria. Eur J Pediatr Surg 12:366, 2002. 100. Cavalcanti DP, Salomao MA: Dandy-Walker malformation with postaxial polydactyly: further evidence for autosomal recessive inheritance. Am J Med Genet 85:183, 1999. 101. Humbertclaude V, Coubes PA, Leboucq N, et al.: Familial DandyWalker malformation and leukodystrophy. Pediatr Neurol 16:326, 1997. 102. Hunter AGW, Jimenez C, Tawagi FGR: Familial renal-hepaticpancreatic dysplasia and Dandy-Walker cyst: A distinct syndrome? Am J Med Genet 41:201, 1991. 103. Kudo M, Tamura K, Fuse Y: Cystic dysplasic kidneys associated with Dandy-Walker malformations and congenital hepatic fibrosis: report of two cases. Am J Clin Pathol 84:459, 1986. 104. Bonioli E, Bellini C, Di Stefano A: Unusual association: Dandy- Walker like malformation in the Rubinstein-Taybi syndrome. Am J Med Genet 33:420, 1989. 105. Ruvalcaba RHA, Reichert A, Smith DW: A new familial syndrome with osseous dysplasia and mental deficiency. J Pediatr 79:450, 1971. 106. Caruso PA, Poussaint TY, Tzika AA, et al.: MRI and (1)H MRS in Smith-Lemli-Opitz syndrome. Neuroradiology 46:3, 2004. 107. Doss BJ, Jolly S, Qureshi F, et al.: Neuropathologic findings in a case of OFDS type VI (Varadi syndrome). Am J Med Genet 77:38, 1998. 108. Dobyns WB, Kirkpatrick JB, Hittner HM, et al.: Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly. Am J Med Genet 22:157, 1985. 109. Yoder BJ, Prayson RA: Shah-Waardenburg syndrome and Dandy-Walker malformation: an autopsy report. Clin Neuropathol 21:236, 2002. 110. Kaplan LC, Anderson GG, Ring BA: Congenital hydrocephalus and Dandy-Walker malformations associated with warfarin use during pregnancy, Birth Defects Orig Artic Ser XVIlI(3A):79, 1982. 111. Kojima T, Waga S, Shimuzu T, et al.: Dandy-Walker cyst associated with occipital meningocele. Surg Neurol 17:52, 1982. 112. Aleksic S, Budzilovich G, Greco MA, et al.: Cerebellocele and associated central nervous system anomalies in the Meckel syndrome. Child Brain 11:99, 1984.

Brain 113. Friede RL: Uncommon syndromes of cerebellar vermis aplasia. II: Tectocerebellar dysraphia with occipital encephalocele. Dev Med Child Neurol 20:764, 1978. 114. Sergi C, Hentze S, Sohn C, et al.: Telencephalosynapsis (synencephaly) and rhombencephalosynapsis with posterior fossa ventriculocele (‘Dandy-Walker cyst’): an unusual aberrant syngenetic complex. Brain Dev 19:426, 1997. 115. Ohaegbulam SC, Afifi H: Dandy-Walker syndrome: incidence in a defined population of Tabuk, Saudi Arabia. Neuroepidemiology 20:150, 2001. 116. Broda1 A, Hauglie-Hanssen E: Congenital hydrocephalus with defective development of the cerebellar vermis (Dandy-Walker syndrome). J Neurol Neurosurg Psychiatry 22:99, 1959. 117. Boaz JC, Edwards-Brown MK: Hydrocephalus in children. Neurosurgical and neuroimaging concerns. Pediatr Neuroimag Clin NA 9:73, 1999. 118. Lipton HL, Preziosi TJ, Moses H: Adult onset of the Dandy-Walker syndrome. Arch Neurol 35:672, 1978. 119. Elterman RD, Bodensteiner JB, Barnard JJ: Sudden unexpected death in patients with Dandy-Walker malformation. J Child Neurol 10:382, 1995. 120. Gerszten PC, Albright AL: Relationship between cerebellar appearance and function in children with Dandy-Walker syndrome. Pediatr Neurosurg 23:86, 1995. 121. Cinalli G, Vinikoff L, Zerah M, et al.: Dandy-Walker malformation associated with syringomyelia. J Neurosurg 86:571, 1997. 122. Nyberg DA, Cyr, DR, Mack LA, et al.: The Dandy-Walker malformation: prenatal sonographic diagnosis and its clinical significance. J Ultrasound Med 7:65, 1988. 123. Serlo W, Kirkinen P, Heikkinen E, et al.: Ante- and postnatal evaluation of the Dandy-Walker syndrome. Child Nerv Syst 1:148, 1985. 124. Canalli G: Alternatives to shunting. Child Nerv Syst 15:718, 1999. 125. Villavicencio AT, Wellons JC 3rd, George TM: Avoiding complicated shunt systems by open fenestration of symptomatic fourth ventricular cysts associated with hydrocephalus. Pediatr Neurosurg 29:314, 1998. 126. Naidich TP, Radkowski MA, McLone DG, et al.: Chronic cerebral herniation in shunted Dandy-Walker malformations. Radiology 158:431, 1986. 127. Kawaguchi T, Jokura H, Kusaka Y, et al.: Intraoperative direct neuroendoscopic observation of the aqueduct in Dandy-Walker malformation. Acta Neurochirurgica 145:63, 2003. 128. Kumar R, Jain MK, Chhabra DK: Dandy-Walker syndrome: different modaslities of treatment and outcome in 42 cases. Childs Nerv Syst 17:348, 2001. 129. Cedzich C, Lunkenheimer A, Baier G, et al.: Ultrasound-guided puncture of a Dandy-Walker cyst via the lateral and III ventricles. Child Nerv Syst 15:472, 1999. 130. Mohanty A: Endoscopic third ventriculostomy with cystoventricular stent placement in the management of Dandy-Walker malformation: technical case report of three patients. Neurosurgery 53:1223, 2003. 131. Grinberg I, Northrup H, Ardingder H, et al.: Heterozygous deletion of the linked genes ZICI and ZIC4 is involved in Dandy-Walker malformation. Nat Genet 36:1053, 2004.

15.13.2 Arachnoid Cysts Definition

An arachnoid cyst is a cystic, non-parenchymal cavity contained entirely within, and caused by a splitting of, the arachnoid membrane, which at the cyst margins is continuous with normal, noncystic membrane. Arachnoid cysts are lined by a thick collagen layer, the external wall is in contact with the dura mater, and the internal with the pia mater. Blood vessels are present, generally veins in the outer and arteries in the inner wall, and may traverse the cyst. They are susceptible to hemorrhage.1,2 The cyst walls are smooth, may be septate, have no epithelial or glial lining, and contain CSF-like material that may show hemosiderosis, inflammatory cells, or hylaloid changes.2–5 This definition excludes secondary cysts due to chronic arachnoiditis, and post-traumatic leptomeningeal cysts.

689

Diagnosis

The clinical impact of arachnoid cysts is largely dependent on their size and location, as well as on whether any secondary complications such as gradual or rapid expansion, hemorrhage, or infection occur. Thus, small lesions may be incidental at autopsy and, increasingly, arachnoid cysts are a chance finding at prenatal sonography or during postnatal neuroimaging studies. Symptomatic infants or children generally present with macrocephaly, signs of increased intracranial pressure due to the cystic mass, and/or hydrocephalus and may show transillumination of the skull.6 With cysts of the middle fossa and cerebral convexity, the skull is commonly asymmetric with bulging of the temporal squama.7 In older patients presenting signs include chronic, sometimes positional, headache and seizures.4 Data from a review of 285 pediatric cases showed the rate of signs and symptoms at presentation to be raised intracranial pressure (48.8%), lateralizing signs (36.5%), macrocrania (30.5%), developmental delay (20.7%), seizures (18.2%), ocular (14.0%), cerebellar (11.9%), endocrinologic (4.9%), and speech problems (1.8%).2 The EEG was normal in only 19% of patients, but in only 32% was the abnormal EEG apparently related to the site of the cyst. It should be kept in mind that, in some cases, signs such as seizures, developmental delay, or speech problems may be unrelated to the arachnoid cyst, and that reported series are highly biased toward symptomatic cases. Increased intracranial pressure may result from a mass effect of the cyst or be due to secondary hydrocephalus. The latter is more common in association with cysts of the suprasellar area and posterior fossa.8 In adults a midline shift may be a more common presentation than hydrocephalus.9 Ocular signs are commonly strabismus, nystagmus, and papilledema, but can include proptosis.10,11 A history of recent head trauma was present in 16.5% of cases reported in one recent series.2 The location of a cyst will not only affect the type of symptoms it causes but also the likelihood and age at which it will do so. Thus, the frequency of cysts at various locations can be affected by the age of the population being reported (Table 15-19). There is a trend toward earlier presentation of posterior fossa, suprasellar, and supracollicular cysts (Fig. 15-69) than those in the middle (temporal) fossa (Fig. 15-70), so that the latter comprise a greater proportion of adult series. Not included in Table 15-19 is the small series by Hanieh et al.8 in which 7 of 17 (29%) pediatric and 0 of 24 adult patients had suprasellar lesions. It has also been suggested that the distribution of lesions as detected by newer neuroimaging methods will be different from that of earlier autopsy and/or surgical series.14 Brain tissue adjacent to the cyst tends to be compressed, flattened, and even invaginated, but is not destroyed unless secondary complications have intervened. Thus, the destruction and abnormality of adjacent cortex can distinguish porencephaly. Similarly, subdural hygromas are xanthochromic, flat, do not invaginate the cortex, and have vascular new membranes or fibrosis. Most cysts are single and unilateral, with a predisposition in males for the left middle fossa.14 An apparent exception are interhemispheric cysts in older individuals, which have a protean presentation and are more often right-sided and in females.17 There is a peak in diagnosis during the first 2 years with a fairly steady, but lower, rate of ascertainment in subsequent years.2 The mean age at diagnosis in pediatric series is in the range of 5 to 6 years, but it is closer to 20 years in some adult series.2,12 Small temporal fossa-sylvian fissure cysts that can go undetected on routine CT cuts are found in the anterior/inferior temporal fossa, do not cause bone or brain displacement, and are

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Neuromuscular Systems

Table 15-19. Percent distribution of arachnoid cysts according to location Population Type

Pediatric12

Temporal fossa

< 15 yrs2

< 18 yrs13

Population General14

Population General15

65.2

75%

34.8

25%

47.0

34.6

47.7

Suprasellar

9.8

11.3

20.0

Cerebral convexity

4.9

12.9

8.9

6.7

6.5

Interhemispheric Posterior fossa

20.6

Quadrigeminal

3.9

Cerebello-medullary

4.4

2.3 1.3

2.9

Multiple Other

3.3 13.3

5.2 2.0

Clival-interpeduncular ‘‘Intraventricular’’

Population General9

15.5

Supra collicular Cerebello-pontine

< 11 yrs16

2.2 2.0

10.4

Supratentorial

42

83.6

Infratentorial

46.2

16.2

67

37

Total cases in study

95

285

90

biconvex to semicircular.18 As sizes increase, the cysts come to occupy the anterior-middle fossa, displace the sides of the sylvian fissure, and have a more angular shape. They produce displacement of the temporal and frontal lobes, but, although they often expand the temporal fossa and temporal squama, there is no midline shift. As volumes increase, the cysts appear more rounded, the midline is

Fig. 15-69. Axial CT scan of a right-sided cyst in the quadrageminal cisterna, causing some ventricular compression.

126

102

shifted, and the brain is compressed. Such cysts may occupy the whole temporal fossa and expand over the cerebral convexity. These cysts have been classified as types I, II, and III by Galassi et al.18 Typical presenting complaints include intractable or periodic headache, seizures, cranial deformity, abducens palsy, and contralateral motor weakness.8,10,11,15,19 Proptosis with changes in the bony orbital wall may occur with cysts involving the frontal part of the temporal area.11 Complications may include spontaneous or traumatic hemorrhage from abnormal cerebromeningeal vessels

Fig. 15-70. Axial CT scan showing a temporal arachnoid cyst of moderate size in the sylvian area. Note the angular contour and slight bulging of the temporal skull.

Brain

or cortical veins,18 expansion along the optic canal,7 developmental delay and behavioral disturbance,7,20 sexual precocity,21 and the amenorrhea-galactorrhea syndrome. Rossitch and Oakes22 reported a child with bilateral temporal arachnoid cysts and the Kluver-Bucy syndrome of bilateral temporal lobe dysfunction, including memory and language deficit, placidity, oral behavior, and abnormal sexuality. Hemorrhage may lead to chronic subdural or extradural hygroma.15 Up to 5–10% of temporal lobe cysts are bilateral.14 Cysts of the cerebral convexity may present with cranial asymmetry and headache, and seizures are relatively frequent among this group.8 Because of their central location, any significant expansion of the suprasellar cysts can have a marked impact, including expansion of the sella turcica and invagination of the floor of the third ventricle, which may disrupt the pituitary stalk, tuber cinereum, and mammillary bodies.4 The foramina of Monro are commonly obstructed, with resultant hydrocephalus. Apposition to and indentation of the wall of the third ventricle sometimes leads to confusion with a glioependymal cyst. Depending on expansion, the optic nerves and chiasm and the inferomedial thalami, among other areas, may be affected. Common presenting signs include hydrocephalus, headache, emesis, and hypothalamic disorders.8,9 Visual disturbances and developmental delay may also be seen, and ‘‘bobble-head’’ movements have been reported.23 Arachnoid cysts of the infratentorial region tend to occur toward the midline and to assume the shape of the respective site. Supracollicular cysts will present early because of aqueduct compression, whereas others may become quite large, indent the vermis, and spread the cerebellar hemispheres (Fig. 15-71). Hydrocephalus

Fig. 15-71. Sagittal MRI scan of large retrocerebellar arachnoid cyst, causing compression of the cerebellum. Intact fourth ventricle and aqueduct are visible. (Courtesy of Dr. S. Grahovac, Department of Radiology, Ottawa Hospital, Ottawa.)

691

results from defective CSF resorption.7,20 Clinical presentation may be that of macrocephaly with increased intracranial pressure, nonspecific headache, dizziness, gait disturbance, and nystagmus8–10or may include hearing loss, tinnitus, vertigo, or third nerve paralysis. Cases may be mistaken for Me´nie`re disease.24 The differential diagnosis includes Dandy-Walker cysts and other posterior fossa cysts. High-resolution CT or MRI studies should distinguish a normal, even if compressed, cerebellum with an arachnoid cyst. Arachnoid cysts do not enhance on CT, and on MRI their contents are equivalent to CSF on T1 and T2 weighting; they also do not enhance with gadolinium.10 CT ventriculography using metrizamide can distinguish between suprasellar cysts and a very dilated third ventricle, or between a Dandy-Walker and a retrocerebellar cyst. Phase contrast cine-MRI has been used to distinguish arachnoid cysts from an expanded subarachnoid space,25 and the presence of the corpus callosum and other MRI details allows large interhemispheric arachnoid cysts to be distinguished from a third ventricle dorsal cyst.26 Arachnoid cysts may be obscured by tearing at surgery or autopsy, but can be recognized by the compression of contiguous brain tissue.3 There are now numerous reports of the prenatal sonographic recognition of arachnoid cysts, with the diagnosis being made as early as 13 weeks gestation by transvaginal ultrasound.27 In the series of 15 cases reported by Bannister et al.,28 the diagnosis was made before 20 weeks in five, between 20 and 30 weeks in four, and after 30 weeks in six. Piere-Kahn et al.29 reported 54 cases of the prenatal diagnosis of intracranial cysts, from which they excluded DW, MCM, and porencephaly. They did not attempt to differentiate arachnoid cysts from other types, as they do not consider this can be done with assurance prenatally, but presumably their cases included a substantial proportion of arachnoid cysts. Of their cases, 55% were diagnosed between 20 and 30 weeks gestation, and all of the remaining cases, which were diagnosed after 30 weeks, had a normal ultrasound at 22 weeks. Only one cyst had a sylvian fissure location, and the experience of others also raises the question as to whether the distribution of locations of cysts detected prenatally is different from the postnatal experience.27,28 On prenatal sonogram the arachnoid cyst is anechoic, tends to be aseptate with a regular outline, and blood flow is absent on Doppler study. The differential diagnosis will vary with its location, but in the midline it may be confused with a cavum septum pellucidum,30 a dorsal cyst of the third ventricle, or a high-riding third ventricle associated with callosal agenesis.5 Pierre-Kahn et al.29 note that with a large interhemispheric cyst it may not be possible to distinguish callosal agenesis from a flat corpus callosum. In the posterior fossa the diagnoses to be considered include DW, MCM, and Blake’s pouch cyst (BPC). A normal fourth ventricle and cerebellum would exclude DW, as well as BPC. And MCM should not lift the tentorium. However, a large posterior fossa cyst may compress the cerebellar vermis and spread the hemispheres, and a small cyst may not lift the tentorium so that the prenatal separation of these malformations is not always possible. MRI has been strongly advocated as providing more detail of the cyst, its surroundings, and the other parts of the brain.29 Although porencephaly can generally be distinguished by accompanying parenchymal changes, the contours, the sonographic characteristics of the contents, the impact on neighboring white matter, or accompanying arterial anomalies,5 the distinction is not always possible.29 Glioependymal and other less common cysts, as well as an aneurysm of the vein of Galen, should also be considered.

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Etiology and Distribution

Arachnoid cysts are noted in 1/200 routine autopsies, account for about 1% of intracranial tumors,4 and in one recent series were responsible for about half of intracranial cysts.9 Newer imaging techniques may result in an apparent increased frequency, and Wester14 noted that 80% of patients ascertained from 1988 to 1997 were found in the second half of the study period. Twenty seven of 1772 (1.5%) German potential military pilot recruits who were screened by MRI were found to have an arachnoid cyst(s).75 The etiology of arachnoid cysts remains subject to debate. During embryogenesis a loose mesenchyme surrounds the neural tube. An outer zone forms a dense cellular layer of which an outer portion becomes the dura mater, while the looser material below forms the pia mater and arachnoid mater, which are separated by an extracellular ground substance that will form the eventual subarachnoid space. At about 15 weeks, the CSF begins to be free to move from the ventricles through the roof of the fourth ventricle, and it replaces the ground substance of the loose inner layer, leaving an inner wall (pia) and an outer wall (arachnoid) and forming the subarachnoid space. It has been suggested that the active pumping pressure of CSF, once the foramina of Magendie and Luschka are open, may play an active role in development of the space,9 but this is hard to reconcile with presence of the space in patients with closed foramina. The arachnoid consists of three layers31: 1) a compact outer layer of arachnoid barrier cells that are attached without any intervening space to the inner dural layer of loosely packed border cells, 2) a network of collagen and branching arachnoid cells that form a loose mesh called the trabecular layer, and 3) a single layer of thin arachnoid cells forming the lining of the subarachnoid space. Microscopic examination of an arachnoid cyst shows continuation of the barrier cell layer over the outer surface. The cyst forms within and splits the loose trabecular layer, which is replaced by a thicker collagenized tissue in the region of the cyst. This is most marked over the domed outer surface. There is no organized cellular lining of the cyst, although some arachnoid cells may be present; and in some cases there may be some evidence of cells with secretory ability.32 The theory that the cyst arises secondary to a tension caused by an underdevelopment or atrophy of the adjacent brain parenchyma is without merit. Brain tissue can be seen to rebound once pressure from the cyst is removed; there is no evidence of a CNS deficit that would be expected; and careful pathologic studies have failed to show a deficit of parenchymal tissue. One possibility is that cysts result from variations in the condensation that forms the outer layer; another is that variation in CSF flow causes an invagination into this layer that then evolves into a cyst. Other theories, including defective venous development and CSF absorption, have been proposed.4,10 Hypotheses as to why a cyst continues to expand include pulsatile cerebral blood flow, a ball or slit valve effect, active secretion, and an osmotic effect. While there is some evidence to support all except the last suggestion, the final answer is not in. Virtually every series of patients with arachnoid cysts has a significant excess of affected males, and the assumption has been that males suffer greater rates of head trauma that either brings a chance associated arachnoid cyst to attention or that the trauma causes the cyst. However, Westen14 has made the interesting observation that this male predominance is due solely to an excess of left-sided temporal fossa cysts. Of his 126 patients, 92 were male and 34 female; and of the unilateral lesions, 66 were in males and 14 in females, 54 were left-sided and 26 right-sided. These findings

are hard to ascribe to ascertainment or a traumatic cause and suggest some developmental susceptibility in this area of arachnoid. Westen14 argued for an abnormality in the merging of the arachnoid membranes of the forward growing temporal lobe and the frontal lobe as causing the higher rates in this area, and noted parallel differences in males and females in sidedness in disorders such as ADHD. The role of trauma in the development of at least some arachnoid cysts continues to have its supporters. Rainer et al.2 reported a history of ‘‘minor head trauma’’ in 16.5% of their patients, but the usual problem is determining whether the association is causal or simply chance. Trauma was suspected as a cause in 7 of 90 patients reported by Choi and Kim13 because of the appearance of new and progressive symptoms following the trauma. The latency between the trauma and diagnosis averaged 2.2 years (range 10 months to 6.2 years). In two cases normal imaging studies were available from the immediate post trauma and early follow-up periods, thus providing good evidence for onset after the accident, and the possibility that trauma can act as a trigger, at least in some cases. Although genetic factors appear to play a minor role in the cause of arachnoid cysts, the use of modern neuroimaging has meant they have been found in an increasing number of syndromes (Table 15-20). However, whether the association of arachnoid cysts with many of these syndrome and other conditions such as adult polycystic kidney disease,56 oculopharangeal muscular dystrophy,57 schizencephaly (Section 15.11), and intracranial tumors4 are coincidental or indicative of a common pathogenesis is unknown. Several sets of affected siblings have been reported; in two sets the lesions were bilateral temporal, another brother and sister had virtually identical unilateral cysts,58 two mentally retarded brothers were reported with retrocerebellar cysts,59and siblings were reported with cysts of the quadrigeminal cistern.60 The strong correlation for site of lesion among siblings supports a genetic etiology in these cases, and it is possible that neuroimaging studies carried out on asymptomatic family members might yield more familial cases. Finally, the association of bilateral arachnoid cysts with type 1 glutaric aciduria is especially important as such patients are at risk from surgery.10,42 Prognosis, Treatment, and Prevention

Arachnoid cysts are benign, and any sudden change in size or signs is suggestive of hemorrhage or, less commonly, infection. There is evidence that the size of these cysts shows an inverse relationship to the relative freedom of communication with subarachnoid CSF, as determined by metrizamide-contrast-enchanced CT.4,18 As discussed, cyst location affects the age of onset and pattern of presenting signs. Therefore, it can affect surgical outcome indirectly by its impact on the age of the patient and directly by affecting the ease of the operative approach. Outcome studies tend to be biased toward patients who have had surgical treatment of the cyst. Richard et al.61 found that of 60 children treated from ages 1 to 20 years, 64% had complete recovery, 15% had a slight deficit, 13% had severe postoperative deterioration, and 8% had died. Outcome was highly dependent on location, and 93% of patients with temporal cysts had either fully recovered or had minimal deficit. None had died. Only 64% of patients with cysts at other locations did as well, and 16% had died. Rainer et al.2 provided follow-up on 91.6% of their 285 children, of which 41% were considered entirely normal, 33.4% improved, 19.6% unchanged, and only 0.56% worse off. There were no data on 5.4%. Postnatal growth and developmental delay were noted in 14 of 90 patients reported by Choi and Kim,13 of which seven had suffered perinatal trauma and showed failure after a period of normal growth and development. Treatment resulted

Table 15-20. Syndromes with arachnoid cysts Syndrome

Prominent Features

Causation Gene/Locus

Aicardi

Chorioretinal lacunae, infantile spasms, hypsarrhythmia, vertebral segmentation defects, polymicrogyria, periventricular nodules, colpocephaly, hypoplastic cerebellar vermis; arachnoid cysts in 77%, most hemispheric

XLD (304050) Male lethal Xp22

Arachnoid cyst-absent tibiapolydactyly34

Ventriculomegaly, cleft lip, tibial aplasia/hypoplasia, pre- or postaxial polydactyly of feet, postaxial polydactyly of hands, variable short radii, gut malrotation, agenesis of diaphragm, retrocerebellar arachnoid cyst

AR (601027)

Cataracts-contracturescortical dysplasia35

Postnatal growth and developmental failure, prominent supraorbital ridge, cataracts, large joint contractures, osteoporosis, cavum septum pellucidum, right temporal arachnoid cyst, cerebellar atrophy, multiple foci of cortical dysplasia in frontal and parietal lobes

AR

Cerebral dysplasia-arachnoid cyst36

Mild mental retardation, cerebral dysplasia, hypotonia in infancy, temporal arachnoid cysts

AD

Chromosome: ring (20)(p13q13.3)37

Mental retardation, emotional lability, strabismus; hypoplasia of the corpus callosum, cerebellar pyramid, uvula, and nodule; occipital arachnoid cyst

Chromosome imbalance

Chromosome: Triple-X38

Tall stature, disproportionately long limbs, lowered mean OFC, mean IQ 85-90; commonly poor coordination, delayed motor milestones, poor verbal learning and expressive language. Case with right closed-lip schizencephaly, arachnoid cyst, abnormal left gyri

Chromosome imbalance

Chromosome: trisomy (9)(q22-qter), monosomy (X)(q22-qter)39

Fetus with prominent nose, micrognathia, overlapping fingers, right cerebellar arachnoid cyst

Chromosome imbalance

Chromosome: trisomy (12)(q24.31)40

Mental retardation, abnormal skull shape, hypertelorism, flat nasal bridge, abnormal auricles, short neck, heart and genitourinary anomalies. One case with arachnoid cyst

Chromosome imbalance

Distichiasis-lymphedema41

Double rows of eyelashes, ectropion lower lids, late-onset lymphedema, spinal arachnoid cysts that can be symptomatic

AD (153400)

Encephalocraniocutaneous lipomatosis76

Unilateral cerebral anomalies include hemiatrophy and defective operculization of insula, ipsilateral protruberant soft scalp masses with overlying alopecia, papular skin lesions on face and eyes, pterygium-like scleral lesions that may lead to scarring, and progressive intracranial calcifications associated with vascular malformations; a few cases with arachnoid cyst

Unknown (176920)

Glutaric aciduria type 142

Acute or subacute onset of encephalopathy from 3 months to 3 years, persistent dystonicdyskinesis and later psychomotor dysfunction with cerebral atrophy; macrocephaly may predate signs; increased urine glutaric, 3-OH glutaric and glutaconic acid

AR (231670) GCDH, 19p13.2

Hendriks: deafness-callosal agenesis-arachnoid cyst43

Normal intelligence, sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, hydrocephalus

AR

Hughes: acromegaloid appearance44

Progressive acromegaloid appearance, thickened intraoral mucosa, thickening of lips and skin about eyes, bulbous nose, thick frenula, broad hands, tapered fingers, doughy skin. Case with macrocephaly, right middle fossa arachnoid cyst.

AD (102150)

Hydrocephalus-Sprengel shoulder-skeletal45

Mild mental retardation or psychosis, arachnoid or cerebellar cysts, hydrocephalus, abnormal white matter, Sprengel shoulder anomaly, brachydactyly of variable type

AD (600991)

Langer-Giedion: trichorhino-phalangeal II46

Mild short stature and microcephaly, mild to moderate mental retardation, sparse hair, prominent ears; square tipped and bulbous nose with thick and notched alae; long, simple philtrum; coned epiphyses, proximal hooked metaphyseal phalanges, long bone exostoses

AD (150230) del 8q24

Lowe: oculocerebrorenal47

Normal to moderate retardation, tantrums, irritability, stereotypy, obsessive, cataracts, renal tubular acidosis with generalized aminoaciduria and hypophosphatemia; female carriers may have lens changes

XLR (309000) OCRL-1, Xq25

Majewski: short ribpolydactyly48

Lethal short ribbed micromesomelic dwarfism, short tibiae, pre- and postaxial polydactyly, median cleft lip, genital anomalies, hypoplastic epiglottis and larynx, glomerular cysts, tortuous cerebral vessels, cerebellar vermis hypoplasia, posterior fossa arachnoid cysts, agenesis or hypoplasia of the corpus callosum, pachygyria, neuronal heterotopia

AR (263520)

Marinesco-Sjogren49

Mental retardation, congenital cataracts, cerebellar ataxia, muscle wasting with neurogenic atrophy and vacuolar degeneration, distal weakness, ataxia, cerebellar atrophy mostly of vermis, skeletal anomalies including scoliosis, posterior vertebral scalloping, enlargement of intervertebral foramina, short metatarsals and metacarpals. Case report with arachnoid cyst and absent septum pellucidum.

AR (248800) 5q31

Maternal diabetes50

Higher rate of NTDs, cardiac defects (specifically transposition), sacral agenesis, proximal focal femoral deficiency; holoprosencephaly, arachnoid cyst reported

In utero exposure

Merlob: Morning Glory anomaly porencephaly51

Macrodolichocephaly, long palpebrae, epicanthus, absent eye movements, central retinal colobomas, anteverted nares, tented lips, high palate, hydronephrosis, unilateral porencephaly and atrophy, parasagittal arachnoid cyst

Unknown

33

(continued)

693

694

Neuromuscular Systems

Table 15-20. Syndromes with arachnoid cysts (continued) Syndrome

Prominent Features

Causation Gene/Locus

Mohr [OFD II]

Mild short stature, telecanthus, low nasal bridge and broad tip, malar and mandibular hypoplasia, midline cleft lip or tongue, tongue nodules, oral frenula, hallucal duplication, polydactyly, DW malformation

AR (252100)

Mucopolysaccharidoses53

Arachnoid cysts appear more common in these conditions and may relate to the deposit of glycosaminoglycans in the meninges

AR/XLR

Oculo-cerebro-cutaneous77

Orbital cysts, microphthalmia, lid coloboma, periorbital skin appendages, areas of skin hypoplasia/aplasia, skeletal anomalies, agenesis of the corpus callosum; arachnoid cyst recorded in atypical case and author unpublished case

Unknown (164180)

Silverman: dyssegmental dwarfism54

Short, flat face, cleft palate, narrow chest, metaphyseal flaring, coronal cleft vertebrae with anterior wedging, kyphoscoliosis, large first metatarsal and proximal phalanx hallux, poorly modeled talus and calcaneus. Case with lens subluxation, retinopathy, arachnoid cyst, and a venous angioma in the near left basal ganglia

AR (224410)

Tariverdian: acromegalic face55

Severe mental retardation, long and acromegalic face, large nose and jaw, thick lips, megalotestes, stereotypic hand movements, slight 3rd ventriculomegaly, small subarachnoid cyst

XLR

52

in a reversal of previously progressive neurologic signs and improved growth and development. Ehrensberger et al.9 surgically treated 21 of 37 patients with supratentorial arachnoid cysts and obtained good results in 15, fair results in five, and poor results in one. Macrocephaly, ocular symptoms, cranial vault thinning, and headache all responded well, and they noted a slight improvement in general development. Only six cases of infratentorial cysts were treated, and macrocrania, ocular signs, seizures, and hemisyndromes showed good improvement, while headache and development were ultimately unchanged. Precocious puberty has also shown some reversal.21 The relationship of seizures to arachnoid cysts and their possible response to treatment remains unclear. Some series of treated patients report a postoperative decline in seizures, whereas others show no difference in the frequency of seizures between treated and untreated patients.9,10 Also, EEG changes often do not relate to the site of the cyst. Bolthauser et al.62 treated 11 posterior fossa arachnoid cysts. One patient suffered a probable operative complication, one continued to display a mild truncal ataxia, and the remaining nine showed normal neurologic and intellectual function. Mortality appears to be uncommon in current series and may occur due to infection.15 There is concern that rapid decompression of a cyst may lead to hemorrhage, but this appears to be uncommon.8 Traumatic or spontaneous rupture of an arachnoid cyst with a resultant acute or chronic subarachnoid or subdural hemorrhage appears to be an uncommon complication.63 Yamamoto et al.64 found 12 cases of arachnoid cyst among 541 patients with chronic subdural hematoma, and noted that the mean age at diagnosis (27.8 years) was significantly younger than in the general group of patients (69.5 years). Evacuation of the hemorrhage provided adequate therapy. It has been suggested that attention deficit hyperactivity disorder (ADHD) is more common in patients with leftsided temporal cysts10; but as these cysts and ADHD are both more common in males, the significance of the association, if any, is uncertain. Several authors have attempted to address the question of whether long-term compression by a cyst can affect the function of the adjacent parenchyma. Hund-Georgiadis et al.65 found no evidence using fMRI that hemispheric language organization was affected, even with lesions adjacent to the left inferior frontal gyrus. Wester and Hugdahl66 found no alteration in handedness in 51 patients with temporal or frontal arachnoid cysts. However, they did find a reduction in the expected proportion of patients

showing normal right ear advantage, and that the proportion returned to the control rate postoperatively. They speculated as to whether this finding alone was enough to justify surgery in an otherwise asymptomatic patient. Successful treatment usually results in a diminution in the size or disappearance of the cyst and a reexpansion of the compressed brain. Changes in size are more apparent for the smaller, less complex type I and II cysts than for type III, but good clinical outcomes are obtained for all groups.15 Galarza et al.67 reported a correlation between good outcome and a 50% reduction in the size of the cyst, regardless of the treatment approach. Patients with frank mental retardation have not shown improvement; this raises the question of whether in such cases the arachnoid cyst is coincidental or is part of a broader neurologic maldevelopment. Predicting the outcome for fetuses found to have an arachnoid cyst is complicated by a greater degree of uncertainty as to the specific diagnosis, a reduced ability to determine the presence of additional malformations and/or a syndrome, and probable differences in the natural history compared to postnatally ascertained patients. Under these circumstances, some parents will elect to terminate the pregnancy.27,30 A patient with bilateral cysts on either side of the thalamus detected at 29 weeks was managed expectantly and was normal without surgical intervention at 2 years of age.5 Four of 15 cases followed by Bannister et al.28 were terminated, one with callosal agenesis and one with DW and polydactyly. The two others turned out to be incorrect diagnoses, with one having a sagittal sinus thrombosis and the other a glioependymal cyst. Of the remaining 11 pregnancies that continued, one was delivered early because of increasing hydrocephalus and resulted in a child with moderate mental retardation, one had Pallister-Hall syndrome and another Aicardi syndrome, one was lost to follow-up, and seven showed normal early milestones. Of the 54 fetuses with unspecified intracranial cysts reported by PeirreKahn et al.,29 nine were terminated on the bases of additional findings including callosal agenesis (4), abnormal gyration (3), rapidly progressive ventriculomegaly, and suspicion of prior cerebral hemorrhage in another. Forty of the 45 children who were followed were considered normal, and 28 of 33 who were formally assessed had an IQ
90. Of those with a lower IQ, there were two with a temporal, two with a retrocerebellar, and one with an interhemispheric cyst. Forty-one of the 45 were considered neurologically normal, and three of the four that were abnormal were also intellectually impaired. In utero management requires that every

Brain

effort be made to best define the cyst and to look for the presence of any associated CNS or non-CNS anomalies. Continuing pregnancies should be monitored for the possible development of hydrocephalus or a rapid advancement of the cyst, in which case early delivery may be considered. Although chromosome abnormalities are uncommon in association with arachnoid cysts, a fetal karyotype should be considered because abnormal karyotypes have been reported (Table 15-20). This may be most important in cases of retrocerebellar cysts if DW remains a possibility. There are a variety of choices of surgical treatment for arachnoid cysts, and the clinical outcome appears equivalent for any successful procedure. Thus, choice becomes largely a matter of personal preference, the suitability of a technique to a particular location, and balancing the immediate and long-term morbidity, including the likelihood of requiring subsequent operative intervention. Most authors accept that symptomatic cysts should be treated. There is more debate as to whether asymptomatic cases should be treated. Factors that persuade some to treat include significant contiguous brain compression, evidence of developmental delay or non-visual behavior, or a suprasellar location where there is a risk for hypothalamic damage.9 Galassi et al.68 and others8 suggest that intracranial pressure monitoring can aid in the selection of patients for surgery. Of the 285 patients reported by Rainer et al.,2 7.9% were not treated; the patients who were treated were received cystoperitoneal shunt (19.4%), ventriculoperitoneal shunt (15.1%), cyst marsupialization (17.3%), cyst excision (26.0%), marsupialization and shunting (7.3%), and other (6.7%). The cyst disappeared in 18% and decreased in size in 61%, and there was a general correlation between outcome and cyst shrinkage. With the exception of the treatment of suprasellar lesions with shunts, no technique appeared particularly adapted to a specific location. Repeat and/or secondary procedures were required for 30% of cystoperitoneal and 56% of ventriculoperitoneal shunts, 19% of marsupializations, 6.8% of microsurgical excisions, 25% of marsupialization with shunts, and 36% of other treatments. Perhaps more striking, the 19 of 63 cystoperitoneal shunt patients who needed further surgery underwent a total of 47 procedures compared with only 20 surgeries among the 17 of 144 patients in the combined marsupialization and microsurgical excision groups. Another problem with shunting is the development of shunt dependency, which was reported in 6 of 24 patients reported by Choi and Kim,13 and in eight patients reported by Kim et al.69 Over drainage of CSF and presence of a shunt for more than a year may be contributing factors. A further complication of shunting, perhaps related to rapid decompression and/or over drainage, is lack of growth of the posterior fossa and the development of a Chiari I anomaly.69,70 In general, there appears to be a trend away from shunting as a primary approach.12,19,67,71 Levy et al.19 advocate a keyhole craniotomy approach over endoscopy for fenestration, as providing better visualization and hemostasis. Of 50 patients they treated, only 2 (4%) required a subsequent shunt. Fewel et al.12 treated 80% of 95 children with primary fenestration and noted that 73% of the children without preoperative hydrocephalus required no further treatment, compared with only 32% of those who had hydrocephalus. Marinov et al.72 concluded that the relationship between hydrocephalus and arachnoid cysts is complex and not simply one of physical obstruction. A technique meeting with increasing favor is cystoventricular drainage/ shunting.73 Hanieh et al.8 believe that drainage of cysts in the sellar area to the subarachnoid space works poorly and advocate transcallosal cysto-lateral-ventricle shunting. Marinov et al.73

695

found the subfrontal approach superior to the transventricular for treating suprasellar locations. Radical cyst removal and decompression, when not compromised by adhesion to the spinal cord or nerve roots, is the treatment of choice for spinal arachnoid cysts and results in a variable degree of symptomatic improvement.74 The immediate improvement may relate to decompression of the spinal cord. The longterm outcome is less predictable and may include some continued gain or, conversely, some deterioration from the short-term status. Alvisi et al.74 have suggested deterioration may represent spinal cord vascular insufficiency already present at the time of surgery. References (Arachnoid Cysts) 1. Starkmann SP, Brown TC, Linell EA: Cerebral arachnoid cysts. J Neuropathol Exp Neurol 17:484, 1958. 2. Oberbauer RW, Haase J, Pucher R: Arachnoid cysts in children: a European co-operative study. Child Nerv Syst 8:281, 1992. 3. Friede RL: Developmental Neuropathology. Springer-Verlag, New York, 1975, p 196. 4. Naidich TP, McLone DG, Radowski MA: Intracranial arachnoid cysts. Pediatr Neurosci 12:112, 1986. 5. Barjot P, von Theobald P, Refahi N, et al.: Diagnosis of arachnoid cysts on prenatal ultrasound. Fetal Diagn Ther 14:306, 1999. 6. Anderson FM, Landing BH: Cerebral arachnoid cysts in infants. J Pediatr 69:88, 1966. 7. Di Rocco C, Di Trapani G, Iannelli A: Arachnoid cyst of the fourth ventricle and ‘‘arrested’’ hydrocephalus. Surg Neurol 2:467, 1979. 8. Hanieh A, Simpson DA, North JB: Arachnoid cysts: a critical review of 41 cases. Child Nerv Syst 4:92, 1988. 9. Ehrensberger J, Gysler R, Illi OE, et al.: Congenital Intracranial cysts: clinical findings, diagnosis, treatment and follow-up. A multicenter, retrospective long-term evaluation of 72 children. Eur J Pediatr Surg 3:323, 1993. 10. Gosalakkal JA: Intracranial arachnoid cysts in children: a review of pathogenesis, clinical features, and management. Pediatr Neurol 26:93, 2002. 11. Tsitouridis I, Papastergiou C, Emmanouilidou M, et al.: Arachnoid cyst of the frontal part of the temporal lobe producing exophthalmos: CT and MRI evaluation. Clin Imaging 26:302, 2002. 12. Fewel ME, Levy ML, McComb JG: Surgical treatment of 95 children with intracranial arachnoid cysts. Pediatr Neurosurg 25:165, 1996. 13. Choi J-U, Kim D-S: Pathogenesis of arachnoid cyst: congenital or traumatic. Pediatr Neurosurg 29:260, 1998. 14. Wester K: Peculiarities of intracranial arachnoid cysts: location, sidedness, and sex distribution in 126 consecutive patients. Neurosurgery 45:775, 1999. 15. Galassi E, Gaist G, Giuliani G, et al.: Arachnoid cysts of the middle cranial fossa: experience with 77 cases treated surgically. Acta Neurochir Suppl 42:201, 1988. 16. Pascual-Castriviejo I, Roche MC, Martinez Bermejo A, et al.: Primary intracranial arachnoidal cysts. A study of 67 childhood cases. Child Nerv Syst 7:257, 1991. 17. Yamasaki F, Kodama Y, Hotta T, et al.: Interhemispheric arachnoid cyst in the elderly: case report and review of the literature. Surg Neurol 59:68, 2003. 18. Galassi E, Tognetti F, Gaist G, et al.: CT scan and metrizamide CT cisternography in arachnoid cysts of the middle cranial fossa: classification and pathophysiological aspects. Surg Neurol 17:363, 1982. 19. Levy ML, Wang M, Aryan HE, et al.: Microsurgical keyhole approach for middle fossa arachnoid cyst fenestration. Neurosurgery 53:1138, 2003. 20. Di Rocco C, Caldarelli M, Di Trapani G: Infratentorial arachnoid cysts in children. Child Brain 8:119, 1981. 21. Clark SJ, Van Dop C, Conte FA, et al.: Reversible true precocious puberty secondary to a congenital arachnoid cyst. Am J Dis Child 142:255, 1988. 22. Rossitch E, Oakes WJ: Kluver-Bucy syndrome in a child with bilateral arachnoid cysts: report of a case. Neurosurgery 24: 110, 1989.

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23. Wiese JA, Gentry LR, Menezes AH: Bobble-head doll syndrome: a review of the pathophysiology and CSF dynamics. Pediatr Neurol 1:361, 1985. 24. O’Reilly RC, Hallinan EK: Posterior fossa arachnoid cysts can mimic Meniere’s disease. Am J Otolaryngol 24:420, 2003. 25. Yu Q, Kong X, Liu D: Differential diagnosis of arachnoid cyst from subarachnoid space. Chinese Med J 116:116, 2003. 26. Lena G, van Calenberg F, Genitori L, et al.: Supratentorial interhemispheric cysts associated with callosal agenesis: surgical treatment and outcome in 16 children. Childs Nerv Syst 11:568, 1995. 27. Bretelle F, Senat M-V, Bernard J-P, et al.: First-trimester diagnosis of fetal arachnoid cyst: prenatal implication. Ultrasound Obstet Gynecol 20:400, 2002. 28. Bannister CM, Russel SA, Rimmer S, et al.: Fetal arachnoid cysts: their site, progress, prognosis and differential diagnosis. Eur J Pediatr Surg 9 (Suppl 1):27, 1999. 29. Pierre-Kahn, Hanlo P, Sonigo P, et al.: The contribution of prenatal diagnosis to the understanding of malformative intracranial cysts: state of the art. Child Nerv Syst 16:618, 2000. 30. Hassan J, Sepulveda W, Teixeira J, et al.: Glioependymal and arachnoid cysts: unusual causes of early ventriculomegaly in utero. Prenat Diagn 16:729, 1996. 31. Schuchenmayr W, Friede RL: Fine structure of arachnoid cysts. J Neuropathol Exp Neurol 38:434, 1979. 32. Go KG, Houthoff HJ, Blaauw EH, et al.: Arachnoid cysts of the sylvian fissure. Evidence of fluid secretion. J Neurosurg 60:803, 1984. 33. Smith CD, Ryan SJ, Hoover SL, et al.: Magnetic resonance imaging of the brain in Aicardi’s syndrome. Report of 20 patients. J Neuroimaging 6:214, 1996. 34. Holmes LB, Redline RW, Brown DL, et al.: Absence/hypoplasia of tibia, polydactyly, retrocerebellar arachnoid cyst, and other anomalies: an autosomal recessive disorder. J Med Genet 32:896, 1995. 35. Shotelersuk V, Desudchit T, Suwanwela N: Postnatal growth failure, microcephaly, mental retardation, cataracts, large joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy. Am J Med Genet 116A:164, 2003. 36. Tolmie JL, Day RE, Fredericks B, et al.: Dominantly inherited cerebral dysplasia: arachnoid cysts associated with mild mental handicap in a mother and her son. J Med Genet 34:1018, 1997. 37. Gomes Mda M, Lucca I, Bezerra MSA, et al.: Epilepsy and ring chromosome 20: case report. Arq Neuropsiquiatr 60:631, 2002. 38. Ehara H, Eda I: Schizencephaly in triple-X syndrome. Pediatr Int 43:296, 2001. 39. Hogge WA, Schnatterly P, Ferguson JE: Early prenatal diagnosis of an infratentorial arachnoid cyst: association with unbalanced translocation. Prenat Diagn 15:186, 1995. 40. Masuno M, Fukushima Y, Sugio Y, et al.: Partial distal trisomy with arachnoid cyst. Jpn J Hum Genet 32:39, 1987. 41. Schwartz JF, O’Brien MS, Hoffman JD: Hereditary spinal arachnoid cysts, distichiasis and lymphedema. Ann Neurol 7:340, 1980. 42. Lu¨tcherath V, Waaler PE, Jellum E, et al.: Children with bilateral temporal arachnoid cysts may have glutaric aciduria type 1 (GAT1); operation without knowing that may be harmful. Acta Neurochir 142:1025, 2000. 43. Hendriks YMC, Laan LAEM, Vielvoye GJ, et al.: Bilateral sensorineural deafness, partial agenesis of the corpus callosum, and arachnoid cysts in two sisters. Am J Med Genet 86:183, 1999. 44. da-Silva EO, Duarte AR, Andrade L, et al.: A new case of the acromegaloid facial appearance syndrome? Clin Dysmorphol 7:75, 1998. 45. Ferlini A, Ragno M, Gobbi P, et al.: Hydrocephalus, skeletal anomalies, and mental disturbances in a mother and three daughters: a new syndrome. Am J Med Genet 59:506, 1995. 46. Takemura T, Yoshioka K, Okada M: A case of Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II) associated with epilepsy. No To Hattatsu 26:434, 1994. 47. Wang CL, Liu CY, Yuh YS, et al.: Lowe syndrome: report of one case. Zhonghua Min Guo Xiao Er Ke Hui Za Zhi 34:45, 1993. 48. Prudlo J, Stoltenburg-Didinger G, Jimenez E, et al.: Central nervous system alterations in a case of short-rib polydactyly syndrome, Majewski type. Dev Med Child Neurol 35:158, 1993.

49. Williams TE, Buchhalter JR, Sussman MD: Cerebellar dysplasia and unilateral cataract in Marinesco-Sjogren syndrome. Pediatr Neurol 14:158, 1996. 50. Kouseff, Villaveces C, Martinez CR: Unique brain anomalies in an infant of a diabetic mother. Acta Paediatr Scand 80:110, 1991. 51. Merlob P, Horev G, Kremer I, et al.: Morning Glory fundus anomaly, coloboma of the optic nerve, porencephaly and hydronephrosis in a newborn infant: MCPH entity. Clin Dysmorphol 4:313, 1995. 52. Reardon W, Harbord MG, Hall-Craggs MA, et al.: Central nervous system malformations in Mohr syndrome. J Med Genet 26:659, 1989. 53. Petitti N, Holder CA, Williams DW 3rd: Mucopolysaccharidosis III (Sanfilippo syndrome) type B: cranial imaging in two cases. J Comput Assist Tomogr 21:897, 1997. 54. Prabhu VG, Kozma C, Leftridge CA, et al.: Dyssegmental dysplasia Silverman-Handmaker type in a consanguineous Druze Lebanese family: Long term survival and documentation of the natural history. Am J Med Genet 75:164, 1998. 55. Tariverdian G, Froster-Iskenius U, Deuschl G, et al.: Mental retardation, acromegalic face, and megalotestes in two half-brothers: a specific form of X-linked mental retardation without fra(X)(q)? Am J Med Genet 38:208, 1991. 56. Allen A, Wiegmann TB, MacDougal1 ML: Arachnoid cysts in a patient with autosomal-dominant polycystic kidney disease. Am J Kidney Dis 8:128, 1986. 57. Jadeja KJ, Grewel RP: Familial arachnoid cysts associated with oculopharangeal muscular dystrophy. J Clin Neurosci 10:125, 2003. 58. Wilson WG, Deponte KA, Mcllhenny J, et al.: Arachnoid cysts in a brother and sister. J Med Genet 24:714, 1987. 59. Suzuki H, Takanashi J, Sugita K, et al.: Retrocerebellar arachnoid cysts in siblings with mental retardation and undescended testis. Brain Dev 24:310, 2002. 60. Sinha S, Brown JI: Familial posterior fossa arachnoid cyst. Child Nerv Syst 20:100, 2004. 61. Richard KE, Dahl K, Sanker P: Long term follow up of children and juveniles with arachnoid cysts. Childs Nerv Syst 5:184, 1989. 62. Bolthauser E, Martin F, Altermatt S: Outcome in children with space occupying posterior fossa arachnoid cysts. Neuropediatrics 33:118, 2002. 63. Gelabert-Gonzalez M, Fernandez-Villa J, Cutrin-Prieto J, et al.: Arachnoid cyst rupture with subdural hygroma: report of three cases and literature revue. Childs Nerv Syst 18:609, 2002. 64. Mori K, Yamamoto T, Horinaka N, et al.: Arachnoid cyst is a risk factor for chronic subdural hematoma in juveniles: twelve cases of chronic subdural hematoma associated with arachnoid cyst. J Neurotrauma 19:1017, 2002. 65. Hund-Georgiadis M, Yves Von Cramon D, Kruggel F, et al.: Do quiescent arachnoid cysts alter functional organization? An fMRI and morphometric study. Neurology 59:1935, 2002. 66. Wester K, Hagdahl K: Verbal laterality and handedness in patients with intracranial arachnoid cysts. J Neurol 250:36, 2003. 67. Galarza M, Pomata HB, Pueryrredo´n F, et al.: Symptomatic supratentorial arachnoid cysts in children. Pediatr Neurol 27:180, 2002. 68. Di Rocco C, Tamburrini G, Caldarelli M, et al.: Prolonged ICP monitoring in children with sylvian fissure arachnoid cysts. Minerva Pediatr 55:583, 2003. 69. Kim S-K, Cho B-K, Chung Y-N, et al.: Shunt dependency in shunted arachnoid cyst: a reason to avoid shunting. Pediatr Neurosurg 37:178, 2002. 70. Di Rocco C, Tamburrini G: Shunt dependency in shunted arachnoid cyst: a reason to avoid shunting. Pediatr Neurosurg 38:164, 2003. 71. Pierre-Kahn A, Carpentier A, Parisot D, et al.: Traitement des kystes intraˆcraniens de l’enfant: de´rivation pe´ritone´ale ou fenestration endoscopique? Neurochirurgie 48:327, 2002. 72. Marinov M, Undjian S, Wetzka P: An evaluation of the surgical treatment of intracranial cysts in children. Child Nerv Syst 5:177, 1989. 73. McBride LA, Winston KR, Freeman JE: Cystoventricular shunting of intracranial arachnoid cysts. Pediatr Neurosurg 39:323, 2003.

Brain 74. Alvisi C, Cerisoli M, Giulioni M, et al.: Long-term results of surgically treated congenital intradural spinal arachnoid cysts. J Neurosurg 67:333, 1987. 75. Weber F, Knopf H: Cranial MRI as a screening tool: findings in 1,772 military pilot applicants. Aviation Space Environ Med 75:158, 2004. 76. Fishman MA: Encephalocraniocutaneous lipomatosis. J Child Neurol 2:186, 1987. 77. Giorgi PL, Gabrielli O, Catassi C, et al.: Oculo-cerebro cutaneous syndrome: description of a new case. Eur J Pediatr 148:325, 1989.

Glioependymal/ependymal cysts Definition

Cysts with an internal ependymal lining and generally surrounded by glial tissue, and lacking any external epithelium or lining. In some locations differentiation from a respiratory tract or esophageal origin may be difficult.1,2 Diagnosis

These uncommon cysts may be an incidental finding at autopsy or may present at different ages with signs dependent on their size and location (Fig. 15-72). The differential diagnosis depends on their site and neuroradiologic appearance but includes arachnoid cysts, interventricular neuroepithelial (colloid) cysts, Rathke pouch cysts, and rare intracranial neuroenteric cysts, and a variety of potentially neoplastic or infectious cysts. Glioependymal cysts of the cerebral cortex are much less common than arachnoid cysts and, although reported to occur in childhood, are most often diagnosed in adults who present with signs of increased intracranial pressure. Presentation with macrocephaly/ventriculomegaly in a fetus with cerebellar hypoplasia has also been reported, although the prenatal interpretation was an arachnoid cyst.3 The cysts rarely communicate with the ventricular system and are usually intracerebral, but may also be interhemispheric. Occasional location within the leptomeninges may mimic an arachnoid cyst.4 Location in the basal portions of the brain is

Fig. 15-72. Glioependymal cysts (arrow) located in the cisterna ambiens of a neonate whose inability to sustain respiration was probably due to multiple capillary telangiectasias and venous angiomas in the brain stem, cerebellum, thalamus, and hypothalamus. The cyst was presumably an incidental finding. (Courtesy of Dr. C Jiminez, Department of Pathology, Children’s Hospital of Eastern Ontario, Ottawa.)

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uncommon.5 Glioependymal cysts in a supracollicular location usually present before age 1 year with signs of hydrocephalus due to compression of the quadrigeminal plate leading to aqueductal obstruction. Infratentorial location is rare but presents in a fashion similar to that discussed for arachnoid cysts.6,7 Some authors are of the opinion that reported spinal glioependymal cysts in fact have a respiratory epithelial origin.1,8 Classical presentation of a colloid cyst is with intermittent headache and ocular signs, which may include unilateral papilledema.9 Sudden death has also been reported.10 As is the case with arachnoid cysts, expanding glioependymal cysts may distort adjacent normal brain sructures. Microscopic examination confirms the diagnosis and, in the case of intracerebral locations, demonstrates a cyst wall of glial tissue with complete or incomplete ependymal lining of simple cuboidal, ciliated, or occasionally multilayered epithelium.1,4,6 The cyst may contain tissue consistent with choroid plexus and fluid that ranges from CSF-like to highly proteinaceous. Immunohistochemical staining studies carried out by Ho and Chason6 suggested a neuroglial origin of the inner layers, and an outer layer, which on electromicroscopy was separated by a continuous basement membrane consisting of fibrous tissue. Barth et al.11 have reported interhemispheric glioependymal cysts associated with agenesis of the corpus callosum, nodular heterotopias, cerebellar hypoplasia, and abnormal foramen magnum. The authors found several similar cases in the literature, including a case by Brihaye et al.12 that may have been a case of Aicardi syndrome. Tange et al.13 have reported an additional case with callosal agenesis, a left frontotemporal microgyria, and a left interhemispheric glioependymal cyst. A single patient with a ‘subependymal germinal matrix cyst’ in association with a wide anterior fontanel, face dysmorphia, small eyes with medial colobomas, an endocardial cushion defect and small penis was reported by Hanson and Greaves.14 Etiology and Distribution

Glioependymal cysts are uncommon in all locations, and there is no evidence to support a genetic etiology. The cysts are considered by some to originate from neuroglial heterotopias, which are often seen to contain ependymal cells, usually in clusters, but occasionally with a cyst-like structure.15 This would be in keeping with the cases associated with absent corpus callosum and heterotopias referred to above. Others consider that a portion of neural tube is pinched off into either the cerebral tissue cyst or the subarachnoid space. It may sit on glial tissue, forming a typical glioependymal cyst, or on connective tissue as an ependymal cyst.16 Colloid cysts may be found in up to 1/1000 asymptomatic individuals, and account for 0.55-2% of intracranial tumors.9 Histologic examination of some colloid cysts of the third or fourth ventricle have been interpreted as supporting a neuroepithelial origin from the roof of the diencephalon and fourth ventricle and thus that they should be termed neuroepithelial cysts.17,18 Other case studies have been more compatible with an endodermal/respiratory origin.19 Intracranial neuroenteric cysts are extremely rare, with most cases reported in the posterior fossa,20,21 but cases have been reported from the suprasellar region,22 and the anterior cranial fossa.23These cysts show evidence of endodermal origin22 and may represent an error of early gastrulation.20 They are discussed further in Chapter 17. Why these cysts apparently slowly enlarge and become symptomatic later in life is still debated. Secretion of a hyperosmolar protein solution followed by osmotic expansion is difficult to reconcile with the time frame in most cases. There is also nothing to

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suggest that these are degenerative cysts. Electron microscopy provides evidence of secretory activity in the ependymal cells.6,16 This includes cytoplasmic vacuoles that appear to rupture and swollen microvilli that detach into the lumen. A chronic low-level secretory activity might cause a gradual expansion that is accommodated for a variable period within the cranial cavity. Of further interest was the finding by Ho and Chason6 of intracytoplasmic lumens and cilia in the ependymal cells and surrounding glia, both of which raise the possibility of neoplastic change. There is the potential that a low-grade neoplasia accounts for a late-onset expansion of a previously small glioependymal cyst. Prognosis, Treatment, Prevention

Diagnosis before the advent of permanent neurologic signs provides a favorable prognosis. Occasionally a cyst may be separated and removed intact from the surrounding normal brain, but in most cases a procedure allowing permanent drainage to the ventricular or subarachnoid spaces is adequate. Recurrence within a family is not expected, and prevention is not a consideration. There is evidence that a proportion of colloid cysts show autosomal dominant inheritance.24 References (Glioependymal/Ependymal Cyst) 1. Friede RL: Developmental Neuropathology, Springer-Verlag, New York, 1975, p 196. 2. Haddad FS, Abla A, Allam C: Ependymal brain cyst. Surg Neurol 18:246, 1982. 3. Hassan J, Sepulveda W, Teixeira J, et al.: Glioependymal and arachnoid cysts: unusual causes of early ventriculomegaly in utero. Prenat Diagn 16:729, 1996. 4. Markwalder T-M, Markwalder RV, Slongo T: Intracranial neuroepithelial cyst mimicking arachnoid cyst. Surg Neurol 16:411, 1981. 5. Harrison MJ: Cerebral arachnoid cysts in children. J Neurosurg 34:316, 1971. 6. Ho KL, Chason JL: A glioependymal cyst of the cerebellopontine angle. Acta Neuropathol 74:382, 1987. 7. Rilliet B, Bemey J: Benign ependymal cyst of the pons. Child Brain 8:1, 1981. 8. Findler G, Hadani M, Tadmor R: Spinal intradural ependymal cyst: a case report and review of the literature. Neurosurgery 17:484, 1985. 9. Hwang DH, Townsend JC, Ilsen PF, et al.: Colloid cyst of the third ventricle. J Am Optom Assoc 67:227, 1996. 10. Kava MP, Tullu MS, Deshmukh CT, et al.: Colloid cyst of the third ventricle: a cause of sudden death in a child. Ind J Cancer 40:31, 2003. 11. Barth PG, Uylings HBM, Stam FC: Interhemispheral neuroepithelial (glio-ependymal) cysts, associated with agenesis of the corpus callosum and neocortical maldevelopment. Child Brain 11:312, 1984. 12. Brihaye J, Gillet P, Parmentier R, et al.: Age´ne´sie de la commissure calleuse associe´ a` un kyste e´pendymaire. Schweizer Arch Neurol Psychiatr 77:415, 1956. 13. Tange Y, Aoki A, Mori K, et al.: Interhemispheric glioependymal cyst associated with agenesis of the corpus callosum—case report. Neurol Med Chir 40:536, 2000. 14. Hanson JW, Greaves JP: Case report 47: colobomas, unilobar lungs, endocardial cushion defect. Synd Ident 4(2):11, 1976. 15. Cooper IS, Kernohan JW: Heterotopic glial nests in the subarachnoid space: histopathologic characteristics, mode of origin and relation to meningeal gliomas. J Neuropathol Exp Neurol 10:16, 1951. 16. Friede RL, Yasargil MG: Supratentorial intracerebral epithelial (ependymal) cysts: review, case reports, and fine structure. J Neurol Neurosurg Psychol 40:127, 1977. 17. Ciric I, Zivin I: Neuroepithelial (colloid) cysts of the septum pellucidum. J Neurosurg 43:69, 1975. 18. Jan M, Zeze VB, Velut S: Colloid cyst of the fourth ventricle: diagnostic problems and pathogenic considerations. Neurosurgery 24:939, 1989.

19. Ho KL, Garcia JH: Colloid cyst of the third ventricle: ultrastructural features are compatible with endodermal derivation. Acta Neuropathol 83:605, 1992. 20. Harris CP, Dias MS, Brockmeyer DL, et al.: Neurenteric cysts of the posterior fossa: recognition, management, and embryogenesis. Neurosurgery 29:893, 1991. 21. Chaynes P, Bousquet P, Sol JC, et al.: Recurrent intracranial neurenteric cysts. Acta Neurochir 140:905, 1998. 22. Sampath S, Yasha TC, Shetty S, et al.: Parasellar neurenteric cyst: unusual site and histology: case report. Neurosurgery 44:1335, 1999. 23. Bavetta S, El-Shunnar K, Hamlyn PJ: Neurenteric cyst of the anterior cranial fossa. Br J Neurosurg 10:225, 1996. 24. Partington MW, Brookalil AJ: Familial colloid cysts of the third ventricle. Clin Genet 66:473, 2004.

Choroid Plexus Cysts Definition

A cyst containing cerebrospinal fluid, lined by simple cuboidal or columnar epithelium, and connected to, or contained within, the choroid plexus. Most often found in the posterior lateral ventricles, it is commonly a chance finding on ultrasound of the fetus or neonate, and it remains problematic as to whether this type of cyst is a true malformation or simply a variation in normal development. Diagnosis

Small, asymptomatic cysts of the choroid plexus (CPC) are detectable in over one-half of routine adult autopsies.1 On rare occasions, a child or adult may become symptomatic with headache, seizures, or focal neurological signs due to continuous or intermittent obstruction of the foramen of Monro by the cyst.2 The headache may vary with the position of the patient. Neuroepithelial (colloid) cysts of the third ventricle may share an embryological origin with choroid plexus cysts.3 Greater and more sophisticated use of second-trimester fetal ultrasound has led to a renewed interest in these cysts. First reported in five cases by Chudleigh et al.,4 surveillance for CPC is now part of the standard prenatal assessment sonogram, and they are recognized as a ‘soft’ ultrasound marker for trisomy 18. Evidence that better ultrasound equipment has led to more frequent diagnoses is provided by the report of Ostlere et al.,5 who detected cysts in 1/90 pregnancies when using state of the art equipment compared with 1/300 when using an older model. The cysts are generally located in the atrium of the lateral ventricles, are detected between 16 and 21 weeks gestation, and range in size from 3 to 20mm in diameter (most < 10 mm); the overwhelming majority disappear by 23-24 weeks gestation (Fig. 15-73). The proportion that is determined to be bilateral versus unilateral may in part be due to technical variation, but is about 50%. A papilloma of the choroid is distinguishable because it is a solid tumor with marked echogenicity. Rarely a choroid plexus cyst may occur in the body of the lateral ventricle and may simulate hydrocephalus.6,7 It should be distinguished by its echogenic wall and course over time.8 Distribution and Etiology

There is now substantial literature concerning the prevalence of fetal CPC. Peleg and Yankowitz9 reviewed 33 series published to 1997, and found an overall prevalence of 2,347/286,441 (0.82%) with a range of 0.18% to 3.64%. Some of the inter-survey variation is likely associated with small sample sizes, but differences in the minimal diameter of cyst detectable (or required) to diagnose CPC, the gestation at study, the inclusion of high risk pregnancies in

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Fig. 15-73. Fetal ultrasonogram at 22.7 weeks gestation demonstrating bilateral choroid plexus cysts that measure 1.2 x  1.5 cm. The fetus had trisomy 18, presented with polyhydramnios, and had other detectable malformations.

some studies, and other unidentifiable local practice variables are undoubtedly at play. In a study that did not define a lower limit of cyst size, Digiovanni et al.10 found a rate of 89/8270 (1.08%) at 18.2 þ/ 1.9 weeks gestation, whereas a multicenter study of 101,600 women at 14–24 weeks gestation, in which the cyst was required to be >3 mm, found a prevalence of 0.65%.11 Recent meta-analyses that have only included prospective series of unselected women, and which do show some overlap in their data-set, have obtained rates of 0.96% and 1.16%.11,12 Guariglia and Rosati13 obtained a rate of 1.48% among a group of 1692 women, over 37 years of age, using transvaginal ultrasound at 11 to 16 weeks gestation. These data appear comparable to that from later gestation. Although the majority of fetal cysts are not detectable beyond 23–24 weeks, they have been reported as incidental findings in neonates.14 Indeed the prevalence in the newborn, whose sonographic study is facilitated by the open fontanel, appears greater than in the fetus. Hung and Liao15 used ultrasound to detect CPC in 186 of 2111 (8.8%) normal newborns. Abnormalities of the choroid plexus, including CPC, appear to be common in the Aicardi syndrome.16 It is generally believed that the high prevalence of CPC and their developmental time course are related to the normal embryology of the choroid plexus, as described by Shuangshoti and Netsky.17 From 7 to 9 weeks the plexus begins as a ‘‘club-shaped’’ evagination of neuroepithelium into the ventricles and contains loose mesenchymal stroma and ill-defined vascular structures. From 9 to 16 weeks the stroma is loose and the plexus becomes increasingly lobulated and reaches its maximum size, which fills three-fourths of the lateral ventricles by 11 weeks. The tips of interlobular clefts may be pinched off, resulting in trapped neuroepithelial lined tubules in the interstitium. From 17 to 28 weeks the loose stroma decreases, and connective tissue fibers increase. Numerous tubules of a size suggestive of incipient choroid plexus cysts are present. From 29 weeks until term the stroma continues to be replaced by connective tissue. Presumably a small number of the entrapped tubules may become dilated enough to be detected as cysts, and some may persist into adulthood.

Prognosis, Treatment, Prevention

There is no evidence that, in the otherwise normal newborn, that isolated CPC (iCPC) whether detected prenatally or after birth, is of any consequence. All of 76 chromosomally normal newborns, diagnosed prenatally with iCPC and followed to a mean age of 35.5 months (þ/ 16.2), showed normal Denver II Developmental Screen results.10 Hung and Liao15 were able to perform serial ultrasounds on 155 of their 186 cases of iCPC ascertained through a newborn screening ultrasound. The CPC resolved in 137 of the 155 infants by 6 months, and all of the 179 infants followed to a mean age of 35 months (range 30–42) showed normal development. An infant who was noted to have a unilateral ventriculomegaly of 13 mm at 32 weeks gestation, which increased to 17 mm by the time of delivery at 38 weeks, was found to have a CPC measuring 1.7  2.5  3 cm in the left lateral ventricle.6 The cyst was unchanged at 6 months and 11 months follow-up, and the child was showing normal development. Isolated case reports of complications due to the local impact of a CPC do appear, but are uncommon. Seizures have been attributed to a large CPC causing local compression,18 and intermittent or chronic obstruction through a ball valve effect does occur and can present late in life.2,7 Symptomatic cases can be treated by extirpation of all or part of the cyst.7,18 and, in the absence of preexisting permanent damage, a full recovery can be anticipated. It is the association of CPC with trisomy 18, and the debate surrounding the magnitude of the risk and how to advise a woman whose fetus has been found to have a CPC, that has brought notoriety to the CPC. CPC are not associated with an increased risk of Down syndrome.19,20 There is no doubt that CPC are observed more frequently in trisomy 18 than in the general population of fetuses, and their presence was recorded in 82 of 151 (54%) of the cases summarized by Peleg and Yankowitz.9 This rate is significantly higher that the rate reported from some more recent studies.12,21 As pointed out by Hershey et al.,22 if there was no association then one would expect significantly more cases to be seen with trisomy 21

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than with trisomy 18 because of the relative rates of the two trisomies in the general population at that stage of gestation. Quite the reverse has been reported. However, early studies of the relationship of CPC to trisomy 18 suffered from a bias towards reporting positive studies and the inclusion of high-risk pregnancies. Chitty et al.,19 in comparing studies of unselected patients with those of selected patient populations, and populations that were not clearly defined, found respective rates of aneuploidy of 0.59%, 1.07% and 2.3%, respectively. There appears to be a consensus that management should not be influenced by the size of the cysts or whether they are unilateral, bilateral, multiple or regressing.9,19 There is also agreement that amniocentesis should be offered in cases where CPC are associated with an ultrasound detected malformation, regardless of maternal age.19–21,23 However, it is the presence of the other major malformation that provides the major component of the sensitivity and positive predictive value for aneuploidy.24 The literature has been more divided or undecided on the question of whether amniocentesis should be offered routinely in the face of iCPC (summarized in Bird et al.21). A number of recent metaanalysis, based upon prospective series of unselected women, have concluded that factors other than just the iCPC should be included when providing clinical advice regarding fetal karyotyping.11,12,19,20,25 Demasio et al.11 found that 1% of women under 35 had a fetus with iCPC, but that none of the 1017 fetuses had trisomy 18. The authors concluded that iCPC is not a risk factor for trisomy 18 in women under 35 years, and that amniocentesis should not be offered in this circumstance because of its inherent risks. These data are in keeping with the findings of Chitty et al.19 for women under 36 years. Other authors have adopted the approach of calculating a likelihood ratio for trisomy 18, given the presence of an iCPC. The values obtained have ranged from 7.09 (CI 3.97–12.18) to 13.8 (CI 7.2–25.14).12,20,26 The advantage of using a likelihood ratio is that it can be combined with other independent risk factors, such as maternal age or maternal serum screening, to provide an individualized estimate of risk.21 Tables combining maternal age and a CPC likelihood ratio are available.12,20 Presumably the likelihood ratio one chooses to use would best match the local referral population, and in some jurisdictions the risk threshold would be a matter of public policy. Bahado-Singh et al.24 developed one algorithm using CPC, maternal age, femur length as a multiple of the median, and single umbilical artery, and a second where a major malformation replaced single umbilical artery. The latter provided a sensitivity of 72.3% with a false positive of 0.9%. By excluding cases beyond 17.5 weeks, the sensitivity rose to 82.8% and the false positive to 4.0%. Given the current primacy of patient autonomy it is difficult to counter the view that women should be informed when their fetus has CPC.19,27 However, personal experience has been that, even when ‘expressing an optimistic view’ regarding outcome,19 that there is significant potential for maleficence when discussing variations in fetal brain development with parents. Given the very low individualized risks that can be calculated for iCPC in the fetuses of young women, there is reason to reconsider this approach. References (Choroid Plexus Cysts) 1. Shuangshoti S, Netsky MG: Neuroepithelial (colloid) cysts of the nervous system. Neurology 16:887, 1966. 2. Hatashita S, Takagi S, Sakakibara T: Choroid plexus cyst of the lateral ventricle in an elderly man. J Neurosurg 60:435, 1984. 3. Shuangshoti S, Roberts MP, Netsky MG: Neuroepithelial (colloid) cysts. Arch Pathol 80:214, 1965. 4. Chudleigh P, Pearce JM, Campbell S: The prenatal diagnosis of transient cysts of the fetal choroid plexus. Prenat Diagn 4:137, 1984.

5. Ostlere SJ, Irving HC, Lilford RJ: Fetal choroid plexus cysts: a report of 100 cases. Radiology 175:753, 1990. 6. Gucer F, Yuce MA, Karasalihoglu S, et al.: Persistent large choroid plexus cyst. A case report. J Reprod Med 46:256, 2001. 7. Parizek J, Jakubec J, Hobza V, et al.: Choroid plexus cyst of the left lateral ventricle with intermittent blockage of the foramen of Monro, and initial invagination of the III ventricle in a child. Child Nerv Syst 14:700, 1998. 8. Gabrielli S, Reece A, Pilu G, et al.: The clinical significance of prenatally diagnosed choroid plexus cysts. Am J Obstet Gynecol 160:1207, 1989. 9. Peleg D, Yankowitz J: Choroid plexus cysts and aneuploidy. J Med Genet 35:554, 1998. 10. Digiovanni LM, Quinlan MP, Verp MS: Choroid plexus cysts: infant and early childhood developmental outcome. Obstet Gynecol 90:191, 1997. 11. Demasio K, Canterino J, Ananth C, et al.: Isolated choroid plexus cyst in low risk women less than 35 years old. Am J Obstet Gynecol 187:1246, 2002. 12. Ghidini A, Strobelt N, Locatelli A, et al.: Isolated fetal choroid plexus cysts: role of ultrasonography in establishment of the risk of trisomy 18. Am J Obstet Gynecol 182:972, 2000. 13. Guariglia L, Rosati P: Prevalence and significance of isolated fetal choroid plexus cysts detected in early pregnancy by transvaginal sonography in women of advanced maternal age. Prenat Diagn 19:128, 1999. 14. Fakhry J, Schecter A, Tenner MS, et al: Cysts of the choroid plexus in neonates: documentation and review of the literature. J Ultrasound Med 4:561, 1985. 15. Hung KL, Liao HT: Neonatal choroid plexus cysts and early childhood developmental outcome. J Formos Med Assoc 101:43, 2002. 16. Uchiyama CM, Carey CM, Cherny WB, et al.: choroid plexus papilloma and cysts in the Aicardi syndroime. Pediatr Neurosurg 27:100, 1997. 17. Shuangshoti S, Netsky MG: Histogenesis of choroid plexus in man. Am J Anat 118:283, 1966. 18. Darmoul M, Zemmel I, Bouhaouala MH, et al.: Kyste symptomatique du plexus choroı¨de du ventricle late´ral. Neurochirurgie 45:45, 1999. 19. Chitty LS, Chudleigh P, Wright E, et al.: The significance of choroid plexus cysts in an unselected population: results of a multicenter study. Ultrasound Obstet Gynecol 12:391, 1998. 20. Yoder PR, Sabbagha RE, Gross SJ, et al.: The second-trimester fetus with isolated choroid plexus cysts: a meta-analysis of risk of trisomies 18 and 21. Obstet Gynecol 93:869, 1999. 21. Bird LM, Dixson B, Masser-Frye D, et al.: Choroid plexus cysts in the mid-trimester fetus—practical application suggests superiority of an individualized risk method of counseling for trisomy 18. Prenat Diagn 22:792, 2002. 22. Hershey DW, Chitkara U, Clark SL: Fetal choroid plexus cysts. Obstet Gynecol 73:301, 1989. 23. Sullivan A, Giudice T, Vavelidis F, et al.: Choroid plexus cysts: is biochemical testing a valuable adjunct to targeted ultrasonography? Am J Obstet Gynecol 181:260, 1999. 24. Bahado-Singh RO, Choi S-J, Oz U, et al.: Early second-trimester individualized estimation of trisomy 18 risk by ultrasound. Obstet Gynecol 101:463, 2003. 25. Gross SJ, Shulman LP, Tolley EA, et al.: Isolated fetal choroid plexus cysts and trisomy 18. Am J Obstet Gynecol 172:83, 1995. 26. Gupta JK, Khan KS, Thornton JG, et al.: Management of fetal choroid plexus cysts. Br J Obstet Gynecol 104:881, 1997. 27. Snijders RJM, Shawa L, Nicolaides KH: Fetal choroid plexus cysts and trisomy 18: assessment of risk based on ultrasound findings and maternal age. Prenat Diagn 14:1119, 1994.

15.14 Chiari Malformations Definition

Chiari malformations include a spectrum of anomalies involving caudal displacement and herniation of cerebellar structures. Four

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types (I-IV) were described by Hans Chiari in 1886, and more recently a type 0 and type 1.5 have been proposed.1 Type I is a congenital or acquired anomaly that involves a variable caudal displacement of the cerebellar tonsils but not the brain stem, cerebellar vermis, or fourth ventricle, into the cervical canal. The level is rarely below C2, and there is no kink in the cervicomedullary junction or association with spina bifida.1–3 The posterior fossa is small, and hydrocephalus occurs in < 10%, but an associated syrinx is common. Type 0 is clinically equivalent to type I and demonstrates posterior tilting of the pons and medulla with a caudal displacement of the medulla and tip of the obex, but normal positioning of the tonsils.1 In type II, the cerebellar vermis, tonsils, and the medulla and/or fourth ventricle are displaced caudally into the cervical canal; the upper cervical nerve roots tend to exit from the cord and run rostrally. The medulla comes to lie over the upper cervical cord, and the cervicomedullary junction is often kinked (Figs. 15-74 to 15-77).4 Involvement of the vermis often includes the paravermian tonsils, nodulus, uvulus, and pyrimus, but may include more rostral elements.2,3 There is a virtual 100% association with meningomyelocele, and syringomyelia, hydrocephalus, and other CNS anomalies are common.The eponym Arnold-Chiari malformation should be

Fig. 15-74. Gross pathologic view of the dorsal aspect of the ArnoldChiari type II malformation in an infant with a meningomyelocele. The probe is at the level of the foramen magnum, and the cerebellar vermis and part of the medulla are seen below this level (arrow). (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario, Ottawa.)

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Fig. 15-75. Sagittal section of Chiari type II malformation showing kinking and beaking of the midbrain (arrow). (Courtesy of the Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario, Ottawa.)

reserved for type II Chiari.5 Chiari type 1.5 has been used by some authors for cases where there is caudal displacement of the brain stem and cerebellum equivalent to that seen in type II, but in the absence of a meningomyelocele.1 In type III Chiari malformation there is a caudal position of the brain stem in the spinal canal with herniation of all or part of the cerebellum into an occipito-cervical encephalomeningocele.1,2,6 The herniation may include part of the hindbrain; hydrocephalus and other CNS anomalies are common, and the condition is rare and clinically severe. Type IV Chiari malformation includes cerebellar hypoplasia, a small posterior fossa, and Fig. 15-76. Sagittal section of the brain stem, cerebellum, and upper cervical spinal cord in a newborn infant with Chiari type II malformation. In this anomaly, the cerebellum and medulla oblongata protrude through the foramen magnum into the spinal canal and produce an S-shaped kink in the upper spinal cord (arrows). (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

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Fig. 15-78. MRI in sagittal plane of patient with Chiari type I malformation illustrating small posterior fossa with low posterior insertion of the tentorium and caudal protrusion of cerebellum through a large foramen magnum. Note syrinx at level of C2-C3. (Courtesy of Drs. S. Grahovac and Z. Grahovac, Ottawa Hospital, Ottawa.)

Fig. 15-77. MRI in sagittal plane of patient with Chiari type II malformation, a spina bifida, tethering of the cord and intradural lipoma. (Courtesy of Dr. L. Auruch, Ottawa Hospital.)

abnormality of the pons with a resultant anomalous shape of the brain stem.1,2,7 There is marked dilation of the fourth ventricle. However, there is no caudal displacement of the contents of the posterior fossa, and the term is therefore being abandoned. Diagnosis

MRI is the method of choice for the diagnosis of type I Chiari (C-I) (Figs. 15-78, 15-79), and its increased use has led to greater recognition of this anomaly in asymptomatic and minimally symptomatic individuals. The usual age at presentation is in the third decade, but there typically has been significant delay in making a specific diagnosis because of the frequently protean presentation.8,9 In the largest and most systematic study to date, Milhorat et al.10 observed a mean age at presentation of 24.9 years (þ/ 15.9) and a mean age at diagnosis of 30.8 years (þ/ 15.7). There was no clinically significant difference between patients with and without accompanying syringomyelia. However, 36.8% of the patients had lifelong complaints, such as headache and clumsiness, and C-I has been recognized increasingly in children.8,11,12 Greenlee et al.13 described 31 affected children under age 6 years. Complaints of headache, visual disturbance, dizziness, or sensory changes have often led to misdiagnosis as multiple sclerosis, migraine, fibromyalgia, amyotrophic lateral sclerosis, or post-traumatic syndrome, and fully 59% of the patients reported by Milhorat et

al.10 had been labeled as psychogenic by at least one physician. Although most patients do not identify a precipitating cause for the onset of symptoms, trauma, infection, coughing/sneezing, and pregnancy may each be a trigger in some cases.10 Headache and neck pain are the most common presenting complaints,14 occurring in 82% of one series.10 Typically the headache is described as heavy, crushing, or pressure-like, over the occiput and extending to the vertex. It may also occur behind the eyes and radiate to the neck and shoulders. Factors that exacerbate or trigger the headache include increased physical activity, Valsalva, coughing and sneezing, postural change, and the head-down position. Except in severe cases, the headache is usually not pounding, and when ‘‘cough-associated’’ it is often of short duration.14 Migraine and tension headache occur in patients with C-I at the same frequency as in the general population, and the C-I-associated headaches of longer duration can often be distinguished from other cervicogenic causes by the concurrence of dizziness.14 The cause of the headache in C-I is unclear. Milhorat et al.10 suggest there is a loss of compliance of the CSF space due to the crowded posterior fossa, and thus a diminished capacity to accommodate acute changes in pressure. Taylor and Larkness14 consider that acute pressure changes (cough/Valsalva) cause transient pressure dissociation between the intracranial and intraspinal compartments, thus driving down the cerebellum and causing traction and pain. Patients with coughassociated headache have higher intrathecal pressures, which return to normal after treatment, than do C-I patients without headache.15 Ocular complaints, defined as two or more signs and symptoms, were noted in 78% of the patients studied by Milhoret et al.,10 and they included retrobulbar pain/pressure (63%), visual phenomena (55%), blurred vision (46.5%), photophobia (28.3%), diplopia (19.5%), decreased acuity (9.3%), extraocular muscle palsy (4.7%), and papilledema (2.5%). Two or more neuro-otologic signs were recorded in 74% of patients and, in descending order of

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Fig. 15-79. Coronal section of MRI scan showing herniation of the cerebellar tonsils in a patient with Chiari type I malformation (arrows).

prevalence, they were dizziness (57%), dysequilibrium, pressure in the ears, tinnitus, diminished hearing, nystagmus, vertigo, oscillopsia, and hyperacusis (6.9%). Twenty-four patients with disabling vertigo underwent more extensive study, and 16 had sensorineural deafness and 14 vestibular dysfunction. Evidence of lower cranial nerve (9th–12th), brain stem, and cerebellar dysfunction was reported in 52% of cases. In descending order of prevalence, they were dysphagia (43%), sleep apnea, tremor, palpitations, diminished coordination, throat pain, facial pain and/or numbness, syncope, shortness of breath, and hypertension (7.7%). On examination symptoms included decreased gag reflex (16.8%), tremor, dysmetria, facial sensory loss, vocal cord paralysis, and truncal ataxia. The 65.4% concurrence of syringomyelia in that series is in keeping with other reports,2,7,16 and 94% of those patients had typical central cord signs and symptoms (Section 17.3). Cervical and/or thoracic or holocord syringomyelia are observed. A surprising finding was that 66% of patients without a syrinx showed central-cord symptoms. One can speculate that an incipient syrinx with edema of the cord can cause neurologic dysfunction. The presentation in children is generally similar to that in adults.8,17 Of 68 children ranging in age from 17 months to 21 years reported by Park et al.,12 63% had pain, 26% numbness, 19% weakness, and 16% incoordination. No neurologic signs were observed in 56%, while 18% had anomalies of cranial nerves, 28% had central cord signs, and 13% cerebellar signs. Scoliosis is an important pediatric sign, and it is associated with the presence of syringomyelia. It was present in 28% of the children reported by Park et al.,12 in 16% as the sole presenting complaint, and in 23% of the young children studied by Greenlee et al.13 A progressive left-sided curve with pain suggests a possible accompanying C-I malformation. A syrinx appears to be as common in the pediatric population as in the adults, and its presence is associated with development of scoliosis, central cord signs, and preoperative pain.12 Five of seven children reported by Dauser et al.18 had a

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syrinx, and all five had scoliosis. Certain signs may predominate in very young children. Specifically, oropharyngeal dysfunction affected 35% of the children studied by Greenlee et al.,13 and 69% of those under age 3 years, of which 3 of 16 had a fundoplication prior to correct diagnosis. Brill et al.11 presented 11 children with C-I, who ranged in age from 1.5 to 5.5 years and had seizures and/or developmental delay. They speculated that the C-I was a marker for a wider CNS dysgenesis. One patient was microcephalic, and most either had decreased tone, hemiparesis, or hyperreflexia. A similar group of nine patients from a series of 35 with C-I were reported by Grosso et al.19 The association seems to be very non-specific and could simply represent the chance ascertainment of C-I in children studied because of their underlying problems. The overwhelming majority of patients with C-I show normal intelligence. Several authors have stressed the importance of being mindful of the possibility of C-I in patients who present with apnea.20–23 These patients may be at greater risk for postoperative complications. The causes of apnea are varied and include respiratory center dysfunction with decreased or increased drive,21 dysfunction of the reticular activating center, and vocal cord paralysis.20,24 Such patients can suffer from choking and have higher rates of sleep fragmentation and less REM sleep.22 Other interesting presentations or signs to be noted have included longstanding trigeminal neuralgia,25 blepharoclonus,26 syncopy,27 paroxysmal rage,28 and a pair of siblings who were discordant for syrinx and had a disassociated sensory loss in a range that did not overlap with areas of hyperhydrosis.29 Symptomatology in C-I is generally attributed to direct cerebellar compromise, brain stem and cranial nerve compression and traction, and syrinx-associated central cord syndrome. Malhorat et al.10 were able to identify five distinct types of presentation: 1) headache, 2) pseudotumor-like, 3) Me´nie`re-like, 4) dysfunction of lower cranial nerves, and 5) spinal cord dysfunction (even without a syrinx). The proportion of patients who are asymptomatic at the time of diagnosis will vary with age, the decade(s) of the study, and the criteria used to diagnose C-I. Rates in two recent studies were 14%30 and 22% (defined as having <2 signs/symptoms).10 In one pediatric series, 57% of 49 children were asymptomatic.17 Typically C-I is defined by the level of the tips of the cerebellar tonsils below the foramen magnum, as defined by a line from the basion to the opisthion. Aboullez et al.31 found this distance was þ2.9 mm (þ/ 3.4; 1 SD) in a control sample, and Barkovich et al.32 found a mean of 1 mm with a range of 8 to þ5 mm, with 14% of the tonsils of normal persons below the foramen magnum. In most series, a level of >5 mm is considered as C-I, with 3 to 5 mm being borderline. For a number of reasons this definition is not adequate. Problems include that the normal position of the cerebellar tonsils may vary by race,33 that they rise with age,34 and that signs and symptoms correlate poorly with the tonsillar position. Other criteria such as pegged or pointed tonsillar tips, and crowding of the subarachnoid space at the craniocervical junction, have been suggested.1,2,32 Milhorat et al.10 noted that all of their 364 patients had compressed CSF spaces behind and lateral to the cerebellum, while only 91.2% had tonsillar levels of >5 mm, 84.1% had a significant loss of supraoccipital height, and 81.9% had an increased slope of the tentorium. All of their 47 patients who underwent cine-flow MRI studies, including 21 with their cerebellar tonsils at < 5 mm, showed diminished CSF flow in the posterior subarachnoid, prepontine, and premedullary spaces. Direct measurement of the volume of the posterior fossa can also be useful. Other radiologic signs that may aid diagnosis include basilar invagination, platybasia, atlanto-occipital assimilation, cervical spine widening, Klippel-Feil anomaly, a retroflexed odontoid, scoliosis, or

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presence of a compressed fourth ventricle, and syringomyelia or syringobulbia. The suggestion that C-I with a syrinx be called type A, and without a syrinx type B, has been adopted by some authors.16 Type II Chiari (C-II) is believed to occur in all cases of meningomyelocele and is rarely reported in its absence.35 While the designation as C-I.5 has been suggested by some for this latter circumstance, it implies a malformation that is somehow intermediate between C-I and C-II, which may not be supported by current views on pathogenesis (vide infra). However, although C-II can be assumed in any child with meningomyelocele, only a minority will be symptomatic, two-thirds of those by age 3 months.35,36 C-II is the leading cause of death in treated patients with meningomyelocele up to the age of 2 years.37 Signs of brain stem dysfunction tend to appear sometime after closure of the meningomyelocele and are a consequence of the small posterior fossa with caudal displacement of the hindbrain into the cervical canal, with obstruction of CSF flow from the fourth ventricle. The lower cranial nerves that must travel rostrally to exit the cranium are stretched and compressed, and are at risk for necrosis.3 Children present with dysphonia, a crowing stridor, reduced strength and facility of swallowing. Sleep apnea is common, and the vocal cords may fail to adduct and abduct; this complication was found in half the infants in one small series.38 Glossopharyngeal dysfunction leads to a decrease in posterior pharyngeal sensation and an increase in the risk of aspiration, compounded by vocal cord involvement in many cases. Loss of function of both vagal nerves causes death from autonomic failure.39 There is also some risk of infarction of the portion of the cerebellum that is compressed below the foramen magnum. In a study of 46 asymptomatic and 18 symptomatic patients with C-II, concurrent abnormalities in masseter and blink reflexes were found to provide good discrimination between the two groups.40 There does not appear to be any clinically significant correlation between the level of the meningomyelocele and the likelihood of symptomatic C-II. Older children and adolescents present with a variety of signs relating mostly to upper cervical cord or brain stem compression and/ or hydrocephalus, including loss of head control and arm function, opisthotonos, hemi/quadriparesis, nystagmus, and a hoarse voice. In contrast to C-I, evidence of developmental anomalies at the histologic level are relatively common in C-II, with heterotopias in the white matter, abnormal cranial nerve and olivary nuclei, and disordered lamination.7 The caudal displacement of posterior fossa contents into the spinal canal is difficult to detect by CT, and other characteristic findings should be relied on for diagnosis when using this technique. Some of these changes are more apparent after shunting for hydrocephalus.41 The signs that are, in various combinations, virtually pathognomonic of C-II include a lacunar skull, concave petrous pyramids with a posterior surface groove, hypoplasia of the falx and tentorium, and an abnormal quadrigeminal plate with a spectrum of collicular fusion and midbrain beaking that indents the midline cerebellum and may come to overlie the pons. The caudally bent and fused quadrigeminal plate is seen as rounded or spiked, and occasionally the pineal is stretched over its surface.41,42 The indented cerebellum shows apparent bulging upward through the hypoplastic tentorium and also extends lateroventral to the midbrain. The fourth ventricle is generally invisible, sagittally flattened, or small, and there is poor visualization of the basal cisternae.43 MRI best demonstrates the anatomic changes in C-II, including the caudal displacement of the cerebellum, cervicomedullary junction kinking, caudal position and elongation of the

fourth ventricle, and quadrigeminal beaking (refer to Figs. 15-74 through 15-77). In most cases, the cerebellum has a flattened superior surface and suggests that the ‘‘upward bulging’’ seen on CT is an artifact.44 Study of the posterior fossa for the banana sign (Chapter 16) is part of the prenatal sonographic evaluation for meningomyelocele, and D’Addrio et al.45 have shown that fetuses with C-II have a clivus-supraocciput angle that is less than the 5th centile on their nomogram. A number of groups have been exploring midtrimester, in utero surgical repair of meningomyelocele (Chapter 16), and a claim has been made that this may reverse, or at least diminish the severity of, C-II. However, Beuls et al.37 used highfield MR on an ex utero fetus to show changes due to the early rhombencephalic herniation that they considered irreversible. They suggest that the in utero surgery may prevent the subsequent cerebellar changes that develop in the third trimester and postnatally due to hypoplasia of the posterior fossa. The diagnosis of Chiari type III (C-III) follows from the MRI evaluation of a child with a low occipital or high cervical mass, and the demonstration of an encephalomeningocele containing significant components of the cerebellum. Most cases are clinically severe and present at birth, but the diagnosis has been made as late as the age of 14 years.46 Early death due to respiratory insufficiency is a common consequence. Surviving infants tend to suffer from increased intracranial pressure and hydrocephalus, and compression of the cerebellum, lower cranial nerves, and brain stem can lead to headache, syncope, ocular dysfunction, dysphasia, aspiration, sensory loss, weakness, ataxia, hypotonia or hypertonia, and sphincter dysfunction.46 Developmental delay, seizures, abnormal tone, upper and/or lower motor neuron abnormalities, and lower cranial nerve deficits are common in survivors.6 Histology of the cerebellum demonstrates heterotopias, gliosis, fibrosis, and necrosis.46 Neuroimaging will demonstrate a deficit in the lower occipital squama and/or posterior arches of C1 or C2, a small posterior fossa, low tentorial attachment, scalloped clivus, a beaked tectal plate, usually marked hydrocephalus, and the cerebellar herniation.6 Dysgenesis of the corpus callosum is common. A case of C-III with only a small cerebellar herniation was diagnosed at 34 weeks gestation using single shot fast spin echo MRI so as to reduce motion artifact.47 Table 15-21 lists a number of syndromes in which Chiari malformations have been reported to occur. Syndromes with meningomyelocele and C-II are listed in Section 16.1. The possible importance of genetic factors in the etiology of non-syndromic C-I has not been the focus of most series, and data are sparse. However, there are a number of case reports of familial occurrence, and concordance has been reported in monozygous twins and triplets.10,55,85 Milhorat et al.10 recorded family history in their series and found that 43 patients (12%) had at least one close relative affected with C-I plus a syrinx (19), C-I alone (17), or syringomyelia of unknown cause (7). An additional 72 patients provided a history of other relatives who had compatible symptoms but were yet to be investigated. Females were also overrepresented in familial cases, male-to-male transmission was noted, and individual families were compatible with autosomal recessive and autosomal dominant inheritance (including incomplete penetrance). Certainly there should be a high index of suspicion in relatives of patients with confirmed C-I. Etiology and Distribution

The prevalence of C-I, using as a definition the position of the tonsillar tips at
5 mm below the foramen magnum, is surprisingly

Table 15-21. Syndromes with Chiari malformation Syndrome

Prominent features

Causation Gene/Locus

Alcohol, prenatal

IUGR, postnatal growth failure, developmental delay, fine motor dysfunction, short palpebrae, maxillary hypoplasia, short nose, thin and smooth upper lip, small distal phalanges. Case report with Chiari, chance?

In utero exposure

Antley-Bixler49

Brachycephaly, craniosynostosis, large fontanelle, midface hypoplasia, proptosis, choanal atresia/stenosis, radioulnar stenosis, femoral bowing, less frequent internal anomalies, hydrocephalus in 17%. Case with C-I.

AR (207410) Cytochrome P450 reductase, 7q11.2

Beare-Stevenson50

Tall skull, craniosynostosis; cutis gyrata of scalp, face, ears, lips, and limbs; acanthosis nigricans, prominent eyes, hypertelorism, choanal atresia, cleft palate/ uvula, umbilical protrusion, bifid scrotum. Two cases with Chiari malformation.

AD (123790) FGFR2, 10q25-10q26

Blepharophimosis-ptosisepicanthus inversus-type II51

Short palpebrae, ptosis, epicanthus inversus, telecanthus, smooth eyelid skin, flat nasal bridge, abnormal pinnae, normal intelligence; type I with female infertility, type II with normal fertility. Two cases with C-I.

AD (110100) FOXL2, 3q23

Blue rubber bleb nevus52

Cutaneous and often oral and gastrointestinal cavernous hemangioma; lesions are soft with a rubbery texture, blue in color, may be tender; histology shows irregular blood-filled spaces in the subcutaneous tissue and lower dermis

AD (112200)

Cataracts-deafness-Down syndrome appearance53

Postnatal growth and developmental delay, sensorineural deafness; variable radioulnar synostosis, chondrolysis, hernias, J-shaped sella, C-I

Unknown

Costello54

Noonan-like face coarsens with age, characteristic nasal papillomata, mental retardation, hypertrophic cardiomyopathy, thickened mitral valves vertical talus, dislocated hips, acanthosis nigricans; tumors include epithelioma, ganglioneuroblastoma, embryonal rhabdomyosarcoma

Uncertain (218040) 22q13.1

Craniocervical malformations55

Variable combinations of underdeveloped occipital bone, basilar impression, vertebral fusions (short neck), syringomyelia, developmental delay and seizures common, C-I

Sporadic, some AD (118420)

Craniosynostosis, several types56

Probably due to lambdoid fusion and a small posterior fossa, C-I anomalies are more common with clover-leaf skull, Crouzon and Apert syndrome

AD

Craniosynostosis-bifid thumb-micropenis57

Craniosynostosis, clover-leaf skull, low-set ears, hypotelorism, prominent eyes, epicanthus, short and anteverted nose, bifid thumbs, small 5th finger, limited extension at the knees, bilobed lungs, polymicrogyria, hypoplastic frontal lobes, Chiari malformation

Unknown

Cutis marmorata telangiectasia congenita58

Diffuse telangiectasias of the mucous membranes and skin, including palms and soles; may ulcerate; can be asssociated with hemihypertrophy; closely related to macrocephaly-cutis marmorata

Unknown

Daentl59

Short stature, progressive glomerulosclerosis, sparse hair, thin skin, blue sclera, delayed dentition, joint laxity, normal intelligence, C-I

AR/XLR

Duane anomaly-Chiari malformation60

Duane retraction of the eye reported in two cases with C-I; possible non-random association

Unknown

Ethymalonic aciduria61

Axial hypotonia, spastic diplegia, persistent diarrhea and petechiae in first 3 months, distal edema, orthostatic acrocyanosis, MRI abnormalities of caudate nuclei, putamen, periventricular white matter and dentate nuclei, excretion of 2-ethylmalonic acid and specific acylglycines and acylcarnitines. Case with C-I.

AR (602473) EHTHE1 (Mitochondrial matrix protein), 19q13.32

Fetal cyclophosphamide62

IUGR, microcephaly, coronal synostosis, low-set ears with abnormal pinnae, preauricular pit, hypotelorism, blepharophimosis, proximal thumbs, bilateral absent 4th and 5th toes, partial absent septum pellucidum, simple gyri, C-I

In utero exposure

Frontometaphyseal dysplasia63

Coarse face, prominent suprorbital ridges, poor sinus formation, prominent antigonial notch, partial joint ankylosis, poor metaphyseal modelling, increased interpedicular distances

XLD (305620) FLNA, Xq28

Goldenhar64,65

Variable asymmetric lower face, especially mandibular hypoplasia, microtia, preauricular tags and pits, macrostomia, upper vertebral anomalies, epibulbar dermoids, vaiety of CNS defects in low frequency

Sporadic, some AD (164210), 14q32

Hajdu-Cheney66

Coarse face, short neck, hirsutism, lax joints, acro-osteolysis, bathrocephaly, vertebral anomalies, normal intelligence; CNS anomalies include hydrocephalus (7/49) and syringomyelia

AD (102500)

Hypophophatemic rickets67

Short stature with vitamin D-resistant rickets, defective renal reabsorption of phosphate, hypophosphatemia, may have osteosclerosis and/or craniosynostosis; C-I due to bony anomaly and small posterior fossa

XLD (307800) PHEX, Xp11.2

Hypopituitarism-Chiarisyringomyelia68

Association between breech presentation, developed hypopituitarism and syringomyelia, perhaps due to birth trauma; association with Chiari I and hypothalamic-pituitary anomalies also noted

Birth trauma possibly

48

(continued)

705

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Neuromuscular Systems

Table 15-21. Syndromes with Chiari malformation (continued) Syndrome

Prominent Features

Causation Gene/Locus

Kabuki

Variable developmental delay, hypotonia, long palpebral fissures with everted lateral 1/3 of the lower lid, ptosis, broad nasal tip, cleft/high-arched palate, prominent ear lobes, congenital heart and renal anomalies, prominent fetal finger pads, joint hypermobility, patellar dislocation, premature thelarche

Uncertain AD? (147920)

LEOPARD69

Multiple lentigines, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, sensorineural deafness. Case report with C-I.

AD (151100) PTPN11, 12q24.1

Macrocephaly-cutis marmorata58

Congenital reticular vascular pattern seen in association with hemihypertrophy, hemiatrophy, aplasia cutis congenita, cavernous hemangiomas of the skin, developmental delay; macrocephaly, seizures, and other associations are uncommon and include digital and congenital heart defects. Two cases with C-I.

Unknown (602501)

Neurocutaneous melanosis70

Classical and variant forms of cutaneous pigmented nevi and leptomeningeal melanosis with malignant change, intracranial anomalies and cysts, arachnoid villi infiltration in some cases

Unknown

Neurofibromatosis71,72

Cafe´-au-lait spots, neurofibromata, Lisch nodules, occasional plexiforum neuromas, pseudarthrosis, and diverse complications of tumors; C-1 appears to be an uncommon complication

AD (162200) NF1, 17q11.2

Noonan73

Variable mental retardation and short stature, ptosis, downslanting palpebrae, low/ abnormal ears, short/webbed neck, malformation, pulmonary valve stenosis/dysplasia; hydrocephalus in about 5%; C-I reported

AD (163950) PTPN11, 12q24.1

Oculo-skeletal-abdominal74

Blepharophimosis, epicanthus inversus, hypertelorism, simple philtrum, high palate, accessory nipples, platybasia, short posterior fossa, occipital horn, AC-II

AR

Otopalatodigital II75

Mandibular hypoplasia, cleft palate, malar hypoplasia, downslanting palpebrae, narrow ribs, bowed forearms and legs, absent fibulas and carpals, pelvic hypoplasia. Case report with C-I.

XLR (311300) FLNA, Xq28

Pfeiffer: oligodactylyabnormal facies76

Absent fibula and ulna, oligodactyly, contractures, bowed femora, cleft lip/palate, absent cerebellar vermis and velum medullare, lethal. C-II?

AR (228930)

Pierre-Robin77

Hypoplastic mandible in association with a U-shaped cleft palate and glossoptosis; report in association with C-I possibly chance

Multifactorial

Renal-coloboma78

Eye anomalies include coloboma, morning glory disc, myopia, microphthalmos; renal includes glomerulonephritis, immune complex disease, interstitial fibrosis, tubular atrophy, renal failure. Case reported with C-I.

AD (120330) PAX2, 10q24-q25

Schwartz-Jampel79

Myotonic myopathy, blepharophimosis, difficulty opening mouth, myopathic face, ptosis, muscle wasting, joint limitation, kyphoscoliosis, lumbar lordosis, pectus carinatum, bowed long bones, wide metaphyses, platyspondyly, coronal cleft vertebra

AR/AD (255800) HSPG2 (perlecan), 1p36.1

Seckel80

Severe IUGR, proportionate growth failure, severe mental retardation, receding forehead and chin, downslanting palpebrae, prominent curved nose, dislocated radial head. Case with postnatal onset C-I.

AR (210600) ATR, 3q22.1-q24 SCKL2, 18p11.31-q11.2

Spondyloepiphyseal dysplasia tarda81

The uncommon autosomal dominant form of SED-tarda with epiphyseal changes and platyspondyly; all three affected members of a family had C-I

AD

Trisomy 1882

Typical findings of trisomy 18, normal spine, C-II. One case.

Chromosomal imbalance

Velocardiofacial83

Long narrow face, retrognathia, prominent nose with hypoplastic tip and alae, cleft palate, small optic discs, short stature, narrow hands, mild to moderate delay, congenital heart; especially conotruncal defects; craniovertebral anomalies and C-I may be common

AD (192430) del 22q11.2 del 10p

Williams syndrome84

Mild microcephaly and growth failure, short palpebrae, stellate irides, periorbital fullness, anteverted nares, full lips, supravalvular aortic stenosis, friendly personality. Several cases of C-I reported.

AD (194050) del 7q11.23 Elastin, LIMK1

149

common, and suggests that a greater proportion of cases than thought previously are asymptomatic. Elster and Chen86 found 68 cases among 12,226 unselected MRI studies (0.55%), and Meadows et al.30 found 175 among 22,591 studies (0.77%). A lower rate of 0.24% was obtained in a Japanese series.33 There is an unexplained female excess of about 3:2 in most series, although Milhorat et al.10 obtained a 3:1 ratio. The sex difference is not apparent in all pediatric series,12 and pregnancy/delivery has been suggested as a possible trigger. Comparative measurements of the posterior brain to fossa volumes in men and women would be of

interest (vide infra). The frequency and sex distribution of C-II is directly related to population rates of neural tube defects (NTDs), which are discussed in Section 16.1. C-III is the least common of the established types, and it accounted for only 5 of 514 cases (0.97%) of Chiari malformations in three series reviewed by Caldarelli et al.6 The largest series of patients with C-III was nine, and in 2003 Cakirer46 described two cases and was able to find 22 others in the literature. There is a growing consensus that C-I is a primary defect of the para-axial mesoderm, with evidence derived mainly from the

Brain

absence of associated neuroectodermal anomalies in patients and their relatives, and from studies suggesting a decreased size of the posterior fossa. Vega et al.87 used several posterior fossa length and angle measurements from standard radiographs and CT scans to estimate the posterior fossa volume. The most discriminating variables were clivus length and posterior fossa area in the midsagittal plane, which allowed correct classification of 76% of patients and 79% of controls into their correct group. However, there was overlap, and 10 of 23 patients showed no evidence of occipital dysplasia. Other studies have included those of Nishikawa et al.,88 who showed that patients and controls had comparable posterior brain volumes (PBV) and axial length of the hindbrain, but that the patients had higher PBV to posterior fossa volume (PFV) ratios. They demonstrated that the supraocciput and exocciput were small, and that patients with the additional problem of basilar invagination had the most elevated PBV/PFV ratios and lower levels of herniation. Christophe and Dan89 used MRI to study children and noted that midsagittal vermis area, and vermis to PFV ratio, were elevated in C-I. However, the length of the tonsillar herniation and the presence of absence of a syrinx showed no correlation with any measurement, suggesting that other factors must be at play in determining symptomatology. In that regard, Stovner et al.90 noted significantly smaller and shallower posterior fossa in patients with C-I than in controls. Perhaps surprising was that there was a positive correlation between a relatively larger posterior fossa and the degree of tonsillar herniation, as well as with the occurrence of pyramidal and cerebellar signs. There was no such correlation with hydrocephalus or syringomyelia. This observation led the authors to propose that more severe early herniation in a small posterior fossa has the secondary effect of forcing an expansion of the posterior fossa. This might explain the overlap of measurements between patients and controls that has been noted in most studies. A primary para-axial defect is compatible with the experimental vitamin A animal model of Chiari malformation developed by Marin-Padilla and Marin-Padilla,91 and with the association of C-I with conditions that may reduce the size of the posterior fossa, such as achondroplasia, hypophosphatasia, craniosynostosis, and cerebellar tumors.92 Thompson et al.93 observed that 10 of 23 (37%) of their patients with craniosynostosis had a low position of the hindbrain. Overnight intracranial pressure (ICP) monitoring showed a correlation between elevated ICP and the extent of tonsillar descent, and with the size of the posterior fossa. They suggest that elevated ICP and the abnormal basiocciput caused by the craniosynostosis act synergistically to cause the herniation. Diminished volume due to occipital collapse was the explanation given for a case of C-I associated with a craniocervical lymphangiomatosis.94 Somewhat unexpected was the observation that 30% of a series of 50 patients with isolated metopic ridging met the radiologic criteria of C-I.95 Decreased PFV and/or occipital dysplasia have also been observed in apparent autosomal dominant C-I.33,85 Many questions remain as to why some patients become symptomatic and others do not. Wu et al.17 found a correlation between the distance of tonsillar descent and a clinical severity score, but not with any specific clinical measure. There is preliminary evidence that obstructed CSF flow at the craniovertebral junction, as demonstrated by cine-flow MRI, is correlated with clinical symptoms and with the occurrence of a syrinx,96,97 and further studies may provide more specific correlation with types of presentation and outcomes. Relevant to a possible role for CSF flow is the observation that seven of ten children with prior demonstration of normal cerebellar tonsillar position developed C-I after

707

lumboperitoneal shunting for communicating hydrocephalus.98 Four were symptomatic and were successfully treated, two by a ventriculoperitoneal shunt and two by decompression. It also remains unclear why only certain patients develop a syrinx. Tubbs et al.99 found no relationship between the distal level of the conus medullaris and the degree of tonsillar herniation, but only patients with the conus terminating at or below the L2–L3 disc space developed syringomyelia. Anatomical variation of the posterior fossa may also be associated with Chiari type 0 (C-0). Tubbs et al.100 studied six patients with syryngomyelia and their obex at >2 SD below normal. They noted an increased anteroposterior midsagittal distance of the spinomedullary junction at the level of the foramen magnum, an increased angle of the clivus with the floor of the fourth ventricle, and an increased anteroposterior midsagittal distance at the foramen magnum. A number of theories have been proposed concerning the pathogenesis of C-II. The traction theory held that fixation at the level of the associated meningomyelocele prevents the normal ascent of the cord within the spinal canal and causes a traction downward on the cranial contents, with a resulting upward course of the cervical nerves. Against this theory are the normal course of the thoracic nerve roots, the shorter than normal cervical cord, the presence of the medullary kink, and the inconsistent tethering of the spinal cord. Nor does this theory explain the associated gross and microscopic pathologic findings.101,102 Furthermore, Goldstein and Kepes103 failed to produce C-II in animals in which the lower spinal cord had been experimentally fixed, and were able to show that traction on the cord only extends for four segments. Variations of this theory are subject to most of the criticisms of the original.104 The hydrodynamic theory considers that a delay in opening of the foramina of Magendie and Luschka leads to pressure, which if directed to the forebrain results in a posterior fossa that is inadequate to accommodate its contents. Gardner et al.105 proposed that an imbalance of forces from the pulsatile lateral ventricles results in a downward position of the tentorium and an inadequate posterior fossa. Fluid pressure down the cord would account for the commonly associated syrinx. Again, associated skeletal and other anomalies and the actual small size of the posterior fossa and often slit-like fourth ventricle are not well explained. The theory does not fit well with current views on the pathogenesis of the frequently concurrent syrinx, and Hung106 was able to produce C-II in rats that had no evidence of hydrocephalus or aqueductal stenosis. Theories that propose an intrinsic defect of the hindbrain fail to account for the strong association with a NTD or the frequent supratentorial anomalies.102 Primary failure of the pontine flexure to develop suffers the same criticism and experimentally has not been shown to cause C-II.107 Jennings et al.108 carried out a careful neuroanatomical dissection of a 130-day human fetus with myeloschisis and C-II. They noted an apparent dysynchrony between the developing neuroectoderm and mesoderm, most marked in the rhombencephalon and cervicomedullary junction. Noting that initial neural tube closure begins in the seven somite embryo at the cervicomedullary junction, and then progresses caudad and cephalad, they proposed that C-II results from caudal displacement of this initial point of fusion. They argued that this mechanism would account for the established associated anomalies of medullary nuclei and would produce a wave of caudal induction of neural tube closure, out of synchrony with the ability of the neuroectodermal and mesodermal tissue to respond.

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Most currently favored views on the pathogenesis of C-II focus on the role of CSF leakage via the meningomyelocele; thus, a defect in neurulation is considered primary (see Chapter 16). As articulated by McLone and Knepper,102 and based partly on their experimental work with the Splotch mouse model, completion of normal neurulation results in a transient closure of the neurocele (early neural tube). It is hypothesized that this closure normally results in a distention of the neurocele, which has important mechanical roles with direct effects on development of the CNS. With respect to the C-II, the relative collapse of the fourth ventricle due to CSF loss through the spina bifida would result in failure to expand the posterior fossa, and thus an eventual PFB to PFV dissociation. Thus, as articulated by Hori,109 the C-II malformation is in fact a deformation due to a small posterior fossa, which is secondary to the NTD. The difference would relate only to the early timing and severity of the posterior fossa hypoplasia and the occurrence of additional cervical underdevelopment. This is compatible with the experimental hamster model involving underdevelopment of the occipital bone, developed by MarinPadilla and Marin-Padilla,91 which produced changes compatible with both C-I and C-II. According to McLone and Knepper,102 lack of mechanical induction forces throughout the CNS is proposed to have broad secondary effects causing abnormalities in cranial nerve nuclei, heterotopias, cranial lacunae, and thalamic and other anomalies associated with spina bifida. Although nothing is known about the cause of C-III, a deficient expansion of the neurocele because of a high cervicaloccipital neurulation defect is a reasonable hypothesis. Prognosis, Treatment, and Prevention

The prognosis for incident cases of C-I is not known, but it is clear that when the prevalence among series of consecutive MRI studies is compared to the number of individuals who are surgically treated, a significant proportion of cases remains asymptomatic. It is also relatively uncommon for symptoms to appear beyond middle age. Notwithstanding a bias toward ascertainment of symptomatic cases in neurosurgical series, an important percentage of individuals (over 50% in one report110) have been asymptomatic. Further complicating the understanding of prognosis and thus the choice of treatment is the fact that some young patients may show spontaneous, permanent or temporary, resolution of C-I, even of an associated syrinx.111–113 The explanation for this occurrence is unclear but could relate to a tear allowing escape of CSF, a relatively improved growth of the posterior fossa, or perhaps necrosis or atrophy of the cerebellar tonsils. The goals of surgical intervention are to 1) equalize intracranial with intraspinal pressure, 2) restore the posterior fossa subarachnoid space, 3) relieve brain stem pressure, 4) reduce or eliminate syringes, and 5) resolve (or at least stabilize) signs and symptoms.114 Toward those ends, a number of approaches have been attempted including cervical decompression with or without durotomy to the foramen magnum, varying extents of suboccipital and cervical decompression with and without durotomy/ duroplasty, stenting of the fourth ventricle, and plugging of the obex in the face of syringomyelia.115 The latter procedure has largely been abandoned. There is consensus that decompression of the posterior fossa (PFD) is the principal treatment for C-I, with or without a syrinx, and discussion centers around the extent of the occipital craniotomy, whether or not to perform durotomy/ duroplasty, whether to remove/coagulate the cerebellar tonsils, and whether the area of the foramen of Magendie should be explored for obstruction.

Another critical question is who should be treated. Haroun et al.116 explored the issues surrounding treatment through a survey of North American Pediatric Neurosurgeons, and Schijman and Steinbock did the same internationally.115 Unfortunately, the response rate was only 33% and 30.8% respectively, but 77 and 76 individuals did reply. Only 9% and 8% of surgeons, respectively, would recommend operation on an asymptomatic person with isolated C-I. There was also consensus (97%) that patients with progressive scoliosis associated with C-I and a syrinx should be offered surgery, and Schijman and Steinbock115 recorded that 68% would carry out PFD for C-I associated scoliosis even in the absence of syringomyelia. In the international survey, 28% would offer surgery if there was a 2-mm wide syrinx, and this rose to 75% if the syrinx was 8-mm wide. Almost two-thirds of the surgeons voiced the belief, perhaps based on the long-term follow-up of nine patients by Nishizawa et al.,117 that an asymptomatic syrinx is very unlikely to later become symptomatic. The greater propensity to treat the larger lesion is in keeping with the experience of Tubbs et al.72 that asymptomatic syringes that occupy
50% of the cross section of the spinal cord will progress. There is agreement that symptomatic C-I should be treated, but the frequently protean and non-specific presentation can present difficulty in deciding whether or not a patient’s signs or symptoms are related to a C-I. This is relevant to a current controversy as to whether some patients with orthostatic hypotension, fibromyalgia, and/or chronic fatigue syndrome can benefit from PFD. As reviewed by Garland and Robertson,118 all positive evidence to date has been in the form of presentations at meetings, television interviews, and the internet, and the only prospective study has failed to show benefit. Headache and neck pain are the most frequent presenting complaints of C-I, but they are both non-specific. Thus, only 46% of neurosurgeons would recommend surgery to a patient with C-I and occipital headache as the only finding,115 with the remainder either following with repeat MRI or requesting further studies such as cineflow MRI. The percentage that would operate increased to 90 if the patient had an associated syrinx 8 mm in width. Batzdorf,119 in a review of studies published from 1970 to 1989, recorded an overall post-surgical clinical improvement for 53% of patients, but the range in the literature is broad. Factors of importance in making such assessments include the measures used to assess improvement, the age of the patients, the duration and nature of the signs and symptoms, the size of the series, and the length of follow-up. Up to 95% of neurosurgeons surveyed include a PFD in their treatment of C-I,115 and most include a C1 (C1/C2) laminectomy to relieve obstruction from herniation at that level. Specific variations in the approach are generally due to personal opinion as to which method best resolves clinical symptoms, and an assessment of the likelihood of complications. Sindou et al.120 treated 44 adult patients with C-I, 15 of which had an accompanying syrinx, with suboccipital craniectomy, C1 (C1/ C2) laminectomy, extreme lateral foramen magnum opening, and an expansile duroplasty. Outcomes were measured using the Karnofsky Disability Scale and produced excellent to good results, both for those with and without syringomyelia. Follow-up was from 1 to 10 years, and there were no serious complications. The recent results presented by Dones et al.121 were not so optimistic. Of 26 patients treated by PFD, 23 also had a >C1 laminectomy, 13 had dural grafts, and 6 of 16 with a syrinx also had a syrinx to subarachnoid space shunt. All were treated because of ‘‘intractable, progressive, and disabling’’ symptoms. Surgery provided stabilization of symptoms, but neck pain, headache, diplopia, muscle atrophy/weakness, numbness, temperature/pain dissociation,

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spasticity, and sphincter problems showed little if any improvement. Although numbers were small, dysphagia, vertigo, and nystagmus were more likely to resolve. In addition, complications of surgery included hydrocephalus (2), pseudomeningitis (2), and CSF leak (2). The argument for minimizing the lateral extent of the craniectomy is that the objective is not to actually enlarge the posterior fossa, that the small defect poses less future risk to the patient, and that it is less likely to result in cerebellar ‘‘ptosis.’’ Tubbs et al.72 used this approach on a series of 130 pediatric patients and obtained postoperative relief of symptoms in 83%. They had no cases of cerebellar ptosis. Krieger et al.122 also used a limited craniectomy with C1 laminectomy, durotomy with an oxidized cellulose overlay, to treat a series of 31 children, 26 of whom had an associated syrinx. Ninety-four percent of the total signs and symptoms were significantly resolved by 6 months, and 23 (88%) of the syringes improved. The reason for durotomy/duroplasty is twofold. Principally, it is to relieve any restriction to expansion of the cerebellum/brain stem,120 but it also provides a route to determine if the foramen of Magendie is patent, which Tubbs et al.72 emphasize may be veiled over by arachnoid adhesions, thus obstructing CSF flow. The authors found this in 10 cases and believe it important as nine of those patients had a syrinx, compared to 66 of 120 (55%) of those in the group without adhesions. They also noted that a patient without a duroplasty, who continued to suffer headache, was later relieved by that procedure. On the other hand, opening the dura may increase the risk of CSF leak, infection, and the development of a pseudomeningocele. Greater elasticity of the pediatric dura may allow this procedure to be eliminated in a significant proportion of children, and as a compromise in patients ranging in age from 3 months to 26 years, Genitori et al.110 did not open the dura, but removed its outer layer to increase elasticity. They obtained resolution or improvement in all 16 patients with signs limited to the brain stem and in 9 of 10 patients with a syrinx (7 holocord). James and Brant115 obtained good results in a mixed C-I/C-II pediatric population without including duroplasty. A less common primary approach to C-I surgery has been to reduce the obstruction at the foramen magnum by cerebellar tonsillectomy. Resected tonsillar tissue shows cortical atrophy and gliosis and presumably has little, if any, functional importance. Lazareff et al.123 performed tonsillar resection in seven, and coagulation in eight patients. All showed postoperative improvement, including reduction of a syrinx in seven of eight patients. Fischer124 performed sub-pial tonsillar resection along with PFD and duroplasty, and concluded that the tonsillectomy was safe but added no benefit. Tubbs et al.72 performed unilateral tonsillar coagulation in 22 of their 130 (17%) patients, and eight required repeat surgery for continued syringomyelia. Those authors also noted that placement of a fourth ventricle to cervical subarachnoid shunt led to a poorer outcome. An important consideration is the common association of craniovertebral joint (CVJ) anomalies with C-I. Menezes125 found ‘‘hindbrain syndrome’’ in 100 of 2100 (4.8%) patients with a variety of CVJ anomalies and in 92 of 242 (33%) of those with atlas assimilation. He noted an apparent progression from atlantoaxial instability with a reducible ventral impression on the spinal cord in the young, to basilar invagination and non-reducibility in older individuals. Symptomatic patients had a foramen magnum canal diameter of < 19 mm. Reducible lesions were treated with PFD (34). Of the 66 non-reducible lesions, 22 had prior PFD, and 27 had a syrinx to subarachnoid shunt with later symptomatic deterioration. All 66 improved with ventral or ventrolateral de-

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compression, and this included resolution of syringes. Zileli and Cagli126 used a combined anterior transoral and posterior approach to treat nine patients with C-I associated basilar invagination and had good outcomes with no significant morbidity. Clinical outcomes of treatment vary with presentation. Asymptomatic patients may remain so for extended periods,110,117 and many will presumably do so throughout their lives. Headache, neck pain, and sleep apnea appear to show good response in most series,72,119,127 and papilledema, which is uncommon, is also expected to resolve.128 Brain stem signs respond well in some series,110,129 but not in others,119 and motor and sensory signs associated with central cord syndrome tend to show poor recovery.72,129 Sindou et al.120 pointed out that the three patients with a poor response to surgery out of their series of 15 with syringomyelia had a holocord syrinx and were in the clinically worst group preoperatively. There is consensus that the shorter the duration of symptoms, the more likely there will be a postoperative improvement.72,117,121 Postoperative complications include recurrence of symptoms, and there is agreement that long-term follow-up is necessary. Rosen et al.130 have suggested that use of non-autologous graft material may play a role in recurrent symptoms, and failure to recognize anterior compression from CVJ anomalies may also be a factor.125 Postoperative headache, nausea, and vomiting are not uncommon122 and are generally self-limited. Park et al.12 found the latter more common in patients with a syrinx. Poca et al.131 carried out intracranial pressure (ICP) monitoring in 12 patients, beginning 1 day before surgery and continuing for 7 days post surgery. They observed a significant postoperative rise in ICP and in the percent of B-waves, which began to return to normal between 4 and 7 days. The authors hypothesized that the phenomenon was due to rapid revascularization of the cerebellum, and postoperative neuroimaging showed compression of the quadrigeminal cistern and a decrease in the size of the fourth ventricle. Six patients developed mild supratentorial ventriculomegaly, and seven experienced the onset or worsening of headache in the postoperative period. This rise in ICP may be relevant to the uncommon development of acute, and usually self-limited, hydrocephalus shortly after surgery.72,121,122,132 Other complications have been mentioned previously. The situation with respect to pregnant women with C-I requires special consideration because of the risk of acute deterioration due to the pressure stresses of delivery. Parker et al.133 discussed uncomplicated delivery by cesarean section and operative vaginal delivery in two women managed with epidural anesthesia. With respect to anesthesia, it is important to recognize that patients with lower cranial nerve impairment are at increased risk for choking and aspiration.134 There is anecdotal evidence that patients with C-I may be at risk from chiropractic manipulation.135 Although patients with C-I may develop scoliosis in the absence of a syrinx, the association of syrinx and scoliosis is strong. There is also good evidence that PFD, and/or the treatment of symptomatic CVJ anomalies, will lead to either complete resolution or a reduction in the size of the syrinx in a high proportion of cases.12,72,110,122,124,125,136,137 In a review of the literature to 1995, Fischer124 noted that in 51 of 55 cases, the syrinx had diminished or disappeared after PFD. Munishi et al.136 provide some data that duroplasty may be of some marginal benefit in patients with syringomyelia, whereas Park et al.12 found no difference ascribable to operative approach. Genitori et al.110 later removed the cerebellar tonsils in two patients whose syrinx had not responded and obtained improvement; and assuring patency of the foramen of Magendie may play a role in response.72

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What remains to be clearly resolved is what impact resolution of the syrinx has in halting or reversing the progression of scoliosis. Several authors have claimed an arrest or improvement of the scoliosis in a significant proportion (~2/3) of their patients.72,110,137 However, Farley et al.138 has pointed out that the data sets tend to be small and the follow-up short term. The response of the scoliosis does not appear to correlate with the degree of resolution of the syrinx,137 and several groups have noted that more severe initial curves (>408) are more likely to progress despite PFD and resolution of a syrinx.72,137 Results may also be better in younger children.137 Farley138 followed nine children, with a mean age at presentation of 8 years (4–13), and average thoracic curve of 46.38 (þ/18, 1 SD), for a period of 1 to 11 years. At presentation, six of the patients were candidates for spinal fusion and none of them improved, despite resolution of the syrinx. Disappointing was the observation that of the remaining three children, whose initial curves were between 208 and 348, two were stable for 5 years but then progressed, while the third was stable after 2 years of follow-up. Of his group, five had, and three were awaiting, spinal fusion by the end of the study period. Although C-II virtually always accompanies myeloschisis, the recognition that it may be symptomatic is relatively recent. Estimates of the prevalence of symptoms range from 8.7–20% of cases. A point of debate has been how much of the symptomatology of C-II is intrinsic to the neuropathology, and how much is acquired due to compression and/or hemorrhage.139 Hemorrhage is thought to result from compromise of the cranial venous outlets associated with raised intracranial pressure.3 Hori109 has stated that most pathologic studies of C-II reveal only minor heterotopias without significant dysgenesis, which would suggest that much of the symptomatology is acquired. On the other hand, Gilbert et al.140 found evidence of brain dysplasia in 76% of 25 symptomatic patients. Current thinking favors two groups of symptomatic patients: 1) those who present very early with acute deterioration and have brain dysplasia141,142 and 2) those who present at an older age with more protean onset due to the posterior fossa syndrome. For example, in one series of 22 infants and children, only 4/14 infants who underwent surgical decompression because of persistent symptoms became asymptomatic, and seven died, whereas five patients who presented after age 3 years all showed complete recovery.35 Patients symptomatic with vagal and nasopharygeal signs had a 50% mortality, and only half of the survivors showed improvement. Rubin and Wherrett143 reported a beneficial response to atropine sulfate in a young girl with respiratory compromise that they proposed was vagally mediated. Complications related to the posterior fossa and brain stem dysfunction continue to be the leading cause of death in young children with meningomyelocele.144 Efforts have been made to predict which children will become symptomatic and/or improve with treatment. Assessments by Wolpert et al.141 and Narayan et al.145 failed to show any relationship between the MRI determined level of the herniation and whether the patient would become symptomatic, and if so the type of symptoms that would occur or would respond to treatment outcome. Teo et al.139 found that the MRI level correlated well with what was found at operation. Although the MRI showed no correlation with surgical results, it did have predictive value for the likelihood of recurrence. Dyste et al.8 used logistic regression analysis and determined that the presence or absence of muscle atrophy, ataxia, or scoliosis predicted outcome with 95% confidence. However, the majority of their cases were C-I.

Brain stem auditory evoked responses may show improvement after shunting or treatment; they tend also to be normal in patients older than 8 years at presentation and do not appear to correlate with the severity of the myeloschisis or to have predictive value with respect to which cases will become symptomatic.146 Similarly, findings on MRI do not appear to allow prediction as to who will be symptomatic or to their long-term prognosis.141 Some recent studies that have reviewed surgical results from children and young adults with C-II have been encouraging. Teo et al.139 reported 30 patients treated with PFD that included C1 laminectomy in 29, and in 27 duroplasty, release of adhesions, and reestablishment of CSF flow from the fourth ventricle. At 1 year, 24 (80%) of patients had complete relief of symptoms, in four (14%) they were partly resolved, and in one each they were worse and unchanged. Of note, by a mean of 49 months, 10 of the 24 with resolved symptoms had a recurrence; all responded to reoperation. Hudgins and Boydston144 stress the importance of not overlooking regrowth of bone as a cause for recurrent symptoms, and recommended thin-slice CT for diagnosis. James and Brant115 obtained good results in 18 young patients with C-II while avoiding durotomy and its possible complications. They did have two late deaths among their group, but both patients had been tracheostomy-dependent prior to PFD and died later of related complications. There were no recurrences of symptoms with follow-up ranging from 26 months to 18 years. Bruxton et al.147 reported treating a patient with a cervical meningomyelocele, C-II, hydrocephalus, cervical syrinx by neuroendoscopic third ventriculostomy with resolution of the hydrocephalus and the syrinx. The results of surgical treatment in adults are also quite variable, with about one-half of patients showing improvement, 30% remaining stable, and the remainder deteriorating.4,9 As with C-I, outcome is dependent on the measures examined. The prognosis for normal intelligence in survivors parallels that for meningomyelocele (Chapter 16). There are few data on the optimal treatment of patients with C-III, as few cases have been reported and only a fraction of those have survived. Patients generally present the double issues of an encephalomeningocele and marked hydrocephalus. Most surgeons have elected to first treat the cranial defect and shunt the hydrocephalus later.6 However, an unremarkable recovery was described by Snyder et al.148 with a reversal of the order of intervention, and surgery was limited to ventriculoperitoneal shunting in the first of two patients described by Cakirer.46 The posterior lesion was relatively mild in that case. His second patient appears to have undergone concurrent closure and shunting, but no follow-up information was given. Prevention of Chiari malformations is directly related to reduction in the rate of NTDs and is considered in Section 16.1. On prenatal sonography, the abnormal cerebellar anatomy associated with meningomyelocele may be seen as an abnormal crescent shape, with the concave surface anterior, and this is considered further in Section 16.1. C-III can be considered a form of NTD, and its prevalence might be affected by measures taken to reduce the rates of NTD. C-I would appear to be largely non-preventable, but heightened awareness of its relative frequency and presentation would reduce delays in the diagnosis of symptomatic cases, thereby reducing patient suffering, and hopefully non-reversible complications. References (Chiari Malformations) 1. Schijman E: History, anatomic forms, and pathogenesis of Chiari malformations. Childs Nerv Syst 20:323, 2004.

Brain 2. Strayer A: Chiari I malformation: clinical presentation and management. J Neurosci Nurs 33:90, 2001. 3. Chuman RM: The Chiari malformations: a constellation of anomalies. Sem Pediatr Neurol 2:220, 1995. 4. Eisenstat DDR, Berstein M, Fleming JFR, et al.: Chiari malformation in adults: a review of 40 cases. Can J Neurol Sci 13:221, 1986. 5. Blumenthal DT, Riggs JE: Please don’t call me ‘Arnold-Chiari’ unless you mean it. Arch Neurol 54:16, 1997. 6. Caldarelli M, Rea G, Cincu R, et al.: Chiari type III malformation. Childs Nerv Syst 18:207, 2002. 7. Neisen CE: Malformations of the posterior fossa: current perspectives. Sem Pediatr Neurol 9:320, 2002. 8. Dyste GN, Meneqes AH, Van Gilder JC: Symptomatic Chiari malformations: an analysis of presentation, management, and long term outcome. J Neurosurg 71:159, 1989. 9. Levy Wl, Mason L, Hahn JF: Chiari malformation presenting in adults: a surgical experience in 127 cases. Neurosurgery 12:377, 1985. 10. Milhorat TH, Chou MW, Trinidad EM, et al.: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery 44:1005, 1999. 11. Brill CB, Gutierrez J, Mishkin MM: Chiari I malformation: association with seizures and developmental disabilities. J Child Neurol 12:101, 1997. 12. Park JK, Gleason PL, Madsen JR, et al.: Presentation and management of Chiari I malformation in children. Pediatr Neurosurg 26:190, 1997. 13. Greenlee JDW, Donovan KA, Hasan DH, et al.: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under age 6 years. Pediatrics 110:1212, 2002. 14. Taylor FR, Larkins MV: Headache and Chiari I malformation: clinical presentation, diagnosis, and controversies in management. Curr Pain Headache Report 6:331, 2002. 15. Sansur CA, Heiss JD, DeVroom HL, et al.: Pathophysiology of headache associated with cough in patients with Chiari I malformation. J Neurosurg 98:453, 2003. 16. Amer TA, El-Shmam OM: Chiari malformation type I: a new MRI classification. Magnet Res Imag 15:397, 1997. 17. Wu YW, Chin CT, Chan KM, et al.: Pediatric Chiari I malformations: do clinical and radiological features correlate. Neurology 53:1271, 1999. 18. Dauser RC, DiPietro MA, Venes IH: Symptomatic Chiari I malformation in childhood: a report of 7 cases. Pediatr Neurosci 14:184, 1988. 19. Grosso S, Scattolini R, Paolo G, et al.: Association of Chiari malformation, mental retardation, speech delay, and epilepsy: a specific disorder? Neurosurgery 49:1099, 2001. 20. Shiihara T, Shimizu Y, Mitsui T, et al.: Isolated sleep apnea due to Chiari type I malformation and syringomyelia. Pediatr Neurol 13:266, 1995. 21. Rabec C, Laurent G, Beaudouin N, et al.: Central sleep apnea in Arnold-Chiari malformation: evidence of pathophysiological heterogeneity. Eur Respir J 12:1482, 1998. 22. Botelho RV, Bittencourt LR, Rotta JM, et al.: Polysomnographic respiratory findings in patients with Arnold-Chiari type I malformation and basilar invagination, with or without syringomyelia: preliminary report of a series of cases. Neurosurg Rev 23:151, 2000. 23. Yoshimi A, Nomura K, Furune S: Sleep apnea syndrome associated with a type I Chiari malformation. Brain Dev 24:49, 2002. 24. Allsop GM, Karkanevatos A, Bickerton RC: Abductor vocal fold palsy as a manifestation of type one Arnorld Chiari malformation. J Laryngol Otol 114:221, 2000. 25. Rosetti P, Taib NOB, Brotchi J, et al.: Arnold Chiari type I malformation presenting as a trigeminal neuralgia: case report. Neurosurgery 44:1122, 1999. 26. Jacome DE: Blepharoclonus and Arnold-Chiari malformation. Acta Neurol Scand 104:113, 2001. 27. Chiari type I presenting as left glossopharyngeal neuralgia with cardiac syncope. Neurosurg Rev 25:99, 2002. 28. Hudgins RJ: Paroxysmal rage as a presenting symptom of the Chiari I malformation. Report of two cases. J Neurosurg 91:328, 1999. 29. Stovner LJ, Sjaastad O: Segmental hyperhydrosis in two siblings with Chiari type I malformation. Eur Neurol 35:149, 1995.

711 30. Meadows J, Kraut M, Guarnieri M, et al.: Asymptomatic Chiari type I malformations identified on magnetic resonance imaging. J Neurosurg 92:920, 2000. 31. Aboulezz AO, Sartor K, Geyer CA, et al.: Position of cerebellar tonsils in the normal population and in patients with Chiari malformation: a quantitative approach with MR imaging. J Comput Assist Tomogr 9:1033, 1985. 32. Barkovich AJ, Wippold FJ, Sherman JL, et al.: Significance of cerebellar tonsillar position on MR. AJNR Am J Neuroradiol 7:795, 1986. 33. Furuya K, Sano K, Segawa H, et al.: Symptomatic tonsillar ectopia. J Neurol Neurosurg Psychiatry 64:221, 1998. 34. Nash J, Cheng JS, Meyer GA, et al.: Chiari type I malformation: overview of diagnosis and treatment. Wisc Med J 101:35, 2002. 35. Bell WO, Charney EB, Bruce DA, et al.: Symptomatic Arnold-Chiari malformation: review of experience with 22 cases. J Neurosurg 66:812, 1987. 36. Holliday PO, Pillsbury D, Kelly DL: Brainstem auditory evoked potentials in Arnold-Chiari malformation: possible prognostic value and changes with surgical decompression. Neurosurgery 16:48, 1985. 37. Beuls E, Vanormelingen L, van Aalst J, et al.: The Arnold-Chiari type II malformation at midgestation. Pediatr Neurosurg 39:149, 2003. 38. Choi SS, Tran LP, Zalzal GH: Airway abnormalities in patients with Arnold-Chiari malformation. Otolaryngol Head Neck Surg 121:720, 1999. 39. Kirsch WM, Duncan BR, Black FO, et al.: Laryngeal palsy in association with meningomyelocele, hydrocephalus and the Arnold-Chiari malformation. J Neurosurg 28:207, 1968. 40. Koehler J, Schwarz M, Urban PP, et al.: Masseter and blink reflex abnormalities in Chiari II malformation. Muscle Nerve 24:425, 2001. 41. Naidich TP, Pudlowski RM, Naidich JB: Computed tomographic signs of Chiari II malformation. Part II: midbrain and cerebellum. Neuroradiology 134:391, 1980. 42. Naidich TP, Pudlowski RM, Naidich JB, et al.: Computed tomographic signs of the Chiari II malformation. Part I: skull and dural partitions. Neuroradiology 134:65, 1980. 43. Naidich TP, Pudlowski RM, Naidich JB: Computed tomographic signs of the Chiari II malformation. Part III: Ventricles and Cisterns. Neuroradiology 134:657, 1980. 44. Gammal TE, Mark EK, Brooks BS: MR imaging of Chiari II malformation. AJR Am J Roentgenol 150:163, 1988. 45. D’Addario V, Pinto V, Del Bianco A, et al.: The clivus-supraocciput angle: a useful measurement to evaluate the shape and size of the fetal posterior fossa and to diagnose Chiari II malformation. Ultrasound Obstet Gynecol 18:146, 2001. 46. Cakirer S: Chiari III malformation. Varieties of MRI appearances in two patients. Clin Imag 27:1, 2003. 47. Lee R, Tai KS, Cheng PW, et al. Chiari III malformation: antenatal MRI diagnosis. Clin Radiol 57:759, 2002. 48. Kan DC, Tsai FJ, Peng CT, et al.: Fetal alcohol syndrome with ArnoldChiari malformation: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 39:116, 1998. 49. Chang Y-T, Tsai F-J, Shen W-C, et al.: Antley-Bixler syndrome associated with Arnold-Chiari malformation. Acta Paediatr 89:737, 2000. 50. Wang TJ, Hung KS, Chen PKT, et al.: Brief report of special case, Beare-Stevenson cutis gyrata syndrome with Chiari malformation. Acta Neurochir 144:743, 2002. 51. Paquis P, Lonjon M, Brunet M, et al.: Chiari type I malformation and syringomyelia in unrelated patients with blepharophimosis. J Neurosurg 89:835, 1998. 52. Kunishige M, Azuma H, Masuda K, et al.: Interferon alpha-2a therapy for disseminated intravascular coagulation in a patient with rubber bleb nevus syndrome. Angiology 48:273, 1997. 53. Gripp KW, Nicholson L, Scott CI Jr: Apparently knew syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation. Am J Med Genet 61:382, 1996. 54. Delrue MA, Chateil JF, Arveiler, et al.: Costello syndrome and neurological abnormalities. Am J Med Genet 123A:301, 2003.

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55. Coria F, Quintana F, Rebollo M, et al.: Occipital dysplasia and Chiari type I deformity in a family. J Neurol Sci 62:147, 1983. 56. Cinalli G, Renier D, Sebag G, et al.: Chronic tonsillar herniation in Crouzon’s and Apert’s syndrome: the role of premature synostosis of the lambdoid suture. J Neurosurg 83:575, 1995. 57. Cohen MM Jr, MacLean RE: Craniosynostosis: Diagnosis, Evaluation, and Management, ed 2. Oxford University Press, New York, 2000. 58. Tubbs RS, Smyth MD, Wellons JC, et al.: Cutaneous manifestations and the Chiari I malformation. Pediatr Neurol 29:250, 2003. 59. Daentl DL, Townsend JJ, Siegel RC, et al.: Familial nephrosis, hydrocephalus, thin skin, blue sclera syndrome: clinical, structural and biochemical studies, Birth Defects Orig Artic Ser XIV(6B):315, 1978. 60. Prats JM, Garaizar C: Duane retraction syndrome associated with Chiari I malformation. Pediatr Neurol 10:340, 1994. 61. Nowaczyk MJM, Blaser SI, Clarke JTR: Central nervous system malformations in ethylmalonic encephalopathy. Am J Med Genet 75:292, 1998. 62. Enns GM, Roeder E, Chan RT: Apparent cyclophosphamide (cytoxan) embryopathy; a distinct phenotype? Am J Med Genet 86:237, 1999. 63. Boduroglu K, Tuncbilek E: Frontometaphyseal dysplasia: a case with Arnold-Chiari malformation and bracket epiphysis of the first metacarpal bone. Pediatr Int 41:181, 1999. 64. Aleksic S, Budzilovich G, Greco MA, et al.: Intracranial lipomas, hydrocephalus and other CNS anomalies in oculoauriculovertebral dysplasia (Goldenhar-Gorlin syndrome). Child Brain 11:285, 1984. 65. Mesiwala AH, Shaffrey CI, Gruss JS, et al.: Atypical hemifacial microsomia associated with Chiari I malformation and syrinx: further evidence indicating that Chiari I malformation is a disorder of the paraaxial mesoderm. J Neurosurg 95:1034, 2001. 66. Ade`s LC, Morris LL, Haan EA: Hydrocephalus in Hajdu-Cheney syndrome. J Med Genet 30:175, 1993. 67. Caldemeyer KS, Boaz JC, Wappner RS, et al.: Chiari I malformation: association with hypophosphatemic rickets and MR imaging appearance. Radiology 195:733, 1995. 68. Arifa N, Leger J, Garel C, et al.: Anomalies malformatives ce´re´brales associe´es a l’insuffisance somatotrope chez l’enfants: marqeurs pour le diagnostic? Arch Pediatr 6:14, 1999. 69. Agha A, Hashimoto K: Multiple lentigines (Leopard) syndrome with Chiari I malformation. J Dermatol 22:520, 1995. 70. Frieden IJ, Williams ML, Barkovich AJ: Giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children. J Am Acad Dermatol. 31:423, 1994. 71. Dooley J, Vaughan D, Riding M, et al.: The association of Chiari Type I malformation and neurofibromatosis type I. Clin Pediatr 32: 189, 1993. 72. Tubbs RS, McGirt MJ, Oakes WJ: Surgical experience in 130 patients with Chiari I malformations. J Neurosurg 99:291, 2003. 73. Colli R, Columbo P, Russo F, et al.: Type I Arnold Chiari malformation in a subject with Noonan syndrome. Pediatr Med Chir 23:61, 2001. 74. Mingarelli R, Scanderberg AC, Dallapiccola B: Two sisters with a syndrome of ocular, skeletal, and abdominal abnormalities (OSA syndrome). J Med Genet 33:884, 1996. 75. Hung P-C, Wang H-S, Lui T-N: Coexistence of oto-palato-digital syndrome type II and Arnold-Chiari I malformation in an infant. Brain Dev 21:488, 1999. 76. Pfeiffer RA, Stoss H, Voight HJ, et al.: Absence of fibula and ulna with oligodactyly, contractures, right-angle bowing of femora, abnormal facial morphology, cleft lip/palate and brain malformation in two sibs: a possibly new lethal syndrome. Am J Med Genet 29:901, 1988. 77. Lee J, Hida K, Seki T, et al.: Pierre Robin syndrome associated with Chiari I malformation. Childs Nerv Syst 20:1, 2004. 78. Eccles MR, Schimmenti LA: Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations. Clin Genet 56:1, 1999. 79. Samimi SS, Lesley WS: Craniocervical CT and MRI imaging of Schwartz-Jampel syndrome. AJNR Am J Neuroradiol 24:1694, 2003. 80. Hopkins TE, Haines SJ: Rapid development of Chiari I malformation in an infant with Seckel syndrome and craniosynostosis. Case report and review of the literature. J Neurosurg 98:1113, 2003.

81. Gripp KW, Scott CI Jr, Nicholson L, et al.: Chiari malformation and tonsilar ectopia in twin brothers and father with autosomal dominant spondylo-epiphyseal dysplasia tarda. Skeletal Radiol 26:131, 1997. 82. Case ME, Sarnat HB, Monteleone P: Type II Arnold-Chiari malformation with normal spine in trisomy 18. Acta Neuropathol 37:259, 1977. 83. Hultman CS, Riski JE, Cohen SR, et al.: Chiari malformation, cervical spine anomalies, and neurologic deficits in velocardiofacial syndrome. Plast Reconstr Surg 106:16, 2000. 84. Mercuri E, Atkinson J, Braddick O, et al.: Chiari I malformation in asymptomatic young children with Williams syndrome: clinical and MRI study. Pediatr Neurol 12:84, 1995. 85. Atkinson JLD, Kokmen E, Miller GM: Evidence of posterior fossa hypoplasia in the familial variant of adult Chiari I malformation: case report. Neurosurgery 42:401, 1998. 86. Elster AD, Chen MY: Chiari I malformations: clinical and radiologic reappraisal. Radiology 183:347, 1992. 87. Vega A, Quintana F, Berciano J: Basichondrocranium anomalies in adult Chiari I type malformation: a morphometric study. J Neurol Sci 99:137, 1990. 88. Nishikawa M, Sakamoto H, Hakuba A, et al.: Pathogenesis of Chiari malformation: a morphometric study of the posterior fossa. J Neurosurg 86:40, 1997. 89. Christophe C, Dan B: Magnetic resonance imaging cranial and cerebral dimensions: is there a relationship with Chiari I malformation? A preliminary report in children. Eur J Paediatr Neurol 3:15, 1999. 90. Stovnes LJ, Bergan U, Nilsen G, et al.: Posterior cranial fossa dimensions in the Chiari I malformation: relation to pathogenesis and clinical presentation. Neuroradiology 35:113, 1993. 91. Marin-Padilla M, Marin-Padilla TM: Morphogenesis of experimentally induced Arnold-Chiari malformation. J Neurol Sci 50:29, 1981. 92. Lonser RR, Heiss JD, Oldfield EH: Syringomyelia, hemangioblastomas, and Chiari I malformation. Case illustration. J Neurosurg 90:169, 1999. 93. Thompson DN, Harkness W, Jones BM, et al.: Aetiology of herniation of the hindbrain in craniosynostosis. An investigation incorporating intracranial pressure monitoring and magnetic resonance imaging. Pediatr Neurosurg 26:288, 1997. 94. Jea A, McNeil A, Bhatia S, et al.: A rare case of lymphangiomatosis of the craniocervical spine in conjunction with a Chiari I malformation. Pediatr Neurosurg 39:212, 2003. 95. Tubbs RS, Elton S, Blount JP, et al.: Preliminary observations on the association between simple metopic ridging in children without trigonocephaly and the Chiari I malformation. Pediatr Neurosurg 35:136, 2001. 96. Ventureyra ECG, Aziz HA, Vassilyadi M: The role of cine flow MRI in children with Chiari I malformation. Childs Nerv Syst 19:109, 2003. 97. Bhadelia RA, Bogdan AR, Wolpert SM, et al.: Cerebrospinal flow waveforms: analysis in patients with Chiari I malformation by means of gated phase-contrast MR imaging velocity measurements. Radiology 196:195, 1995. 98. Payner TD, Prenger E, Berger T, et al.: Acquired Chiari malformations: incidence, diagnosis, and management. Neurosurgery 34:429, 1994. 99. Tubbs RS, Elton S, Bartolucci AA, et al.: The position of the conus medullaris in children with Chiari I malformation. Pediatr Neurosurg 33:249, 2000. 100. Tubbs RS, Elton S, Grabb P, et al.: Analysis of the posterior fossa in children with the Chiari 0 malformation. Neurosurgery 48:1050, 2001. 101. McLendon RE, Grain BJ, Oakes WJ, et al.: Cerebral polygyria in the Chiari type II (Arnold-Chiari) malformation. Clin Neuropathol 4:200, 1985. 102. McLone DG, Knepper PA: The cause of Chiari II malformation: a unified theory. Pediatr Neurosci 15:1, 1989. 103. Goldstein F, Kepes JJ: The relationship of the Arnold-Chiari malformation to lumbar meningomyeloceles: an experimental study. Proc Fifth Int Congr Neuropathol, Excerpta Medica, 1965, p 734. 104. Roth M: Cranio-cervical growth collision: another explanation of the Arnold-Chiari malformation and of basilar impression. Neuroradiology 28:187, 1986.

Brain 105. Gardner WJ, Karnosh U, Angel J: Syringomyelia: a result of embryonal atresia of the foramen of Magendie. Trans Am Neurol Assoc 82:144, 1957. 106. Hung C-F: The relationship between hydrocephalus and Chiari type II malformation in the experimental rat fetuses with Arnold-Chiari malformation. Proc Natl Sci Council, Part B, Rep China 10:118, 1986. 107. Warkany J, O’Toole BA: Experimental spina bifida and associated malformations. Childs Brain 8:18, 1981. 108. Jennings MT, Clarren SK, Kockich VG, et al.: Neuroanatomic examination of spina bifida aperta and the Arnold-Chiari malformation in a 130 day human fetus. J Neurol Sci 54:325, 1982. 109. Hori A: Treatment of the Chiari malformation by Drs. H.E. James and A. Brant. Childs Nerv Syst 18:461, 2002. 110. Genitori L, Peretta P, Nurisso C, et al.: Chiari type I anomalies in children and adolescents: minimally invasive management in a series of 53 cases. Childs Nerv Syst 16:707, 2000. 111. Avellino AM, Kim DK, Weinberger E, et al.: Resolution of spinal syringes and Chiari I malformation in a child. J Neurosurg 84:708, 1996 112. Sun JCL, Steinbok P, Cochrane DD: Spontaneous resolution and recurrence of a Chiari I malformation and associated syringomyelia. J Neurosurg (Spine) 92:207, 2000. 113. Sun PP, Harrop J, Sutton LN, et al.: Complete spontaneous resolution of childhood Chiari I malformation and associated syringomyelia. Pediatrics 107:182, 2001. 114. Schijman E, Steinbok P: International survey on the management of Chiari I malformation and syringomyelia. Childs Nerv Syst 20:ePub Feb 14, 2004. 115. James HE, Brant A: Treatment of the Chiari malformation with bone decompression without durotomy in children and young adults. Childs Nerv Syst 18:202, 2002. 116. Haroun RI, Guarnieri M, Meadow JJ, et al.: Current opinions for the treatment of syringomyelia and Chiari malformations: survey of the Pediatric Section of the American Association of Neurological Surgeons. Pediatr Neurosurg 33:311, 2000. 117. Nishizawa S, Yokoyama T, Yokota N, et al.: Incidentally identified syringomyelia associated with Chiari I malformations: is early intervention surgery necessary? Neurosurgery 49:637, 2001. 118. Garland EM, Robertson D: Chiari I malformation as a cause of orthostatic intolerance symptoms: A media myth? Am J Med 111:546, 2001. 119. Batzdorf U: Syringomyelia related to abnormalities at the level of the craniovertebral junction. In: Current Neurosurgical Practice. Syringomyelia: Current Concepts in Diagnosis and Treatment. Williams-Wilkins, Baltimore, 1991, p 163. 120. Sindou M, Cha´vez-Machuca J, Hasish H: Cranio-cervical decompression for Chiari I malformation, adding extreme lateral foramen magnum opening and expansile duroplasty with arachnoid preservation. Technique and long-term functional results in 44 consecutive adult cases - comparison with literature data. Acta Neurocir 144:1005, 2002. 121. Dones J, De Jesu´s O, Colen CB, et al.: Clinical outcomes in patients with Chiari I malformation: a review of 27 cases. Surgical Neurol 60:142, 2003. 122. Krieger MD, McComb JG, Levy ML: Toward a simpler surgical management of Chiari I malformation in a pediatric population. Pediatr Neurosurg 30:113, 1999. 123. Lazareff JA, Galarza M, Gravoti T, et al.: Tonsillectomy without craniectomy for the management of infantile Chiari I malformation. J Neurosurg 97:1018, 2002. 124. Fischer EG: Posterior fossa decompression for Chiari deformity, including resection of the cerebellar tonsils. Childs Nerv Syst 11:625, 1995. 125. Menezes AH: Primary craniovertebral anomalies and the hindbrain herniation syndrome (Chiari I): data base analysis. Pediatr Neurosurg 23:260, 1995. 126. Zileli M, Cagli S: Combined anterior and posterior approach for managing basilar invagination associated with type Chiari I malformation. J Spinal Disord Tech 15:284, 2002.

713 127. Omer S, Al-Kawi MZ, Bohlega S, et al.: Respiratory arrest: a complication of Arnold-Chiari malformation in adults. Eur Neurol 36:36, 1996. 128. Vaphiades MS, Eggenberger ER, Miller NR, et al.: Resolution of papilledema after neurosurgical decompression for primary Chiari I malformation. Am J Ophthalmol 133:673, 2002. 129. Bindal AK, Dunsker SB, Tew JM: Chiari I malformation: classification and management. Neurosurgery 37:1069, 1995. 130. Rosen DS, Wollman R, Frim DM: Recurrence of symptoms after Chiari decompression and duroplasty with nonautologous graft material. Pediatr Neurosurg 38:186, 2003. 131. Poca MA, Sahuquillo J, Ibanez J, et al.: Intracranial hypertension after surgery in patients with Chiari I malformation and normal or moderate increase in ventricular size. Acta Neurochir (Suppl) 81:35, 2002. 132. Bosma JJD, Kumaran N, May PL: Cerebral edema following EVD insertion for delayed hydrocephalus after foramen magnum decompression in Chiari I malformation. Childs Nerv Syst 18:474, 2002. 133. Parker JD, Broberg JC, Napolitano PG: Maternal Arnold-Chiari I malformation and syringomyelia: a labor management dilemma. Am J Perinatol 19:445, 2002. 134. Chang CZ, Howng SL: Surgical outcome of Chiari I malformations— an experience sharing and literature review. Kaohsiung J Med Sci 15:659, 1999. 135. Leong WK, Kermode AG: Acute deterioration in Chiari type I malformation after chiropractic cervical manipulation. J Neurol Neurosurg Psychiatry 70:816, 2001. 136. Munshi I, Frim D, Stine-Reyes R, et al.: Effects of posterior fossa decompression with and without duraplasty on Chiari malformationassociated hydromyelia. Neurosurgery 46:1384, 2000. 137. Brockmeyer D, Gollogly S, Smith JT: Scoliosis associated with Chiari I malformations: the effect of suboccipital decompression on scoliosis curve progression. Spine 28:2505, 2003. 138. Farley FA, Puryear A, Hall JM, et al.: Curve progression in scoliosis associated with Chiari I malformation following suboccipital decompression. J Spinal Disord Tech 15:410, 2002. 139. Teo C, Parker EC, Aureli S, et al.: The Chiari II malformation: a surgical series. Pediatr Neurosurg 27:223, 1997. 140. Gilbert JN, Jones KL, Rorke LB, et al.: Central nervous system anomalies associated with meningomyelocele, hydrocephalus, and the Arnold-Chiari malformation: reappraisal of theories regarding the pathogenesis of posterior neural tube closure defects. Neurosurgery 18:599, 1986. 141. Wolpert SM, Scott RM, Platenberg C, et al.: The clinical significance of hindbrain herniation and deformity as shown on MR images of patients with Chiari-II malformation. Am J Neuroradiol 9:1075, 1988. 142. Charney EB, Rorke LB, Sutton LN, et al.: Management of Chiari-II complications in infants with meningocele. J Pediatr 111:364, 1987. 143. Rubin BK, Wherrett BK: Myelodysplasia and the Arnold-Chiari malformation. Am J Dis Child 140:971, 1986. 144. Hudgins RJ, Boydston WR: Bone regrowth and recurrence of symptoms following decompression in the infant with Chiari II malformation. Pediatr Neurosurg 23:323, 1995. 145. Narayan P, Mapstone TB, Tubbs RS, et al.: Clinical significance of cervicomedullary deformity in Chiari II malformation. Pediatr Neurosurg 35:140, 2001. 146. Mosi K, Uchida Y, Nishimura T, et al.: Brainstem auditory evoked potentials in Chiari-II malformation. Childs Nerv Syst 4:153, 1988. 147. Buxton N, Jaspan T, Punt J: Treatment of Chiari malformation, syringomyelia and hydrocephalus by neuroendoscopic third ventriculostomy. Minim Invasive Neurosurg 45:231, 2002. 148. Snyder WE Jr, Luersen TG, Boaz JC, et al.: Chiari III malformation treated with CSF diversion and delayed surgical closure. Pediatr Neurosurg 29:117, 1998. 149. Cipero KL, Clayton-Smith J, Donnai D, et al.: Symptomatic Chiari I malformation in Kabuki syndrome. Am J Med Genet 132A:273, 2005.

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16 Brain and Spinal Cord Alasdair G.W. Hunter

16.1 Disorders of Neural Tube Closure Definitions

Anencephaly: Complete (holo) or partial (mero) absence of the brain, which is considered to arise from primary failed closure of the cephalic neural tube, resulting in protrusion of the unclosed brain through a defective calvarium (exencephaly) and its subsequent degeneration (Fig. 16-1).1 Iniencephaly: A dysraphic process of the occipital region where the foramen magnum is contiguous with the normal region of the posterior fontanel and the defective occiput may be contiguous with the vertebrae of the lower spine. The head is severely retroflexed, and there is marked cervicothoracic lordosis and absent neck. An extensive rachischisis is usually present but often obscured by skincovered brain and cerebellum (iniencephaly clausus) that protrude into the cervicothoracic spine.1 In other cases the rachischisis is visible on the surface (iniencephaly apertus) (Fig. 16-2). Spina bifida (rachischisis): A bony defect of closure, usually posterior, of the spine. The defect may be covered by essentially normal skin (occulta) or be associated with a protruding sac (cystica). A sac containing abnormal meninges and cerebrospinal fluid (CSF) is a meningocele; one containing elements of spinal cord and/ or nerves is a meningomyelocele (Figs. 16-3 and 16-4). Myeloschisis

occurs when the open neural tube is not covered and is thus open to the exterior.1 Cephalocele: A herniation of brain (encephalocele) or of a nonbrain-containing sac (cranial meningocele) through a congenital defect of the skull (Figs. 16-5 and 16-6). The protrusion is covered by intact skin or thin epithelium unless a secondary deterioration has occurred.1 Diagnosis Anencephaly

Anencephaly is immediately apparent at birth and represents the end stage of degeneration and regeneration of the exposed cephalic neural tissue (Fig. 16-1). Failure of the cephalic neural tube to close appears to be the primary defect. The neural groove and folds can be seen by embryonic stage 8 (day 18) and have deepened and begun to fuse by stage 10 (day 22). The cephalic neural tube closes in a bidirectional fashion by stage 11 (day 24). It has been argued, based primarily on experimental animal models, examination of the pattern of neural tube defects (NTD) in humans, and the different sex ratios associated with lesions at different levels of the neural axis, that there are up to five initiation sites for fusion in humans.2,3 However, careful study of a series of staged human embryos has shown only two de novo sites of

Fig. 16-1. Frontal and posterior views of infant with anencephaly.

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Fig. 16-2. Posterior photograph of newborn with iniencephaly and associated craniorachischisis demonstrating upward-looking face. (Courtesy of Department of Pathology, Children’s Hospital of Eastern Ontario, Ottawa.)

Fig. 16-3. Newborn with thoracolumbar myelomeningocele. Infant had clubfeet and mild hydrocephaly. The spinal lesion was membrane covered with irregular cutaneous borders (right).

fusion: in the rhombencephalon that proceeds rostrally and caudally, and in the prosencephalon that fuses caudally.4 Given that closure can continue normally below the level interrupted by an NTD, it is not helpful to think of closure as a process akin to zipping. Debate continues over whether failure of closure is due to a deficiency in the axial cephalic mesoderm or in the neuroepithelium itself, but in either case the net result is an eversion of the cephalic neural tube and absence of the cranium.5 This neural tube tissue may undergo some overgrowth with secondary hypervascularization.6 With time, the exposed tissue is subject to a secondary destructive/regenerative process and forms a spongy mass of connective tissue, collagen, and vascular tissue, thus forming the ‘‘area cerebrovasculosa.’’1 This course of events has been observed in a number of animal models,7 exencephaly has been observed in human embryos,1 and the transformation from exencephaly to anencephaly has been documented with antenatal ultrasonography.8 There is little support for the view that anencephaly results from secondary destruction of an initially closed neural tube or that disruption is secondary to a compromised vascular supply. The initial presence of the forebrain, albeit abnormal, appears sufficient to allow development of a normal vascular pattern, eyes, and cranial nerves.1 Distinction should be made between anencephaly and acalvaria (acrania), in which there is an absence of the calvarial bones but normal skull base and facial bones. The brain is often of normal structure but may protrude and is covered by a thin membrane.9 In anencephaly there is deformity and displacement of calvarial bones.10 The patients reported by Hammond and Norman may have a variant of acalvaria.10 Complete absence of the brain (holoanencephaly) accounts for about 65% of cases and is associated with craniorachischisis about 80% of the time.11 In the latter situation the cervical spine is often markedly retroflexed, causing the infant to gaze upward in a position similar to iniencephaly, with which it should not be confused. The frontal bone and parietal and occipital squamae are rudimentary, the occipital foramen is open posteriorly, and

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Fig. 16-4. Dorsal photograph of fetus showing typical appearance of a low lumbar meningomyelocele.

the skull base and remaining cranial bones are abnormal.1 There are shallow orbits, and the eyes face more to the side than normal and are proptopic (Fig. 16-1). The cranial nerves are hypoplastic and end proximally in the cerebrovasculosa. Meroanencephaly is a milder defect of anterior neural tube closure, as there is partial skull formation with the cerebrovasculosa protruding through a midline defect. Although often mentioned as rare in the literature, it may account for up to 35% of cases.11 In a prospective study of anencephaly, no recognizable cerebral tissue could be found in 68% of cases, while in the remainder there was some, usually dysplastic, cerebral, cerebellar, or brain stem, tissue.11 The authors disagreed with the view that there was a correlation between the severity of the classification of anencephaly and the presence of remnants of brain tissue. The natural history of anencephaly is about evenly divided between live births and stillbirths. Polyhydramnios is reported in about three-fourths of cases and, while a majority are premature with a mean gestation of 37.5 weeks, it has been observed that those who are premature are less likely to present with polyhydramnios.11 In the absence of aggressive support, most infants will die within 48 hours of birth, and a history of prolonged survival of an anencephalic newborn should lead to reconsideration of the diagnosis. The prime differential is amniotic band disruption, which may come to resemble anencephaly superficially, but which can be distinguished by the specific pathology of the brain and other evidence of constriction bands. The possibility that anencephaly might sometimes give rise to amniotic bands should be kept in mind, especially in regard to genetic counseling.12 There continues to be some disagreement as to whether the adenohypophysis is always present, albeit often ectopic.1,11 It is agreed that the neurohypophysis may be present or absent. Lack of the hypothalamus, and hence the production of ACTH, results

Fig. 16-5. A. Infant with large myeloencephalocele. The cranium is greatly reduced in size. B. Similarly large encephalocele in an infant with Meckel syndrome and less apparent reduction in cranial size.

in an involution of the fetal adrenal cortex and thus small adrenal glands with adult architecture with absence of the fetal cortex. Overall growth is not significantly affected, insulin being the major fetal growth hormone; the thyroid axis remains intact. Absence of the normal pituitary axis may account for the frequent occurrence of micropenis in males. Anencephaly is often accompanied by additional malformations.13 Facial clefts and nasal, oral, and ear anomalies are expected on the basis of simultaneous involvement of the rostral neural crest cells. Other commonly reported malformations include those of the gastrointestinal system (1–16%), major renal (1–6%) and cardiac anomalies (4–15%) and others.13 Melnick and Myrianthopoulous found that 16% of cases had a small heart (>2 standard deviations below normal weight).11 This could reflect a decreased workload due to absent cerebral flow. Properly performed routine obstetric ultrasound can have a sensitivity as high as 100% for anencephaly.14,15 The diagnosis is based on a coronal view that reveals absence of the calvaria and brain above the level of the orbits. In almost one-half of the cases the cerebrovasculosa may be seen above this level as a solid, cystic, or mixed echo; it may appear brain-like.16 The diagnosis can be made reliably in the first trimester, but the ultrasound findings differ from those seen later in gestation. The exencephalic cerebral hemispheres

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may float surrounded by amniotic fluid, and in coronal section can present an appearance that has been likened to a ‘‘Mickey Mouse’’ face.17 Measurement of crown-chin to crown-rump ratio may assist in the diagnosis.18 Amniotic bands can be distinguished by their asymmetry and often by the presence of associated disruptive changes.19 Craniofacial axial skeletal changes characteristic of anencephaly can also allow distinction of patients whose amniotic bands are secondary.19 Vaginal probe ultrasound may provide additional clarity where the diagnosis is uncertain. Factors that reduce overall sensitivity include diagnostic error and failure to offer screening, which is often related to presentation late in gestation.20,21 Iniencephaly

Polyhydramnios usually accompanies iniencephaly, and the marked distortion of fetal anatomy often leads to dystocia and the necessity for operative delivery. The infant tends to be short, with a disproportionately larger head. The diagnosis is immediately apparent as the head is severely retroflexed, the face looks upward, and there is an exaggerated cervicothoracic lordosis.1 The face is usually, but not always, normal. The neck is absent, resulting in continuity of the skin of the mandible and thorax. A defect of the occiput, together with partial or total absence of cervical and thoracic vertebrae, allows the brain and cerebellum to be in contact with the thoracic spine. Anencephaly and/or a meningomyelocele are often present, the latter frequently covered by the caudally displaced brain and cerebellum. In the aperta form some brain tissue is contained in an occipital encephalocele or has been exteriorized and appears as exencephaly or anencephaly (Fig. 16-2). Cases in association with holoprosencephaly also occur. Very little pathologic data on iniencephaly are available. Aleksic et al.22 noted a number of nonspecific central nervous system (CNS) anomalies, including microcephaly, polymicrogyria, glial heterotopias, cerebellar neuronal heterotopias, ventricular atresias, and disorganized brain stem. Four of five cases had cerebellar anomalies that were considered to share some features with the Dandy-Walker and Arnold-Chiari anomalies and thus to resemble what has been termed tectocerebellar dysraphia with occipital encephalocele or type III Arnold-Chiari malformation.23 The pathogenesis of iniencephaly is uncertain. Gardner24 is the prime proponent of the hydrodynamic theory of secondary distension/opening and has argued that anencephaly with rachischisis and retroflexion, iniencephaly, and Klippel-Feil are part of the same spectrum. The current consensus is that most NTD are disorders of closure, but experimental data, including some by proponents of the closure theory, show that on occasion a closed neural tube may reopen.1,25 Kjaer et al.26 provide a detailed radiologic and histologic description of a 16-week fetus detected by prenatal ultrasound. Vertebrae in the thoracolumbar junction, which was contiguous with the occipital squama, were disorganized, and the notochordal remnants looped dorsally in that region. Above that level the vertebrae were small and underossified with posterior notches. Cartilaginous anomalies were noted and the notochordal remnants were an abnormal star shape (normally ribbonlike), and were dorsal, instead of ventral, to the midpoint of the vertebral bodies. They speculated that the basis of the malformations lies in the genes/ pathways involved in regulating axis orientation prior to induction by the notochord. In general, the demographic variables associated with iniencephaly parallel those of anencephaly, although the female predominance is even greater (10:1). This, together with a frequent concurrence of other NTD and a general similarity, if at a somewhat higher rate, of the type of associated extracranial anomalies, suggest

a shared pathogenesis. Furthermore, anencephaly and iniencephaly involve the body axis posterior to the sella turcica, which is the upper limit of the notochord. Iniencephaly does have a higher frequency of associated neurenteric anomalies that may tether the gut and prevent its normal descent to a position below the diaphragm.24 Wilson et al.27 reported a unique case of iniencephaly in which the posteriolateral border of the soft palate arose at the oral commissures, the palate appeared anteverted with the uvula pointing forward. Iniencephaly may be difficult to distinguish from craniorachischisis with retroflexion of the cervical spine. In the latter, the cervical and thoracic vertebrae remain identifiable. Perhaps this distinction is arbitrary because the two lesions may represent variants of the same pathogenesis. There are no data on recurrences that might shed light on this question. Prenatal diagnosis of iniencephaly has been accomplished on a number of occasions with ultrasonography. The diagnosis may be initially suspected on the basis of reduced fetal length and the abnormal flexion of the embryo. Confirmation requires careful examination of the occiput and foramen magnum and study of the vertebral bodies using mediansagittal sectioning. Spina Bifida

The protrusion of neural tissue through the defective vertebral arches of a posterior spina bifida cystica (SB) is readily apparent at birth, and what generally remains is to determine the exact nature and extent of the lesion and whether there are associated malformations. The lesion can occur at any location along the spine and vary in size from a single vertebral level to the entire neuraxis. The relative proportion of the SB at the different locations may vary according to ascertainment, but the data of Matson28 are representative: cervical, 3.7%; thoracic, 7.5%; thoracolumbar, 9.9%; lumbar, 42.2%; lumbosacral, 27.7%; sacral, 8.6%; and anterior regardless of vertebral level, 0.44%. About 90% of SB in neonates are meningomyeloceles, but Warkanyl argues that this malformation has its origin in the embryo as an uncovered myeloschisis. In affected animal embryos sacrificed early in gestation, the neural plate is seen to lie open, and there is overgrowth of neural tissue at the unclosed lateral margins. Over time the exposed neural plate undergoes degenerative change, and epithelialization of the exposed surface proceeds from the lateral margins, eventually covering the lesion. The ventral subarachnoid space fills with fluid and pushes the open medullary plate outward to the surface of the domed, saclike lesion. The apex is often a soft, friable, ‘‘area medullavasculosa’’ consisting of blood vessels, pia mater, and neural remnants. Human fetuses have been described that apparently represent various steps along this maturation spectrum. Careful examination of animals and human fetuses may show a rostral, flattened, closed section of neural tube bending dorsally to join the posterior wall of the sac.1 This area would be likely to leak CSF following minimal trauma and is often red and bleeding. The dorsal movement of the plate may lead to stretching and tearing of the spinal nerves. Even with complete destruction of a section of cord, the nerves remain at the exits of the spine, providing proof of earlier presence of the cord. There is evidence that the epithelialization proceeds under, rather than over, the remaining neural elements, thus contributing to their destruction. This fact may partially explain the finding that apparently normal fetal leg movement observed during early ultrasonography is no longer present in the infant at birth.17 In a minority of cases this cycle of degeneration/ regeneration and epithelization does not occur, and the medullary plate remains open and exposed as a myeloschisis, which may be totally destroyed and absent by the time of birth.

Brain and Spinal Cord

The majority of experimental models and observations of human embryos support the view that the typical myeloschisis results from failure of closure of the neural tube.1,25 However, there have also been studies that appear to show reopening of a previously closed tube through either increased CSF pressure or tissue destruction.24,25 Such alternate mechanisms may account for some meningomyeloceles that do not show the typical pathology described above. In about 10% of SB the malformation consists of dorsal protrusion of fluid-distended meninges through the vertebral defect as a meningocele. This anomaly can usually be distinguished by its transillumination. The underlying cord and nerves are usually normal in their structure and course, although displacement into the sac may occur. Normal skin usually, but not always, covers the sac. In the less common myelocystocele (Section 17.6), the medullary plate has closed normally, and it is the expansion of the central canal that causes the closed spinal cord to balloon through the posterior defect. In this uncommon malformation, leptomeninges and skin cover the lesion and nerves do not cross the lesion, which presumably arises following closure of the posterior neuropore. A different pathogenesis is supported by a particular association with cloacal anomalies. Hydrocephalus complicates some 90% of cases of lumbosacral SB and is usually apparent during the neonatal period. It is generally associated with the Arnold-Chiari malformation (Section 15.14), but other changes such as aqueductal stenosis may be present and lead to uncertainty as to the primary cause of hydrocephalus in some infants. Significant ventricular dilation may occur before the head circumference increases abnormally. Cervical, thoracic, and sacral lesions are less often associated with hydrocephalus. Additional malformations may be noted at the site of the spina bifida and include cord duplications, lipomas, teratomas, dermoids, and vertebral body defects. Magnetic resonance imaging (MRI) and computed tomography (CT), respectively, provide an assessment of the extent of the cord and vertebral malformations. Evidence of neurologic impairment is apparent at birth and varies with the type, severity, and level of the lesion. The termination of the cord may be as low as L5, compared with the normal at T12-L1. Lesions below L2 primarily involve the cauda equina, and varus or valgus foot deformities, dislocated hips, and knee and hip contractures provide ample evidence of the prenatal onset of the paresis. Careful determination of motor and sensory levels, bladder function, and anal tone, together with radiologic evaluation and the definition of the scope of the lesion, is essential. Meningoceles and spina bifida occulta (SBO) are usually asymptomatic at birth; the latter is in most cases a normal variant involving SI and/or S2.30 However, both may be associated with diastematomyelia, spinal cord duplications, dermal sinuses, various tumors, and tethering of the cord (Section 17.1). Tufts of hair, hemangiomas, lipomas, skin tags, or pigmented nevi over the spine may provide evidence of more significant underlying dysraphism. Other spinal malformations, including anterior SB and neurenteric connections, are considered in Sections 17.1 to 17.8. Patients considered at high risk to bear a child with an NTD because of family history, specific maternal illness or medication, or an elevated maternal serum a-fetoprotein (MSAFP) are now usually further evaluated with targeted ultrasound. There is an expectation by the public and physicians caring for pregnant women that malformations as significant as an open spina bifida should be detected on routine obstetric ultrasonography. Ultrasound also provides the physician managing a patient with an elevated MSAFP and/or amniotic fluid AFP with a greater assurance as to a course of action if

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the malformation can be visually demonstrated. As mentioned, the presence or absence of fetal leg movement is not a reliable indicator,29 although true deformations such as clubfeet may be helpful.31 Furthermore, direct sonographic visualization of a meningomyelocele may be difficult in the second trimester. A protruding sac is not always visible on lateral view, perhaps because it has not fully developed or because intraamniotic pressure compresses it flat. Romero et al.31 describe the normal and abnormal spinal anatomy in the different planes of scanning. On sagittal view there are two parallel lines, representing the dorsal neural arches and the vertebral bodies, which converge at the sacrum. In SB the dorsal line and overlying soft tissue are absent. On coronal view two parallel lines are seen when the transducer is in a dorsal position, and these may be seen to spread in the presence of SB. The authors favor the transverse scan with the fetal spine toward the transducer. In SB the integrity of the encircled neural canal is broken by loss of the posterior lamina, the lateral processes are spread apart, and overlying soft tissue is disturbed or absent. However, direct visualization is not always successful, especially early in the second trimester and when the lesion is low lumbosacral-sacral. Sensitivity and specificity vary and are highly dependent on whether one is screening a high-risk or low-risk population.31 Prenatal ultrasound and fetal MRI have been shown to have equivalent accuracy in determining the level of the lesion, but both have about a 20% likelihood of being in error by two or more vertebral segments.469 In contrast to the difficulties with direct visualization of SB, study of the brain and cranium has proved to be of great importance. Although ventriculomegaly is present in less than 70% of cases in the mid-trimester,32 evidence of raised CSF pressure is noted in a majority of cases before 20 weeks as a compression of the choroid plexus and, therefore, a decreased choroid plexus to ventricular volume ratio.31,33 Ventriculomegaly of the posterior horns is more common than of the anterior, and microcephaly was noted in 61% of one series.34 Downward displacement of the cerebellar vermis, fourth ventricle, and medulla oblongata into the upper cervical spine (Chiari II malformation) may result in an anterior curve and loss of the cisterna magna (banana sign) (Fig. 16-7). The cerebellum may not be visible in some cases.32,34 Another useful sign associated with meningomyelocele is a bilateral, concave, frontal contour of the cranium (lemon sign) (Fig. 16-7).33,34 The sensitivity and specificity of these signs will vary with the a priori population risk, gestational timing, and operator skill. There has been significant variation in the results reported. Van den Hof et al.35 evaluated the cranial ultrasound findings in 1561 fetuses at high risk for NTD, of which 130 were ultimately diagnosed as affected with SB. Of 107 cases of SB diagnosed before 24 weeks gestation, 105 (98%) had a lemon sign and 103 (96%) a cerebellar abnormality. The banana sign was noted in 69% of the cases and ‘‘absent’’ cerebellum in 27%. Beyond 24 weeks only 13% had a lemon sign, 91% had a cerebellar anomaly, 17% had a banana sign, and 74% had an ‘‘absent’’ cerebellum. In nine of 1367 cases with no NTD there was a lemon sign, while none showed cerebellar anomalies. Only one fetus with SB diagnosed at 25 weeks lacked either a skull or brain anomaly. In this high-risk population, the positive and negative predictive values at  24 weeks gestation were 92% and 99.8%, respectively, for the lemon sign and 100% and 99.7%, respectively, for the cerebellar anomalies. At over 24 weeks gestation the comparable figures were 100% and 67% for the lemon sign and 100% and 96% for cerebellar anomalies. High-risk centers should approach a 100% accuracy in the evaluation of patients at risk for spina bifida,32 and these results may further improve with the

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Neuromuscular Systems

Fig. 16-7. Top: Fetal ultrasonogram showing the bifrontal indentation or ‘‘lemon sign’’ associated with a meningocele. Bottom: Mid-trimester cranial ultrasound showing a ‘‘banana’’ sign (arrow heads). (Courtesy of the Department of Obstetrics and Gynecology, Ottawa Hospital.) Fig. 16-6. A. Moderate sized and partially denuded meningoencephalocele in a 26 week fetus. B. Small, asymmetric encephalocele in a 16-year-old male. His family history included two other individuals with encephaloceles, one with anencephaly and one with cutis aplasia. (From Stevenson and DeLoache.48)

application of newer techniques such as three-dimensional ultrasound36 and advanced, fast MRI sequencing.37 Results for the detection of spina bifida during routine obstetric ultrasound will also vary with gestational age at scan, equipment, operator experience, and the time devoted to the study.32 In one multicenter ultrasound screening study of 61,972 singleton pregnancies, none of 29 cases of spina bifida was detected at the 10 to 14 week scan, whereas 28 of the 29 cases were noted on the 16 to 22 week scan.38 The authors did note a ‘‘lemon’’ sign in three other affected fetuses at 12, 13, and 14 weeks gestation, so that a higher detection rate at earlier gestation may be possible. In the multicenter European study of 670,766 unselected deliveries, spina bifida was detected in 171 of 231 (74%) of cases subject to a midtrimester (prior to 24 weeks) ultrasound scan.20 Although individual ultrasound centers may outperform MSAFP, overall MSAFP appears to have a higher sensitivity than routine obstetric ultrasound for open spina bifida.32 Cephaloceles

The majority of cephaloceles occur along the midline of the cranium and are apparent upon examination of the newborn (Figs. 16-5 and 16-6). Occipital lesions predominate in most series and may account

for up to 74% of cases, while parietal, frontal, nasal (frontoethmoidal and basal), and nasopharyngeal lesions constitute about 13%, 6.5%, 5%, and 1.5%, respectively.28,39,40 Although the internal skull defect is midline, the external defect is influenced by the surrounding facial skeleton, which can lead to a variety of observed lesions. A classification involving the four major groups of occipital, encephalocele of the cranial vault (five subtypes), frontoethmoidal (three subtypes), and basal (four subtypes) has been suggested.41 Nasal encephaloceles are frontoethmoidal that present with a facial mass and basal that are not visible but can cause upper airway obstruction or rhinorrhea. If the lesion is small it may remain asymptomatic until such time as it enlarges enough to obstruct the nares or begins to leak CSF. In older children it can be distinguished from a nasal polyp because of its gray color and pulsations.1 Frontoethmoidal lesions are often accompanied by a cranium bifidum and varying frontonasal dysplasia. They may apear above the nasal bones (nasoethmoidal) or may protrude into the orbit (nasoorbital), causing deformation of the eye.41 Basal encephaloceles are uncommon and affect about one in 35,000 births. Both the transsphenoidal and the sphenoethmoid subtypes are commonly associated with optic nerve and hypothalamicpituitary dysfunction.42 There may be an accompanying cleft palate. Encephaloceles are relatively more common in early abortuses than they are at birth, and, as the clinical severity shows some correlation with site, it is probable that some differences in the relative proportions at the different locations will depend on ascertainment.43 However, this does not explain the apparent high

Brain and Spinal Cord

rate of frontal encephaloceles in southeast Asia1,44 or the 37.5% of parietal encephaloceles in the series reported by Yokota et al.45 Cephaloceles range from very small sizes to larger than the head, from pedunculated to sessile, and from covered by normal skin and hair to covered by a thin papery membrane that readily breaks down. Size is not the most critical prognostic factor, because a large mass may be a cranial meningocele without brain content, while a small lesion may be an encephalocele containing important brain tissue or be associated with significant underlying CNS malformations. In most cases cephaloceles can be readily distinguished from cephalohematomas, cysts, caput succedaneum, or cystic hygroma by physical examination. The intracranial connection can be demonstrated by routine skull radiographs (Fig. 16-8); additional neuroimaging techniques such as sonography, CT, or MRI are essential to document the contents of the cephalocele and to search for the exceedingly common additional intracranial malformations. Of particular note are microcephaly, hydrocephalus, absent corpus callosum, and posterior fossa anomalies related to Dandy-Walker and ArnoldChiari malformations. The combination of an occipitocervical encephalocele, a small posterior fossa, and a caudally positioned brain stem is alternatively described as tectocerebellar dysrapia or Chiari III anomaly. It accounts for less than 1% of Chiari malformations and may be associated with additional CNS lesions including agenesis of the corpus callosum, fused thalami, arrhinencephaly, and syringomyelia.23 Cephaloceles may also appear as small, parietal or occipital, nonpedunculated alopecic or nodular lesions, which have been designated atretic cephaloceles.45 In this case the major differential diagnosis is that of cutis aplasia, which may itself have an underlying bony defect and is most commonly seen at or around the parietal

Fig. 16-8. Lateral radiograph of skull demonstrating soft tissue mass of an encephalocele and skull defect (arrows).

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hair whorl but not necessarily exactly in the midline. Drolet et al.46 have pointed to a ring of coarse hair surrounding the scalp lesion as being suggestive of an underlying neural tube closure defect. The origin of atretic cephaloceles is presumed to arise from in utero involution of a small meningocele, and heterotopic glial rests may be found on careful examination. However, Drapkin47 has proposed that some of these lesions, located in the region of the posterior fontanel, represent neural crest remnants. These anomalies contain leptomeningeal tissue, with or without dysplastic glial tissue, and are usually surrounded by fibrous tissue. In some there is no underlying defect while in others a skull defect allows passage of a fibrous connection to the dura, through which it passes to connect via a distorted sagittal sinus to the falx at the dorsal midbrain or anterior cerebellar vermis. The masses may be solid or cystic, containing a CSF-like fluid, but there is no connection to the ventricular system. Associated brain malformations are rare, and most patients do well. In some cases aplasia may in fact represent a forme fruste of a neural tube defect, and the family reported by Stevenson and DeLoache48 illustrates the point well. Multiple lesions, or those well off the midline, are unlikely to represent part of the neural tube spectrum, but in some cases the distinction may not be possible. Yokota et al.45 draw an important distinction between atretic parietal lesions, which they observed were all associated with hydrocephalus and dorsal cysts, and occipital locations, which consisted mainly of a small fibrous tissue core ending at the dura and which all had a favorable prognosis without need for surgical intervention. The latter appears to be the same condition that Schlitt et al.49 recently defined as a recognizable syndrome. There are also cases of nontraumatic brain herniation through small bony defects in the tegmen antri into the middle ear, which may present later in life and are in a way the parallel of cephaloceles.50 The high frequency of associated midline defects in encephalocele, such as absent corpus callosum, dorsal cysts, and DandyWalker anomalies, does support the view that closure was abnormal. The high frequency of hydrocephalus in occipital encephaloceles is usually attributed to disturbance of CSF dynamics due to the entrapped brain tissue. However, the possibility remains that some cases of encephalocele may represent ‘‘blow-out’’ of brain through a point of least resistance due to early increased CSF pressure. This might account for the encephalocele seen in Apert syndrome, in which the coronal sutures are fused, the cranial base is short, and the midline sutural area is wide.51 Cephaloceles are much less common than either SB or anencephaly and are said to affect one in 5000 to 10,000 births. However, they are overrepresented among known syndromes with NTD (Table 16-1) and also appear to have a generally higher rate of associated non-CNS malformations than do other NTD.52 Great care should, therefore, be taken to search for additional malformations in any child with a cephalocele. This is equally true when the diagnosis is made by prenatal sonography. The fact that cephaloceles are relatively less common than SB or anencephaly and that the epithelium may be adequate to prevent significant exudation of AFP means that most cases subject to prenatal sonography will be recruited from a low-risk population. Great care must be exercised in the diagnosis, and it is not sufficient simply to demonstrate a paracranial mass. The differential diagnosis includes cystic hygroma, scalp edema, blebs, abnormal ears, branchial cleft cysts, the amniotic band syndrome, and cloverleafskull.53,54 Authors agree that demonstration of a bony defect under the putative cephalocele is critical to the diagnosis of cephalocele,

Table 16-1. Syndromes in which neural tube defects have been reported Prominent Features

Causation Gene/Locus

Acrocallosal58

Absent corpus callosum, macrocephaly, short nose, hypertelorism, post- and preaxial polydactyly

AR (200900) 12p13.3–p11.2

Aminopterin, prenatal59

IUGR, microcephaly, craniosynostosis, hypoplasia of cranial bones, upswept frontal hair, broad nose, prominent eyes, small jaw, malar flatness, low-set ears (anencephaly/cephalocele)

Folic acid antagonist in utero

Amniotic bands60

Random patterns of disruption and deformation include secondary anencephaly, encephaloceles in unusual sites, nonanatomic clefting, amputations, distal syndactyly, facial destruction

Unknown

Ankyloblepharon-cleft lip/palate61

Strands of tissue limit eye opening, cleft lip and/or palate; cases with imperforate anus; one report with meningomyelocele

AD (106250)

Anophthalmia-clefting-microtia62

Two sibs with anophthalmia; one with clefting, microtia, and sacral spina bifida; second had earlobe anomaly

Uncertain (600776)

Anophthalmia-NTD63

Anophthalmia, normal motor development, minor ear anomaly, lumbosacral myelomeningocele; single case

Unknown

Brachydactyly-anencephaly64

Variable dominant brachydactyly considered most like type ‘‘C’’; family had two cases of anencephaly/exencephaly, unclear whether they also had brachydactyly

AD

Cantrell pentalogy65

High abdominal wall defect, low sternal defect, deficient anterior diaphragm and diaphragmatic pericardium, congenital heart, 10% with CNS anomalies including anencephaly and SB

Unknown

Caudal duplication66

Variable duplication of colon, bladder, internal genitalia, anus, sacrum; associated with omphalocele, meningocele, vertebral anomalies

Unknown

Cerebro-costo-mandibular67

Neonatal respiratory distress, feeding problems, postnatal growth failure, microcephaly, developmental delay, micrognathia, high/cleft palate, rib gaps, vertebral anomalies, high mortality. One case had meningomyelocele and sib had L5-S1 SBO

AR & AD; most sporadic (117650)

CHARGE68

Association of coloboma, heart malformation, choanal atresia, growth and/or mental retardation, ear anomalies and/or deafness; absent corpus callosum (4/47), arrhinecephaly (2/47), septal agenesis (2/47), vermian agenesis (1/47), meningomyelocele (1/47)

AD (214800) CHD7, 8q12.1

CHILD69

Congenital hemidysplasia, ichthyosiform erythroderma, limb defects; unilateral erythema; scaling, alopecia; nail anomaly; hyperkeratosis; hypomelia; varied bone hypoplasia; punctate epiphyseal calcifications; ipsilateral defects of heart, kidney, brain; usually male lethal

XLD (308050) NSDHL, Xq28 NAD[P]H steroid dehydrogenase-like protein

Chromosome abnormalities70

Anencephaly: r(13), trisomy 18, 21. SB: triploidy; tetraploidy; duplication (2)(pter-p13),(3)(q23-qter), (11)(q23-qter), (13) (pter-q14), (22)(pter-q11); deletion (13)(q14-qter), r(22); mosaic trisomy 8, 9, 14

Chromosome imbalance

Coloboma-microphthalmiaclefting71

Four-generation family with variable uveal colobomata, extraocular movement disorder, mid-range sensorineural deafness, hematuria, learning problems; one of 16 with anencephaly

AD (120433)

DiGeorge72

Highly variable spectrum of subtle facial signs, thymic aplasia/ hypoplasia, cardiac (especially conotruncal) defects, developmental delay. Meningomyelocele perhaps an occasional finding.

AD (188400) microdeletion 22q11.2

Disorganization-like73

Homologue of mouse disorganization mutant? Wide range of major malformations include gastroschisis, cranioschisis, odd skin appendages, hamartomas

(223200) 10p14-p13

Durkin-Stamm: sacral teratomas74

Sacral neuroectodermal tumors, anal stenosis/imperforate anus, penoscrotal hypospadias, deformed hypoplastic lower limbs. One of two cases had a meningocele.

Unknown

Ectrodactyly-urinary obstruction75

Variable syndactyly hands and feet to typical split hand and foot; ureteric atresia; SBO; SB; diaphragmatic defect

AD

Syndrome

Syndromes With Anencephaly/SB +/– Encephalocele

(continued)

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Table 16-1. Syndromes in which neural tube defects have been reported (continued) Causation Gene/Locus

Syndrome

Prominent Features

Facial duplication-anencephaly association76

Variable duplication of craniofacial structures from complete to subcutaneous midline nasal cleft. Hypothesis that primary duplication of segment of neural tube results in migration of neural crest cells between the two tubes and greater risk of failed closure.

Unknown

Femoral duplication77

Proximal femoral duplication, single bone in lower leg, absence/ hypoplasia of toes, cloacal exstrophy, meningomyelocele

Unknown

Focal dermal hypoplasia78

Streaks of hypoplastic and abnormally pigmented skin, protruding lipomatous nodules, angiofibromatoid perianal and perioral nodules, abnormal nails and teeth, syndactyly, eye anomalies. One case with myelomeningocele.

XLD; male lethal (305600) Xp22.31

Fullana: caudal deficiency-asplenia79

IUGR, marked caudal regression, hypoplastic pelvis, imperforate/ stenotic anus, myelomeningocele, laterality anomalies with asplenia, complex cardiac anomalies. Variant of X-linked laterality syndrome?85

AR or SLR

Goldberg: hemangioma-sacral anomalies80

Extensive sacral/lower limb capillary hemangiomas, imperforate anus, renal anomalies, malformed genitalia, sacral skin tags, abnormal sacrum, lipomyelomeningocele

Unknown

Hemi 381

Hypertrophy of one-half or one-fourth of the body, ipsilateral increased muscle mass, increased bone width but not bone length, areflexia, decreased pain and temperature sensation, progressive scoliosis. One patient had meningomyelocele, and all three reported had a family history of NTD

Unknown

Homozygous-Waardenburg I82

Anencephaly, hypoplastic nose, arthrogrypotic limbs, abnormal spine, imperforate anus

AD (193500) PAX3, 2q35

Hypothyroid-deafnessmyelomeningocele83

Single case. Mild facial dysmorphism; telecanthus; low, posteriorly rotated ears; thyroid agenesis; sensorineural deafness.

Unknown

Kousseff: sacral defects-conotruncal heart defects84

Minor facial anomalies including apparent low rotated ears and retrognathia, conotruncal cardiac malformations, sacral myelomeningocele (canalization defect?)

AR (245210)

Laterality sequence85

Embryos within a family may express bilateral left- or right-sidedness with varying pattern of lung and cardiac malformations, situs inversus, poly/asplenia. Several cases with SB.

XLR (306955) ZIC3, Xq26.2 AD (601086), AR (605376) EBAF, 1q42.1 CFC1, Chr2 CRELD1, 3p25.3 ACVR2B, 3p22-p21.3 NKX2-5, 5q34

Lateral meningocele-abnormal facies86

Narrow face, down-slanting palpebrae, flattened maxilla, hypoplastic mandible, small pinnae, laxity, keloids, developmental delay; moderate increased bone density; wormian bones, abnormal sella, and posterior fossa; small cerebral gyri and cerebellum; thoracolumbar meningoceles

AD (130720)

Manouvrier-Moerman: radioulnar synostosis87

Male fetus with anencephaly, radial defect, renal agenesis; female relatives with radioulnar synostosis, triphalangeal thumbs/thumb aplasia, and history of miscarrying males

XLD? (300233)

Maternal diabetes88

Caudal regression including sacral agenesis, renal anomalies, congenital heart malformations, cardiomyopathy, proximal focal femoral deficiency, NTD

Abnormal glucose metabolism

Maternal hyperthermia89–92

Retrospective studies of prolonged high fever after neural tube closure suggest variable pattern of neurologic anomaly; case-control studies of early exposure more strongly associated with anencephaly than SB and cephalocele. See also Table 16-3.

Temperature elevation

Melanocytosis-myelomeningocele93

Macular, nonhomogeneous dark blue pigment over much of infant’s back, becoming blue-grey to dark grey; intradermal excess of heavily pigmented dendritic melanocytes. Single case.

Unknown

NTD-clefting-limb reduction94

Anencephaly þ/ meningomyelocele, radial ray defects, cleft lip/ palate. Three unrelated cases.

Unknown

OEIS association95

Omphalocele, bladder exstrophy, imperforate anus, spinal dysraphism, abnormal genitalia, renal anomalies, postaxial polydactyly fingers and toes, gut atresias

Unknown

(continued)

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Table 16-1. Syndromes in which neural tube defects have been reported (continued) Causation Gene/Locus

Syndrome

Prominent Features

PHAVER96

Epicanthus, downslanting palpebrae; low, posteriorly rotated ears; complex heart defects; broad thumbs and great toes; duplication of proximal phalanx of thumb; vertebral anomalies; contractures. Sibs, one with myelomeningocele.

AR (261575)

Polycystic kidneys-microcephaly, brachymelia97

Type I polycystic kidneys, short limbs, brachydactyly, characteristic face, hypertelorism, up-slanting palpebrae, flat nasal tip, fleshy ears, heart defect. One of six had myelomeningocele.

AR (263210)

Prune belly98

Lack of abdominal musculature due to abdominal distension secondary to urinary tract obstruction. Single case associated with anencephaly: authors posit lack of antidiuretic hormone as no renal obstruction was found.

Unknown

Renal-mu¨llerian agenesis99

Thoracolumbar meningomyelocele, severe kyphoscoliosis, bilateral renal agenesis, fused adrenals, multilobed spleen, congenital heart defect, absence of bladder, uterus, upper two-thirds of vagina

Unknown

Sacral agenesis-variable spina bifida324

A five-generation family with complete penetrance of sacral agenesis, some with open SB, others with SBO always involving L5. Possible relationship to mouse T locus on mouse 17?

AD

Scalp defect-craniosynostosis100

Bifid nose; soft, normal tissue, scalp tumors; scalp defects; joint contractures; small lumbar meningocele

Unknown

Schisis association56

Neural tube defects occur in a nonrandom association with omphalocele, diaphragmatic hernia, oral clefts. Sibs show an increased risk of NTD and oral clefts.

Unknown

Situs ambiguus-AR101

Variable mixed midline laterality defects. Affected sibs; CNS includes hypoplastic corpus callosum, cerebellar dysgenesis, vermis hypoplasia, optic coloboma.

AR

Short rib-polydactyly102

Two unrelated cases with anencephaly and short rib polydactyly overlapping Beemer and Majewski types. Part of a spectrum? One variably affected sib.

AR? (263520)

Tetraphocomelia-Rodriguez type103

Single case, marked tetraphocomelia, anencephaly and spina bifida, oblique facial clefts, abnormal nose, caudal regression

Unknown

Thoracoabdominal association104

Malformations of the schisis type were found in five males connected through normal females, in whom only one of anencephaly, cleft lip, renal agenesis, tetralogy of Fallot, and hydrocephalus was found in each

XLR (313850)

Valproate embryopathy105

Brachycephaly, high forehead, prominent eyes, crease of skin below eye, thin and long upper lip, prominent lower lip, long philtrum, metopic ridge, lumbosacral NTD

Valproate in utero

Vitamin A embryopathy106

Microtia/anotia, asymmetric second arch anomalies, flat nose, hypertelorism, micrognathia, limb and heart defects. CNS includes hydrocephalus, microcephaly, porencephaly, focal agyria, heterotopias, vermis hypoplasia, Dandy-Walker.

Teratogen

Waardenburg-Type I107

White forelock, sensorineural deafness, dystopia canthorum, heterochromia irides, high nasal bridge, hypoplastic nares, synophrys

AD (193500) PAX3, 2q35

Wolf: enteric duplication108

Dextrocardia and tricuspid insufficiency, absent left ribs 1–3, thoracoabdominal enteric duplication

Unknown

X-linked neural tube defects109

Several families have been reported in whom both spina bifida and anencephaly appear to segregate in an X-linked manner

XLR (301410) Xq27.3

Acrocephalosyndactly-LorenzTelkamp110

Single case. Coronal synostosis, hypertelorism, micropenis, severe developmental delay, bilateral parieto-occipital protrusions

Unknown

Acromelic-frontonasal dysplasia111

Epibulbar dermoid, cleft nose, notched alae, midline cleft lip/palate, renal anomalies, pre- and postaxial polydactyly, delayed development; CNS includes absent corpus callosum, Dandy-Walker, hydrocephalus, encephalocele

Unknown

Xq25-q26.1

Syndromes With Encephalocele

(continued)

724

Table 16-1. Syndromes in which neural tube defects have been reported (continued) Causation Gene/Locus

Syndrome

Prominent Features

Agonadism-dysraphism112

Single case. Absent gonads, 46,XX, omphalocele, encephalocele, spinal dysraphism.

Unknown

Anophthalmia-nasal proboscis113

Macrocephaly, hydrocephalus, craniosynostosis, anophthalmia and proboscislike nose. One of two unrelated girls had frontal encephalocele.

Unknown (605627)

Anterior encephaloceleanophthalmia114

Single male case with anterior encephalocele, anophthalmia, and dilated cerebral vessels

Unknown

Apert51

Craniosynostosis, primarily coronal, short skull base; ‘‘mittenlike’’ syndactyly hands and feet; various CNS findings including megalencephaly, heterotopias, gyral anomalies, encephalocele; may have mental retardation

AD (101200) FGFR2, 10q26

Boomerang dysplasia115

Short-limbed dwarfism with stiff, bowed limbs, flat nose, normal HC, and large fontanel. One case reported with anterior encephalocele, multinucleated giant chondrocytes.

AD or XLD (112310)

Brachial amelia-cleftingholoprosencephaly116

Holoprosencephaly, upper limb amelia, facial clefting. Single case report of a severe case with anterior encephalocele and other anomalies.

Unknown (601357)

Branchio-oculo-facial-CNS117

Single case. Branchial cleft fistulae, holoprosencephaly, encephalocele, microphthalmia, heart defect, facial anomalies.

Unknown

Cerebro-renal-digital-Piantanida118

Mental retardation, cerebellar vermis agenesis, polydactyly, unusual appearance. Two sibs, one with cystic dysplastic kidney, other a meningocele.

AR?

Craniomicromelia119

IUGR, short limbs, absent coronal sutures, short palpebrae, pinched nose, hypoplastic alae, microstomia, cleft palate, large fontanels, absent second-finger phalanges, occipital protrusion containing cerebellum

AR (602558)

Chromosome abnormalities57,70

Trisomies 13, 18; mosaic trisomy 20; deletion (13q), (2)(q21-q24); monosomy X; duplication (6)(q21-qter), (7)(pter-p11), (8)(q23-qter)

Chromosome imbalance

Craniotelencephalic dysplasia120

Craniosynostosis; frontal encephalocele at metopic region; microphthalmia; various anomalies including septo-optic dysplasia, agenesis of the corpus callosum, lissencephaly, arhinencephaly

AR (218670)

Cranium bifidum occultum121

Mother with occipital occult cranial defect had child with pedunculated midline occipital encephalocele; similar reports since

Uncertain

Donnai: Meckel-like122

Marked hydrocephalus, alobar holoprosencephaly-cebocephaly, anophthalmia, postaxial hexadactyly, cerebellar hypoplasia, occipital encephalocele. Same as Young: holoprosencephaly-pseudotrisomy 13 syndrome?

Unknown

DK-phocomelia with thrombocytopenia123

Occipital encephalocele, absent corpus callosum, variable upper limb and digital absence anomalies, hypoplastic thumbs, thrombocytopenia/ reduced mega-karyocytes, renal agenesis to milder defects, vaginal atresia, other variable brain anomalies

Case with del(13q) (223340)

Dyssegmental dysplasia (RollandDesbuquois)124

Bones not bowed, ilia and scapulae normal, mild sagittal cleft vertebrae, quite normal growth plate, patches of broad collagen fibers, radiographic occipital defects. Live several days to years. One case with encephalocele.

AR (224400)

Dyssegmental dysplasia (SilvermanHandmaker)124

Clefting; encephaloceles; marked micromelia; thick and bowed bones; severe vertebral segmentation defects; small, round, and dense ilia; scapular changes; large calcospherites; collagen fibre disarray; stillborn or die within 48 h

AR (224410) HSPG2, 1p36.1 perlecan

Encephalocele-arthrogryposishypoplastic thumbs125

Single case. Restriction at knees, elbows, and wrists, dysplastic kidney, hypoplastic/absent thumb. Normal development.

Unknown

Encephalocele-radial anomalies126

Encephalocele, esophageal atresia, abnormal lung lobulation, congenital heart, radial ray defects, visceral anomalies

Unknown

Facio-auriculo-vertebral127

Spectrum disorder of first and second arches, usually asymmetric; lower face hypoplasia involving periocular, malar/mandibular, aural anomalies; cardiac and vertebral anomalies similar to VATER association. About 12 cases with posterior cephalocele but CNS is usually normal.

Sporadic; occasionally AR, AD (164210, 257700)

(continued)

725

Table 16-1. Syndromes in which neural tube defects have been reported (continued) Causation Gene/Locus

Syndrome

Prominent Features

Fraser: cryptophthalmos128

Cutaneous syndactyly of hands and feet, broad nose, depressed tip with groove or coloboma nares, abnormal ears, cleft lip/palate, laryngeal anomalies, renal agenesis/dysgenesis, abnormal internal/external genitalia, mental retardation

AR (219000)

Fried: Meckel-like129

Lobar holoprosencephaly, large occipital encephalocele, microcephaly, absence deformities left forearm, complex congenital heart defects, absent mu¨llerian derivitives on left

Unknown

Fronto-facio-nasal, dysplasia130

Cranium bifidum occultum/anterior encephalocele, blepharophimosis, lagophthalmos, S-shaped palpebral fissures, telecanthus, nose hypoplastic/bifid, midface hypoplasia, cleft lip/palate, limbic dermoid, facial tags

AR (229400)

Frontonasal dysplasia131

Widow’s peak, hypertelorism, flat frontonasal encephalocele, broad nose with flat tip and separated nostrils, median cleft lip, correlation between mental retardation and severity of facial and extracranial anomalies

Sporadic; occasionally AD (136760)

Joubert syndrome132

Episodic tachypnea/apnea, agenesis of cerebellar vermis, abnormal eye movement, developmental delay. Groups with and without retinal/ renal anomalies

AR (213300) NPHP1, 2q13 AHI1, 6q23.2-q23.3 9q34.3

Keutel: humero-radial synostosis133

Humero-radial synostosis, may have hypoplasia of humerus and thumb, minor facial anomalies, hypoplastic ribs, microcephaly, occipital cephalocele in one case

AR (236400)

Knobloch: vitreoretinopathy134

Severe myopia, progressive retinal detachments leading to blindness, poor response to treatment, early lens opacities. One spontaneous lens dislocation. Four of five sibs with concurrent encephalocele.

AR (267750) COL18A1, 21q22.3

Laryngeal atresia-hydrops135

Syndactyly of all fingers, single palmar creases, toe camptodactyly, flexion anomalies major joints, encephalocele through parietal bone (blowout due to fetal valsalva?). Sib with fetal ascites, vaginal atresia

Unknown

Meckel-Gruber136

Microcephaly, encephalocele, microphthalmia, cleft lip/palate, cystic dysplastic kidneys, liver fibrosis/cysts, abnormal genitalia, polydactyly hands/feet

AR (249000) 8q24 11q13 17q22-q23

MELAS137

Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes. Single case with L3 spina bifida.

MTTL1 MTND6 MTTQ Mitochondrial

Micromelia-polysyndactyly-fragile bones138

Single case. Prenatal fractures, frontonasal dysplasia, microphthalmia, cleft palate, micrognathia, tetramicromelia, pre- and postaxial fourlimb polydactyly. Occipital encephalocele.

Unknown

Mohr139

OFD II. Broad nasal tip, accessory oral frenula, lingual tumors, preaxial foot, postaxial hand polydactyly. Case with occipital subarachnoid cyst, occipital meningocele.

AR

Morning glory-sphenoidal encephalocele140

Characteristic optic nerve, hypertelorism, microphthalmia, other eye anomalies, midline cleft, pituitary/hypothalamic dysfunction, hydrocephalus, absent corpus callosum, sphenoidal encephalocele

Unknown

MURCS association141

Short stature, cervicothoracic vertebral defects, Rokitansky anomaly, renal agenesis/ectopia. Note similarity to renal-mu¨llerian agenesis. Sibs reported.

Unknown

Nishimaki: microphthalmia-Dandy Walker142

Single case. Microphthalmia, coloboma, cleft palate, occipital encephalocele.

Unknown

Oculo-auriculo-frontonasal143

Normal development, frontonasal dysplasia, ocular dermoids, eyelid colobomata, preauricular tags

Uncertain (601452)

Oculocerebrocutaneous144

Orbital cysts, microphthalmia, lid coloboma, skin defects, skeletal anomalies, agenesis of the corpus callosum, multiple cysts of brain

Unknown (164180)

Oculo-encephalo-hepatorenal145

Epicanthus, nystagmus, ptosis, micrognathia, abnormal external genitalia, syndactyly, postaxial polydactyly, cystic renal dysplasia, cerebellar defects, mental retardation, postnatal growth failure, periodic breathing. One of three cases had meningoencephalocele and hepatic fibrosis.

AR (213010)

(continued)

726

Brain and Spinal Cord

727

Table 16-1. Syndromes in which neural tube defects have been reported (continued) Causation Gene/Locus

Syndrome

Prominent Features

Opitz C-trigonocephaly146

Mental retardation, trigonocephaly, wide alveolar ridges, wide oral frenula, short neck, polydactyly, visceral anomalies. Brain defects include absent corpus callosum, cerebellar vermis agenesis, DandyWalker. One case with encephalocele.

AR (211750)

Pallister-Hall147

Low ears, broad nasal bridge, buccal frenula, cleft palate, nail dysplasia, postaxial polydactyly, syndactyly, renal anomalies, imperforate anus. CNS includes hypothalamic hamartoblastoma, arrhinencephaly, hydrocephaly, absent corpus callosum, encephalocele, Dandy-Walker, polymicrogyria, heterotopia.

AD (146510) GLI3, 7p13

Pectoralis major-renal anomalies148

Posterior encephalocele, absent sternal portion of pectoralis major, Sprengel anomaly, short and webbed neck, fused vertebrae C3-C6, absent right kidney. Single case.

Unknown

Phocomelia-encephaloceleurogenital anomalies149

Bilateral radial aplasia, absent right thumb, hypoplastic left thumb, fused pelvic kidney, dextroposed heart, hypoplastic lung, thin corpus callosum, large encephalocele from roof of fourth ventricle. Same as DK-phocomelia syndrome?123

Unknown

Porphyria-acute intermittent homozygote150

Optic nerve changes, cataracts, ataxia, developmental delay, skin photosensitivity; microcephaly, porencephaly, vermis hypoplasia, anterior encephalocele

AD (176000) Homozygote

Pseudotrisomy 13151

Holoprosencephaly, micro/anophthalmia, cleft lip and/or palate, congenital heart, abnormal lung lobulation, renal anomalies, postaxial polydactyly, normal karyotype

AR (264480)

Radial ray-omphalocelediaphragmatic hernia152

Exomphalos, diaphragmatic hernia, abnormal thumbs, radioulnar synostosis, down-slanting palpebrae, micrognathia, renal and anal anomalies. One case probable encephalocele.

AR?

Renal-hepatic-pancreatic- Dandy Walker153

Cystic dysplastic kidneys; hepatic fibrosis; variable ocular, visceral, and cardiac defects. Several cases with encephalocele.

AR (267010)

Roberts-SC phocomelia154

Microbrachycephaly, marked prenatal and postnatal growth failure, mild to severe mental retardation, sparse and silvery hair, cleft lip/palate, thin nares, hypoplastic alae, varying hypomelia, characteristic centromeric puffing. Two cases with frontal encephalocele, one with exencephaly.

AR (268300)

Sakoda: anophthalmia-cortical dysgenesis155

Single case. Anophthalmia, cleft lip/palate, short stature, hemivertebrae, basal encephalocele, absent corpus callosum, cerebral dysgenesis.

Unknown

Scalp defect-craniostenosis156

Left frontal cranial defect, with tumors of normal scalp, cutis aplasia, sinus tracts, distorted internal brain anatomy, bifid nose, no alar or septal cartilage, high palate, small lumbar meningocele, undescended testes

Unknown

Tectocerebellar dysraphia-occipital encephalocele23

VSD, small mandible, cleft palate. CNS anomalies include posterior encephalocele, absent corpus callosum, hydrocephaly, cerebellar vermis agenesis, heterotopias.

Unknown

Tsai Huang: short rib-polydactyly157

Occipital encephalocele, deep midline fissure of upper/lower lips, situs inversus

Walker-Warburg158

Type II lissencephaly, cerebellar malformations, vermis hypoplasia, retinal dysplasia, microphthalmia, congenital muscular dystrophy, posterior encephalocele in one of three cases

AR (236670) POMT1, 9q34.1 FCMD, 9q31

Warfarin embryopathy159

Hypoplastic nasal bones, chondrodysplasia calcificans punctata, microphthalmia, cardiac anomalies, CNS damage due to bleeding. Occipital encephalocele reported at least twice.

Coumadin exposure in utero

Weissenbacher-Zweymuller (OSMED)160

Congenital rhizomelic dwarfism with later catch-up. Flat midface, cleft palate, micrognathia.

AD (120290) COL11A2, 6p21.3

although there is some disagreement as to whether it is always demonstrable.54,55 Romero et al.31 caution that the cranial sutures may be mistaken for a defect on axial scans. The nonhomogeneous echo from brain contained within the sac is a further useful sign but is not always visualized, even when present.41 Concurrent brain anomalies

such as hydrocephalus, posterior fossa cysts, or absent corpus callosum would favor the diagnosis of cephalocele. Cystic hygromas originate about the neck and contain multiple septa when associated with chromosomal defects, but are nonseptate with other anomalies. They attach to the midline and extend to the nuchal level.31,55 They

728

Neuromuscular Systems

are most often associated with Turner syndrome and therefore often have associated fetal ascites. If amniocentesis is performed, either to rule out or to establish an associated chromosome diagnosis, it must be remembered that amniotic fluid AFP level is not always elevated with an encephalocele, and it may be elevated if fluid from a cystic hygroma is inadvertently sampled. Infants having all types of NTD have a relatively high rate of non-CNS malformations not directly related to closure of the neural tube. The actual rates vary with the method of ascertainment, with the severity of malformations included, and particularly as to whether stillbirths and neonatal deaths are included and whether autopsies are performed, but they average to about 20%, or somewhat higher with encephalocele.52 The associated anomalies are nonrandom and are predominantly failures of fusion or ‘‘schisis’’ anomalies such as cleft lip/palate, cardiac septal anomalies, diaphragmatic hernia, omphalocele, and hypospadias.56 Any child with an NTD should be carefully examined and observed for associated anomalies and recognized syndromes (Table 16-1). In addition to the conditions with encephalocele listed in Table 16-1 are a number of other associations such as those with absent corpus callosum, with iniencephaly, and with ArnoldChiari and Dandy-Walker malformations, which have been discussed. Cohen57 has summarized a number of others, including facial clefting with various types of encephalocele, transsphenoidal encephalocele with hypothalamic/pituitary dysfunction, and ectrodactyly with craniosynostosis. He lists a number of occurrences in a variety of syndromes and conditions, many noted via personal communications, in which cephalocele is not usually considered a feature. These include neurofibromatosis, tuberous sclerosis, prenatal rubella, thrombocytopenia-absent radius, and Poland and Marfan syndromes. These may simply represent chance but could be rare pleiotropic events. The chance concurrence in various syndromes is even more likely with the more common anencephaly or SB. Distribution and Etiology Geographic Differences

Open NTD have undoubtedly been subject to more epidemiologic scrutiny and speculation than any other group of malformations. This is a logical consequence of their relatively high prevalence; significant mortality rate, which may account for over 50% of deaths due to malformations; and high burden on the health of survivors.161 Although small lesions can initially be overlooked and complications of pregnancy can lead to a bias toward hospital rather than community delivery, the generally obvious and dramatic nature of these malformations assures a high probability of early diagnosis.162 This means that properly designed studies of adequately large and defined populations may be reasonably compared across geography and time. Such studies have provided fascinating data. It is important to note whether live births, stillbirths, and induced abortions have been included when comparing data. Geographic differences in birth prevalence of NTD are wellestablished, and although Northern Ireland and South Wales are traditionally considered the epicenters with rates per thousand of anencephaly as high as 6.7 and of SB as high as 4.1, other countries have reported rates much above the average.161,162 Some differences in rates of iniencephaly may reflect variations in diagnostic precision.26 In general, the geographic differences are greater for anencephaly than for SB, and rates vary as much as 40-fold from high to low prevalence areas.161 North America has typically shown an east to west decline in birth prevalence,163,164 although this is

becoming less apparent as prevalence declines.165 Significant rate differences have been noted within relatively small geographic areas and between racial and ethnic groups in the same area.1,162–178 Table 16-2 provides some representative examples of geographic variation. More examples and greater detail have been compiled by Koch and Fuhrmann179 and by Stone.180 At first glance these distributions suggest a significant genetic contribution to the etiology of NTD; however, ethnic and cultural differences in diet, socioeconomic, and other factors could equally be at play. For example, apparent higher rates in the offspring of Puerto Rican-born Brooklyn mothers than in the offspring of native black and white mothers were largely eliminated by correcting for private versus public medical care.181 Emigrants from areas of one prevalence level to an area with a different rate tend to assume the new rate, although some ethnic difference in prevalence may remain for at least a generation in the new locale.52,163 Secular Changes

National and regional birth defect monitoring programs in Canada, the Czechoslovakian Republic, England and Wales, Finland, France, Hungary, Israel, Italy, Japan, Mexico, The Netherlands, New Zealand, and the United States have demonstrated varying downward trends in the birth prevalence of anencephaly, spina bifida, and encephalocele.182 Generally, the higher the initial rate, the greater the decline, and there is perhaps a greater consistency to the decline in anencephaly than for the other two malformations. Most of this decline pre-dates efforts to encourage women to supplement their diets with folic acid, and there is not evidence to attribute the decline to these efforts.183 However, a more recent and further decline noted by several studies (Table 162) may reflect the effect of food fortification with folic acid. Important exceptions to this downward trend have occurred in South Africa and South America and require explanation. Decreases in frequency appear to affect the magnitude of other demographic differences such as the excess of females and seasonality of births, which have been observed in a number of surveys. These observations further support the action of important environmental factors in the etiology of NTD and suggest that the major impact may be on a subset of cases. As reviewed by Stone,180 North American data support a rising prevalence beginning in the late 1890s, reaching an apogee in 1930–1934 before declining. A lesser peak in 1950–1954 and a further smaller peak in the early 1960s interrupted the fall. Similar changes occurring several years later were noted in the United Kingdom. In a number of areas, declines have been reported but appear to have plateaued at a level significantly higher than those observed in traditionally low incidence regions.182,184 It appears likely that cultural, environmental, and true ethnic and racial differences in genetic susceptibility are correlated with differences in incidence. Further understanding of this may be gained by detailed population studies such as that of Hall et al.,167 who found that the high incidence of NTD among the British Columbia Sikh population was due to greater susceptibility to high SB and to multiple NTD than the rest of the British Columbia population. Similarly, it will be useful to have more data regarding whether specific subgroups of patients are responsible for the changing rates. For example, Yen et al.165 showed that in Atlanta the decline in SB was restricted to isolated SB and was not seen in cases with associated malformations. The numbers in the group with malformations were small but are of interest because the decline in isolated SB was for all levels of lesion, and yet Hall et al.167 found associated malformations to be more common with high SB.

Brain and Spinal Cord

729

Table 16-2. Selected geographic and secular rates of anencephaly, SB, and total NTD per 1000 births 1950

1960

1970

1980

1990

2000

SB

Australia, South168,185

1.12

|- 0.99—0.70 |

Australia, Victoria186

0.25

|- 0.91 -----------------------0.96-F–0.68-| |-- 1.87 |

Canada, Central52,166,249

|------------- 1.08 -----------|

|-0.75-F-0.42-|

Canada, Nova Scotia188

|-1.34-1.56-F-0.52-| |--- 2.15 ---------------------------------0.38 ¼¼¼¼¼ |

England and Wales184 |-1.3-| |—0.96 |

Germany, Berlin179 Hungary189

|---------- 0.81 --------| |—1.9 ----------------------------------0.86 ----| |- 2.72 -----------------0.55 ¼¼¼ |

|reland190 169

|srael

|-- 0.19 --- 0.51 ------------0.69-|

|srael, Palestinian178

|--------- 2.23 -----|

Sweden170

|—1.1------------------0.07 ------------------ 0.36 ---------- 0.45 --|

USA, Atlanta165

|- 2.0 -------------------------------- 0.6 ---|

ANENCEPHALY

|- 0.86—0.58 |

Australia, South168,185 Australia, Victoria186

|- 0.57 ---------------------0.80-F*–0.32-| |-- 1.45 |

52,166,249

Canada, Central

|---------------- 0.58 ------|

|-0.38-F-0.16-|

Canada, Nova Scotia188

|-1.09-0.82-F-0.31-| |--- 1.49 --------------------------0.29 ¼¼¼¼¼ |

England and Wales184 Germany, Berlin179

|-1.4-| |-1.05 -|

189

Hungary

|---------- 0.43 --------| |—1.1 ------------------------------------------0.93 ----| |- 1.78 ---------------0.44 ¼¼¼ |

|reland190 |srael169

|-- 0.40 --- 0.49 ----0.69-|

|srael, Palestinian178

|--- 2.41 -------|

172

|—1.45 ---------------------------- 1.1 ---------------- 0.7 -------------- 0.42 -------|

Netherlands

New Zealand191

|-.43-.32-|**

|- 1.17 --------------------------- 0.39 -----|

TOTAL NTD

Australia, Victoria186

|- 2.0 ---F–1.21-|

Britain, Southeast173

|—3.7 -------- 2.8 ----------- 1.2 --|

Britain, Liverpool174

|------------ 6.84 --------------- 6.26 ------------2.1–1.64 --|

Canada, Central187,249

|-1.17--|

188

|-1.13-F-0.58-| |-2.51-2.61-F-0.94-|

Canada, Nova Scotia

|--- 4.03 ---------------------------------0.76 ¼¼¼ |

England and Wales184 Hungary189

|—1.1 --------------------------------------0.93 ----|

|reland175,190

|- 8.54-| 176,192

|- 4.69 ---------------1.16 ¼¼ |

|------ 2.0 ----1.1 --------|

USA, Southeast

USA, Utah177,193

|-- 6.5 |

|—1.0 -----------------1.0 --------------------------1.1 -----0.8 -----|

|-1.89-0.95 -| |-0.98-- ¼¼¼¼ - 0.6-|

Most data do not include pregnancy terminations prior to 20 weeks; more important in recent years. F is introduction of food fortification with folic acid (F* is voluntary)(this occurred generally from 1998). Systematic efforts to encourage women to supplement their diets generally occurred in the early to mid-1990s. ¼ ¼ periods of stable rates. ** Congenital anomalies in the Netherlands. TNO Prevention and Health, 2000.

Comparisons of demographic variables between populations with differing rates may also prove useful. Sex Ratio

Most surveys of NTD report a significant excess in females, the difference being extreme for iniencephaly and greater for anencephaly than for SB and encephalocele. There is a significant early

loss of fetuses with NTD, and it is not known whether the female excess at birth reflects a true difference in incidence or a selective loss of male embryos. The latter possibility would not be eliminated by a failure to find an excess of miscarriage in NTD families or a lack of distortion of the sex ratio among normal sibs. Most NTD occur in families with no prior history of affected individuals, and one would expect that if there were an excess of

730

Neuromuscular Systems

affected males being miscarried that the majority would occur in sibships without liveborn affected children and therefore be unascertained. Second, given that general miscarriage rates are in the range of 15%, a small increase due to recurrent NTD, although reported in a number of studies, could be obscured. Finally, given the relatively low recurrence rate of NTD, it would require extremely large numbers to observe a distortion in sex ratio in unaffected sibs due to a preferential loss of affected males. In fact, Fraser et al.194 summarized their own data and several reports from the literature and found an excess of males among unaffected sibs of the proposita. That finding would be compatible with a relatively high incidence of NTD preferentially affecting females, with many being miscarried. In contrast, Ka¨lle´n et al.195 found a reduced sex ratio among all classes of NTD but a significant excess of males in cases lost prior to 20 weeks gestation. They found a lower ratio for stillbirths than among live births for both anencephaly and SB, regardless of whether or not there were other associated malformations. It has further been claimed that the magnitude of the female excess varies inversely with overall prevalence of NTD.162,196 In a study of declining rates of NTD in the United States, a greater decline was found in cases lacking associated malformations, and the fall in female predominance was limited to that group.165 This relationship with sex ratio led James197 to hypothesize that a predominantly female-specific environmental factor acts to cause anencephaly. Fraser et al.194 were unable to find support for an independent female factor, and James,197 himself, was unable to find evidence that factors were acting on a specific group of highrisk female embryos. A number of studies have failed to find a correlation between declining prevalence and sex ratio.52,162,179 Frecker and Fraser,162 who did not find a correlation between secular peaks and increased numbers of affected females, did find such a relationship within geographic pockets of high incidence. They hypothesized that a female factor exists and may be concentrated more in certain areas but does not account for secular or seasonal variations. Further support for the concept that environmental factors may have sex-specific effects comes from the observation of a male excess of cases born to folic acid–supplemented women198 and an increased relative risk of spina bifida limited to males during the period of the 1944–1946 Dutch famine winter.199 Studies comparing sex ratios between cases with high and low spina bifida have shown inconsistent results.187,200 Seasonal Variations

Seasonal variations in birth prevalence of NTD have been an inconsistent finding. Although variations in statistical approach may account for some differences,201 there have been adequate positive reports to discount the possibility of a simple chance association. There has also been a significant group of studies in which no such seasonality has been observed.179,196,202 Furthermore, areas that at one time were reported to have significant seasonal differences did not have such variations in later surveys,1,202 and in some cases seasonality has been limited to a specific interval during the years studied.190 This has led to suggestions that seasonality may be a factor in areas of high incidence, perhaps acting mainly on females, but others have suggested that it is a function of transition from one frequency to another.202,203 Fraser et al.202 surveyed the literature and plotted frequency at birth against ratio of highest to lowest monthly frequency and found support for the claim that seasonal variation was less likely to be observed at either very high or very low incidence.

Important in any study of seasonal variation are corrections for any variation in season of birth in the general population, and for the propensity to prematurity in infants with anencephaly. The review by Fraser et al.202 suggested that it might be equally important to examine anencephaly and SB separately. They found that the seasonal peaks of the two lesions tended to vary independently. Peaks for conception for anencephaly occurred in all seasons except August to November (northern hemisphere), and peaks for SB were almost always May to August. Different timing, as expected, has been noted in the southern hemisphere.204 These findings suggest the possibility of different, and seasonal, environmental factors, acting separately on either the upper or lower regions of neural tube closure. Seasonal variations in diet, exposure to environmental toxins, or infectious agents are likely candidates for study. The somewhat converse relationship between peaks for anencephaly and SB means that seasonal variation may be obscured if the two malformations are reported together. Frecker and Fraser162 did not find evidence that female births correlated with the months of high frequency. The frontoethmoidal encephaloceles that are common in Southeast Asia may show a deficit of cold season conceptions, an increased interpregnancy interval, and a lack of familial propensity.44 Socioeconomic Status

A number of major surveys have documented an increasing risk of NTD with a decline in socioeconomic status. This has perhaps been most clearly shown in Great Britain, where there has been a twofold to fourfold greater prevalence among middle and lower social classes than in upper social classes.205 Comparable results have been reported in other countries, including the United States,165,206 Canada,52,164 Australia,207 and Turkey.208 However, not all studies have been positive, even in areas that have shown prior positive results or where there is a positive association with other nonneural tube malformations.190,209 The effect of socioeconomic status remains after correcting for other demographic variables and, although present in some low-risk areas, it tends not to be reported from low-prevalence areas.191,210,211 Indeed, socioeconomic differences in some studies may account for apparent ethnic differences in prevalence, while in others there is a suggestion that they may interact with ethnic susceptibility.52,181 Failure to measure important cultural variables, such as the use of prenatal screening and interruption of pregnancy, can confound conclusions as to whether local ethnic differences are genetic, socioeconomic, or cultural.212 Again it is important to consider anencephaly and SB separately. As an example, Canfield et al.212 found that correction for socioeconomic status reduced the relative risk of Hispanics for anencephaly but that it increased for SB. The nature of the factors causing this relationship between socioeconomic status and prevalence is not known, but candidates include diet, housing, and exposure to environmental toxins or pathogens. Smithells et al.213 reported higher values for red blood cell folate (not serum), white blood cell vitamin C, riboflavin saturation, and vitamin A among social classes I and II compared with classes III to V. It has been noted that the secular peaks of NTD births followed, by about one generation, the Great Depression, World War I, and World War II, and this has raised the question as to whether socioeconomic underprivilege during childhood might increase a woman’s risk to bear a child with an NTD. Sever and Emanuel210 summarized data in support of this hypothesis and carried out a case-control study where mothers of children with NTD were matched with mothers of unaffected children with respect to socioeconomic status. Whereas no significant difference

Brain and Spinal Cord

was found in the occupational class scores of the respective husbands, the case mothers, based on their fathers’ status, were found to have been significantly less advantaged as children than were the controls. Some support for this theory was provided by Hunter.52 It is plausible that folate deficiency in the maternal grandmother at the time of her pregnancy with a female fetus might affect the methylation cycle of future ova in that fetus. Maternal Age and Parity

Maternal age and parity cannot be considered independent of one another. In many countries the precise nature of the relationship has undergone a dynamic change in the past 10 to 15 years, with mean family size falling to less than two and many women postponing reproduction. Often the traditional association of increased maternal age with high parity and low socioeconomic status has been replaced by low parity and high economic status. Thus, there is a potential minefield of confounding variables that may affect epidemiologic studies of these factors. Many earlier studies, particularly from high-risk areas, claimed peaks of occurrence at either high and low (‘‘U’’ curve) or at high (‘‘J’’ curve) maternal age.52,214 Similar findings do continue to be reported.204 However, in a number of instances when the same population has been restudied at a time of lower birth prevalence, the association has disappeared.52,191 Similar patterns of association with parity in high-risk areas have been observed, while in low-risk areas there are reports of a monotonic relationship with parity.211 Several authors have claimed that the maternal age affect disappears when data are controlled for parity.179 Differences between studies may occur due to secular changes in age-specific incidence happening at the time of cross-sectional studies.52,214 Janerich214 has shown that an apparent U-shaped relationship on cross-sectional data revealed an apparent declining risk

731

with increasing maternal age when examined longitudinally. The differences were explained by a falling age-specific risk over the study years that correlated best with the mother’s, rather than the child’s, date of birth. Figure 16-9 illustrates how exposure to a ‘‘teratogen,’’ causing lifelong propensity to bear children with NTD, would produce different associations with parity and age if cross-sectional studies were carried out at different 5-year intervals. A more complex picture would result after introducing an additional cohort of women exposed ‘‘a generation’’ later to a similarly acting agent. Prior Reproductive History

A number of studies have reported a higher rate of fetal wastage, particularly immediately prior to the propositus, in sibships of propositi with NTDs.215 The finding is opposite from what would be expected from studies of maternal bias in recalling abortion216 and led Knox217 to postulate that trophoblastic rests from a prior abortion interfere with the next pregnancy to cause NTD. It was argued that the particular increase in abortion prior to the propositus would not be expected if these families were simply more prone to abortion. Cuckle218 compared the rate of NTD in the third pregnancy in families with four types of outcomes in their first two pregnancies: (1) NTD þ spontaneous abortion (SA); (2) NTD þ no SA; (3) no SA þ NTD; and (4) SA þ NTD. The relative risk for the NTD þ SA families was significantly higher than for the other groups and was 6.2 times that of the SA þ NTD families. However, an uneven distribution of abortion across birth ranks is inconsistent, and when the excess of abortion is prior to, rather than after, the proband, it is not always preferentially in the pregnancy immediately before the affected birth.52,219 Any excess of abortions in NTD families may simply represent loss of affected pregnancies. Roberts and Lloyd220 suggested an inverse relationship between rates of NTD and those of

Fig. 16-9. Graphic representation of the effect of a putative agent acting on a cohort of women and placing them at increased risk for NTDs.

732

Neuromuscular Systems

SA. Japan is a low-prevalence area, and up to 90% of fetuses with NTD are said to be aborted;221 comparable British data are 60%.222 The excess of normal male siblings reported in several studies and the greater female excess among stillbirths compared with live births supports the view that the abortions are primarily affected female fetuses, although one recent study supports a selective loss of male fetuses prior to 20 weeks gestation.187 Observations that the excess of abortion is restricted to the period prior to the birth of the propositus may reflect studies carried out during or just after a decline in incidence. More of the earlier pregnancies would be affected with NTD; most would be aborted and would cause a higher abortion rate. By ascertaining sibships because of a liveborn with an NTD, there is selection for an increased abortion rate in prior pregnancies. This bias would not affect subsequent pregnancies because NTD would account for a minority of total abortions and rates would have fallen. Indeed, some studies in high-risk populations continue to find a risk from prior abortion,211 some show no difference,223 and others from areas where rates have fallen appear to show a protective effect from prior pregnancy loss.215,224 The results of Cuckle218 comparing SA þ NTD to NTD þ SA families appear to confound this simple interpretation of fetal loss, but the study involved small numbers and particularly high recurrence risks, and the intergroup differences resulted from one of the three (South Wales) surveys used and might reflect chance. Carmi et al.225 found an increased rate of prior spontaneous abortion among both a high-risk (Bedouin) and a low-risk (Jews) population. However, the rate was higher for Jews, and specifically for SB rather than anencephaly. The authors proposed that anencephaly has a greater ‘‘genetic liability’’ than SB, so that the latter would require a greater environmental trigger (e.g., trophoblastic rest) in order to occur. However, this multifactorial model would predict a different recurrence risk for anencephaly than for SB, and it attributes the higher rates in the Bedouin to genetics factors, which is perhaps unlikely given the rapid declines in rates observed in many high-risk areas. A decreased interpregnancy interval prior to the pregnancy affected by an NTD has been an inconsistent finding used to support the Knox hypothesis. Most studies have not controlled for socioeconomic status and pregnancy replacement, which could affect pregnancy interval. A recent study found that a prior pregnancy interval of <6 months was a risk factor for an NTD, but that the risk was greater for prior normal pregnancies than for those ending in an SA.215 A full-term pregnancy is a greater drain on maternal nutrient resources than an SA, and such results might be explained by a depletion of maternal folate reserves.226 Population studies tend to show an excess of birth defects among twins, and often this is seen to be limited to like-sexed twins, or even more specifically, to monozygotic (MZ) pairs. Neural tube defects are one of the malformations found in excess in some,187,227,228 but not all,190 studies. Garabedian and Fraser229 reported an excess of like-sexed twins in families of patients with an NTD, but the excess was limited to cases where the lesion was above T11. The twin findings have led several authors to suggest a common relationship between MZ twinning and NTD. Recent data suggest that concordance rates among twins are low, are higher for SB than for anencephaly, and are compatible with singleton recurrence risks.230–232 Windham et al.231 found a higher rate of like-sexed (by inference MZ) anencephaly, but not other NTD among twins. However, from their own data and from a review of the literature, Little and Nevin232 concluded that the rates of anencephaly and of SB did not differ between like-sexed and dis-

similar-sexed twins. Ka¨lle´n et al.195 found 10 of 327 NTD twin pairs, where the first twin had an NTD, to be concordant for an NTD. Causal Heterogeneity

This brief epidemiologic overview has provided evidence of dynamic interactions of environmental and genetic factors at work in the etiology of NTD. At times the data are confusing and conflicting, and, while this may sometimes simply reflect methodologic differences or sampling error, there is reason to believe that an underlying etiologic heterogeneity exists and that the relative weighting of causative factors varies with time, geography, and genetic background. This has led several groups to search more critically for subgroups of patients with NTD. Khoury et al.233 examined a number of epidemiologic variables in children born with isolated NTD and compared the results with those from children who also had associated malformations. The former group showed a female predilection, a secular decline in prevalence of both males and females with anencephaly and with SB, and an east–west gradient. These findings were not apparent for the children with associated malformations. Other differences included more female twins with isolated NTD, more male twins with malformations, and a greater concordance for NTD among those with malformations. The latter finding suggests the possibility of undiagnosed genetic syndromes. The differences between the groups suggest causal heterogeneity. Granroth et al.171 and Seller2 found no difference in sex ratio for either patients with isolated anencephaly or those with associated malformations. Hall et al.234 found a reversed sex ratio in cases with associated malformations. Hunter,52 who also found a female excess for anencephaly but not for cases with associated malformations, suggested that males, the least susceptible sex, would require a greater teratogenic insult to develop an NTD, and this greater insult would be more likely to cause associated anomalies. Seller and Kalousek235 studied 150 fetuses from abortions induced because of an NTD and were unable to confirm the findings of Khoury et al.233 In 139 cases there was no specific syndrome diagnosis, and 67% of these had no associated malformation. Patients with isolated NTD and those with additional anomalies did not differ with respect to prior reproductive history, type and frequency of prior NTD in the sibship, or sex ratio. Hunter52 also did not find that the presence or absence of an associated anomaly influenced recurrence risk. Seller and Kalousek235 found that associated anomalies occurred in 58% of craniorachischisis, 19% of anencephaly, and 33% of SB. Spina bifida was further subdivided by level, and malformations were reported in 90% of upper-thoracic, 30% of thoracolumbar, and 0% of lumbosacral lesions. Of particular interest was the fact that, although the malformations were of the ‘‘schisis’’ type, different anomalies tended to correlate with specific levels of the NTD. This was interpreted as local mechanical induction of the associated lesion, and reduced length of the spinal axis was considered important. Toriello and Higgins236 divided 195 propositi with nonsyndromic SB into those at or above T11 (37 cases) and those at or below T12 (158 cases). Those with upper defects were found to have a higher rate of abortion in the sibship and were more likely to directly follow an abortion than was a normal sibling. These patients also had a significantly higher rate of associated malformations. Ka¨lle´n et al.237 noted a higher rate of non-NTD–associated malformations in cases with high SB and encephalocele than in anencephaly or lower SB. Hall et al.234 used a variety of classifications, including a division of SB similar by level to that of Toriello and Higgins,236 in a study of all forms of NTD. Their patients did not differ by type or site of lesion,

Brain and Spinal Cord

birth order, maternal and paternal age, or sex ratio, as had been reported by Seller.238 Again, associated malformations clustered in patients with severe anomalies (craniorachischisis, multiple lesions) and upper SB. Sikhs were also overrepresented in this group. Negative results for any association with level of lesion, sex ratio, miscarriage rate, and maternal age have been reported by others.200 Hunter et al.239 found a higher rate of associated malformations among patients with high-level lesions. They also stressed that there can be important differences between the clinical and radiologic definition of the level of the lesion. Some interstudy differences between populations may relate to differential prenatal ascertainment of cases with and without malformations and to differing levels of participation in prenatal diagnosis.237 Perez-Molina et al.240 found an association of upper, but not lower, NTD with maternal illness of less than a month’s duration, most importantly flu, and with drug treatment exposure. In the study of Garabedian and Fraser,229 who showed an excess of like-sexed twinning in the families of NTD with high lesions, the occurrence of an affected sib was greater in the families with high defects and twins. The association of additional malformations with high SB and their virtual absence with low SB has been used to support the concept of causal heterogeneity. However, if Seller and Kalousek235 are correct in their proposal that the malformations are ‘‘induced’’ by the local malformation of the neural tube, then this argument is not valid. The rate of non-NTD malformations in sibs did not differ by site of lesion in the propositus, although sibs of Sikh patients had an excess of isolated hydrocephalus. It has been stated that there is a high correlation between the level of lesions in the propositi and those of their affected sibs.234,236 However, the numbers were small and were not examined with respect to observed versus expected sib pair combinations. This cannot be done with the data provided, as Hall et al.234 do not specify the propositus in the high SB–anencephaly pairs and Toriello and Higgins236 limited their study to spina bifida so that the denominator required to calculate expected values is incomplete. Frecker et al.241 reported several cases of lack of concordance for the level of lesion as defined above, and pointed out that they were reporting from a high incidence area and that factors predisposing to high and low lesions, not present in low-risk areas, might be at work. In a high-prevalence area, Garabedian and Fraser242 did not find evidence for concordance of level with recurrences within families, nor did they find a difference in recurrences between low- and high-level propositi. In contrast, and from a low-prevalence area, Hunter et al.239 did show a trend to a higher NTD rate in sibs and more distant relatives when the propositus had a high lesion. Blatter et al.200 found a greater risk for a high SB when the propositus had a family history of NTD. Park et al.243 found no difference in exposure to potential exogenous etiologic factors between anencephaly, high SB, and low SB. They did find, for an area with relatively low recurrence rates, that affected sibs were more common when the index case had a high SB than anencephaly, and they had no affected sibs when the propositus had a low SB. The numbers were small for this type of analysis. It is becoming increasingly difficult to ascertain large numbers of cases for study. Hall et al.,234 Toriello and Higgins,236 Seller and Kalousek,235 and others have supported the view that the high lesions reflect disordered neural tube closure (neurulation), while low SB is related to canalization of the lower cord. While it seems likely that these two embryologic processes would be subject to different teratogenic processes, it is problematic whether their respective territories should be subdivided at the level of T12. While these authors have considered that the posterior neuropore

733

may close at the level of the 25th somite and that there may be a zone of overlap between neurulation and canalization, this does not appear to be the case. Closure takes place at about the 25th somite stage, but at the position of future somite 31, and there is no evidence of overlap in humans.244 This position is equivalent to S2, and disordered canalization would be reflected in sacral anomalies. The view that the majority of mammalian SB cases reflect abnormalities of neurulation was set forth by Copp and Brook,245 who used the curly tail (ct) mouse in which 90% of ct/ct homozygotes have SB. They injected India ink into the upper neural tube and identified the site of the posterior neuropore by observing the site of egress of the ink. They demonstrated that in all cases the rostral limit of the SB was cephalad to the posterior neuropore, that is, to the site of neural tube closure. In some cases the SB extended below the posterior neuropore and represented secondary interference with the process of canalization. Specific Environmental Factors

Geographic differences and secular changes point to the importance of causative forces in the environment, while association with socioeconomic status raises the potential importance of nutritional variables. Many early suggestive correlations such as with tea or blighted potatoes have not withstood the scrutiny of further study.25 Folic acid has emerged as the single most important environmental determinant of the prevalence of NTD. Early and recent casecontrol studies have shown lowered levels of serum and/or red blood cell (RBC) folate in women who deliver children with an NTD.246 Interventional and randomized control studies have shown a clear reduction in the recurrence risk within sibships, and in the population rates of NTD following periconceptional supplementation.247,248 Finally, several disparate geographic areas have shown a marked drop in the rates of NTD following the fortification of foods with folic acid.188,249,250 This topic is discussed further under the ‘‘prevention’’ section. The challenge that has arisen from these data is to explain the observed differences among women in their plasma and RBC folate levels, which cannot be attributed to variation in diet. Folate metabolism is an obvious starting point. Methylene-H4-folate reductase (MTHFR) catalyzes the reduction of methylene-H4-folate to methylH4-folate that serves as the methyl donor for the methylation of homocysteine to methionine. The latter is catalyzed by methionine synthase (MTR). MTR is cobalamin dependent, and its reductive activation requires methionine synthase reductase (MTRR). The C677T thermolable MTHFR variant occurs in 1–20% of different populations and has been subject to numerous casecontrol studies. The results have been mixed, in some cases reflecting small sample size and/or inadequate selection of controls, while in others including populations that may differ in folate intake, with high intakes potentially masking the genotypic effect. A meta-analysis gave a pooled odds ratio of 1.8 (CI 1.4–2.2) for C677T homozygosity and of 2.0 (CI 1.5–2.8) for C677T in combination with the A1289C variant.251 This compound heterozygote has been shown to have the equivalent effect on lowering plasma folate as does the C677T homozygote.252 There is some evidence that the fetal MTHFR genotype may play a role. Johanning et al.253 showed a marked decrease in the risk ratio for fetuses heterozygous for C677T for the period mid-1994 to 1998 as compared to 1988 to mid-1994. They suggested that increased folic acid intake during the latter time period was a cause for the difference. Variation in MTHFR activity does not account for all differences in folate related risk, and this has led to the study of other

734

Neuromuscular Systems

enzymes in related pathways. Although the 2756A ! G MTR and the 66A ! G MTRR variants do not appear to affect plasma homocysteine levels,254 there is some evidence that the maternal genotype may influence the risk of NTD.255 These and other polymorphisms, including R653Q in MTHF dehydrogenase/ MTHF cyclohydrolase/formyl tetrahydrofolate synthase,256 thymidylate synthase,257 dihydrofolate reductase,470 betainehomocysteine methyltransferase,471 the role of co-factors such as cobalamin,258 and dietary components such as methionine intake,259 merit further study. There is initial evidence that gene– gene interaction may be important and further large studies will be of interest.472 Rothenberg et al.473 found that autoantibodies that block binding of trihydrofolic acid to folate receptors were significantly more common in women who had a child with an NTD than in controls. A wide range of additional environmental variables has been reported as possibly explaining some proportion of NTD cases. Often the agents have not been the focus of the original study and the conclusions have been post hoc. In other examples the sample size has been small and confidence intervals have included 1.0. It is beyond the context of this chapter to review all such studies, but several of the more topical and/or important are summarized in Table 16-3. Those with a deeper interest in a particular topic should consult a wider number of original sources. Familial and Genetic Factors

The association of NTD with chromosomal and single gene syndromes clearly establishes a genetic component to their causation. A variety of karyotypic anomalies have been reported in association with NTD (Table 16-1). Unless there is a recurrent pattern, it is not possible to determine whether or not the chromosome imbalance is causative. If a specific association is established, there remains the question as to whether the NTD results from a generalized disturbance of embryogenesis or from the duplication/deficiency of a gene with direct involvement in closure of the neural tube. Intuitively, the latter would seem more likely when the association is with a small chromosomal segment296 than with a complete trisomy, such as trisomy 18. The likelihood of finding a chromosome abnormality in a case of NTD is strongly dependent upon gestational timing and the presence or absence of associated anomalies. In a study that used transcervical embryoscopy to study missed abortions, Philipp and Kalousek297 found that 10 of 99 embryos had an NTD, that all of those had additional anomalies, and that all eight that were karyotyped showed a chromosome imbalance. Those were predominantly triploids and aneuploids that are uncommon in midtrimester and rare at birth (e.g., trisomy 9 and 14). In mid-trimester most chromosome studies are performed on cases detected by ultrasound. Overall, the rates of chromosome abnormalities range from about 7–16%,298–300 with the highest frequency in studies that include apparent balanced chromosome rearrangements. Trisomy 18 may account for up to 70% of cases at this gestational age, although triploids and duplication/deficiencies continue to be seen. Cases that lack associated malformations are significantly less likely to have a chromosome abnormality.298,300 Presumably, ultrasound technique and the care with which the products of terminated pregnancies are examined will influence the reported frequencies. Noncontiguous NTD are uncommon, 14 of 948 cases in one series,301 and a significant proportion (three of 14) may result from trisomy 18. In contrast to the findings in embryos and fetuses, chromosome anomalies are uncommon in liveborn children with

NTD, and the need for chromosome studies should be based on clinical assessment. There are over 60 loci and strains that confer an increased risk for NTD in mice.302 Relatively few mouse models fit that of the multifactorial, genetic/environmental interaction that appears to account for most isolated human NTD. Many mouse knockout models are early embryonic lethals and are associated with additional malformations. However, partial inactivation of some of these same genes is compatible with survival to term with exencephaly.302 Complex gene interactions are also being found.302,303 There continues to be controversy as to whether the accepted sites of closure initiation in mice303 also occur in human embryos.4 However, it is likely that the underlying essential processes that lead to the development of an NTD will be similar. An association between an increased rate of closure of the neural tube with a decreased curvature along the craniocaudal axis has been noted across species, including in humans.304 Furthermore, almost all mouse mutations that cause NTD result from failure of elevation of the neural folds rather than from failure of their fusion. The location and extent of the failure varies with the locus involved and determines the site of the lesion (e.g., exencephaly, craniorachischisis, SB). The failure can result from a range of underlying pathogenic mechanisms. These may include an abnormal ventral curvature due to tissue tethering; inadequate supporting mesenchyme; defective basal lamina; abnormally wide floorplate and notochord; inadequate neuroepithelium, in some cases due to excess apoptosis; and lack of normal redundancy to allow catch-up and rescue from an initially delayed elevation.302,303 Several mouse mutations demonstrate interaction with environmental factors such as folic acid, folinic acid, methionine, and inositol;302 others show a female predominance302,305 or sensitivity to specific drugs such as valproate.306 A null mutation for Dnmt3b that normally methylates DNA in the mouse embryo results in exencephaly,307 and it has been speculated that the female need to methylate the inactive X-chromosome might delay cell division and neural fold elevation.302 At the cellular level, there is growing evidence that mutations in genes affecting the structure and function of the actin cytoskeleton may impede elevation of the neural folds.302,308,309 Notwithstanding the large number of loci in mice that have been shown to influence neural tube closure, there is consensus that single point mutations do not account for most NTD in mice or in humans. There are relatively few human data relating to mutation screening of the equivalent human genes, but to date they do appear to confirm that point mutations resulting in major disruption of a single gene will be an uncommon cause of NTD.310–313 Acceptance of the multifactorial model of NTD has led several groups to perform association studies with polymorphisms at various loci. The relationship to MTHFR variants and the related folate pathways has been discussed above. Given the wide variation in the distribution of associated environmental factors, the choice of controls for any such studies is critical and one may anticipate that results will differ between populations. For example, polymorphisms of the folate pathways may show associations in a folate-deficient environment but not where foods are fortified with folic acid. Morrison et al.,313 in a mixed Dutch/English study of cysteine betasynthetase (CBS), methionine synthetase (MS), MTHFR, the human brachyury equivalent (T), and BRCA1, found an association between NTD and a T allele. This was not seen in a Midwestern U.S. population studied by Trembath et al.314 The latter authors did not find any association of NTD with polymorphisms of the folate receptors alpha and beta, MS or PAX3. An exon 7 Ala ! Glu mutation in MTHFR was associated with NTD in their Iowa population but

Table 16-3. Some environmental factors studied in relation to the cause of NTD Exposure

Information

Conclusion

Alcohol abuse

Not a common manifestation of fetal alcohol syndrome. Does occur in animal models and is reported in humans.25

Uncommon cause

Altitude

Case-control study showed lower rate of both anencephaly and spina bifida in women living at high compared to low altitude.260

Not a risk factor

Antiepileptic drugs

Many antiepileptic drugs are antifolinic (FAA), and case-control studies have shown a statistically increased OR for several.261 Significant ORs have been shown for trimethoprin, carbamazepine, and valproate. The latter appears to have a propensity for lower SB.262 There are not adequate data to fully assess some newer drugs.

Increased risk for several drugs

Bicornuate uterus

Case-control study suggested an increased risk for some malformations but not for NTD.263

Not a risk factor

Living within 3 km of a chemical landfill site was associated with an OR for NTD of 1.86 (CI 1.24–2.79).264 A case-control study of occupational and hobby exposure to a long list of organic chemical showed no significant results.265

Perhaps some risk with residential exposure but no specifics known

Pesticides

A case-control study based on the California registry showed no evidence of increased pesticide exposure in case mothers or fathers.266

No evidence of risk

Glycol ethers

Study results have been inconsistent and numbers of exposed small.267

Unproven

Recreational drugs

Case-control study from California registry showed no association of NTD with maternal or paternal use of cannabis, amphetamines, or cocaine.268

Not a risk factor

Chorionic villus sampling

Data for CVS after 10 weeks gestation do not provide evidence of an increased risk for malformations.269 Exposure is after the time of neural tube closure.

Not a risk factor

Electrical current

There is a negative case-control study for electric blankets (OR 0.9, CI 0.5–1.16).270

Not a risk factor

Fumonisins

A mycotoxin whose temporal association of high levels in corn flour products with a cluster of NTD suggested a possible association.271 Animal data are variable but some models show an increase of NTD.272

Possible risk Altered folate receptors?

Gastrointestinal bypass surgery

A report of three cases among a small sample of patients with documented low B12 and anemia.273 No cases in a subsequent group.

Unclear Nutritional risk?

Infertility

Early studies raised concerns about an increased risk. Recent case-control study was negative (OR 1.2, CI 0.7–2.1).274

Not a risk factor

Infertility drugs

Case-control studies of ovulation induction and infertility treatment have shown no evidence of risk for NTD.274,275

Not a risk factor

Infertility: In vitro fertilization

A case-control study has shown an increased rate of NTD after in vitro fertilization (IVF), but the increase was attributable to the greater rate of twinning.276 Monochorionic twin rates are more frequent with IVF.

Risk related to twinning

Maternal diabetes

Rates are up to 20-fold that of the general population; may be reduced by excellent periconceptional and first trimester control88

Risk factor

Maternal hyperthermia

A definite teratogen in experimental animals.89 The weight of earlier retrospective studies52,90,92,277 and of more recent case-control studies278,279 support a role for sustained (>24 hours) high (>38.98C) temperature as a cause of NTD, most specifically anencephaly. It is still difficult to disassociate the fever’s cause from the fever as causative.89,279

High and sustained fever likely a risk factor Fevers should be reduced

Maternal obesity

Case-control studies show an increased risk with obesity and a gradient effect.280,281 Risks may be highest for isolated, high SB, and for female fetuses.282 Hyperglycemia delays rostral initiation sites in rats.284

Risk factor Hypersinsulinism pathway?283

Maternal smoking

Case-control study showed decreased risk of total NTD (OR 0.75; CI 0.61– 0.91), anencephaly, and SB for mothers who smoked.280 Smokers have reduced plasma and RBC folate levels.285

Reduced risk Increased early losses?

Maternal thalassemia

Carriers of a or b-thalassemia may have low folate levels. One small study showed carriers at an increased risk for NTD pregnancies (OR 3.99; CI 1.07–14.94).286

More data needed

Chemicals General

(continued)

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Table 16-3. Some environmental factors studied in relation to the cause of NTD (continued) Exposure

Information

Conclusion

Maternal weight gain in pregnancy

A case-control study associated poor weight gain during pregnancy with an increased risk of NTD but concluded it was a result of, and not a cause of, NTD.287

Noncausative association

Blatter et al.288 have associated agricultural occupations with a higher risk of NTD. Living within 0.25 miles of an agricultural crop was a risk factor in another study.266 (See chemicals, general and pesticides.)

Possible link but unknown cause

Statistically significant association with welding;200 chlorophenate exposure.289 Many other initial observations, such as with painters or printers, have been post hoc52 and often not confirmed on subsequent study.290

Results are often not reproducible

Vitamin A

NTD reported with exposure to isotretinoin and etretinate.25 A proven teratogen; interacts in several mouse models of NTD.291

Known teratogen, NTD uncommon

Water treatment

Byproducts of chlorination of water-containing organic compounds can be mutagenic. Case-control studies have raised some concerns, specifically for the trihalomethanes; borderline significance levels.292,293

Further data needed

Zinc deficiency

An association of high levels of NTD in countries with endemic zinc deficiency. Case-control studies have shown lower serum zinc in case mothers294 and higher dietary intake with lower rates of NTD.295

Possible role, may impair folate absorption

Occupation Maternal

Paternal

was not reproducible in two other samples. Joosten et al.315 focused on the promoter region of platelet-derived-growth-factoralpha-receptor (PDGFRA) because NTD-associated mutations of PAX1 have been shown to deregulate activation of the promoter. They identified five promoter haplotypes with differing transcriptional activity and found that those with increased activity were associated with sporadic NTD. Low-activity homozygotes were absent in sporadic NTD cases, while low/high heterozygotes were overrepresented in familial and sporadic cases. A negative association study for MLP, which codes the MARCKSlike protein, was reported by Stumpo et al.316 Felder et al.311 found some evidence of genotype disequilibrium for an exon 5 BMP4 polymorphism. Klootwijk et al.474 found no evidence that ZIC1, ZIC2, or ZIC3 plays a significant role in human NTD. Finally, Kirillova et al.317 examined first-trimester abortions affected by NTD and found an association of cervical notochordal duplication in craniorachischisis (but not in SB) and abnormally broad and/or numerous expression domains for sonic hedgehog (SHH). These findings show a parallel with those in the loop-tail mouse and would seem a logical area for future study.318 The mouse T c/tw5 compound heterozygote mutant raises the possibility that there could be exceptions to the predominant origin of NTD as a failure to close.319 In this model there is normal elevation and fusion of the neural folds, followed by blister formation and rupture under the intact epidermis due to defective neuroepithelial basal lamina, resulting in an open NTD. Spina bifida occulta (SBO) is very common and, therefore, it is important to know whether it carries with it any increased risk to progeny for an open NTD. In mice, with the exception of ‘‘fused’’ (Fu/Fu) where homozygotes may have either SBO or SBA303 and ‘‘curtailed’’ (T c) where T c/T w5 has SBA and Tc/þ has SBO,319 the evidence supports an independent pathogenesis for SBA and SBO. Carsin et al.320 concluded from a review of the literature that rates of SBO in the parents of children with SB are not significantly different in cases than in controls and that there is no greater than expected rate of two parents having SBO. The contrary study of Lorber and Levick321 had a frequency of only 4.5% SBO in controls, which is far

below expectation for the general population.30,320 Likewise, detailed examination of the pedigrees recorded by Fineman et al.322 suggests that their conclusion that there is a common autosomal dominant SBA/SBO gene is problematic, although they do provide evidence that SBO may be inherited as an autosomal dominant trait. In a small study, Sebold et al.485 showed that the risk for a NTD among the siblings of patients with a lipomeningocele was equivalent to that when the propositus had an open NTD. More data from well-designed studies are needed before a firm conclusion can be drawn as to whether there is any relationship between SBO and SBA. In an area where the prevalence of NTD declined with folic acid food fortification, there was no parallel decline in the rate of lipomeningocele, suggesting a different etiologic basis for the two types of NTD.475 An apparently unique family in which three sibs had atretic occipital cephaloceles was reported by Martinez-Lage et al.323 Most families affected by NTD have a single affected child; a minority have one or more affected close or distant relatives and, occasionally, one encounters a family in which there is an unusually high rate of occurrence of NTD (Fig. 16-10). Such families are certainly suggestive of a single major gene and they are probably underreported. Although families with more than two affected siblings could represent expression of an autosomal recessive gene, such families are also expected to occur with other genetic models.322 There have been at least four reports of NTD appearing to occur on an X-linked recessive basis.109 The phenotype is markedly variable within families and may include anencephaly, encephalocele, and both high and low SB, thus suggesting a very broad effect of the gene on the neural tube. While most infants with NTD do not represent known genesis syndromes or have family histories suggestive of a particular pattern of Mendelian inheritance, it has been established through numerous studies that siblings born subsequent to a child with an NTD are at significantly greater risk than the general population. Koch and Fuhrmann325 summarized much of these data, and sibling risks ranged from 1.34% (Israel 1958–1968) to 8.9% (Belfast 1964–1968). Generally, recurrence rates are higher in areas of high

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Fig. 16-10. Two examples of pedigrees from the Children’s Hospital of Eastern Ontario files that show an unusual propensity to NTD.

incidence, and some data have suggested that they fall with secular declines in incidence. There are relatively few recent data pertaining to this question. Wang et al.326 were able to show that within China sib recurrence rates were higher (8.32%) in the high-prevalence area than in the average (4.5%) and low-prevalence (3.7%) areas. The prevalence of NTD has fallen in Ireland and the sib recurrence rate (3.3%) obtained by Byrne et al.327 was significantly lower than historical values, although it remained above that in a concurrently studied Italian population (1.6%), which had a lower prevalence. It is of note that the occurrence of other, non-NTD malformations in the sibs of the Irish children was higher than among the comparison Italian families (11.5% versus 3.3%). Temporal and betweenpopulation variation is such that genetic counseling is best based on local and reasonably current data. Failing that, Edward’s approximation, based upon local prevalence data, and/or the incidence for a similar ethnic group can be used as a guide. An increased sibling recurrence risk is not in itself proof of a genetic component as siblings share environment as well. Higher rates of consanguinity in families of affected children and greater recurrence risks in families with more than one affected child support genetic factors.25 The risk to subsequent children with two affected sibs has ranged from 4.9% to 25% and again shows some correlation with prevalence, although very small numbers are often involved in these estimates.52,328 The increased occurrence of NTD in second- and third-degree relatives has been noted in a number of studies.52 An interesting phenomenon has been the fairly consistent finding that the matrilineal is higher than the patrilineal rate. Byrne et al.329 noted the importance of matrilineal genetic factors and suggested a role for imprinting. A recent negative study had a low rate of participation (35.5%) and involved only 36 families, although it did find more history of epilepsy on the matrilineal side.330 A matrilineal excess of NTD has also been noted in half-sibs: one study reported that 3.1% of maternal and 0.6% of paternal half-sibs were affected.325 Recurrence rates in children of maternal aunts of propositi approach 1%.52 This phenomenon is often ascribed to better data recall in the maternal family. However, it has been noted when both sides of the family have been directly contacted. The phenomenon has also been reported in the curly tail mouse.52,331 Increased sibling recurrence rates are not specific for the type of lesion, and there are many reports of concurrence of anencephaly/ SB/encephalocele within the same family. However, Fraser et al.194 summarized data from a number of surveys and showed that there was some correlation as to the specific type of NTD (anencephaly versus SB) between sibs. The ratio of anencephaly to SB in sibs was 1.18:1 if the propositus had anencephaly and 0.61:1 if the propositus had SB. Cowchock332 provided evidence that the correlation pertained to sibships where the index case was male and implied a greater environmental impact on females. There is evidence that multiple block or hemivertebrae, as well as occult dysraphism involving the conus, provides a risk to first-degree relatives equiva-

lent to the presence of an open NTD.333,334,485 There were methodologic problems in a study that claimed to find an excess of scoliosis and pilonidal sinus in the parents of propositi with NTD.335 In summary, the nature of the genetic contribution to NTD remains unclear, and debate continues between proponents of multifactorial, multigenic, and monogenic models. Some predictions as to how sex ratios, recurrence risks, fetal loss, and frequencies should interrelate and vary are compatible with the multifactorial threshold model, while others are not.162,336 In some cases segregation analysis appears to favor monogenic inheritance, while in others the multifactorial threshold model appears equally valid 24,25,241,337 There is undoubtedly a great deal of pathogenic/causal heterogeneity that varies with time, place, and ethnicity. Although attempts to subgroup patients for study based on various clinical characteristics remain inconclusive, there is reason to believe that continued efforts in this direction, specifically looking for any pattern of lesion resulting from known etiology, will ultimately be rewarded with an understanding of the pathogenesis of these important malformations. Prognosis, Treatment, and Prevention Anencephaly

Anencephaly is a uniformly lethal malformation, and no postnatal treatment is indicated. Prior to the era of prenatal diagnosis there was an approximate balance between stillbirths and live births.11 There is a high early mortality among live births. Baird and Sadovnick486 in a retrospective review found 43% survived to 24 hours, 15% to greater than 3 days, and 5% to 7 days. Thirty-eight of 181 cases had additional malformations, the presence or absence of which was not found to influence stillborn versus liveborn status. One female survived 8 days and one 14 days. In a study from Western Australia covering the years 1966 to 1990, 76.4% died within 24 hours and none survived more than 5 days.338 In contrast, 9% of 205 anencephalic babies seen at Cedars-Sinai hospital in Los Angeles between 1978 and 1982 lived more than a week,339 and survival to 7 and 10 months has been reported.340 Prolonged survival should lead to careful reassessment and consideration of alternate diagnoses such as the amniotic band syndrome. The use of organs from anencephalic neonates for transplantation has led to much discussion and debate. A 1990 review identified 80 infants with anencephaly that had been included in transplantation protocols.13 Forty-one were ultimately used as donors, with 37 donating kidneys, two livers, and three hearts. Eleven kidneys, no liver, and one heart transplant were considered successful, and there have been subsequent reports. Certain factors, including a high frequency of additional organ malformations,341 a high rate of tissue degradation if organs are harvested at the time of natural death, even with recussitation,342 and the severe shortage of organs available for perinatal transplantation, have led some to call

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for changes to legislation concerning the definition of brain death in anencephaly.343,344 However, the natural decline in the prevalence of NTD and the widespread detection of anencephaly by prenatal serum and ultrasound screening, with consequent termination of the pregnancy, means that even with a change in legislation, the impact on organ availability is likely to be minimal. There is also concern that pressure to continue a pregnancy might be placed upon women who would otherwise select to terminate a pregnancy affected by anencephaly because of its lethal nature and increased associated maternal obstetric morbidity. A change in legislation in Germany that allows anencephalic infants to be considered brain dead and thus allow organ retrieval apparently had little, if any, effect upon the availability of organs.344 Thus, several medical associations and individuals have concluded, given the minimal likelihood of significant benefit for organ availability, that the philosophical and ethical concerns raised by changing the definition of brain death in anencephaly outweigh the possible benefits of a legislative change.343,344 Iniencephaly

Iniencephaly also has an extremely grave prognosis. Katz et al.345 reviewed over 250 reported cases and, including their own patient, found only four long-term survivors. Since then a mildly affected 17year-old boy has been described.346 The survivors have had mild iniencephaly without encephalocele, without the severe anomalies and absences of the cervical vertebrae or other significant extracranial anomalies. These individuals are often first diagnosed as having a Klippel-Feil anomaly and they appear to have a reasonably good prognosis, which emphasizes the need for careful and thorough examination, including karyotype and a-fetoprotein when this diagnosis is made prenatally. Spina Bifida

Active intervention in the treatment of children with open SB was not an option in the first half of the twentieth century, and few children were treated unless they survived to about 18 months and the lesion had epithelialized on its own. Attempts to close myelomeningoceles were confounded by postoperative infection and by the inability to control subsequent hydrocephalus.347 With the development of ventriculoatrial and later ventriculoperitoneal shunts, treatment entered a new era. An early trial of early versus late closure was interrupted because results of early intervention on motor function were considered so obviously superior. However, there was an error in the methodology used to assess neuromotor function,347 and several other groups failed to replicate the apparent advantages of early versus late closure. By the early 1970s the initial enthusiasm for early aggressive treatment of all children with SB began to be questioned. The early shunts were ventriculoatrial or ventriculojugular and had significant complications, including recurrent mechanical malfunction, septicemia, endocarditis, thromboembolism, pulmonary hypertension, and glomerulonephritis.348 The high blockage rate of early ventriculoperitoneal shunts was overcome with new shunt materials, and this is now the procedure of choice, with the advantage that it can be performed on very young children. Although it may result in increased intraabdominal fluid pressure and a high rate of inguinal hernias, more serious problems of bladder or bowel perforation, kinking, or breakage have been less common.348 Historically important was a retrospective review by Lorber349 of a series of patients treated early, in which he concluded that they had poor intellectual, orthopedic, and renal function and little social adaptation or quality to their life. He suggested that certain

criteria could be used to identify patients who should not receive surgical treatment but would be sedated and receive normal nursing care and food on demand. Many medical centers adopted selective treatment of affected infants, and there followed a prolonged debate over the scientific validity of the selection criteria, as well as the ethical and legal implications of such a policy. That debate is not reviewed here but certain points are germane. The 100% mortality rate in a group of 25 children that Lorber did not treat was atypical, and a policy of late treatment of surviving infants was introduced. Many children with one or more of the broad criteria that Lorber349 used to select for nontreatment have done well with treatment, and thus the criteria fail in the major test of actually predicting which children will or will not do well. Attempts to refine the assessment by including such factors as the presence of lacunar skull deformity or the thickness of the remaining pallium failed. The balance has tilted back to the point that, in countries with an adequate health infrastructure, the overwhelming majority of children with SB are treated aggressively. Proponents of universal treatment argue that the outcome in groups of patients who are not subject to selective treatment are equal and even superior to those that are. McLone350 reported an 86% rate of survival, 87% rate of achievement of urinary continence, 54% rate of ambulation, and 73% rate of normal development. Such encouraging reports may be overly optimistic. Patients may be preselected by the referral pattern to the treatment center; follow-up is often short term and does not account for later loss of ambulation, orthopedic and other complications of schooling, and adaptation to adult life. For example, the longterm follow-up of a series of 117 patients treated nonselectively 22 to 28 years prior found that 56 (47.8%) had died.351 Of the survivors, 33 (54.1%) could live independently, 11 (18.0%) required assistance, and 17 (27.9%) required full-time care. The level of ability and achievement was a function of intelligence and neurologic level. The latter shows correlation with the sensory level at birth.352 Of particular concern are children who survive with significant retardation and require custodial care. There is a far from absolute correlation between the level of the initial lesion, as well as the thickness of the pallium, and intelligence.353 If ventriculitis can be avoided, a delay in closure is not detrimental to intellect.354,355 A significant proportion of infants with SB have associated malformations of the brain in addition to Arnold-Chiari type II, which is seen in about 90% of cases. Gilbert et al.,356 in an autopsy series of 25 patients, found hypoplasia of cranial nerve nuclei in 20%, CSF obstruction in the ventricular system in 92%, anomalies of neuronal migration in 92%, cerebellar dysplasia in 72%, fused thalami in 16%, agenesis of the corpus callosum in 12%, and absent olfactory tracts in 8%. These underlying malformations may have more to do with ultimate developmental prognosis than most variables examined to date, and there continues to be a need for prospective data obtained with modern diagnostic techniques. Even the most ardent advocates of universal treatment agree that ‘‘to mandate by law or standard of practice that all children born with a myelomeningocele must be operated upon is an absurdity.’’357 Notwithstanding the fact that it may take many families up to 6 months before they understand much of the information with which they are presented, parents have the right to play a pivotal role in any decision regarding treatment; however, the consultative process often does not occur.357,358 It is the opinion of this author that regulations such as those in the U.S. Federal Register are unethical in that they strip parents,

Brain and Spinal Cord

physicians, and indeed advocates of the child of their autonomy in decisions regarding treatment.359 These regulations essentially mandate treatment of all children unless irreversibly comatose or if treatment would merely prolong dying or would be futile in terms of survival of the infant.357 Decisions based on assessment of future quality of life are clearly proscribed. In a fascinating example of double-speak, the regulations360 also state that ‘‘the parents’ role as decision maker must be respected and supported unless they choose a course of action inconsistent with the applicable standards established by law,’’ that is, the regulations. Rather than legislation, what is required is a better understanding of the communication process between parents and informed, unbiased professionals. Charney360 carried out a structured interview study with 47 mothers and 29 fathers who had been involved in the decisions regarding the treatment of their newborn with SB and who had been referred to a single tertiary care center. The parents had met with a specific team involved with the care of newborns with SB and after being given general information were given the choice of immediate surgery or of delaying the decision about operative intervention. Whereas only 34% of parents were satisfied with the information provided at the delivering hospital, 80% were satisfied with the communication at the referral center. Satisfaction was higher among fathers and among those who remembered being involved in the decision-making process. Personal philosophy, social values, religion, and medical information were important factors in the decision-making process, while financial concerns were important in only two (3%) cases. Ninety-eight percent thought parents should make the final decision. Advances in the ability to provide an accurate prognosis for the individual child would be of great value. Today, the diagnosis of SB is often anticipated before birth either because of indicative late pregnancy ultrasound results or because a pregnancy ascertained in a screening program has continued to term. This provides some opportunity to prepare the parents and staff and also raises the controversy over the preferred mode of delivery. Luthy et al.361 studied a cohort of infants with SB without severe hydrocephalus and concluded that those delivered by cesarean section before onset of labor had a higher level of motor function than those delivered vaginally or by cesarean section after onset of labor. The groups did not differ in their requirements for shunting, rates of infection, or Bayler Mental Development Index, but the former group did have an earlier diagnosis and availability of specialist postnatal care. Hill et al.362 and Lewis et al.476 found no difference in motor function between infants delivered by prelabor cesarean section compared with those with other modes of delivery. Merrill et al.363 were unable to find any correlation between the mode of delivery and perinatal mortality, motor sensory function, or long-term outcome. They made the valid point that a multicenter, randomized trial is needed before cesarean section is accepted as the preferred mode of delivery for infants with SB. A recent retrospective cohort study also failed to show any benefit of elective caesarean delivery on motor function or ambulatory ability.487 There is some evidence that the vertebral level of the SB, and therefore a gross estimate of the severity, may influence the parental decision as to whether to continue a pregnancy.364 This leads to the question as to whether a more refined prenatal prediction of prognosis is possible. The thickness of the overlying sac may indicate the presence of skin and subcutaneous tissue and help to distinguish a meningocele, with its better prognosis, from myelomeningocele.365 The less common skin-covered myelomeningocele may also have a more favorable course. An important consideration for parents is whether a child will be ambulatory. Biggio et al.366 confirmed that prenatal ultrasound determination of the

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level of the lesion can, to a degree, predict the likelihood of ambulation. None of 11 children with a thoracic lesion walked, compared to six of 12 with an L1-L3 SB and all 10 of those affected below L3. The presence or absence of clubfoot or venticulomegaly was not an independent predictor. In a study with numbers too small to draw conclusions, Petrikovsky and Paulakis367 proposed that lower limb withdrawal from an amniocentesis needle might predict a greater likelihood of ambulation. However, the question of fetal leg movement is controversial, and Sival et al.352 clearly showed normal endogenous prenatal leg movement of spinal origin, regardless of the level of the lesion, and that these movements were not a prediction of postnatal motor function. Evidence that the open neural tube will suffer progressive damage due to chronic exposure in the intrauterine environment has led to trials of fetal surgical closure of SB. Notwithstanding the fact that the only controls have been either literature or historical comparisons, there is convincing evidence that prenatal surgical repair, ranging from 22 to 30 weeks gestation, reduces the rate of hindbrain herniation and the need for postnatal shunting.368,369,477 There is some preliminary and conflicting evidence that prenatal surgical closure results in better than predicted leg function477 but not urodynamic outcome.370 However, to date there is no evidence that prenatal surgical closure improves postnatal motor or urodynamic function,370 and there is a dramatic increase in the rate of obstetric complications, including oligohydramnios, preterm contractions and delivery, and premature rupture of membranes, as well as less frequent serious maternal complications. Long-term evaluation of many outcome variables, including intellect and motor function, preferable from randomized trials, are required to properly assess the future role of this approach. In the interim it should continue to be considered experimental and restricted to centers willing to carry out appropriate assessments of outcome. Parents require information as to the probability that the baby will survive, and population-based data that reflect current practice are preferable. About 10–15% of babies with SB are stillborn.338 Survival rates have shown significant improvement in recent decades. In British Columbia from 1952 to 1986, the 1-, 5-, and 10-year survival rates for the years 1952 to 1969 were 37%, 32%, and 29%, respectively, and for the period 1970 to 1986 they were 67%, 65%, and 64%, respectively.371 In a nonselected 1975 to 1990 cohort from Newfoundland there was a 9% perioperative mortality in a patient group that had a high proportion requiring transport from outlying areas.372 Five of the 179 (2.8%) patients followed in a rehabilitation center died during the follow-up period. For the years 1994–1997, a UK general practice registry obtained a standardized mortality for NTD (compared to the general population) of 1.9 to 2.9.373 A study from Western Australia of 5-year cohorts from 1966 to 1990 shows very clearly the effect of selective treatment on percent survival.338 The most recent group (1986–1990) had an 84.4% 1-month and 70% 5-year survival. Mortality is associated with more rostral lesions and with the presence of hydrocephalus. This improvement is considered to reflect the impact of a multidisciplinary team approach and is most dramatic for the 1st year of life. In the British Columbia data there was a significant but less marked improvement in survival from age 1 to 6 years, but not from 7 to 16 years. For children who are born alive, who do not suffer other life-threatening malformations, and who are not considered too severely affected for treatment even in nonselective programs, initial survival rates of 85% and higher can be anticipated. Mortality should be minimal for the remainder of childhood beyond the 1st year of life.338,353,355–358 However, beyond the age of 10 years the rates may remain about twice that of the general population.

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With modern antibiotic coverage there is no evidence that delay in closure, even up to 1 month, increases the probability of ventriculitis or developmental delay.355,358 Parents can thus be given time to come to an informed decision, secure in the knowledge that they are not placing their child at unnecessary risk. A team of physicians and allied health professionals with an organized structured approach and adequate resources is clearly best able to cope with the many and complex problems that can arise over the lifetime of the individual with SB. Liptak et al.374 have reviewed these needs and provided an example treatment protocol. Most SB can be treated by primary closure, and there are a number of techniques for producing various full thickness skin flaps and/or incorporating muscle into the closure as required.375 In the absence of hydrocephalus small lesions can be closed and shunting then carried out as required. A choice to temporize with medical management may be reasonable,374 because placement of a shunt can lead to complications such as infection or shuntdependency, which have significant morbidity and mortality (see Section 15.8). Wakhlu and Ansari478 have proposed that specific measurement of increases in bifrontal, bicaudate, and lateral ventricular diameter can predict the postoperative development of hydrocephalus, and thus the need for shunting. Larger lesions that leak CSF will likely break down as hydrocephalus develops following closure, and thus benefit from prior shunting. Several groups have argued that simultaneous repair and ventriculoperitoneal shunting decreases the number of anesthetics, episodes of CSF leakage, repair breakdown, and length of hospital stay, but does not lead to a greater number of complications or shunt procedures.376 Up to 36% of patients with SB have been noted to have a short trachea, which increases the risk of bronchial intubation at the time of surgery.377 The initial requirement for a shunt and the later need to revise a shunt may be predictive of long-term physical and social function. Hunt et al.378 divided the 57 long-term survivors of their nonselectively treated cohort into achievers (truly independent living and/or active driving and/or competitive employment) and nonachievers (none of the above). Eight of 9 who never required a shunt, as compared to only 20 of the 48 who were shunted, were achievers. Perhaps of greater significance, given that shunt dysfunction is the most common postoperative problem, was the fact that 11 of 16 (69%) who never required a shunt revision, as compared to nine of 32 (28%) of those who had needed a revision, were achievers. Five of 10 of those whose only revision was under the age of 2 years were achievers. Only symptomatic patients were subject to shunt revision. Nonrevised patients had fewer episodes of raised intracranial pressure or visual defects. Mataro et al.379 have provided evidence that shunting may improve neuropsychological functioning in patients with raised intracranial pressure in the face of apparently arrested hydrocephalus. Taken together these data suggest that chronic, subclinical shunt dysfunction may lead to secondary cerebral damage, although the reverse causal relationship could apply. That is, an underlying brain anomaly leads to a poorer outcome and to a greater need for later shunt revision. However, a high index of suspicion for shunt dysfunction and a low threshold for revision may be warranted. Clinical symptoms include changes in behavior, poor feeding, vomiting, increasing head size, and, in the older child, headache. Modern neuroimaging has significantly aided the management of this problem. Third ventriculostomy may be an alternative to shunting or to shunt revision in patients over the age of 6 months.380,381 Lennerstrand et al.382 found that the most common neuroophthalmologic complications were disorders of ocular motility, including strabismus. All their patients showed some degree of

displacement and deformation of the tectal region of the mesencephalon, cerebellum, and medulla oblongata, and the extent varied with the degree of hydrocephalus and anatomy of the associated ArnoldChiari anomaly. Strabismus and spontaneous nystagmus correlated best with the severity of hydrocephalus, while other specific oculomotor defects showed weaker associations with either lower or upper brain stem deformities. Less frequent long-term complications include corneal opacities due to neuropathic keratitis and optic atrophy.378 About 15% of infants may be symptomatic from an associated Arnold-Chiari malformation. Most common is respiratory stridor, which is usually self-limited and resolves by age 3 months.383 However, about one child in 25 may present with signs of lower cranial nerve dysfunction, including drooling, problems with suck and swallowing, nasal regurgitation, episodic apnea, retrocollis, and even opisthotonus. Progressive upper limb weakness, neck weakness, and nystagmus may be noted in the older child. Symptoms may progress relatively rapidly to death unless treated by decompression of the vermis and brain stem.347,383 Later onset complications can affect the functioning of the spinal cord. Growth of an accompanying lipoma can cause compression. More often, failure of development of the conus medullaris or scarring causes tethering of the cord. In a child with high-level paraplegia this may be of little consequence, but with levels at L4-L5 and below this may lead to severe local pain and to protean progression of an initially asymmetric, ascending motor deficit.383 Periodic somatosensory-evoked potential studies may prove useful in detecting this problem before permanent damage can occur. Syringomyelia is not uncommon in children with myelodysplasia, and progressive expansion of the syrinx may become symptomatic. In the cervical region this may lead to progressive upper-limb, neck, or shoulder weakness, often in association with lower cranial nerve dysfunction.347,374,383 Denervation of the paraspinal muscles may lead to progressive scoliosis at a level above the SB or to rapid motor deterioration accompanying acute shunt dysfunction.382 A variety of treatments have been attempted, including marsupialization or direct shunting of the cavity or obstruction of the obex, but none has proved entirely successful in all cases (see Section 17.4).347,383 Renal malformations are nonrandomly associated with NTD and occur in up to 15% of cases studied at autopsy.384 Although many of the anomalies are relatively unimportant ureteral duplications, as a group they are an important cause of immediate mortality and later morbidity. Hunt and Whitaker384 found renal anomalies in 9% of their patients and noted a correlation between the neurosensory level and the type of renal anomaly. Renal agenesis occurred with SB at level T5-T8, horseshoe kidney with SB at level T9-L1, and duplications with SB at level L5 and below. Three of five cases of renal agenesis were associated with SB at level T10 and four of eight horseshoe kidneys with SB at level S1. The natural history of children with myelomeningocele who survived infancy was that 9% died of renal failure in the mid-teens, 40% had decreased renal function, and 40–70% had dilated or scarred renal systems.385 Patients who are ambulatory are equally likely as those who are nonambulatory to suffer lower urinary tract dysfunction and require early and full urodynamic studies.386 An ileal conduit appears to reduce evidence of radiologic renal damage, but significant mortality remains; furthermore, the quality of life remains compromised, and complications such as ureteroileal obstruction, pyocystis, bowel obstruction, conduit elongation, calculi, pyelonephritis, stomatitis, and azotemia often require further surgery.387 Shapiro et al.387 found that only 13% of patients had no complications after ileal conduits, and significant complications occurred up to 13 years postsurgery.

Brain and Spinal Cord

In the mid-1960s intermittent clean catheterization (ICC) was introduced. Uehling et al.388 had a failure rate of 25% in introducing patients to and maintaining them on this regime. Of 53 patients treated with ICC and anticholinergic medication for at least 5 years, 81% were dry, 15% wet at night only, and 4% had occasional daytime wetness. Urinary tract infections were less frequent; 70% showed no change, 17% improved, and 13% decreased with respect to renal function. The procedure requires significant commitment but is now standard therapy for neurogenic bladder with detrusor hyperactivity. Brem et al.385 compared results in 28 children treated by ICC and 14 with an ileal conduit. While bacteriuria and reflux were both more common in the latter group, the proportion of cases showing deteriorating renal function (four of 28 and three of 14, respectively) were not different and did not correlate with reflux or bacteriuria. However, reflux may have its major impact during renal growth, and most of the children were over age 5 years at the time of study. Importantly, eight children were noted prior to treatment to have small, noncompliant, trabeculated bladders, indicating high intravesicle pressure. The seven children whose renal status deteriorated all came from this group. Uehling et al.388 also noted that failure to establish dryness occurred in patients with detrusor hypertonicity and trabeculated bladders and that these factors were predictors of deteriorating function. It is thus critical that such patients be recognized and treated early with ICC and/or by medication or surgery if there is evidence of early renal damage. In general, patients find ICC more acceptable than an ileal conduit, and a number of patients have undergone successful reanastomosis of the urinary tract, allowing for ICC and manual or valsalva expulsion of urine, with or without use of anticholinergics.389 A significant proportion of patients are unable to achieve adequate detrusor suppression, often due to medication side effects, with oral anticholinergics. Appropriate preparations of medication for intravesicular use appear to be an affective alternative and have reduced levels of side effects.390 Over the past 10 to 15 years there have been several surgical approaches attempting to improve urinary control and to protect long-term renal function in children with SB. Shiomi et al.391 reported improvement in both urinary continence and reduced constipation by fixing a seromuscular ileal flap to the bladder. Concurrently they attempted to normalize the vesicourethral angle to improve the effectiveness of abdominal or direct pressure in voiding and to lift the sigmoid through attaching the ileal mesentery to its taenia libera. Forty-five of 46 patients reported a sensation of bladder distension, presumably due to stretch of the ileal segment, and incontinence improved in 36 of 37 patients. A significant number of patients showed improved renal status, and when deterioration occurred it was associated with hypertonic bladders, which the authors conclude are not suitable for this procedure. Several techniques have been directed at the bladder sphincter, including forming a fascial or muscular sling,392 direct bladder neck repair as in the Pippi Salle procedure where a flap is formed in the midline bladder wall,393 and insertion of an artificial sphincter.394 Certainly the goals of these approaches are laudatory but to date the procedures all have significant complication and failure rates and are not demonstrably superior to ICC with cholinergic medication. They may be appropriate for selected patients, notably those who cannot be managed adequately with ICC. Despite current management of renal problems, a proportion of patients with SB will progress to end-stage renal disease. Long-term peritoneal or hemodialysis is often compromised by body habitus and/or poor vascular access. There is

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growing experience with successful renal transplantation in patients with SB.395 Rectal incontinence has great potential to add to the handicap of persons with SB and to inhibit their integration into society. Neurosensory and neuromotor impairment deprive them of normal rectal sensation and voluntary control of the external sphincter. The internal sphincter generally maintains reflex relaxation on rectal filling, and untreated patients typically present with severe problems of incontinence. Colostomies obviate this problem but are invasive, are not without complications, and provide a less than ideal solution. In general, the current approach is to provide a routine of bowel emptying that anticipates reflex relaxation of the internal sphincter. White et al.396 used a routine of regular bowel evacuation with bisacodyl suppositories, usually right after meals to take advantage of the gastrocolic reflex. About one-half of their patients attained complete continence, while most of the others had some staining that was considered a minor problem. Many developed regular bowel habits and required no assistance. The children with regular bowel habits averaged 3.3 years of age, compared with 6.5 years for those requiring aid, thus leading these and other authors397 to stress the importance of early intervention. Manometric assessment of internal and external sphincter tone and of sensation with filling of the proximal rectum may identify a subgroup of patients who may be trained to use residual gluteal contraction to increase external sphincter tone, and once successful to do so in response to rectal sensation and thus control defecation.398 Rectal sensation was the major determinant of success and did not occur with neuromotor levels above L4-L5. Ponticelli et al.397 stressed the important role of formal involvement of a proctocolonic specialist and demonstrated that 60% of patients with SB improved under such care, as compared to no improvement or deterioration among the control patients. Their results were comparable between conventional treatment and a biofeedback regime. The seromuscular ileal flap used by Shiomi et al.391 to treat urinary incontinence was reported to give a fecal substitute sensation in 31 of 46 patients and to improve constipation in 22. If these results are confirmed in other reports, a trial combining this surgery with biofeedback would seem in order and has significant potential to improve quality of life. Antegrade colonic enemas administered through an appendicostomy, which can be performed laparoscopically, may provide good to excellent results in patients who do not respond to conventional approaches.399 Complications are uncommon but can sometimes be severe. Patients with lower-level lesions are more likely to walk, and at an earlier age, than those with high-level lesions, but up to 20% of patients with thoracic SB will be at least community ambulatory.400 Despite the fact that problems such as cord tethering, rapid growth requiring frequent modification of orthotics, and weight gain may lead to early cessation of walking, such mobility is considered a reasonable goal as long as the efforts do not interfere with overall mobility and development.400,401 Liptak et al.374 discuss the debate between the respective advocates of long-leg bracing and parapodium versus the wheelchair for children with high-level lesions. Physiotherapy and orthopedic management are aimed at maintaining flexibility, alignment of the spine, and the relationship of the hip-knee-ankle.1,374 Clubfeet are often resistant to manipulation and require surgical treatment. A variety of bracing or surgical techniques, including tendon and muscle transfer, may be applied to maintain or increase mobility. About 10% of neonates with SB have dislocated hips.402 The risk appears negligible with levels below L4; it is about 25% with L3-L4 lesions, where it

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is secondary to unopposed hip flexors and adductors, and dislocation occurs later due to spasticity in patients with higher-level SB. The Ilizarov procedure has been successfully used in ambulatory patients who have developed a significant leg-length discrepancy.403 Up to 10% of children with thoracal or thoracolumbar myelodysplasia present with a kyphosis with its apex typically at the second or third lumbar vertebrae.404 With a wide SB the paraspinal muscles are displaced forward, and the kyphosis rapidly progresses to become severe and rigid with sitting, pushing the body forward and requiring the arms to be used for support. This complication occurs in one-third of patients with thoracal and 5% of those with thoracolumbar myelodysplasia by adolescence374 and causes pain, ulceration, and respiratory compromise. McMaster404 reviewed the timing of treatment and recommended a long fixation at the age of 8 to 10 years. Tethered cord must be considered in any patient who presents with a new or progressive scoliosis, increasing spasticity, decreasing motor function, or pain at the site of surgical closure.405 Leg weakness, prolonged immobility following extensive surgery, and frequent urinary tract infections may place patients with SB at increased risk for deep vein thrombosis.406 Children with spina bifida are exposed to multiple surgical and diagnostic procedures and up to 80% may develop a latex sensitivity, which may progress despite efforts to ensure a latexfree environment.407 It is recommended that children with SB be treated in a latex-free environment from birth. Young children who are active and exploring their environment are at risk from injury due to pressure, heat, and trauma because of lack of sensation. The heavier, less mobile individual, whether in braces or in a wheelchair, is subject to pressure sores. Patients and guardians must be taught to avoid these problems as much as possible, and a number of surgical flap procedures have been developed in an attempt to provide sensation to the exposed surface.408 Care for the child with myelomeningocele should be total and include assessments of growth, development, and personal and family adjustment.374 Neurologic problems above the level of the SB are common, and it is important that children be screened for these problems.409 Growth curves for children with SB are available; a significant portion have short stature, primarily affecting the lower body and correlating in severity with the level of the lesion.410 Although significant progress has been made in decreasing the handicap of persons with SB, many difficulties remain with respect to self-esteem and autonomy, acceptance by peers, appropriate schooling, and the adaptation of parents. The influences on the successful long-term adjustment of patients with SB are complex and require more study. Minchom et al.411 found that children with greater physical severity of SB had higher self-worth and physical appearance self-scores than their peers with less severe disability. Although those children did have lower IQ scores, which were protective, low IQ did not account for these data. In contrast, the less severely affected children rated themselves higher for academic achievement. A possible explanation for these findings is that the more mildly affected children perceive themselves in more direct competition with the mainstream, and yet they are less likely to have their handicap recognized and addressed. Zurmo¨hle et al.412 did not find a relationship between medical severity of the SB or IQ and evidence of psychological problems or maladjustment. Placement in a school for the disabled was associated with significantly elevated anxiety scores and the authors recommend placement in mainstream schools. Patients expressed concerns about their limited potential for long-term independence, and boys were particularly

worried about their career prospects. Urinary incontinence, particularly in girls, may be a significant factor in reduced self-esteem.484 Adolescents with meningomyelocele are at risk for obesity, and lack of activity may lead to poor levels of physical fitness.479 Of particular importance is the transition to adult life and the provision of ongoing support and medical care.413 During this transition, medical continuity is easily lost, and a majority of affected individuals are under- or unemployed, few have boyfriends or girlfriends, and most continue to live with their parents in relative isolation.414,415 Buran et al.480 studied 66 adolescents with meningomyelocele and found that they had a number of positive attitudes and were, in general, capable of performing activities of daily living, but they were underinvolved in normal adolescent activities. The authors suggest that these differences may be at the root of why affected persons tend to be underemployed and do not live as independent adults. The ability of the family to provide support for achievement, to stress independence, and to foster socialization may play an important role in the successful attainment of employment, community mobility, and social activity.416 A team approach to care should continue into, and extend throughout, adulthood in order to anticipate and treat problems.417,418 Even patients with lower sacral lesions required ongoing monitoring.419 Management issues include symptomatic Chiari malformation, syringomyelia, shunt malfunction, renal and bowel complications, hypertension, scoliosis, contractures, seizures, social integration, and employment.420–422 Much is still to be learned about the prospects for long-term health for those individuals treated in the modern era. Caretakers must remain mindful that many such children by accident of birth do not have access to modern care and that the cost of treatment is often prohibitive. Cephalocele

Several factors when considered carefully may aid in assessing the fetus or neonate with a cephalocele. Of paramount importance is the content of the lesion, the presence or absence of other intracranial anomalies, and the distinction between a cranial meningocele and an encephalocele.1,423 Although the former may be associated with anomalies such as hydrocephaly, Dandy-Walker, or other posterior fossa cysts, the majority of such children will do well with closure and shunting as required. In general, patients with frontoethmoid encephaloceles have the best prognosis, and those with occipital malformations do better than those with parietal defects. The more rostral the parietal anomaly, the more guarded is the outlook. The poor prognosis of the atretic parietal cephalocele with dorsal cyst has already been discussed.45 However, this apparent correlation of prognosis with site in part reflects the likelihood that the lesion will contain important cortex and the frequency of associated brain malformations. For example, in the series of Simpson et al.,423 12 of 21 occipital encephaloceles contained recognizable cortex and/or cerebellum, seven had glial nodules or rests, and two were not studied. Seven of the children were hydrocephalic and five microcephalic. Six of 10 parietal encephaloceles contained cortex, three glial rests, and one was not studied; four had associated holoprosencephaly, and two more were microcephalic. Most patients whose encephalocele contained only glial nodules or glial rests did well. However, 15 of 20 children in whom the encephalocele contained parietal or occipital cortex had either died or were totally dependent for their care. In many cases surgical enlargement of the cranial cavity and preservation of the cerebral tissue and its vascular supply had been attempted.

Brain and Spinal Cord

Although size of the cephalocele cannot be considered in isolation of other findings, it does correlate with outcome. In the series by Simpson et al.,423 only two children with lesions less than 5 cm did poorly compared with 15 of 20 with cephaloceles greater than 5 cm. In the latter group, two of the five with good outcome had meningoceles. The onset of hydrocephalus or seizures is associated with a poor prognosis.424 Nasal cephaloceles are an exception to the above discussion in that outcome is favorable in up to 70%, with about 20–25% suffering severe disability,425 and does not vary with size. Prognosis is determined more by the presence or absence of cerebral dysplasia.423 Surgical treatment has several purposes that include preventing damage to the stalk and consequent infection and/or CSF leakage, watertight closure of the dura and closure of the bony defect to prevent further herniation of cranial contents, and correction of any craniofacial deformation.41,426 It is recommended that any hydrocephalus be treated first, and that a multidisciplinary team be involved. Three-dimensional CT scanning has been found to be useful for surgical planning.427 There is some disagreement as to whether a one-stage procedure to correct both the cranial and facial anomalies is the best approach.425 Frontoethmoidal and basal encephaloceles have an epithelial or skin covering, and this generally allows time for careful planning. However, treatment should not be delayed such that further facial distortion is allowed to occur. Mild to moderate hypertelorism will usually regress if the encephalocele is treated before the age of 2 years.425,428 In some cases treatment may be urgent because of nasal obstruction. With the exception of transsphenoidal lesions, which may contain parts of optic tracts, pituitary, hypothalamus, and the circle of Willis, the sac usually contains glial tissue that can be removed without consequence.41 The precise surgical approach will vary with the size and location of the lesion, but an intradural approach is recommended by some groups.425,428 Mortality, which used to be 7–20%, is now zero in several series.425,428 Cephaloceles comprise a significant fraction of prenatally ascertained CNS malformations, and accurate prediction of outcome is important for parents. A proportion of cases die in utero,429,430 and it is likely not valid to extrapolate prognosis from live birth data. Unfortunately, prenatal data are limited and do not always provide complete information. In a series of cephaloceles representing prenatal ultrasounds from the 1980s, Goldstein et al.429 presented a gloomy picture. Of 14 primary cases, five pregnancies were terminated, two resulted in in-utero death, and there were four perinatal deaths and two survivors; one survivor with an occipital lesion was severely delayed, and the solitary case of a survivor with ethmoid cephalocele was developmentally delayed. Nine of the 14 had nonCNS anomalies noted. Nine were karyotyped and four were abnormal. Cranial anomalies including ventriculomegaly, the lemon sign, partial absence of the corpus callosum, and microcephaly were common, and the authors were not able to accurately distinguish meningocele from encephalocele, both of which did poorly. A more recent study by Bannister et al.430 presents a somewhat more optimistic result. Thirty-one fetuses with a cephalocele were divided into those with associated malformations (complex: 18) and those without associated malformations (isolated: 13). They were further grouped as to whether the sac was seen to contain brain tissue, a nubbin of tissue, or no tissue. No information about chromosome testing was provided, but eight of the 18 complex cases had findings compatible with Meckel-Gruber syndrome. Thirteen of the 18 pregnancies were terminated, three fetuses died in utero, there was one perinatal death, and the one survivor, whose sac contained a nubbin of tissue, had significant problems. Of the 13 isolated cases, in seven the sac was judged to contain significant

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brain tissue; six were terminated, and one died in utero. Of the remaining six whose sac contained a nubbin or no tissue, all were liveborn and at follow-up, ranging from 18 months to 9 years, they had all shown normal milestones and had average school performance. Two were reported to be clumsy. Thus, although the numbers were small, the study suggests that with skilled, modern ultrasound, useful prognostic information can be obtained at prenatal ultrasound. In summary, whether the examination is prenatal or postnatal, the assessment of a cephalocele should be directed at its size, location, cerebral content, and associated intracranial and extracranial malformations.54,423 Very large lesions, those containing cortex, and those associated with absent corpus callosum, holoprosencephaly, or microcephaly have a very guarded outlook for survival and intellect, and a decision not to intervene may be taken. Prevention. Folic acid (FA) has been shown to significantly reduce the recurrence431 and occurrence rates of NTD.432,433 Although the impact is greatest in high-risk areas, there is an effect in lower prevalence regions.434 The past decade has seen a shift in the debate from whether a large proportion of NTD can be prevented by FA to how this can best be accomplished.435–437 There are three basic approaches, which are not entirely mutually exclusive: to educate women to increase their dietary folate through selection of foods, to encourage women to supplement their diet with a pill containing 0.4 mg/day of FA, or to fortify a basic food element, such as grains, with FA. Natural folates are less bioavailable than FA and are subject to degradation during food preparation. A major change in diet would be required to ensure adequate folate intake438 and, even so, the approach would not likely be successful with a large proportion of women.439 There have been a number of well-organized, population-based programs to entice potentially pregnant women to take supplemental FA prior to conception. Despite these efforts and a demonstrable increased awareness of FA by women, at least half of women fail to take supplementation at the critical period.192,440,441 The issue is complicated by the fact that in many countries over half of all pregnancies are not planned. A multinational study has found no evidence that efforts directed toward perinatal supplementation with FA have resulted in any decline in the prevalence of NTD.183 Failure of the first two approaches has led several organizations to advocate the mandatory fortification of grains with FA, and in January 1998, the U.S. Food and Drug Administration mandated the fortification of grains to the level of 140 mg/100 g of product. Canada followed suit in November 1998 and some 20 additional countries did so thereafter.435 The United Kingdom, New Zealand, and Australia are notable exceptions, although the latter has allowed its first ever Health Claim: voluntarily fortified foods may make the label claim that folic acid reduces the risks of NTD. The two major objections raised to fortification have been that it will mask B12 deficiency and potentiate the risk of consequent neurologic damage,436 and that it will increase the dizygous twinning rate with its consequent health risks.441,442 Certainly the latter question requires careful monitoring with respect to its possible effect upon costs and benefits of fortification, although the most recent data have not shown that folic acid supplementation increases the rate of multiple births.442,481 Current attempts to model this question require broad assumptions about the outcomes of twin pregnancies and have wide confidence intervals.443 It is this author’s opinion444 that the health risks attributed to the masking of B12 deficiency have been exaggerated and, in any event, would be largely avoided by the addition of 25 mg of crystalline B12 per 100 g of fortified product.

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Evidence is accumulating that FA fortification at 140 mg/100 g is effective in elevating maternal red cell and serum folate levels,444–446 and data are beginning to appear in support of a reduction in the prevalence of NTD attributable to this action.187,188,249,482 The paper by Ray et al.445 is of note because it showed an increase in folate, but not B12, levels, thus pointing to an effect of fortification rather than multivitamin supplementation as the critical variable. However, with the current level of fortification, an important fraction of women remain below the protective threshold.444,445 This has led a national panel in the United Kingdom to recommend a doubling of fortification levels,446 and others have suggested going still higher.437 Vitamin B12 and folate have an intimate metabolic interrelationship; individuals with low folate levels tend to also have low B12 values, and both have been reported to be low in mothers bearing children with NTD. Gardiki-Kouidou and Seller447 reported low levels of vitamin B12, elevated transcobalamins I, II, and III, and unsaturated vitamin B12 binding capacity in the amniotic fluid of pregnancies bearing fetuses with NTD or other midline defects or in which a prior sibling had an NTD. An association between the risk of NTD and maternal B12 levels at the 5th and 25th percentiles has been reported,448 and there is some evidence that low B12 levels may interact with enzymatic variants to increase the risk of NTD.449 Thus, including B12 with food fortification to reduce concerns about masking may also serve to further reduce the rate of NTD. Papers that report an increased rate of aneuploidy in prenatally ascertained cases of NTD usually state that the information is useful for recurrence risk counseling in future pregnancies, but they tend not to specify how the information should be used.297–299 Data from spontaneous abortion studies show that women who miscarry a previable trisomic fetus, unlike those who carry late into pregnancy or to term, are not at increased risk for a liveborn infant with trisomy, nor are those who carry a triploid fetus at greater risk. Therefore, the issue is whether a woman who is found before or during the mid-trimester to carry a fetus with a trisomy or triploidyassociated NTD is at increased risk to have a future child with an isolated NTD. This author is unaware of any data germane to this question. While counseling that the NTD was likely related to the underlying chromosomal abnormality, the conservative approach would be to ensure adequate folate intake and to offer targeted ultrasound and MSAFP in a future pregnancy. Prenatal diagnosis and selective abortion of affected pregnancies has had an important impact upon the birth prevalence of NTD. An elevation in amniotic fluid a-fetoprotein (AFAFP) in pregnancies with anencephaly or SB was reported in 1972 and was rapidly applied to, and accepted by, high-risk families.450–452 In 1973 and 1974 it was noted that MSAFP level was raised in a significant proportion of pregnancies with anencephaly or SB, thus raising the prospect of screening the general ‘‘low-risk’’ population, who account for 90–95% of all affected births.450 a-Fetoprotein is a glycoprotein of molecular weight about 70,000 and is produced in sequence by the yolk sac, fetal gastrointestinal tract, and, finally, liver.452 It reaches the amniotic fluid through the gut and urine or, in abnormal circumstances such as NTD or omphalocele through exposed blood vessels, and can be used in both the first and second trimester for screening. Critical issues are germane to the introduction of any MSAFP screening program. Test sensitivity and specificity are subject to several technical and interpretive variables. Elevated MSAFP is nonspecific and occurs in normal pregnancies and, with greater frequency, in association with multiple gestation, other open lesions such as

omphalocele or gastroschisis, congenital nephrosis, placental anomalies associated with growth retardation, feto-maternal transfusion, and fetal death. MSAFP levels increase at a rate of about 17% per week to peak at 30 weeks, making use of gestation-specific values an absolute requirement.450 The distribution of values is not Gaussian and is therefore assessed in terms of multiples of the median (MOM). Evans et al.483 noted a significant reduction in the number of elevated MSAFP values in the postfortification era, which they attribute to a folic acid–induced reduction in the prevalence of NTD. The prior risk of an individual to bear a child with an NTD will vary with geography, race and ethnic group, family history, and medical history such as the presence of maternal diabetes or seizures treated with valproate. Thus, an elevated MSAFP value does not carry with it the same risk in every pregnancy of the fetus having an NTD. Interpretation is further challenged because actual MSAFP values differ by race, weight, and presence or absence of diabetes. For example, African Americans have a lower incidence of NTD than do whites, but tend to run higher MSAFP values in both affected and unaffected pregnancies.453 A cut-off of 2.5 MOM based on white norms would lead to a very significant number of amniocenteses in African Americans, and differing corrective approaches have been proposed.450,452 Problems such as assay drift, having an adequate number of samples, correction for a fall of MSAFP associated with increasing maternal weight, and the need for laboratories to report a patient-specific risk for fetal malformation rather than simply a value of MOM are all important considerations.454 MSAFP screening appears capable of detecting 80–90% of cases of NTD, 95–100% of cases of anencephaly, and 70–80% of cases of SB. A variety of computer programs in use with different screening programs take account of the various factors that affect prior risks in calculating the odds of a pregnancy having an NTD, given a particular MSAFP screening result. There is some correlation between the magnitude of the MSAFP elevation and the likelihood of malformation, growth failure, prematurity, or fetal death.455 MSAFP is considered to have a higher sensitivity than routine obstetric ultrasound for the detection of NTD32 and is certainly more cost-effective when added to a biochemical screening program for trisomy. Ultrasound is the next step in most, if not all, populationbased MSAFP screening programs after an elevated value is reported. A repeat MSAFP is no longer recommended by most centers. The central role of ultrasound is to rule out benign causes for the MSAFP elevation, such as incorrect gestational timing or multiple gestation, and to assess the fetus for malformations or other problems such as growth failure or death. It has been found that infants with SB tend to have a reduced biparietal diameter (BPD). Correction of gestation based on BPD in these pregnancies will underestimate gestation and therefore make the value appear more abnormal.450 Targeted ultrasound should detect all anencephaly and almost every case of open NTD14 (see section on diagnosis). Many programs consider a normal targeted ultrasound adequate follow-up for an elevated MSAFP. However, most have available the option of amniocentesis and AFAFP but uptake is increasingly limited to cases where the ultrasound visualization was not adequate. If a pregnancy does proceed to AFAFP measurement, the sensitivity, corrected for gestational age, has been estimated at 98.2 for anencephaly and 97.6 for SB.450 Specificity may be improved by the addition of amniotic fluid acetylcholinesterase determination, which may be of particular value in cases of fluid contamination by fetal blood and in distinguishing gut anomalies.456 Interpretation may be difficult when one member of a multiple gestation is affected, because AFAFP and acetylcholinesterase become elevated in the sac of the normal

Brain and Spinal Cord

co-twin.457 It appears that MSAFP values do not elevate when there is concurrence of an NTD with trisomy.458 A normal MSAFP screen and targeted ultrasound are adequate tests for women at high risk because of family history. The possibility of a false-positive MSAFP elevation leading to induced abortion of a normal pregnancy can be minimized by strict attention to quality assurance not only in the laboratory, but also in the process of communication between the program, the patient, and her physician. Milunsky and Alpert459 put it clearly when they stated that ‘‘a screening program should be established only where there is linked excellent interdisciplinary support among obstetricians, laboratory, clinical geneticist, ultrasonographer, and an identified program coordinator.’’ It is paramount that any population screening remains informed and voluntary. Extensive physician and patient education is required, and all who may potentially be screened should receive literature appropriate to their level of understanding and have the opportunity to discuss the process and outcomes with an informed professional. As for other types of prenatal diagnosis, level of uptake is greatly influenced by knowledge and physician ‘‘advocacy.’’460 Virtually all women, including those who might elect not to be screened and those who would not terminate an affected pregnancy, express positive attitudes toward the availability of screening. Screening raises concerns of a potentially increased level of anxiety in the population of pregnant women. Kyle et al.460 found that anxiety following introduction of information about screening was greater in women who had little prior information. BerneFromell and Kjessler461 reported lower levels of maternal anxiety in regions where screening was available than where it was not and that screened women with a normal result had levels of anxiety comparable with those in the unscreened population. Burton et al.462 followed anxiety and attitude toward pregnancy in screened and unscreened mothers from 16 weeks gestation to 6 months postdelivery. Anxiety was at no time higher in the women or their spouses who were screened, and screened women had a more positive attitude toward the pregnancy than their unscreened counterparts. Population screening has been judged cost-effective even in geographic areas of low prevalence.463 Tosi et al.464 in a more theoretical analysis concluded that screening was cost-effective above a prevalence of 0.7 in 1000. The analysis was somewhat sensitive to varying the actual cost of the test and was markedly affected by the specificity but not the sensitivity of the test procedure. Such analyses are also sensitive to projected health care costs, and the estimate used by Tosi et al.464 for 10 years of care for a child with SB was $42,507, significantly lower than the estimates of others. Silver et al.465 concluded that measurement of AFAFP at the time of genetic amniocentesis and mid-trimester ultrasound for trisomy risk is not cost-effective for detecting NTD. The impact of prenatal screening on the birth prevalence of NTD varies with the specific malformation, the availability and uptake of a population-based MSAFP program, and the general use and quality of routine obstetric ultrasound. Many centers do not collect data on terminations of pregnancy, thus precluding any assessment of the role played by prenatal diagnosis in any change in birth prevalence. Nor is it generally possible to determine what proportion of prenatal diagnoses is due to MSAFP or to ultrasound. Brock450 reported that by 1982 about 60% of NTD in Scotland were prenatally detected and aborted and that in Edinburgh the figure was 83%, with 91% of those found through MSAFP screening. Between 1984 and 1990 in the North of England, for those cases where there

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had been a mid-trimester ultrasound, 92.6% of anencephaly and 53.8% of SB were diagnosed antenatally; from 1991 to 1996 the respective figures were 99.4% and 75.4%.466 For all cases of NTD, comparing the two periods, the percentage terminated rose from 60.3% to 78.6% and the proportion of live births fell from 37.7% to 15%. From 1990 to 1991 in Atlanta, 48.6% of anencephaly, 23.1% of SB, and 9.1% of encephaloceles were detected for an overall rate of only 32.1%.467 In Ontario, the detection rates for all NTDs, live births, and stillbirths plus therapeutic abortions were, respectively, 61%, 15%, and 25% in 1986 compared to 42%, 10%, and 47% in 1999.187 About 50% of Ontario women participate in the MSAFP program and almost all will have at least one obstetric ultrasound. Although Limb and Holmes468 restrict their data to anencephaly, it is of special interest because they distinguish the primary method of antenatal detection. From 1972 to 1974, 18% of cases were detected by ultrasound, 29% by third-trimester radiographs, and 53% were not detected. From 1982 to 1984, 91% were detected by ultrasound and 9% by MSAFP, and from 1988 to 1990, 60% were found by ultrasound and 40% through MSAFP. All cases were terminated prenatally. Williamson et al.20 examined the obstetric history of 148 women who had given birth to a child with an NTD. In 26 (18%) cases the diagnosis was made but the women decided to continue their pregnancy; in 24 (16%) the diagnosis was made in a multiple gestation that continued to term. No prenatal diagnosis or a diagnosis beyond 25 weeks was made in 98 cases. In six of these cases the women had declined screening, in 30 screening was not offered because of late gestation, in eight there was a false-negative MSAFP, in 29 there was a false-negative ultrasound, and in 17 both the MSAFP and ultrasound were falsely negative. Thus, although the screening tests lack maximum sensitivity (SB estimated at 70–84% for ultrasound and 84–92% for MSAFP), several other factors can diminish the effectiveness of prenatal detection and prevention of NTD. References (Disorders of Neural Tube Closure) 1. Warkany J: Congenital Malformations, Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 189. 2. Seller MJ: Sex, neural tube defects, and multisite closure of the human neural tube. Am J Med Genet 58:332, 1995. 3. Golden JA, Chernoff GF: Multiple sites of anterior neural tube closure in humans: evidence from anterior neural tube defects (anencephaly). Pediatrics 95:506, 1995. 4. O’Rahilly, Muller F: The two sites of the neural folds and the two neuropores in human embryo. Teratology 65:162, 2002. 5. Kashimi AH, Hutchins GM: Meningeal-cutaneous relationships in anencephaly: evidence for a primary mesenchymal abnormality. Hum Pathol 32:553, 2001. 6. Oi S, Matsumae M, Takei F, et al.: Neurovascular developmental interaction: a specific form of vascular maldevelopment in the malformed brain. I. An experimental study and proposal of a new teratological concept. Child Nerv Syst 12:242, 1996. 7. Matsumoto A, Hatta T, Moriyama K, et al.: Sequential observations of exencephaly and subsequent morphological changes by mouse exo utero development system: analysis of the mechanism of transformation from exencephaly to anencephaly. Anat Embryol (Berl) 205:7, 2002. 8. Timor-Tritsch IE, Greenebaum E, Monteagudo A, et al.: Exencephalyanencephaly sequence: proof by ultrasound imaging and amniotic fluid cytology. J Matern Fetal Med 5:182, 1996. 9. Weissman A, Diukman R, Auslender R: Fetal acrania: five new cases and review of the literature. J Clin Ultrasound 25:511, 1997. 10. Hammond R, Norman MG: Cranial ectomesodermal hypoplasia: a new entity. Report of 2 cases (abstr). Can J Neurol Sci 19:403, 1992.

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456. Loft AG: Immunochemical determination of amniotic fluid acetylcholinesterase in the antenatal diagnosis of open neural tube defects. Dan Med Bull 42:54, 1995. 457. Holbrook RH Jr, Krovoza AM, Schelley S, et al.: Elevated alphafetoprotein and positive acetylcholinesterase in twins, one with anencephaly. Prenat Diagn 7:653, 1987. 458. Williamson RA, Weiner CP, Murray J: Maternal serum alphafetoprotein in presence of both neural tube defects and chromosome anomalies. Lancet 2:757, 1986. 459. Milunsky A, Alpert E: Results and benefits of a maternal serum alphafetoprotein screening program. JAMA 252:1438, 1984. 460. Kyle D, Cummins C, Evans S: Factors affecting the uptake of screening for neural tube defect. Br J Obstet Gynaecol 95:560, 1988. 461. Berne-Fromell K, Kjessler B: Anxiety concerning fetal malformation in pregnant women exposed or not exposed to an antenatal serum alphafetoprotein screening program. Gynecol Obstet Invest 17:36, 1984. 462. Burton BK, Dillard RG, Clark EN: Maternal serum alpha-fetoprotein screening: the effect of participation on anxiety and attitude toward pregnancy in women with normal results. Am J Obstet Gynecol 152: 540, 1985. 463. Sadovnick AD, Baird PA: A cost benefit analysis of a population screening programme for neural tube defects. Prenat Diagn 3: 117, 1983. 464. Tosi LL, Detsky AS, Roye DP, et al.: When does mass screening for open neural tube defects in low-risk pregnancies result in cost savings? Can Med Assoc J 136:255, 1987. 465. Silver RK, Leeth EA, Check IJ: A reappraisal of amniotic fluid alphafetoprotein measurement at the time of genetic amniocentesis and midtrimester ultrasongraphy. J Ultrasound Med 20:631, 2001. 466. Rankin J, Glinianaia S, Brown R, et al.: The changing prevalence of neural tube decfects: a population-based study in the North of England, 1984–96. Paediatr Perinatol Epidemiol 14:104, 2000. 467. Roberts HE, Moore CA, Cragan JD, et al.: Impact of prenatal diagnosis on the birth prevalence of neural tube defects, Atlanta, 1990–1991. Teratology 49:386, 1994. 468. Limb C, Holmes LB: Anencephaly: changes in prenatal detection and birth status, 1972 through 1990. Am J Obstet Gynecol 170:1333, 1994. 469. Aaronson OS, Hernanz-Schulman M, Bruner JP, et al.: Myelomeningocele: prenatal evaluation—comparison between transabdominal US and MR imaging. Radiology 227:839, 2003. 470. Johnson WG, Stenroos ES, Spychala JR, et al.: New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet 124A:339, 2003. 471. Morin I, Platt R, Wesberg I, et al.: Common variant in betainehomocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet 119A:172, 2003. 472. Relton CL, Wilding CS, Pearce MS, et al.: Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. J Med Genet 41:256, 2004. 473. Rothenberg SP, da Costa MP, Sequeira JM, et al.: Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. N Eng J Med 350:134, 2004. 474. Klootwijk R, Groenen P, Schijvenaars M, et al.: Genetic variants in ZIC1, ZIC2, ZIC3 are not major factors for neural tube defects in humans. Am J Med Genet 124A:40, 2003. 475. McNeely PD, Howes WJ: Ineffectiveness of dietary folic acid supplementation on the incidence of lipomeningocele: pathogenetic implications. J Neurosurg 100(supp 2):98, 2004. 476. Lewis D, Tolosa JE, Kaufmann M, et al.: Elective cesarean delivery and long-term motor function or ambulation status in infants with meningomyelocele. Obstet Gynecol 103:469, 2004. 477. Johnson MP, Sutton LN, Rintoul N, et al.: Fetal myelomeningocele repair: short term clinical outcomes. Am J Obstet Gynecol 189:482, 2003. 478. Wakhlu A, Ansari NA: The prediction of postoperative hydrocephalus in patients with spina bifida. Childs Nerv Syst 20:104, 2004.

Brain and Spinal Cord 479. Van den Berg-Emons HJ, Bussmann JB, Meyerink HJ, et al.: Body fat, fitness and level of everyday physical activity in adolescents and young adults with meningomyelocele. J Rehabil Med 35:271, 2003. 480. Buran CF, Sawin KJ, Brei TJ, et al.: Adolescents with myelomeningocele: activities, beliefs, expectations, and perceptions. Dev Med Child Neurol 46:244, 2004. 481. Shaw GM, Carmichael SL, Nelson V, et al.: Food fortification with folic acid and twinning among California infants. Am J Med Genet 119A:137, 2003. 482. Centers for Disease Control and Prevention: Spina bifida and anencephaly before and after folic acid mandate—United States, 1995–1996 and 1999–2000. MMWR Morb Mortal Wkly Rep 53:362, 2004.

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483. Evans MI, Llurba E, Landsberger EJ: Impact of folic acid fortification in the United States: markedly diminished high maternal serum alphafetoprotein values. Obstet Gynecol 103:474, 2004. 484. Moore C, Kogan BA, Parekh A: Impact of urinary incontinence on self-concept in children with spina bifida. J Urol 171:1659, 2004. 485. Sebold CD, Melvin EC, Siegel D, et al.: Recurrence risks for neural tube defects in siblings of patients with lipomyelomeningocele. Genet Med 7:64, 2005. 486. Baird PA, Sadovnick AD: Survival in liveborn infants with anencephaly. Am J Med Genet 28:1019, 1987. 487. Lewis D, Tolosa JE, Kaufman M, et al.: Elective cesarean delivery and long-term motor function or ambulation status in infants with meningomyelocele. Obstet Gynecol 103:439,2004.

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17 Spinal Cord Alasdair G.W. Hunter

17.1 Primary Tethered Cord Definition

The lower end of the spinal cord is held by one or more of a number of tethering mechanisms that are most often associated with various forms of occult spinal dysraphism (OSD) (Fig. 17-1). In most cases the termination of the spinal cord is below the normal level for age and it is frequently associated with a short and thickened filum terminale. The normal level of the end of the spinal cord within the spine varies during development. During the first trimester it occupies the entire length of the spinal canal, but by 6 months gestation it terminates at L3-L4, and at birth it is at L2L3. It ends at the adult L1-L2 position by age 3 months.1–4 However, there is variation. A high-resolution ultrasound study of 114 infants found the terminal conus had its tip between L2-L4 in 78% of neonates who were between 30 and 39 weeks gestation, and that it lay from Th12/L1 to the L1/L2 interspace in 84% of those between birth and 63 weeks.5 An autopsy study of the size, origin, and termination of the filum terminale found that 14.6% of cases met one of the anatomic criteria for primary tethered cord (PTC).6 There are slight but not significant variations among what different authors consider abnormally low. Most consider 2 mm the upper limit of normal thickness of the filum,3,4 while others have a limit as high as 2 to 3 mm, or as low as 1.5 mm.1,2 Diagnosis

The clinical symptoms and neurologic signs of PTC can be extremely protean, and yet there is good evidence that timely diagnosis and surgical repair can prevent or minimize the long-term complications. Thus, it is important to recognize the signs of accompanying OSD and to maintain a high index of suspicion when faced with soft signs of neurologic dysfunction at the lumbosacral level. The routine examination of a newborn should include a search for dorsal midline cutaneous signs such as hemangiomas, patches of hypertrichosis, skin tags, dermal tracts, a significant dimple or swelling above the gluteal cleft, or scoliosis. Simple isolated dimples below the gluteal cleft are not associated with OSD and PTC.7,8 Atypical dimples that lie
2.5 cm above the anus, especially if
5 mm across, are more sinister.7 Isolated nevus flammeus, espe-

cially the high cervical type, is not a concern, but occasionally it may be the sole marker in the lumbosacral area, where it occurs in 0.77% of neonates.9 One patient from a series of 11 with giant melanotic nevi was found to have a tethered cord.10 Nelson et al.2 include a mongolian spot, but this author is unaware of any such association with pathology. Cord tethering due to attachment to a fibrous band running to an overlying lumbosacral area of cutis aplasia has been reported, but it is problematic as to whether this represents an example of OSD or an atretic form of classic neural tube defect.11 The underlying anomalies may include simply a low cord with a short thickened filum, lipomas, lipomyelocele, dermoid or epidermoid cysts, split cord malformation (SCM),* defects of caudal regression, various vertebral body and arch malformations, and a dermal sinus. Andar et al.12 have challenged the view that there is no correlation between clinical symptoms and signs and the specific underlying pathology, and have concluded that lower limb neurologic-orthopedic syndrome is the common presentation of SCM, and that it relates to an intrinsic malformation of the cord rather than to the PTC. They question whether the common urodynamic presentation associated with occult lipomeningocele may also represent an abnormality at the level of the cord. There is some correlation between specific anomalies and age at onset. Major anomalies such as SCM, congenital scoliosis, and caudal regression are more likely to present in childhood. More simple tethering such as by a slowly growing epidermoid tumor or lipoma is the more common finding in adults, in whom clinical signs may also reflect the impact of degenerative disc disease and spondylosis.4 The age at diagnosis varies widely within and between series, from birth to late adulthood.1,3,4,13,14 With the exception of a significant excess of females with congenital scoliosis, there does not appear to be any distortion of the sex ratio.15,16 The neurologic impairment in PTC is attributable to the lumbosacral cord. Yamada et al.17 concluded that the lumbosacral dysfunction might result from impaired mitochondrial oxidative function associated with vascular compromise following the intermittent abnormal stretching of the cord in that region. In the absence of external clues, the diagnosis of PTC in the infant is difficult. Bladder dysfunction may be reflected as hypertonia or hypotonia and may result in an abnormal voiding pattern. One *Split cord malformation is used in place of diastematomyelia (see 17.5).

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Fig. 17-1. Sagittal magnetic resonance imaging scan showing tethering of the cord at the lumbosacral junction (black arrow). Patient has a split cord malformation (white arrowhead). (Courtesy of Dr. L. Auruch, Ottawa Hospital.)

series reported urodynamic abnormalities in 55% of children at the time of diagnosis with OSD, and OSD was found in four of 148 children with daytime wetting.18 In the older child this may be reflected as a delay in toilet training or later loss of dryness. Increased urinary frequency or bladder incontinence may occur in the older patient.1,4 Patients are frequently ascertained through orthopedic clinics because of lower limb complaints, which may include leg cramps and pain, gait disturbance, weakness, and foot inversion. Examination will confirm weakness and may detect increased deep tendon reflexes, clonus, pes cavus or talipes equinovarus, absent ankle jerks, upgoing toes, absent vibration sense, decreased sensation usually over the distribution of S1-S2, and decreased anal tone. Kyphoscoliosis and limb length discrepancies may also be found. An attempt has been made to grade patients according to their severity of symptoms: 0, none; 1, slight neurologic impairment, minor foot anomalies, and normal gait and bladder function; 2, weak lower limbs with normal bladder function, or isolated bladder impairment; 3, moderate limb weakness with gait and bladder dysfunction; 4, severe paraplegia, walking with support; 5, paraplegia, nonambulatory.13 Frank fecal incontinence is an ominous sign. Presentation in the adult may mimic disc disease or spinal tumors in both symptoms and signs. Pain is the most frequent complaint and may be gluteal, coccygeal, perineal, vaginal, anorectal, or limb. In the legs it is often bilateral and diffuse, although typical radicular pain may occur. As mentioned, PTC is usually a consequence of occult spinal dysraphism, and the underlying pathogenetic mechanism is quite variable. In exceptional cases the conus may actually terminate at L2, and the filum may be of normal caliber.19 In such cases the diagnosis is purely clinical and confirmed by upward retraction of the cord at surgery.1 In other cases a short, thick filum terminale is the only pathologic finding.4,5,17,20 The short filum terminale

passes through the posterior sacral meninges to attach to the sacral periosteum.21 Various types of lipomatous growths associated with a short and/or thickened filum terminale are the most common associated findings.4,5,17,20 The lipoma is usually a reasonably encapsulated mass of mature fat tissue divided into lobules by fibrous bands. It should be noted that a small lipoma may be an incidental finding in normal asymptomatic individuals.1 While these growths can occur at any level, they are most common in the lumbosacral region. There is no evidence that they cause damage due to compression. Although the entire mass may be intraspinal, there is often a subcutaneous, at times discontinuous, component.13,21 The actual relationship of the conus medullaris, filum terminale, and lipoma is variable, but in all cases there is anchoring through the lipoma that extends through the dura and attaches.21 The lipoma may lie within, or at times completely replace, the filum terminale. It may also occur in the region of normal closure of the conus medullaris with the filum continuing caudad. There is generally no true cleavage plane between the conus and a lipoma.13 At times a diffuse intracordal lipomatosis may be seen. In the case of lipomyelocele, the meninges are protruded through a spinal defect, and the cord may be eccentric. Some authors include lipomyeloschisis in this spectrum, while others specifically exclude this anomaly.21 In this condition the end of the cord is not completely closed and is contiguous with the lipoma, which is traversed by many septa, and there is no interface between the cord and the lipoma. In SCM there is a segmental duplication of the cord that forms two hemicords, each with a central canal, ventral horn, and dorsal horn, and separated by a bony, cartilaginous, or fibrous septum, resulting in fixation of the cord, which rejoins caudad (Fig. 17-1). Vertebral abnormalities are present in at least 60% of cases.13 Other mass lesions that may be found include dermoid cysts, which combine ectodermal and mesodermal cell rests and are often associated with a caudocranially directed dermal sinus. Epidermoid cysts are less common and slower growing, and tend to present in adulthood, when they may be overlooked at the time of surgery. Teratomas may also result in PTC. Congenital scoliosis may occur with single hemivertebrae, as a unilateral unsegmented bar with contralateral hemivertebrae, or as a more complex anomaly, and many of the anomalies so far discussed occur frequently in association with these spinal malformations. McMaster15 found intraspinal abnormalities in 18.3% of 251 patients with congenital scoliosis. Malformations were most common in patients with a unilateral unsegmented bar, and SCM was by far the most common finding. Thirty of the 46 patients with intraspinal anomalies had neural compromise, as did an additional 12 patients who had no demonstrable spinal abnormality. Blake et al.16 found cord abnormalities in 77% of patients with complex scoliosis, and 58% of all cases had changes demonstrated by myelography. SCM was the single most common malformation (21%), and PTC was present with the same frequency. OSD with the potential for PTC is common in patients with anorectal malformations, being noted in 18 of 41 (44%) in one series of children who had no neurologic or orthopedic signs, and in six of 45 (14%) of a second group in whom no correlation with the level of the atresia was apparent.22,23 PTC may be associated with caudal dysgenesis syndrome, although in these circumstances the majority of initial neurologic signs reflect the cord deficit and are proportional to the level of the dysgenesis. Barkovich et al.24 found PTC in two of 13 cases of caudal dysgenesis. There is evidence that caudal regression limited to S2 and lower is highly associated with PTC, but that higher levels of regression have an untethered, blunt, or wedge-shaped cord that ends at T11-T12.25

Spinal Cord

Segmental spinal dysgenesis is a rare malformation, somewhat akin to caudal dysgenesis, but where the absent and abnormal vertebral bodies are more proximal and the distal spinal column and cord are intact. There is usually a low conus and thickened filum.26 There is dysgenesis of the underlying spine (which may include absent nerve roots) and a fixed congenital neurologic deficit commensurate with the level of the lesion but usually with some preservation of function in the lower cord. Progressive kyphoscoliosis and cord compression may lead to increasing impairment. Although the conus is low and filum thickened, symptoms of tethering might not occur because of fixation of the cord by the higher spinal lesion. The diagnosis of PTC is readily amenable to several neuroimaging techniques. The posterior spinal processes do not ossify until several months of age and spinal sonography, especially during the first 4 weeks of life, offers a rapid, noninvasive technique to evaluate the asymptomatic neonate who is deemed to be at risk because of external dorsal midline abnormalities.2 At this age sonography permits assessment of the cord for malformations or enlargements; the conus medullaris is easily seen as a tapering of the distal cord and can be located relative to its vertebral level. The filum terminale can be followed as an echogenic band as it passes dorsal to the distal dural sac, usually at the S2 level. A dermal sinus tract can be seen as a hypoechogenic band running from the skin surface and interrupting normal tissue planes, but its relationship to the dura requires additional neuroimaging techniques. Lipomas are also readily defined. In many cases no further preoperative neuroimaging is required, and McLone (commentary on Brophy et al.20) has stated that half the patients in their series could have undergone surgical repair without further investigation. Plain spinal radiographs may provide confirmatory evidence in support of PTC. Merx et al.21 found neural arch anomalies in all patients over 2 years of age; 28 of 30 had open sacral and 18 of 30 open lumbar arches. Other anomalies included vertebral scalloping, fusion, scoliosis, and sacral hypoplasia. Lesoin et al.27 defined four criteria suggestive of underlying PTC: spina bifida occulta (not isolated) of L5-S1, dehiscence of the entire sacrum, absence of normal tapering of the distal sacrum, and anterior angulation of the sacrum with scalloping of the surface of the vertebral bodies. Additional techniques are required to define the abnormalities of the cord itself. Myelography and computed tomography-myelography have been largely replaced by magnetic resonance imaging (MRI) that has the advantage of obviating the risk of cord damage associated with lumbar puncture and seems an adequate technique in most cases. It may be at slight disadvantage with respect to demonstrating the precise relationship of the conus, cauda, and filum to an adjacent lipoma and for the precise evaluation of bony landmarks,13,20 but in most cases results are satisfactory. Brophy et al.20 noted both false-positive and false-negative results with MRI but did not consider any to have been of significance with respect to surgical intervention. The abnormalities that were inaccurately detected included failure to note a thickened filum with dermoids, misdiagnosis of a lipoma, and two cases of lipoma thought to be in the filum but which were attached to the conus. Tripathi et al.28 considered that MRI provided precise results in 91 of 92 cases studied and suggested the addition of a plain radiograph to better define bony landmarks. In a cost analysis study, Medina et al.29 compared MRI, ultrasound (US), plain radiographs, and no imaging in newborns with different hypothetical levels of risk for an OSD. At putative risks of <3.8%, US was most effective and cost-efficient. At higher a priori risks, MRI was most effective with an incremental cost-effectiveness of $1000 per quality adjusted life

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year gained. One may argue with their assigned risk of 0.30 to a child with a simple gluteal dimple, and therefore whether US is truly better than no imaging in that situation. Urodynamic studies are an important adjunct to the evaluation of the patient at risk for PTC and abnormalities are found in 40–60% of cases. In a study of 28 neonates and young infants, 25 of whom presented because of isolated cutaneous signs, 10 were found to have urodynamic abnormalities although only two had urinary complaints.30 Of interest, five patients with abnormal findings were less than 3 months of age. Flanigan et al.31 performed urodynamic evaluations on 24 of 60 patients who presented with orthopaedic complaints, because they also had new or increasing bladder incontinence, retention, or frequency. The bladder was hyperreflexic in 29% and areflexic in 71% of cases. All patients were over age 8 years. Torre et al.32 used pre- and postoperative perineal muscle electromyography, sacral reflexes, and lower limb and perineal-evoked potentials to assess children with spinal dysraphism. They obtained a sensitivity of 100% for vesicosphincter dyssynergy and 86% for bladder dysmotility, and suggested that this noninvasive approach was sufficient to assess patients with tethered cord, spinal lipoma, and syringomyelia. Etiology and Distribution

There do not appear to have been any population-based surveys of the prevalence of PTC or OSD. Surface signs suggestive of OSD were found in 95 of 4989 neonates, of which 75 were isolated simple sacral dimples that are not associated with OSD.8 Seven of the remaining 19 cases who had imaging studies had anomalies, but in two this was only a cord ending at the L3 level. This provides a minimal newborn rate for OSD of five per 4989 (0.01%) because a significant number of cases of OSD do not have a skin marker. Lipomas are considered the most common occult lesion and are associated with PTC in over 90% of cases, but they account for less than 1% of primitive intraspinal tumors.13 Dermoids account for about 10% of spinal tumors presenting by age 15 years, and about half are associated with PTC.13 Caudal dysgenesis occurs in one of 7500 births and about 16% of cases occur in infants of diabetic mothers, of whom about 1% deliver a baby with caudal dysgenesis.33 Some 15% of cases of caudal dysgenesis are associated with PTC and, as discussed, these tend to be the milder lesions. The majority of patients with PTC are diagnosed in childhood, although the condition is becoming increasingly recognized in adults. Maiuri et al.4 were able to find reports of 80 cases in adults and added seven of their own. Although some authors appear to consider OSD as a forme fruste of myeloschisis, there is a consensus that the etiology and embryology of these conditions are distinct. While 20% of myelomeningoceles have an associated upper urinary tract anomaly and over 90% have an associated Arnold-Chiari type II malformation, these malformations are distinctly uncommon in OSD.3,34 In addition, the majority of occult dysraphic changes are in the region of junction between neurulation and canalization or below that level. The fact that the incidence of occult lipomyeloceles has not declined parallel to that of open neural tube defects with folic acid fortification of foods also supports a separate etiology.45 The latter finding suggests that the timing of genetic or teratogenic insult is later for PTC and associated OSD than for myelomeningocele. There are scattered reports of recurrent OSD within families, and although such cases have led to the suggestion of occasional autosomal recessive inheritance of anomalies such as lipomyelomeningocele,46 multifactorial inheritance is equally compatible with these occurrences. A recent small study, in which the propositus had an OSD, reported recurrence risks for open neural tube defects

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in the younger siblings, and for all NTD (occult and open) among all siblings, that were equivalent to those for open NTD.47 However, the confidence intervals of the risk estimates were extremely wide and more supportive data are required before it can be concluded that OSD is a risk factor for an open NTD in a subsequent pregnancy. There is support for the view that in the same way that calvarial growth is dependent upon growth of the brain, elongation of the spine is dependent upon growth of the spinal cord.3 Under normal circumstances, the spinal cord undergoes unfolding and stretching in flexion and folding and compression during extension of the spine. The lumbar nerve roots are subject to stretching and relaxation with flexion and extension of the cervical spine.35 Others have demonstrated that the normal spinal cord has significant elasticity, which is maximal in the lumbosacral region.3 As already discussed, the spinal cord initially occupies the entire spinal column. The segment distal to the second segment of the coccyx undergoes a dedifferentiation and programmed cell death to form the filum terminale, which normally undergoes elongation to accommodate continued growth as the conus moves to its higher level. Rates of elongation of the spine and spinal cord are in harmony by age 2 months.26 Simple ‘‘overgrowth’’ of the spinal cord or failure of dedifferentiation of the filum would not lead to the tension in the conus that has been well-documented at surgery, and there is no evidence that affected persons have an excessively long spine. Nor would either of these explanations account for the associated malformations of the spine, filum, and adjacent tissues. Thus, the evidence from the effects of surgical release, experimental studies, and the absence of more distant associated malformations suggests a local embryologic basis for PTC. The resultant tension is essentially confined to the adjacent spinal cord, in most cases the lumbosacral region, and local metabolic disturbance has been demonstrated.17 The local lesions that prevent ascent of the conus are those that have been discussed, and they do so by directly anchoring the spinal cord to the surrounding tissue, as, for example, to a dermal sinus or a lipoma that penetrates the dura. Sectioning of the thickened filum terminale demonstrates abnormal fibrofatty tissue and occasional ependymal rests, which Sarwar et al.3 consider to be remnants of an elastic tissue scar that caused contraction of the filum. These authors hypothesized that the primary event is a local hemorrhage or related teratogenic event during late embryogenesis or early fetal life. Healing would incorporate tissue rests and result in scarring and contraction. It is further suggested that the reactive tissue causes an impaired cerebrospinal (CSF) absorption, leading to ectasia of the dural sac, prevention of neural arch closure, and abnormalities of the adjacent mesodermal and ectodermal tissue. A local hemorrhage might well involve these tissues directly. However, it is not clear how this mechanism could lead to a low conus and thick filum in thoracolumbar segmental dysgenesis. The progressive nature of the condition during postnatal growth can be explained by chronic cord hypoxia due to recurrent stretching of the tethered cord, failure to accommodate growth spurts, and greater susceptibility to the degenerative changes of adult life. PTC has been reported in King syndrome,36 ethylmalonic encephalopathy,37 and in two sibs with an interstitial microdeletion of 1p,38 but it is unclear as to whether these are chance associations. Prognosis, Treatment, and Prevention

There are few data as to what proportion of persons with OSD will develop symptoms of PTC or at what age they will do so. This confounds the debate as to whether all PTC should be relieved at the time of diagnosis. An additional complexity is that the ap-

pearance of some signs and symptoms that have been considered as evidence of progressive damage may represent neurologic maturation of the intrinsic malformation.12 The arguments in support of treatment of all cases of PTC have been that symptoms are less common in younger patients,39 that in general they are progressive, that surgery with minimal attendant morbidity can result in improvement or stabilization39,40 but that, once established, some signs and symptoms may prove irreversible.3,20,30,31,34 However, some patients may remain asymptomatic, at least in the short term.40 Cornette et al.41 screened a series of 22 patients for the development of upper motor neuron signs. Five patients were symptomatic at birth, and seven became symptomatic by a mean age of 13 months. Ten remained asymptomatic with a mean followup age of 67 months. The majority of patients present in childhood, although there is an increasing awareness of onset of symptoms in adulthood.4 A number of patients become symptomatic during their adolescent growth spurt. Cornette et al.41 argue that there are no prospective data that support intervention in asymptomatic patients. Neurologic and urologic function returned to normal postoperatively in all seven of the children in their series who developed signs, and 10 children had not become symptomatic. It must be stressed that these children were followed very carefully and were treated within an average of 5 months of the development of signs. However, complete recovery from chronic neurologic compromise is unlikely, and if asymptomatic patients are not treated surgically, they must be followed closely over the longer term. Patients with urologic dysfunction secondary to PTC are at significant risk for progressive renal damage and ultimate renal failure.23,42 Treatment involves freeing up of the cord with transection of the filum and removal of any mass as completely as possible. The use of microsurgical and CO2 laser techniques has proven useful in some cases.4,20,27 Simple transection of the filum may prove inadequate. Once the conus has been cleared adequately, it may be seen to rise in the spinal canal, and the nerve roots may assume a more normal horizontal plane. In SCM it is necessary to remove the sagittal septum and the midline sleeve of dura in order to properly free the cord. Operative treatment of segmental dysgenesis is indicated when there is evidence of spinal cord compression or progression of symptoms in a child with preserved function below the level of the lesion.26 MRI has not proven helpful in the follow-up study of the position of the conus, as it does not appear to change significantly.20 Intraoperative neurophysiologic monitoring may provide a useful adjunct in helping to distinguish the filum from nerve roots and to minimize the risk of iatrogenic neurologic damage.43 Surgical treatment is efficacious in the relief of pain in even longstanding cases and in preventing progression of neurodegeneration. Some sensorimotor improvement may occur, but it is unlikely to be complete, especially in long-standing cases. Sphincter dysfunction is the least likely to show improvement. Keating et al.30 studied the urodynamics of 28 infants age 2 years. Twenty-five had been referred because of external cutaneous signs, and none had clinical symptoms of urinary tract dysfunction. Eighteen of them had normal urodynamics, and all 12 who were restudied postoperatively remained normal. They were all normally toilet trained and dry. Of the 10 patients with abnormalities detected preoperatively, six were normally toilet trained, two were improved, and one had shown deterioration. Eleven of 12 patients who presented between ages 2 and 12 years had urodynamic abnormalities, and three of them had urologic complaints. Only three reverted to normal status. The authors emphasized that a fixed deficit can occur early. Hellstrom et al.34 studied 18 patients ranging in age from newborn to 29 years, of whom four had urologic complaints alone

Spinal Cord

and six had combined limb and bladder signs. Nine patients had a flaccid bladder and five an uninhibited bladder, while two had mixed bladder dysfunction. The authors restudied the patients at least 6 months postoperatively and found that, of the patients with a flaccid bladder, two obtained weak contractions, two became normal, and two were left with a mixed bladder dysfunction. All four patients restudied who had initially had an uninhibited bladder showed improvement, and three were normal. Hypersensitivity to bethanechol did not predict outcome. Flanigan et al.31 also noted slight postoperative improvement in some cases. In another adult series Iskandar et al.44 reported significant improvement in 22 of 27 patients who presented with pain, 13 of 27 with motor/sensory impairment, and 11 of 18 with bowel or bladder problems. Seventy-five percent of the patients considered they were improved; most who had worked returned to work and two who had been unable to work returned to work. Unfortunately no data were provided as to the preoperative duration of symptoms. Patients with neurogenic bladders should also receive anticholinergic medications and/or be trained in intermittent catheterization as appropriate. Significant bowel incontinence should be managed as it would with an open neural tube defect. Tortori-Donati et al.13 used the clinical scale referred to earlier. All 18 patients in categories 0–1 were treated in the 1st year of life and showed no deterioration. Twenty-two of 26 patients in categories 2 to 3 were stabilized, two showed improved walking, and one had further deterioration of sphincter function. The authors did follow two neurologically normal, untreated patients by clinical and laboratory tests. Patients who have been treated should be followed closely by clinical and laboratory testing because retethering of the cord can occur. There is no known way of preventing occult spinal dysraphism or PTC, but its impact can be greatly reduced by careful physical examination and a high index of suspicion leading to appropriate investigations and surgical treatment. It may be prudent to consider women who have had a child with an OSD as being at increased risk for a pregnancy with an open NTD, until and if further data prove this to be incorrect. References (Primary Tethered Cord) 1. Moufarrij NA, Palmer JM, Hahn JF, et al.: Correlation between magnetic resonance imaging and surgical findings in tethered spinal cord. Neurosurgery 25:341, 1989. 2. Nelson MD, Segall HD, Gwinn JL: Sonography in newborns with cutaneous manifestations of spinal abnormalities. Am Fam Physician 40:198, 1989. 3. Sarwar M, Virapongse C, Bhimani S: Primary tethered cord syndrome: a new hypothesis of its origin. AMJR Am J Neuroradiol 6:235, 1984. 4. Maiuri F, Gambardella A, Trinchillo G: Congenital lumbosacral lesions with late onset in adult life. Neurol Res 11:238, 1989. 5. Wolf S, Schneble F, Troger J: The conus medullaris: time of ascendence to normal level. Pediatr Radiol 22:590, 1992. 6. Pinto FC, Fontes RB, Leonhardt Mde C, et al.: Anatomic study of the filum terminale and its correlations with the tethered cord syndrome. Neurosurgery 51:725, 2002. 7. Kriss VM, Desai NS: Occult spinal dysraphism in neonates: assessment of high risk cutaneous stigmata on sonography. AJR Am J Roentogenol 171:1687, 1998. 8. Gibson PJ, Britton J, Hall DM, et al.: Lumbosacral skin markers and identification of occult spinal dysraphism in neonates. Acta Paediatr 84:208, 1995. 9. Ben-Amitai D, Davidson S, Schwartz M, et al.: Sacral nevus flammeus simplex: the role of imaging. Pediatr Dermatol 17:469, 2000. 10. Foster RD, Williams ML, Barkovich AJ, et al.: Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children. Plast Reconstr Surg 107:933, 2001.

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11. Lacro RV, Jones KL, Josephson K, et al.: Aplasia cutis congenita and other cutaneous lesions at the vertex of the scalp: cutaneous markers for defects in neural tube closure. Proc Geenwood Genet Center 7:149, 1988. 12. Andar UB, Harkness WF, Hayward RD: Split cord malformation of the lumbar region. A model for the neurosurgical management of all types of ‘‘occult’’ spinal dysraphism? Pediatr Neurosurg 26:17, 1997. 13. Tortori-Donati P, Cama A, Rosa ML, et al.: Occult spinal dysraphism: neuroradiological study. Neuroradiology 31:512, 1990. 14. Moffie D, Stefanko SZ, Makkink B: Congenital malformations of the spinal cord without early symptoms. Clin Neurol Neurosurg 88:27, 1986. 15. McMaster MJ: Occult intraspinal anomalies and congenital scoliosis. J Bone Joint Surg Am 66A:588, 1984. 16. Blake NS, Lynch AS, Dowling FE: Spinal cord anomalies in congenital scoliosis. Ann Radiol 29:377, 1986. 17. Yamada S, Zinke DE, Sanders D: Pathophysiology of ‘‘tethered cord syndrome.’’ J Neurosurg 54:494, 1981. 18. Lewis MA, Shaw J, Sattar TM, et al.: The spectrum of spinal cord dysraphism and bladder neuropathy in children. Eur J Pediatr Surg 7 (suppl 1):35, 1997. 19. Selcuki M, Unlu A, Ugur HC, et al.: Patients with urinary incontinence often benefit from surgical detethering of tight filum terminale. Childs Nerv Syst 16:150, 2000. 20. Brophy JD, Sutton LN, Zimmerman RA, et al.: Magnetic resonance imaging of lipomyelomeningocele and tethered cord. Neurosurgery 25:336, 1989. 21. Merx JL, Bakker-Niezen SH, Thijssen HOM, et al.: The tethered spinal cord syndrome: a correlation of radiological features and preoperative findings in 30 patients. Neuroradiology 31:63, 1989. 22. Tsakayannis DE, Shamberger RC: Association of imperforate anus with occult spinal dysraphism. J Urol 154:754, 1995. 23. De Gennaro M, Rivosecchi M, Lucchetti MC, et al.: The incidence of occult spinal dysraphism and the onset of neurovesical dysfunction in children with anorectal anomalies. Eur J Pediatr Surg (suppl)1:12, 1994. 24. Barkovich AJ, Raghavan N, Chuang S, et al.: The wedge-shaped cord terminus: a radiographic sign of caudal regression. AJNR Am J Neuroradiol 10:1223, 1989. 25. Pang D: Sacral agenesis and caudal spinal cord malformations. Neurosurgery 32:755, 1993. 26. Scott RM, Wolpert SM, Bartoshesky LE, et al.: Segmental spinal dysgenesis. Neurosurgery 22:739, 1988. 27. Lesoin F, Petit H, Destee A, et al.: Spinal dysraphia and elongated spinal cord in adults. Surg Neurol 21:119, 1984. 28. Tripathi RP, Sharma A, Jena A, et al.: Magnetic resonance imaging in occult spinal dysraphism. Australas Radiol 36:8, 1992. 29. Medina LS, Crone K, Kuntz KM: Newborns with suspected occult spinal dysraphism: a cost-effectiveness analysis of diagnostic strategies. Pediatrics 108:e101, 2001. 30. Keating MA, Rink RC, Bauer SB, et al.: Neurological implications of the changing approach in management of occult spinal lesions. J Urol 140:1299, 1988. 31. Flanigan RC, Russell DP, Walsh JW: Urologic aspects of tethered cord. Urology 33:80, 1989. 32. Torre M, Planche D, Louis-Borrione C, et al.: Value of electrophysiological assessment after surgical treatment of spinal dysraphism. J Urol 168:1759, 2002. 33. Hori A: Dimyelia, diastematomyelia, and diplomyelia. Clin Neuropathol 7:314, 1988. 34. Hellstrom WJG, Edwards MSB, Kogan BA.: Urological aspects of the tethered cord syndrome. J Urol 135:317, 1986. 35. Breig A, El-Nadi AF: Biomechanics of the cervical spinal cord. Acta Radiol 4:602, 1966. 36. Graham GE, Silver K, Arlet V, et al.: King syndrome: further clinical variability and review of the literature. Am J Med Genet 78:254, 1998. 37. Nowaczyk MJ, Blaser SI, Clarke JT: Central nervous system malformations in ethylmalonic encephalopathy. Am J Med Genet 75:292, 1998. 38. Campbell CG, Wang H, Hunter AGW: Interstitial microdeletion of chromosome 1p in two sibs. Am J Med Genet 111:289, 2002. 39. Peter JC: Occult dysraphism of the spine. A retrospective analysis of 88 operative cases, 1979–1989. S Afr Med J 81(7):351, 1992.

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40. Koyanagi I, Iwasaki Y, Hida K, et al.: Surgical treatment supposed natural history of the tethered cord with occult spinal dysraphism. Childs Nerv Syst 13:268, 1997. 41. Cornette L, Verpoorten C, Lagae L, et al.: Tethered cord syndrome in occult spinal dysraphism. Timing and outcome of surgical release. Neurology 50:1761, 1998. 42. Silveri M, Capitanucci ML, Capozza N, et al.: Occult spinal dysraphism: neurogenic voiding dysfunction and long-term urologic follow-up. Pediatr Surg Int 12:148, 1997. 43. Von Koch CS, Quinones-Hinojosa A, Gulati M, et al.: Clinical outcome in children undergoing tethered cord release utilizing intraoperative neurophysiological monitoring. Pediatr Neurosurg 37:81, 2002. 44. Iskandar BJ, Fulmer BB, Hadley MN, et al.: Congenital tethered cord syndrome in adults. J Neurosurg 88:958, 1998. 45. McNeely PD, Howes WJ: Ineffectiveness of dietary folic acid supplementation on the incidence of lipomeningocele: pathogenetic implications. J Neurosurg 100(suppl 2):98, 2004. 46. Kannu P, Furneaux C, Aftimos S: Familial lipomyelomeningocele: a further report. Am J Med Genet 132A:90, 2005. 47. Sebold CD, Melvin EC, Siegel D, et al.: Recurrence risks for neural tube defects in siblings of patients with lipomyelomeningocele. Genet Med 7:64, 2005.

17.2 Neurenteric Malformations Definition

Neurenteric malformations are a broad spectrum of spinal cord malformations considered to arise from abnormal persistence of the normal embryonic connection between endoderm and ectoderm. This has been called the split notochord syndrome by some authors.1 Included are malformations in which there is a persistent connection of gastrointestinal structures to, and even through, the neural tube. The connection may take a variety of forms. Less severe anomalies include isolated gastrointestinal cysts and duplications, some cases of diastematomyelia, and isolated intraspinal neurenteric cysts that are lined by cells of endodermal origin. Diagnosis

The most severe malformations are not compatible with life and are generally limited to fetuses and stillbirths.2 Attempts have been made to categorize these lesions according to their severity.3 At one extreme, the gut passes through a cleft vertebra onto the surface of the back in an area of medullovasculosa, or in other cases may pass to the surface through a bisected spinal cord. Sometimes the connection is absent or consists of endodermal and ectodermal remnants at the site of their respective embryologic territories. These malformations are more often found in the cervical and upper thoracic region, and the neurenteric connection implies distortion of normal anatomic relationships. The diaphragm is defective, the esophagus is short, and the abdominal viscera, which are often malformed, are found in the thorax. Not infrequently, additional severe malformations such as anencephaly and rachischisis are seen. Equivalent anomalies are seen less often in the lumbosacral region. In such instances the connection may involve the lower gut or a presacral enteric pouch extending through an anterior cleft vertebra to the spinal canal, lower back, or perineum.3 Associated malformations are less common. The diagnosis of the most severe neurenteric malformations is usually made through careful pathologic examination of a malformed fetus or stillbirth. Clearly the diagnosis should be considered in any child with multiple malformations that include the diaphragm, abnormal positions of abdominal organs, and vertebral malformations. The spine should

be carefully examined and a thorough neurologic examination performed in any child presenting with intrathoracic or intraabdominal duplications or enterogenous cysts. In less severe cases that may be compatible with survival, the spinal cord may remain intact or be split as in diastematomyelia, and there may or may not be a fibrous connection from the gut to the cord. At the milder end of the spectrum are found isolated anterior cleft vertebrae as well as various intrathoracic, intraabdominal, intrapelvic, and intraspinal enteropathogenic cysts. The extraspinal cysts are often associated with anterior cleft vertebrae but are not always connected to the spine. Occasionally they connect to the spinal canal, and associated intraspinal cysts and bisection of the cord have been reported.3 Dorsal enteric remnants may present as cutaneous fistulae or sinuses or as a pre- or postvertebral or intraspinal neurenteric cyst.4 In the present context intraspinal neurenteric cysts merit further discussion. Most authors limit the term neurenteric cyst to those whose tissues are of purely endodermal origin,5,6 although others consider that they are part of a continuum, with intraspinal teratomas at one extreme and dermoid cysts at the other.3 As with the more severe neurenteric anomalies, these cysts are more common in the cervical and upper thoracic regions. A summary from the literature found that 54% of these malformations are cervical, 12–21% thoracic, 15–20% thoracolumbar, and the remainder more caudal.7 They may lie completely anterior to the spinal cord and attach to a vertebral body or to the dura, or they may be intraleptomeningeal and abut a completely normal cord. Of neurenteric cysts in the spine, >90% are intradural, extramedullary; <5% are intravertebral; and <5% are intramedullary.7 The histopathology of the cyst varies in complexity from a simple layer of nonciliated cuboidal or columnar epithelium attached to a basement membrane to masses that contain additional normal gastrointestinal elements such as complex mucosal invaginations, glandular tissue, smooth and striated muscle, elastic fibers, nerve fibers, and ganglion cells.3 As one would expect from the intimate embryologic relationship between the gastrointestinal and respiratory systems, neurenteric cysts may display characteristics of respiratory tissue including ciliated epithelium and cartilage. The cyst is supported by a loose fibrous tissue with some vascular elements.3,5 The presence of a basement membrane distinguishes neurenteric from ependymal cysts.5 Appropriate histologic stains will demonstrate mucin-containing cells. These cysts tend to be translucent with a blue-gray color and to contain a clear viscous fluid. However, the contents may be milky or discolored.3,5,6 In rare instances, the cysts may be multiple.8 Most cases of intraspinal neurenteric cysts are diagnosed in infancy or childhood, although there are a significant number of case reports of symptoms appearing in late adulthood. The signs and symptoms are those expected of a slowly enlarging, usually extramedullary, anterior spinal mass. Pain related to the size of the lesion is a prominent feature and may be associated with meningismus or radicular symptoms. The pain may be intermittent, sharp, and, depending on location, exacerbated by certain movements.8 Sensory and motor signs occur, and dorsal column involvement may be marked despite the ventral location of the cyst. Less commonly there may be a delay in diagnosis because recurrent or chronic pain is unaccompanied by neurologic signs or a malformation that is visible on a standard radiograph. At least one child’s complaints have been dismissed as psychogenic.9 Symptomatology will also vary with the level of the malformation and has included the cauda equina syndrome and those secondary to compression at the craniocervical junction. More unusual are the

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cases of a 22-month-old child who presented with acute neurologic symptoms after a vesiculourethrogram,10 another with a history of recurrent meningitis,11 and one with recurrent fever attributed to an inflammatory response secondary to degenerative changes in the cyst.12 Ultrasound prenatal diagnosis of neurenteric cyst has been reported, and in one case it was associated with fetal hydrops.13 Of special interest is a subgroup of patients who present with a more indolent and intermittent course and who may be misdiagnosed for many years as having other unrelated conditions. The history may be characterized by periodic, asymmetric, sequential loss of function, which recovers in the reverse order of loss.3 In other instances presentation is later in life and relatively acute, perhaps related to the attainment of a critical size by a slow-growing tumor, irritation due to leakage, or degenerative changes in the spine.6 The reason for the intermittent course is unclear but could relate to a balance between resorption and production of cyst contents or periodic leakage of fluid. Examples of such cases include a 54-year-old man who had been diagnosed for 20 years as having multiple sclerosis and a 40-year-old person who presented with many years’ history of an intermittent spastic paraplegia and was found to have an intramedullary bronchogenic cyst.8,14 The differential diagnosis of neurenteric cyst includes arachnoid cyst, dermoid, cystic teratoma, paracytic cysts, ependymal cysts, and a cystic chordoma tumor.15 Nonspecific cutaneous signs such as areas of hypertrichosis, a dermal sinus, or dimple point to a congenital malformation, including a neurenteric cyst, as opposed to other tumors as a cause for progressive symptoms. Plain films and tomograms will often reveal associated malformations of the spine, including diastematomyelia, hemivertebrae and block vertebrae, anterior or posterior spina bifida, and widened vertebrae. Neurenteric cysts may be seen in congenital scoliosis.16 Myelography in the symptomatic patient characteristically shows a high grade block, a rounded ventral defect, and sometimes a displacement of the cord (Fig. 17-2).6,17 If the cyst is not attached to the dura, it may be seen to move with normal cerebrospinal fluid pulsations.6 At this time magnetic resonance imaging (MRI) is considered the diagnostic modality of choice,7,15 and a standard spinal radiograph or additional computed tomography may help to define any associated skeletal anomalies. Malignancy can be ruled out by the absence of a mural nodule or contrast enhancement of the cyst wall.7 Histology will confirm the nature of the lesion. Etiology and Distribution

By all accounts, neurenteric malformations are uncommon and sporadic. In their extensive summary in 1976, Wilkins and Odum3 found 18 reports referring to the severe syndrome with gut and spinal involvement and were able to review 62 cases in all. They identified 47 reports of intraspinal neurenteric cysts. They account for 0.7–1.3% of spinal tumors.7 Two of 251 patients with congenital scoliosis studied by McMaster16 had a neurenteric cyst. Although the severe syndrome and simple intraspinal neurenteric cysts have a similar distribution of location along the spine, they show a markedly different sex ratio, with 69% being female in the severe syndrome and 72% male in the case of intraspinal neurenteric cysts.3 The etiology of neurenteric malformations is unknown, and, although there is general acceptance that the malformations result from an abnormal endoectodermal connection, authors continue to differ as to the precise embryogenesis. The primitive streak begins to develop in the caudal epiblast of the bilaminar (epiblast/hypoblast) human embryo at day 14. Future endodermal and mesodermal cells move inward through a rostral pit known as Hensen’s node and the more caudally located primitive streak

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Fig. 17-2. Myelogram showing displacement by upper thoracic, anterior neurenteric cyst. Spinal dysraphism and central foramen (canal of Kovalevsky, arrow) are visible. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

and move anteriorly and laterally until the end of the 4th week.3 The notochord is formed by mesodermal cells passing forward from Hensen’s node. By day 18, at the caudal aspect of the notochord, a connection from the yolk sac to the amnion that is known as the neurenteric canal is apparent. The notochord that induces the overlying neural tube separates from the endoderm in a craniocaudal direction. This separation is complete by the end of week 5. The primitive streak begins to regress by day 20, with Hensen’s node and the neurenteric canal moving from a lower cervical location to its final site of closure in the caudal extreme of the embryo in the tail region, which later regresses. Various theories have attempted to explain the severe condition in which the gut is connected and open to the dorsal surface of the embryo. Predominant has been the idea that the neurenteric canal remains open and/or fails to move caudally. However, it is hard to account for the predominance of cervicothoracic lesions in embryos that have normal caudal elements. Such a theory might explain a connection between the dorsal rectum and lower sacrum.2 A case associated with partial sacral agenesis and lined by transitional epithelium suggests occasional involvement of the cloaca in this malformation.18 It has thus been generally accepted that neurenteric malformations result from persistent endodermalectodermal connections. It is unclear whether the primary event is a split in the notochord that allows herniation of the endoderm between the split or whether persistence of the endodermalectodermal connection causes the notochord to split with its consequent impact on the vertebral and neural tube development.3 In either case, depending on location, size, and persistence, one

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could see the entire spectrum of malformations from enteric connections to the dorsal surface, ectodermal or endodermal rests in various locations forming dermoid cysts, various enterogenic cysts, and even teratomas if pluripotent cells are involved. Different malformations might retain various degrees of continuity. Lack of any remnants could account for simple vertebral anomalies such as diastematomyelia. Persistent connections between the gut and cervical spine would interfere with normal descent of the gut and closure of the diaphragm. This pathogenic model does not readily explain the occurrence of isolated neurenteric cysts in the brain. Prognosis, Treatment, and Prevention

The prognosis for infants with the severe neurenteric syndrome is poor, with most being stillborn or dying in the neonatal period. Infants with associated split cord malformation (diastematomyelia) may suffer tethered cord syndrome, and a delay in diagnosis and treatment may lead to permanent neurologic deficit. The presence or absence of additional malformations such as rachischisis or diaphragmatic hernia may be a significant determinant of prognosis in individual patients. In contrast, the outlook for patients with simple intraspinal neurenteric cysts is very good. In most cases, even when there has been a long intermittent history of symptoms, there is complete recovery of neurologic function and relief from pain.3,6 However, some neurologic deficit may remain.16 Occasionally infection of a cyst may lead to meningitis with serious consequences, and rare cases of acid-secreting mucosa may lead to ulceration and abscess formation. Treatment is the surgical removal of as much of the cyst and membranes as possible. Simple posterior decompression may lead to recurrence of symptoms.6 Although the cyst is mucous secreting, postoperative arachnoiditis is not a problem. A careful search should be made for intrathoracic or intraabdominal connections that should be removed, and it is suggested that cysts anterior to the spinal canal be approached through a separate anterior incision.3 A variety of surgical approaches have been adopted to deal with the specific location and/or associated anomalies.19–21 A combined intraoral and occipital approach has been suggested for lesions at the cervicospinal junction,11 and a combined anterior and posterior technique may provide stability and benefit those patients who have associated spinal anomalies.21 There is no known means of primary prevention, and familial recurrence does not appear to be a concern. A father with vertebral anomalies and a neurenteric cyst, whose daughter died of multiple malformations and had similar vertebral defects but no neurenteric cyst, has been reported.22 Level two ultrasound in severe cases may be offered for reassurance. It is prudent to consider cases associated with anencephaly, rachischisis, or multiple hemivertebrae as open neural tube defects, although it remains possible that they represent a different etiopathology and recurrence risk from simple neural tube defects. References (Neurenteric Malformations) 1. Bentley JFR, Smith JR: Developmental posterior enteric remnants and spinal malformations: the split notochord syndrome. Arch Dis Child 35:76, 1960. 2. Warkany J: Congenital Malformations: Notes and Comments. Chicago: Year Book Medical Publishers, Inc, 1971, p 700. 3. Wilkins RH, Odum GL: Spinal intradural cysts. In: Handbook of Clinical Neurology, vol 20. PJ Vinken, GW Bruyn, eds. North Holland, Amsterdam, 1976, p 55. 4. Smith JR: Accessory enteric formations: a classification and nomenclature. Arch Dis Child 35:87, 1960.

5. Freide RL: Developmental Neuropathology. Springer-Verlag, Berlin, 1975, p 266. 6. Almeida AC, Stewart DH Jr: Neurenteric cyst: case report and literature review. Neurosurgery 8:596, 1981. 7. Lippman CR, Arginteanu M, Purohit D, et al.: Intramedullary neurenteric cysts of the spine: case report and review of the literature. J Neurosurg 94:305, 2001. 8. Vinters HV, Gilbert JJ: Neurenteric cysts of the spinal cord mimicking multiple sclerosis. Can J Neurol Sci 8:159, 1981. 9. Mochida J, Yamada S, Toh E, et al.: Intradural neurenteric cyst of the cervical spine misdiagnosed as a psychogenic disorder in a 7-year-oldchild. Spinal Cord 35:700, 1997. 10. Rizk T, Lahoud GA, Maarrawi J, et al.: Acute paraplegia revealing an intraspinal neurenteric cyst in a child. Childs Nerv Syst 17:754, 2001. 11. Menezes AH, Ryken TC: Craniocervical intradural neurenteric cysts. Pediatr Neurosurg 22:88, 1995. 12. Kadhim H, Proano PG, Saint Martin C, et al.: Spinal neurenteric cyst presenting in infancy with chronic fever and acute myelopathy. Neurology 54:2011, 2000. 13. Wilkinson CC, Albanese CT, Jennings RW, et al.: Fetal neurenteric cyst causing hydrops: case report and review of the literature. Prenat Diagn 19:118, 1999. 14. Duthel R, Brunon J, Michel D, et al.: Kyste bronchogenic intramedullaire. Apropos d’un cas. Discussion du syndrome d’adhesion entoectodermique. Neurochirurgie 29:155, 1983. 15. Ergun R, Akdemir G, Gezici AR, et al.: Craniocervical neurenteric cyst without associated anomalies. Pediatr Neurosurg 32:95, 2000. 16. McMaster MJ: Occult intraspinal anomalies and congenital scoliosis. J Bone Joint Surg Am 66A:588, 1984. 17. Rodacki MA, Teixeira WR, Boer VHT, et al.: Intradural extramedullary high cervical neurenteric cyst. Neuroradiology 29:588, 1987. 18. Mendel E, Lese GB, Gonzales-Gomez I, et al.: Isolated lumbosacral neurenteric cyst with partial sacral agenesis: case report. Neurosurgery 35:1159, 1994. 19. Fuse T, Yamada K, Kamiya K, et al.: Neurenteric cyst at the craniovertebral junction: report of two cases. Surg Neurol 50:431, 1998. 20. Devkota UP, Lam JM, Ng H, et al.: An anterior intradural neurenteric cyst of the cervical spine: complete excision through central corpectomy approach—case report. Neurosurgery 35:1150, 1994. 21. Mooney JF 3rd, Hall JE, Emans JB, et al.: Spinal deformity associated with neurenteric cysts in children. Spine 19:1445, 1994. 22. Orstavik KH, Steen-Johnsen J, Foerster A, et al.: VACTERL or MURCS association in a girl with neurenteric cyst and identical thoracic malformations in the father: a case of gonosomal mosaicism? Am J Med Genet 43:1035, 1992.

17.3 Intraspinal (Nonneurenteric) Cysts In addition to the classical neurenteric cyst, there are a variety of individually rare congenital cystic malformations that present with a similar clinical pattern due to compression of the spinal cord and/or nerve roots. These tumors are considered in this section. 17.3.1 Cystic Teratoma Definition

A true neoplasm containing derivatives of all three germ layers and occurring in locations and relationships where they are not normally found.1 Wilkins and Odum2 consider teratomas to be part of the neurenteric spectrum and that the definition includes a malformation with derivatives containing two or more germ layers in an abnormal anatomic location.

Spinal Cord

Diagnosis

True cystic teratomas are distinguished from complex neurenteric cysts by the lack of ordered relationships between the different tissue types. Furthermore, elements of alimentary origin usually contribute a minor component to these tumors.1 A single case in the cervical spine with pulmonary differentiation has been reported.3 Color Doppler may help to distinguish a cystic teratoma from a meningomyelocele on prenatal ultrasound.4 The clinical course of intraspinal cystic lesions is often prolonged, intermittent, and characterized by signs and symptoms of cord compression. They are usually found dorsal to the cord and may occur anywhere along its length. In the lumbosacral region, symptomatology may relate to tethering of the cord (Section 17.1), and dermal anomalies may present over the spine. Hoefnagel et al.5 and Newcastle and Francoeur6 carried out sex chromatin studies on a total of 11 patients with ‘‘teratomatous’’ cysts that would in the present context be considered to be neurenteric cysts of varying complexity. In four of the eight male patients the cyst epithelium was considered sex chromatin positive, while its connective tissue was negative, as expected. It is this finding that has led to the suggestion that these cysts are not neurenteric but rather are true teratomas originating from a pluripotent cell arising from fusion of two haploid cells. However, the reliability of the sex chromatin under these circumstances may be questioned, and this author is unaware that these data have been confirmed by chromosome analysis from these cysts. Etiology and Distribution

These lesions appear to be uncommon and do not show a propensity for a particular sex. In 1978, Rosenbaum et al. were able to find 22 cases.7 The etiology is uncertain but is thought by some to reflect growth from a focus of pluripotent cells that have escaped the normal embryonic controls. Luks et al.8 reported a child with lower vertebral anomalies and a partially cystic mass that communicated with the dura and that contained all three cell lines. The findings were in keeping with both a cystic teratoma and a tailgut anomaly and suggest the origins were that of a primary malformation. Prognosis, Treatment, and Prevention

As for intraspinal cysts in general, the prognosis for patients with cystic teratoma is generally good. Calcification and/or the finding of a cystic lesion generally point to a benign course. The signs and symptoms often do not appear until adulthood and respond well to laminectomy and removal of the major portion of the cyst. Some cases may be associated with primary tethered cord, which must be recognized and treated before permanent neurologic damage occurs. There does not appear to be any means of primary prevention, and familial recurrence is not a concern. 17.3.2 Epidermoid and Dermoid Cysts Definition

An epidermoid cyst is lined by a stratified squamous epithelium and has a nonuniform convoluted capsule of connective tissue. Dermoid cysts are similar, but have a greater degree of complexity in that they contain dermal appendages such as sebaceous and occasionally sweat glands, as well as hair and hair follicles. Diagnosis

Epidermoid and dermoid cysts are benign, grow slowly, and generally present after an asymptomatic period with gradually

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increasing signs of spinal cord compression. Symptoms and signs vary with location and may include local and/or radicular pain and neurologic dysfunction. The common lumbosacral location may be associated with signs of primary tethered cord. Acute neurologic deterioration is uncommon but has been reported.9 Cokca et al.10 reported an intramedullary, thoracolumbar, dermoid cyst that presented as an abscess due to Brucella abortus. Calcium deposits and cholesterol clefts may occur within the walls of the cyst, and, although unusual, the former may occasionally be seen radiographically.11 It is to be expected that this might be more often detected with spinal computed tomography (CT) examination. The contents of these cysts reflect keratinized epithelial debris and, in the case of dermoid cysts, include glandular secretions. The fat content may be extremely high. Epidermoid cysts tend to be pearly white, while dermoid contents tend to be buttery yellow.2 Rupture of a cyst, either spontaneously, secondary to external trauma, or at the time of surgery, may release these contents and result in acute chemical meningitis. Keratin may be seen in the cerebrospinal fluid under polarized light.2 Gliosis may be present in some cysts that have an intramedullary location. The frequent association of these cysts with additional malformations such as occult spina bifida, diastematomyelia, and dermal signs, including dermal sinus, was discussed with respect to primary tethered cord (Section 17.1). Dermal sinuses are seen in about onethird to one-half of patients with dermoid cysts and somewhat less frequently in those with epidermoid cysts. It appears that they are most common in the lumbosacral region, at which site they are more often posterior and in a subdural or subarachnoid location. The cysts are frequently attached to the cord or cauda equina. Intramedullary epidermoid and dermoid cysts appear to differ as to their distribution along the spine, with the majority of epidermoid cysts occurring in the thoracic region and the majority of dermoid cysts at the level of the conus.2 They are occasionally found in unusual sites such as within an anterior meningocele.12 Cervical location is rare. Any deviation in sex ratio is not significant. Manno et al.13 reported the age of onset of symptoms in 51 cases of congenital epidermoid cyst. The presence of a dermal sinus or spina bifida led to early diagnosis, while among the remaining cases there was a fairly steady rate of presentation during the first 4 decades, with a few presenting in their 50s and 60s. In general, dermoid cysts present earlier. Etiology and Distribution

While these are among the more common of congenital spinal cysts, they account for only 1.5%–2% of spinal tumors, 4.5% in the pediatric group.2 There are a number of hypotheses as to their origin. Their association with cases of split cord malformation has led to the suggestion that they represent part of the spectrum resulting from persistent or abnormal ectodermal-endodermal connections in the embryo, thus relating them directly to neurenteric cysts.14 Other possibilities include entrapment of cutaneous ectoderm at the time of neural tube closure or the aberrant development of cells that had been destined to form neural tissue. In support of the former suggestion is the occurrence of such cysts at the site of surgical closure of meningomyeloceles, including at least one case that followed fetal surgery, and their production in animals by deliberate introduction of skin fragments into the subarachnoid space.2 Delayed occurrence of an intraspinal epidermoid cyst many years after surgery related to a lipomyelomeningocele has caused symptomatic retethering of the spinal cord.14a Of particular note is the occurrence of epidermoid cysts in children previously subject to lumbar puncture. Unlike the typical congenital cyst, these cysts are often multiple, are not associated

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with additional spinal malformation, and have a lumbar rather than the more typical thoracic distribution.15 Prognosis, Treatment, and Prevention

The generally good prognosis for these cysts may be compromised by infection via an associated dermal sinus, delayed recognition and treatment of an associated primary tethered cord, or the presence of additional malformations. Treatment involves laminectomy and removal of as much cyst as possible. Chronic leakage and chemical meningitis may cause adherence of these cysts to the spinal cord, and care must be taken to avoid further damage to the cord. A concurrent dermal sinus should be completely removed. Careful avoidance of practices likely to cause iatrogenic epidermoid cysts via lumbar puncture may decrease the overall incidence. Although posterior fossa dermoids have been seen in patients with Klippel-Feil malformation and familial frontonasal dermoids have been reported, there does not appear to be any syndromic or genetic association with these spinal lesions. 17.3.3 Arachnoid Diverticulum (Cyst) Definition

Arachnoid diverticulum is an outpouching of normal or slightly thickened leptomeninges. True noncommunicating cysts are also occasionally seen. Diagnosis

The majority of spinal arachnoid diverticula are incidental findings at myelography performed for unrelated reasons. They are most commonly noted in the dorsal thoracic region and will fill with contrast medium if the patient is suitably positioned to permit filling.2 Uncommonly, such diverticula are symptomatic and present with local or radicular pain and paresis appropriate to the level of the lesion. True arachnoid cysts are most often solitary, intradural, posterior, and thoracic but extradural, anterior, lumbosacral, and cervical, and multiple lesions do occur. Symptomatic true arachnoid cysts often present an indolent, intermittent course— perhaps due to periodic drainage of the cyst—that is clinically indistinguishable from other intraspinal cysts of similar location. Symptoms most often appear in adulthood and may be extremely protean; however, they may present in young children. Kazan et al.16 described two young adults with anterior cervical arachnoid cysts who presented with progressive paraparesis following minor trauma. They found only eight prior cases of these cysts at that location. The fact that some patients are reported to have their symptoms relieved in a prone position has led to the hypothesis that the signs are due to downward traction of the filled cyst on the cord. This hypothesis may also explain the occasional patient who has neurologic signs above the level of the cyst.17 Symptomatic kinking due to herniation of the spinal cord into the cyst may also occur.18 Widening of the spinal canal at the level of the cyst may be seen on radiographs. Cerebrospinal fluid pressure and composition are not significantly affected. Such cysts in the sacral location have, in the past, sometimes been called occult intrasacral meningoceles. Expansion of the cyst may cause erosion of the adjacent sacral bones.19 There is potential to mistake such a lesion for a malignant process on routine radiographs, although magnetic resonance imaging (MRI) and metrizamide CT usually should allow distinction to be made (Fig. 17-3). There is no distortion of sex ratio. MRI appears to be the diagnostic procedure of choice, although several views may be

Fig. 17-3. Axial computed tomography scan of sacral arachnoid cyst showing erosion of the adjacent vertebra and displacement of the spinal theca.

required to discern the true nature of the lesion.20 Kyphoscoliosis may be an associated sign. Etiology and Distribution

Multiple small diverticula appear to be a common finding in about one-half of asymptomatic adults who are undergoing myelography for intervertebral disc disease. Symptomatic arachnoid diverticula and cysts are uncommon and show no predilection for a particular sex. The diverticula are considered to arise through protrusion of a weakness of the arachnoid, probably because of faults in the distribution of the trabeculae, most often in the septum posticum that divides the cervical and thoracic posterior subarachnoid space longitudinally.2 The cysts are thought to arise by loss of communication between a diverticulum and the subarachnoid space. This is supported by the similar anatomic territory of both diverticula and cysts. The association between arachnoid cysts and neurocutaneous melanosis,21,22 and with other complex spinal malformations,23 suggests a congenital origin for some spinal arachnoid cysts. Rabb et al.23a have pointed out an apparent association of arachnoid cysts with neural tube defects. Six of their 11 patients with arachnoid cysts had myelomeningoceles and one a diastematomyelia. There is also good evidence that arachnoid cysts may be acquired as a result of either sharp or blunt trauma, such as that associated with prior vertebral fractures, and that they may follow arachnoiditis secondary to myelography. Fobe et al.24 documented the evolution of posttraumatic hemorrhage through to the development of an intradural arachnoid cyst over an 18-month period. There is no evidence of a genetic predisposition in man, although equivalent cysts occur in mice with the spastic mutation.25 Arachnoid cysts have been reported in association with giant melanocytic nevi21,22 and in a case of Noonan syndrome.26

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Prognosis, Treatment, and Prevention

Etiology and Distribution

As mentioned, most arachnoid cysts and diverticula are asymptomatic, and those that do result in symptoms generally respond well to laminectomy and removal of the posterior cyst wall. The degree of recovery may be dependent upon the duration of symptoms and the presence of secondary complications, such as the presence of a syrinx that has been reported in several cases. The anterior portion may be adherent to, or consist of, pia mater, making it hazardous to attempt complete removal.2 Some patients may achieve symptomatic relief by periodically lying in the prone position. Kunz et al.20 have suggested that surgery should be reserved for patients with recent onset of neurologic symptoms and only those in whom complaints can be clearly attributed to the cyst. Postsurgical recurrence is unlikely, but Alvisi et al.27 have reported some deterioration in some patients over the longer term. This deterioration was not predictable, and they hypothesized that it resulted from vascular insufficiency of the cord that was already present at the time of surgical relief of cord compression. Some further progression might occur from the mechanical effects of laminectomy on the stability of the spine.

These cysts are uncommon and account for about 1.5% of intraspinal tumors. Chynn28 found 57 cases in the literature and reported two affected siblings. There is a 2:1 male predominance. The most commonly held theory is that their origin is as a diverticulum of the dura, although some believe that both arachnoid and dura are involved and later fuse to form a single layer. It is unclear what role genetic factors play in the etiology, as siblings and parents have not been subject to investigation on any routine basis and many cases may remain asymptomatic. Extradural cysts have been reported in a case of lymphedema-distichiasis syndrome.31

17.3.4 Extradural Cyst

1. Friede RL: Neuropathology. Springer-Verlag, New York, 1975, p 269. 2. Wilkins RH, Odum OL: Spinal intradural cysts. In: Handbook of Clinical Neurology, vol 20. PJ Vinken, OW Bruyn, eds. North Holland, Amsterdam, 1976, p 55. 3. Ramdial PK, Nadvi SS, Mallet R: Cervical spine dysraphism with teratoma exhibiting pulmonary differentiation: case report and review of the literature. Pediatr Dev Pathol 1:528, 1998. 4. Sherer DM, Fromberg RA, Rindfusz DW, et al.: Color Doppler aided prenatal diagnosis of a type 1 cystic saccrococcygeal teratoma simulating a meningomyelocele. Am J Perinatol 14:13, 1997. 5. Hoefnagel D, Benirschke K, Duarte J: Teratomous cysts within the vertebral canal: observations on the occurrence of sex chromatin. J Neurol Neurosurg Psychiatry 25:159, 1962. 6. Newcastle NB, Francoeur J: Teratomatous cysts of the spinal canal; with ‘‘sex chromatin’’ studies. Arch Neurol 11:91, 1964. 7. Rosenbaum TJ, Soule EH, Onofrio BM: Teratomatous cyst of the spinal canal. Case report. J Neurosurg 49:292, 1978. 8. Luks FI, Paepe ME, DiLorenzo M, et al.: Tailgut remnant—or teratoma? Eur J Pediatr Surg 3:182, 1993. 9. Deogaonkar M, Goel A, Pandya SK: Thoracic intradural anterior epidermoid manifesting as sudden onset of paraplegia—case report. Neurol Med Chir 35:678, 1995. 10. Cokca F, Meko O, Arasil E, et al.: An intramedullary dermoid cyst abscess due to Brucella abortus biotype 3 at T11-L2 spinal levels. Infection 22:359, 1994. 11. Roth M, Hanak L, Shroder R: Intramedullary dermoid. J Neurol Neurosurg Psychiatry 29:262, 1966. 12. Shamoto H, Yoshida Y, Shirane R, et al.: Anterior sacral meningocele completely occupied by an epidermoid tumor. Childs Nerv Syst 15: 292, 1999. 13. Manno NJ, Uihlein A, Kernohan JW: Intraspinal epidermoids. J Neurosurg 19:754, 1962. 14. Sheehan JP, Sheehan JM, Lopes MB, et al.: Thoracic diastematomyelia with concurrent intradural epidermoid spinal cord tumor and cervical syrinx in an adult. Case report. J Neurosurg 97:231, 2002. 14a. Song JH, Kim MH, Shin KM: Intraspinal epidermoid cyst occurring 15 years after lipomyelomeningocele repair. Case report. J Neurosurg 90 (suppl 2):252, 1999. 15. Potgieter S, Dimin S, Lagae L, et al.: Epidermoid tumors associated with lumbar punctures performed in early neonatal life. Dev Med Child Neurol 40:266, 1998. 16. Kazan S, Ozdemir O, Akyuz M, et al.: Spinal intradural arachnoid cysts located anterior to the cervical spinal cord. Report of two cases and review of the literature. J Neurosurg 91:211, 1999.

Definition

An extradural cyst is a cyst that lies outside the dura and whose wall most closely resembles that of normal dura.28 Diagnosis

These cysts characteristically present with increasing spastic paraplegia in the adolescent or young adult. As is true for many cystic intraspinal lesions, the course may be intermittent and lead to misdiagnosis. Variation in size due to periodic drainage and expansion that may occur through a ‘‘ball valve’’ mechanism may be significant in this regard. Takahashi et al.29 described a man who presented with a spastic paraplegia and hypesthesia below T11-T12. His history was that 29 years prior he had a gait disturbance and severe bilateral lower limb paralysis that resolved over a period of 3 years. The cysts are almost always in the middle to lower thoracic spine, and the paresis is related to the level of compression. Pain may be totally absent and is rarely a prominent complaint.28 The fact that most of these cysts extend over several vertebrae may provide a clue to the diagnosis on plain spinal radiographs, where the interpedicular distance may be widened and the pedicles atrophied and flattened over an extended portion of thoracic spine. Chynn28 has emphasized the need to compare the interpedicular distances with the normal curve of relative widths for the particular region of the spine. Relative rather than absolute measurements may be of diagnostic significance. Epiphysitis and exaggerated posterior convexity of the contiguous vertebral bodies may also be seen. Kyphosis is a common pretreatment accompanying feature and has been hypothesized to be due to compromised venous drainage because of pressure from the cyst.30 Although the differential diagnosis includes several of the cysts already discussed, including neurenteric, the extent of the changes over the spine and the absence of associated spinal malformations may suggest the diagnosis. Equivalent changes may also be seen in chronic intramedullary glioma and in syringomyelia.28 Myelography will demonstrate the extradural block to cerebrospinal fluid, but specific diagnosis requires that the patient be placed in a supine position to allow filling through the dorsal connection to the subdural area. MRI should be well-adapted to the definition of this lesion.

Prognosis, Treatment, and Prevention

As with other spinal cysts, the prognosis for symptomatic relief following surgical removal of the cyst is good. The size of extradural cysts may necessitate quite extensive laminectomy for their removal and thus place the adolescent or young adult at risk for progressive kyphosis. It has been suggested that a brace be used as prophylaxis postoperatively.28 References (Intraspinal Cysts)

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17. Inoue H, Nishinaka K, Urushitani M, et al.: A case of thoracic extradural arachnoid cyst presenting with slowly progressive muscle weakness in the right upper and lower limbs. Rinsho Shinkeigaku 36:47, 1996. 18. Martin G: Spinal cord herniation into an extradural arachnoid cyst. J Clin Neurosci 7:330, 2000. 19. Sundaram M, Awwad EE: Magnetic resonance imaging of arachnoid cysts destroying the sacrum. AJR Am J Roentgenol 146:359, 1986. 20. Kunz U, Mauer UM, Waldbaur H: Lumbosacral extradural arachnoid cysts: diagnostic and indication for surgery. Eur Spine J 8:218, 1999. 21. Kasantikul V, Shuangshoti S, Pattanaruenglai A, et al.: Intraspinal melanotic arachnoid cyst and lipoma in neurocutaneous melanosis. Surg Neurol 31:138, 1989. 22. Holmes G, Wines N, Ryman W: Giant congenital melanocytic nevus and symptomatic thoracic arachnoid cyst. Australas J Dermatol 42:124, 2001. 23. Tsugu H, Fukushima T, Oshiro S, et al.: A case report of caudal regression syndrome associated with intraspinal arachnoid cyst. Pediatr Neurosurg 31:207, 1999. 23a. Rabb CR, McComb JG, Raffel C, et al.: Spinal arachnoid cysts in the pediatric age group: an association with neural tube defects. J Neurosurg 77:369, 1992. 24. Fobe JL, Nishikuni K, Gianni MA: Evolving magnetic resonance spinal cord trauma in a child: from haemorrhage to intradural arachnoid cyst. Spinal Cord 36:864, 1998. 25. Meier H, Chai CK: Spasticity, an hereditary neurological mutation in the mouse characterized by vertebral arthropathy and leptomeningeal cyst formation. Exp Med Surg 28:24, 1970. 26. Gomez-Escalionilla Escobar CJ, Gimenez Torres MJ, Garcia Morales MJ, et al.: Intradural spinal arachnoid cyst associated with Noonan’s syndrome. Rev Neurol 32:833, 2001. 27. Alvisi C, Cerisoli M, Guilioni M, et al.: Long-term results of surgically treated congenital intradural spinal arachnoid cysts. J Neurosurg 67:333, 1987. 28. Chynn KY: Congenital spinal extradural cyst in two siblings. Am J Roentgenol Ther Nucl Med 101:204, 1967. 29. Takahashi H, Taniguchi M, Ota T, et al.: Congenital extradural cyst causing a 30-year history of myelopathy with long term remission. No Shinkei Geka 21:443, 1993. 30. Cloward RB, Bucy PC: Spinal extradural cysts and kyphosis dorsalis juvenitis. Am J Roentgen Radiat Ther 38:681, 1937. 31. Brice G, Mansour S, Bell R, et al.: Analysis of the phenotypic abnormalitiesinlymphodema-distichiasis syndromein74patientswithFOXC2 mutations or linkage to 16q24. J Med Genet 39:478, 2002.

17.4 Syringomyelia Definition

Use of the terms syringomyelia and hydromyelia continues to be inconsistent, but new understanding of the pathogenesis of syrinx cavities has led to significant changes in the definitions used in this subsection. Major pathologic and clinical contributions have been made by Milhorat et al.,1,2 and Klekamp has provided an invaluable summary of both historical and current concepts.3 Syringomyelia refers to any expansion of the central canal, whether or not it is accompanied by expansion into the parenchyma of the spinal cord. It can be considered communicating syringomyelia (CS) when it connects directly with, almost always, a hydrocephalic ventricular system and noncommunicating syringomyelia (NCS) when there is an interposed segment of closed central canal between the syrinx and the ventricles. Extracanalicular syringomyelia has been suggested for the parenchymal syrinx that has no connection to an expanded central canal.1 Myelomalacia (myelomalacic syrinx) seems more appropriate because it is consistent with the finding that these lesions are virtually always in the watershed regions and are secondary to direct spinal cord injury.

This type of syrinx will not be considered further here. The term hydromyelia arose from the concept that increased intraventricular pressure was transmitted to the spinal cord, causing expansion of the central canal. Current evidence is that this does not occur and, therefore, the term should be abandoned. Diagnosis

Although the central canal is usually a small vestigial structure, it usually remains patent, at least through the upper and the middle cord. Occasionally at autopsy it may be judged to be excessively dilated in an otherwise asymptomatic individual. It is important not to erroneously ascribe neurological symptoms to small (1– 5 mm), slitlike, central syrinx cavities that remain stable over time and likely represent benign remnants of the central canal that are visible in some adults.4 Careful evaluation will provide an alternate explanation for the symptoms in a high percentage of cases. Symptomatic syringomyelia is highly correlated with the presence of abnormalities of the posterior fossa, such as Arnold-Chiari (AC) types I and II, Dandy-Walker cyst, and other posterior fossa cysts,1,2,5 and with abnormalities of the spinal cord, including cord tethering and spinal cord tumors. Thus, the cord abnormality may be found at the time of investigation of symptoms due to the associated intracranial or spinal anomalies (see separate entries for details of presentation). However, especially with respect to AC I, it is often the onset of signs ascribable to the syringomyelia that leads to the diagnosis of the posterior fossa malformation. CS and NCS differ with respect to the underlying etiology and their presentation of clinical signs.1,2 CS is accompanied by hydrocephalus, including that seen in association with Chiari II and meningomyelocele. In the latter, the cerebellar herniation may compress the upper end of the syrinx-ventricular system connection. The syrinx tends to be longer in younger patients where it may involve the length of the cord (holocord). This likely relates to the relative patency of the central canal that becomes increasingly ablated with age. Holocord CS commonly connects to an associated myelomeningocele, and this association may relate to a very early disturbance in cerebrospinal fluid (CSF) flow. Progressive scoliosis is the most common clinical sign in patients who have syringomyelia associated with a meningomyelocele.6 CS is much less likely (<5%) than NCS (~45%) to have an associated parenchymal (paracentral) extension, and this provides an explanation for the differing clinical presentation. Of 28 patients studied by Milhorat et al.2 whose syrinx was limited to an expansion of the central canal, 16 (57%) were asymptomatic and the syrinx was often a serendipitous finding at cranial magnetic resonance imaging (MRI). The remaining patients had bilateral, nonspecific findings such as long tract signs, spastic weakness, segmental pain, or problems with balance. Cranial nerve and segmental motor signs were absent. NCS is most often associated with Chiari I anomalies, stenosis of the cervical canal, spinal arachnoiditis, and basilar impression. The fact that it most often presents in adulthood may relate to the timing of disturbance to CSF flow due to the causative factors and the degree of ablation of the central canal that is present in adults and prevents connection to the ventricular system. It is not uncommon for the paracentral extension to connect through the pia at the dorsal root entry zone.1 The paracentral extensions that often accompany NCS are lined by simple glial tissue and show evidence of destruction of grey matter, loss of myelinization, fat-laden macrophages, and Wallerian degeneration. Undoubtedly, this associated pathology provides much of the explanation for the greater likelihood that

Spinal Cord

NCS will present signs specific to the level, laterality, and quadrant of the cavitation. Only four of 36 (11%) patients with NCS and extension studied by Milhorat et al.2 were asymptomatic. Cranial nerve signs were present in a significant proportion, and long tract signs, pain, sensory disturbance, segmental weakness, and muscular atrophy were common. The typical clinical course is protean with long delays and frequent misdiagnosis as other neurodegenerative disorders. Standard cranial computed tomography (CT) may delay the diagnosis because the upper cord is not examined, the presence of AC I may be overlooked, and the diagnosis of a syrinx is missed.7 More liberal use of MRI should lead to earlier diagnosis before classic signs and symptoms have been longstanding. There is probably no significant difference in the prevalence between males and females.1,2,7 Syringomyelia is a progressive condition, and the specific signs and symptoms and their degree of asymmetry vary with both the level and lateral location of the lesion and its duration.6,8 The spectrum of signs and symptoms in NCS and myelomalacia are similar, and distinction is on the basis of history and imaging studies.2 Common presenting symptoms are gait disturbance and combined motor weakness and sensory change.8 Less often, scapular winging, torticollis, and movement disorders such as athetosis and dystonia are present.9,10 Complaints include leg stiffness and leg and hand weakness. The most frequently noted signs are sensory disturbances that, in the case of dissociated sensory loss, may be relatively specific for syringomyelia. Scoliosis may be an early manifestation that may precede motor and sensory signs, and it is common by the time of diagnosis. Motor paresis is virtually limited to the upper limb and is often asymmetric. Weakness with lower motor neuron involvement is an early sign of syringomyelia and is usually accompanied by muscle wasting, even in cases in which paresis has not been noted.11 Lower motor neuron compromise may lead to loss of deep tendon reflexes in the upper limbs, while they may be increased, notably in the lower extremities, by involvement of the pyramidal tracts. Severe progression may be evidenced by a spastic paraplegia of the lower limbs, and destruction of anterior horn cells may produce fasciculations. Involvement of intercostal, diaphragmatic, and abdominal muscles is uncommon. Although not often present until 2 to 3 years or more after onset of the syrinx, dissociated sensory loss, where there is a discrepancy in the degree or level of loss of the different sensations, is a significant indicator of syringomyelia. Diminished pain and temperature sensations most often present in a bilateral, asymmetric, segmental fashion that usually affects the cervical and upper thoracic dermatomes. The severity of pain versus temperature impairment may vary between dermatomes. Damage to the anterolateral tract may cause a funicular pattern of sensory loss. Paresthesias characterized by complaints such as numbness, tingling, and other unusual or unpleasant sensations may predate onset of motor or sensory loss over the same distribution. Pain described as tearing and burning may at times be intense and, like paresthesia, may forebode a period of rapid deterioration. It is the second most common presenting complaint, occurring in 18–65% of patients, and is often cervical or suboccipital.8 Pain may also occur secondary to arthropathy and its related degenerative changes. Touch and position sense may also be involved. The lack of normal sensation may lead to a variety of types of painless trauma, including burns, freezing, and fractures, with their consequent scarring and deformity. Autonomic disturbances are common and include hyperand hypohidrosis, bladder and gastrointestinal dysfunction, which

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may affect various levels, and vasomotor instability. The vascular problems are of particular note, as they may lead to trophic changes in the skin, bone, and joints. Soon after onset the hands may be cold and cyanotic; with progression they become edematous and hyperhidrotic and show disturbed nail and skin growth, infections, and other degenerative changes that may progress to the point of phalangeal resorption.11 Osteoporosis with fractures that may heal poorly, orthostatic hypotension, and neurogenic arthropathies, including those of the spine, have also been common. Such chronic changes are less often seen with earlier diagnosis and management. Signs of brainstem involvement are present in a significant minority of patients and may result from posterior fossa compression as well as specific syringobulbia.2,6 This usually occurs later in the course of the disease and most often involves the nuclei of the lower cranial nerves, particularly the trigeminal,8 because of the upper cervical extension of its sensory nucleus. Rarely, a patient may present with isolated cranial nerve involvement. Dissociated sensory disturbance is again typical and may be accompanied by nystagmus, atrophy, and various trophic changes of the face. In a series of 275 patients with hindbrain-related syringomyelia, 14% had ocular symptoms that included diplopia, oscillopsia, tunnel vision, and problems with lateral gaze.12 Clinical examination demonstrated nystagmus, strabismus, pale discs, anisocoria, ptosis, and visual field defects. Isolated syringobulbia is rare. Some patients note an exacerbation of clinical signs with certain head or neck movements or with increases in intraabdominal pressure,3 and occasionally the presentation is acute.13 Syringomyelia of the lower spinal cord may be seen in association with a tethered cord, but the lesion itself is generally asymptomatic.1,2 Standard radiographs may show widening, or relative widening, of the involved cervical canal and demonstrate malformations of the skull base or upper cervical vertebrae that are associated with, but not pathognomonic of, posterior fossa malformations. The clinical presentation of a patient may be very characteristic of syringomyelia, but further diagnostic studies are required to confirm and establish the extent of the syrinx and to look for associated pathology. The changes on electromyography will depend on the state of progression and may be nonspecific.14 Early one may see decreased action potential with maximal exertion and signs of early anterior horn cell loss. Later denervation leads to fewer action potentials of increased size and duration, and eventual fasciculation with increased potentials may be recorded. Common findings include continuous, spontaneous motor unit activity, synchronous motor unit potentials, long latency responses, myokymic discharges, and respiratory synkinesis,14and several authors have proposed that there is a basic underlying increased excitability of spinal motor neurons.10,14 Posterior tibial somatic evoked potentials (SEP) are more sensitive than median nerve SEP,15 and cortical and cervical evoked potentials are abnormal in a high proportion of patients, even in the absence of a clinical motor deficit. Trigeminal SEP are abnormal in up to 85% of patients with a high cervical syrinx.15 Cutaneous, and the later portion of mixed nerve, silent periods may be absent or shortened, and comparison of the two sides may distinguish cases with a unilateral paracentral expansion.16 MRI is noninvasive and well-suited to defining the size and extent of the syrinx (Fig. 17-4). In a study of 58 patients with both CS and NCS, Sherman et al.17 found that from one to 20 segments were involved (average ¼ 7), and the syrinx had a diameter of 2 to 15 mm (average ¼ 6 mm). Gliosis is often associated with syringomyelia, probably as a reaction to the expanding lesion, and is well-seen as an increased signal intensity on T2 weighted images. A sign common in patients with communicating syrinx and that may be absent in cases

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Neuromuscular Systems

Certain genetic conditions, for example, neurofibromatosis or Von Hippel Lindau syndrome, may be susceptible to the development of a syrinx because of their propensity to develop posterior fossa or high cervical cord tumors. Given the strong association between syringomyelia and abnormalities of the posterior fossa, there is the potential for a syrinx to complicate any syndrome with AC I anomalies or posterior fossa cysts. Dilation of the central canal may occur in 20–25% of patients with meningomyelocele, and up to half of those may present with progressive symptoms.24 The etiology of the syrinx in Down syndrome is unknown, but it might relate to chronic subclinical cervical cord trauma associated with the atlanto-odontoid instability seen in 10–20% of cases. Symptomatic syringomyelia appears to be a relatively uncommon finding in the syndromes listed in Table 17-1. Etiology and Distribution

Fig. 17-4. Sagittal magnetic resonance imaging scan of a patient with idiopathic communicating syringomyelia who presented with neck pain. Arrow points to dilated central canal.

associated with tumors is the CSF flow void sign. This relates to a loss of signal intensity due to pulsatile movement of the CSF within the cavity, and it was present in all but very narrow lesions. Modified MRI techniques, such as three-dimensional constructive interference in a steady state18 (CISS) and spatial modulation magnetization19 (SPAMM) have been advocated as providing, respectively, better resolution of syrinx detail and prediction of postsurgical outcome. Notwithstanding the ability of defining the spinal level of the syrinx, its diameter, the degree of cord atrophy, the amount of gliosis, the presence of septa, and the loss of subarachnoid space, CT-myelography may still be required in some cases to demonstrate the cause of the obstruction to CSF flow.20 The differential diagnosis of syringomyelia includes amyotrophic lateral sclerosis, peripheral neuropathy, spinal cord tumors, multiple sclerosis, muscular dystrophy, spinal muscular atrophy, degeneration of the cervical spine with radicular changes, and traumatic lesions of the peripheral nerves. Confusion is more likely early in the disease before the appearance of sensory dissociation. Amyotrophic lateral sclerosis and peripheral neuropathies may tend to be more diffuse in their involvement, and nerve conduction studies may be of particular value in the latter. There have been sufficient case reports to suspect a true association between multiple sclerosis and syringomyelia.21 Williams et al.22 found that with MRI a combination of distinct margins and a uniform signal intensity equivalent to CSF was most useful in distinguishing syringomyelia from intramedullary tumors, but at times MRI will fail to identify a tumor or a syrinx will be mistaken for a tumor.23

Communicating syringomyelia is an uncommon lesion that, based on data from a number of published series, appears to account for about 0.4% of admissions to neurologic services.10 Prevalence estimates prior to the introduction of MRI will have significantly underascertained cases. Syringomyelia is associated with a wide variety of abnormalities of the posterior fossa including AC I, AC II, Dandy-Walker, arachnoid cysts, and fibrous dysplasia, as well as postinfectious and surgical arachnoid scarring, congenital scoliosis, and tethering of the cord. Attempts to explain the pathophysiology of syringomyelia date to 1700 and have been reviewed recently by Klekamp.3 Failure to distinguish posttraumatic myelomalacia has added confusion over the years. An early idea that gained some dominance was that increased intracranial pressure, often secondary to a posterior fossa abnormality, caused the CSF to enter the central canal via the obex. Thus, occlusion of the obex became part of the successful treatment of AC I-associated syrinx, and animal models of syringomyelia were produced by occluding all outlets to the fourth ventricle. However, against this explanation are the facts that blocking the obex it not a necessary part of treating the syrinx and that pressure within the syrinx exceeds intraventricular pressure, even in the presence of hydrocephalus. Furthermore it does not readily account for NCS. Williams41 proposed that a ball valve obstruction, operating with intermittent marked increases in subarachnoid pressure due to actions such as Valsalva or coughing, led to a syrinx, but generally neuropathologic examination does not show evidence of any such mechanism. There is growing acceptance that syringomyelia is the secondary result of associated anomalies that obstruct the CSF flow and/or cause spinal cord tethering and a resultant disturbance of extracellular fluid (ECF) dynamics locally within the extracellular space (ECS) of the spinal cord. Klekamp3 provides an analysis of current research and a synthesis of current thinking. CSF normally flows from the spine in the direction of the ventricles and at a decreasing rate as one descends the cord. The intramedullary ECS and the subarachnoid space (SAS) form a continuum separated by the slowly permeable, metabolically active ependyma and the pia, which is wellfenestrated and allows the free passage of fluid from the ECS to the SAS. It has been shown that spinal edema is removed by a gradient of flow from the ECS to the SAS. Arachnoid scarring results in a decreased clearance of spinal edema through its effect on CSF flow, and by increasing SAS and ECS pressures it can result in the accumulation of edema. There is evidence that ECF flow is in part mediated through systolic and diastolic pressures, respectively, toward the SAS and ependyma, and that cord blood flow and SAS pressures can influence each other. Flexion and extension of a tethered spinal cord

Spinal Cord

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Table 17-1. Syndromes in which syringomyelia has been reported Causation Gene/Locus

Syndrome

Prominent Features

Carbohydratedeficient-glycoprotein III-like25

Joint, distal extremity; nail and skin anomalies. Neurodevelopmental anomalies, frontal lobe atrophy, elevated CH transferrins, no mutations in CDGS-1

Unknown

Cleidocranial dysplasia26

Disordered formation of membranous bones, increased skull AP diameter, large fontanelles, prognathism, malar flatness, dental anomalies, partial to complete absence of clavicles. Syrinx rare

AD (119600) Transcription factor, CBFA1, 6p21

Down27

A number of variations in brain anatomy, to which syringomyelia seems not related in pathologic studies

Trisomy 21

Facio-auriculovertebral28

Asymmetric hypoplastic ears with preauricular tags, macrostomia, epibulbar dermoids, cardiac and cervical spine anomalies. Case report with syrinx

AD (164210) most sporadic, 14q32

Familial spinal arachnoiditis29

Bandlike fibrous thickening of spinal arachnoid leads to progressive spastic paraplegia, numbness

AD (182950)

Fischer-Volavsek30

Sparse scalp hair, eyelashes, and eyebrows; abnormal nails; palmoplantar hyperhidrosis; eyelid edema; occasional mental retardation

AD

Hajdu-Cheney31

Coarse face, short neck, hirsutism, lax joints, acroosteolysis, bathrocephaly, vertebral anomalies, normal intelligence. CNS includes hydrocephalus (7/49) and syringomyelia (2/49)

AD (102500)

HypopituitaryArnold-Chiari IIsyringomyelia32

Small pituitary, invisible pituitary stalk, breech presentation, Arnold-Chiari I, syringomyelia

Possible birth injury

Joint-skin laxity and Dandy-Walker33

Dandy-Walker, joint and skin laxity with dystrophic scaring. Delayed hydrocephalus, contractures, syringomyelia

AR ?

Maroteaux-Lamy MPS VI34

Dysostosis multiplex, corneal clouding, prolonged normal intellect, allelic variability

AR (253200) Arylsulfatases B, ARSB, 5q11

Myotonic dystrophy35

Myotonia, muscle wasting greatest distally, cataracts, premature balding, cardiac conduction defects

AD (160900) Protein kinase, DMPK, 19q13.2

Nager36

Marked micrognathia, malar hypoplasia; limb anomalies include absent radius, radioulnar synostosis, hypo/aplastic thumbs; heterogeneity possible

AD (154400)

Neurocutaneous melanosis37

Numerous and/or large congenital pigmented nevi, meningeal pigmentation, high risk of malignancy and death in childhood

Sporadic (249400)

Noonan38

Short stature, ptosis, hypertelorism, downslanting palpebrae, fleshy rotated ears with prominent lobule, pectus, pulmonic stenosis, webbed neck, intellectual impairment variable

AD (163950) PTPN11, 12q24.1

Trichorhinophalangeal39

Sparse hair, pear-shaped nose with bulbous tip, notched alae, tapering fingers, coned epiphyses, prominent ears. Variable with size of microdeletion

AD (190350) Zinc finger protein, TRPS1, 8q24.12

Van Buchem40

Osteosclerosis of skull, mandible, clavicles, ribs, and diaphyses of long bones, variable cranial nerve compression. Onset at puberty

AD (239100) 17q11.2

can alter the intramedullary pressures in the absence of a CSF flow abnormality, unlike the situation for a freely mobile cord. The theory is that an impediment to clearance of ECF into the SAS causes dilation of perivascular channels, an increase in ECF volume, and ultimately the development of the syrinx. The fact that a significant proportion of syrinxes break through to the SAS supports the view and observations that intrasyrinx pressure exceeds that within the SAS. Presumably, whether the syringomyelia is a CS or a NCS and the degree to which the paracentric area versus the central canal is involved would depend upon local factors, such as the degree of ablation of the central canal. Understanding the pathophysiology is crucial to selecting appropriate treatment approaches, and more research is needed to test aspects of this theory. Genetic factors appear to play a minor role, if any, and there are very few well-documented instances of familial syringomyelia. Apparent dominant and recessive inheritances have been reported.42

Prognosis, Treatment, and Prevention

Any attempt to assess the prognosis for patients with syringomyelia is complicated by a number of factors. Series often lump myelomalacia and syringomyelia; the underlying etiologies and treatments vary; cases are ascertained at different ages and in different ways; the duration of symptoms and the length of postintervention follow up are variable; and the level, severity, and type (CS versus NCS) are not always considered. It seems logical that minimal signs of short duration due to a readily treatable cause and with no or minimal paracentral expansion and medullary destruction will have a superior outlook. In assessing prognosis it is important to exclude adults with a nonpathologic remnant central canal.4 Schliep11 found that about one-half of 79 patients who were studied showed chronic progression, one-fourth showed static and progressive phases, and 2% improved and 22% remained unchanged for up to 15 years.

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About one-half of 55 untreated patients followed by Boman and Livanaine43 showed significant periods of stability. However, 20% of their patients had died at a mean age of 47 years, and only 25% were able to continue working. A significant proportion (~30%) of patients with AC I-associated syringomyelia do undergo spontaneous resolution of the syrinx and its associated signs, both neurologic and musculoskeletal, and this correlates with a milder disability at presentation, rounded lower edges of the cerebellar tonsils, mild tightness of the foramen magnum, and elevation of the cerebellar tonsils over time.44 Milhorat et al.45 concluded that patients with syrinx pressures greater than 7.7 cm of H2O had more rapidly progressive symptoms and showed greater postoperative improvement but were more likely to suffer dysesthetic pain after surgery. Specialized MRI studies of CSF movement may also provide some prediction of postsurgical outcome.19 Patients with longstanding syringobulbia are at significant risk for potentially lethal disturbances of respiratory function during sleep. Dysphagia and dysphonia may be predictive.46 The differing spectrum of etiologies and a higher frequency of CS may partly explain the milder symptomatology at diagnosis and generally better prognosis in children. The assessment of treatment outcomes is complicated by many of the same factors that bedevil an understanding of prognosis. Favorable short-term results may not be borne out over time. Belief that pressure from the ventricular system into the central canal plays a role in causation has influenced the approach to treatment. Traditional approaches have been to drain the syrinx, often using tissue or other materials to block the obex, and in the presence of hydrocephalus to drain the ventricular system. Kruse et al.47 have suggested that careful intraventricular pressure measurement, lumboventricular or intraventricular perfusion studies, and measurement of CSF outflow resistance may identify a subgroup of patients with impaired CSF absorption who may benefit from ventriculoperitoneal shunting. There is evidence that patients who undergo plugging of the obex may experience greater postoperative morbidity and mortality.48 Drainage techniques, to some extent directed to the underlying pathology, have included terminal ventriculostomy, which involves transverse section of the filum terminale, syrinx-subarachnoid shunting, and syrinx-peritoneal shunting. A proportion of patients will report some initial subjective improvement after simple terminal ventriculostomy, but most will deteriorate later.49 There is a growing consensus that surgical efforts should be directed at establishing a normal CSF flow.20 However, in the presence of hindbrain abnormalities, posterior fossa decompression that usually includes a suboccipital craniectomy and cervical laminectomy of C1 and C2 may be inadequate on its own to prevent further deterioration. This led a number of groups to use the newer plastics and microsurgical techniques to carry out syrinx to subarachnoid space shunting as a primary treatment.6,50 Hemirather than complete laminectomy may reduce the risk of neurologic damage at the time of shunt placement. However, even with current surgical approaches to shunting, a significant proportion of patients (up to 50%) will experience complications, such as shunt failure, that lead to recurrent expansion of the syrinx.51 There are some convincing data from patients with postinfectious arachnoiditis or arachnoid webs to the effect that, if the primary cause of abnormal CSF flow can be identified and corrected, patients will do better than if treated by shunting.20,52 Patients with syringomyelia associated with meningomyelocele should be considered separately. In general, symptoms correlate with the extent and severity of the syrinx.24 In a series of 1195 patients, 231 had an MRI because of progressive neurologic

deterioration, 112 of these were found to have a syrinx, and 45 were considered to have severe syringomyelia that required treatment.53 The authors drew a number of conclusions from a careful evaluation of outcomes related to the initial symptomatology, the type of lesion (holocord versus segmental), and the interventions that had occurred. It is important to ensure normal ventriculoperitoneal shunt functioning prior to any surgery, because some children will respond to simple shunt revision and because failure to do so prior to decompressing the posterior fossa can result in serious complications. Algorithms were derived for treatment of patients depending upon symptoms and type of syrinx. Briefly, those presenting with signs of upper cord compression should have a posterior fossa decompression; those with bowel, bladder, or lower limb signs a cord detethering; those with a holocord syrinx and mixed signs a cavity shunt; and those with a segmental syrinx and mixed signs a detethering procedure. In patients who have occult spinal dysraphism, the syrinx tends to be found distal to a lipoma and responds to untethering of the cord.54 There does not appear to be a good argument for shunting procedures in these cases. Operative mortality is less than 5% in most current series and is due to respiratory failure, hematoma formation, acute hydrocephalus, and infarction of the posterior cerebellar artery.6 Aseptic meningitis, bradycardia, apnea, and respiratory dysfunction may occur but should not have long-term consequences. Some authors advocate cesarean section for women with syringomyelia on the grounds that pressure changes during delivery may lead to progression of the syrinx. MRI can be used to document resolution of the cavity and selectively to follow patients for recurrence before they become symptomatic. Levy et al.55 reviewed the results of treatment of 648 cases and found that 46% had improved, 32% were stable, and 20% had progressed. However, there is a need to rule out late-onset deterioration through follow-up of a series in which the syrinx has been decompressed successfully and has remained so. There does not appear to be an evident method for primary prevention of syringomyelia. Given the association with AC I, patients with this diagnosis should be investigated for syrinx and treated before they are symptomatic. However, the majority of patients with AC I do not develop syringomyelia, and treatment is not be indicated in the absence of a cavity. References (Syringomyelia) 1. Milhorat TH, Capocelli AL Jr, Anzil AP, et al.: Pathological basis of spinal cord cavitation in syringomyelia: analysis of 105 autopsy cases. J Neurosurg 82:802, 1995. 2. Milhorat TH, Johnson RW, Milhorat RH, et al.: Clinicopathological correlations in syringomyelia using axial magnetic resonance imaging. Neurosurgery 37:206, 1995. 3. Klekamp J: The pathophysiology of syringomyelia—historical overview and current concept. Acta Neurochir (Wien) 144:649, 2002. 4. Holly LT, Batzdorf U: Slitlike syrinx cavities: a persistent central canal. J Neurosurg 97:161, 2002. 5. Banna M: Syringomyelia in association with posterior fossa cysts. AJNR Am J Neuroradiol 9:867, 1988. 6. Isu T, Iwasaki Y, Akino M, et al.: Hydrosyringomyelia associated with a Chiari I malformation in children and adolescents. Neurosurgery 26:591, 1990. 7. Cahan LD, Bentson JR: Considerations in the diagnosis and treatment of syringomyelia and the Chiari malformation. J Neurosurg 57:24, 1982. 8. Wisoff JH: Hydromyelia: a critical review. Childs Nerv Syst 4:1, 1988. 9. Hill MD, Kumar R, Lozano A, et al.: Syringomyelic dystonia and athetosis. Mov Disord 14:684, 1999.

Spinal Cord 10. Nogues MA, Leiguarda RC, Rivero AD, et al.: Involuntary movements and abnormal spontaneous EMG activity in syringomyelia and syringobulbia. Neurology 52:823, 1999. 11. Schliep G: Syringomyelia and syringobulbia. In: Handbook of Clinical Neurology, vol 32. Congenital Malformations of the Spine and Spinal Cord. PJ Vinken, GW Bruyn, eds. North Holland, Amsterdam, 1978, p 255. 12. Rowlands A, Sgouros S, Williams B: Ocular manifestations of hindbrainrelated syringomyelia and outcome following craniovertebral decompression. Eye 14:884, 2000. 13. Meves SH, Postert T, Przuntek H, et al.: Acute brainstem symptoms associated with cervical syringomyelia. Eur Neurol 43:47, 2000. 14. Nogues MA, Stalberg E: Electrodiagnostic findings in syringomyelia. Muscle Nerve 22:1653, 1999. 15. Emery E, Hort-Legrand C, Hurth M, et al.: Correlations between clinical deficits, motor and sensory evoked potentials and radiologic aspects of MRI in malformative syringomyelia. 27 cases. Neurophysiol Clin 28:56, 1998. 16. Stetkarova I, Kofler M, Leis AA: Cutaneous and mixed nerve silent periods in syringomyelia. Clin Neurophysiol 112:78, 2001. 17. Sherman JL, Barkovich AJ, Citrin CM: The MR appearance of syringomyelia: new observations. AJR Am J Roentgenol 148:381, 1987. 18. Hirai T, Korogi Y, Shigematsu T, et al.: Evaluation of syringomyelia with three-dimensional constructive interference in a steady state (CISS) sequence. J Magn Reson Imaging 11:120, 2000. 19. Lee SK, Chung TS, Kim YS: Evaluation of CSF motion in syringomyelia with spatial modulation magnetization (SPAMM). Yonsei Med J 43:37, 2002. 20. Mallucci CL, Stacey RJ, Miles JB, et al.: Idiopathic syringomyelia and the importance of occult arachnoid webs, pouches and cysts. Br J Neurosurg 11:306, 1997. 21. Iwasaki Y, Ikeda K, Ichikawa Y, et al.: Multiple sclerosis and syrinx formation. Acta Neurol Scand 101:346, 2000. 22. Williams AL, Haughton VM, Mojunas KW, et al.: Differentiation of intramedullary neoplasms and cysts by MR. AJR Am J Roentgenol 149:159, 1987. 23. Sridhar K, Ramamurthi R, Vasudevan MC: Isolated eccentric syrinx of the conus medullaris simulating a tumor. Br J Neurosurg 13:423, 1999. 24. Caldarelli M, Di Rocco C, La Marca F: Treatment of hydromyelia in spina bifida. Surg Neurol 50:411, 1998. 25. Stibler H, Gylje H, Uller A: A neurodystrophic syndrome resembling carbohydrate-deficient glycoprotein syndrome type III. Neuropediatrics 30:90, 1999. 26. Dore DD, MacEwen GD, Boulos MI: Cleidocranial dysostosis and syringomyelia. Clin Orthop 214:229, 1987. 27. Hunter AGW: Down syndome. In: Management of Genetic Syndromes, ed 2. SB Cassidy, JE Allanson, eds. John Wiley and Sons, New York, 2005, p 191. 28. Inci S, Saglam S: Syringohydromyelia as a complication of Goldenhar syndrome. Childs Nerv Syst 11:708, 1995. 29. Nagai M, Sakuma R, Aoki M, et al.: Familial spinal arachnoiditis with secondary syringomyelia: clinical studies and MRI findings. J Neurol Sci 177:60, 2000. 30. Freire-Maia N, Pinheiro M: Ectodermal Dysplasias: A Clinical and Genetic Study. Alan R Liss, New York, 1984, p 117. 31. Ramos FJ, Kaplan BS, Bellah RD, et al.: Further evidence that the Hajdu-Cheney syndrome and the ‘‘serpentine fibula-polycystic kidney syndrome’’ are a single entity. Am J Med Genet 78:474, 1998. 32. Fujita K, Matsuo N, Mori O, et al.: The association of hypopituitarism with small pituitary, invisible pituitary stalk, type I Arnold-Chiari malformation and syringomyelia in seven patients born in breech presentation: further proof of the birth injury theory on the pathogenesis of ‘‘idiopathic hypopituitarism.’’ Eur J Pediatr 151:266, 1992. 33. McKee SA, Barnicoat A, Fryer A, et al.: Joint laxity with Dandy-Walker malformation and contractures: a distinct recessive syndrome? Clin Dysmorphol 20:177, 2002. 34. Hite SH, Krivit W, Haines SJ, et al.: Syringomyelia in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): imaging findings following bone marrow transplantation. Pediatr Radiol 27:736, 1997.

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35. Levisky RB, Vianna-Morgante AM, Frota-Pessoa O, et al.: Myotonic dystrophy, syringomyelia, and 2/3 translocation in the same family. J Med Genet 14:51, 1977. 36. Groeper K, Johnson JO, Braddock SR, et al.: Anaesthetic implications for Nager syndrome. Paediatr Anaesth 12:365, 2002. 37. Peters R, Jansen G, Engelbrecht V: Neurocutaneous melanosis with hydrocephalus, intraspinal arachnoid collections and syringomyelia: case report and literature review. Pediatr Radiol 30:284, 2000. 38. Finsterer J: Holocord syringomyelia and the dominant feature in Noonan’s syndrome. Eur Neurol 44:181, 2000. 39. Momeni P, Glockner G, Schmidt O, et al.: Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Nat Genet 24:71, 2000. 40. Prabhu N, Joeph S, Gupta A, et al.: Syringomyelia with Van Buchem disease. AJNR Am J Neuroradiol 18:393, 1997. 41. Williams B: Progress in syringomyelia. Neurol Res 8:139, 1986. 42. Busis NA, Hochberg FH: Familial syringomyelia. J Neurol Neurosurg Psychiatry 48:936, 1985. 43. Boman K, Livanaine M: Prognosis of syringomyelia. Acta Neurol Scand 43:61, 1967. 44. Sudo K, Tashiro K, Miyasaki K: Features of spontaneous improvements in syringomyelia with low situated cerebellar tonsils. Acta Neurol Belg 93:279, 1998. 45. Milhorat TH, Capocelli AL, Kotzen RM, et al.: Intramedullary pressure in syringomyelia: clinical and pathophysiological correlates of syrinx distension. Neurosurgery 41:1102, 1997. 46. Nogues M, Gene R, Benarroch E, et al.: Respiratory disturbances during sleep in syringomyelia and syringobulbia. Neurology 52:1732, 1999. 47. Kruse A, Rasmussen G, Borgesen SE: CSF-dynamics in syringomyelia: intracranial pressure and resistance to outflow. Br J Neurosurg 1: 477, 1987. 48. Matsumoto T, Symon L: Surgical management of syringomyelia— current results. Surg Neurol 32:258, 1989. 49. Williams B, Fahy G: A critical appraisal of ‘‘terminal ventriculostomy’’ for the treatment of syringomyelia. J Neurosurg 58:188, 1983. 50. Padovani R, Cavallo M, Gaist G: Surgical treatment of syringomyelia: favourable results with syringosubarachnoid shunting. Surg Neurol 32:173, 1989. 51. Batzdorf U, Klekamp J, Johnson JP: A critical appraisal of syrinx cavity shunting procedures. J Neurosurg 89:382, 1998. 52. Parker F, Aghakhani N, Tadie M: Non-traumatic arachnoiditis and syringomyelia. A series of 32 cases. Neurochirurgie 45(suppl 1):67, 1999. 53. La Marca F, Herman M, Grant JA, et al.: Presentation and management of hydromyelia in children with Chiari type-II malformation. Pediatr Neurosurg 26:57, 1997. 54. Koyanagi I, Iwasaki Y, Hida K, et al.: Surgical treatment of syringomyelia associated with spinal dysraphism. Childs Nerv Syst 13:194, 1997. 55. Levy WJ, Mason L, Hahn JF: Chiari malformation presenting in adults: a surgical experience in 127 cases. Neurosurgery 12:377, 1983.

17.5 Split Cord Malformation (Diastematomyelia) and Diplomyelia Definition

Diastematomyelia derives partly from the Greek root diastema, which means split or fissure and in the strict sense refers to a split of the spinal cord. Diplomyelia derives from the Greek diplo, meaning double, and therefore describes a true duplication of the spinal cord. In practice, the terms have often been used interchangeably, and this has led to some confusion in the literature. Variations in the definition of diplomyelia have also appeared in the literature.

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Giordano et al.1 refer to a ‘‘more or less perfect duplication of the spinal cord without the presence of bony septal division,’’ whereas Wolf et al.2 consider it a variant of diastematomyelia in which ‘‘the spinal cord remains divided caudal to the diastematomyelia spur.’’ Hori et al.3 considered diplomyelia as an isolated additional accessory spinal cord that is usually located anteriorly or posteriorly and not laterally to the normal cord. This latter situation appears to be very uncommon in humans but is typical of several of the T It-complex mutations on chromosome 17 of the mouse.4 The current trend is to use the term split cord malformation (SCM)5 to replace the terms diastematomyelia and diplomyelia. However, the malformations described by Pang et al.,5,6 and indeed almost all such anomalies, are characterized by the presence of some form of median partition. SCM I lesions are defined as two hemicords, each in their own dura and separated by a rigid osteocartilaginous median septum. In SCM II the two hemicords are within a single dural tube and are separated by a nonrigid fibrous median septum. To this author it seems reasonable to use this terminology for these types of malformations (Fig. 17-5), thus replacing the term diastematomyelia, but to retain the term lateral-diplomyelia for the very uncommon occurrence of parallel cords in the absence of any median septum. Ventraldiplomyelia would be applied to the rare malformation as described by Hori et al.3 Diagnosis

SCM may occur in association with additional malformations of the nervous system and, depending on their location and type, may lead to secondary degenerative changes not directly related to the specific local malformation. Although the frequency of SCM in patients with open neural tube defects (NTD) has varied significantly between series,6–8 recognition of this association is important to the surgeon treating patients with spina bifida. However, SCM may also present with clinical signs due to intrinsic cord malformation at the site of the lesion. The great majority of SCM are lumbar, with cervical and thoracic lesions being uncommon and sacral anomalies very rare.6,8 Cervical anomalies may be seen in association with Arnold-Chiari malformation and with the KlippelFeil malformation, especially when associated with synkinesis.1,9,10 In common with other manifestations of the occult spinal dysraphism spectrum, SCM shares a female preponderance and is frequently accompanied by dorsal, midline, cutaneous signs such as hypertrichosis, hemangiomas, lipomas, dermal sinuses, and atretic meningoceles. Cutaneous signs were found in 92% of patients reported by Pang et al.6 and in 69% of those who did not have an associated meningomyelocele reported by Ersahin et al.8 A patch of hypertrichosis is the most common finding. It is hoped that awareness of the cutaneous stigmata suggestive of an underlying neurologic anomaly will lead to an increased proportion of presymptomatic diagnosis of SCM. Most patients who become symptomatic will do so in childhood, although increasingly, adult cases are being recognized.2,6 There is no significant difference between SCM I and SCM II in the type of presentation. Progressive sensorimotor deterioration, including paraparesis and bladder and bowel dysfunction, is the most common presentation in childhood. Orthopedic deformities may include pes cavus, pes valgus, calcaneovarus, trophic ulcers, and leg atrophy. A significant minority of children have pain6; scoliosis, which may be congenital, is common.8 In about half of cases, significant asymmetry of the neurologic/orthopedic signs will provide a clue to the specific diagnosis of SCM.6 Sometimes one of the hemicords ends in a myelomeningocele or may be affected by

Fig. 17-5. Metrizamide-enhanced computed tomography scans of spine showing normal cord (A) that widens asymmetrically (B) and splits into two unequal parts (C). (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

an epidermoid cyst and thus results in paralysis of the ipsilateral limb.2 The median bony spur or fibrocartilaginous band may compromise the width of the spinal canal. Upper and lower motor neuron signs, probably due to compression against the central spur, may be seen in association with severe scoliosis. Pain is a more common presenting sign in adults, and adults can also be expected to show progression of neurologic signs. Presumably, they have grown with a tenuous balance between the abnormal cord within its distorted bony skeleton and the common associated lesions that put them at risk for tethered cord. At some point, because of either trauma or degenerative changes,

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there is a decompensation and onset of neurologic complaints. Some cases may be incidental findings at autopsy. Wolf et al.2 have suggested that upper and lower motor neuron signs and leg pain with a completely normal contralateral leg is highly suggestive of SCM in the adult. Some abnormality of the spine is apparent on plain radiographs in virtually all cases of SCM (Fig. 17-6). Single or multiple vertebral segments may be involved. The most common signs (seen in >10% of cases) in descending order of frequency include bifid lamina, increased interpedicular distance, a bony median septum, scoliosis, bifid vertebra, and blocked vertebrae.8 Hillal et al.11 have stated that the combination of occult spina bifida and vertical fusion of the lamina over two or more adjacent segments is highly suggestive of SCM. Myelography with the patient in both the prone and supine positions has been the traditional confirmatory diagnostic tool, and the need to document the position of the conus medullaris, especially in lumbar lesions, has been stressed (Fig. 17-7). Metrizamide-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) have supplanted this technique (Fig. 17-6), although there is some opinion that thin-cut axial CT6and CT-myelography8 provide better specific delineation of the malformation than does MRI. When present, a spina bifida is usually found below the level of the septum. Each hemicord will usually have its own dural covering, but in some cases the split cord is contained within a single tube. Such patients may have ectopic dorsal nerve roots. The halves of the cord are often asymmetric and rotated through 908 so that the anterior columns are in apposition. The halves of the cord may be very dysplastic in cases associated with meningomyelocele. Rare cases of SCM involving the cervical cord and basicranium and

Fig. 17-6. Plain radiograph of lumbosacral spine showing abnormal widening, associated hemivertebrae, and fusion of pedicles, as well as bony spur (arrow). (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

Fig. 17-7. Myelogram in the same patient shown in Figure 17-5 showing defect of split cord malformation spur at level of L4 and low level of cord with nerve roots continuing to come off to the level of the defect.

dividing the brainstem, cerebellum, and cord have been reported,10 as has duplication of the pituitary and cervical cord.12 In diplomyelia the two cords have their own pia-arachnoid and dura, separate central canals, and well-developed anterior and posterior horns. Distinction should be drawn between SCM and dimelia, which represents a duplication of the cord as a component of partial twinning.3,13 Cases of minimal partial twinning should be distinguishable by the presence of other evidence of partial duplication, which may be limited to the vertebral axis itself. Etiology and Distribution

If one excludes cases associated with meningomyelocele, then SCM appears to be uncommon. Although no estimates of prevalence could be found, it likely accounts for less than 5% of various closed spinal malformations. There is no universally accepted pathogenetic explanation for SCM. Klessinger and Christ grouped the theories into three categories.14 Group 1 is disorders of neurulation and includes ‘‘overconvergence’’ of neural folds that each fuse to the dorsal surface of the plate, thus forming two tubes; overgrowth of the basal plate of the neural tube; and a hydromyelic, secondary opening of the neural tube. Group 2 attributes SCM to duplication or splitting of the notochord; group 3 to abnormalities in separation of the germ

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layers during gastrulation. The latter includes putative endodermalectodermal adhesions, abnormal formation of paired notochordal and neuroepithelial cells that form two cords, and abnormalities related to the neurenteric canal—largely based upon the concurrence of SCM with neurenteric cysts (Section 17.2). Those authors14 introduced a quail somite into the closed neural tube of chicks, but, while they were able to mimic some of the components of SCM, the model did not create the full spectrum of SCM, suggesting an earlier embryologic origin. Emura et al.15 induced SCM, very like that seen in humans, in a newt model by producing a dorsal midline fistula in the neural plate. While the known association of SCM and meningomyelocele might suggest a common origin, the fact that the spina bifida is generally below the level of the SCM raises the possibility that the SCM interferes with caudal neural tube closure. Genetic factors and teratogens do not appear to play a significant role in the development of this malformation, although three sets of affected sisters have been reported.16 Prognosis, Treatment, and Prevention

In the absence of associated life-threatening or handicapping anomalies, SCM carries a good prognosis for normal intellect and survival, although permanent, often asymmetric, disability may occur as described in the discussion of diagnosis. At the outset, these reflect the intrinsic abnormality of the cord, but it is very important to recognize that progressive neurologic deterioration may occur because of tethering of the cord, progressive scoliosis with entrapment of a hemicord against the midline septum, or the similar impact of degenerative spinal changes. There is no evidence that treatment can reverse signs that are due to intrinsic abnormality of the cord or those that are acquired and are long standing. However, with extremely low mortality and little morbidity, surgical treatment appears to prevent further deterioration and may allow reversal of some neurologic deficit that is of recent onset.8 It may also provide relief of radicular pain. Ongoing orthopedic treatment may be required, particularly for the management of scoliosis, which is very common, and for leg and foot deformities. Treatment requires laminectomy with excision of the septum and complete freeing of the cord, and intradural exploration is needed to remove the dural septum in the case of duplex tubes. Fat and/or fibrous tissue may obstruct the approach. Attention must be paid to the possibility of an associated tethered cord that must be treated; Ersahin et al.8 explored the filum for tethering even when the MRI does not show thickening. The fact that symptomatic individuals are significantly older than those who are asymptomatic supports surgical treatment of children at the time of diagnosis in the hope of preventing future neurologic impairment. Asymptomatic adults, or those with long-standing and stable signs, might reasonably be followed with close periodic neurologic evaluation. Surgical treatment of the diastematomyelia should always antedate treatment of scoliosis in order to prevent further compromise of the cord. References (Split Cord Malformation [Diastematomyelia] and Diplomyelia) 1. Giordano GB, Davidovits P, Cerisoli M, et al.: Cervical diplomyelia revealed by computed tomography (CT). Neuropediatrics 13:93, 1982. 2. Wolf A, Bradford D, Lonstein J, et al.: The adult diplomyelia syndrome. Spine 12:233, 1987. 3. Hori A, Fischer G, Dietrich-Schott B, et al.: Dimyelia, diastematomyelia, diplomyelia. Clin Neuropathol 1:23, 1982.

4. Cogliatti SB: Diplomyelia: caudal duplication of the neural tube in mice. Teratology 34:343, 1986. 5. Pang D, Dias MS, Ahab-Barmada M: Split cord malformation: part I: a unified theory of embryogenesis for double split cord malformations. Neurosurgery 31:451, 1992. 6. Pang D. Split cord malformation: part II: clinical syndrome. Neurosurgery 31:481, 1992. 7. Emery JL, Lendon RG: The local cord lesion in neurospinal dysraphism (meningomyelocele). J Pathol 110:83, 1973. 8. Ersahin Y, Mutluer S, Kocaman S, et al.: Split spinal cord malformations in children. J Neurosurg 88:57, 1998. 9. Keim HR, Greene AF: Diastematomyelia and scoliosis. J Bone Joint Surg 55A:1425, 1973. 10. Herman TE, Siegel MJ: Cervical and basicranial diastematomyelia. AJR Am J Roentgenol 154:806, 1990. 11. Hillal SK, Marton D, Pollack E: Diastematomyelia in children. Radiology 112:609, 1974. 12. Roessmann U: Duplication of the pituitary gland and spinal cord. Arch Pathol Lab Med 109:518, 1985. 13. Prevot J, Guerot S, Metaizeau JP, et al.: Duplication comple´te du rachis lombo-sacre´. A propos d’un cas. Chir Pediatr 25:87, 1984. 14. Klessinger S, Christ B: Diastematomyelia and spina bifida can be caused by the intraspinal grafting of somites in early avian embryos. Neurosurgery 39:1215, 1996. 15. Emura T, Asashima M, Furue M, et al.: Experimental split cord malformations. Pediatr Neurosurg 36:229, 2002. 16. Balci S, Caglar K, Eryilmaz M: Diastematomyelia in two sisters. Am J Med Genet 86:180, 1999.

17.6 Myelocystocele Definition

A myelocystocele is a closed neural tube defect composed of localized extreme enlargement of the central canal (hydromyelia) that produces a fluid-filled sac, covered by meninges (a meningocele) and normal skin, that protrudes between the defective dorsal dura and spinal processes.1 It is most commonly located at the end of the neural tube, where it is trumpet shaped and referred to as a terminal myelocystocele.2 Occasionally, the meningocele is anterior and can herniate through a sacral laminar defect. Diagnosis

The most likely presentation of a myelocystocele is as a mass that is usually visible at birth and characteristically lies within, and obliterates, the gluteal cleft. The marked expansion of the central canal is presumably an early developmental anomaly arising after neural tube closure but before most of the cellular development of the spinal cord has occurred. Thus, there are not the signs of cord disruption seen in syringomyelia. In addition, unlike a typical myelomeningocele, where the nerves traverse the cavity and are subject to entrapment and damage, the spinal nerves simply pass around the swelling.1 Thus, neurologic signs and symptoms may be initially minimal or absent.3,4 Terminal myelocystoceles are more common than those of the upper spine. The swelling may be small to massive and is most likely to be mistaken for a sacrococcygeal teratoma. Superficial signs of occult dysraphism may be present. Motor and sensory deficits related to the lower spine are sometimes present at birth or may appear later and progress. In some cases a small mass may be overlooked, and in the absence of initial neurologic impairment, the diagnosis may be delayed. Terminal myelocystocele is significantly associated with malformations of the OEIS complex: a caudally located ‘‘pseudo’’

Spinal Cord

omphalocele, cloacal exstrophy, imperforate anus, and spinal malformations.5,6 In many cases where myelocele has been reported in association with these types of malformations, specific studies to distinguish myelocele from myelocystocele have not been reported.4,5 One of 20 patients reported by Byrd et al.6 had a Chiari II malformation, but this does not appear to be a common concurrence in terminal myelocystocele. However, eight of their patients had a Chiari I anomaly. Of 29 patients reported in two recent series, four had hydrocephalus and three cervicothoracic hydromyelia— common enough to suggest a true association. The pathologic anatomy of the terminal myelocystocele is quite complex. There is a closed spina bifida containing a meningocele that is lined by arachnoid and is continuous with the subarachnoid space (Fig. 17-8). The spinal cord extends low in the vertebral column, and the hydromyelic component crosses the meningocele, passing through it at a point where the arachnoid is reflected back against the spine, and then flares out into a second large cyst distal to the meningocele. The rostral end of the myelocystocele is continuous with the central canal. There is an ependymal lining throughout that is usually surrounded by attenuated neural and glial elements. The cyst may be surrounded by fibrolipomatous tissue in the subcutaneous region. The spinal cord and meninges are anchored at the point of their posterior herniation by a fibrous band across the most cranial split lamina of the spine.4 There have been relatively few reports of myelocystoceles of the cervicothoracic cord.3,4,7,8 The initial sign may be a swelling over the spine, which may gradually increase in size. Dorsal skin anomalies, typical of occult spinal dysraphism, may be present. A

Fig. 17-8. Line drawing representing a myelocystocele. A. Meningocele. B. Terminal cyst. C. Dorsal spina bifida. D. Fibrous band. E. Subarachnoid space. F. Central canal.

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Chiari II malformation is often associated.7,8 Routine radiographs will reveal a spina bifida, and the precise nature of the lesion can be elucidated by magnetic resonance imaging (MRI). In this location the connection of the subcutaneous swelling to the expanded central canal may be narrow and become completely obstructed. Notwithstanding such an apparent block, the mass may continue to expand slowly3; this patient had mature, pedunculated, ectopic cerebellar tissue on the ventral floor of the central canal at the site of the myelocystocele. Lassman et al.9 recognized a mild form of lumbar hydromyelia and spina bifida in which only the attenuated dorsal wall of the cord actually enters the meningocele. This so-called myelocystomeningocele is perhaps similar to the cervicothoracic myelocystoceles that have been described.3,7,8 Standard radiographs of the spine will demonstrate the distal spina bifida (which occasionally extends rostrally as high as the lower thoracic vertebrae), as well as a variety of additional anomalies including everted and/or hypoplastic laminae, variable sacral agenesis, fused and hemivertebrae, and rotation of the distal spine. The spinal canal will tend to be wide in the transverse and narrow in the sagittal plane.4 The cysts may be outlined with ultrasound, but MRI is considered the most precise diagnostic tool.6 Etiology and Distribution

Myelocystocele is a rare, sporadic lesion with no known familial recurrence. Lemire and Beckwith10 found 11 cases among 144 (7.6%) skin-covered lumbosacral masses. However, no cases were included among 173 additional patients summarized from previous papers, thus giving an overall rate of only 3.5% of such masses. This is equivalent to the 4% frequency noted by McLone and Naidich.4 Although early reports suggested an excess of affected white males,4 the recent series have shown a predominance of females.5,6 The embryology of the neural tube was discussed in some detail in the section on neural tube defects and will not be repeated here. The important point from the perspective of the terminal myelocystocele is that it occurs in a region that appears analogous to the zone of canalization in experimental animals, a region where the spinal cord is laid down as a solid structure derived from the caudal cell mass. The cells in this area become polarized in a dorsoventral direction; several small lumina form and then coalesce into a single central canal as the cells bridging the lumina lose their connections.11 Presumably, at some point after neural tube closure there is some obstruction to the flow of cerebrospinal fluid (CSF) up the spine, which therefore dilates the terminal ventricle. The expansion would then disrupt the dorsal mesenchyme secondarily, while the ectoderm remains intact, thus explaining the closed spina bifida and the myelocele.4 Increasing expansion would flare the rostral spinal cord and extend the cyst caudally. Tibbles and Wiley12 exposed Syrian hamsters and CD-1 mice to vitamin A at the critical time for neural tube closure. Within 18 hours, they observed distortion of the neural folds at the level of the caudal neuropore, vascular damage with hematoma formation, anomalies of the notochord, and defective secondary neurulation. There was no detectable difference between the species, and yet spina bifida occurred in the mice and myelocystocele in the hamsters. The authors postulated that the findings might relate to the known differences in the somite level of the posterior neuropore at the time of closure in the two species and the relative contribution of the tail region to the ultimate spinal cord. The association with the OEIS complex is presumably related to the intimate contact of this portion of the neural tube and cells destined to form the urogenital and hindgut regions.

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The cervical myelocystocele reported by Suneson and Kalimo3 contained structures resembling choroid plexus. Thus, a possible mechanism for expansion of the canal would be ectopic CSFsecreting tissue that remains active at a time when the distal and proximal central canal has become vestigial. Prognosis, Treatment, and Prevention

As discussed, many children are born without neurologic deficit, whereas others may have sensory and/or motor impairment. In some cases such signs may progress so that early treatment is advocated. Treatment has sometimes resulted in improvement, while generally there is simply stabilization of signs. Unlike the case with classic neural tube defects, there is no association with intracranial anomalies, and the expectation should be for normal intellectual development. In children with various manifestations of the OEIS complex, the prognosis may be affected by those anomalies that may be lethal in some cases and in any case will require extensive operative treatment and care. Byrd et al.13 reported that all 15 of their patients, many of whom had the OEIS complex, were neurologically intact, whereas all the patients reported by Choi and McComb5 had significant impairment. It is not clear why there is such a disparity between these two reports, although it may relate to differences in ascertainment and the severity of the associated closed spinal dysraphism reported in the more recent series. Treatment is surgical and requires careful dissection to the level of the spinal cord through the meningocele, with care taken to avoid nerve roots that exit the cord, traverse the meningocele, and reenter the spinal canal.4,6 The cyst may be opened distal to the last nerve roots and partially resected before closing the spinal canal and reconstructing the meninges and subarachnoid space. Although there has been some suggestion that either isolated myelocystocele or the OEIS complex may be associated with certain teratogen exposures, the human data are anecdotal and the majority of cases give no such history of exposure. Thus, there is no primary means of prevention. Genetic counseling may provide reassurance, as there have been no intrafamilial recurrences. Myelocystocele has been identified, although not specifically diagnosed, on prenatal ultrasound. The diagnosis may be considered if very low cystic spinal lesions are noted on prenatal ultrasound. A normal amniotic fluid a-fetoprotein level would indicate a lower likelihood of an open neural tube defect, but definitive distinction from a closed spina bifida likely remains a diagnostic challenge. It should be considered when a caudal mass is observed in a patient with prenatally diagnosed OEIS complex.14 References (Myelocystocele) 1. Warkany J: Congenital Malformations. Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 279. 2. Peacock WJ, Murovic JA: Magnetic resonance imaging in myelocystoceles. J Neurosurg 70:804, 1989. 3. Suneson A, Kalimo H: Myelocystocele with cerebellar heterotopia. J Neurosurg 51:392, 1979. 4. McLone DG, Naidich TP: Terminal myelocystocele. Neurosurgery 16:36, 1985. 5. Choi S, McComb JG: Long-term outcome of terminal myelocystocele patients. Pediatr Neurosurg 32:86, 2000. 6. Byrd SE, Harvey C, McLone DG, et al.: Imaging of terminal myelocystoceles. J Natl Med Assoc 88:510, 1996. 7. Nishino A, Shirane R, So K, et al.: Cervical myelocystocele with Chiari II malformation: magnetic resonance imaging and surgical treatment. Surg Neurol 49:2679, 1998.

8. Steinbok P, Cochrane DD: The nature of congenital posterior cervical or cervicothoracic midline cutaneous mass lesions. Report of eight cases. J Neurosurg 75:206, 1991. 9. Lassman LP, James CCM, Foster JB: Hydromyelia. J Neurol Sci 7: 149, 1968. 10. Lemire RJ, Beckwith JB: Pathogenesis of congenital tumors and malformations of the sacrococcygeal region. Teratology 25:201, 1982. 11. Klika E, Jelinek R: The structure of the end and the tail bud of the chick embryo. Folia Morphol 17:29, 1969. 12. Tibbles L, Wiley MJ: A comparative study of the effects of retinoic acid given during the critical period for inducing spina bifida in mice and hamsters. Teratology 37:113, 1988. 13. Byrd SE, Harvey C, Darling CF: MR of terminal myelocystoceles. Eur J Radiol 20:215, 1995. 14. McLaughlin JF, Marks WM, Jones G: Prospective management of exstrophy of the cloaca and myelocystocele following prenatal ultrasound recognition of neural tube defects in identical twins. Am J Hum Genet 19:721, 1984.

17.7 Anterior and Lateral Meningoceles Definition

Anterior and lateral meningoceles are occult protrusions of the meninges beyond the normal confines of the spinal canal. In one of the two distinct types there is a true anterior spinal dysraphism; in the other, which is highly associated with neurofibromatosis and Marfan syndrome, there is an anterolateral herniation through a normal or enlarged intervertebral foramen or intervertebral space. Diagnosis

With few exceptions, these lesions do not produce any external signs of their presence. The diagnosis rests on a high index of suspicion when confronted by signs and symptoms due to pressure that may cause pain or dysfunction of contiguous structures, perhaps due to gradual expansion of the lesion. The specific presentation, as well as the relative proportion of dysraphic versus the herniation type of lesion, is highly dependent on the level of the spinal cord that is involved. The anterior sacral meningocele is generally a true dysraphic condition and is accompanied by a bony anomaly of the anterior sacrum that ranges in severity from complete sacrococcygeal agenesis, usually sparing S1 and S2, to simple enlargement of the intervertebral foramen. In some cases a lateral defect in the sacrum produces a radiographic appearance reminiscent of a scimitar (Fig. 17-9).1 Other spinal malformations such as hemivertebrae or posterior spina bifida may accompany an anterior sacral meningocele. However, while a posterior sacral defect is common, it is rare to find an associated intrasacral meningocele or a posterior sacral meningocele.1 From their extensive review of the literature, Wilkins and Odum found that 52% of sacral meningoceles were on the right and 36% were on the left; the remainder were midline.1 This malformation generally presents as a space-occupying lesion that compresses the rectum, bladder, and uterus. The most common presentation is that of problems with defecation, followed by urinary frequency or obstruction and dystocia.1 It is an uncommon but important cause of constipation in childhood. Low back or pelvic pain is seen in about one-fourth and abdominal pain in one in eight cases. Radicular pain may be seen in about one in 10 patients, but sensory and motor disturbances are quite uncommon. Uncommon presentations include perianal

Spinal Cord

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Fig. 17-9. Anteroposterior radiograph of the pelvis of a patient with a 6-month history of constipation and an anterior sacral meningocele, illustrating the scimitar sign. (Courtesy of the Department of Radiology, Children’s Hospital of Eastern Ontario.)

abscess,2 rectal fistula,3 and recurrent meningitis.4 In 14 of 122 cases reviewed by Wilkins and Odum,1 the patient presented with an abdominal mass, whereas five had been found to have a rectoanal or pelvic mass and three a gluteal mass. The latter results from extension through the greater sciatic foramen. However, in virtually all cases, rectal or vaginal examination will reveal a mass. A number of patients complain of headache associated with maneuvers, such as Valsalva or direct pressure on the meningocele during rectal or vaginal examination, that increase cerebrospinal fluid (CSF) pressure. Typical anterior sacral meningocele has been reported in neurofibromatosis and Marfan syndrome. Associated genital and anal malformations are common and include anal atresia/stenosis, bicornuate or double uterus and vagina, duplex kidney and/or collecting system, and presacral tumors including teratomas, epidermoids, and dermoids. The diagnosis of anterior sacral meningocele is highly probable in the patient who presents with a presacral mass that is palpable on rectovaginal examination and is associated with radiographic anomalies of the spine. However, bony sacrococcygeal anomalies may occur alone and other presacral lesions including duplication cysts, neurenteric anomalies, cystic sacrococcygeal teratoma, anal duct or gland cyst, necrotic rectal leiomyosarcoma, extraperitoneal adenomucinosis, cystic lymphangioma, necrotic sacral chordoma, and tailgut cyst, are included in the differential diagnosis.5 Myelography with delayed films to allow contrast to enter the meningocele if the stalk is narrow has proven a reliable diagnostic approach (Fig. 17-10), but has largely been replaced by magnetic resonance imaging (MRI) that provides good definition of the lesion and its connection to the spinal canal, and of any tethering of the cord.6 The lumbar spine is a very uncommon site, and almost all cases have involved lateral protrusion through an intervertebral foramen. Half the lesions have been small herniations found in association with neurofibromatosis. As such they simply represent the lower limit of the more common thoracic distribution of these lesions.7 The remaining cases have been larger and presented as abdominal masses that may displace intestinal organs, and are found in association with additional congenital anomalies including vertebral defects, Arnold-Chiari malformation, hydromyelia, polydactyly, and concurrent posterior meningocele.1 A true anterior meningocele protruding through a defective vertebral body is very

Fig. 17-10. Lateral view of myelogram in a patient with an anterior meningocele showing extension of the subarachnoid space to the distal sacrum and protrusion forward to the region of a retrorectal mass.

rare in the lumbar spine, but may be suspected when a typical ‘‘butterfly’’ vertebral body, or defective pedicle, is seen on plain film and can be confirmed by computed tomography (CT) or MRI examination.8 The overwhelming majority of anterolateral thoracic meningoceles appear to represent herniations of the arachnoid and dura mater through intervertebral or intravertebral foramina. These lesions tend to continue to expand over time and are rarely detected in childhood. Fully two-thirds of reported cases have been complications of neurofibromatosis.6 A minority of cases appear to represent true congenital malformations. These cases are not associated with neurofibromatosis and are generally anterior protrusions that may be found in children with additional vertebral, rib, and other malformations.1 Multiple, bilateral, lateral meningoceles are the defining feature of the lateral meningocele syndrome (Table 17-2), and they have been reported rarely as an isolated finding.10 Large pseudomeningoceles may be acquired following brachial plexus injury or avulsion.11 About 40% of the patients reviewed by Wilkins and Odum1 were asymptomatic, with a posterior mediastinal mass detected as an incidental finding on a chest radiograph taken for other purposes. When symptomatic, patients may complain of radicular chest or back pain, probably related to distortion of the adjacent intercostal nerves, pulmonary compromise, or irritation producing cough. Spontaneous hemothorax has also been reported.

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Neuromuscular Systems Table 17-2. Syndromes with anterior or lateral meningoceles as a feature Causation Gene/Locus

Syndrome

Prominent Features

Currarinocaudal triad23

Anal stenosis/ectopia/atresia, partial sacral agenesis with intact S1, anterior meningocele/teratoma/enteric cyst, constipation, neurogenic bladder, tethered cord

AD (176450) HLXB9, 7q36

Marfan13

Body disproportion due to long extremities, ectopia lentis, aortic dilation; up to two-thirds show widening of spine (especially L5–S1) and about one-fifth show more marked bony erosion or meningocele

AD (154700) FBN1, 15q21.1

Noonan21

Characteristic face, short stature, right–sided heart lesions, pectus excavatum, webbed neck, variable developmental delay, multiple bilateral thoraco-lumbar meningoceles similar to neurofibromatosis with combined phenotype have been reported

AD (193520) PTPN11, 12q24.1

Lateral meningoceleabnormal facies22

Narrow face, downslanting palpebrae, flattened maxilla, hypoplastic mandible, small pinnae, laxity, keloids, developmental delay, moderate increased bone density, wormian bones, abnormal sella and posterior fossa, small cerebral gyri and cerebellum, thoracolumbar meningoceles

AD (130720)

Kyphoscoliosis is a common associated finding and may be the presenting complaint. The meningocele generally exits at the convexity of the apex of the curve, and the majority occur at a single level, the specific location of which is evenly distributed along the thorax. The size of the mass may increase over time and cause erosion of the contiguous bony structures. Vessels and nerves may become stretched over its surface. The connection to the spine is usually by a narrow pedicle.1,9 There is a slight rightsided predominance for thoracic lesions, and about 60% have been reported in females, the latter perhaps reflecting a general greater connective tissue laxity. The majority of thoracic meningoceles are lateral and have been reported in patients with neurofibromatosis; therefore, the most important differential diagnosis is that of an hourglass neurofibroma, which can produce the same signs and symptoms. Neuroimaging techniques are required to make the distinction. In some cases a neuroma may be present within the meningocele. In addition, a number of retropleural intrathoracic tumors and cysts must be considered. In a patient with neurofibromatosis or evidence of congenital malformations of the axial skeleton, one should have a high index of suspicion and proceed first with neuroimaging rather than with techniques such as bronchoscopy. MRI should define the anomaly in most cases, and may be supplemented by CT or CT-myelography if the diagnosis is not clear. It should be pointed out that dysplastic dural and bony changes in the spine are extremely common in neurofibromatosis and do not necessarily predict the presence of a neurofibroma or meningocele.9 In their review of anterior and lateral meningoceles, Wilkins and Odum1 were unable to find any reports of lesions in the cervical region. They have been reported in neurofibromatosis,9 and Sharma and Newton12 reported one case of lateral cervical meningocele and were able to find one similar report in the literature. They suggested the differential diagnosis should include extradural cysts and cystic hygroma. Dural ectasia, specifically in the region of L5-S1, appears even more common in Marfan syndrome than in neurofibromatosis and was found in 63% of patients studied prospectively by Pyeritz et al.13 In 22% the ectasia was judged severe and included an undefined number of meningoceles, but only 3.5% of patients were symptomatic. No progression, as judged by CT scan, was seen in 15 patients followed from 2 to 5 years,13 and there appears to be a

growing consensus that asymptomatic patients with Marfan syndrome should be followed expectantly.14,15 Ahn et al.16 have produced radiologic criteria for the definition of ductal ectasia in Marfan syndrome. An unusual presentation is that of a ventral herniation of the spinal cord through what is assumed to be a congenital anterior dural ectasia/meningocele.17,18 Patients tend to present in middle age with longstanding, unexplained neurosensory signs, and to progress to a Brown-Sequard (hemicord) syndrome. The MRI shows an increased posterior subarachnoid space and a forward kinking of the cord into the defect. Etiology and Distribution

By any standard, anterior and lateral meningoceles of the type that represent the result of abnormal embryogenesis are uncommon malformations. Most are found in the sacral region, and Wilkins and Odum1 were able to find reports of 125 cases from 1837 to 1978 and to add one of their own. Two cases were associated with neurofibromatosis and one with Marfan syndrome. However, perhaps because of greater awareness and improved imaging techniques, reports of this lesion in Marfan syndrome are becoming more frequent. The lumbar region is an uncommon site and appears to form a transition between the predominantly malformative type of lesion seen in the sacrum and those of the thorax, which are usually of the small ectatic type. About one-half of lumbar anterior or lateral meningoceles have been reported in patients with neurofibromatosis, and most of the others have had associated malformations. Wilkins and Odum were able to find 97 cases of thoracic meningoceles in the literature and added three of their own. About two-thirds of the patients have had neurofibromatosis. True anterior lesions, usually with associated malformations, are unusual. As many anterior or lateral meningoceles may be small, and because they do not directly involve the neural tissue, they are often asymptomatic and are therefore probably significantly underascertained or, in the case of neurofibromatosis, misdiagnosed as neurofibroma. Meningoceles of the type reported with neurofibromatosis and Marfan syndrome are considered to be related to an underlying dural or bony dysplasia. Bony abnormalities are now recognized to be common primary abnormalities in neurofibromatosis, particularly in the thoracic spine, are unrelated to neurofibromas, and

Spinal Cord

include vertebral scalloping, enlarged foramina, and deformed pedicles and kyphosis. Similar thinning of the laminae and pedicles and erosion of the foramina are seen in Marfan syndrome, particularly in the region of L5-S1.13 These anomalies may be seen in the absence of meningoceles, but presumably provide a weak substrate through which protrusion occurs. Connective tissue weakness likely forms the basis for the changes in Marfan syndrome. Lateral meningoceles may also occur in the absence of any evident bony abnormality. Anterior meningoceles of the type more commonly seen in the sacrum result from a primary maldevelopment of the anterior spine and meninges. There is a consensus that the apparent female excess represents biased ascertainment because of repeated pelvic examinations, dystocia, or investigation of associated uterovaginal malformations. Many male patients may remain asymptomatic and undiagnosed. At least one-half of the cases can be identified as forming complete or partial Currarino caudal triad19 (Table 17-2) of anal anomalies, presacral cyst, and anterior meningocele. Sacral agenesis has been divided into five types20: (1) complete sacral agenesis missing some lumbar vertebrae, (2) complete sacral agenesis with no lumbar vertebrae missing, (3) subtotal sacral agenesis with S1 present, (4) hemisacrum, and (5) coccygeal agenesis. Type 4 is the only one showing familial occurrence, and it is the form seen in Currarino syndrome and in all patients with HLXB9 mutations. The expression of this syndrome is extremely variable, and it is important to evaluate family members with MRI or CT because bony sacral defects are not always present. It appears likely that most, if not all, reports of autosomal dominant anterior meningocele/sacral defect fall into the Currarino spectrum and are due to HLXB9 mutations.19 However, no HLXB9 mutation has been found in a significant proportion of sporadic patients with this triad, and the cause of these phenocopies is unknown. Prognosis, Treatment, and Prevention

Wilkins and Odum stress that an anterior or lateral sacral meningocele is one of the few truly correctable malformations of the central nervous system. Presentation is generally not related to the neurologic signs, and sensory or motor changes or bladder/bowel dysfunction are uncommon. However, failure to recognize the true nature of the lesion may lead to significant morbidity and even mortality related to aspiration or operation through an unclean anterior, abdominopelvic operative field with consequent meningitis. A staged approach with an earlier diversion colostomy should be considered to prevent such complications when dealing with the Currarino triad.23 Surgical repair can be undertaken by laminectomy, aspiration, and watertight closure of the stalk, if the lesion is small with a narrow pedicle. Closure by laparoscopy, and complete excision using a posterior sagittal approach, have been used. A retroanal or transabdominal approach may be complicated by frequent adhesions of the meningocele to the rectum and by epidural veins stretched over the sac. Wilkins and Odum1 advocate aseptic aspiration and simple sealing off of the pedicle and that the meningocele not be excised. The choice of surgical approach will depend upon the specific findings of the case and the preference of the surgeon. Symptomatic ‘‘ectatic’’ meningoceles may be treated by closure of the pedicle, usually with an anterolateral thoracotomy approach. Endoscopy has also been used. Excision of the sac is probably unnecessary and adds to the risk of nerve damage during the procedure. An anterior approach has been suggested if the meningocele is known to contain a neuroma. Patients have

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also been successfully treated by lumboperitoneal shunt procedures, and this may be the most practical approach when the lesions are multiple. There does not appear to be any means of primary prevention. Patients should receive genetic counseling, which should include evaluation of relevant family members for neurofibromatosis or components of the Currarino triad as appropriate to the circumstances. References (Anterior and Lateral Meningoceles) 1. Wilkins RH, Odum GL: Anterior and lateral spinal meningocele. In: Handbook of Clinical Neurology, vol 32. Congenital Malformations of the Spine and Spinal Cord. PJ Vinken, GW Bruyn, eds. North Holland, Amsterdam, 1978, p 193. 2. Buxton N, Bassi S, Firth J: Anterior sacral meningocele presenting as a peri-anal abscess. J R Coll Surg Edinb 47:582, 2002. 3. Fitzpatrick MO, Taylor WA: Multiple anterior sacral meningocele associated with a rectal fistula. Case report and review of the literature. J Neurosurg 91:124, 1999. 4. Funayama CA, De F Turcato M, Moura-Ribeiro R, et al.: Recurrent meningitis in a case of anterior sacral meningocele and agenesis of sacral and coccygeal vertebrae. Arq Neuropsiquiatr 53:799, 1995. 5. Dahan H, Arrive L, Wendum D, et al.: Retrorectal developmental cysts in adults: clinical and radiologic-histopathologic review, differential diagnosis, and treatment. Radiographics 21:575, 2001. 6. Lee SC, Chun YS, Jung SE, et al.: Currarino triad: anorectal malformation, sacral bony abnormality, and presacral mass—a review of 11 cases. J Pediatr Surg 32:58, 1997. 7. Miles J, Pennybacker J, Sheldon P: Intrathoracic meningocele: its development and association with neurofibromatosis. J Neurosurg Psychiatry 32:99, 1969. 8. Duffrin H, Auer R, Moolsintong P, et al.: MRI, CT and plain film appearance of anterior spina bifida. Magn Reson Imaging 5:499, 1987. 9. O’Neill P, Whatmore WJ, Booth AE: Spinal meningoceles in association with neurofibromatosis. Neurosurgery 13:82, 1983. 10. Chen SS, Shao KN, Feng RJ, et al.: Multiple bilateral thoracic meningoceles without neurofibromatosis: a case report. Zhonghua Yi Xue Za Zhi (Taipei) 61:736, 1998. 11. Hader WJ, Fairholm D: Giant intraspinal pseudomeningoceles cause delayed neurological dysfunction after brachial plexus injury: report of three cases. Neurosurgery 46:1245, 2000. 12. Sharma V, Newton G: Lateral cervical meningocele. J Korean Med Sci 7:179, 1992. 13. Pyeritz RE, Fishman EK, Bemhardt BA, et al.: Dural ectasia is a common feature of the Marfan syndrome. Am J Hum Genet 43:726, 1988. 14. Nallamshetty L, Ahn NU, Amn UM, et al.: Dural ectasia and back pain: review of the literature and case report. J Spinal Disord Tech 15:326, 2002. 15. Rigante D, Segni G: Anterior sacral meningocele in a patient with Marfan syndrome. Clin Neuropathol 20:70, 2001. 16. Ahn NU, Sponseller PD, Ahn UM, et al.: Dural ectasia in the Marfan syndrome: MRI and CT findings and criteria. Genet Med 2:173, 2001. 17. Hausman ON, Moseley IF. Idiopathic dural herniation of the thoracic spinal cord. Neuroradiology 38:503, 1996. 18. White BD, Firth J: Anterior spinal hernia: an increasingly recognized cause of thoracic cord dysfunction. J Neurol Neurosurg Psychiatry 57: 1433, 1994. 19. Kochling J, Karbasiyan M, Reis A: Spectrum of mutations and genotypephenotype analysis in Currarino syndrome. Eur J Hum Genet 9: 599, 2001. 20. Belloni E, Martucceillo G, Verderio D, et al.: Involvement of the HLXB9 homeobox gene in Currarino syndrome. Am J Hum Genet 66: 312, 2000. 21. Hughes, HE, Hughes RM, Summers A, et al.: Noonan syndrome and lateral meningoceles: another link with neurofibromatosis. Proc Greenwood Genet Center 6:159, 1986.

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22. Chen KM, Bird L, Barnes P, et al.: Lateral meningocele syndrome: vertical transmission and expansion of the phenotype. Am J Med Genet 133A:115, 2005. 23. Ilhan H, Tokar B, Atasoy MA, et al.: Diagnostic steps and staged operative approach in Currarino triad: a case report and review of the literature. Childs Nerv Syst 16:522, 2000.

17.8 Tailgut Cyst Definition

Tailgut cyst is a presacral, multilocular, mucous-secreting cyst, sometimes referred to as a retrorectal cystic hamartoma, found at a site distal to the normal embryonic termination of the hindgut.

Etiology and Distribution

In a series of 363 sacrococcygeal lesions, Bale1 reported that two (0.55%) were tailgut cysts. This is thus a rare malformation. It is not clear whether the female excess among reported cases is real or a bias of ascertainment due to presentation during childbirth and gynecologic examinations. The etiology is thought to be related to development of the caudal gut. During development, the ectoderm and endoderm (the future cloacal membrane) remain in intimate contact below the level of Hensen’s node. As the embryo folds inward during the 4th week, and thus encloses the future gut, the cloacal membrane comes to lie ventral and encloses the caudal portion that is distal to the eventual hindgut and is called the tailgut. This portion regresses by the 6th week and mucous-secreting remnants are believed to result in tailgut cysts.

Diagnosis

Small cysts may be an asymptomatic finding at autopsy or may be discovered during standard rectal or gynecologic examinations or childbirth. A case has been noted on prenatal ultrasound. Symptomatic patients typically present with a history of constipation, a feeling of fullness of the rectum, abdominal pain, anal or posteroanal fistula, or recurrent rectal abscess.1 A dimple or sinus is sometimes seen either within or immediately behind the anal verge and may connect by a fibrous cord to the underlying cyst. The differential diagnosis thus includes a precoccygeal dermoid cyst, rectal duplication cyst, anal gland cyst, anterior sacral meningocele, and cystic teratoma. Standard radiographs may reveal deformation of the coccyx, which in some cases is long and taillike. Ultrasound, including transrectal, computed tomography (CT), and magnetic resonance imaging (MRI) may be used to clarify the clinical diagnosis. The cysts are generally 2 to 5 cm in diameter and are multilocular or multicystic. There is no serosa or capsule, and the absence of structures suggestive of gut wall allows differentiation from a hindgut cyst. The epithelial lining varies in specific histology, and malignant transformation has been reported. There appears to be an association with bifid uterus, cervix, and vagina.1

Prognosis, Treatment, and Prevention

These cysts are often asymptomatic and do not produce neurologic signs. There are at least 15 reported cases of malignancy in tailgut cysts and, although there may be a significant reporting bias, it is recommended they be removed and undergo careful pathologic study when discovered.2,3 Most of the malignancies have been adenocarcinomas, but a neuroendocrine and a carcinoid tumor have been reported. Transabdominal and posterior parasacral surgical approaches have been used successfully. References (Tailgut Cysts) 1. Bale PM: Sacrococcygeal developmental abnormalities and tumors in children. Perspective Pediatr Pathol 8:9, 1984. 2. Prasad AR, Amin MB, Randolph TL, et al.: Retrorectal cystic hamartoma: report of 5 cases with malignancy arising in 2. Arch Pathol Lab Med 124:725, 2000. 3. Moreira AL, Scholes JV, Boppana S, et al.: p53 mutation in adenocarcinoma arising in a retrorectal cyst hamartoma (tailgut cyst): report of 2 cases—an immunohistochemistry/immunoperoxidase study. Arch Pathol Lab Med 125:1361, 2001.

18 Muscle Judith G. Hall

M

uscle is a quite unique organ within the body. It has the ability to produce movement and force in response to both internal and external stimuli. Changes in muscle mass and function have major influences on the structure of other tissues and organ systems during fetal life as well as throughout infancy and childhood. The volume and weight of muscle are related to its use postnatally; however, muscle normally represents about 55% of body weight. Muscle size is dynamic and can atrophy or hypertrophy depending on use. Muscle represents one of the largest and most distributed tissues in the body. Muscle tissue can have a variety of disturbances in its formation and morphogenesis, which lead to primary and secondary congenital anomalies. In addition, there are several types of muscle: voluntary, cardiac, and smooth muscle, as well as mixtures and transitions. This chapter will describe conditions with absence, hypoplasia, and hyperplasia of voluntary muscle, as well as localized abnormalities and variations in muscle and atavisms. Historically, a great deal of attention was paid to the dissection and description of human musculature, particularly voluntary muscles.1,2 The early anatomists and pathologists noted variations and anomalies. The mechanisms of embryology, physiology, and molecular biology were poorly understood at that time. The genetic mechanisms producing and maintaining muscle, as well as its interaction with other tissues, are just beginning to come to light.3 Much of the recent work has focused on degenerative muscle diseases, cell biology, and embryology. Knockout mice have been important in understanding the hierarchy of genes involved in muscle development and maintenance.4 Issues of dysmorphogenesis and interactions with other tissues have yet to be explored. The studies of patients with various syndromes usually overlook the musculature and rarely include careful dissection of muscles or detailed histologic, biochemical, and molecular examinations at autopsy. A great deal of work waits to be done both in the normal situation and in the abnormal, using imaging and in vivo measurements to study muscle activity. To appreciate the mechanisms underlying disorders of formation and maintenance of muscle, techniques such as functional magnetic resonance imaging (MRI), radionucleic tagging, functional molecular, and animal models The author acknowledges the important contributions of Hans U. Zellweger and James W. Hanson to the first edition of this text, which provided the basis of this chapter.

should be utilized in various syndromes to help inform both normal and abnormal muscle morphogenesis. Muscle can have both direct and indirect effects on the morphogenesis of the tissues. As muscle forms, it is quite clear that it interacts with the connective tissue, bones, and structures around the muscle fibers. The size and ultimate configuration of a specific muscle is determined after birth by its use at various ages. The dynamic forces of the muscle also affect the growth and the modeling of the bone to which it is attached, in response to use, trauma, and disuse. The craniofacial configuration is very much influenced by the use of facial muscles.5 During growth, long bones respond to increased muscular use by increased cortex or to decreased use by developing as long gracile structures. Although this chapter deals with congenital anomalies, bone shape and structure continues to be remodeled and repaired throughout life. The situations of muscle ‘‘disuse’’ during intrauterine life (fetal akinesia) clearly affect the development of bone in the fetus, and also affect other structures such as lung, gut, palate, and overall growth.6 During the embryonic and fetal development of the ear, muscles shape the cartilage; during development of the craniofacies, muscles affect the shape of the face; in utero, tongue and jaw movement affect interoral structures such as the palate and palatine ridges.6 There are developmental, functional disorders of muscle, which lead to secondary developmental abnormalities of the skeleton such as scoliosis and long bone bowing. Lack of movement related to loss of muscle function leads to reduced joint motion and abnormal joint surfaces. Contractures develop with disuse, which range in severity usually related to how long there has been decreased movement. Secondary webs of skin may develop across a joint with decreased movement if there is decreased movement of that joint during a time of long bone growth. Without normal fetal movement, normal flexion creases and normal contours of the limbs do not develop. Finally, it is important to note that there is a particularly integral relationship between muscle and the central nervous system during development. Abnormal central nervous system development can have a devastating impact on muscle development and function; vice versa, abnormal embryonic/ fetal muscle may lead to failure of the central nervous system neurons to mature.7 Normal vascular development is also important to normal muscle development because the loss of normal vascular supply 783

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may lead to loss or hypoplasia of muscle. Normally, the vascular supply seems to develop in response to muscle growth and utilization. However, if there is failure of vessel development or loss of functional blood vessels due to clots or compression, there will be secondary loss of muscle. If this occurs during fetal life, retrograde loss of neurons may occur. Descriptions of muscle structural anomalies need to include the blood vessels in order to distinguish the primary cause of muscle abnormalities. Disorders of cardiac muscle development are discussed elsewhere, but obviously hypertrophy or hypoplasia of cardiac muscle could have profound effects on other body structures if it affects vascular flow. Abnormalities of smooth muscle may be more subtle. Congenital anomalies or loss of smooth muscle are welldocumented in the blood vessels as well as in the gastrointestinal and urinary genital tracts. Specific voluntary muscles may be affected as in the loss of eye muscles, tongue, facial muscles, or abdominal wall muscles. The terminology used to describe abnormalities of muscle mass has often been used indiscriminately: atrophy (decrease in size), hypoplasia (underdevelopment), and aplasia (failure to develop) have been used interchangeably, leading to confusion. In addition, hyperplasia (increased tissue and cells) and hypertrophy (enlargement of existing tissue and cells) are usually not distinguished. Every effort to describe abnormalities accurately should be made. This chapter attempts to deal with primary disorders of muscle morphogenesis rather than the secondary effects of muscle on other tissues. Embryology

The advances in molecular biology have led to extensive studies of the development of muscle during early and late embryology.3 However, the relationship of muscle to the surrounding tissues is still poorly understood.3 Skeletal muscle is comprised of aggregates of multinucleated cells called muscle fibers. These muscle fibers are produced by the fusion of embryonic myoblasts. They are relatively long and have a histologic pattern of striations across the muscle fibers (Fig. 18-1). The cross-striated pattern seen in striated muscle is the consequence of the aggregation of bundles of myofibrils, which form the basic repetitive subunit of the contractural apparatus known as the sarcomere. Thin filaments representing actin and thick filaments representing myosin are arranged in a hexagonal array with each thick filament of myosin surrounded by six thin filaments of

Fig. 18-1. Organization of muscle fibers and myofibrils.

actin. There are a number of other proteins involved in the contractural body. These include a variety of tropomyosins and tropins. Myofibrils are embedded in the sarcoplasmic reticulum. The cell membrane surrounding the sarcomere is called the sarcolemma. Embedded in the sarcoplasmic reticulum are transverse fibrils that conduct polarization from the myoneural junction in a way so as to ensure uniform muscle contraction. The inner surface of the sarcomere membrane has a number of structures and proteins necessary to maintain its structural integrity. If any of these is missing, degeneration of muscle tissue can occur or the muscle may fail to perform in a normal way. Each muscle fiber is surrounded by connective tissue known as endomysium. The muscle fibers are surrounded by a layer of perimysium. The entire muscle is surrounded by a dense sheet of connective tissue known as epimysium. A single afferent nerve fiber and all the muscle fibers that it innervates are referred to as a motor unit. A single nerve fiber may innervate from one to 160 muscle fibers. The junction between the nerve ending and the sarcolemma that surrounds the muscle fiber is known as the motor end plate. The ultrastructure and physiology of these structures have been well worked out. Any failure in the motor end plate structure may lead to a dystrophy or a muscle disease process.8 The connective tissue elements of the craniofacial muscles are of neural crest origin, while the myoblasts are mesodermally derived. In other muscles, both the connective tissue and myoblasts are of mesodermal origin. There are very specific parts of the mesoderm that participate in the formation of striated muscle. The structural development has been well-described. However, the molecular basis is only beginning to be defined.3 Early in embryonic development, the mesoderm is formed as cells gastrulate through the primitive streak. Paraxial, intermediate, and lateral plate mesoderm form bilaterally. The paraxial mesoderm consists of elongated cell masses on each side of the neural groove. Intermediate mesoderm, which forms the kidney and internal genitalia, is located lateral to the paraxial mesoderm. The lateral plate mesoderm splits into the ventral splanchnopleure and the dorsal somatopleure. As gastrulation begins, the paraxial mesoderm is unsegmented. Beginning in the 3rd week of human gestation, somites are generated in an oscillating pattern in the presomitic paraxial mesoderm. This involves the notch signaling pathway. Segmentation progresses from the cranial to caudal direction. The process is completed during the 5th week of gestation. There are 38 to 39 pairs of somites (four occipital, eight cervical, 12 thoracic, five lumbar, five sacral, and four to five coccygeal). Additionally, at cranial levels, seven to eight segments termed somitomeres are formed. The somites differentiate into dermatomyotomes and sclerotomes, while the somitomeres lack a sclerotomal component. The sclerotomes arise from the ventral medial portion of the somites, while the lateral portion gives rise to the dermomyotome. The myotomes are comprised of an epaxial component that gives rise to the true back muscles and a hypaxial component from which the body wall and intercostal muscles are derived. The occipital and cervical somites give rise to the muscles of the tongue and diaphragm, as well as the limb bud and girdle. Paraxis and Pax-3 are associated with epithelialization in these tissues, while myogenesis is dependent on the myo D family.3 The sclerotomes contain the precursors of fibroblasts, chondroblasts, and osteoblasts, which will interact with the myotomes later in development. Muscle fibers pass through four stages prior to reaching maturation: the premyoblast, myoblast, myocyte, and myotube stages. Each stage is recognized now to have different genes and growth

Muscle

factors expressed.3 Myotubes begin to differentiate into skeletal muscle early in the 5th week, with the exception of some truncal muscles (rectus abdominus, erectors of the spine, and some small paravertebral muscles). Premyoblasts are undifferentiated, elongated spindle shaped and undergo multiple cell divisions. When they stop dividing, they become myoblasts.9 In this postmitotic state, the mononuclear cells are able to synthesize the myofilamentous proteins (myosin, actin, and other contractile proteins). Myoblasts contain randomly distributed myofilaments, central nuclei, ribosomes, Golgi apparatus, and mitochondria. Myofilaments are seen parallel with Z-line formation. Myocytes represent an intermediate stage between myoblasts and myotubes. Myocytes are mononuclear cells in close contact with each other. Myotubes form by the fusion of the plasma membranes of several myocytes. There are three types of myotubes: primary, secondary, and tertiary, which can be identified because they react to different monoclonal myosin heavy-chain antibodies9 and undergo differing development. Primary myotubes arise independently from any innervation and develop into type 1 fibers rich in oxidative enzymes. The small secondary fibers constitute the majority of myofibers recognized at week 20 of gestation. They are dependent on the presence of nerve fibers. The tertiary myotubes can be recognized as distinct by their immunologic staining between weeks 16 and 23 of gestation.8 All three types of myotubes contain multiple centrally located nuclei, various organelles, Golgi apparatus, tubules, cytoskeletal filaments, and contractile thin (actin) and thick (myosin) filaments. Intermediary filaments do not contain contractile proteins; rather, they contain such protein subunits as desmin, filamin, tubulin, titin, nebulin, and other proteins that have a stabilizing effect on the sarcomeres. During the next step of muscle development, the centrally located nuclei migrate to the periphery, and contractile filaments fill in the central core spaces.8 At this point, the myotubes have become myofibers. Growth of the myofibers takes place by the addition of new sarcomeres at the ends of the muscle fibers. Satellite cells (myoblasts that were dormant in early stages of muscle maturation) multiply, but the nuclei of the myofibers have lost the ability to divide. Tendons grow independently from the developing myofibers, but may play a role in orienting the muscle and eventually fuse with the muscle. If no fusion occurs, both tissues degenerate into nonspecific connective tissue. The primary myotubes develop independently from nerves. However, if innervation of the muscles does not take place shortly after they have been formed, they degenerate into nonspecific connective tissue. This type of secondary degeneration of the muscle is seen in neural tube defects, in some cases of arthrogryposis, and in cases of agenesis of parts of the spinal cord.10 Innervation is mandatory for the maintenance of the muscle. The innervation also plays a role in the differentiation of slow-twitch and fast-twitch fibers. A slow-twitching muscle can be changed into a fast-twitching muscle by transplantation of a nerve originally innervating a fast-twitching muscle, and vice versa. In humans, the earliest evidence of motor end plate formation is found during the 9th to 10th week of development.11 By week 28, the motor end plate is similar to that of adults. The differentiation of type 1 muscle fibers with high oxidative and low glycolytic activities occurs at a slow pace. The type 2 muscle fibers can be divided into type 2A (strongly reacting to adenosine triphosphatase [ATPase] at pH 9.4) and type 2B (strongly reacting with ATPase at pH 4.6).12 Before week 20 of gestation, the fibers are rounded and small and stain uniformly, and the muscle fibers are widely separated by a loose connective

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tissue, which later disappears. After week 20, the fibers are more densely aggregated and assume a polygonal shape, and the two fiber types become discernible. After week 28, the previously centrally located nuclei migrate to the subsarcolemmal area. The muscle fibers are still small, with a diameter usually under 25 mm. Formation of individual muscle groups requires coordinated differentiation of local myogenesis processes.3 Muscle is first organized to form a scaffold for further development. Thereafter, additional myotubes are generated with a wave of cell proliferation. Maturation is influenced by innervation, growth factors, and the demands on the muscle. Shifts from embryonic to adult muscle isoforms occur as well. Increase in muscle mass involves increases in the number and volume of muscle fibers. During prenatal life, increase is mainly numerical (hyperplasia). The number of myofibers remains more or less fixed during postnatal life. The muscle fibers enlarge rapidly (hypertrophy) during infancy and early childhood and are largest in adolescence and young adults. The growth pattern of muscle fibers varies from individual to individual. Infants and even 2-year-old toddlers with ‘‘essential hypotonia’’ have extremely small muscle fibers and only develop normal fiber size during preschool age.8 Muscle mass can be increased, decreased, or disorganized. Muscular hypoplasia refers to the failure of the muscle to achieve the conventionally accepted lower limit of growth, or in the case of aplasia the failure to form at all. Inadequate muscle is formed (or may be lost after formation) in conditions such as prune belly syndrome and in some variants of arthrogryposis. Muscle growth is under hormonal influence. Testosterone and other steroids have a growth-promoting effect. Muscular hyperplasia indicates a condition in which the anlage of muscle is excessive, resulting in an increased number of muscle fibers. One speaks of muscular hypertrophy if muscle mass increases secondary to external influences in which there are no new cells but rather an increase in protein synthesis in the muscle.14,15 The size of muscle fibers and of the whole muscle mass increases with muscle activity (hypertrophy). Isotonic contraction has a stronger effect on muscle growth, as evidenced by the muscular hypertrophy seen among body builders. It is not always possible clinically to distinguish muscle hyperplasia from muscle hypertrophy. Thus, the term muscular hypertrophy is often used for muscle enlargement. The terms hypotrophy or atrophy are used when a previously present muscle mass decreases or disappears (e.g., muscle atrophy after disuse or immobilization or atrophy due to diseases within the motor unit). It is sometimes difficult to differentiate hypoplasia from hypotrophy, notably in cases when hypotrophic fibers and developmentally arrested fibers coexist, as is seen in some congenital myopathies and in malformations of the ventral horns of the spinal cord. In the latter situation, arrest of muscle fiber development (hypoplasia) is combined with atrophy of disuse. Inactivity and immobilization of muscle leads to decreased muscle mass (e.g., atrophy due to disuse as evidenced by the severe atrophy of muscles immobilized by a cast). Starvation has a similar effect. Immobilized muscles that are relaxed show more marked atrophy than muscles immobilized under tension; the latter may even show some hypertrophy.13 Aging leads to shrinking and loss of muscle fibers. Profound muscle atrophy also follows denervation of muscle. Here paralytic (disuse) atrophy combines with the loss of the trophic influence nerves exert on muscles (including decreased blood flow). Histologically, one finds a gradual

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reduction of muscle fibers. Sarcoplasm and myofibrils, likewise, decrease in volume. Longitudinal and cross-striations as well as motor end plates are preserved until late in the atrophic process, even in the denervated muscle.14 Muscle dysplasia may be characterized by such manifestations as replacement of muscle mass by fat and fibrous tissue, disarray of myofilaments, abnormal inclusions, poor differentiation of fiber types, and arrest of muscle fiber development in which fibers may display various stages of fetal muscle. Muscle dystrophy is a progressive degenerative disorder of muscle characterized by random variation in fiber size, increase in endomysial and perimysial fibrosis, and degeneration and regeneration of muscle fibers. This group of disorders and other metabolic degenerative conditions of muscle are not considered in this chapter. When muscle fibers or parts of muscle fibers are injured, some regeneration is possible. Satellite cells accumulate in the areas of the injury, fuse, and form myotubes, which then follow the steps of normal muscle development. The newly formed myotubes fuse with the noninjured fiber parts. It is then possible to see different phases of development within the same muscle fiber.15 References 1. Becker PE: Angeborene Muskeldefkte und Muskelvarietaeten. In: Handbuch der Humangenetik, Band III/1. Thieme Verlag, Stuttgart, 1964, p 527. 2. Bergman RA, Thompson SA, Afifi AK: Compendium of Human Anatomic Variation: Text, Atlas, and World Literature. Urban & Schwarzenberg, Baltimore, 1988. 3. Rawls A, Rhee JM: Development of muscle and somites. In: Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis. CJ Epstein, RP Erickson, A Wynshaw-Boris, eds. Oxford University Press, New York, 2004, p 120. 4. Capetanaki Y, Milner DJ, Weitzer G: Desmin in muscle formation and maintenance: knockouts and consequences. Cell Struct Funct 22:103, 1997. 5. Hanson JW, Ardinger HH, Staley RN, et al.: Craniofacial growth and development in myotonic dystrophy. Proc Greenwood Genet Center 5:102, 1986. 6. Hanson JW, Smith DW, Cohen MM Jr: Prominent lateral palatine ridges: developmental and clinical relevance. J Pediatr 89:54, 1976. 7. Konigsberg IR: The embryonic origin of muscle. In: Myology. AG Engel, BQ Banker, eds. McGraw-Hill, New York, 1986. 8. Zellweger HU, Hanson JW: Muscle. In: Human Malformations and Related Anomalies, vol. 2. RE Stevenson, JG Hall, RM Goodman, eds. Oxford University Press, New York, 1993, p 845. 9. Price HM, Van de Velde RL: Ultrastructure of the skeletal muscle fibre. In: Disorders of Voluntary Muscle, ed 4. J Walton, ed. Churchill Livingstone, New York, 1981. 10. Draeger A, Weeds AG, Fitzsimmons RB: Primary, secondary, and tertiary myotubes in developing skeletal muscle: a new approach to the analysis of human myogenesis. J Neurol Sci 81:19, 1987. 11. Buller AJ, Eccles JC, Eccles RM: Interactions between motoneurons and muscles in respect of the characteristic speeds of their contraction. J Physiol (London) 150:417, 1960. 12. Brooke MH, Kaiser KK: Muscle fiber types: how many and what kind? Arch Neurol 23:369, 1970. 13. Dubowitz V: Developing and Diseased Muscle: A Histochemical Study. Spastic International Medical Publications, Heinemann Medical Books, London, 1968. 14. Adams RD: Diseases of Muscle, ed. 3. Harper & Row, Hagerstown, MD, 1975. 15. Emery AEH: Duchenne Muscular Dystrophy. Oxford University Press, New York, 1987.

18.1 Generalized Abnormalities of Muscle Mass: Increased Muscle Mass Hypertrophia Musculorum Vera (HMV)

Hypertrophia musculorum vera (HMV) is the presence of enlarged muscles at birth. It is recognized in infancy or childhood.8 Enlargement of muscle by hypertrophy is not associated with enlargement of bone or connective tissue. Because of the relatively large muscle, affected children have an athletic appearance. The muscles are firm or even hard on palpation. The muscle tone may be increased, normal, or hypotonic. Myotonic reactions such as delayed relaxation and percussion myotonia are absent, although sometimes a small, localized indentation may be present after tapping with the reflex hammer. Reflexes may be difficult to elicit, normal, or hyperactive. The condition is benign. However, since the athletic body build resembles that of Thomsen myotonia congenita and of Becker autosomal recessive myotonia, evaluation is usually indicated. The electromyogram is normal. Muscle biopsy shows normal or sometimes enlarged muscle fibers,1 but not dystrophic changes. HMV is undoubtedly of heterogeneous etiology. In 1913, Spiller2 described cases of HMV and reviewed earlier reported cases. Together with later authors,3–6 he questioned whether there was a single etiology or disorder. Krabbe6 described a postneuritic HMV occurring after infectious diseases, notably typhoid fever. Hall et al.7 suggested a genetic basis, observing a boy who was the product of an incestuous relationship who presented conspicuous HMV, muscular hypertonia, and developmental delay. The muscle biopsy was normal, and the muscle fiber diameter was within the normal range. Poch et al.8 described a large, threegenerational family with 14 cases of HMV. Male-to-male transmission was noticed. The patients developed marked hypertrophy of the calves, and in some cases of the masseters, in their teens. Cramps and paresthesias occurred in the affected muscles in some affected individuals; others had no complaints. No other abnormal neurologic symptoms were noticed. Electromyograms (EMG) were normal in some and slightly abnormal in others (fibrillations at rest in the affected muscles but not in unaffected muscles). Myotonic discharges were absent. The serum enzymes were normal. Muscle biopsies of the gastrocnemius were performed in two cases and showed enormous muscle fiber hypertrophy, with fiber diameter in the range of 200 mm. Some fibers showed centralization of nuclei. One of the patients showed, besides the muscular hypertrophy, signs of hypothyroidism, which raises the question of a possible relationship in this family to the Kocher-Debre´Se´me´laigne syndrome (see below). De Lange9 described three unrelated children with muscular hypertrophy, hypertonia, developmental delay, and death in early childhood. The autopsy of one case revealed central nervous system (CNS) malformations, with micropolygyria, status spongiosus, hypoplasia of the corpus callosum, and moderate ventriculomegaly. However, most cases of HMV are of normal intelligence. De Lange compared her cases with an observation of Bruck,10 who described a 10-month-old-girl with generalized muscle hypertrophy with macroglossia, mental retardation, and defective hearing. The cases of Hall, de Lange, and Bruck should be distinguished from the true HMV, where intelligence is normal. The muscular hypertrophy of these patients could have been secondary to a static encephalopathy. Patients with severe extrapyramidal hyperkinesis may display a remarkable muscular hypertrophy, which may be particularly impressive because of the almost total lack of subcutaneous fat.

Muscle

Kocher-Debre´-Se´me´laigne Syndrome

Muscular hypertrophy may be seen in some individuals with hypothyroidism. Historically, it was called myxedematous athletism and pseudomyotonia myxedematosa11,12 and reversed with treatment of the hypothyroid. Kocher13 described its presence in an exhaustive clinical description of cretinism. Some cases of myxedema displayed considerable muscular hypertrophy, with hypertonia or even stiffness of the limbs. Hypotonia and weakness occurred in other patients with myxedema. Older individuals with muscular hypertrophy and hypothyroidism complain of muscle pains. They fatigue rapidly after mild exercises, their movements are slow, and myotatic reflexes are delayed. Macroglossia may be seen. Debre´ and Se´me´laigne described two infants with typical findings of hypothyroidism, with macroglossia and other hypothyroid symptoms, combined with generalized muscular hypertrophy giving an athletic appearance.14 Subsequently, the terms KocherDebre
-Se
me
laigne syndrome and Debre
-Se
me
laigne syndrome were coined, and a number of additional cases were reported.12,15–21 Cross et al.17 reported the occurrence of agoitrous cretinism with muscular hypertrophy in two offspring of a consanguineous marriage. McKusick22 proposed autosomal recessive inheritance of this syndrome (McK 218700). However, the genetic basis appears to be complex since not all hypothyroid, myxedematous, or cretinous individuals have muscular hypertrophy. A thorough study of the electromyographic, light microscopic, and ultrastructural changes in seven cases of Debre´-Se´me´laigne syndrome and three cases of hypothyroidism without muscle hypertrophy were reported by Afifi et al.16 Creatine kinase was regularly increased in their cases but was normalized after thyroid medication. The EMG was normal in one case and myopathic in six cases. Muscle biopsies were performed in several patients: two showed marked centralization of nuclei, two had variable fiber size, and several showed ringbinden. Other cases were normal by light microscopic examination. Electron microscopic studies showed a number of abnormalities; however, these were inconsistent. Abnormalities included very large, rounded fibers, increased vascularity, increased intermyofibrillar spaces, mitochondrial aggregates, large mitochondria, increased glycogen deposits, dilated sarcoplasmic reticulum, ringbinden (annulets), Z-line abnormalities, and disarray and loss of myofilaments. Many myofilaments had lost their longitudinal orientation and pointed in various directions. Similar alterations were found in the muscle biopsies of patients with hypothyroidism without muscular hypertrophy. The presence of muscular hypertrophy in some but not in other cases of hypothyroidism is not understood. Hypothyroidism is clearly heterogeneous. A separate genetic predisposition or some type of environmental factor may be responsible for the muscular hypertrophy.22 Whatever the case, the muscular hypertrophy disappears when thyroid medication is given, while other hypothyroid manifestations, notably the mental retardation in cretinism syndrome, may not respond to therapy.23,24 Hyperekplexia (Kok Syndrome)

Hyperekplexia, also called startle disease and stiff baby syndrome, is characterized by extreme startle responses in which affected individuals become stiff when startled.25–36 Affected individuals exposed to a sudden auditory stimulus or a sudden and unexpected physical contact become extremely stiff, lose their balance, and fall helplessly to the ground, whereupon their stiffness disappears. The condition was first described by Kirsten and Silfverskio¨ld25 and Kok and Bruyn.26 It is transmitted as an autosomal dominant trait,

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and large families with multiple cases have been described.27–30 Andermann et al.31 reviewed the literature and pointed out that hyperekplexia is of interest in that it is associated with extreme muscular hyperplasia and muscle stiffness. The term hyperplasia is used instead of the term hypertrophy because the children are born with it. Most publications fail to mention the hyperplasia of the muscles, although the pictures that accompany the case descriptions and the personal observations of a family with the syndrome convincingly show marked muscular hyperplasia. Besides hypertonia and hyperplasia, there are no abnormal neurologic findings. The muscle stiffness may be so extreme that mothers have difficulties dressing or diapering affected children. Likewise, it may be almost impossible to remove objects from the grip of the child’s hands. Apnea and sudden death have been reported as a consequence of stiffness of respiratory musculature.35 Myotatic reflexes may be difficult to interpret and are hyperactive in some instances. EMG is normal in some cases; others show simultaneous muscle activity of the protagonists and antagonists. Hypertonia and hyperplasia diminish after infancy. Cognitive development and intelligence are normal. Motor development may be somewhat slow because of the stiffness. Diazepam has helped to decrease the hypertonia in some but not all instances. Weigner36 linked the startle response to the stiffness of the death-feign reflex, which some animals develop when they become aware of predators, and postulated that it involved alteration in the g-aminobutyric acid (GABA)-ergic pathways from the basal ganglia to the lower brain-stem. However, the cause of the muscular hyperplasia is not known. Pyloric Stenosis

Pyloric stenosis is covered elsewhere, but can be considered a muscular hypertrophy, although the normally muscular valve becomes overgrown with fibrous tissue. Tongue Hypertrophy

Macroglossia is known to be associated with hypothyroid disease, storage disease, and Beckwith-Weidemann syndrome. In all cases, it represents an increase in connective tissue rather than muscular hypertrophy. The one familial report did not distinguish.37 References (Increased Muscle Mass) 1. Ford FR: Diseases of the Nervous System in Infancy, Childhood and Adolescence, ed 6. Charles C. Thomas Publishers, Springfield, IL, 1973. 2. Spiller WG: The relationship of the myopathies. Brain 36:75, 1913. 3. Krabbe KH: Les hypertrophies muscularies post-nevritiques. Rev Neurol 28:802, 1921. 4. Engle AG, Banker BQ: Myology. McGraw-Hill, New York, 1988. 5. Walton J: Disorders of Voluntary Muscle, ed 5. Churchill Livingstone, Edinburgh, 1988. 6. Krabbe KH: The myotonia acquisita in relation to the postneuritic muscular hypertrophy. Brain 57:184, 1934. 7. Hall BE, Sunderman FW, Gittings JC: Congenital muscular hypertrophy. Am J Dis Child 52:773, 1936. 8. Poch GF, Sica EP, Taratuto A, et al.: Hypertrophia musculorum vera. Study of a family. J Neurol Sci 12:53, 1971. 9. De Lange C: Congenital hypertrophy of the muscles, extrapyramidal motor disturbances and mental deficiency. Am J Dis Child 48:243, 1934. 10. Bruck F: Ueber einen Fall von congenitaler Markroglossie combiniert mit allgemeiner waher Muskelhypertrophie und Idiote. Deutsch Med Wochenschr 15:229, 1889. 11. Wilson J, Walton J: Some neuromuscular manifestations of hypothyroidism. J Neurol Neurosurg Psychiatry 22:320, 1959. 12. Pende N, Pende V: L’athletismo mixedematoso. Fiola Endocrinol 5:138, 1952.

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13. Kocher T: Zur Verhuetung des Cretinismus und cretinoider Zutaende nach neuern Forschungen. Deutsch Z Chir 34:556, 1892. 14. Debre´ R, Se´me´laigne G: Syndrome of diffuse muscular hypertrophy in infants causing athletic appearance. Am J Dis Child 51:1351, 1935. 15. Norris FJ Jr, Panner BJ: Hypothyroid myopathy. Clinical, electromyographical, and ultrastructural observations. Arch Neurol 14:574, 1966. 16. Afifi AK, Najjar SS, Mire-Salman J, et al.: The myopathology of the Kocher-Debre-Semelaigne syndrome. Electromyography, light- and electron-microscopic study. J Neurol Sci 22:445, 1974. 17. Cross HE, Hollander CS, Rimoin DL, et al.: Familial agoitrous cretinism accompanied by muscular hypertrophy. Pediatrics 41:413, 1968. 18. Darre H, Mollaret P, Zaydon M: Hypertrophie musculaire generalisee du nourisson et hypothyroidie congenitale. Rev Neurol 72:249, 1939. 19. Hesser FH: Hypertrophia musculorum vera (dystrophia musculorum hyperplastica) associated with hypothyroidism: a case study. Bull Johns Hopkins Hosp 66:353, 1940. 20. Heuyer G, Lebovin G, Koupernick C, et al.: Myxoedeme congenitale, hypertrophie musculaire gneralisee, malformation vertebrale et atrophie coricale. Arch Fr Pediatr 7:698, 1950. 21. Najjar SS, Nachman HS: The Kocher- Debre´-Se´me´laigne syndrome. J Pediatr 66:901, 1954. 22. McKusick VA: OMIMÔ. Online Mendelian Inheritance in Man. National Center for Biotechnology Information. http://www.ncbi.nlm. nih.gov/omim/. 23. Emser W, Schimrigk K: Myxedema myopathy: a case report. Eur Neurol 16:286, 1977. 24. Khaleeli AA, Gohil K, McPhail G, et al.: Muscle morphology and metabolism in hypothyroid myopathy: effects of treatment. J Clin Pathol 36:519, 1983. 25. Kirsten L, Silfverskio¨ld B: A family with emotionally precipitated drop seizures. Acta Psychiatr Scand 33:471, 1958. 26. Kok O, Bruyn GW: An unidentified hereditary disease, letter. Lancet 1:1359, 1962. 27. Klein R, Haddow JE, DeLuca C: Familial congenital disorder resembling stiff-man syndrome. Am J Dis Child 124:730, 1972. 28. Lingam S, Wilson J, Hart EW: Hereditary stiff-baby syndrome. Am J Dis Child 135:909, 1981. 29. Suhren O, Bruyn GW, Thynman JL: Hyperexplexia, a hereditary startle syndrome. J Neurol Sci 3:577, 1966. 30. Gaustaut H, Villeneuve A: The startle disease of hyperekplexia: pathological surprise response. J Neurol Sci 5:523, 1967. 31. Andermann F, Keene DL, Andermann E, et al.: Startle disease or hyperekplexia: further delineation of the syndrome. Brain 103:985, 1980. 32. Morley DJ, Weaver DD, Garg BP, et al.: Hyperexplexia: an inherited disorder of the startle response. Clin Genet 21:388, 1982. 33. Markand ON, Garg BP, Weaver DD: Familial startle disease (hyperexplexia): electrophysiological studies. Arch Neurol 41:71, 1984. 34. Melki I, Rizkallah E, Akatcherian C: L’hyperekplexia: la ‘‘maladie du sursaut.’’ Pediatrie 43:35, 1988. 35. Vigevano F, Di Capua M, Dalla Bernardina B: Startle disease: an avoidable cause of sudden infant death. Lancet 1:216, 1989. 36. Weigner ME: Stiff baby syndrome: an expression of the same neural circuitry responsible for opiate induced muscle rigidity. Anesthesiology 66:580, 1978. 37. Reynoso MC, Hernandez A, Soto F, et al.: Autosomal dominant macroglossia in two unrelated families. Hum Genet 74:200, 1986.

18.2 Generalized Abnormalities of Muscle Mass: Decreased Muscle Mass Decreased Muscle Mass Associated With Multiple Congenital Contractures

The terms multiple congenital contractures (MCC)1 and arthrogryposis multiplex congenita (AMC)2 are commonly used to describe conditions characterized by congenital stiffness of multiple

joints secondary to immobilization of the fetus. These disorders are covered in the chapter on limb anomalies. Since MCC is quite heterogeneous, it is mandatory to establish, when possible, the correct etiologic diagnosis in order to provide appropriate information on natural history, therapy, and recurrence risk. Decreased Muscle Mass Without Associated Congenital Contractures

Primary dysgenesis of muscle, fetal dysplasia, and heredodegenerative disease of the motor unit with prenatal onset can lead to conditions characterized by muscular hypoplasia, muscular hypotonia, and weakness, without MCC (Fig. 18-2). Congenital disorders of muscle including congenital muscular dystrophies, metachromatic leukodystrophy, spinal muscular atrophy, and metabolic diseases such as lysosomal, mitochondrial, and peroxisomal disorders are not discussed in this chapter. The conditions included here were known in earlier years as amyotonia congenital of Oppenheim (after it was clear that they were not degenerative nor had spinal muscular atrophy), muscular infantilism, congenital muscular aplasia, or hypoplasia musculorum generalisata congenital.1–5 Decreased muscle mass is an essential feature of these conditions. Muscular hypotonia and more or less pronounced muscular weakness are also features. Tendon reflexes are usually preserved, though they may be difficult to elicit. Electromyelograms (EMG) are normal. Muscle biopsies show normal or small muscle fibers (often suggestive of disuse), and some fibers are replaced by fat and fibrotic tissue. With advancing age, strength and muscle mass may increase slightly in some cases, although the musculature remains subnormal in size. The terms listed above are no longer used or are only reluctantly accepted and have been replaced by the term essential or benign congenital hypotonia.6–9 Congenital muscular hypoplasia is encountered in many conditions. Many patients with Camurati-Englemann disease show impressive hypoplasia of their muscles.10 In some patients with Camurati-Englemann disease who were followed since early childhood, the muscular hypoplasia was present from the beginning and before pains caused by the diaphyseal dysplasia would have hampered muscular activity. Disuse atrophy provoked by the pain from the skeletal disorder is, therefore, the less likely cause of the decreased muscle mass, and muscular hypoplasia may be a primary feature.11,12 Reduced muscle mass, however, is not a consistent feature of Camurati-Englemann disease and may be a reflection of the specific mutation. Hundley and Wilson13 reviewed 77 cases and found it in only one-half of the cases. Muscular hypoplasia occurs, also, in some cases of Marfan syndrome and in the marfanoid hypermobility syndrome.14 According to Beighton and McKusick, muscular underdevelopment and hypotonia are frequently, but not invariably, present in Marfan syndrome. However, in rare cases, the muscular hypoplasia was so prominent that a primary muscle disease such as muscular dystrophy was suspected.15,16 The subsequent course of the disease allowed muscular dystrophy to be excluded. Marfan syndrome is due to the presence of fibrillin abnormalities, which lead to the connective tissue abnormalities. In many cases, the specific mutation cannot be determined.17 The development of histochemistry, electron microscopy, immunocytochemistry, and molecular techniques has lead to a new understanding of congenitally decreased muscle mass. A host of congenital, ‘‘nonprogressive’’ myopathies were discovered in the 1960s and 1970s and are now being defined at the gene and molecular level. These are not discussed here, with the exception

Muscle

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Fig. 18-2. Muscle hypoplasia. A, B, C. With contractures, 2 months, 10 years, and 13 years, respectively. D. Generalized muscle hypoplasia in Allan-Herndon syndrome.

of congenital nemaline myopathy, because their features are dominated by hypotonia and not structural anomalies. Nemaline myopathies are genetically heterogeneous;18 autosomal recessive and autosomal dominant variants have been described.19 Moreover, nemaline bodies or rods can be found in various other conditions such as Duchenne muscular dystrophy, central core disease,20 minicore disease, mitochondrial disorders,21

polymyositis, muscle severed from its tendon, and other conditions22 including pterygium syndrome and MCC. It may be that nemaline bodies, at least in some instances, represent a manifestation of muscle dysgenesis. Nemaline bodies apparently derive from the Z-disk. Both nemaline bodies and Z-disks consist of mostly a-actinin and some desmin, the latter located in the periphery of the Z-disks. The content of the a-actinin in nemaline

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Neuromuscular Systems

myopathy is two to three times greater than in normal muscle.23 Stuhlfauth et al.24 proposed that this may be due to lack of the control mechanisms that limit the deposition of a-actinin to the Z-disks. References (Decreased Muscle Mass) 1. Oppenheim H: Ueber Allgemeine und localisiere Atonie der Muskulatur (Myatonia) im fruehen Kindesalter. Mschr Psychiatr Neurol 8:232, 1900. 2. Gibson A: Muscular infantilism. Arch Intern Med 27:338, 1921. 3. Krabbe KH: Kongenit generaliseret muckelaplasi, abstracted. Nordisk Med 35:1756, 1947. 4. Krabbe KH: Congenital generalized muscular atrophies. Acta Psychiatr Neurol Scand 33:94, 1958. 5. Schreier K, Huperz R: Ueber die Hypoplasia musculorum generalisata congenita. Pediatr Ann 186:241, 1956. 6. Astroem KE, Adams RD: Hypoplasia (hypotrophy) of muscle. In: Disorder of Voluntary Muscle, ed 4. J Walton, ed. Churchill Livingstone, Edinburgh, 1981, p 159. 7. Gardner-Medwin D: Neuromuscular disorders in infancy and childhood. In: Disorders of Voluntary Muscle, ed 5. J Walton, ed. Churchill Livingstone, Edinburgh, 1988, p 666. 8. Zellweger H: Die essentielle Hypotonie bei degenerativien Kindern. Helv Pediatr Acta 1:495, 1946. 9. Walton JN: Amyotonia congenita: a follow-up study. Lancet 1:1023, 1957. 10. Cohn HJ, States JD: Progressive diaphyseal dysplasia, report of a case with autopsy findings. Lab Invest 5:492, 1956. 11. Sparkes RS, Graham CB: Camurati-Englemann disease. Genetics and clinical manifestations with a review of the literature. J Med Genet 9:73, 1972. 12. Yoshioka H, Mino N, Kiyosawa N, et al.: Muscular changes in Engelmann’s disease. Arch Dis Child 55:716, 1980. 13. Hundley JD, Wilson FC: Progressive diaphyseal dysplasia. Review of the literature and report of seven cases in one family. J Bone Joint Surg 55:461, 1973. 14. Beighton B, McKusick VA: Heritable Disorders of Connective Tissue, ed 5. Mosby, St. Louis, 1993. 15. Walker BA, Beighton PH, Murdoch JL: The marfanoid hypermobility syndrome. Ann Intern Med 71:349, 1969. 16. Fahey JJ: Muscular and skeletal changes in arachnodactyly. Arch Surg 39:741, 1939. 17. Goebel HH, Muller J, DeMyer W: Myopathy associated with Marfan’s syndrome. Fine structural and histochemical observations. Neurology 23:1257, 1973. 18. Arts WF, Bethlem J, Dingemans KP, et al.: Investigations on the inheritance of nemaline myopathy. Arch Neurol 35:72, 1978. 19. Kondo K, Yuasa T: Genetics of congenital nemaline myopathy. Muscle Nerve 3:308, 1980. 20. Rowland LP, McLeod JG: Classification of neuromuscular disorders. J Neurol Sci 124(suppl):109, 1994. 21. Afifi AK, Smith JW, Zellweger H: Congenital nonprogressive myopathy. Central core disease and nemaline myopathy in one family. Neurology 15:371, 1965. 22. Shapira YA, Yarom R, Blank A: Nemaline myopathy and a mitochondrial neuromuscular disorder in one family. Neuropediatrics 12:152, 1981. 23. Dubowitz V: Muscle Biopsy, ed 2. Bailliere-Tindal, London, 1985. 24. Stuhlfauth I, Jennekens FG, Willemse J, et al.: Congenital nemaline myopathy. II. Quantitative changes in alpha-actinin and myosin in skeletal muscle. Muscle Nerve 6:69, 1983.

18.3 Localized Abnormalities of Muscle The muscle system in humans is subject to irregularities producing almost every possible variation and anomaly.1–4 Some may be considered as mere variations; others are malformations. Variations

of muscle shape, mass, and location are numerous. One-fourth to one-half of carefully dissected bodies show findings that differ from the ‘‘normal’’ description found in textbooks of human anatomy.3 Most muscle variations are of no real clinical significance, except for the surgeon, who may unexpectedly encounter them during surgical interventions. Variations of muscle have been exhaustively collected and discussed diligently in several monographs and are not discussed here, with the exception of brief mention of some atavistic remnants resembling earlier stages of phylogenetic development.1–4 The main discussion is concerned with muscle abnormalities (malformations) producing clinical pathology. Variations of Voluntary Muscle with Decreased Mass

Absence of single muscles or of parts of a muscle is presumably not rare, yet an exact incidence is not known, since absent muscle mass often escapes recognition in the living. Postmortem studies often yield absence of muscle or parts of muscle. Earlier data have been compiled by Bing5 and Abromeit.6 A list of muscles that are often absent or defective is given in Table 18-1. The overwhelming majority of muscle deficiencies are unilateral and occur in both males and females. Most of them are observed sporadically. Reports of familial occurrence of muscle defects are rare. However, accurate family studies with respect to such muscle variations have usually not been undertaken. Variations in the absence of parts of muscle do not usually cause a functional deficit, because the remaining parts of the muscle may become hypertrophic. If a whole muscle is absent, its function may well be taken over by other muscles. Bergman et al.7 illustrated such compensation by an interesting observation concerning total absence of the right serratus anterior. To compensate for the missing serratus function, an extra fascicle of latissimus dorsi originating unusually high on the thoracic spine had been formed, which covered the apex of the scapula, keeping the scapula fixed to the thorax and allowing abduction of the arm (functions normally

Table 18-1. Isolated muscle deficiencies Muscle

Pectoralis muscles

Number of Cases

186

Various muscles of face

44

Trapezius, cucullaris

33

Quadriceps femoris

26

Serratus anterior

22

Omohyoideus

16

Long head of biceps brachii

13

Abdominal muscles

11

Muscles of hand except palmaris*

9

Sternomastoid

8

Semimembranosus

7

Latissimus dorsi

5

Deltoids

5

Any other muscle

Each <5

Compiled from Bing5 and Abromeit.6 See also listing of rare muscle deficiencies in Adams.4 *See discussion of absence of mm. pyramidalis, palmis longus, and brevis under ‘‘muscle atavisms.’’

Muscle

performed by the serratus). Functional deficits usually only become obvious when a group of muscles is absent. References (Localized Abnormalities of Muscle) 1. Wood J: Muscle varieties. J Anat Physiol 1:44, 1867. 2. Becker PE: Angeborene Muskeldefkte und Muskelvarietaeten. In: Handbuch der Humangenetik, Band III/1. Thieme Verlag, Stuttgart, 1964, p 527. 3. Bergman RA, Thompson SA, Afifi AK: Compendium of Human Anatomic Variation: Text, Atlas, and World Literature. Urban & Schwarzenberg, Baltimore, 1988. 4. Adams RD: Diseases of Muscle: A Study in Pathology, ed 3. Harper & Row, New York, 1975. 5. Bing R: Ueber angeborene Muskeldefekte. Virchows Arch Pathol Anat 170:175, 1902. 6. Abromeit B: Beitrag zur Kenntnis der kongenitalen Muskeldefekte. Mschr Psychiatr Neurol 25:440, 1901. 7. Bergman RA, Thompson SA, Saadeh FA: Anomalous fascicle and high origin of latissimus dorsi compensating for absence of serratus anterior. Anat Anzeiger 167:161, 1988.

18.4 Aglossia Aglossia, absence of the tongue, is a rare anomaly and thought to primarily be related to vascular loss rather than failure of formation. Embryologically, the tongue develops primarily from the ventral aspect of the first, second, and third pharyngeal arches. Mesenchymal cells of cephalic neural crest origin are major contributors to this area, as are mesoderm-derived myoblasts. Aglossia is frequently seen in Mo¨bius syndrome and with limb anomalies; however, it has been seen with other structural craniofacial anomalies1 and with thyroid dysfunction.2 Many teratogens can interfere with normal tongue formation. References (Aglossia) 1. Neidich JA, Whitaker LA, Natiwicz M, et al.: Aglossia with congenital absence of the mandibular rami and other craniofacial abnormalities. Am J Med Genet Suppl 4:161, 1988. 2. Kantaputra P, Tanpaiboon P: Thyroid dysfunction in a patient with aglossia. Am J Med Genet 122A:274, 2003.

18.5 Facial Muscle Deficiency Facial muscle deficiency can be related to decreases of muscle due to vascular compromise, a developmental defect, or secondary to cranial nerve or nucleus (V, X, XI, XII) defects. Every combination has been described. Lack of facial movement may be symmetric or asymmetric, localized or generalized. It can be limited to eye muscles or to the perioral muscles, or present in all the muscles of the face and tongue. Mo¨bius syndrome (congenital facial diplegia) can be unilateral or bilateral and can involve other never palsies, particularly bulbar. Dysplasia, aplasia, or atrophy of supranuclear structures alone or together with other cranial nerve nuclei is seen. In rare instances the primary problem has been found to be the lack of facial and external eye muscles. Congenital bilateral paresis of the facial muscles is the most consistent finding of the Mo¨bius syndrome. Danis1 analyzed 81 cases of congenital facial diplegia. In 19 (29%) of cases, the facial diplegia was the only finding. In

791

62 cases (77%), bilateral abducens palsy was found. In a smaller percentage, weakness of the tongue, of other ocular muscles, and rarely of the masticatory muscles was found. Feeding difficulties were noted in early infancy, and dysarthria appeared later. Frequently associated anomalies were bilateral talipes equinovarus (30%) and brachysyndactyly. Electrodactyly or transverse reduction defects at various levels of the upper and lower limbs were found in some cases. Secondary facial features, including epicanthal folds and micrognathia, are common. Branchial arch defects can be seen, including ear structured anomalies. Most cases are sporadic, but familial cases have been described and great variability of the involved area is seen in Mo¨bius syndrome2 thought to be familial. Vascular origin has been suggested by many in which presumed central nervous system (CNS) vascular compromise leads to failure of the nucleus to develop properly with secondary loss and degeneration of the musculature, since on CNS examination the cranial nerve nuclei are deficient.3,4 The association of other structural anomalies known to be due to vascular compromise, such as limb defects, is supportive of this concept.3,4 Teratogens leading to vascular compromises such as ergotamine have also been associated with Mo¨bius syndrome.5 Chromosomal anomalies have been associated with familial cases,6–10 suggesting that there may be specific genes disrupted. References (Facial Muscle Deficiency) 1. Danis P: Les paralysies oculo-faciales congenitales. Ophthalmology 110:113, 1945. 2. Baraitser M: Genetics of Moebius syndrome. J Med Genet 14:415, 1977. 3. Bavinck JNB, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Moebius anomalies. Am J Med Genet 23:903, 1986. 4. Lipson AH, Gillerot Y, Tannenberg AEG, et al.: Two cases of maternal antenatal splenic rupture and hypotension associated with Moebius syndrome and cerebral palsy in offspring. Eur J Pediatr 155:800, 1996. 5. Graf WD, Sheoard TH: Uterine contraction in the development of Mo¨bius syndrome. J Child Neurol 12:225, 1997. 6. Ziter FA, Wiser WC, Robinson A: Three-generational pedigree of a Moebius syndrome variant with chromosome translocation. Arch Neurol 34:437, 1977. 7. Shapiro DN, Sublett JE, Li B, et al.: The gene for PAX7, a member of the paired-box-containing genes, is localized on human chromosome arm 1p36. Genomics 17:767, 1993. 8. Slee JJ, Smart RD, Viljoen DL: Deletion of chromosome 13 in Moebius syndrome. J Med Genet 28:413, 1991. 9. Nishikawa M, Ichiyama T, Hayashi T, et al.: Mo¨bius-like syndrome associated with a 1;2 chromosome translocation. Clin Genet 51:122, 1997. 10. Kremer H, Padberg GW, Kuyt LP, et al.: Localization of a gene for Moebius syndrome to chromosome 3q by linkage analysis in a Dutch family. Hum Mol Genet 5:1367, 1996.

18.6 Asymmetric Crying Facies Asymmetric crying facies involves asymmetric dysfunction of facial muscles, usually associated with absence, hypoplasia, or fatty/ fibrous replacement of specific muscles. It is usually noted shortly after birth when the oral muscle dysfunction is most striking.1 Occasionally, familial occurrence of paresis of facial muscles is reported, which can vary as to side and severity from generation to generation.2

792

Neuromuscular Systems

The incidence of facial muscle palsy is probably decreasing since many cases in the past were related to birth trauma3 to the exposed facial nerve during delivery. Probably about 0.5% of newborns have some abnormality of facial muscle function.2 There seems to be no gender selection. However, an increase in congenital heart disease is seen, as well as Mo¨bius syndrome-associated anomalies. Some improvement in facial movement and function has been seen with segmental gracilis muscle transplant.4 References (Asymmetric Crying Facies) 1. Roedel R, Christen HJ, Laskawi R: Aplasia of the depressor anguli oris muscle: a rare cause of congenital lower lip palsy? Neuropediatrics 29: 215, 1998. 2. Ho¨lmich LR, Medgyesi S: Congenital hereditary paresis of ramus marginalis nervus facialis in five generations. Ann Plast Surg 33:96, 1994. 3. Smith JD, Crumley RL, Harker LA: Facial paralysis in the newborn. Otolaryngol Head Neck Surg 89:841, 1981. 4. Zuker RM, Goldberg CS, Manktelow RT: Facial animation in children with Mo¨bius syndrome after segmental gracilis muscle transplant. Plast Reconstr Surg 106:1, 2000.

18.7 Deficiency of Eye Muscles Extraocular muscle deficiency can lead to a variety of abnormal eye movements. These abnormal movements, moreover, are not of a neurologic type, such as nystagmus, but rather represent the inability to deviate the globe in a specific direction. Ophthalmoplegia is well-known to occur in mitochondrial disorders; however, it is not usually congenital and will not be covered here.1 Ptosis,2 blepharoptosis,3 and isolated muscle deficiency (unilateral and bilateral superior oblique,4 superior rectus,5 inferior oblique,6 and lateral rectus7) are usually sporadic, but can occur in families. They are most often associated with longstanding atrophy and fibrosis of the muscle. Again, a vascular basis for the loss of function could either involve the nerve, the nucleus, or the muscle itself. The muscle dysfunction can be isolated or seen in association with structural eye anomalies, such as Axenfeld anomaly. Specific genes are being isolated in familial forms, as in congenital fibrosis of extraocular muscles type I where a mutation in kinesin (KI2F21A) has been associated with the congenital fibrosis.8 References (Deficiency of Eye Muscles) 1. Jones KJ, North KN: External ophthalmoplegia in neuromuscular disorders: case report and review of the literature. Neuromuscul Disord 7:143, 1997. 2. Aberfeld DC: Hereditary ptosis. Birth Defects Orig Artic Ser VII(2):63, 1971. 3. Deenstra W, Melis P, Kon M, et al.: Correction of severe blepharoptosis. Ann Plast Surg 36:348, 1996. 4. Mudgil AV, Walker M, Steffen H, et al.: Motor mechanisms of vertical fusion in individuals with superior oblique paresis. J AAPOS 6:145, 2002. 5. Mather TR, Saunders RA: Congenital absence of the superior rectus muscle: a case report. J Pediatr Ophthalmol Stabismus 24:291, 1987. 6. Stager DR Jr, Beauchamp GR, Wright WW, et al.: Anterior and nasal transposition of the inferior oblique muscles. J AAPOS 7:167, 2003. 7. Sandall GS, Morrison JW Jr: Congenital absence of lateral rectus muscle. J Pediatr Ophthalmol Strabismus 16:35, 1979. 8. Yamada K, Andrews C, Chan WM, et al.: Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 35:318, 2003.

18.8 Deficiency of Esophageal Muscles Achalasia involves the inability to produce normal swallowing because of the absence or diminished peristalsis and failure or relaxation of the lower esophageal sphincter. Most often this is related to motor disorder and failure of maturation of coordinated muscle activity, but it can also be related to hypoplastic or absent muscles in the esophagus. Degeneration or failure of formation of Auerbach’s plexus can also lead to secondary loss of functional muscle.1 Achalasia occurs in approximately one in 100,000 individuals. Children account for 3–5% of the total.2 The disease has equal frequency in males and females.1,3 Familial achalasia is rare but has been reported, suggesting a genetically determined disorder.4 It usually appears to have an autosomal recessive pattern of inheritance5–7; however, vertical transmission has also been reported.8 Achalasia has been reported in association with Addison disease9; mitral valve prolapse10; Down syndrome11; Riley-Day syndrome12; familial glucocortical deficiency with deficient tear duct production13; autosomal recessive deafness with short stature, vertigo, and muscle wasting14; and familial microcephaly and mental retardation.15 Management has much improved and includes dilation and surgery.1 References (Deficiency of Esophageal Muscles) 1. Buick RG: Achalasia and miscellaneous anomalies of the oesophagus. In: Surgery of the Newborn. NV Freeman, DM Burge, M Griffiths, PSJ Malone, eds. Churchill Livingstone, Edinburgh, 1994, pp 395–407. 2. Mayberry JF, Atkinson M: Studies of incidence and prevalence of achalasia in the Nottingham area. Quarterly J Med 56:451, 1985. 3. Buick RG, Spitz L: Achalasia of the cardia in children. Br J Surg 72:341, 1985. 4. London FA, Raab DE, Fuller J, et al.: Achalasia in three siblings: a rare occurrence. Mayo Clinic Proc 52:97, 1977. 5. Westley CR, Herbst JJ, Coldman S, et al.: Infantile achalasia. Inherited as an autosomal recessive disorder. J Pediatr 87:243, 1975. 6. Uzunow G: Familial achalasia of the esophagus in infancy. Radiologia Diagnostica 23:31, 1982. 7. Bosher LP, Shaw A: Achalasia in siblings. Am J Dis Child 135:709, 1981. 8. Frieling T, Berges W, Brochard F, et al.: Family occurrence of achalasia and diffuse spasm of the oesophagus. Gut 29:1595, 1988. 9. Hammami A, Trabelsi M, Bennaceur B, et al.: An association of Addison’s disease, achalasia of the cardia and alacrimation. Apropos of 2 cases. Pediatr Ann 36:279, 1989. 10. Lemmer JH, Coran AG, Wesley JR, et al.: Achalasia in children: treatment by anterior esophageal myotomy (modified Heller operation). J Ped Surg 20:333, 1985. 11. Camarasa Piquer F, Caritg Bosch J, Seculi Palacios J, et al.: Esophageal achalasia: apropos of a case of Down’s syndrome. An Espanol Pediat 29:68, 1988. 12. Riley CM, Day RL, Greeley DML, et al.: Central autonomic dysfunction with defective lacrimation. Report of five cases. Pediatrics 3:468, 1949. 13. Allgrove J, Clayden GS, Grant DB: Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1: 1284, 1978. 14. Rozychi DL, Ruben RJ, Rapin I, et al.: Autosomal recessive deafness associated with short stature, vertigo, muscle wasting and achalasia. Arch Otolaryngol 93:194, 1971. 15. Khalifa MM: Familial achalasia, microcephaly, and mental retardation. Case report and review of literature. Clin Pediatr 27:509, 1988.

Muscle

793

Fig. 18-3. Absence of left pectoral muscle, breast, and nipple in 17-year-old male with Poland-Mo¨bius syndrome. Note inability to close eyes in facial view at right.

18.9 Defects of Pectoralis Muscles and Other Muscles of the Shoulder Girdle The incidence of pectoralis defects varies between one in 4,000 and one in 11,000.1 Hundreds of cases have been reported.2 The defect occurs in males and females with about equal frequency. There are no ethnic predispositions. The defects are most often unilateral, and bilateral occurrence of isolated pectoralis defect is rare.3 Isolated partial defects of the pectoralis muscle rarely cause muscle weakness. Hypertrophy of the remaining parts of the pectoralis compensates for the defect. The functional loss or complete absence of the pectoralis is usually compensated for by neighboring muscles. No consistent abnormalities in muscle histology have been reported. Fibrous and fat tissue were sometimes found in the place of the absent muscle.3 Unilateral pectoralis defect may lead to asymmetry of the thorax, the side with the defect being smaller than the other side. Skin and subcutaneous fat covering the defect are thin and atrophic. The breast may be hypoplastic or completely absent, and the nipple may be absent, as well, on the affected side (Fig. 18-3). Anterior parts of the upper ribs may also be defective. The shoulder on the affected side may be higher, and the scapula is smaller and winged. Unilateral partial aplasia of the serratus anterior, notably of its upper portion, is frequently encountered and leads to asymmetry of the posterior aspect of the thorax.4 Other muscles of the area may be hypoplastic or aplastic as well. This kind of more extensive defect is often bilateral. Cases have been reported in which trapezius, sternocleidomastoid, and parts of both pectorals were absent as well as biceps, and triceps bilaterally.5 Absence of neck muscle can be observed with multiple congenital contractures. Cases of bilateral absence of trapezius and sternal portion of the pectoralis major muscles have been reported by Horan and Bonafede6 and unilateral by DeBeer et al.7 Familial occurrence of pectoralis and other muscle defects is rarely reported. Becker,1 Gross-Kieselstein and Shalev,8 Cotterman

and Falls,9 Meberg and Skogen,10 and Shalev et al.11 have reported families with marked intrafamilial variability. Shalev et al.11 suggested that embryonic vascular variation might predispose to loss of developing muscle and underlying connective tissue. Mollica12 reported a family with vertical transmission of limb palsy reminiscent of brachial palsy; however, it was present on different sides in multiple individuals without any history of birth trauma. Muscles on the affected side were already hypoplasic at birth. David and Winter13 reported a family suggesting autosomal dominant inheritance. More extensive familial mesenchymal defects involving girdle muscles have been reported by Meberg and Skogen,10 Selmar et al.,14 David and Winter,13 and Soltan and Holmes.15 The triceps aplasia in these families may cause bilateral biceps and elbow contractures, with marked webbing of the volar side of the elbows. Uncomplicated pectoralis defect and Poland syndrome appear to be causally related.16 The observations of David and Winter13 and Shavel et al.11 suggest that defects (hypoplasia, aplasia) of diversified muscles may represent manifestations of one and the same pathologic entity. Nevertheless, until the etiology is clear, careful distinguishing descriptions are important. References (Defects of the Pectoralis Muscles and Other Muscles of the Shoulder Girdle) 1. Becker PE: Angeborene Muskeldefekte and Muskelvarietaeten. In: Handbuch der Humangenetik, Band III/1 Thieme Verlag, Stuttgart, 1964, p 527. 2. Zellweger HU, Hanson JW: Muscle. In: Human Malformations and Related Anomalies, vol 2. RE Stevenson, JG Hall, RM Goodman, eds. Oxford University Press, New York, 1993, p 845. 3. Hirschfeld R: Kongenitale Muskeldefekte. In: Handbuch Neurology, vol. 2. M Lewandowsky, ed. Springer Verlag, Berlin, 1911, p 168. 4. Hedge HR, Shokeir MHK: Posterior shoulder girdle abnormalities with absence of pectoralis major muscle. Am J Med Genet 13:285, 1982. 5. Ford FR: Diseases of the Nervous System in Infancy, Childhood and Adolescence, ed 5. Charles C Thomas Publishers, Springfield, IL, 1966.

794

Neuromuscular Systems

6. Horan FT, Bonafede RP: Bilateral absence of the trapezius and sternal head of the pectoralis major muscles. J Bone Joint Surg 59A:133, 1977. 7. DeBeer PH, Brys P, De Smet L, et al.: Unilateral absence of the trapezius and pectoralis major muscle: a variant of Poland syndrome. Genet Couns 13:449, 2002. 8. Gross-Kieselstein E, Shalev RS: Familial absence of trapezius muscle with associated shoulder abnormalities. Clin Genet 32:145, 1987. 9. Cotterman CW, Falls HF: Unilateral developmental anomalies in sisters. Am J Hum Genet 1:203, 1949. 10. Meberg A, Skogen P: Three different manifestations of congenital muscular aplasia in a family. Acta Paediatr Scand 76:375, 1987. 11. Shalev SA, Hall JG: Poland anomaly—report of an unusual family. Am J Med Genet 118A:180, 2003. 12. Mollica F, Li Volti S, Grasso A, et al.: Familial congenital brachial palsy. Am J Med Genet 41:322, 1991. 13. David TJ, Winter RM: Familial absence of the pectoralis major, serratus anterior, and latissimus dorsi muscles. J Med Genet 22:390, 1985. 14. Selmar P, Skov T, Skov BG: Familial hypoplasia of the thenar eminence: a report of three cases. J Neurol Neurosurg Psychiatry 49:105, 1986. 15. Soltan HC, Holmes LB: Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 108:112, 1986. 16. Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Mo¨bius anomalies. Am J Med Genet 23:903, 1986.

18.10 Poland Anomaly Alfred Poland,1 in 1841, reported the first case of a complex unilateral dysplasia involving the chest muscles, arm, hand, and fingers. He described the postmortem findings from a 27-year-old man. There was no clinical history available except that the man had never been able to move his left arm to his right shoulder. The sternocostal part of the pectoralis major, the pectoralis minor, and parts of the anterior left serratus were absent, and the remaining pectoralis major and serratus muscles were hypertrophic. The thoracic blood vessels were rather small on that side. The muscles of the right arm were more developed than the muscles of the left arm. The left hand was smaller than the right hand. There was partial syndactyly, and the middle phalanges of the second, fourth, and fifth fingers were absent. In subsequent years, a number of case reports appeared; reviews were written by Ireland et al.,2 Mace et al.,3 and Beals and Crawford,4 and the term Poland anomaly became the most commonly used term to describe pectoralis defect and ipsilateral brachysyndactyly. Some authors describe Poland anomaly if only the pectoralis is defective, without the ipsilateral limb abnormalities; however, it is more useful to make a distinction if the limb is involved as it is done here. Right-sided involvement is more common than left and males are more frequently involved than females. The brachydactyly is usually due to the partial or total absence of the middle phalanges. In some cases a hypoplastic middle phalanx is fused with the distal phalanx (terminal symphalangism). Cutaneous syndactyly between some fingers can be complete or incomplete. Ectrodactyly, camptodactyly, and transverse reduction defects involving the hands and/or parts of the forearm and rarely parts of the upper arm have been described as well as clawed hands, with only one or two fingers and absence of fingers two to four.5–9 In most cases there is marked clinodactyly of the fifth finger. The thumb may be normal or shortened2,3 but is usually the least affected digit.

The skin, chest wall, and mammary gland changes are similar to those in the isolated pectoralis muscle defects (e.g., thin and atrophic skin, chest wall deformity and rib defects, hypoplastic or completely absent breast, small or absent nipple). Cutaneous dimples may be noted over the shoulder and elbow. Radiologically, aplasia or hypoplasia of phalanges, metacarpals, carpal bones, radius, and ulna may be seen. Axillary webbing is, likewise, encountered. The ipsilaterality of associated findings is maintained in the over whelming majority of the cases; contralateral distribution of the lesions is exceptional.2 In fact, a literature review by Pers10 revealed that only 25% of all cases of syndactyly had Poland anomaly. Ireland et al.2 treated close to 1000 patients with hand anomalies and found that only 9.2% of all syndactyly patients showed defects of the pectoral muscles. A number of other malformations have been described in association with pectoralis muscle defects and Poland anomaly.11 Agenesis or hypoplasia of the ipsilateral kidney and duplication of the collecting system have been reported.3,7,12–15 Hedge13 provides a good review of this combination. The combination of renal abnormalities and breast muscle defects is intriguing. Qvist et al.14 explain it by the simultaneous differentiation of the prethoracic mesenchyme into pectoralis muscles and the regression of the mesonephros and differentiation of the metanephros in weeks 7 and 8 of gestation. Other authors have suspected a later vascular compromise. A peculiar finding is the uncommon but nonrandom occurrence of acute lymphoblastic and acute myeloblastic leukemias in Poland anomaly. Poland anomaly has been estimated to occur in three to 16 per 100,000 people.16,17 Leukemia occurs in about four of 100,000 children under age 15 years. Miller and Miller7 collected four cases of acute leukemia in children with Poland anomaly. A further case of acute lymphocytic leukemia and Poland anomaly was reported by Boaz et al.17 Thus, the incidence of leukemia in Poland anomaly appears greater than would be expected. Other malformations occurring with Poland anomaly are unilateral or bilateral talipes, brachysyndactyly of the toes, metatarsus adductus,18 inguinal and umbilical hernias, undescended testicles,19 plagiocephaly,4 anomalies in the cervical and upper thoracic spine such as Sprengel anomaly, hemivertebrae, spinal bifida occulta,3,20 dextrocardia,21–23 encephalocele,24 hypospadias,12 dermatoglyphics,24 hemiatrophy of the body,25 and microcephaly.26,27 The combination of Poland anomaly with Mo¨bius syndrome deserves special consideration (see later). On rare occasion, affected individuals may have bilateral involvement, but perhaps these cases represent a different condition.28–30 The cause of Poland anomaly as well as of pectoralis muscle defects without hand involvement, is not known. Monozygotic twins who are discordant, with respect to Poland anomaly, have been described.31 Familial Poland anomaly is rare, according to a review by Cobben et al.9 Familial occurrence has been reported by Fuhrmann et al.,32 David,33 Lowry and Bouvet,34 Fraser et al.,35 Jones,20 Bartoshesky et al.,36 Sujansky et al.,37 and Rojas-Martinez et al.38 These observations of familial Poland anomaly indicate that genetic predisposition may play a role in the causation of the anomaly. However, because of the variation seen in families and the usual sporadic nature, environmental factors (such as maternal hypotension) or genetic factors (such as thrombophilias) may be necessary, in addition, to precipitate the anomaly. Goldberg and Mazzei18 attributed the Poland anomaly to pressure from the developing upper limb against the chest in stage 19 (days 44–48) of embryonic development. This does not explain the strict unilaterality of the syndrome seen in most cases. Poland observed smallness of the thoracic vessels on the affected side.

Muscle

Bouvet et al.39 performed rheographic measurements of the arms of eight children with Poland anomaly. Their results suggested a possible hypoplasia of the ipsilateral subclavian artery. Bavinck and Weaver40 presented an elaborate analysis of the embryology of the intrathoracic and cephalic arterial system and conjectured that the Poland anomaly as well as the Mo¨bius and Klippel-Feil anomalies could be caused by a disruption sequence affecting the subclavian and/or vertebral arteries on days 37 to 42 of gestation (stages 17–18). Soltan and Holmes41 and Shalev and Hall8 conjectured that vascular anomalies together with thrombophilia could be responsible for the variety of defects seen in their families. References (Poland Anomaly) 1. Poland A: Deficiency of the pectoral muscles. Guy’s Hosp Rep 6:191, 1841. 2. Ireland DCR, Takayama N, Flatt AE: Poland’s syndrome, a review of 43 cases. J Bone Joint Surg 58A:52, 1976. 3. Mace JW, Kaplan JM, Schanberger JE, et al.: Poland’s syndrome. Report of seven cases and review of the literature. Clin Pediatr 11:98, 1972. 4. Beals RK, Crawford S: Congenital absence of the pectoral muscles. A review of twenty-five patients. Clin Orthop 119:166, 1976. 5. Steigner N, Stewart RE, Setoguchi Y: Combined limb deficiencies and cranial nerve dysfunction: report of six cases. Birth Defects Orig Artic Ser XI(5):133, 1975. 6. Joachimsthal VG: Ueber einen Fall von angeborenem Defekt an der rechten Thoraxhaelfte und der entsprechenden Hand. Berlin Klin Wochenschr 33:804, 1896. 7. Miller RA, Miller DA: Congenital absence of the pectoralis major muscle with acute lymphoblastic leukemia and genitourinary anomalies. J Pediatr 87:146, 1975. 8. Shalev SA, Hall JG: Poland anomaly—report of an unusual family. Am J Med Genet 118A:180, 2003. 9. Cobben JM, Robinson P, van Essen AJ, et al.: Poland anomaly in mother and daughter. Am J Med Genet 33:519, 1989. 10. Pers M: Aplasia of the anterior thoracic wall, the pectoral muscles and the breast. Scand J Plast Reconstr Surg 2:125, 1968. 11. Warkany J: Congenital Malformations. Yearbook Medical Publishers, Chicago, 1971. 12. Curran AS, Curran JP: Associated acral and renal malformations: a new syndrome? Pediatrics 49:716, 1972. 13. Hedge HR, Leung AKC, Robson WLM: Acro-pectoro-renal field defect with contralateral ureteropelvic junction obstruction. Clin Genet 47:210, 1995. 14. Qvist N, Nielsen K, Christensen PV: Aplasia of major pectoral muscle combined with renal aplasia and cystic malformation of common iliac vein. Urology 29:434, 1987. 15. Temtamy SA, McKusick VA: The genetics of hand malformations. Birth Defects Orig Artic Ser XIV(3):323, 1978. 16. McGillivray BC, Lowry RB: Poland syndrome in British Columbia: incidence and reproductive experience of affected persons. Am J Med Genet 1:65, 1977. 17. Boaz D, Mace JW, Gotlin RW: Poland’s syndrome and leukaemia. Lancet 1:349, 1971. 18. Goldberg MJ, Mazzei RJ: Poland syndrome: a concept of pathogenesis based on limb bud embryology. Birth Defects Orig Artic Ser XIII(3D):103, 1977. 19. Castilla EE, Paz JE, Orioli IM: Pectoralis major muscle defect and Poland complex. Am J Med Genet 4:263, 1979. 20. Jones KL: Smith’s Recognizable Patterns of Human Malformations, ed 5. WB Saunders Company, Philadelphia, 1997. 21. Sugerman GI, Stark HH: Moebius syndrome with Poland’s anomaly. J Med Genet 10:192, 1973. 22. Fraser FC, Ronen GM, O’Leary E: Pectoralis major defect and Poland sequence in second cousins: extension of the Poland sequence spectrum. Am J Med Genet 33:468, 1989.

795 23. Bamforth JS, Fabian C, Machin G, et al.: Poland anomaly with a limb body wall disruption defect: case report and review. Am J Med Genet 43:780, 1992. 24. Hedge HR, Shokeir MHK: Posterior shoulder girdle abnormalities with absence of pectoralis major muscle. Am J Med Genet 13:285, 1982. 25. Berger O: Angeborener Defekt des Brustmuskels. Virchows Arch 72:438, 1878. 26. Fryns JP, de Smet L: On the association of Poland anomaly and primary microcephaly. Clin Dysmorphol 3:347, 1994; 6:95, 1997. 27. Moebius PJ: Ueber angeborene doppelseitige Abducens-Facialis Laehmung. Muench Med Wochenschr 35:91, 1888. 28. Shipkov CD, Anastassov YK: Bilateral Poland anomaly: does it exist? Am J Med Genet 118A:101, 2003. 29. Legume C, Godel V, Nemet P: Heterogeneity and pleiotropism in the Moebius syndrome. Clin Genet 20:254, 1981. 30. Maroteaux P, Le Merrer M: Bilateral Poland anomaly versus thoracic dysplasia. Am J Med Genet 80:538, 1998. 31. Liebenam J: Zwillingspathologische Untersuchungen aus dem Gebiet der Anomalien der Koeperform, partiellem Riesenwuchs, angeborenem Pectoralisdefkt, Dystosis cleidocranialis, Dystosis craniofacialis. Z Menschl Vererb Konstitut Forschg 22:373, 1939. 32. Fuhrmann W, Mosseler U, Neuss H: Zur Klinik und Genetik des Poland Syndromes. Deutsch Med Wochenschr 96:1076, 1971. 33. David TJ: Nature and etiology of the Poland anomaly. N Engl J Med 287:487, 1972. 34. Lowry RB, Bouvet JP: Familial Poland anomaly. J Med Genet 20:152, 1983. 35. Fraser FC, Ronen GM, O’Leary E: Pectoralis major defect and Poland sequence in second cousins: extension of the Poland sequence spectrum. Am J Med Genet 33:468, 1989. 36. Bartoshesky LE, Gans B, Goldberg M: Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 109:396, 1986. 37. Sujansky E, Riccardi VM, Matthew AL: The familial occurrence of Poland syndrome. Birth Defects Orig Artic Ser XIII(3A):117, 1977. 38. Rojas-Martinez A, Garcia-Cruz D, Rodriguez Garcia A, et al.: PolandMoebius syndrome in a boy and Poland syndrome in his mother. Clin Genet 40:225, 1991. 39. Bouvet JP, Leveque D, Bernetieres F, et al.: Vascular origin of Poland syndrome? A comparative rheographic study of the vascularisation of the arms in eight patients. Eur J Pediatr 128:17, 1978. 40. Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Mo¨bius anomalies. Am J Med Genet 23:903, 1986. 41. Soltan HC, Holmes LB: Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 108:112, 1986.

18.11 Poland-Mo¨bius Syndrome There are many reports of the Poland anomaly and Mo¨bius syndrome occurring together, usually designated as the PolandMo¨bius association or syndrome.1–23 It was first described by Schmidt in 1897.19 The Mo¨bius syndrome was recognized well before that24–26 because of the striking lack of eye movement. The name Mo¨bius was attached to the syndrome after Mo¨bius’s comprehensive studies of congenital ophthalmoplegia in 1888 and 1892.27,28 As noted above, Mo¨bius syndrome is a heterogeneous condition29 and presumably most often of neuroectodermal or vascular origin.30 The spectrum of limb malformations described in the Mo¨bius syndrome is somewhat different from those occurring in the Poland anomaly and the Poland-Mo¨bius syndrome. Limb malformations in the Mo¨bius syndrome are often bilateral, involving upper and lower extremities, and are more severe; limb abnormalities in the Poland-Mo¨bius syndrome are similar to those occurring in the

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Poland anomaly alone. They are mostly unilateral and ipsilateral to the pectoralis defect; they are less severe and with few exceptions are limited to the upper limb. This could indicate that the pathogenic mechanisms underlying the limb malformations in the Poland and Poland-Mo¨bius syndromes are different from those of the Mo¨bius syndrome alone. These interesting differences certainly deserve further investigation before definite conclusions are drawn. There are a few exceptional cases of Poland-Mo¨bius syndrome, with malformation of the limbs contralateral to the pectoralis defect.4,8,9,15 The contralateral limb abnormalities were limited to clubfeet in the cases of Danis,8 McGillivray and Lowry,4 and Parker et al.,15 while syndactyly of the contralateral hand was observed in the case of Edgerton et al.9 According to Parker et al.,15 the association of the Poland and Mo¨bius syndromes occurs frequently enough to represent a special malformation syndrome of unknown etiology. Whether the Poland-Mo¨bius syndrome is pathologically distinct from other oromandibular limb hypogenesis patterns such as the aglossia-adactylia syndrome, Hanhart syndrome, oromandibular limb hypoplasia, limb deficiency-hypoglossia-micrognathia syndrome, and peromelia with micrognathia syndrome is unclear. Unilateral or bilateral congenital palsy of the sixth and seventh cranial nerves occurs in both groups. The limb malformations are more severe in aglossia-adactylia, involve upper and lower extremities, and are bilateral in contradistinction to the Poland-Mo¨bius syndrome.31–33 Familial cases of Poland-Mo¨bius syndrome have not been reported in the literature thus far. References (Poland-Mo¨bius Syndrome) 1. Poland A: Deficiency of the pectoral muscles. Guy’s Hosp Rep 6:191, 1841. 2. Clarkson P: Poland’s syndactyly. Guy’s Hosp Rep 111:335, 1962. 3. David TJ: Nature and etiology of the Poland anomaly. N Engl J Med 287:487, 1972. 4. McGillivray BC, Lowry RB: Poland syndrome in British Columbia: incidence and reproductive experience of affected persons. Am J Med Genet 1:65, 1977. 5. Bosch-Banyeras JM, Zuasnabar A, Puig A, et al.: Poland-Mo¨bius syndrome associated with dextrocardia. J Med Genet 21:70, 1984. 6. Caravella L, Rogers GL: Dextrocardia and ventricular septal defect in the Mo¨bius syndrome. Ann Ophthalmol 10:572, 1978. 7. Dalloz JC, Nocton F: Le syndrome de Moebius. A propos de deux observations nouvelles. Arch Fr Pediatr 21:1025, 1964. 8. Danis P: Les paralysies oculo-faciales congenitales. Ophthalmology 110:113, 1945. 9. Edgerton MT, Tuerk DB, Fisher JC: Surgical treatment of Moebius syndrome by platysma and temporalis muscle transfers. Plast Reconstr Surg 55:305, 1975. 10. Gadoth N, Biedner B, Torok G: Mo¨bius syndrome and Poland anomaly: case report and review of the literature. J Pediatr Ophthalmol Strabismus 16:374, 1979. 11. Hanissian AS, Fuste F, Hayes WT, et al.: Mo¨bius syndrome in twins. Am J Dis Child 120:472, 1970. 12. Herrmann J, Pallister PD, Gilbert EF, et al.: Studies of malformation syndromes of man XXXXI B: nosologic studies in the Hanhart and the Mo¨bius syndrome. Eur J Pediatr 122:19, 1976. 13. Henderson JL: The congenital facial diplegia syndrome, pathology, clinical features, pathology and aetiology: a review of sixty-one cases. Brain 62:381, 1939. 14. Jorgenson RJ: Moebius syndrome, ectrodactyly, hypoplasia of tongue and pectoral muscles. Birth Defects Orig Artic Ser VII(7): 283, 1971. 15. Parker DL, Mitchell PR, Holmes GL: Poland-Mo¨bius syndrome. J Med Genet 18:317, 1981.

16. Pierson M, Tridon P, Andre JM: Syndrome de Moebius associe a des malformations des malformations des extremetees. A propos de cinq observations. J Genet Hum 22:329, 1974. 17. Richards RN: The Moebius syndrome. J Bone Joint Surg 35A:437, 1953. 18. Rogers GL, Hatch GF Jr, Gray I: Mo¨bius syndrome and limb abnormalities. J Pediatr Ophthalmol 14:134, 1977. 19. Schmidt A: Angeborene multiple Hirnnervenlaehmung mit Brustmuskeldefkt. Deutsch Z Nervenheilk 10:401, 1897. 20. Stevenson RE: The Poland-Moebius syndrome. Proc Greenwood Genet Center 1:26, 1982. 21. Sugarman G, Stark HH: Mo¨bius syndrome with Poland’s anomaly. J Med Genet 10:192, 1973. 22. Szabo L: Moebius’ syndrome und Polandsche Anomalie. Z Orthop und Ihre Grenzgebiete 114:211, 1976. 23. Temtamy SA, McKusick VA: The genetics of hand malformations. Birth Defects Orig Artic Ser XIV(3):323, 1978. 24. Von Graefe A: Graefe-Saemisch Handbuch Augenheilk, vol 6, Engleman, Leipzig, 1880, p 60. 25. Harlan GC: Congenital paralysis of both abducens and both facial nerves. Trans Am Ophthalmol Soc 3:216, 1881. 26. Chisholm JM: Congenital paralysis of the sixth and seventh pairs of cranial nerves in an adult. Arch Ophthalmol 11:323, 1882. 27. Moebius PJ: Ueber angeborene doppelseitige Abducens-Facialis Laehmung. Muench Med Wochenschr 35:91, 1888. 28. Moebius PJ: Ueber infantilen Kernschwund. Muench Med Wochenschr 39:17, 41, 55, 1892. 29. Legum C, Godel V, Nemet P: Heterogeneity and pleiotropism in the Moebius syndrome. Clin Genet 20:254, 1981. 30. Kanski JJ: Clinical Ophthalmology, ed 2. Butterworth, London, 1988. 31. Jones KL: Smith’s Recognizable Pattern of Human Malformations, ed 5. WB Saunders Company, Philadelphia, 1997. 32. Johnson GF, Robinow M: Aglossia-adactylia. Radiology 128:127, 1978. 33. Robinow M, Marsh JL, Edgerton MT, et al.: Discordance in monozygotic twins for aglossia-adactylia, and possible clues to the pathogenesis of the syndrome. Birth Defects Orig Artic Ser XIV(6A):223, 1978.

18.12 Poland-Like Gluteal–Lower Leg Anomaly Patients with a gluteal–lower leg anomaly have been reported, and have a certain resemblance to the Poland anomaly since the proximal limb joint and ipsilateral digits are involved with brachysyndactyly. Riccardi1 described a 21-month-old girl with hypoplasia of the right-side gluteal muscles, shortening of the right leg, and brachysyndactyly of the right foot, without any neurologic and urogenital abnormalities. Two somewhat similar cases were reported by Moeschler et al.2 One 19-month-old boy showed left gluteal hypoplasia and brachysyndactyly of the left foot, with fusion of metatarsal bones and misshapen talus. The other patient showed hypoplasia of the left glutei and left lower leg, with ectrodactyly of the left foot and ipsilateral renal aplasia. Vascular studies were not mentioned in these reports. Corona-Rivera et al.3 and Silengo et al.4 reported additional cases. References (Poland-like Gluteal–Lower Leg Anomaly) 1. Riccardi VM: Unilateral gluteal hypoplasia and brachysyndactyly: lower extremity counterpart of the Poland anomaly. Pediatrics 61:653, 1978. 2. Moeschler JB, Edwards MJ, Graham JM: Lower extremity equivalent of the Poland anomaly. Pediatr Res 25:78A, 1989. 3. Corona-Rivera JR, Corona-Rivera A, Totsuka-Sutto SE, et al.: Corroboration of the lower extremity counterpart of the Poland sequence. Clin Genet 51:257, 1997. 4. Silengo M, Lerone M, Seri M, et al.: Lower extremity counterpart of the Poland syndrome. Clin Genet 55:41, 1999.

Muscle

18.13 Prune Belly Syndrome Aplasia of muscles of the abdominal wall was described 150 years ago by Froehlich.1 His publication is considered the first description of the prune belly syndrome (PBS). Few publications appeared between 1839 and 1900; they were reviewed by Stumme.2 Since then, several hundred cases of obstructive uropathy, which were not always strictly separated from PBS, have been reported. Silverman and Huang3 and Eagle and Barnett4 published large reviews. In recent years, reviews have included efforts to delineate three conditions: (1) isolated abdominal wall deficiency, (2) PBS, and (3) obstructive uropathy without abdominal wall involvement.5–7 Different processes may be involved in each. Prune belly is a descriptive term for wrinkled or nutshell-like abdominal skin with a flaccid, and most often thinned, abdominal wall.8,9 The umbilicus is often replaced by an elongated, vertical, linear scar. It occurs quite often as a sequela of transient or persistent fetal ascites,10,11 in which it is assumed that the pressure from the ascites and edema compresses the fetal muscle, which then dies and is lost. Loss of abdominal wall musculature is not always present in congenital obstructive uropathy (Fig. 18-4). PBS is seen most frequently in males, probably because there are more sites at which genitourinary (GU) obstruction can occur, and is characterized by the following triad of manifestations in males: (1) dysgenesis or partial or total aplasia of muscles of the abdominal wall; (2) undescended abdominal testes; and (3) complex malformations of the urinary tract.12 The testes are usually histologically normal. They may be attached to the lateral wall of the distended urinary bladder. Unilateral or bilateral testicular agenesis has been observed in rare instances13,14; however, usually the failure to descend is not intrinsic to the testicle, but rather related to loss of the gubernacular muscle.

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Developmental abnormalities may affect structures of the whole urinary tract. The prostate gland may be small (rarely completely absent) and may have reduced glandular tissue as well as smooth muscle hypoplasia. The proximal (prostatic) portion of the urethra is dilated, suggesting there has been obstruction by the prostatic tissue during development. Obstruction or stenosis of the proximal urethra at birth is uncommon in PBS (in contrast to obstructive uropathy), yet earlier functional obstruction has been thought to have occurred in utero by various investigators.6,15,16 Constrictions in the distal urethra have also been noted in PBS.17,18 The urinary bladder is usually pear-shaped, with the thin end fixed to the umbilical area. In some instances the bladder is widely dilated and sometimes communicates with persistent urachus. The ureters are irregularly thickened; very thick areas alternate with areas of lesser thickness, suggesting the smooth muscle has been disrupted, probably by dilation caused by obstruction further down the tract. The thickened walls consist mainly of abundant fibrous tissue, while the smooth muscle is hypoplastic and in certain places is almost absent, again suggestive of earlier compression.12 Disarray of smooth muscle fibers in the ureters has been demonstrated by Welch and Kraney.19 Areas of hypertrophic smooth muscle have also been observed.14,20 Endovesicular and endoureteral pressure are normal or slightly increased at birth and not as high as is seen in obstructive uropathy, which may be a later developing developmental process. The kidneys are usually dysgenetic; they may be small and dysplastic, with embryonal tubules, cartilage, and cysts and a reduced number of functional nephrons. Defects of the autonomic nerves supplying the urinary tract have been described by Henley and Hyman21 but are not always seen. Alterations of the GU tract in PBS are usually symmetric or only slightly asymmetric. Abdominal and visceral muscle malformations also are occasionally identified in the related disorder of exstrophy of the cloaca, OEIS complex, or vesicointestinal fissure. In this disorder there is incomplete development of both the inferior abdominal wall and the

Fig. 18-4. Prune belly in a newborn male showing thin, wrinkled, and flaccid abdominal wall (left and middle). Mild prune belly appearance with poor abdominal musculature in a newborn female (right).

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urorectal septum, implying an early defect in lateral plate mesoderm. In addition to absence or hypoplasia of the abdominal musculature, Cripe et al.22 observed abnormal organization and layering of the muscles of the small intestine and bowel as well as of the smooth muscle of the bladder. These authors concluded that the disorganization of the gastrointestinal musculature represents a primary malformation and accounts for the bowel dysmotility and pseudoobstructive symptoms commonly observed in those patients. A variety of other malformations may be seen in association with PBS. They include talipes equinovarus and rarely transverse reduction defects of lower limbs21–25; malrotations of the gut; common mesentery, intestinal, and anal atresias26,27; omphalocele; gastroschisis; hypoplasia of the lungs; cardiovascular malformations28,29; neural tube defects; and other dysgenetic alternations of the neuraxis, notably dysgenesis of the anterior horns of the spinal cord.30 The prognosis of PBS is guarded. Stillbirths and deaths in the perinatal period and in infancy are frequent. Some deaths are due to pulmonary hypoplasia (related to oligohydramnios), renal failure, and infections. Incomplete and milder forms of PBS with longer survival have been reported,31–34 notably among females. PBS occurs predominantly in the male; 90% of all cases are males.35 In females it is often difficult to differentiate PBS from isolated abdominal muscle deficiency, since one important diagnostic criterion of the triad, cryptorchidism, is not present. Likewise, this distinction may be impossible in cases when examination of the urinary tract does not reveal any conspicuous abnormalities.23,36 Dysplasia of the abdominal wall musculature, especially in females, has diverse etiologies. An important cause is fetal hydrops and ascites just as in PBS. In this context, it is not without interest that an unusual number of female infants with monosomy X and Turner-like phenotypes have been observed in association with prune belly.37–40 It cannot be overlooked, however, that one of the two Turner cases studied by Lubinsky et al.37 had a megaureter on one side and a small kidney on the other side, which makes the differential diagnosis even more difficult. An interesting observation was reported by Adeyokuanu and Familuzi.40 The authors reported two sibs with dilation of ureters and bladder: one boy died at the age of 2 months with typical PBS, and the other showed monosomy X. Other chromosomal abnormalities have not been reported in PBS, with the exception of those in two brothers studied by Harley et al.17 Both had PBS and showed a chromosomal mosaicism, with a monosomy 16 cell population. Familial cases have been reported rarely.14,17,40–42 The inheritance pattern of these cases is not clear; autosomal recessive as well as X-linked recessive inheritance have been considered. Even in monozygotic twins, only one twin is usually affected with PBS.43,44 References (Prune Belly Syndrome) 1. Froehlich F: Der Mangel der Muskeln, insbesondere der Seitenbachmuskeln. Thesis, Wuerzburg, 1839. 2. Stumme EG: Ueber die symmetrischen kongenitalen Bauchmuskelddefekte und ueber die Kombination derselben mit andern Bildungsanomalien des Rumpfes. Mitt Grenzgeb Med Chir 11:548, 1903. 3. Silverman FN, Huang N: Congenital absence of the abdominal muscles associated with malformation of the genitourinary tract: report cases and review of literature. Am J Dis Child 80:91, 1950. 4. Eagle JF Jr, Barrett CS: Congenital deficiency of abdominal musculature with associated genitourinary abnormalities: a syndrome. Report of nine cases. Pediatrics 6:721, 1950. 5. Nunn N, Stephens FD: The triad syndrome: a composite anomaly of the abdominal wall, urinary system and testes. J Urol 86:782, 1961.

6. Stevenson RE, Schroer RJ, Collins J, et al.: Fetal ascites: the underlying cause for prune belly. Proc Greenwood Genet Center 6:16, 1987. 7. Straub E, Spranger J: Etiology and pathogenesis of the prune belly syndrome. Kidney Int 20:695, 1981. 8. Osler W: Congenital absence of the abdominal muscles with distended and hypertrophied urinary bladder. Bull Johns Hopkins Hosp 12:331, 1901. 9. Welling P, Pfeiffer RA, Kosenow W, et al.: Beobachtungen zum Bauchmuskelaplasie Syndrom. Z Kinderheilk 118:315, 1975. 10. Pagon RA, Smith DW, Shepard TH: Urethral obstruction malformation complex: a cause of abdominal muscle deficiency and the ‘‘prune belly.’’ J Pediatr 94:900, 1979. 11. Nakayama DK, Harrison MR, Chinn DH, et al.: The pathogenesis of prune belly. Am J Dis Child 138:834, 1984. 12. Zellweger HU, Hanson JW: Muscle. In: Human Malformations and Related Anomalies, vol. 2. RE Stevenson, JG Hall, RM Goodman, eds. Oxford University Press, New York, 1993, p 845. 13. Lee SM: Prune-belly syndrome in a 54-year-old man. JAMA 237:2216, 1977. 14. Riccardi VM, Grum CM: The prune belly anomaly: heterogeneity and superficial X-linkage mimicry. J Med Genet 14:266, 1977. 15. Deklerk DP, Scott WW: Prostatic maldevelopment in the prune belly syndrome: a defect in prostatic stromal-epithelial interaction. J Urol 120:341, 1978. 16. Moerman P, Fryns JP, Goddeeris P, et al.: Pathogenesis of the prunebelly syndrome: a functional urethral obstruction caused by prostatic hypoplasia. Pediatrics 73:470, 1984. 17. Harley LM, Chen Y, Rattner WH: Prune belly syndrome. J Urol 108:174, 1972. 18. Smythe AR: Ultrasonic detection of fetal ascites and bladder dilation with resulting prune belly. J Pediatr 98:978, 1981. 19. Welch KJ, Kraney GP: Abdominal musculature deficiency syndrome prune belly. J Urol 111:693, 1974. 20. King CR, Prescott G: Pathogenesis of the prune-belly anomaly. J Pediatr 93:273, 1978. 21. Henley WL, Hyman A: Absent abdominal musculature, genitourinary anomalies and deficiency in pelvic autonomic nervous system. Am J Dis Child 86:795, 1953. 22. Cripe LH, Mitros FA, Soper RT, et al.: Association of visceral myopathy with viscio-intestinal fissure. Teratology 35:50A, 1987. 23. Lattimer JK: Congenital deficiency of the abdominal musculature and associated genitourinary anomalies. Report of 22 cases. Trans Am Assoc Genitourinary Surg 49:28, 1957. 24. Carey JC, Eggert L, Curry CJ: Lower limb deficiency and the urethral obstruction sequence. Birth Defects Orig Artic Ser XVIII(3B):19, 1982. 25. Perez-Aytes A, Graham JM, Hersh JH, et al.: Urethral obstruction sequence and lower limb deficiency: evidence for the vascular disruption hypothesis. J Pediatr 123:398, 1993. 26. Gaboardi F, Sterpa A, Thiebat E: Prune-belly syndrome: report of three siblings. Helv Paediatr Acta 37:283, 1982. 27. Oliveira G, Boechat MI, Ferreira MA: Megacystis-microcolon-intestinal hypoperistalsis syndrome in a newborn girl whose brother had prune belly syndrome: common pathogenesis? Pediatr Radiol 13:294, 1983. 28. Irish MS, Holm BA, Glick PL: Congenital diaphragmatic hernia. A historical review. Clin Perinatol 23:625, 1996. 29. Burke EC, Shin MH, Kelalis PP: Prune-belly syndrome. Clinical findings and survival. Am J Dis Child 117:668, 1969. 30. Burton BK, Dillard RG: Brief clinical report: prune belly syndrome: observations supporting the hypothesis of abdominal overdistention. Am J Med Genet 17:669, 1984. 31. Banker BQ: Dysgenesis of the spinal cord and prune belly syndrome. In: Myology. AG Engel, BQ Banker, eds. McGraw-Hill, New York, 1986, p 2131. 32. Woodhouse CR, Ransley PG, Innes-Williams D: Prune belly syndrome— report of 47 cases. Arch Dis Child 57:856, 1982. 33. Wheatley JM, Stephens FD, Hutson JM: Prune-belly syndrome: ongoing controversies regarding pathogenesis and management. Sem Pediatr Surg 5:95, 1996.

Muscle 34. Vermeij-Keers C, Hartwig NG, van der Werff JF: Embryonic development of the ventral body wall and its congenital malformations. Semin Pediatr Surg 5:82, 1996. 35. Romanet P, Aira G, Payet G: Aplasie congenitale de la musculature de la paroi abdominale ‘‘prune belly’’ syndrome. Arch Fr Pediatr 37:401, 1980. 36. Rabinowitz R, Schillinger JF: Prune belly syndrome in the female subject. J Urol 118:454, 1977. 37. Lubinsky M, Koyle K, Trunca C: The association of ‘‘prune belly’’ with Turner’s syndrome. Am J Dis Child 134:1171, 1980. 38. Stanga E: Ueber multiple Abartungen mit Flughautbildung (Pterygium Syndrom) und kongenitaler Aplasie der Bauchdeckenmuskulatur. Pediatr Ann 187:384, 1956. 39. Guillen DR, Lowichik A, Schneider NR, et al.: Prune-belly syndrome and other anomalies in a stillborn fetus with a ring X chromosome lacking XIST. Am J Med Genet 70:32, 1997. 40. Adeyokuanu AA, Familuzi JB: Prune belly syndrome in two siblings and a first cousin. Am J Dis Child 136:23, 1982. 41. Garlinger P, Ott J: Prune belly syndrome. Possible genetic implications. Birth Defects Orig Artic Ser X(8):173, 1974. 42. Gaboardi F, Sterpa A, Thiebat E, et al.: Prune-belly syndrome: report of three siblings. Helv Paediatr Acta 37:283, 1982. 43. Ives EJ. The abdominal muscle deficiency triad syndrome—experience with ten cases. Birth Defects Orig Artic Ser X(4):127, 1974. 44. Lubinsky M, Rapoport P: Transient fetal hydrops and ‘‘prune belly’’ in one identical female twin. N Engl J Med 308:256, 1983.

18.14 Isolated Deficiency of Abdominal Muscles A number of reports of the absence of just abdominal muscles have been published over the years,1–12 including descriptions of absent or rudimentary quadratus lumborum in addition to the abdominal wall muscle alterations.11 The alterations of the abdominal musculature include aplasia, hypoplasia, and dysgenesis.2,4–6,12,13 In other instances, the lateral abdominal muscles are completely absent. If the absence is a failure of formation of the muscle then it must occur before week 12 of gestation, since that is when delamination of the abdominal wall muscle tissue normally takes place. In other cases, these can be localized defects suggestive of vascular compromise. Of course, gastroschisis is thought to occur when there is rupture of a localized defect of the abdominal wall near the umbilicus secondary to vascular compromise. Among the various abdominal muscles that may have deficiency, the transverses abdominis is most often affected, then rectus abdominis, the internal and external obliques, and finally the supraumbilical segment of the rectus abdominus. The hypoplasia of muscle tissue may be present only in patches.14 In severe cases, the abdominal wall is so thin that all abdominal organs can be easily seen and palpated. When the defect is localized, abdominal contents may push against the skin and poke out through the defect past the rest of the abdomen, with increased intra-abdominal pressure. In areas where the muscle is absent, it is replaced by fibrous tissue and fat that can be quite dense. The muscle fibers vary in size; most of them are small and are separated from each other as in the early phases of skeletal muscle development. Myotube-like changes were described by O’Kell.12 Large fibers can be seen as well, although they are less frequent. Central nuclei are more frequent than normal. Absence of muscle spindles may be present.4 Most muscle studies in prune belly syndrome (PBS) indicate a dysgenetic rather than a degenerative process, yet some parts of the muscle even show normal

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histology. Moerman et al.,4 on the other hand, found degeneration of the nuclei, fiber splitting, hyalinization, and loss of crossstriation in some fibers in seven well-studied cases. Afifi et al.13 described electron microscopic studies of the rectus muscle of a 2year-old girl with isolated abdominal muscle deficiency and found disarray of the myofilaments and severe streaming and even absence of Z-disks. In addition, their sample showed necrotic fibers, some invaded by macrophages. The findings of Afifi et al.13 were suggestive of a congenital myopathy with degeneration; however, insults at various stages in embryonic/fetal development from compression or vascular compromise may give very different pictures later in development. The etiology and pathogenesis of PBS are still unclear. Banker5 assumed that the muscular defect and the genitourinary (GU) abnormalities result from a primary mesodermal defect; however, other more recent publications maintain the theory4,15 that GU obstruction leads to compression and secondary loss of the developing abdominal well muscle. Still others support the idea that destructive pressure from ascites or edema interfere with muscle development, while others support vascular compromise with secondary loss of muscle. References (Isolated Deficiency of Abdominal Muscles) 1. Froehlich F: Der Mangel der Muskeln, insbesondere der Seitenbachmuskeln. Thesis, Wuerzburg, 1839. 2. Nunn N, Stephens FD: The triad syndrome: a composite anomaly of the abdominal wall, urinary system and testes. J Urol 86:782, 1961 3. Straub E, Spranger J: Etiology and pathogenesis of the prune belly syndrome. Kidney Int 20:695, 1981. 4. Moerman P, Fryns JP, Goddeeris P, et al.: Pathogenesis of the prunebelly syndrome: a functional urethral obstruction caused by prostatic hypoplasia. Pediatrics 73:470, 1984. 5. Banker BQ: Dysgenesis of the spinal cord and prune belly syndrome. In: Myology. AG Engel, BQ Banker, eds. McGraw-Hill, New York, 1986, p 2131. 6. Greinacher I, Straub E: Da Prune Belly Syndrome und dessen inkomplette. Formen Mschr Kinderheilk 125:325, 1977. 7. Parker RW: Case of an infant in whom some abdominal muscles were absent. Lancet 1:1252, 1895. 8. Guthrie L: Congenital deficiency of the abdominal muscles. Trans Pathol Soc London 47:137, 1896. 9. Garrod AE, Davies W: On a group of associated congenital malformations. Med Chir Trans R Med Chir Soc London 48:363, 1905. 10. Monie IW, Monie BJ: Prune belly syndrome and fetal ascites. Teratology 19:111, 1979. 11. Housden LG: Congenital absence of the abdominal muscles. Arch Dis Child 9:219, 1934. 12. O’Kell RT: Embryonic abdominal musculature associated with anomalies of the genitourinary and gastrointestinal systems. Am J Obstet Gynecol 105:1283, 1969. 13. Afifi AK, Rebeiz J, Mire J, et al.: The myopathology of the prune belly syndrome. J Neurol Sci 15:153, 1972. 14. Zellweger HU, Hanson JW: Muscle. In: Human Malformations and Related Anomalies, vol. 2. RE Stevenson, JG Hall, RM Goodman, eds. Oxford University Press, New York, p 845. 15. Stevenson RE, Schroer RJ, Collins J, et al.: Fetal ascites: the underlying cause for prune belly. Proc Greenwood Genet Center 6:16, 1987.

18.15 Diaphragmatic Defects Diaphragmatic hernia is covered elsewhere; however, it does represent a structural abnormality of muscle. It can occur as an isolated defect or together with other abnormalities such as limb

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defects,1,2 cardiac defects, and cleft lip and palate.3 Thirty-nine percent have nonpulmonary malformations.4 Thirty-four percent of those diagnosed prenatally have karyotype abnormalities.5,6 Depending on where the hernia occurs there is greater or lesser chance of recurrence. Bochdalek hernias have the lowest risk of recurrence (about 1%) and complete absence of the diaphragm the highest.7,8 Etiology of sporadic cases is unclear,9 but Fryns syndrome and Pallister-Killian syndrome must be considered.10 References (Diaphragmatic Defects) 1. McCredie J, Reid IS: Congenital diaphragmatic hernia associated with homolateral upper limb malformation: a study of possible pathogenesis in four cases. J Pediatr 92:762, 1978. 2. Martinez-Frias ML: Epidemiological analysis of the association of congenital diaphragmatic hernia with upper-limb deficiencies: a primary polytopic developmental field defect. Am J Med Genet 62:68, 1996. 3. Fauza DO, Wilson JM: Congenital diaphragmatic hernia and associated anomalies: their incidence, identification, and impact on prognosis. J Pediatr Surg 29:1113, 1994. 4. Cunniff C, Jones KL, Jones MC: Patterns of malformation in children with congenital diaphragmatic defects. J Pediatr 116:258, 1990. 5. Howe DT, Kilby MD, Sirry H, et al.: Structural chromosome anomalies in congenital diaphragmatic hernia. Prenat Diagn 16:1003, 1996. 6. Enns GM, Cox VA, Goldstein RB, et al.: Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review. Am J Med Genet 79:215, 1998. 7. Czeizel A, Kovacs M: A family study of congenital diaphragmatic defects. Am J Med Genet 21:105, 1985. 8. Irish MS, Holm BA, Glick PL: Congenital diaphragmatic hernia. A historical review. Clin Perinatol 23:625, 1996. 9. Tibboel D, Gaag AV: Etiologic and genetic factors in congenital diaphragmatic hernia. Clin Perinatol 23:689, 1996. 10. Veldman A, Schlosser R, Allendorf A, et al.: Bilateral congenital diaphragmatic hernia: differentiation between Pallister-Killian and Fryns syndromes. Am J Med Genet 111:86, 2002.

18.16 Variations with Accessory Muscle Tissue Variation of muscle tissue where there is additional muscle tissue may cause discomfort. The so-called axillary arch muscle or ‘‘Achselbogen-muskel’’ is an accessory muscle. Its possible relationship to the panniculus carnosus has been discussed by Weissberg.1 The axillary arch muscle originates from the lower digitations of the serratus anterior or from the lateral margin of the latissimus dorsi, extends through the axillary groove, and inserts into the dorsal aspects of the pectoralis major. The axillary arch muscle can be recognized clinically as a longitudinal bulge dividing the axillary groove into two parts. Pichler2 found it in 3–4% of living individuals, and Kopsch3 found it in 7–8% of autopsies. The axillary arch muscles can, in some instances, lead to entrapment of the vessels and nerves in the axilla and compromise the circulation to the arm or produce neurologic pains when the arm is raised.4 Another muscle anomaly in the axillary region is the accessory subscapularis-teres-latissimus muscle, which arises at the lateral margin of the scapula either from the subscapularis or from the latissimus dorsi. It penetrates through the brachial plexus and merges with the tendon of the pectoralis major. The muscle has a width and length of several centimeters. Kameda5 found this variation in 10 of 190 autopsies. Its clinical implications have not been described. Variations of accessory muscle producing clinical symptoms occur also in the popliteal fossa. A third head of the gastrocne-

mius has been reported.6,7 This third gastrocnemius head may compromise the circulation. Constant or intermittent compression of the popliteal artery causes swelling of the ankles, pain and tiredness in the lower legs, and cramps and intermittent claudication. Similar entrapment can be caused by fibrotic bands between the two heads of the gastrocnemius and by a deviant course of the popliteal artery.8 The entrapment of the popliteal vessels occurs predominantly among young and muscular individuals. It can be recognized on ultrasound examination of the popliteal fossa, with Doppler studies, and with angiography. Dunn9 examined a 20-year-old man who had noticed a painful swelling in the right popliteal fossa. At surgery, an extra 3  5-cm, fleshy hamstring belly was found, which crossed the popliteal fossa without compromising the neurovascular structures. Congenital hypertrophy of intrinsic foot muscles has been described by Dunn,9 Estersohn et al.,10 and Jahss.11 Estersohn et al.10 described a congenital hypertrophic abductor digiti quinti of the right foot in a woman who complained of pain in the foot and the right lower leg. She had to wear special shoes to prevent painful compression of the extra muscle. Removal of the hypertrophic muscle rendered her pain-free. The excised extra muscle showed normal muscle fibers, with some inflammatory reaction, the latter probably due to pressure. A considerable swelling of the middle two-thirds of the arch of the left foot of a 4-year-old girl came to the attention to Jahss.11 A possible malignancy was included in the differential diagnosis, but the operation revealed an excessive hypertrophy of the median head of the head of the m. quadratus plantae. It is quite probable that most of such localized muscle hypertrophies remain unrecognized, especially if they do not cause discomfort. References (Variations with Accessory Muscle Tissue) 1. Weissberg H: Ueber einen Fall von muskulaerem Achselbogen. Anat Anz 74:105, 1932. 2. Pichler K: Ueber den Langer’schen Achselbogen. Anat Anz 49:310, 1916. 3. Kopsch F: Lehrbuch und Atlas der Anatomie des Menschen, vol 1. Georg Thieme Verlag, Leipzig, 1939, p 450. 4. Karacagil S, Eriksson I: Entrapment of the axillary artery by anomalous muscle. Case report. Acta Chirurgie Scand 153:633, 1987. 5. Kameda Y: An anomalous muscle (accessory subscapularis-teres-latissimus muscle) in the axilla penetrating the brachial plexus in man. Acta Anatom 96:513, 1976. 6. Iwai T, Sato S, Yamada T, et al.: Popliteal vein entrapment caused by the third head of the gastrocnemius muscle. Br J Surg 74:1006, 1987. 7. McDonald PT, Easterbrook JA, Rich NM, et al.: Popliteal artery entrapment syndrome. Clinical, noninvasive and angiographic diagnosis. Am J Surg 139:318, 1980. 8. Iwai T, Konno S, Soga K, et al.: Diagnostic and pathological considerations in the popliteal artery entrapment syndrome. J Cardiovasc Surg 24:243, 1983. 9. Dunn AW: Anomalous muscles simulating soft-tissue tumors in the lower extremities. Report of three cases. J Bone Joint Surg 47:1397, 1965. 10. Estersohn HS, Agins SW, Ridenour J: Congenital hypertrophy of an intrinsic muscle of the foot. J Foot Surg 26:501, 1987. 11. Jahss MH: Pseudotumors of the foot. Orthop Clin North Am 5:67, 1974.

18.17 Muscle Atavisms Animals, including lower mammals, have muscles that are directly attached to the skin; they are called skin muscles or panniculus

Muscle

carnosus.1,2 The skin muscle enables the animal to move localized parts of the skin, apparently as a protective measure to shake off localized noxious agents such as insects. In humans, the limbs, notably the arms, have developed to a degree such that they can reach around the body. Thus, skin muscles have become obsolete and have regressed, yet remnants of the panniculus carnosus are still found in some individuals. One such remnant is probably the musculus sternalis.1–6 The musculus sternalis originates from any of the following structures: upper rectus sheet, fascia of the external oblique muscle, lower sternum, and lower ribs. It extends upward, covering sternum and/or costosternal junctions to merge with the sternal head of the sternomastoid, manubrium sterni, or pectoral muscle. It measures between 0.5 and 4 cm in width and can be unilateral or bilateral. It occurs in 3–5% of normal individuals and has no clinical significance.7 The musculus sternalis is found more often than expected among anencephalic infants. The musculus sternalis can be recognized in the living. It becomes apparent with dorsiflexion of the head with certain movements of the ipsilateral arm.8 Other muscles that may contain remnants of the panniculus carnosus are pectoral muscles, trapezius, serratus, pyramidalis, palmaris longus, and some craniofacial muscles. On the other hand, muscles that carry remnants of the panniculus carnosus are also found to be more often absent or partially defective than other muscles. The m. pyramidalis is absent in 16–17% and the m. palmaris longus in 11% of all carefully dissected bodies.9–11 Newer studies have shown that the absence of the palmaris longus differs among various ethnic groups.12 Four percent of 1500 blacks and Asians (Chinese, Japanese, Indians) and 16.4% of 9562 whites had absent palmaris longus. It is interesting to note that 42% of 164 anencephalics had no palmaris longus.7 Regression of the m. pyramidales may be related to another evolutionary process; it is an important muscle in certain lower mammals, for instance, in marsupials, in which it participates in the formation of the pouch. It has lost its functional importance in humans. Another muscle frequently absent in humans is the m. psoas minor. It is functionally important in leaping in animals, and thus seems to be of lesser importance for humans.13 According to Bergman et al.,1 bilateral agenesis of the psoas minor occurs in about 50% of carefully dissected bodies and when present shows considerable variations. Other atavistic remnants are the ‘‘brevis’’ muscles of the hand. Some individuals show peculiar swellings of the dorsum of the hands, which can be mistaken for ganglia or tumors. These swellings consist of the muscle belly of the finger extensors. They are called brevis muscles. Normally the muscle belly of the finger extensors of humans is located proximal to the carpal bone, where it is normally located in lower animals.14 It can present as a swelling on the dorsum of the hand. At times, it can become extremely painful, necessitating surgical intervention.6 Shortness and also ossification of the costocoracoid ligament are rare variations, usually without clinical significance. In some instances, however, it can lead to complaints such as rounded, sloping shoulders, narrow upper thoracic cage with shortened internipple distance, and fixation of scapula to the first rib, reducing shoulder joint mobility. Such individuals may be unable to raise their arms above the head, which may impede certain activities. However, the condition is surgically correctible. Shortness of the costocoracoid ligament is usually sporadic, though familial cases suggesting autosomal dominant inheritance have been reported.15 The condition is physiologically normal in certain lower animals, such as monotremes, where it is supposed to convey stability to the

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shoulder girdle.16 Reactivation of a dormant atavistic gene could account for the abnormal costocoracoid ligament in humans.17 Comparative anatomy has gone out of fashion; however, developmental genetics will probably give insight to these disorders. References (Muscle Atavisms) 1. Bergman RA, Thompson SA, Afifi AK: Compendium of Human Anatomic Variation: Text, Atlas, and World Literature. Urban & Schwarzenberg, Baltimore, 1988. 2. Klingler JS: The dermal muscles. In: Outlines of Comparative Anatomy of Vertebrates, ed 3. Blakiston, Philadelphia, 1926, p 145. 3. Turner W: On the musculus sternalis. J Anat Physiol 1:246, 1867. 4. Rueckert J: Ueber angeborenen Defect der Brustmuskeln. Muench Med Wochenschr 37:469, 1890. 5. Ruge G: Der Hautrumpfmuskel des Menschen. Gegenbaurs Morphol Jahrb 47:677, 1914. 6. Rauhut F: Einige Muskelanomalien der Hand und deren praktischchirugische Bedeutung. Zentralbl Chir 111:620, 1986. 7. Zellweger HU, Hanson JW: Muscle. In: Human Malformations and Related Anomalies, vol. 2. RE Stevenson, JG Hall, RM Goodman, eds. Oxford University Press, New York, 1993, p 845. 8. Pichler K: Ueber den Langer’schen Achselbogen. Anat Anz 49:310, 1916. 9. LeDouble AF: Traite des Variations du systeme Musculaire de l’Homme. Schligher Freres, Paris, 1897. 10. Bing R: Ueber angeborene Muskeldefekte. Virchows Arch 170:175, 1902. 11. Abromeit B: Beitrag zur Kenntnis der kongenitalen Muskeldefekte. Mschr Psychiatr Neurol 25:440, 1901. 12. Gates RR: Human Genetics. Macmillan Co, New York, 1946, p 957. 13. Weissberg H: Ueber einen Fall von muskulaerem Aschselbogen. Anat Anz 74:105, 1932. 14. Bunnell S, Boehler J: Chirurgie der Hand, 1. Teil. Maudrich, Wein, 1958. 15. Bamforth JS, Bell MH, Hall JG, et al.: Congenital shortness of the costocoracoid ligament. Am J Med Genet 33:444, 1989. 16. Griffith M: The Biology of the Monotremes. Academic Press, London, 1987. 17. Cantu JM, Ruiz C: On atavisms and atavistic genes. Ann Genet 28:141, 1985.

18.18 Muscle Abnormalities Associated with Chromosomal Disorders Numerous muscle variations, aplasias, hypoplasias, and supernumerary muscles or extra muscle slips occur with greater frequency in individuals with chromosomal anomalies than in euploid individuals.1–7 However, muscle anomalies in trisomies 13, 18, and 21 and in some aneusomies often involve the same muscle and muscle groups as in euploid individuals. Absence of the m. palmaris longus, which occurs in one of eight individuals, was noted in all patients with trisomy 13 and trisomy 18. Absence of the palmaris brevis is found in 2% of normal controls, yet it was missing in 13 of 14 (93%) patients with trisomy 13 and in five of 16 (31%) patients with trisomy 18.1,2 The psoas minor, which is frequently missing in normal controls, was consistently absent in those with trisomy 18.3 Some of the muscles absent in normal trisomic individuals are muscles that differentiate rather late during embryonic development. The higher frequency of muscle anomalies in aneuploid individuals might be explained by the fact that aneuploid cells divide more slowly than euploid cells or that developmental processes are delayed in aneuploid individuals. Facial muscles, which are remnants of the panniculus carnosus, tend to be hypoplastic in some normal individuals and may be absent in 18 trisomic individuals.3

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Slowness of regression of embryonal muscle in aneuploidy may lead to its persistence or at least to persistence of some muscle slips. Various supernumerary muscles have been reported in aneuploid and aneusomic individuals.1 An extra muscle originating from the lateral margin of the latissimus dorsi and inserting in the pectoralis major or coracoid process, the so-called m. pectorodorsalis, was found in seven of eight individuals with trisomy 13 and in one patient with partial distal 13q trisomy. The m. pectorodorsalis was not found in trisomy 18. An axillary arch (Achselbogen muscle), which is present in 7–8% of normal individuals, was found in seven of eight patients (87.5%) with trisomy 13. The latter patients quite often show unusual muscle bundles originating from the central parts of the diaphragm and reaching to the pericardium. An extra muscle slip originating from the occipital insertion of the trapezius and inserting in the preauricular fascia of the parotid area or in the platysma is found with great consistency in trisomy 21 and trisomy 18 cases and in some cases of trisomy 13.7 Generalized muscular hypoplasia has also been found in some cases of trisomy 21 (personal observation), in cases of partial trisomy 21, and in cases of partial trisomy, notable in partial trisomy 10p.4 The many muscle variations occurring in patients with

chromosomal abnormalities have been thoroughly discussed by Bersu and Ramirez-Castro,3 Colacino and Pettersen,5 and Pettersen et al. 1,2 References (Muscle Abnormalities Associated with Chromosomal Disorders) 1. Pettersen JC: Anatomical studies of a boy trisomic for the distal portion of 13q. Am J Med Genet 4:383, 1979. 2. Pettersen JC, Koltis GG, White MJ: An examination of the spectrum of anatomic defects and variations found in eight cases of trisomy 13. Am J Med Genet 3:183, 1979. 3. Bersu ET, Ramirez-Castro JL: Anatomical analysis of the developmental effects of aneuploidy in man—the 18-trisomy syndrome: I. Anomalies of the head and neck. Am J Med Genet 1:173, 1977. 4. Grosse KP, Schwanitz G, Singer H, et al.: Partial trisomy 10p. Humangenetik. 29:141, 1975. 5. Colacino SC, Pettersen JC: Analysis of the gross anatomical variations found in four cases of trisomy 13. Am J Med Genet 2:31, 1978. 6. Pfeiffer RA, Huether W: Trisomie des Chromsoms Nr 18 unter dem Bilde der Arthrogrypsos multiplex congenita. Med Klin 58:1110, 1963. 7. Pichler K: Ueber den Langer’schen Achselbogen. Anat Anz 49:310, 1916.

Part V Skeletal System

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19 Pectoral Girdle, Spine, Ribs, and Pelvic Girdle Louanne Hudgins and Keith Vaux

T

he skeletal system is composed of the axial skeleton (cranium, vertebral column, ribs, and sternum) and the appendicular skeleton (pectoral girdle, pelvic girdle, and bones comprising the limbs). This chapter will review normal development and malformations of the pectoral girdle, spine, ribs, and pelvic girdle. Normal and abnormal development of the cranium are discussed in Chapter 7 and the limbs in Chapters 20 to 22. The skeleton develops from the somatic layer of the paraxial and lateral plate mesoderm and from neural crest cells.1,2 At the same time the notochord and neural tube are forming, the paraxial mesoderm lateral to these structures form two longitudinal columns. These columns become segmented into blocks of mesoderm toward the end of the 3rd week. From the occipital region caudally, these blocks are referred to as somites. Each somite differentiates into two parts: the sclerotome, located ventromedially, which forms the vertebrae and the ribs, and the dermomyotome, located dorsolaterally, which forms the dermis and the myoblasts. The embryonic connective tissue, the mesenchyme, forms at the end of the 4th week from the sclerotome cells. Mesenchymal cells differentiate into fibroblasts, chondroblasts, and osteoblasts, which are the cells that form bone. The somatic mesoderm layer of the body wall also contributes mesoderm cells for formation of the pelvic and shoulder girdles. In some bones, such as the flat bones of the skull, the mesenchymal cells differentiate bone directly through a process known as intramembranous ossification. In most bones, however, mesenchymal models of the bones are transformed into cartilage bone models, which later become ossified by endochondral bone formation. At the 4-week stage, the sclerotomes appear as paired condensations of mesenchymal cells around the notochord. Each sclerotome consists of loosely packed cells cranially and densely packed cells caudally. Some of the densely packed cells form the intervertebral disc while others fuse with the loosely arranged cells in the caudal sclerotome to form the centrum, which is the primordium of the body of the vertebra. The mesenchymal cells surrounding the neural tube form the vertebral arch while the mesenchymal cells of the body wall form the costal processes that form the ribs. The authors acknowledge the important contributions of Charles I. Scott, Jr. to the first edition of this text, which provided the basis for this chapter.

In the 6th week, chondrification centers become apparent in each vertebra. A cartilaginous centrum is formed by fusion of the two centers at the end of the embryonic period. At the same time, the centers in the vertebral arches fuse with each other and the centrum, forming a cartilaginous arch. In the embryonic period, ossification of the vertebrae begins and is not completed until the 3rd decade of life. The ribs also become cartilaginous in the embryonic period. They ossify during the fetal period. Seven pairs of ribs are considered true ribs in that they attach through their own cartilages to the sternum. The next five pairs of ribs are considered false ribs because they attach to the sternum through the cartilage of another rib or ribs. The eleventh and twelfth pairs of ribs are floating ribs because they do not attach to the sternum. The sternum forms from a pair of vertical mesenchymal bands, referred to as sternal bars, located in the ventrolateral body wall. They fuse in the midline to form the cartilaginous models of the manubrium, the segments of the sternal body, and the xiphoid process. Fusion at the inferior end of the sternum can be incomplete, resulting in a bifid or perforated xiphoid process. Ossification of the sternum begins prenatally; however, the ossification center for the xiphoid process does not appear until childhood. The mesenchymal bones of the appendicular skeleton form in the limb buds during the 5th week. Chondrification of the mesenchymal bone models occurs during the 6th week. Initially, the clavicle forms by intramembranous ossification; however, growth cartilages later form on both ends. The model of the pectoral girdle appears slightly before the pelvic girdle. Malformations of individual bones involving the pectoral girdle, spine, ribs, and pelvic girdle are rare. More frequently, abnormalities involving several of these bones will be noted as part of an underlying skeletal dysplasia or multiple malformation syndrome3–6. The reader is referred to the resources listed below to assist in diagnosis. References 1. Moore KL: The Developing Human: Clinically Oriented Embryology, ed 7. Saunders, Philadelphia, 2003. 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams & Wilkins, Baltimore, 2004. 805

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3. Gorlin RJ, Cohen MM, Hennekan RCM: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001. 4. Online Mendelian Inheritance in Man, OMIM (TM). McKusickNathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/ 5. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders and Skeletal Dysplasias, ed 4. Mosby-Year Book, Inc., St. Louis, 1996. 6. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias, ed 2. Oxford University Press, New York, 2002.

19.1 Clavicular Hypoplasia/Aplasia Definition

Clavicular hypoplasia/aplasia refers to poorly formed or absent clavicles. Diagnosis

Absence or incomplete development of the clavicle is often manifested by the appearance of narrow and/or sloping shoulders with an elongated neck. The affected individual may be able to painlessly approximate the shoulders in the midline over the anterior chest. Palpation reveals either absence of the clavicle or deficiency, especially toward the acromial end. Radiographs confirm the diagnosis. Etiology and Distribution

Congenital clavicular hypoplasia/aplasia is almost always bilateral and affects both males and females. Its presence should prompt the search for other abnormalities that will allow recognition of a

Fig. 19-1. Top: Aplasia of the clavicle in a 3½-year-old girl with cleidocranial dysplasia. Bottom: Hypoplasia of the clavicles in an infant with cleidocranial dysplasia.

Table 19-1. Conditions in which clavicular hypoplasia/aplasia is a feature Syndrome

Prominent Features

Causation Gene/Locus

Aase

Anemia, triphalangeal thumbs

AR (205600)

Achondrogenensis I

Lethal, micromelia, thin ribs with fractures

AR (200600)

Achondrogenensis II

Lethal, absence of ossification of vertebrae, sacrum, and pelvis

AR (200610)

CHILD

Hemidysplasia, ichthyosiform erythroderma, limb defects

XL (308050)

Cleidocranial dysplasia

Aplasia/hypoplasia of clavicle, open fontanelle

AD (119600) CBFA1, 6p21

Crane-Heise

Cleft lip/palate, agenesis of cervical vertebrae, clubfeet

AR (218090)

Cutis laxa

Occipital horn exostoses, joint laxity

XL (304150) ATP7A, Xq12-q13

Focal dermal hypoplasia (Goltz)

Linear hyperpigmentation of skin, digital and ocular anomalies

XL (305600)

Lenz microphthalmia

Blindness; digital, dental, urogenital, and CV anomalies

XL (309800) Xq27

Mandibulo-acral dysplasia

Hypoplastic mandible, acroosteolysis, skin atrophy

AR (248370) LMNA

Marden-Walker

Blepharophimosis, micrognathia, contractures, immobile facies

AR (248700)

Melnick-Needles

Characteristic facies, curved long bones, flared metaphyses

XL (309350) FLNA, Xq28

Pelvis-shoulder dysplasia

Hypoplasia of scapulas, pelvis, clavicles

AD (169550)

Pycnodysostosis

Acroosteolysis, osteosclerosis, wide cranial sutures

AR (265800) CTSK, 1q21

Ulnar-mammary

Ulnar ray defects, breast hypoplasia

AD (181450) TBX3, 12q24.1

Yunis-Varon

Micrognathia, absent thumbs and distal phalanges

AR (216340)

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specific disorder (Table 19-1). The most frequent of these syndromes is cleidocranial dysplasia, in which other manifestations include a large, late-closing anterior fontanelle and variable short stature (Fig. 19-1).1 The gene for this condition (CBFA1) has been identified and mutation analysis is clinically available. This finding is also seen in a variety of other skeletal dysplasias; therefore, a full skeletal survey is indicated in most individuals. If abnormalities involving other systems are seen, a chromosome analysis is indicated, as this finding has been reported in a variety of chromosome abnormalities. Prognosis, Treatment, and Prevention

Prognosis and treatment depend on the specific diagnosis. In general, clavicular hypoplasia/aplasia does not cause significant functional impairment. Treatment of the clavicular abnormality is concerned principally with prevention of injury to the neurovascular and musculoskeletal structures of the shoulder girdle by limitation of physical activities and sports. Prevention is by appropriate genetic counseling. Reference (Clavicular Hypoplasia/Aplasia) 1. Mundlos S: Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 36:177, 1999.

19.2 Clavicular Pseudarthrosis

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taneously. Surgical treatment by excision of the fibrous interposing soft tissues, bone grafting, and, at times, internal fixation generally provide excellent cosmesis and relief of symptoms. References (Clavicular Pseudarthrosis) 1. Schnall SB, King JD, Marrero G: Congenital pseudarthrosis of the clavicle: a review of the literature and surgical results of six cases. J Pediatr Orthop 8:316, 1988. 2. Ahmadi B, Steel HH: Congenital pseudarthrosis of the clavicle. Clin Orthop 126:130, 1977. 3. Wieland I, Jakubiczka S, Muschke P, et al.: Mutations of the Ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 74:1209, 2004.

19.3 Altered Shape and Other Abnormalities of the Clavicle Definition

The clavicle is a long bone gently curved like the italic letter f, presenting a double curvature, the convexity directed forward at the sternal end and the concavity at the scapular end. Its lateral third has a rounded or prismatic form. Alterations in the basis configuration include thickening, broadening, thinning, or developing a lateral hook shape, any of which may alter relationships with associated anatomic structures. Diagnosis

Definition

Clavicular pseudarthrosis is a congenital defect of the clavicle in which the middle segment is missing. The terminal portions tend to be enlarged, and fibrous tissue often extends between the two. The sternal segment always overlies and is above the acromial segments. There is no callus or reactive bone. Diagnosis

A swelling just lateral to the middle of the clavicle is noted in the newborn. Classically it is painless. Swelling and mobility are progressive with age. It is primarily of cosmetic concern, although infrequently complaints of mild pain and shoulder discomfort are noted, especially on palpation and manipulation. The shoulder on the affected side is slightly forward, lower, and closer to the midline. The diagnosis is easily confirmed by radiography. Etiology and Distribution

Prevalence is unknown. It is probably more frequent than suggested in the literature. The majority are right-sided, with only 10% reported as bilateral.1 When left-sided, dextrocardia may be present.2 Cervical ribs are not infrequent. The etiology is unclear, and most cases are sporadic. Autosomal dominant inheritance has been reported, and it can be found in conditions such as craniofrontonasal dysplasia, an X-linked condition caused by mutations in EPHRIN B1,3 and in the Floating Harbor syndrome, possibly an autosomal dominant trait. Various etiologic theories have been advanced. One hypothesis is that there is failure of coalescence of a double ossification center. Others believe that this abnormality is due to chronic pressure by a high subclavian artery with or without associated cervical ribs. Prognosis, Treatment, and Prevention

About one-half of the cases are asymptomatic, and no treatment is indicated. These cases either remain symptom free or heal spon-

The altered or dysplastic shape of the clavicle is usually a secondary abnormality, found incidentally on radiograph. The functional disability or impairment depends on the severity of the malformation as well as the underlying condition. Etiology and Distribution

Morphologic changes can be found in many syndromes; they are not specific, and their etiologies are varied (Table 19-2). Thickening can be a feature of the mucopolysaccharidoses, mucolipidoses, and osteoscleroses. Slender and gracile clavicles are noted in chromosomal abnormalities such as trisomy 18 and Turner syndrome. A hooklike configuration of the lateral clavicle is found in osteogenesis imperfecta, Cornelia de Lange syndrome, and mosaic trisomy 8. A unilateral supernumerary clavicle has been described.1 Prognosis, Treatment, and Prevention

Both prognosis and treatment are dependent on the specific diagnosis underlying the clavicular abnormality. The majority of these morphologic changes do not require specific attention. Genetic counseling is indicated if a specific syndrome diagnosis is made. Reference (Altered Shape and Other Abnormalities of the Clavicle) 1. Goldthamer CR: Duplication of the clavicle (‘‘os subclaviculare’’). Radiology 68:576, 1957.

19.4 Sprengel Anomaly Definition

Sprengel anomaly is a rare abnormality in which there is congenital upward displacement of the scapula. Synonyms include congenital high scapula, undescended scapula, and elevated scapula.

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Skeletal System Table 19-2. Conditions in which an altered shape of the clavicle is a feature Prominent Features

Causation Gene/Locus

Achondrogenesis, type IA

Lethal, micromelia, thin ribs with fractures

AR (200600)

Cutis laxa

Occipital horn exostoses, joint laxity

XL (304150) ATP7A, Xq12-q13

Fryns

Diaphragmatic hernia, distal limb anomalies

AR (229850)

Fucosidosis

Neurologic deterioration, coarse facies, angiokeratoma

AR (230000) FUCA, 1p34

Lenz-Majewski hyperostotic dwarfism

Progressive skeletal sclerosis, severe growth retardation, MR, proximal symphalangism

AD (151050)

Melnick-Needles osteodysplasty

Characteristic facies, curved long bones, flared metaphyses

XL (309350) FLNA, Xq28

Metaphyseal dysplasia (Pyle disease)

Genu valgum, Erlenmeyer-flask deformity of femurs

AR (265900)

Sclerosteosis

Cutaneous syndactyly, square jaw

AR (269500) SOST, 17q12-q21

Winchester

Short stature, contractures, corneal opacities, generalized osteoporosis

AR (277950)

Condition

Broad or Thick

Thin or Gracile

Fibrochondrogenesis

Lethal, broad metaphyses

AR (228520)

Oto-palato-digital, type II

Microcephaly, cleft palate, overlapping fingers

XL (304120) FLNA, Xq28

Tight skin contracture, lethal

Fetal hypokinesia due to restrictive dermopathy

AR (275210)

Ear-patella-short stature

Microtia, absent patellae, micrognathia

AR (224690)

Thrombocytopenia-absent radius

Thrombocytopenia, absent radii

AR (274000)

Microcephalic osteodysplastic primordial dwarfism, type I

Short limbs, microcephaly

AR (210710)

Schinzel-Giedion midface retraction

Skull anomalies, CHD, hypertrichosis

AR (269150)

Acromesomelic dysplasia, Maroteaux type

Disproportionate short stature involving middle and distal segments

AR (602875) NPR2, 9p13

Jeune (asphyxiating thoracic dystrophy)

Short stature, small thorax, hepatic fibrosis

AR (208500)

Brachydactyly, type E

Short metacarpals and metatarsals

AD (113300) HOXD13, 2q31-q32

Hennekam lymphangiectasia-lymphedema

Intestinal lymphangiectasia; lymphedema of limbs, genitalia, face

AR (235510)

Lateral Hook

Long

Curved

Horizontal

Diagnosis

As viewed from behind, the shoulder and scapula are higher and displaced forward on the affected side (Figs. 19-2 and 19-3). If bilateral, the neck appears short and broad due to elevation of both scapulae. The left side is more often affected. The superior angle of the scapula may be at the level of the fourth cervical vertebrae and the inferior angle at the second thoracic vertebrae. Upward angulation of the clavicle is often noted, and approximately one-third of the patients have a rhomboid- or trapezoid-

shaped omovertebral bone.1 Occasionally it can be palpated. This bone attaches to the scapula from its superior median angle or upper third of the median border to the spinous process lamina or transverse process of one of the cervical vertebrae (fourth to seventh). Abnormalities of the shoulder girdle muscles are frequent, especially involving absence or fibrosis of the trapezius. Weakness and fibrosis can affect the rhomboids, levator scapulae, pectorals, latissimus, serratus anticus, and the sternocleidomastoid muscles. Despite these abnormalities, range of shoulder motion may be unexpectedly full. Cervicothoracic scoliosis and torticollis are common.

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Fig. 19-3. Top: Preoperative radiographic appearance of a Sprengel anomaly of the right scapulae in an 11-year-old girl. Bottom: Postoperative appearance; the right scapula lies below the level of the clavicle.

Fig. 19-2. Elevated right scapula (Sprengel anomaly) in a 12-yearold girl with Klippel-Feil anomaly.

extensive treatment should be and which techniques offer the best results. References (Sprengel Anomaly)

Over 70% of patients with Sprengel anomaly have other anomalies, including Klippel-Feil sequence, MURCS association, rib anomalies, and segmentation anomalies of the vertebrae.2,3 Multiple radiographic techniques and films in several projections are required to identify the various bony abnormalities. Etiology and Distribution

The scapula appears in the 5th week and migrates caudally to its final position at the level of the second to seventh or eighth thoracic vertebra. What causes the failure of descent is not known. Males and females are equally affected. Incidence is not known. The majority of cases are sporadic, although autosomal dominant inheritance has been reported. Prognosis, Treatment, and Prevention

Life-span and intelligence are normal. The degree of functional impairment is related to the degree of scapula deformity and associated anomalies. In mild cases, surgical treatment is not necessary. If the functional handicap and cosmetic appearance are severe, surgical treatment can be offered. This is usually performed between 3 and 7 years of age. Numerous surgical procedures have been developed, and there is considerable controversy as to how

1. Tachdjian MO: Deformities of the neck and upper limb. In: Pediatric Orthopedics, ed 3. J Herring, MO Tachdjian, eds. WB Saunders Company, Philadelphia, 2002. 2. Jeannopoulous CL: Congenital elevation of the scapula. J Bone Joint Surg 34A:883, 1952. 3. Williams MS: Developmental anomalies of the scapula—the ‘‘omo’’st forgotten bone. Am J Med Genet 120A:583, 2003.

19.5 Glenoid Hypoplasia Definition

Glenoid hypoplasia is a small, hypoplastic or absent glenoid cavity of the scapula, characterized by incomplete or irregular ossification of the lower two-thirds of the bony glenoid; it may include the adjacent scapular neck. Diagnosis

In isolated cases, the diagnosis is frequently made as an incidental finding on a chest radiograph or by shoulder radiographs taken for vague shoulder pain.1 Less frequently, there may be some restriction

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of shoulder mobility, shoulder instability, or, rarely, dislocation. Radiographs demonstrate dysplastic, irregular, or underdeveloped bony glenoid and neck of the scapula, occasionally accompanied by malformation of the acromion process, or of the humeral head and neck.2 Computed tomography or magnetic resonance imaging is required for further delineation of the condition.3 Etiology and Distribution

In prenatal development of the scapula, the endochondral ossification process expands from the center of the bone toward the glenoid to produce a slightly convex subchondral plate. The glenoid cartilage is concave and congruent with the convex humeral head. During postnatal development, the bony subchondral plate becomes flattened, gradually becoming concave at around 10 years of age. The glenoid cavity has two primary ossification centers, one superior and one inferior, which appear at age 8 to 10 years and are present until ossification of the skeleton is complete.4 Arrest of development may occur at any time during development, leading to abnormalities in the glenoid capsule. Congenital glenoid hypoplasia may occur as an isolated defect, in association with other malformations, as part of mucopolysaccharidosis or mucolipidoses, as skeletal dysplasias, or as part of a multiple malformation syndrome. The cause of this anomaly and incidence in the general population are unknown, primarily due to lack of recognition and infrequent symptoms in affected individuals. Acquired glenoid hypoplasia may also occur as a result of abnormalities in the innervation to the shoulder, as in Erb’s palsy, or as a result of underlying neuromuscular conditions, including muscular dystrophy. Most cases of glenoid hypoplasia are bilateral and symmetric and usually are sporadic. However, autosomal dominant transmission has been described in several families.5 Glenoid abnormalities have been described in mucopolysaccharidosis (MPS), specifically Hurler syndrome (MPS I), Maroteaux-Lamy (MPS VI), and Morquio (MPS IV); in mucolipidoses (MLP) such as I-cell disease (MLP II) and pseudo-Hurler (MLP III); and in other associated conditions such as mannosidosis and fucosidosis. Glenoid abnormalities are associated with several multiple malformation syndromes and skeletal dysplasias. Prognosis, Treatment, and Prevention

Isolated glenoid hypoplasia is associated with few complications; however, long-term outcomes are unknown. Premature osteoarthritis has been described; however, most symptoms are limited to shoulder stiffness, limited range of motion, and vague shoulder pain. Sports requiring extensive movement and activities that strain the shoulder should be avoided. When associated with multiple malformation syndromes, the prognosis varies, depending on associated abnormalities. References (Glenoid Hypoplasia) 1. Owen R: Bilateral glenoid hypoplasia: report of five cases. J Bone Joint Surg 35B:262, 1953. 2. Currarino G, Sheffield E, Twickler D: Congenital glenoid dysplasia. Pediatr Radiol 28:30, 1998. 3. Manns RA, Davies AM: Glenoid hypoplasia: assessment by computed tomographic arthrography. Clin Radiol 43:316, 1991. 4. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, ed 4. Mosby-Year Book, St. Louis, 1996. 5. Stanciu C, Morin B: Congenital glenoid dysplasia: case report in two consecutive generations. J Pediatr Orthop 14:389, 1994.

19.6 Anomalies of the Sternum Definition

The sternum forms the midline portion of the anterior chest wall and consists of three parts—the manubrium, the mesosternum, and the xiphoid process. A wide variety of defects occur, with pectus excavatum being the most common. Pectus excavatum and carinatum are discussed in the following section. Diagnosis

Defects in the sternum may occur in isolation or as part of a multiple malformation syndrome. Diagnosis is based on the physical exam and/or radiographs. The sternum is visualized on oblique and lateral views. A cleft and notched sternum is not visualized using conventional radiography, but may be suspected by displacement of the medial ends of the clavicle.1 Etiology and Distribution

Sternal development begins in the 6th week post-conception as bands of condensed cells that form from body wall mesoderm. These bands fuse, beginning at the cranial end, and join with the midline ends of the first seven ribs. By 9 weeks post-conception, the sternum is cartilaginous. Six ossification centers develop from superior to inferior and fuse in reverse order of appearance from caudad to cephalad, beginning in early childhood and continuing into the 3rd decade. The xiphoid process may remain cartilaginous throughout life, with the manubriosternal center remaining open in up to 90% of adults. It is hypothesized that the pattern of strain exerted by the ribs on the sternum is responsible for sternal segmentation. Arrested or altered development at any stage in sternum formation can result in anomalies that may be isolated or part of a multiple malformation syndrome. Premature synostosis may result in a short or deformed sternum as is seen in many chromosomal aberrations. Complete congenital nonsegmentation of the sternum is extremely rare. Multiple ossification centers of the manubrium are occasionally seen and can produce asymmetry of the sternoclavicular joints. Separate inferior and superior manubrial centers are common in infants with Down syndrome. Premature synostosis may result in a shortened or malformed sternum and is seen in association with chromosomal anomalies such as trisomy 18, trisomy 21, Turner syndrome, and 4p minus syndrome. Isolated asternia has been reported.2 Cleft or bifid sternum is common, most often occurring in the mesosternum. The xiphoid process may be forked. The sternal cleft may be partial or complete and may be seen in association with vascular dysplasia or cardiac lesions, such as ectopia cordis with a supraumbilical raphe, or in association with other midline defects, such as cleft lip and palate and omphalocele, known as pentalogy of Cantrell. The most severe clefts are associated with ectopia cordis. The pathogenesis of these disorders is unknown; however, early disruption of midline mesodermal structures would lead to incomplete fusion of the sternal bands and overlying soft tissues. Children with diastrophic dysplasia occasionally have a double layered manubrium, which may represent a persistence of the midline embryonic cartilaginous structure.3 Prognosis, Treatment, and Prevention

The prognosis is variable, depending upon the defect and whether an underlying genetic or chromosomal anomaly exists. A cleft

Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

sternum may be asymptomatic and not require intervention. Alternatively, the defect may cause symptoms including respiratory distress, dyspnea, frequent infections, or paradoxical movement of the chest wall. Severe defects and associated anomalies may require surgical intervention.4 References (Anomalies of the Sternum) 1. Effmann EL: Chest wall. In: Caffey’s Pediatric Diagnostic Radiology, ed 10. JP Kuhn, TL Slovis, JO Haller, eds. Mosby, St. Louis, 2003, p 828. 2. Haque KN: Isolated asternia: an independent entity. Clin Genet 25:362, 1984. 3. Currarino G: Double layered manubrium sterni in young children with diastrophic dysplasia. Pediatr Radiol 30:404, 2000. 4. Williams AM, Crabbe DCG: Pectus deformities of the anterior chest wall. Paedatr Respir Rev 4:237, 2003.

19.7 Pectus Excavatum/Pectus Carinatum Definition

A pectus excavatum (also known as funnel chest, hollow-chest, or cobbler’s chest) is an abnormality of the anterior chest wall characterized by an inward depression of the sternum and costosternal rib junctions (Fig. 19-4). A pectus carinatum (pigeon breast) is

Fig. 19-4. Pectus excavatum in a 16-year-old male.

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characterized by forward angulation of the sternum. (Figs. 19-5 and 19-6). Either deformity can be symmetric or asymmetric with varying degrees of torsion of the sternum. Diagnosis

The diagnosis is made clinically. In pectus excavatum, the moderate and severe cases may compress the heart, lung, and esophagus, and the heart may be displaced to the left. Compression atelectasis may also be seen. Both pectus excavatum and pectus carinatum frequently are present at birth, although often overlooked, and may be progressive until adolescence. The deformity becomes more noticeable with age, and the medical evaluation is prompted by cosmetic concerns. There may be associated symptoms such as dyspnea, chest discomfort, palpitations, or early fatigue. Etiology and Distribution

Pectus excavatum is the most common thoracic abnormality, with an incidence of six to eight per 1000 children.1 Boys are more frequently affected with a male to female ratio of 4:1.2 Although most cases of pectus deformities are isolated, they are seen in association with scoliosis and mitral valve prolapse as well as with multiple malformation syndromes, particularly Marfan syndrome (Table 19-3). In familial cases, it is inherited in an autosomal dominant fashion.3 Pectus carinatum is less common and is seen in Marfan syndrome and other malformation syndromes (Table 19-4). It is seen with increased frequency in children with atrial and ventricular septal defects, and scoliosis is also common. Developmentally, the cause of pectus abnormalities is unknown, but they are thought to be caused by an overgrowth of the costal cartilages, which displace the lower sternum posteriorly.4 Prognosis, Treatment, and Prevention

Most infants and children with pectus carinatum and pectus excavatum are asymptomatic. Alternatively, the deformity may impair cardiopulmonary function by restricting pulmonary movement, causing a shifting of the heart and leading to a decrease in pulmonary volume. Others may have progression of the anomaly and present with noisy respirations or other related respiratory abnormalities. Inspiratory stridor in a neonate or young child may cause paradoxical sternal movement, which improves with resolution of the stridor; however, most pectus anomalies are progressive and do not improve with skeletal maturity. Older children may develop poor exercise tolerance, easy fatigability, and dyspnea. The physical signs, combined with the cosmetic concerns, frequently result in surgical intervention in this condition. For cases where surgery is considered, a noncontrast computed tomography will allow three-dimensional delineation of the deformity and allow a pectus index score to be calculated, which can guide selection of repair technique.4 The pectus index measures the chest transverse diameter, divided by the sternum to vertebral distance at the maximal sternal depression. A pectus index greater than 3.25 would support surgical intervention. References (Pectus Excavatum/Pectus Carinatum) 1. Williams AM, Crabbe DCG: Pectus deformities of the anterior chest wall. Paediatr Respir Rev 4:237, 2003. 2. Haje SA, Harcke HT, Bowen JR: Growth disturbances of the sternum and pectus deformities: imaging studies and clinical correlation. Pediatr Radiol 29:334, 1999. 3. Leung AKC, Hoo JJ: Familial congenital funnel chest. Am J Med Genet 26:887, 1987.

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Fig. 19-5. Frontal and lateral views of pectus carinatum in a 15-year-old male.

4. Haller JA, Kramer SS, Lietman S: Use of CT scans in selection of patients for pectus excavatum surgery: a preliminary report. J Pediatr Surg 22:904, 1987.

19.8 Rib Anomalies Definition

The ribs consist of 12 pairs of elastic arches of ribbonlike bone that form a large part of the thoracic wall. The first seven pairs (true or vertebrosternal ribs) are connected posteriorly with the thoracic vertebral column and anteriorly with the sternum via the costal cartilages. The lower five pairs, false ribs, have no direct attachment to the sternum. Ribs seven to nine attach anteriorly to the rib above (vertebrochondral ribs). Floating or vertebral ribs are represented by the lower two rib pairs, which are free at their anterior extremities, terminating in the abdominal wall. Ribs increase in length from the first to the seventh, below which their length decreases. Ribs can have all of the localized lesions that occur in the tubular bones of the appendicular skeleton. Their number may vary from aplasia to extra ones, and there are numerous changes in their architecture. The term rosary is used to denote costosternal junction enlargement. Malformation or deformation of the anterior vertebral-sternal ribs in association with a sternal abnormality re-

sults in chest wall deformities: pectus excavatum (funnel chest) and pectus carinatum (pigeon chest). (See previous section on pectus excavatum/pectus carinatum.) Combinations of rib and sternum changes may result in a small thoracic cage or in one with altered shaped such as long and narrow, bell shaped, or barrel shaped. Diagnosis

Congenital anomalies of the ribs and chest walls may be suspected based on the overall diagnosis of a specific condition or syndrome. Abnormal appearance of the chest wall alone may prompt radiographic evaluation, which will document the extent of the bony changes. Standard radiography can be supplemented by other imaging modalities such as computerized tomography. Etiology and Distribution

The incidence of rib anomalies varies greatly, from 0.15–3.4% in a population of whites and blacks.1 Samoans have a 10.4% incidence, with the predominant anomalies consisting of bifid ribs, rib spurs, and wide or enlarged ribs, mostly involving the third and fourth ribs. In this population males are affected twice as often as females. In one North American study, fusion was the most common pattern of rib anomaly (72%), followed by bifid (28%) and hypoplastic (26%).2 Extra ribs are one of the most common abnormalities; cervical ribs account for 32% and lumbar ribs for 29.3% of all congenital

Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

813

19.9 Cervical Rib Definition

Elongation of the anterior portion of the transverse portion of the seventh cervical vertebra results in a cervical rib. Less commonly, the cervical rib may arise from the sixth cervical vertebra. Diagnosis

The majority of cervical ribs are asymptomatic and are identified on radiographs obtained for unrelated reasons (Fig. 19-7). Most are bilateral although not unusually symmetric. In rare instances, signs and symptoms of compression of the subclavian artery, somatic branches of the brachial plexus, and/or sympathetic nerves may be seen (cervical rib-scalene syndrome). It is thought that compression by the hypertrophied anterior scalene muscle is more important, since not all cases have an associated cervical rib.1 Etiology and Distribution

In adults, the incidence of cervical ribs is 0.7%.2 Most cases are sporadic, and there are three times as many cases in females as in males. Autosomal dominant transmission of cervical ribs and enlarged transverse processes has been reported, documenting variable expression.3,4 Cervical ribs have been reported in a number of syndromes, most notably Simpson-Golabi-Behmel syndrome and cleidocranial dysplasia. Prognosis, Treatment, and Prevention Fig. 19-6. Radiograph of 4-year-old boy with pectus carinatum. Note fusion of central sternebrae (arrow).

costal anomalies.1 Typically, these involve the seventh cervical and the first lumbar vertebrae. They are usually bilateral but often are asymmetric and occur more frequently in females. The extra ribs may occur as an isolated finding or as part of a syndrome (Table 19-5). Similarly, aplasia or other rib anomalies may occur as isolated findings or as part of a syndrome (Table 19-5). Morphologic alterations of the ribs are numerous and include thinning; thickening/widening (e.g., dysostosis multiplex in the lysosomal storage disorders); beaded (e.g., osteogenesis imperfecta); shortened; fused (e.g., basal cell carcinoma syndrome); bifid (e.g., multiple pterygium syndrome); notched/eroded (e.g., Melnick-Needles syndrome); cupped (e.g., Menkes syndrome); and gapped (e.g., cerebro-costo-mandibular syndrome). Marked causal heterogeneity is noted, and none of these changes is pathognomonic.

No treatment is necessary for the majority of cases as 50–75% are asymptomatic. Typically cervical ribs become symptomatic in adult life, with neck pain or pain and paresthesias along the part of the brachial plexus involved and evidence of vascular occlusion in the upper extremity. Often this follows neck injury or certain daily living activities. Physical therapy and bracing are often helpful. Surgical release is indicated for neurovascular compression symptoms. Prognosis is generally excellent. If there is an underlying condition, genetic counseling is indicated. References (Cervical Rib) 1. Silverman FN: Caffey’s Pediatric X-Ray Diagnosis, vol 2, ed 8. Year Book Medical Publishers, Chicago, 1985, p 241. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1972, p 930. 3. Weston WB: Genetically determined cervical ribs: a family study. Br J Radiol 29:455, 1956. 4. Schaper J: Autosomal dominant inheritance of cervical ribs. Clin Genet 31:386, 1987.

Prognosis, Treatment, and Prevention

Prognosis in rib anomalies is dependent on the underlying diagnosis. Genetic counseling is indicated if a specific syndrome diagnosis is made.

19.10 Occipitalization of the Atlas Definition

References (Rib Anomalies) 1. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1972, p 930. 2. Wattanasirichaigoon D, Prasad C, Schneider G, et al.: Rib defects in patterns of multiple malformations: a retrospective review and phenotypic analysis of 47 cases. Am J Med Genet 122A:63, 2003.

Occipitalization of the atlas is the bony or fibrous union between the skull and the atlas, sometimes referred to as assimilation of the atlas. Typically, this involves the anterior arch and the rim of the foramen magnum. A posterior position of the arch is usually present and may narrow the spinal canal. The union may be bilateral or unilateral.

Table 19-3. Conditions in which pectus excavatum is a feature

814

Causation Gene/Locus

Condition

Prominent Features

Aarskog

Ocular hypertelorism, shawl scrotum, brachydactyly

AD/XL (100050) FGD1, Xp11.21

Achondrogenesis, type IA

Lethal, micromelia, thin ribs with fractures

AR (200600)

Acrocraniofacial dysostosis

Craniosynostosis Cleft palate

AR (201050)

Bannayan-Riley-Ruvalcaba

Prenatal/postnatal macrosomia, lipid storage myopathy

AD (153480) PTEN, 10q23.3

Cutis laxa

Occipital horn exostoses, joint laxity

XL (304150) ATP7A, Xq12-q13

Catzel-Manzke

Micrognathia, cleft palate, hyperphalangy of index finger

XL (302380)

Cardio-facial-cutaneous

Congential heart defects, ectodermal anomalies, frontal bossing

AD (115150)

Coffin-Lowry

Microcephaly, course facies, mental retardation

XL (303600) RSK2, Xp22.2-p22.1

Coffin-Siris

Hypoplastic fifth nail, coarse facies, mental retardation

AR (135900)

Cowden

Multiple hamartomas, macrocephaly

AD (158350) PTEN, 10q23.31

Craniofrontonasal dysplasia

Ocular hypertelorism, bifid nasal root Females: craniosynostosis, frontal bossing

XLD (304110) EFNB1, Xq12

Ehlers-Danlos

Macrocephaly, failure to thrive, hypotonia

AR (130070) XGPT1, 5q35.2-q35.3

Freeman-Sheldon

Masklike face, hypoplastic alae nasi, postnatal growth deficiency

AD (193700)

Fragile X

Mental retardation, Macroorchidism, connective tissue abnormality

XLD (309550) FMR1, Xq27.3

Homocystinuria

Subluxation of lens, malar flush, osteoporosis

AR (236200)

Jacobsen

Mental retardation, dysmorphic features, CHD

AD (147791) 11q23

LEOPARD

Lentigines, cardiomyopathy

AD (151100) PTPN11, 12q24.1

Marden-Walker

Blepharophimosis, micrognathia, contractures, immobile facies

AR (248700)

Marfan

Arachnodactyly, Lens subluxation, aortic dilition

AD (154700) FBN1, 15q21.1

Melnick-Needles

Characteristic facies, curved long bones, flared metaphyses

XL (309350) FLNA, Xq28

Oral-facial-digital, type II (Mohr)

Cleft tongue, deafness, partial reduplication of hallux

AR (252100)

Multiple endocrine neoplasia, type 2

Multiple neuromas of tongue and lips

AR (162300) RET, 10q11.2

Neurofibromatosis, type 1

Cafe´-au-lait spots, macrocephaly, fibromatous skin tumors

AD (162200) NF1, 17q11.2

Neurofibromatosis, type 2

Tumors of the eighth cranial nerve, schwannomas of the spinal cord

AD (101000) NF2, 22q12.2

Noonan

Webbed neck, cryptorchidism, pulmonic stenosis

AD (163950) PTPN11, 12q24.1

Robinow

Characteristic facial features, hypoplastic genitalia

AD (180700)

Rubinstein-Taybi

Broad thumbs, mental retardation, beaked nose

AR (268310) CREBBP, 16p13.3

Shprintzen-Goldberg

Craniosynostosis, arachnodactyly, abdominal hernias

AD (182212) FBN1, 15q21.1

Stickler

Myopia, flat midface, hearing loss

AD (108300) COL2A1, 12q13.11-q13.2 COL11A1, 1p21 COL11A2, 6p21.3

Williams

Supravalvular aortic stenosis, mental retardation, hoarse voice

AD (194050) ELN, LIMK1, RFC2, 7q11.2

Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

815

Table 19-4. Conditions in which pectus carinatum is a feature Prominent Features

Causation Gene/Locus

Cutis laxa

Occipital horn exostoses, joint laxity

XL (304150)

Catel-Manzke

Micrognathia, cleft palate, hyperphalangy of index finger

XL (302380)

Cardio-facial-cutaneous

Congenital heart defects, ectodermal anomalies, frontal bossing

AD (115150)

Coffin-Lowry

Microcephaly, course facies, mental retardation

XL (303600) RSK2, Xp22.2-p22.1

Dyggve-Melchior-Clausen

Mental retardation, coarse facies

AR (223800) FLJ90130, 18q12-q21.1

Ellis-van Creveld

Short limbs and ribs, dysplastic nails and teeth, polydactyly

AR (225500) EVC, 4p16

Homocystinuria

Subluxation of lens, malar flush, osteoporosis

AR (236200) CBS, 21q22.3

Jeune (asphyxiating thoracic dystrophy)

Short stature, small thorax, hepatic fibrosis

AR (208500)

LEOPARD

Lentigines, cardiomyopathy

AD (151100) PTPN11, 12q24.1

Marden-Walker

Blepharophimosis, micrognathia, contractures, immobile facies

AR (248700)

Marfan

Arachnodactyly, Lens subluxation, aortic dilition

AD (154700) FBN1, 5p21.1

McDonough

Mental retardation, sparse hair, CHD

AR (248950)

Morquio (MPS IV-A)

Short stature, cloudy corneas

AR (253000) GALNS, 16q24.3

Morquio (MPS IV-B)

Short stature, cloudy corneas

AR (253010) GLB1, 3p21.33

Neurofibromatosis, type 1

Cafe´-au-lait spots, macrocephaly, fibromatous skin tumors

AD (162200) NF1, 17q11.2

Noonan

Webbed neck, cryptorchidism, pulmonic stenosis

AD (163950) PTPN11, 12q24.1

Schwartz-Jampel, type 1

Myotonia, blepharophimosis, joint limitation

AR (255800) HSPG2, 1p36.1

Shprintzen-Goldberg

Craniosynostosis, arachnodactyly, abdominal hernias

AD (182212) FBN1, 15q21.1

Sly (MPS VII)

Dysostosis multiplex, hepatosplenomegaly

AR (253220) GUSB, 7q21.11

Spondyloepimetaphyseal dysplasia, Strudwick type

Severe short stature, pectus carinatum, cleft palate

AD (184250) COL2A1, 12q13.11-q13.2

Spondyloepiphyseal dysplasia tarda

Severe scoliosis, short hands and feet

AD (184100)

Spondyloepiphyseal dysplasia, congenita

Short trunk, myopia

AD (183900) COL2A1, 12q13.11-q13.2

Trichorhinophalangeal, type I

Short hallux, fibrous dysplasia, scoliosis, hypotonia

(190350) TRPS1, 8q24.12

Condition

Diagnosis

This abnormality may be first detected by chance when radiographs are made for other purposes, or it can cause confusing signs and symptoms, including neck pain, paresis, long track signs, hyperreflexia, weakness, disturbances of peripheral sensation, and even cerebellar signs related to basilar impression. Standard radiographs are diagnostic when taken in flexion and extension on lateral projection. There is no motion between the lateral masses of the atlas and the occiput. Computerized tomography and/or

magnetic resonance imaging may be necessary to delineate further the degree and site of impingement of the spinal cord. The diagnosis may be difficult in the young child, because a significant portion of the ring of the atlas is unossified at birth. The 5- to 9-mm radiolucent gap in the posterior neural arch of the newborn generally ossifies by age 4 years. The anterior arch of the atlas, unossified in 80% of newborns, begins to ossify between the 1st and 3rd years, becoming fully visible on radiographs between ages 7 and 10 years. Some 70% of these patients have fusions of the second and third cervical vertebrae.1 Arnold-Chiari

Table 19-5. Conditions in which rib anomalies are a feature Prominent Features

Causation Gene/Locus

Aicardi

Agenesis of the corpus callosum, chrorioretinal abnormality

XL (304050)

Incontinentia pigmenti

Abnormalities involving the skin, hair, nails, teeth, eyes, CNS

XL (308300) NEMO, Xq28

Shprintzen-Goldberg

Craniosynostosis, arachnodactyly, abdominal hernias

AD (182212) FBN1, 15q21.1

Simpson-Golabi-Behmel

Characteristic facies, overgrowth

XL (312870) GPC3, Xq26

Aicardi

Agenesis of corpus callosum, chroioretinal abnormality

XL (304050)

Aase

Anemia, triphalangeal thumbs

AR (205600)

Atelosteogenesis

Distal hypoplasia of humeri and femurs, abnormal ossification of hand bones

AD (108720)

Campomelic dysplasia

Bowing of long bones, genital abnormalities in males

AD (114290) SOX9, 17q24.3-q25.1

Condition

Extra Ribs

Decreased Number of Ribs

Cerebrocostomandibular

Mental retardation, palatal defects, micrognathia

AD (117650)

Costovertebral segmentation anomalies

Multiple vertebral and rib anomalies

AD (122600)

Femoral-facial

Femoral hypoplasia, characteristic facies

AD (134780)

Hydrops-ectopic calcificationsmoth-eaten skeletal dysplasia

Hydrops, markedly short long bones, ectopic ossification centers

AR (215140) LBR, 1q42.1

Jacobsen

Mental retardation, dysmorphic features, CHD

AD (147791) 11q23

Metaphyseal chondrodysplasia, congenital lethal

Long fibulas, disharmonious maturation, turricephaly

AR (250220)

Microphalic osteodysplastic primordial dwarfism, type I

Short limbs, microcephaly

AR (210710)

Spondylyepimetaphyseal dysplasia with joint laxity

Joint laxity, severe scoliosis

AR (271640)

Achondrogenesis, type Ia

Lethal, micromelia, thin ribs with fractures

AR (200600)

Achondrogenesis, type II

Lethal, absence of ossification of vertebrae, sacrum, and pelvis

AD (200610) COL2A1, 12q13.11-q13.2

Achondroplasia

Short limbs, frontal bossing, trident hand

AD (100800) FGFR3, 4p16.3

Atelosteogenesis

Distal hypoplasia of humeri and femurs, abnormal ossification of hand bones

AD (108720)

Barnes (thoraco-laryngo-pelvic dysplasia)

Short ribs, laryngeal stenosis, small pelvis

AD (187760)

Campomelic dysplasia

Bowing of long bones, genital abnormalities in males

AD (114290) SOX9, 17q24.3-q25.1

Cerebro-costo-mandibular

Mental retardation, palatal defects, micrognathia

AD (117650)

Cleidocranial dysplasia

Aplasia/hypoplasia of clavicle, open fontanelle

AD (119600) CBFA1, 6p21

Dyssegmental dysplasia

Multiple rib and vertebral anomalies, narrow chest, reduced joint mobility

AR (224400)

Ellis-van Creveld

Short limbs and ribs, dysplastic nails and teeth, polydactyly

AR (225500) EVC, 4p16

Fibrochondrogenesis

Lethal, broad metaphyses

AR (228520)

Short Ribs

(continued)

816

Table 19-5. Conditions in which rib anomalies are a feature (continued) Causation Gene/Locus

Condition

Prominent Features

Hypophosphatasia

Low alkaline phosphatase, premature shedding of teeth

AR (241500) ALPL, 1p36.1-p34

Jeune (asphyxiating thoracic dysplasia)

Short stature, small thorax, hepatic fibrosis

AR (208500)

Majewski short rib-polydactyly

Lethal, median cleft lip, polydactyly

AR (263520)

Metaphyseal chondrodysplasia, congenital lethal

Long fibulas, disharmonious maturation, turricephaly

AR (250220)

Metaphyseal chondrodysplasia, Jansen type

Disorganization of metaphyses, metacarpals, metatarsals

AD (156400) PTHR, 3p22-p21.1

Saldino-Noonan short rib-polydactyly

Lethal, polydactyly, visceral abnormalities

AR (263530)

Spondylocostal dysostosis (Jarcho-Levin)

Rib and vertebral anomalies

AR (277300) DLL3, 19q13

Thanatophoric dysplasia

Lethal, severe micromelia

AD (187600) FGFR3, 4p16.3

Fryns

Diaphragmatic hernia, distal limb anomalies

AR (229850)

Fucosidosis

Neurologic deterioration, coarse facies, angiokeratoma

AR (230000)

Mucopolysaccharidosis, type VI (Maroteaux-Lamy)

Short stature, cloudy corneas

AR (253200)

Schinzel-Giedion midface retraction

Skull anomalies, CHD, hypertrichosis

AR (269150)

Sclerosteosis

Cutaneous syndactyly, square jaw

AR (269500) SOST, 17q12-q21

Weill-Marchesani

Short stature, brachydactyly, joint stiffness, lens abnormalities

AD (608328) FBN1, 15p21.1

Weaver

Overgrowth, characteristic facies, camptodactyly

AR (277590) NSD1, 5q35 in some cases

Broad Ribs

Thin Ribs (Hypoplastic)

Achondrogenesis, type Ia

Lethal, micromelia, thin ribs with fractures

AR (200600)

Basal cell nevus syndrome

Basal cell nevi, jaw cysts, skeletal anomalies

AD (109400) PTCH, 9q22.3

Campomelic dysplasia

Bowing of long bones, genital abnormalities in males

AD (114290) SOX9, 17q24.3-q25.1

Ear, patella, short stature

Microtia, absent patellae, micrognathia

AR (224690)

Fibrochondrogenesis

Lethal, broad metaphyses

AR (228520)

Focal dermal hypoplasia (Goltz)

Linear hyperpigmentation of skin, digital and ocular anomalies

XL (305600)

Hallermann-Streiff

Proportionate short stature, hypoplastic mandible, beaked nose, cataracts

AR (234100)

Melnick-Needles osteodysplasty

Characteristic facies, curved long bones, flared metaphyses

XL (309350) FLNA, Xq28

Multiple pterygium syndrome, lethal type

Growth retardation, cystic hygroma, hydrops

AR (253290)

Oto-palato-digital, type II

Microcephaly, cleft palate, overlapping fingers

XL (304120) FLNA, Xq28

Pena-Shokeir, type I

Fetal akinesia, camptodactyly, pulmonary hypoplasia

AR (208150)

Pterygium, multiple, X-linked

Growth retardation, cystic hygroma, hydrops

XL (312150)

Stuve-Wiedemann

Bowing of long bones, camptodactyly, contractures

AR (601559) LIFR, 5p13.1

Tight skin contracture, lethal

Fetal hypokinesia due to restrictive dermopathy

AR (275210)

817

818

Skeletal System

19.11 Aplasia/Hypoplasia of the Odontoid Process of the Axis Definition

Fig. 19-7. Cervical rib (arrowhead).

malformation is present in almost 25% of cases,2 and syringomyelia or hydromyelia may be present. Odontoid anomalies of size and shape are frequent, and in 25% of instances, the odontoid is displaced behind the anterior arch of the atlas more than 3 mm.3,4 Dural bands may further complicate the situation, causing constriction of the medulla or spinal cord posteriorly. Etiology and Distribution

The incidence in the general population is not known. There is speculation that it might be more common in India than in other parts of the world.5 It is often found in autosomal dominant conditions such as achondroplasia, in oculo-auriculo-vertebral spectrum, and in Klippel-Feil syndrome. Family radiographic studies have noted the presence of atlanto-occipital anomalies in 3.5% of first-degree relatives of probands, suggesting multifactorial inheritance.5 Prognosis, Treatment, and Prevention

Treatment is aimed at decompressing the affected structures. When compression is anterior, transoral resection of the odontoid and rim of the foramen magnum is performed. For posterior compression, cervical laminectomy of the atlas, excision of any dural bands, and suboccipital craniectomy are performed. A few patients respond to nonoperative measures: immobilization in plaster, traction, and cervical collars. Surgical intervention represents a serious risk of morbidity and mortality. Many patients’ neurologic status remains unchanged following surgery, and death may occur during or shortly after surgery. Those who have asymptomatic occipitalization of the atlas should modify and avoid activities likely to stress or cause injury to the head and neck. References (Occipitalization of the Atlas) 1. McRae DL: Bony abnormalities in the region of the foramen magnum: correlation of the anatomic and neurologic findings. Acta Radiol 40: 335, 1953. 2. McRae DL, Standen J: Roentgenologic findings in syringomyelia and hydromyelia. AJR Am J Roentgenol 89:695, 1966. 3. McRae DL, Barnum AS: Occipitalization of the atlas. AJR Am J Roentgenol 70:23, 1953. 4. Wadia NH: Myelopathy complicating congenital atlanto-axial dislocation. Brain 90:449, 1967. 5. Kalla AK, Khanna S, Singh IP, et al.: A genetic and anthropological study of atlanto-occipital fusion. Hum Genet 81:105, 1989.

Aplasia/hypoplasia of the odontoid process of the axis is the partial or complete absence of the odontoid process (dens), which varies from a short, stubby nipplelike projection to one of nearly normal size. Os odontoideum is characterized by a radiolucent, oval, or round ossicle of variable size with a smooth, dense border of bone, separate from the axis and usually located in the position of the normal odontoid tip (Fig. 19-8). It may at times be near the basal occiput in the area of the foramen magnum, where it can fuse with the clivus. Odontoid aplasia or hypoplasia (Fig. 19-9) is primarily a radiologic distinction and has little or no significance as both may result in atlanto-axial instability with potential neurologic sequelae. Treatment is identical in either case. Another related developmental anomaly is the presence of a separate ossification center at the tip of the V-shaped odontoid process, the ossiculum terminale. It appears at about age 3 years, fuses with the dens by age 12 years, and is considered a normal variant. Should fusion fail to occur, this ossification center is referred to as the ossiculum terminale persistens, another normal variation in development. Diagnosis

Congenital anomalies of the odontoid can be incidental observations on radiographs obtained for other purposes or following trauma that may initiate atlanto-axial instability and/or provoke symptoms in a previously asymptomatic individual. Symptoms may be localized to the neck, such as pain and stiffness, or there can be transient bouts of paresis. More serious symptoms include compressive cord myelopathy and ischemia of the brain-stem by impingement of the vertebral artery, leading to syncope, vertigo,

Fig. 19-8. The os odontoideum has been identified by a small dotted circle in the position where one would expect to see the odontoid tip. A portion of the body of the odontoid is not yet ossified.

Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

819

posterior cervical spine fusion, commonly preceded by halo-skull traction. Asymptomatic patients with odontoid hypoplasia must be carefully monitored, because they are at significant risk for sudden neurologic injury involving daily living activities. There is no consensus as to prophylactic spine fusion for these patients. Certainly, modification of physical activities and lessened participation in sports must be considered. References (Aplasia/Hypoplasia of the Odontoid Process of the Axis)

Fig. 19-9. Partial odontoid hypoplasia in a 4-year-old girl with an unclassified skeletal dysplasia.

seizures, and visual disturbances. Weakness, decreased motor endurance, and upper motor neuron signs are common. These patients have variable spasticity and hyperreflexia or have loss of proprioception and sphincter disturbance. The diagnosis can be made at birth or in childhood with standard radiographs (Fig. 19-8). When there is uncertainty, lateral views of the cervical spine in careful voluntary flexion, extension, and neutral projection are indicated. Computerized tomography is often necessary to confirm the condition. When neurologic symptoms are a prominent clinical feature, magnetic resonance imaging is necessary to delineate the condition, augmented by somatic evoked responses as well as a careful neurologic examination. Etiology and Distribution

The body of the odontoid, phylogenetically derived from the centrum of the first cervical vertebra, separates from the atlas during development and fuses with the superior portion of the axis.1 A wide cartilaginous band is present by birth at the site of this fusion (neurocentral synchondrosis). The tip of the odontoid is not ossified at birth and has a V-shaped configuration. Delayed ossification of the dens may give the impression of hypoplasia or aplasia. Underdevelopment or failure of fusion can result in congenital anomalies of the odontoid. The frequency of odontoid anomalies is unknown. Complete aplasia is extremely rare; most instances involve variable degrees of hypoplasia. It may be found in patients with Down syndrome and is extremely frequent in mucopolysaccharidoses, especially Morquio syndrome.2 Odontoid aplasia/hypoplasia is found in a number of disorders, particularly those involving an intrinsic skeletal anomaly (Table 19-6). As an isolated abnormality, the majority of occurrences are discovered following head and neck trauma. Prognosis, Treatment, and Prevention

The prognosis is excellent when the clinical symptoms are limited to local neck pain and stiffness without neurologic findings.3 When there are neurologic signs and symptoms, the prognosis is guarded and depends on chronicity of the disorder as well as treatment. Nonoperative therapy by cervical traction or plaster casting may be sufficient with a relatively stable atlanto-axial joint. However, those with an atlas dens space (ADS) of more than 5 mm demonstrated on flexion-extension lateral radiograph require stabilization by

1. Parke WW: Development of the spine. In: The Spine, vol 1, ed 2. RH Rothman, FA Simeone, eds. WB Saunders Company, Philadelphia, 1982, p 13. 2. Skeletal Dysplasia Group: Instability of the upper cervical spine. Arch Dis Child 64:283, 1989. 3. Hensinger RN, MacEwen GD: Congenital anomalies of the spine. In: The Spine, vol 1, ed 2. RH Rothman, FA Simeone, eds. WB Saunders Company, Philadelphia, 1982, p 208.

19.12 Segmentation/Formation Defects of the Vertebra Definition

Congenital anomalies of the vertebral body and/or posterior elements may be unilateral or bilateral and can affect the vertebral column at any level from the atlas to the coccyx (Figs. 19-10 and 19-11). Block vertebrae occur when there is lack of segmentation between adjacent vertebral bodies. A hemivertebra results when one of the two chondrification centers of the developing vertebral body fails to appear, resulting in failure of formation of one-half of the vertebra. The corresponding rib is often absent. Failure of fusion of the halves of the vertebral arch results in a major defect, spina bifida. Severe forms of this condition associated with spinal cord anomalies will be described elsewhere. Spina bifida occulta, however, is a relatively common finding involving the cervical, lumbar, and sacral regions. This condition is not associated with neurologic complications and is often a serendipitous finding identified by radiographs for other reasons (e.g., back pain). Diagnosis

Many individuals with anomalies involving the vertebral bodies and/or posterior elements have few, if any, clinical abnormalities to suggest their presence. These abnormalities are often detected only when radiographs are obtained, usually for other reasons. Clinical findings that should prompt radiographic evaluation of the spine include congenital scoliosis, rib anomalies, and midline abnormalities over the spine including tufts of hair, cutis aplasia, hemangiomas, nevi, and dimples above the gluteal fold.1 Neurologic alterations such as limb atrophy, asymmetry, abnormal deep tendon reflexes, and foot deformities should also trigger evaluation. Diagnosis of spine abnormalities is confirmed by anteriorposterior and lateral radiographs. Computed tomography may be necessary to delineate details of the bony abnormalities, while magnetic resonance imaging is necessary to identify associated neurologic abnormalities. Defects in the embryologic development of the spinal vertebrae often result in congenital scoliosis. Nearly one-third of patients with congenital scoliosis have associated congenital anomalies,2 including a wide variety of findings including cardiac malformations, TE fistula, imperforate anus, genitourinary abnormalities,

820

Skeletal System Table 19-6. Conditions in which odontoid aplasia/hypoplasia is a feature Condition

Prominent Features

Causation Gene/Locus

Cartilage-hair hypoplasia

Short limbs, genu varum, long fibulas, fine hair

AR (250250) RMRP, 9p21-p12

Dyggve-Melchior-Clausen

Mental retardation, coarse facies

AR (223800) FLJ90130, 8q12-q21.1

Epiphyseal dysplasia, multiple, with early-onset diabetes mellitus

Short trunk, dysmorphic facies, diabetes

AR (226980) EIF2AK3

Faciogenital dysplasia (Aarskog syndrome)

Characteristic facies, shawl scrotum, ligamentous laxity

XL (305400) FGD1, Xp11.21

Fucosidosis

Neurologic deterioration, coarse facies, angiokeratoma

AR (230000) FUCA1, 1p34

Hunter (MPS II)

Coarse facies, hepatosplenomegaly

XL (309900) IDS, Xq28

Hurler (MPS I-H)

Coarse facies, hepatosplenomegaly, cloudy corneas

AR (607014) IDUA, 4p16.3

Maroteaux-Lamy (MPS VI)

Short stature, cloudy corneas

AR (253200)

Morquio (MPS IV-A)

Short stature, cloudy corneas

AR (253000) GALNS, 16q34.3

Morquio (MPS IV-B)

Short stature, cloudy corneas

AR (253010) GLB1, 3p21.33

Mucolipidosis II

Congenital dislocation of hip, hernias, gum hypertrophy

AR (252500) GNPTA, 4q21-q23

Pseudoachondroplasia

Short limbs, brachydactyly, platyspondyly

AD (177170) COMP, 19p13.1

Pseudodiastrophic dysplasia

Rhizomelia, clubfeet, platyspondyly

AR (264180) 7q21

Sly (MPS VII)

Dysostosis multiplex, hepatosplenomegaly

AR (253220) GUSB, 7q21.11

Smith-McCort dysplasia

Short trunk and limbs, microcephaly

AR (607326) FLJ90130, 18q12-q21.1

Spondylocarpotarsal synostosis

Vertebral fusions, carpal coalitions

AR (272460)

Spondylo-epi-metaphyseal dysplasia (Strudwick)

Severe short stature, pectus carinatum, cleft palate

AD (184250) COL2A1, 12q13.11-q13.2

Spondyloepiphyseal dysplasia, congenita

Short trunk, myopia

AD (183900) COL2A1, 12q13.11-q13.2

Spondyloepiphyseal dysplasia, tarda

Severe scoliosis, short hands and feet

AD (184100)

Spondylometaphyseal dysplasia, Kozlowski type

Short stature, short trunk, platyspondyly

AD (184252) 12q13

limb anomalies, and mandibular and ocular abnormalities. Therefore, a thorough evaluation for other anomalies is indicated in all individuals with segmentation/formation defects of the vertebrae.

authors believe that it is related to those processes involved in body segmentation in general, such as the Notch pathway.5 Prognosis, Treatment, and Prevention

Etiology and Distribution

The incidence of segmentation defects is reported to be between 0.5 and six per 1000,3 but may actually be higher because of underreporting. Minor anomalies of the lumbosacral spine are so common as to be considered a variation of normal. Unfortunately, no good data are available to document the exact incidence of associated anomalies, although it is estimated that anomalies occur at sites other than the spine in 30–60% of children with congenital spinal anomalies.4 Conditions in which these findings are seen are outlined in Table 19-7. The underlying developmental abnormality in segmentation and formation defects of the spine is unknown, although some

Asymmetric or unbalanced segmentation defects generally are progressive and deforming, leading to severe scoliosis. If the defects are balanced and symmetric, then the risk for scoliosis is less and the deformity is not as likely to be severe. Kyphosis or lordosis may occur if the fusion between vertebral bodies is located anteriorly or posteriorly, respectively. Management is characterized by close and careful observation. When there is congenital scoliosis, it is important to realize that the severity of the curve and rate of progression are not necessarily related. The more unbalanced the anomalies, the more likely the scoliosis will progress. Curves in the thoracic region are more progressive that those in the cervicothoracic and lumbar

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4. Jaskwhich D, Ali RM, Patel TC, et al.: Congenital scoliosis. Curr Opin Pediatr 12:61, 2000. 5. Pourquie O, Kusumi K: When body segmentation goes wrong. Clin Genet 60:409, 2001.

19.13 Klippel-Feil Anomaly Definition

Klippel-Feil anomaly (Fig. 19-11) is characterized by the triad of failure of segmentation of two or more cervical vertebrae, short neck with limitation of range of motion, and a low nuchal hairline, although few patients have all three findings.1 Diagnosis

Fig. 19-10. Multiple segmentation abnormalities of the upper thoracic spine in a 1-year-old child with diastrophic dysplasia.

regions. Orthotic treatment is often used. A wide variety of operative procedures has been developed to halt progression of the scoliosis surgically. Prevention is by genetic counseling when the vertebral anomalies are part of a single gene or chromosomal abnormality. References (Segmentation/Formation Defects of the Vertebrae) 1. Kriss VM, Desai NS: Occult spinal dysraphism in neonates: assessment of high risk cutaneous stigmata on sonography. AJR Am J Roentgenol 171:1687, 1998. 2. Winter RB, Moe JH, Eilers VE: Congenital scoliosis: a study of 234 patients treated and untreated. J Bone Joint Surg 50A:1, 1968. 3. Wynne-Davies R: Localized developmental disorders of the skeleton. In: Heritable Disorders in Orthopaedic Practice. Blackwell Scientific Publications, London, 1973, p 162.

Clinically, most individuals present with limitation of neck motion. Flexion-extension of the neck is less limited than lateral rotation. Shortening of the neck may be inapparent or marked such that the head appears to rest on the shoulders. Pterygium colli may be apparent in severe cases, manifested by webs of soft tissue and skin tented between the mastoid process of the skull and the acromion of the shoulder. Many other skeletal anomalies can be seen in conjunction with Klippel-Feil anomaly.2 Unilateral or bilateral Sprengel anomaly is found in 30% of cases. Occasionally an omovertebral bone bridges between the cervical spine and the scapula. Scoliosis, cervical ribs, fused ribs, spina bifida occulta, cleft vertebrae, hemivertebrae, and occipitalization of the atlas occur in a nonrandom association. Anomalies involving other systems are also noted.2 Hearing loss (sensorineural, conductive, and mixed), cleft palate, and ocular anomalies such as strabismus are all seen in about 20% of cases. Primary or secondary neurologic abnormalities may be found and include facial nerve palsies, meningocele, encephalocele, ArnoldChiari malformation, syringomyelia, and hydrocephalus. Intelligence, however, is usually normal. Renal malformations, most frequently unilateral renal agenesis, are noted in one-half of patients.

Fig. 19-11. Hemivertebrae. Left: An adolescent girl showing unilateral fusion. Right: A boy with Klippel-Feil anomaly.

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Skeletal System Table 19-7. Conditions in which there are segmentation/formation defects of the vertebrae Causation Gene/Locus

Condition

Prominent Features

Apert

Craniosynostosis, syndactyly

AD (101200) FGFR2, 10q26

Aicardi

Agenesis of the corpus callosum, chorioretinal abnormality

XL (304050)

Alagille

Arteriohepatic dysplasia, cardiac malformations

AD (118450) JAG1, 20p12

Basal cell nevus (Gorlin)

Basal cell nevi, jaw cysts, skeletal anomalies

AD (109400) PTC, 9q22.3

Coffin-Siris

Mental retardation, absent fifth fingernail

AD (135900)

Dyssegmental dysplasia

Multiple rib and vertebral anomalies, narrow chest, reduced joint mobility

AR (224400)

Femoral-facial

Femoral hypoplasia, characteristic facies

AD (134780)

Hemifacial microsomia

Facial asymmetry, ear anomalies

AD (164210)

Incontinentia pigmenti

Abnormalities involving the skin, hair, nails, teeth, eyes, CNS

XL (308300) NEMO, Xq28

Jarcho-Levin

Rib and vertebral anomalies

AR (277300) DLL3, 19q13

Kabuki

Characteristic facies, mental retardation

AD (147920)

Larsen

Knee dislocations, characteristic facies

AD (150250) LRS1, 3p21.1-p14.1

LEOPARD

Lentigines, cardiomyopathy

AD (151100) PTPN11, 12q24.1

Maxillo-nasal dysplasia, Binder type

Midfacial hypoplasia, lack of anterior nasal spine

AD (155050)

Mental retardation, skeletal dysplasia, abducens palsy

Short stature, metopic ridge

XL (309620) Xq28

Multiple pterygium

Webbing of neck, popliteal and anticubital fossae

AR (265000)

Peters-Plus

Peters anomaly, short limb dwarfism

AR (261540)

Poland

Unilateral absence of pectoralis major, ipsilateral anomaly of upper extremity

AD (173800)

Robinow, dominant

Characteristic facial features, hypoplastic genitalia

AD (180700)

Robinow, recessive

Characteristic facial features, hypoplastic genitalia

AR (268310) ROR2, 9q22

Simpson-Golabi-Behmel

Characteristic facies, overgrowth

XL (312870) GPC3, Xq26

Spondylocarpotarsal synostosis

Vertebral fusion, carpal coalition

AR (272460)

Spondylocostal dysplasia

Multiple vertebral and rib anomalies

AR (277300) DLL3, 19q13.1 Heterogeneous

VATER association

Vertebral anomalies, anal atresia, TE fistula, renal and radial ray defects

Sporadic (192350)

Genital anomalies are not uncommon and include hypospadias and cryptorchidism in males and absent vagina, uterus, or Fallopian tubes in females. Congenital heart defects are seen in less than 10% of cases. A subgroup of individuals with Klippel-Feil anomaly who also have genital and renal anomalies have MURCS association (Mullerian duct aplasia, unilateral renal agenesis, cervical somite anomalies).

Anteroposterior and lateral radiographs will define the pattern and extent of the vertebral anomalies, although this may be difficult in the newborn period and infancy. These films should include the entire spine and ribs, as other skeletal anomalies are frequent. Hearing evaluation and a thorough neurologic exam are indicated to rule out associated central nervous system anomalies. Renal and pelvic ultrasound should also be performed.

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Etiology and Distribution

Although the true incidence of Klippel-Feil anomaly is difficult to determine, an overall incidence of one in 40,000 live births is often quoted. This condition is probably more common since lesser fusions are not detected until later life. Most surveys suggest that a preponderance of cases occur in females. Most cases of Klippel-Feil anomaly are sporadic, although family cases have been reported, consistent with both autosomal dominant and autosomal recessive inheritance. Three morphologic types have been suggested: type I with massive fusion of many cervical and upper thoracic vertebrae into bony blocks; type II with fusion at only one or two interspaces, which can be associated with other bony anomalies; and type III with both cervical and lower thoracic or lumbar fusion.3 Wildervanck syndrome, characterized by Klippel-Feil anomaly, deafness, and Duane syndrome, is thought to be X-linked dominant since there is a paucity of affected males. Because of the wide variety of associated findings with this primary malformation of the spine, the etiology will certainly prove to be heterogeneous. Prognosis, Treatment, and Prevention

Children with congenital fusion of the cervical spine do not commonly have neurologic complaints or signs of cervical instability, although flexion-extension lateral radiographs are indicated prior to general anesthetic.4 Neurologic symptoms typically develop between the 2nd and 3rd decades as a consequence of occipito-cervical anomalies, cervical instability, or degenerative disc/joint disease. Spinal stenosis may be seen when the lower spine is involved. Orthopedic management is indicated when spinal instability or scoliosis is present. Because children with large fusion areas are at high risk for developing instability, contact sports should be avoided.4 As always, a complete family history is indicated and radiographs of select family members may be necessary to determine recurrence risk. References (Klippel-Feil Anomaly) 1. Hensinger RW, Lang LR, MacEwen GD: Klippel-Feil syndrome: a constellation of associated anomalies. J Bone Joint Surg 56A:1246, 1974. 2. Helmi C, Pruzansky S: Craniofacial and extracranial malformation in the Klippel-Feil syndrome. Cleft Palate J 17:65, 1980. 3. Gunderson CH, Greenspan RH, Glaser GH, et al.: The Klippel-Feil syndrome: genetic and clinical re-evaluation of cervical fusion. Medicine 46:491, 1967. 4. Loder RT: Congenital anomalies of the cervical spine. In: The Adult and Pediatric Spine, vol 2, ed 3. JW Frymoyer, SW Wiesel, eds. Lippincott Williams & Wilkins, Philadelphia, 2004.

19.14 Altered Vertebral Body Contour Definition

Variations in vertebral body contour depend on radiographic projection and may be associated with a disease state or be normal variants. Beaked or notched vertebrae have a hooked or steplike appearance on lateral view and are frequently associated with a localized kyphosis (Fig. 19-12). Scalloped vertebrae are manifested by exaggeration of the normal slight concavity of the dorsal surface of the vertebral body (Fig. 19-13). Increased biconcavity of the superior and inferior surfaces of the vertebral body results in a fish vertebra on lateral projection (Fig. 19-14). The term cupid’s

Fig. 19-12. Anterior wedging of the first lumbar vertebra.

bow vertebrae has been given to the anteroposterior appearance of the lumbar vertebrae produced by symmetric parasagittal concavities in the inferior end-plate. Platyspondyly is an abnormal flattening of the vertical diameter of the vertebral bodies. It is present in many skeletal dysplasias with spine involvement, particularly the spondyloepiphyseal dysplasias (Fig. 19-15). Diagnosis

Alterations in vertebral body contour are identified radiographically (Figs. 19-12, 19-13, and 19-14). Beaked, notched, or hooked vertebrae may be seen in normal infants. Mild or physiologic scalloping of vertebrae can be seen in over one-half of adult spines, is always confined to the lumbar region, and is not associated with a widened interpedicular distance. Etiology and Distribution

Beaked, notched, or hooked vertebrae, most frequently found in the thoracolumbar spine, are usually associated with kyphosis (Fig. 19-12).1 They are occasionally found in infants with no underlying disorder, but are commonly seen in young children with hypotonia, neuromuscular diseases, and congenital hypothyroidism. These distinctive vertebrae are thought to be due to anterior

824

Skeletal System

Fig. 19-14. ‘‘Fish-mouth’’ vertebra resulting from exaggerated biconcavity of the vertebral bodies in a 16-year-old boy with osteogenesis imperfecta. Fig. 19-13. Posterior scalloping of the vertebral bodies in the lumbar spine of a patient with achondroplasia.

herniation of the nucleus pulposus. They occur primarily in the thoracolumbar spine, as this is the area of normal or physiologic kyphosis. Maintenance of a ‘‘slouched’’ or ‘‘bent’’ posture, coupled with hypotonia, will place undue stress on the intervertebral disc and promote nucleus pulposus herniation. Frequently these abnormalities of contour are noticed in storage disorders, such as the mucopolysaccharidoses and mucolipidoses, and chromosome abnormalities, particularly those associated with hypotonia. They are also found in a variety of single gene disorders (Table 19-8). Pathologically scalloped vertebrae (Fig. 19-13) are occasionally a manifestation of a bone disorder (achondroplasia, mucopolysaccharidosis), but more often they are secondary to a connective tissue disorder in which dural ectasia occurs (Marfan syndrome, neurofibromatosis type I, Ehlers-Danlos syndromes).2 These vertebral changes may also be associated with disorders in which there is increased intraspinal pressure such as intradural neoplasms, intraspinal cysts, syringomyelia, and hydromyelia. Borderline or uncontrolled communicating hydrocephalus may produce pathologic scalloping of the vertebrae. Fish vertebrae, especially common in the lower thoracic and upper lumbar spine, are characteristic of conditions in which bone is weakened by osteoporosis, osteopenia, or osteomalacia (Fig. 1914). Examples include osteogenesis imperfecta, homocystinuria,

Lowe syndrome, various storage disorders, and rickets. Fish vertebrae are nonspecific radiographic findings that may occur in a spectrum of single gene disorders, in many chromosome abnormalities, and in syndromes or disorders of unknown genesis. Cupid’s bow vertebrae are common in the general population, more frequent in males and in blacks, and, when present, tend to be more subtle than prominent.3 L4 is the most commonly affected vertebra, followed in frequency by L5 and then L3. These contour changes have no pathologic significance. Prognosis, Treatment, and Prevention

The prognosis of these altered vertebral body contours depends on any underlying pathologic disorder. Likewise, treatment is based on a specific diagnosis. Genetic counseling is indicated when a single gene disorder or chromosome abnormality is identified. References (Altered Vertebral Body Contour) 1. Swischuk LE: The beaked, notched or hooked vertebra. Radiology 95:661, 1970. 2. Mitchell GE, Lourie H, Berne AS: The various causes of scalloped vertebrae with notes on their pathogenesis. Radiology 89:67, 1967. 3. Dietz GW, Christensen EE: Normal ‘‘cupid’s bow’’ contour of the lower lumbar vertebrae. Radiology 121:577, 1976.

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Fig. 19-15. Left: Anteroposterior radiograph showing platyspondyly and osteopenia in a 16-year-old boy with osteogenesis imperfecta. Right: Lateral radiograph showing marked platyspondyly in a 6-year-old girl with spondylometaphyseal dysplasia.

19.15 Sagittal Clefts of the Vertebrae Definition

Sagittal clefts of the vertebrae are characterized by congenital division of the vertebral body into two lateral halves (butterfly vertebrae).1 Diagnosis

The patient with one or more sagittal cleft vertebrae may be asymptomatic, have back pain, or present because of scoliosis or shortened height of the vertebral column. Anteroposterior radiographs of the spine demonstrate the butterfly-like appearance of the two halves of the vertebral body (Fig. 19-16). These may occur at any level of the spine but are mostly found in the midthoracic to lumbar region. The two portions are usually of equal size, and a bony bridge may partially unite the two sides. Narrowing of the associated intervertebral disc spaces is also typical. Other malformations of the vertebrae and ribs may occur, and scoliosis or kyphosis may be present. Etiology and Distribution

The etiology and incidence are unknown. Sagittal cleft vertebrae may occasionally be noted as an isolated anomaly when radio-

graphic studies are performed for other purposes. They are one of the diagnostic features of the multiple malformation syndrome, Kabuki syndrome.2 Sagittal cleft vertebrae are also frequently found in the spondylocostal/spondylothoracic dysplasias, a heterogeneous group of segmentation disorders of the vertebral column with both autosomal dominant and autosomal recessive forms.3 Prognosis, Treatment, and Prevention

For the asymptomatic patient with no other associated abnormalities, treatment is not necessary. Modification of daily activities and physical therapy can offer relief from pain. When there is spinal column malalignment, such as in scoliosis and/or kyphosis, spinal fusion may be recommended, depending on the extent of involvement and severity. Genetic counseling is indicated if a specific syndrome diagnosis is established. References (Sagittal Clefts of the Vertebrae) 1. Rischer FJ, Vandermark RE: Sagittal cleft (butterfly) vertebrae. J Bone Joint Surg 27A:695, 1945. 2. Niikawa N, Kuroki Y, Kajii T, et al.: Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 31:565, 1988. 3. Ayme S, Preus M: Spondylocostal/spondylothoracic dysostoses: the clinical basis for prognosticating and genetic counseling. Am J Med Genet 24:599, 1986.

826

Skeletal System Table 19-8. Conditions associated with altered vertebral body contours Causation Gene/Locus

Condition

Prominent Features

Achondroplasia

Short limbs, frontal bossing, trident hand

AD (100800) FGFR3, 4p16.3

Acromesomelic dysplasia, Maroteaux type

Disproportionate shortening of the middle and distal segments

AR (602875) NPR2, 9p

Aspartylglucosaminuria

Mental retardation, sagging cheeks, coarse facies

AR (208400) AGA, 4q32-q23

Diastrophic dysplasia

Coarse facies, malformed ears, hitchhiker thumb

AR (222600) SLC26A2, 5p32-q33.1

Dyggve-Melchior-Clausen

Mental retardation, coarse facies

AR (223800) FLJ90130, 8q12-q21.1

Fucosidosis

Neurologic deterioration, coarse facies, angiokeratoma

AR (230000) FUCA1, 1p34

GM1 gangliosidosis

Neurologic deterioration, cherry red spot, coarse facies

AR (230500) GLB1, 3q21.33

Mannosidosis, alpha

Coarse facies, dysostosis multiplex

AR (248500) MAN2B1, 19cen-q12

Mannosidosis, beta

Coarse facies, mild bone disease

AR (248510) MANB1, 4q22-q25

Marshall

Midface hypoplasia, short nose, ocular findings

AD (154780) COL11A1, 1p21

Niemann-Pick

Hepatosplenomegaly, neurologic deterioration

AR (257200) SPMD1, 11p15.4-p15.1

Pseudoachondroplastic dysplasia I

Short limbs, ligamentous laxity

AD (177150) COMP, 19p13.1

Spondyloepiphyseal dysplasia congenita

Short trunk, myopia

AD (183900) COL2A, 12q13.11-q13.2

19.16 Coronal Clefts of the Vertebrae Definition

Coronal cleft of the vertebra occurs when there is failure of fusion of an uncommon posterior accessory vertebral body ossification nucleus with the normally present solitary central vertebral body ossification center at about 16 to 18 weeks gestation, resulting in a split or cleft appearance of the vertebra.1 Diagnosis

Coronal cleft vertebrae are recognized in lateral radiographic projection of the spine in the fetus and newborn (Fig. 19-17). The cleft appears as a radiolucent band separating the anterior and posterior ossified portions of the vertebral body, and its borders are quite variable in contour. In the cervical and upper thoracic areas, and to a lesser extent in the lower lumbar area, the dorsal portion is slightly smaller.2 Although cleft vertebrae may be found at all levels, they are more obvious in the lumbar spine. Ordinarily these distinctive vertebrae disappear during the first few months of life. Coronal clefting of vertebrae, a radiologic phenomenon, is not associated with external physical stigmata. They are found incidentally on radiographs obtained for other purposes. Etiology and Distribution

The etiology of coronal clefts is unknown. Typically there is a solitary vertebral body ossification center, but a paired center may occur and is considered unusual. On radiographs, it appears as a

radiolucent band separating the two portions. Persistence of the notochord has been proposed as causal, although histologically, notochordal cells have not been demonstrated.3 It consists of hyaline cartilage. Anomalous vascular development with subsequently altered ossification in the terminal ramifications seems plausible. The incidence is not accurately known, but coronal cleft vertebrae have been found in about one-third of fetuses less than 23 weeks gestation. Males are reportedly more commonly affected (10:1).4 Coronal cleft vertebrae are frequently present in a number of single gene disorders (Table 19-9) and in chromosomal abnormalities such as trisomy 13. One study found that clefts were most frequently observed in the following disorders: atelosteogenesis (88%), chondrodysplasia punctata (79%), dyssegmental dysplasia (73%), Kniest dysplasia (63%), and short rib polydactyly (53%).5 Prognosis, Treatment, and Prevention

As this condition is considered a benign normal variant, the prognosis is excellent. However, if coronal clefting occurs in association with sagittal clefting of the same vertebrae or there are other ossification defects, there may be serious consequences such as posterior hemivertebrae and clinical kyphosis. Genetic counseling is indicated for those individuals with specific syndrome diagnoses. References (Coronal Clefts of the Vertebrae) 1. Berk ME, Tabatznik B: Cervical kyphosis from posterior hemivertebrae with brachyphalangy and congenital optic atrophy. J Bone Joint Surg 43B:77, 1961. 2. Cohen J, Currarino G, Neuhauser EBD: Significant variant in the ossification centers of the vertebral bodies. Am J Roentgenol 76:469, 1956.

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Fig. 19-17. Multiple coronal clefts of vertebrae in an infant with the rhizomelic type of chondrodysplasia punctata.

Fig. 19-16. Multiple vertebrae demonstrating sagittal clefting in a 6-month-old infant. 3. Schinz HR, Rondury G: Zur Entwicklung der menschlichen Wirbelsaule; die Fruhossifikation der Wirbelkorper. Fortschr Rontgenstrahlen 66:253, 1942. 4. Silverman FN: Caffey’s Pediatric X-ray Diagnosis: An Integrated Approach, vol 1, ed 8. Year Book Medical Publishers, Chicago, 1985, p 295. 5. Westvik J, Lachman RS: Coronal and sagittal clefts in skeletal dysplasias. Pediatr Radiol 28:764, 1998.

19.17 Spondylolysis and Spondylolisthesis Definition

Spondylolysis refers to a defect in the pars interarticularis of the vertical arch and occurs most often in the fifth lumbar verte-

bra, occasionally in the fourth, and even more rarely in others. Spondylolisthesis (or anterior translocation or displacement) describes forward slipping on one vertebra or another and is classified in five major types: (1) dysplastic, congenital deficiency of the superior sacral or inferior fifth lumbar facets or both; (2) isthmic (spondylolytic), due to (a) a separation or dissolution of the pars interarticularis or (b) elongation of the pars without separation; (3) degenerative; (4) traumatic; and (5) pathologic, due to a local or generalized bone disease.1 Diagnosis

Spondylolysis occurs most often in children between ages 6 and 10 years and usually is asymptomatic, being detected on incidental radiograph evaluation. The greatest risk of progression to vertebral slippage is between ages 10 and 15 years. When symptomatic, the presenting complaint is usually low back pain accentuated by physical activity. Postural changes and gait disturbances are also common symptoms and may occur in the absence of pain. Other findings included local tenderness, limited spine mobility, and tight

828

Skeletal System Table 19-9. Conditions in which coronal cleft vertebrae are a feature Causation Gene/Locus

Condition

Prominent Features

Atelosteogenesis

Distal hypoplasia of humeri and femurs, abnormal ossification of hand bones

AD (108720)

Chondrodysplasia punctata, Conradi type

Asymmetric epiphyseal calcifications

XLD (302960) EBP, Xp11.23-p11.22

Chondrodysplasia punctata, rhizomelic type

Mental retardation, ichthyosis, short stature

AR (215100) PEX7, 6q22-q24

Desbuquois

Micromelia, advanced carpotarsal ossification

AR (254150)

Dyssegmental dysplasia

Narrow chest, reduced joint mobility

AD (224400)

Fibrochondrogenesis

Lethal, broad metaphyses

AR (228520)

Kabuki

Mental retardation, characteristic facies

AD (147920)

Kniest dysplasia

Short trunk, ocular findings, cleft palate

AD (156550) COL2A1, 12q13.11-q13.2

Metatropic dysplasia, type I

Short trunk, dumbbell-shaped metaphyses

AR (250600)

Neonatal osseous dysplasia I

Midface hypoplasia, cleft palate, severe micromelia

AR (256050)

Saldino-Noonan type short rib-polydactyly

Lethal, polydactyly, visceral abnormalities

AD (263530)

Stickler

Myopia, flat midface, hearing loss

AD (108300) COL2A1, 12q13.11-q13.2 COL11A1, 1p21 COL11A2, 6p21.3

Weissenbacher-Zweymuller

Micrognathia, rhizomelic chondrodysplasia

AR (277610) COL11A2, 6p21.3

hamstrings. In children, neurologic findings related to herniated disc and nerve root impingement are infrequent, being more common in adults with spondylolisthesis.2 Occasionally scoliosis is associated. The diagnosis is made radiographically, with films taken in supine and standing positions in both lateral and oblique projection. Computed tomography is used to evaluate the anatomy of the pars interarticularis. Bone scanning may also be a useful diagnostic technique. The degree of slip can be expressed as a percentage of the anteroposterior diameter of the top of the first sacral vertebra.3

There is a high rate of occurrence of these defects among family members. One study reported an incidence of 27% in firstdegree relatives as compared with the expected 4–8% in the general population.4 Patients with each type of spondylolisthesis, isthmic and dysplastic, had relatives with the opposite type. Those with the dysplastic form had more affected relatives (33%) than those with the isthmic type (15%). Autosomal dominant transmission of this trait has been reported, with a penetrance of 75%.6 It also occurs occasionally in patients with Marfan syndrome and basal cell carcinoma syndrome.

Etiology and Distribution

The incidence of spondylolysis is 4–8% in the general population of those individuals over age 6 years. In Alaskan Eskimos, 5% show the abnormality by 6 years and 20% by 35 years, findings attributed to the mechanical stress and fatigue fractures of the pars.4 Other studies have shown a racial and sex difference: 1.1% in black females, 2.3% in white females, 6.4% in white males, and 2.8% in black males.5 The most common type of spondylolisthesis is the ischemic form. Spina bifida occulta is found in 11–18% of those with the dysplastic type.6 The upright habitus of the human is considered a prerequisite for stress and repetitive microtrauma to the low back, which produces pars interarticularis defects, a condition that does not occur in other mammals. Both spondylolysis and spondylolisthesis have an increased incidence in persons participating in heavylabor occupations and in certain sports such as diving, weightlifting, wrestling, high jumping, rowing, and American football. Female gymnasts are also at high risk.

Prognosis, Treatment, and Prevention

Considerable controversy exists over the best treatment of these disorders. Treatment for children is very different than that for adults. No treatment is necessary for the patient with asymptomatic spondylolysis and no slippage. They should be cautioned against certain sporting activities and heavy labor. If pain alone is present, bracing is indicated. When orthotic management is unsuccessful, surgical fusion is necessary. Genetic counseling is indicated if there is a positive family history. References (Spondylolysis and Spondylolisthesis) 1. Wiltse LL, Newman PH, MacNab I: Classification of spondylolysis and spondylolisthesis. Clin Orthop 117:23, 1976. 2. Pizzutillo PD: Spondylolisthesis: etiology and natural history. In: The Pediatric Spine. D Bradford, R Hensinger, eds. JB Lippincott, Philadelphia, 1985, p 395.

Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

829

Sacral agenesis is absence of the terminal segments of the vertebral column, ranging from absence of the lower coccygeal segments to complete aplasia of the vertebrae below the twelfth thoracic segment. Related conditions include sacral dysgenesis, in which part of the sacrum is present, and caudal regression (dysplasia, dysgenesis, deficiency), in which anorectal malformations may be seen.

poses. Absence of the entire lumbosacral spine is quite rare. Most cases are intermediate between these two extremes, and four types can be distinguished.1 Type I can be a total or partial and is characterized by unilateral sacral agenesis. Type II has partial agenesis of the sacrum, a normal or hypoplastic first sacral vertebra, and a stable sacroiliac joint. This is the most frequent type. Type III has total sacral agenesis and variable lumbar agenesis, and the ilia articulate with the lowest vertebra present (Fig. 19-18). Type IV has total sacral agenesis and variable lumbar agenesis, and the caudal endplate of the lowest vertebra rests above either the fused iliac wings or there is an iliac amphiarthrosis. The patient’s clinical appearance depends on the extent of spinal involvement and the degree of neurologic impairment. An assortment of associated congenital anomalies have been reported, including renal malformations, cryptorchidism, hydrocephalus, cleft lip and palate, congenital heart disease, and meningomyelocele, all with low frequency. Prenatal detection is possible by ultrasonography. Fetal magnetic resonance imaging may be helpful in identifying spinal cord involvement.

Diagnosis

Etiology and Distribution

Absence of the lower coccygeal segments is usually recognized incidentally when radiographic studies are performed for other pur-

Congenital absence of the sacrum and lumbar vertebra (caudal dysplasia sequence or caudal regression syndrome) is a rare condition

3. Wiltse LL, Winter RB: Terminology and measurement of spondylolisthesis. J Bone Joint Surg 65A:768, 1983. 4. Wynne-Davies R, Scott JHS: Inheritance and spondylolisthesis. A radiographic family survey. J Bone Joint Surg 61B:301, 1979. 5. Rowe GG, Roche MB: The etiology of separate neural arch. J Bone Joint Surg 35A:102, 1953. 6. Haukipuro K, Keranen N, Koivist E, et al.: Familial occurrence of lumbar spondylolysis and spondylolisthesis. Clin Genet 13:471, 1978.

19.18 Sacral Agenesis Definition

Fig. 19-18. Left: Congenital absence of the sacrum in a 5-year-old girl whose mother has severe diabetes mellitus. Note heart-shaped configuration of the ilia and absence of the lower lumbar vertebrae. Right: Lateral radiograph of the torso illustrating the appearance of the lumbopelvic region in sitting position.

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Skeletal System

with reported incidence varying between 0.01 and 0.5 per 1000 live births.2 Animal experiments have shown that many defects in the developing spine result from a failure of inductive interaction between the neural ectoderm and the presumptive notochord. Another hypothesis suggests that there is failure of formation of the caudal notochord sheath and the ventral spinal cord. The association between diabetes in pregnancy and sacral agenesis is well-described. It is estimated that 16% of human cases of sacral agenesis are associated with maternal diabetes mellitus.3 Many other agents have been used to induce this malformation experimentally in laboratory animals: lithium, vitamin A deficiency, radiation, hyperthermia, fat solvents, and 6-aminonicotinamide. The etiology of congenital absence of the sacrum appears to be heterogeneous. In the past, sirenomelia has been included in the spectrum of caudal dysgenesis. However, it is now considered by some to be an etiologically distinct malformation related to vascular steal. The majority of instances of sacral agenesis are sporadic; however, there are several reports of familial cases consistent with autosomal dominant inheritance. Another classification has been suggested based on the types of skeletal defects, associated anomalies, and pattern of inheritance: (1) caudal dysgenesis with complete absence of the sacrum and lower vertebrae, multiple congenital anomalies, and association with maternal diabetes; (2) agenesis of the distal sacral or coccygeal segments; (3) hemisacral dysgenesis with presacral teratoma; and (4) hemisacral dysgenesis with anterior meningocele (SDAM). An autosomal dominant inheritance pattern has been suggested for all except type 1, which is rarely familial.4 Types 2, 3, and 4 may simply represent variations of the Currarino triad: partial sacral agenesis with intact first sacral vertebra (sickle-shaped sacrum), a presacral mass, and anorectal malformation. At least some cases of Currarino triad are caused by mutations in the homeobox-containing gene HLXB9.5 One study of families with Currarino triad and HLXB9 mutations found significant clinical variability with some affected individuals showing coccygeal hypoplasia only.6 Prognosis, Treatment, and Prevention

Because the small sensory-type nerves are preserved, pressure sores are not a problem. Because proprioception is intact, the patients are aware of their lower limbs, thus warranting salvage of the legs to permit a satisfactory functional status.2 Spinal-pelvic fusion is controversial but may be necessary to stabilize the patient, aid in correcting flexion contractures of the lower limbs, improve sitting balance, and minimize compression of abdominal viscera. When hip motion is restricted, surgical reduction of the femora will allow a sitting posture but results in nonambulation. Prognosis is dependent not only on the orthopedic issues but also on any associated abnormalities. Genetic counseling is indicated if diabetic embryopathy, Currarino triad, or a positive family history for similar findings is present. References (Sacral Agenesis) 1. Renshaw T. Sacral agenesis. A classification and review of twenty-three cases. J Bone Joint Surg 60A:373, 1978. 2. Andrish J, Kalamchi A, MacEwen GD: Sacral agenesis: A clinical evaluation of its management, heredity and associated anomalies. Clin Orthop 139:52, 1979. 3. Passarge E, Lenz W: Syndrome of caudal regression in infants of diabetic mothers: observations of further cases. Pediatrics 35:672, 1965.

4. Welch JP, Aterman K: The syndrome of caudal dysplasia: a review, including etiologic considerations and evidence of heterogeneity. Pediatr Pathol 2:313, 1984. 5. Ross AJ, Ruiz-Perez V, Wang Y, et al.: A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet 20:358, 1998. 6. Kochling J, Karbasiyan M, Reis A: Spectrum of mutations and genotypephenotype analysis in Currarino syndrome. Eur J Hum Genet 9:599, 2001.

19.19 Anomalies of the Pelvic Bones Definition

Anomalies of the pelvic bones include small iliac wings, iliac horns, ischial hypoplasia, and small sciatic notch. Nonossifiction of the pelvic bones can also occur. Diagnosis

Anomalies of the pelvic bones are often identified on skeletal survey for a skeletal dysplasia, as they are unlikely to be symptomatic. Etiology and Distribution

Anomalies of the pelvic bones are rarely seen in isolation. They are almost always associated with an underlying skeletal dysplasia (Table 19-10).1,2 Prognosis, Treatment, and Prevention

Prognosis and treatment are related to the underlying skeletal dysplasia. Genetic counseling is indicated when a specific genetic diagnosis is made. References (Anomalies of the Pelvic Bones) 1. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders and Skeletal Dysplasias, ed 4. Mosby-Year Book, Inc, St. Louis, 1996, p 1044. 2. Online Mendelian Inheritance in Man, OMIM (TM): McKusickNathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/

19.20 Developmental Dysplasia of the Hip Definition

Developmental dysplasia of the hip (DDH) (Fig. 19-19) may be congenital or develop postnatally. Congenital dislocations are classified as either teratogenic, occurring as a result of other developmental anomalies such as myelomeningocele, or typical, which occur in an otherwise normal child. Dislocation results in the incomplete loss of femoral head contact with the acetabulum and leads to progressive deformation of the proximal femur, the acetabulum, and the capsule. Subluxation refers to abnormal movement of the femoral head with joint manipulation. Diagnosis

Diagnosis of the dislocation or subluxation is often made in the newborn period during the routine newborn physical exam. Early and frequent evaluation of the hips in infants is recommended

Table 19-10. Conditions associated with anomalies of the pelvic bones Condition

Prominent Features

Causation

Achondroplasia

Short limbs, frontal bossing, trident hand

AD (100800) FGFR3, 4p16.3

Campomelic dysplasia

Bowing of long bones, genital anomalies in males

AD (114290) SOX9, 17q24.3-q25.1

Cleidocranial dysplasia

Aplasia/hypoplasia of clavicle, open fontanelle

AD (119600) CBFA1, 6p21

Cockayne

Senile appearance, retinal degeneration, deafness, Mental retardation

AR (216400)

Coffin-Lowry

Mental retardation, coarse facies

XL (303600) RSK2, Xp22.2-p22.1

Dygvve-Melchior-Clausen

Mental retardation, coarse facies

AR (223800) FLJ90130, 18q12-q21.1

Dyssegmental dysplasia

Multiple rib and vertebrae anomalies, narrow chest, reduced joint mobility

AR (224400)

Ellis-van Creveld

Short limbs and ribs, dysplastic nails and teeth, polydactyly

AR (225500) EVC, 4p16

Fibrochondrogenesis

Lethal, broad metaphyses

AR (228520)

Hennekam lymphangiectasialymphedema

Intestinal lymphangiectasia; lymphedema of limbs, genitalia, and face

AR (235510)

Jeune (asphyxiating thoracic dystrophy)

Short stature, small thorax, hepatic fibrosis

AR (208500)

Kniest dysplasia

Short trunk, ocular findings, cleft palate

AD (156550) COL2A1, 12q13.11-q13.2

Microcephalic osteodysplastic primordial dwarfism, type I

Short limbs, microcephaly

AR (210710)

Microcephalic osteodysplastic primordial dwarfism, type III

Short limbs, microcephaly

AR (210730)

Mucopolysaccaridosis, type IV B (Morquio)

Short stature, cloudy corneas

AR (253010) GLB1, 3p21.33

Mucopolysaccharidosis, type VI (Maroteaux-Lamy)

Short stature, cloudy corneas

AR (253200) ARSB, 5q11-q13

Oto-palato-digital, type I

Characteristic facies, cleft palate, deafness

XL (311300) FLNA, Xq28

Oto-palato-digital, type II

Microcephaly, cleft palate, overlapping fingers

XL (304120) FLNA, Xq28

Pelvis-shoulder dysplasia

Hypoplasia of scapulas, pelvis, clavicles

AD (169550)

Simpson-Golabi-Behmel, type I

Characteristic facies, overgrowth

XL (312870) GPC3, Xq26

Smith-McCort

Short trunk and limbs, microcephaly

AD (607326)

Same as Dygvve-Melchior-Clausen but normal intelligence

FLJ90140, 18q12-q21.1

Spondyloepimetaphyseal dysplasia, Strudwick type

Severe short stature, pectus carinatum, cleft palate

AD (184250) COL2A1, 12q13.11-q13.2

Spondyloepiphyseal dysplasia congenita

Short trunk, myopia

AD (183900) COL2A1, 12q13.11-q13.2

Stuve-Wiedemann

Bowing of long bones, camptodactyly, contractures

AR (601559) LIFR, 5p13.1

Thanatophoric dysplasia

Lethal, severe micromelia

AD (187600) FGFR3, 4p16.3

Absent or hypoplastic patellae, dysplastic nails

AD (1612000) LMX1B, 9q34.1

Ilial Abnormalities

Iliac Horns

Nail-patella

(continued)

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832

Skeletal System Table 19-10. Conditions associated with anomalies of the pelvic bones (continued) Condition

Prominent Features

Causation

Achondrogenesis, type IA

Lethal, micromelia, unossified vertebral bodies

AR (200600)

Fibrochondrogenesis

Lethal, broad metaphyses

AR (228520)

Smith-McCort dysplasia

Short trunk and limbs, microcephaly

AR (607326)

Same as Dygvve-Melchior-Clausen but normal intelligence

FLJ90130, 18q12-q21.1

Ischial Abnormalities

by the American Academy of Pediatrics and is the cornerstone of early identification.1 The diagnosis of dysplasia requires confirmation by imaging studies. There may be a positive family history for DDH. In some cases, DDH is diagnosed when a parent reports asymmetry during a diaper change, or a difference in leg lengths. The stability of the hip is tested by the Ortolani and Barlow maneuvers, as well as observation of leg length and creases. In the older child, the dislocation becomes more fixed. DDH manifests as restricted hip abduction, asymmetric thigh folds, and leg length

discrepancy with shortened femur on the affected side, known as the Galeazzi sign.2 In an ambulatory child, a slight limp may be noted, occasionally with one-sided toe walking, short leg, and hyperlordosis. Although traditional radiographs remain important, sonographic analysis allows visualization of the femoral head ossification centers and the percentage of acetabular coverage of the femoral head. Magnetic resonance imaging and arthrographs may be used in certain cases.3 Etiology and Distribution

Fig. 19-19. Top: Bilateral congenital dislocation of the hips in a 2½-year-old toddler. Bottom: Congenital dislocation of the right hip with associated acetabular dysplasia.

Hip instability is noted in approximately one to two per 100 liveborn infants; however, true dysplasia is seen in only one per 1000 infants. Intrauterine position is important; breech presentation and being a first child is associated with an increase in DDH. Intrauterine position also accounts for the fact that the left hip is more frequently affected. DDH occurs six to eight times more frequently in females, perhaps due to an increase in laxity produced by the stimulated fetal ovaries.4 Although DDH is multifactorial, there is a higher concordance in monozygotic twins than in dizygotic twins and an increase in incidence if a first-degree relative is affected. However, 60% of infants have no recognizable risk factors. Prognosis, Treatment, and Prevention

The earlier the diagnosis, the less complicated is the treatment. Infants are braced with a Pavlik harness or other brace until the hip is stable and developing normally. Children with DDH require regular follow-up until skeletal maturity. Lasting residual dysplasia of the acetabulum is common, even following early and aggressive treatment, and may progress to degenerative arthritis. Avascular necrosis may present a significant problem if reductions are attempted in older children. References (Developmental Dysplasia of the Hip) 1. American Academy of Pediatrics: Clinical practice guideline: early detection of developmental dysplasia of the hip. Committee on quality improvement, subcommittee on developmental dysplasia of the hip. Pediatrics 105:896, 2000. 2. Babyn PS: Developmental dysplasia of the hip. In: Caffey’s Pediatric Diagnostic Radiology, ed 10. JP Kuhn, TL Slovis, JO Haller, eds. Mosby, St. Louis, 2003, p 2494. 3. Novacheck TF: Developmental dysplasia of the hip. Pediatr Clin North Am 43:829, 1996. 4. Woolf CM, Koehn JH, Coleman SS: Congenital hip disease in Utah: the influence of genetic and nongenetic factors. Am J Hum Genet 20: 430, 1968.

Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

19.21 Coxa Vara Definition

Coxa vara is a reduction in the angle formed by the neck and shaft of the femur from the normal 1208 to 1408 caused by abnormal protrusion of the femoral neck (Fig. 19-20). It is designated as congenital or developmental.

833

ence of a gait disturbance, most typically a waddling gait or a limp. The diagnosis is confirmed by radiographs of the femoral neck, which display the displacement of the femoral neck in a caudad direction. The greater trochanter is displaced in a cephalad direction and may be oriented above the roof of the acetabulum. It may be unilateral or bilateral and may occur in isolation, as part of a multiple malformation syndrome, or in association with endocrine disorders. Coxa vara is commonly seen in association with skeletal dysplasias or may develop following infections or trauma.

Diagnosis

The congenital form frequently goes undiagnosed until the child begins to walk. The femoral head is underdeveloped and a fibrous union is present between the femoral head and shaft. In ambulatory children, the diagnosis is suspected clinically by the pres-

Fig. 19-20. Top: Coxa vara in a 3½-year-old child with metaphyseal chondrodysplasia, McKusick type. Bottom: Coxa vara of unknown etiology in a teenage girl.

Etiology and Distribution

Isolated cases of coxa vara are quite rare; therefore, an aggressive search for associated conditions should be undertaken in patients with coxa vara. Most cases that are isolated are sporadic, although several familial recurrences demonstrating autosomal dominant inheritance have been described.1 Mirror image coxa vara has been described in monozygotic twins.2 Coxa vara occurs equally in boys and girls and in all ethnic groups. Although the exact incidence is unknown, it has been estimated to occur in one per 13,000. The associated conditions are varied and include idiopathic slipped epiphysis, Legg-Perthes disease, rickets, and following femoral neck trauma or infection. It has also been described in patients with sickle cell disease, those who have received radiation, and after steroid treatment. Associated genetic conditions include Gaucher disease, osteogenesis imperfecta, metatrophic dysplasia, and mucopolysaccharidoses (Table 19-11). It is also seen in association with endocrine disorders such as hypoparathyroidism, hyperparathyroidism, and pseudohypoparathyroidism. Prognosis, Treatment, and Prevention

The diagnosis of coxa vara should prompt a search for associated conditions, many which are treatable. Early management is warranted with the goal of preventing degenerative arthritis and the limitation of mobility and pain. The epiphyseal angle predicts progression of the varus deformity, with patients with angles greater than 458 tending to have progression of the condition and those with less than 458 tending to have spontaneous healing. Surgical intervention has been successful for this condition. Genetic counseling is indicated if a specific diagnosis is made. References (Coxa Vara) 1. Say B, Tuncbilek E, Pirnar T, et al.: Hereditary congenital coxa vara with dominant inheritance? Humangenetik 11:266, 1971. 2. Letts RM, Shokeir MHK: Mirror-image coxa vara in identical twins. J Bone Joint Surg 57A:117, 1975.

19.22 Coxa Valga Definition

Coxa valga is an abnormality of the proximal femur characterized by an increase in the angle formed by the femoral neck and shaft, frequently accompanied by partial lateral dislocation of the femoral head from the acetabulum. Diagnosis

Diagnosis is made by radiographs and magnetic resonance imaging. It is frequently associated with conditions that predispose

834

Skeletal System Table 19-11. Conditions in which coxa vara is a feature Condition

Prominent Features

Causation

Achondroplasia

Short limbs, frontal bossing, trident hand

AD (100800) FGFR3, 4p16.1

Cleidocranial dysplasia

Aplasia/hypoplasia of clavicle, open fontanelle

AD (119600) CBFA1, 6p21

Cutis laxa

Occipital horn exostoses, joint laxity

XL (304150) ATP7A, Xq12

Diastrophic dysplasia

Coarse facies, malformed ears, hitchhiker thumb

AR (222600) SLC26A2, 5q32-q33.1

Dygvve-MelchiorClausen

Mental retardation, coarse facies

AR (223800) FLJ90130, 8q12-q21.1

Exostosis, multiple, type I

Madelung-like forearm deformities, short metacarpal, more severe

AD (133700) EXT1, 8q24.11-q24.13

Exostosis, multiple, type II

Madelung-like forearm deformities, short metacarpal

AD (133701) EXT2, 11p12-p11

Kniest dysplasia

Short trunk, ocular findings, cleft palate

AD (156550) COL2A1, 12q13.11-q13.2

Microcephalic osteodysplastic dwarfism, type II

Mental retardation, brachymesophalangy, beaklike nose

AR (210720)

Metaphyseal chondrodysplasia, Schmid type

Moderate short stature

AD (156500) COL10A1, 6q21-q22.3

Osteopetrosis, mild autosomal recessive form

Failure to thrive, macrocephaly, blindness

AR (259710) TCIRG1, 11q13.4-q13.5 CLCN1, 16p13

Rhizomelic dysplasia, Patterson-Lowry type

Rhizomelic short limbs, anomalous segmentation of proximal humeral metaphyses

AR (601438)

Schwartz-Jampel, type 1

Myotonia, blepharophimosis, joint limitation

AR (255800) HSPG2, 1p36.1

Spondyloepiphyseal dysplasia, corner fracture type

Corner fractures of long bones, Hyperconvex vertebral bodies

AD (184255)

Spondyloepiphyseal dysplasia with hypotrichosis

Rhizomelic upper limbs, hypotrichosis, normal nails

AD (183849)

Schwachman

Metaphyseal chondrodysplasia, pancreatic insufficiency, neutropenia

AR (260400) SBDS, 7q11

Spondyloepimetaphyseal dysplasia (Strudwick)

Severe short stature, pectus carinatum, cleft palate

AD (184250) COL2A1, 12q13.11-q13.2

Spondyloepiphyseal dysplasia, congenita

Short trunk, myopia

AD (183900) COL2A1, 12q13.11-q13.2

Spondyloepiphyseal dysplasia tarda

Severe scoliosis, short hands and feet

AD (184100) 12q13

Spondylometaphyseal dysplasia, Kozlowski type

Short stature, short trunk, platyspondyly

AD (184252)

the patient to immobility or disuse, such as rheumatoid arthritis, paralytic disorders, and muscular dystrophy. Etiology and Distribution

The cause is heterogeneous. Inheritance of isolated coxa valgus has not been reported but is a common finding in multiple malformation syndromes, neuromuscular disorders, and chromosomal anomalies.

Prognosis, Treatment, and Prevention

Prognosis depends on the underlying condition. Identification of coxa valga warrants further evaluation to identify the underlying condition. Treatment is supportive and symptomatic. Surgical intervention may be required if the femoral heads become exposed by lateral displacement.

20 Limbs Roger E. Stevenson

L

imbs share with the craniofacies great susceptibility to malformation, disruption, deformation, and morphologic variation. The susceptibility of the limbs to morphologic alteration can be attributed in part to their developmental complexity, the extended period of morphogenesis, and the exposure of the limbs beyond the protection of the body wall. Normal limb development also requires movement, a function influenced primarily by the nervous system and muscles. A vast number of single gene mutations and nearly all human teratogens and cytogenetic aberrations affect limb morphology in some way. Formation of the limbs involves quadrilateral positioning; mirror image construction of the paired limbs; segmentation to permit a range of movements; refinement of the upper limbs for sensation, fine movements, and object manipulation; refinement of the lower limbs for body support and locomotion; rotation of the limbs to a final position best suited for function; and placement of specialized structures, such as nails and dermal ridges. When embryogenesis proceeds normally, the degree of asymmetry between the paired limbs is not visibly obvious. There is no evidence of limb primordium when the embryo is in disc form. Once the embryo gains tubular form, limb development commences.1–5 Progress toward the mature limb configuration is essentially the same for the lower and the upper limbs. The limb first becomes visible as a rounded elevation on the anterior lateral body wall, progresses to a tongue-like extension from the body wall, and distally forms a flattened plate, which subsequently divides into individual digits. The limb segments into proximal, middle, and distal portions; lays down cartilaginous and bony structures in each of the segments; and rotates into a position of function. In all stages, development of the upper limbs precedes development of the lower limbs by 1 to 2 days. Observations in human embryos and experiments, primarily in chick embryos, have elucidated the timing and anatomic details of limb development.1–5 During the past decade, it has become possible to integrate these details with an emerging understanding of the molecular basis for limb embryogenesis.5–12 Anatomic Embryology

Upper limb buds are first visible in older stage 12 human embryos (days 26–30) as an elevation on the anterior lateral aspect of the body wall at the level of the cervical somites.1–5 This ele-

vation grows more distinct and extends from the body wall in an anterior direction, consisting of a mass of somatic mesoderm covered with ectoderm (Fig. 20-1). Ectodermal cells along the apex of the limb bud elongate to form a ridge (apical ectodermal ridge), which is oriented in cephalocaudal alignment (Fig. 202).5–7,13 This ectodermal change appears to be induced by limb mesoderm. The apical ectodermal ridge thus courses along the outermost margin of the limb bud and shares a critical role in limb development with the underlying mesoderm.5–7,13–18 In experiments with chick embryos, removal of mesodermal cells prevents limb development; removal of the apical ectodermal ridge causes cessation of further limb development. Grafting of limb mesoderm to a nonlimb site produces a limb in the abnormal site; grafting of apical ectodermal ridge to a nonlimb site will not produce an ectopic limb. Grafts of an extra apical ectodermal ridge onto a limb bud will produce duplication of limb structures. When hindlimb mesoderm is substituted or combined with forelimb mesoderm at the forelimb site, a hindlimb develops. Nonlimb mesoderm grafted beneath the apical ectodermal ridge prevents further limb development, and the apical ectodermal ridge regresses. Maturation of the apical ectodermal ridge is dependent on the presence of limb mesoderm and is responsible for appropriate outgrowth and segmentation of the limb. This influence is sustained throughout the period of limb embryogenesis.6,7,16 The limb bud at first gains a flipper-like configuration but quickly forms a paddle-like flattening distally, which will become the hand or foot.1,3 This paddle extends circumferentially and, through the process of programmed cell death, the digital rays become defined within the periphery (Fig. 20-3). Further cell death between the rays allows the fingers to become more distinct and finally to become separate digits. Separation of fingers is complete by day 53 postfertilization. Cephalocaudal polarity of the limb depends on the zone of polarizing activity identified at the caudal junction of the early limb bud and the body wall.6,7,18–20 This zone is thought to produce a morphogen that diffuses across the limb bud, resulting in a decreasing caudal-cephalad gradient. According to this concept, the caudalmost portion of limb anatomy (ray 5) requires the highest morphogen concentration, and the most cephalad portion (ray 1) differentiates in the lowest morphogen concentration. Sonic hedgehog and bone morphogenetic proteins appear to be the best 835

836

Skeletal System

Fig. 20-1. Schematic of initiation of limb bud formation. Left: Mesodermal cells that will form limb bud aggregate in the somatic layer lateral plate mesoderm at the level of somites 8–11 (upper limb) and somites 24–27 (lower limb). Right: As the cells proliferate and migrate outward, bulges form at these two levels that represent the early limb buds. (Based on a study of amphibian embryos; redrawn after Balinsky BI: An Introduction to Embryology, ed 4. WB Saunders Company, Philadelphia, 1975.)

Fig. 20-2. As the limb bud elongates, it forms a thickened ridge of ectoderm along the distal surface. This apical ectodermal ridge is required for differentiation of the limb into its various parts; if it is removed, limb development ceases. (Scanning electron micrograph of mouse limb bud from Kelley RO: Proc Greenwood Genetic Center 6:72, 1987.)

candidate morphogens.7 It is anticipated that the distribution of morphogen receptors will play an equally important role in the differentiation of the rays of the limb.20 Elongation of the upper limb bud occurs simultaneously with hand formation. The earliest definition of arm and forearm appears as a bending at about the midshaft, where the elbow joint will form. Bones of the limbs develop on cartilaginous models through the process of endochondral (intracartilaginous) ossification.1–3,21 Cartilaginous models form through condensation of the mesenchyme and differentiation of cells into chondroblasts, which lay down the matrix. The cartilaginous model forms as a solid bar at the site of each limb bone. Ossification begins as a collar about the midportion of the cartilaginous bar, and new bone extends bidirectionally toward the ends. Ossification of the humerus is visible by day 48 postfertilization, of the radius by day 49, and of the ulna by day 53 (Table 20-1). Centrally, the cartilage matrix initially calcifies and then is remodeled into marrow space, with a bony spicule meshwork. This transition is accomplished by capillary invasion from the diaphyseal periosteum into the center of the cartilaginous bar. Through a series of events, perhaps related to oxygen deprivation, the chondrocytes die and the matrix becomes calcified. At the same time, the capillaries introduce osteoblasts into the matrix cavity. These osteoblasts align themselves along the calcified matrix and replace the matrix with bone. Separate ossification centers, called epiphyses, form near the ends of the cartilaginous models. Most epiphyses of the long bones begin ossification following birth. Exceptions are the epiphyses at the distal femurs and the proximal tibias, which are present at birth. Because epiphyses appear and mature at specific chronologic ages, they are useful in determining bone age. The epiphyses of the phalanges are particularly useful in this respect.22 Long bones generally have an epiphysis (secondary ossification center) at each end. Most irregular bones (carpals, tarsals, patellas) have singular ossification centers, and these mature in a manner similar to the epiphyses of the long bones. The calcaneus has two ossification centers, which coalesce as each center enlarges. The short tubular bones (phalanges, metacarpals, metatarsals) begin ossification in the midshaft region just as do the other long bones. In contrast, epiphyses may develop at only one end of these bones or at neither end. The phalanges and first metacarpals and metatarsals have proximal epiphyses only; the lateral four metatarsals and metacarpals have distal epiphyses only. Longitudinal growth of the long bones and the short tubular bones occurs near each end in the cartilaginous plate that separates the shaft of the bone and the epiphysis. Growth and maturation follow an orderly process of chondrocyte proliferation, followed by hypertrophy and calcification and finally by cartilage degeneration and replacement of calcified cartilage by bone. Zones in which each process is occurring can be readily discerned on microscopic examination of the growth plate (Fig. 20-4). Bone expands circumferentially by deposition of new bone under the periosteum and expansion of the marrow cavity by resorption of the bone’s inner table. The irregular bones and the epiphyses of long bones increase in size by expansion of the ossification center in all directions. Longitudinal growth of the long bones continues for variable periods of time until the epiphyses become fused with the shafts. This fusion occurs under the stimulus of androgen or estrogen and is not complete until several years following puberty. Bones are linked together by one of several types of joints. Bones of the limbs are connected exclusively by synovial joints, whereas bones of the trunk, skull, and face may have less mobile

Limbs

837

Fig. 20-3. Sequence of limb bud development in human embryos. (1) Embryo 5928, stage 12 (3–5 mm, day 26 postovulation). Upper limb bud appearing. (2) Embryo 8372, stage 13 (4–6 mm, day 28 postovulation). All four limb buds visible; upper limb bud more protuberant than lower limb bud. (3) Embryo 8314, stage 14 (5–7 mm, day 32 postovulation). Upper limb bud elongated and tapered; lower limb bud enlarging. (4) Embryo 8112, stage 16 (11–14 mm, day 37 postovulation). Handplate rounded without digital rays, lower limb bud elongated without distinct footplate. (5) Embryo 8017, stage 17 (11–14 mm, day 41 postovulation). Handplate has visible digital rays;

footplate has rounded configuration. (6) Embryo 8097, stage 18 (13– 17 mm, day 44 postovulation). Handplate notched along the rim, rays readily discernible, elbow usually seen, early toe rays may be seen. (7) Embryo 8092, stage 19 (17–20 mm CR length, days 47–48 postovulation). Toe rays are more prominent but lack interdigital notches along the rim of the footplate. (8) Enlarged view at stage 19 showing definition of digital rays and digital separation of fingers. As in all stages, hand development is about 2 days ahead of foot development. (Embryos from Carnegie Collection, courtesy of Drs. Ronan O’Rahilly and Fabiola Mu¨ller and the Carnegie Institute of Washington.)

cartilaginous or fibrous joints as well as synovial joints. Synovial joints form from mesenchyme between bones that are juxtaposed. The central mesenchyme degenerates, forming a joint capsule, while the surrounding mesenchyme forms the synovial lining, joint capsule, and ligaments. Muscles develop from the less condensed mesenchyme surrounding the chondroosseous skeleton.3 The muscle mass divides more or less into a dorsal group of muscles, which have extensor functions, and a ventral group of muscles, which have flexor functions. From a position with hand plates facing each other at stage 19 (about 48 days postovulation), the upper limbs rotate 908 laterally, with the palms finally facing anteriorly and the elbows posteriorly by stage 23 (about 56 days postovulation).3 The lower limbs rotate in the opposite direction. The medial 908 rotation brings the knees to an anterior position and the heels posterior. As the end of the 1st embryonic month approaches, neural invasion of the limb commences. Motor neurons from the ventral neural tube and sensory neurons from the neural crest innervate the muscle and skin of the limbs in segmental fashion.1,23 Spinal nerves that correspond to the lower four cervical and first thoracic

myotomes supply the upper limbs. Nerves corresponding to the lumbar and first three sacral myotomes provide innervation for the lower limbs. Capillary networks develop within the mesenchyme of the limb buds, and, through coalescence and enlargement of the vascular channels, a common arterial stem emerges for each limb, the brachial artery in the upper limbs and the sciatic artery in the lower limbs. Through a series of branchings and anastomoses, the stem artery gives rise to the major and subordinate arteries of the limbs. Modification of the epidermis to form nails and hair begins several weeks after the limb has acquired its final form. The epidermis over the digits, palms, and soles becomes patterned with ridges between 10 and 17 weeks and, with movement of the various limb segments, forms flexion and extension creases.24,25 The lower limbs develop in a fashion comparable to the upper limbs, but 1 to 2 days later. The lower limb buds appear at about 28 days opposite the lumbosacral somites. Molecular Embryology

A plausible cast of molecular players involved in the five moreor-less sequential but overlapping processes involved in limb

838

Skeletal System

Table 20-1. Development of the upper limb in the human embryo Feature

Stage

Length (mm)

Postovulatory Weeks

Upper limb bud

12

2.5–5.8

4

Ectodermal ridge

14–17

4.9–14.5

4–5

Mesenchymal scapula

16

9

5

Mesenchymal humerus, radius, ulna

16

7.0–12.2

5

Chondrifying humerus

16,17

7.0–14.5

5

17

8.6–14.5

5

Mesenchymal hand

17

8.6–14.5

5

Chondrifying ulna, metacarpus

17,18

8.6–18.0

5

12

5

Chondrifying radius

Mesenchymal clavicle Ossifying clavicle

18 ?

?–20

5

Chondrifying proximal phalanges

18,19

11.7–21.0

Chondrifying carpus

18–20

11.7–25.0

5–6

Chondrifying middle phalanges

19,20

15.5–25.0

5.5–6

Chondrifying distal phalanges

20,21

18.5–26.4

6

Ossifying humerus

21,22

19.0–27.5

Ossifying radius

21–23

19.0–32.2

6–7

Cavitation in elbow

?

22–28

6–7

Cavitation in shoulder

?

25

6.5

Cavitation in hand

5–5.5

6–6.5

?

26–30

6.5–7

Ossifying ulna

22,23

23.0–32.2

6.5–7

Ossifying distal phalanges

?

26–30

6.5–7

Ossifying scapula

?

30

7

Cavitation in wrist

?

30–31

7

? indicates that stage is uncertain.

development has been identified.5–7 The cast is certain to expand as molecular pathways are further delineated. Initiation triggers outgrowth of lateral plate mesoderm at the four appropriate positions on the flanks of the embryo. An overlapping array of homeobox genes determines where along the lateral cranial-caudal axis these outgrowths are to occur. Whether the outgrowth is to ultimately develop into an upper limb or lower limb is determined in part by the TBX transcription factors: TBX5 specifying upper limb anatomy and TBX4 specifying lower limb anatomy. Actual limb bud outgrowth may be promoted by WNT and FGF, particularly FGF10. Once initiated, further outgrowth and pattern formation sets the number, size, and shape of the skeletal elements to be formed.6 This modeling is accomplished along proximal-distal, cranialcaudal (anterior-posterior), and dorsal-ventral axes. Proximaldistal growth is controlled by the apical ectodermal ridge (AER), whose formation requires induction by bone morphogenetic proteins (BMP) and the homeobox gene MSX2. Restriction of the AER to the cranial-caudal margin of the limb bud is governed by several genes including Radical fringe, Engrailed-1, and Serrate-2. The AER promotes and controls limb outgrowth through production of FGFs (FGF4 and FGF8), which maintain mesenchymal cell proliferation in the underlying progress zone.

A complex of growth factors and transcription factors contribute to the design of dorsal and ventral aspects of the distal limb.5–7 WNT7A is a major determinant of dorsal development, accomplished through upregulation of LMX1B. On the ventral side, WNT7A is repressed by Engrailed-1, a transcription factor induced in ventral ectoderm by BMP. The zone of polarizing activity (ZPA) controls pathways along the cranial-caudal axis of the limb. The ZPA secretes retinoic acid, which in turn induces SHH expression, which, in cooperation with BMP, determines the order of the five digits of the hands and feet.7 Condensation and differentiation of skeletal precursors occur at the sites in limb bud mesenchyme, which will become the chondroosseous skeleton.6 Under the influence of SOX9, mesenchymal cells condense in areas destined to become the cartilaginous template for the skeleton and produce a number of proteins— proteoglycans, versican, tenascin, and syndecan—that form the extracellular matrix. Related members of the SOX family of transcription factors (SOX5,6) are needed to convert cells in the condensed areas into chondrocytes. Other growth factors (TGF-b, BMP, GDF5) likely have roles in the processes of condensation and differentiation. Hypertrophic chondrocytes produce vascular endothelial growth factors (VEGF), which invites vascular invasion, a process necessary to form endochondral bone. Rigidity of bone is accomplished through replacement of matrix proteins with hydroxyapatite. Joint formation is in part due to interaction between GDF5 and its antagonist NOG. Linear growth of the skeletal elements occurs at the ends of the long bones. Both IGF1 and growth hormone function in concert with the IHH-PTH-PTHrP and FGF signaling pathways to control the rates of chondrocyte proliferation and replacement by bone. Skeletal homeostasis depends on the constant remodeling of bone through the resorption activities of osteoclasts and the regenerative activities of osteoblasts. There are many opportunities for malformations and other morphologic changes to occur in limb development. Kornak and Mundlos have classified genetic disorders of the skeleton, including malformations and dysplasias, based on the developmental process that is primarily disturbed.6 Most malformations affect all elements of the limb to some degree. This being the case, most limb malformations will be covered by discussing malformations of the skeleton. Anomalies of the limbs that do not involve bones will be discussed elsewhere. These include anomalies of the nails, skin, muscles, and other soft tissues. References 1. O’Rahilly R, Mu¨ller F: Human Embryology and Teratology, ed 2. Wiley-Liss, New York, 1996. 2. Arey LB: Developmental Anatomy, ed 7, revised. WB Saunders Company, Philadelphia, 1974. 3. Gardner ED: The development and growth of bones and joints. J Bone Joint Surg 45A:856, 1963. 4. Swinyard CA: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. Charles C Thomas Publisher, Springfield, IL, 1969. 5. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams and Wilkins, Philadelphia, 2004. 6. Kornak U, Mundlos S: Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73:447, 2003. 7. Tickle C: Molecular basis of vertebrate limb patterning. Am J Med Genet 112:250, 2002. 8. Innis JW, Mortlock DP: Limb development: molecular dysmorphology is at hand! Clin Genet 53:337, 1998.

Limbs

839

Fig. 20-4. Micrograph and schematic showing transition of cartilage to bone. (Courtesy of Dr. William A. Horton, Shriners Hospital, Portland, Oregon.)

9. Niswander L: Pattern formation: old models out on a limb. Nat Rev Genet 4:133, 2003. 10. Gurrieri F, Kjaer KW, Sangiorgi E, et al.: Limb anomalies: developmental and evolutionary aspects. Am J Med Genet 115:231, 2002. 11. Kronenberg HM: Developmental regulation of the growth plate. Nature 423:332, 2003. 12. Mariani FV, Martin GR: Deciphering skeletal patterning: clues from the limb. Nature 423:319, 2003. 13. Saunders JW Jr, Cairns JM, Gasseling MT: The role of the apical ridge of ectoderm in the differentiation of the morphological structure and inductive specificity of limb parts in the chick. J Morphol 101:57, 1957. 14. Harrison RG: Experiments on the development of the fore limb of Amblystoma, a self-differentiating equipotential system. J Exp Zoolog 25:413, 1918. 15. Zwilling E: Ectoderm-mesoderm relationship in the development of the chick embryo limb bud. J Exp Zoolog 128:423, 1955. 16. Saunders JW Jr: The interplay of morphogenetic factors. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969. 17. Wolpert L: Mechanism of limb development and malformation. Br Med Bull 32:65, 1976. 18. Gilbert SF: Developmental Biology, ed 7. Sinauer Associates Inc, Sunderland, MA, 2003. 19. Thaller C, Eichele G: Identification and spacial distribution of retinoids in the developing chick limb bud. Nature 327:625, 1987. 20. Brockes J: Reading the retinoid signals. Nature 345:766, 1990. 21. O’Rahilly R, Gardner E, Gray DJ: The skeletal development of the hand. Clin Orthop 13:42, 1959. 22. Pyle SI, Waterhouse AM, Gruelich WW: A Radiographic Standard of Reference for the Growing Hand and Wrist. Case Western Reserve University Press, Cleveland, 1971. 23. Tosney KW, Landmesser LT: Development of the major pathways for neurite outgrowth in the chick hindlimb. Dev Biol 109:193, 1985.

24. Babler WJ: Quantitative differences in morphogenesis of human epidermal ridges. Birth Defects Orig Artic Ser XV(6):199, 1979. 25. Stevens CA, Carey JC, Shah M, et al.: Development of human palmar and digital flexion creases. J Pediatr 113:128, 1988.

20.1 Limb Deficiencies Definition

Limb deficiencies include the absence of the skeletal and soft tissue components of all or part of a limb. Because of the division of the limb skeleton into upper and lower limbs, right and left limbs, three segments in each limb, and multiple distal rays in each limb, the possible combinations of limb deficiencies are enormous. One hundred twenty separate bones make up the skeleton of the four limbs, making possible a vast number of different individual or combined deficiencies. Fortunately for the clinician, virtually all limb deficiencies occur in patterns that can be assigned to one of the 13 groups outlined by Swinyard and Marquardt.1 These groups constitute a modification of the classification system developed by Frantz and O’Rahilly2 based on a description of the part(s) of the skeleton that is deficient.1–3 All deficiencies are initially classified as terminal or intercalary, with further subgrouping made on the basis of the axis of the deficiency (transverse or longitudinal) and the individual bones involved (Figs. 20-5 and 20-6). The terminology has been simplified with elimination of the descriptive terms phocomelia, peromelia, dysmelia, ectromelia, hemimelia, and so forth. Only two basic terms are used, amelia and meromelia, indicating complete and partial limb deficiency. Amelia: complete absence of a free limb (exclusive of girdle).

840

Skeletal System

Fig. 20-5. Schematic of four major groups of limb deficiencies. A. Terminal transverse. B. Terminal longitudinal. C. Intercalary transverse. D. Intercalary longitudinal. The deficiencies are further defined by identifying the deficient bone (see text and Fig. 20-6). (Adapted from Cohen MM Jr, Lemire RJ: Malformations of the limbs. In: Practice of Pediatrics, vol 4, chap 30, VC Kelley, ed. Harper & Row, Hagerstown, MD, 1979.)

Meromelia: partial absence of a free limb (exclusive of girdle). Segments: major divisions of the limb, namely proximal, middle, and distal segments, corresponding in the upper limb to arm, forearm, and hand and in the lower limb to thigh, leg (shank), and foot. Intercalary deficiency: absence of proximal or middle segment(s) of a limb with all or part of the distal segment present. Terminal deficiency: absence of all skeletal elements of a longitudinal ray beyond a given point. Since only a single ray exists in the proximal segment of the limbs, all terminal deficiencies of the humerus and femur are also transverse deficiencies. The designation terminal deficiency thus becomes useful only when referring to deficiencies beginning in the middle or distal segment where normally there are two or more longitudinal rays. Transverse deficiency: absence extending across the full width of the limb. Longitudinal deficiency: absence extending parallel with the long axis of the limb and involving preaxial, postaxial, or central components. Preaxial deficiency: absence of the portion of the forearm, hand, leg, or foot on the radial (thumb) or tibial (hallux) side of the limb. Postaxial deficiency: absence of a portion of the forearm, hand, leg, or foot on the ulnar or fibular side of the limb. Central deficiency: absence of one or more central rays of the hand or foot. Rudimentary: a remnant of an osseous element (if the remnant is identifiable, e.g., a humerus, the term rudimentary humerus would be appropriate). Ray: a longitudinal component of the middle or distal limb segments (e.g., the radial or ulnar ray of the forearm); a digit and its corresponding metacarpal or metatarsal of the hand or foot.

A complete description of a limb deficiency may be made according to the following schema: 1. 2. 3. 4. 5. 6. 7.

Total or partial—amelia/meromelia Segment(s) involved—terminal/intercalary Axis of the defect—transverse/longitudinal Limb involved—upper/lower Side involved—right/left Deficient bone(s)—femur/radius/metacarpal 2 to 5/etc. Portion of bone deficient—proximal, middle, distal

The composite description is formed using single terms for components 1 to 5 and 7 and a single or compound term depending on the bone(s) involved for component 6 (Figs. 20-5 and 20-6). This terminology does not imply that the descriptive terms, such as acheiria, adactyly, and radial aplasia, no longer have utility. It merely provides a simple and orderly classification that can be used across specialties. Diagnosis

Deficiencies of bones of the limb may produce limb shortening, malalignment at joints, altered segment ratios, curvature, and loss of symmetry depending on the degree of deficiency. Deficiencies of the lower limb may interfere with ambulation; deficiencies of the upper limbs may impair reach and dexterity. The pectoral and pelvic girdles are usually normal when a limb deficiency is present. A notable exception is in the thalidomide limb deficiencies. Humeral and femoral deficiencies may have normal or near-normal distal segments but rhizomelic shortening or may be accompanied by distal deficiencies of various combinations (Table 20-2).4–10 Long bone deficiencies affect the upper limbs more than twice as frequently as the lower limbs.11–14 Isolated intercalary humeral deficiencies are extremely rare.11,15 Disturbances of ray formation of the distal segment often, but not invariably, accompany deficiencies of one of the long bones of the middle segment.16,17 Radial deficiencies often have deficiencies of the thumb, navicular and

Fig. 20-6. Schematics of the various types of limb deficiencies. A. Normal. B. Amelias. C. Midhumeral and midfemoral terminal transverse meromelias. D. Radioulnar and tibiofibular transverse meromelias. E. Midradioulnar and midtibiofibular transverse meromelias. F. Carpal and tarsal transverse meromelias. G. Phalangeal transverse meromelias. H. Radial and tibial terminal longitudinal meromelias.

I. Midradial and midtibial terminal longitudinal meromelias. J. Humeroradioulnar and femorotibiofibular intercalary transverse meromelias. K. Radioulnar and tibiofibular intercalary transverse meromelias. L. Ulnar and proximal fibular intercalary longitudinal meromelias. (Based on the classification system of Frantz and O’Rahilly.2)

841

842

Skeletal System

Table 20-2. Meromelias: intercalary limb deficiencies of proximal segments (humerus, femur) Syndrome

Major Features

Radiographic Findings a

Causation Gene/Locus

Boehme: upper limb deficiency-heart defects5

Variable upper limb deficiencies, cataracts, scoliosis (similar to Holt-Oram)

(H,R ) Short clavicles, hypoplastic humerus, absent radius and radial digits

AD

Femoral hypoplasiaunusual facies10

Short stature due to short thighs, short nose with full tip, micrognathia, hypoplastic alae nasi, long philtrum, genitourinary abnormalities

(F) Deficiency of femur, variable deficiencies of other long bones

Maternal diabetes and other unknown causes

McKusick-Weilbacher unilateral limb deficiency4

Unilateral lower limb deficiency, cataracts, scoliosis

(F) Hypoplastic femur

AR (246000)

Roberts9

Cleft lip/palate, blonde hair, short and malformed limbs, enlarged phallus

(H,R,U,F,T,Fi) Variable long bone deficiencies, oligodactyly

AR (268300)

Thalidomide, prenatal6–8

Facial hemangioma, ear anomalies, cardiac and visceral defects, variable limb deficiencies, oligodactyly

(H,R,U,F,T,Fi) Variable long bone deficiencies

Prenatal thalidomide exposure

a

Usual bone deficiency noted in parentheses.

multangular bones, and radial hand deviation; ulnar deficiencies inconsistently cause ulnar deviation at the wrist, absence of the pisiform and hamate, and deficiencies of rays 4 and 5 of the hand (Table 20-3, Figs. 20-7 and 20-8).9,10,18–71 Deficiencies of the lower limbs usually cause joint instability because of the necessity for weight bearing. Tibial deficiency is the least common lower limb deficiency (Fig. 20-9)11-14 Although all tarsals, metatarsals, and digits are usually present, a low incidence of deficiency of medial foot bones has been documented.15 Talocalcanean and talocalcaneonavicular fusion is common. Fibular deficiency is associated with several malformation syndromes and mesomelic dysplasias (Table 20-3, Fig. 2010).21,29,31,32,34,35,68,69,71 Often the tibia is bowed to some degree. Clubfoot may occur, reflecting a disturbance in the soft tissues, but all rays of the foot are usually present. However, deficiencies of the fourth and fifth rays may occur, and, as with tibial deficiencies, tarsal fusions are common. Bowing of the middle segment of the limb commonly occurs when one of the long bones of the segment is deficient (Fig. 2011). Convexity of the bowing is directed away from the deficient bone. When intrauterine bowing has been marked, a cutaneous dimple forms over the apex of the bowed bone (see Section 20.5). Although clinical observation of the deficient limb is in many cases adequate to define the deficiency accurately, radiographs are essential and offer a convenient and consistent means of categorizing the malformation based on the skeletal deficiency. Normally, all bones of the limb skeleton are ossified by the time of birth, except for the carpals, five of the seven tarsals, and the patellas (Table 20-4).72,73 Hence, classification can be accomplished at the time of birth, except for deficiencies of these bones. Classification of deficiencies of carpals and tarsals may change with ossification of these bones. Fortunately, isolated deficiency of these bones is rare. In some cases of partial absence of a long bone, the remnant is cartilaginous at birth, becoming ossified later in infancy or childhood. Deficiencies of the limbs are often seen as isolated defects. Nearly one-half of cases, however, have associated malformations, necessitating a careful search for other minor or major anomalies elsewhere in the skeleton as well as in other systems.11,12,74–76 Family history and prenatal exposure history are useful in establishing a specific diagnosis. Cytogenetic analysis may be helpful in docu-

menting the chromosomal cause of certain limb deficiencies and in distinguishing Roberts syndrome and Fanconi pancytopenia from genocopies and phenocopies with similar limb deficiencies. Premature centromere separation predominantly involving the acrocentric chromosomes and chromosomes 1, 9, and 16 may be seen in Roberts syndrome, and increased spontaneous or induced chromosome breakage may be seen in Fanconi anemia.77,78 Other limb deficiencies are associated with abnormalities of the hematopoietic system (thrombocytopenia-absent radius, Aase syndrome). Etiology and Distribution

It is clear that limb reduction defects arise by several pathogenetic mechanisms. A simplistic view holds that about one-third result from primary mesodermal or mesoectodermal defects, one-third from vascular deprivation, and one-third from neuropathic processes. McGuirk et al. attributed 30% of limb reduction defects to genetic causes, 5% to teratogens including maternal diabetes, 34% to vascular disruptions, and 32% to unknown causes.79 The mesodermal or mesoectodermal pathogenesis of human limb deficiencies may be inferred from the extensive observations in animal embryos, mostly chicken and mouse.80–82 At the outset of limb formation (stage 12 in upper limbs, stage 13 in lower limbs), two phenomena appear predominant. First is the aggregation of mesoderm and its assumption of limb formation potential. Second is the induction and maintenance of the apical ectodermal ridge by the underlying limb mesoderm. Interference with either of these early processes by genetic or environmental forces causes limb development to fail entirely, resulting in amelia (Table 20-5, Fig. 2012).6,7,9,83–88 Normal limb production depends on the presence of fully potent mesoderm and the apical ectodermal ridge and on continued interaction between the two until formation is complete. Disturbances of this relationship may cause limb formation to cease, with variable limb deficiencies the result. McCredie and associates6,7,89 have noted that many limb deficiencies tend to follow sclerotomal patterns; that is, the affected skeletal structures are those supplied by a single sensory nerve. Accordingly, these authors suggest that neuropathy of sensory C6 could lead to deficiencies of the radial side of the forearm and hand; neuropathy of C7 could lead to central ray defects, such as split hand; and so forth. They have found that limb reduction defects

Table 20-3. Meromelias: longitudinal deficiencies of the middle segmenta Causation Gene/Locus

Syndrome

Clinical Findings

Radiographic Findings

Al-Awadi: limb deficiency18

Short and malformed limbs with oligodactyly

(U, F) Absent ulna and ulnar digits, single long bone in lower limb

AR (276820)

Baller-Gerold19

Craniosynostosis, oligodactyly, short and curved forearms

(R) Absent radius and radial digits, craniosynostosis

AR (218600)

Boehme: upper limb deficiency-heart defect5,20

See radial deficiency-ventricular septal defect

Brahimi: acromesomelia21

Short limbs, limited forearm rotation

(Fi) Fibular aplasia, short radius and ulna

AR

Burck: mesomelic dysplasia22

Mesomelic short stature, flat facies, long philtrum, depressed nasal bridge, micrognathia

(U) Ulnar hypoplasia, long fibulas, short metacarpals, dislocated patellas, punctate calcifications of carpals, tarsals, and coccyx

Uncertain

Buttiens: distal limb deficiencies23

Distal limb deficiency, micrognathia, microstomia, mental retardation (similar to aglossia-adactyly)

(R) Absent radius, monodactyly, may have distal transverse limb deficiencies

AR (246560)

CHILD24,25

Congenital hemidysplasia, ichthyosiform erythroderma, limb defects

(H,R,U,F,T,Fi) Variable limb deficiencies, ipsilateral to skin changes

XLD (308050) NSDHL, Xq28

Chromosome deletions/ duplications26

Various malformations depending on chromosome involved; see also trisomy 18 and triploidy

Various limb deficiencies

Various chromosome deletions/ duplications

Cortada: scoliosis-ulnar hypoplasia27

Microcephaly, narrow maxillary/mandibular arches, hypodontia, scoliosis, small hands with tapered fingers, mental retardation

(U) Hypoplastic ulna

AR

De Lange28

IUGR, microcephaly, synophrys, heart and genital anomalies, limb deficiencies primarily of upper limb

(U) Absent or hypoplastic ulna, oligodactyly

AD, Sporadic NIPBL, 5p13.1

De la Chapelle dysplasia29

Cleft palate, small thorax, severe limb shortening, protuberant abdomen, short digits, clubfoot

(U,Fi) Short long bones, ulna and fibula triangular, small and irregular lumbar vertebrae, thin ribs, small ilia

AR (256050) DTDST, 5q32-q33.1

Di Bella: ulna agenesis30

Cardiac defects, unilateral forearm deficiency with absent digits 4–5

(U) Absent left ulna and absent digits 4–5, radiohumeral synostosis

Uncertain

Du Pan: fibular hypoplasiabrachydactyly31

Mesomelic limb shortening, brachydactyly

(Fi) Finger camptodactyly, very short toes

AR CDMP1, 20q11.2

Eaton-McKusick32

See Werner mesomelic dysplasia

Fanconi anemia33

Short stature, microcephaly, radial ray deficiencies, pancytopenia, hyperpigmentation

(R) Hypoplastic or aplastic radius

AR (227650)

Femoral hypoplasia-unusual facies10

Short stature due to short thighs, short nose with full tip, micrognathia, hypoplastic alae nasi, long philtrum, genitourinary abnormalities

(F) Deficiency of femur, variable absence of fibula and other tubular bones of extremities

Maternal diabetes and other causes

Fuhrmann34

Hypoplasia or absence of fibula and digits, polydactyly, syndactyly, bowed femurs

(Fi) Fibular hypoplasia or absence, femoral bowing, tarsal coalescence, other bone deficiencies

AR (228930) NOG, 17q21-q22

Hecht: limb deficiency35

Absence or oligosyndactyly of hands and feet, heart defect (half-sibs affected)

(Fi) Fibular hypoplasia or aplasia, variable other deficiencies of bone of middle and distal segments

Unknown (246570)

Holt-Oram36

Variable upper limb deficiencies, atrioseptal defect or other cardiac defects

(R) Radial deficiency, variable bone deficiencies of upper limb

AD (142900)

Humeroradial synostosis37

Fixed extended elbows

(U) Ulnar deficiency, bowed radius, H-R synostosis, absent patellas, short fibulas

AR (236400)

Hutteroth: absent thumb38

Short stature, microcephaly, cardiac defects, absent thumbs, short forearms, mental retardation

(R) Radial hypoplasia, short long bones, absent first ray of hands

Uncertain

Ives-Houston39

Microcephaly, craniosynostosis, intrauterine growth retardation, oligodactyly, lethal

(R) Variable upper limb malformations

AR (251230) (continued)

843

Table 20-3. Meromelias: longitudinal deficiencies of the middle segmenta (continued) Syndrome

Clinical Findings

Radiographic Findings

Causation Gene/Locus

IVIC39,40

Upper limb deficiencies, hearing loss, thrombocytopenia

(R) Variable upper limb malformations

AD (147750)

Langer mesomelic dysplasia41

Short stature

(U, Fi) Short thick long bones, hypoplasia of ulna and fibula, bowed radius, short tibia

XL (312865) SHOX, Xp22.3

Maroteaux: acromesomelic dysplasia42

Marked mesomelic shortening with lesser acromelic shortening, elbow limitation, flat square feet, normal facies

(U) Long bones short and dense, ulna shorter than radius, deficiency of distal ulna, curved radius with deviation of head, short hand and foot bones, slight scaphocephaly

AR (201250)

Microgastria-limb deficiency43,44

Small stomach, variable anomalies of CNS, spleen, kidneys, GI tracts, and skeleton

(R)

Uncertain

Nager45,46

Malar hypoplasia, downslanting palpebral fissures, eyelid colobomas, cleft lip/palate, micrognathia, radial ray defects

(R) Radial ray deficiencies

Usually sporadic, may be AD (154400)

Pallister: ulnar-mammary47

Hypoplasia of apocrine and mammary glands, delayed growth and puberty, hypogenitalism

(U) Ulnar ray deficiencies

AD (181450) TBX3, 12q23q24.1

Pallister: clefting48

Prominent forehead, hypertelorism, downward-slanting palpebrae, flat broad nose, incomplete midline oral clefts, mental retardation

(U) Short ulna

XLD (311450)

Pfeiffer: absent fibulaoligodactyly49

Cleft lip/palate, brain malformation, limb deficiencies, oligodactyly (?same as Fuhrman)

(U,Fi) Absent fibulas, angulated femurs

AR (228930)

Pillay: ophthalmomandibulomelic dysplasia50

Corneal opacities, limited oral movement, short forearms

(U) Ulnar deficiency, temporomandibular fusion

AD (164900)

Prenatal valproate51

Midface hypoplasia, heart defects, lumbosacral spina bifida, limb defects

(R,T) Humerus may be short, oligodactyly, triphalangeal or hypoplastic thumbs

Teratogenic exposure

Radial deficiency-choanal stenosis (Goldblatt)52

Esotropia, choanal stenosis, radial deficiency

(R) Absent or hypoplastic radius and thumbs

AD (179270)

Radial deficiency-hemifacial microsomia53

Hemifacial microsomia, mild radial deficiency

(R) Radial hypoplasia with thumb anomalies

Uncertain

Radial deficiencynephropathy (Siegler)54

Short and malformed forearms, renal ectopia, hydronephrosis oligodactyly (similar to Sofer: radial deficiency)

(R) Absent radius, thumbs

AR

Radial deficiency-ventricular septal defect5,20

Ventricular septal defects, variable defect of forearm

(R) Absent of hypoplastic radius, absent thumb

Unknown

Reinhardt-Pfeiffer55

Mesomelic limb shortening

(U,Fi) Short ulna, fibula

AD

Richieri-Costa: limb deficiency56

Ulnar ray oligodactyly, toenail hypoplasia

(R,U) Radial or ulnar hypoplasia or absence

AD

Roberts9

Cleft lip/palate, blond hair, short and malformed limbs, enlarged phallus

(H,R,U,F,T,Fi) Variable long bone deficiencies, oligodactyly

AR (268300)

Savarirayan mesomelic dysplasia57

Mesomelic limb shortening

(Fi) Glenoid hypoplasia, absent or hypoplastic fibula

Unknown

Schmitt: radial hypoplasiatriphalangeal thumbs58

Short bowed forearms, fingerlike thumb, hypospadias

(R) Radial hypoplasia, triphalangeal thumbs

AD (179250)

Sofer: radial deficiency61

Short stature, short forearms, absent thumbs, malformed ears, renal anomalies, ?chromosome breakage (similar to radial deficiency-nephropathy)

(R) Absent radius and thumb

AD (179280)

Split hand/split foot-limb deficiency59

Usual split hand and split foot but quite variable from monodactyly to polydactyly

(T) Tibial aplasia, rarely ulna and femur deficiency, variable hand and foot deficiencies

AD (183600) SHFM1, genomic duplication of 7q21.2-q21.3 XLD (313350) SHFM2, Xq26 (continued)

844

Limbs

845

Table 20-3. Meromelias: longitudinal deficiencies of the middle segmenta (continued) Syndrome

Clinical Findings

Radiographic Findings

Causation Gene/Locus

AD (608071) SHFM3, genomic duplication 10q24 AD (603273) SHFM4 (EEC), p63, 3q27 AD (606708) SHFM5, 2q31 Thrombocytopenia-absent radius62

Facial hemangioma, heart defects, puffy feet, thrombocytopenia, anemia, short forearms, thumbs present

(R) Absent radius

AR (274000)

Tibial aplasia63

Leg shortening and angulation with clubfoot, skin dimpling at apex of curve

(T) Absent or hypoplastic tibia

Usually sporadic, occasionally AR (275220)

Triploidy64

IUGR, craniosomatic disproportion, syndactyly, visceral anomalies

(R) Absent radius, oligodactyly occasionally

Chromosomal (triploidy)

Trisomy 1864,65

Typical features plus middle and distal ray deficiency, usually unilateral

(R,T) Absent radius or tibia most common but occurs in less than 10% of cases

Chromosome 18 trisomy

Ulbright: renal dysplasia-limb defects60

Renal dysplasia, Potter facies, genital anomalies, rib anomalies

(H,R,U,Fi)

Uncertain

VACTERL association67

Vertebral, anal, cardiac, tracheo-esophogeal, renal, and limb defects

(R) Radial ray deficiencies primarily

Sporadic

Werner mesomelic dysplasia68

Polysyndactyly, short legs

(Fi) Short ovoid tibia

AD (188770)

Weyers ulnar deficiencyoligodactyly69

Single central maxillary incisor, cleft lip/ palate, mesomelic limb shortening, oligodactyly

(U,Fi) Short radius, oligodactyly

Uncertain

a Does not include the single family reports of radial deficiency-Duane anomaly (MacDermot and Winter70), fibular aplasia-split hand/split foot (Evans et al.71).

Fig. 20-7. Radial deficiency (radial terminal longitudinal meromelia) in Holt-Oram syndrome.

846

Skeletal System

Fig. 20-8. Ulnar deficiency (ulnar terminal longitudinal meromelia) in a 2-year-old male. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

associated with thalidomide follow the sclerotome patterns, as do about one-half of limb defects not associated with thalidomide exposure. Among the latter, sclerotomal simulation was found to be more common among lower limb defects (84%) than among upper limb defects (37%).89 Clinical and experimental evidence supports a vascular basis for some limb deficiencies.90–94 Artificial induction of limb bud hemorrhage in rat embryos has been shown to result in limb deficiencies. The deficiencies tend to be distal and transverse in nature (Table 20-6, Figs. 20-13 and 20-14; also see Chapter 22).9,23,24,35,82,95–110 Other limb anomalies such as syndactyly and polydactyly can be induced by hemorrhage as well. Van Allen et al.91 have found that limb deficiencies associated with the limb-body wall complex are consistent with vascular pathogenesis. Other vascular anomalies (renal agenesis, intestinal atresia, cardiac defects, central nervous system defects) often accompany the limb deficiencies. These authors suggest that vascular pathogenesis should also be suspected in apparently isolated limb deficiencies and that this should stimulate the search for internal vascular anomalies. Disruptive processes may occur by which a portion of the limb that has formed normally is destroyed. Such regressive changes may be genetically determined (brachydactyly mutant of rabbits) or environmentally induced (vasopressor activity on the distal limbs and tails in rats, vascular impairment from cocaine or amniotic bands in humans).93,94,106,111 The possibility that cell death, which normally participates in digit separation, can exceed normal bounds producing regression of limb parts has not been excluded as a mechanism for certain distal limb deficiencies in humans. Split hand/split foot, oligodactyly, and symbrachydactyly may arise through such a mechanism. Zwilling80 has suggested that many environmental agents might interfere with normal bone growth after primary limb formation is complete. Whether such insults might eventually result in a limb deficiency is not known. No event has focused medical and public attention on limb malformations more than the thalidomide experience of the late 1950s and early 1960s. An estimated 5800 cases of thalidomide embryopathy occurred between 1958 and 1963.8 A concentration of cases was found in European countries, but the embryopathy was seen throughout the world wherever thalidomide was available. The most conspicuous component of the embryopathy was

the astounding array of limb deficiencies. With the exception of terminal transverse deficiencies and unilateral deficiencies, almost every conceivable configuration and combination of limb deficiency were seen among affected infants (Fig. 20-15). Although extensive investigations have been conducted, the mechanism by which thalidomide causes limb deficiencies and other malformations remains uncertain.112 As was noted above, McCredie et al.6,7,89 suggest an underlying neuropathic process. Other environmental insults of greatest importance as causes of limb deficiencies include maternal diabetes; vascular compromise by amniotic bands or other constrictive forces; and prenatal exposure to warfarin, hydantoin, or cocaine. Maternal diabetes complicates 2–3% of pregnancies. Infants born of diabetic mothers have increased risk of cardiac, central nervous system, spine, and limb malformations. Limb defects have been found in under 1% of infants of diabetic mothers (Fig. 20-16).113–116 Most commonly, defects appear in the lower limbs, and these may be associated with defective development of the lower spine. Focal femoral hypoplasia and sirenomelia are seen with increased frequency among infants of diabetic mothers. Abnormalities of the vasculature have been demonstrated in many cases of limb deficiencies.102,117–120 Whether the vascular abnormalities represent fundamental defects that cause the limb deficiencies through faulty nourishment or secondary defects formed in response to abnormal limb development is debated. Van Allen et al.92 have argued that the vasculature precedes skeletal development and that the vascular pattern largely determines the morphogenesis of the limb. Vascular compromise from various insults may cause limb reduction, usually of terminal transverse nature.102 Constriction of any portion of a limb with amniotic bands may impair vascular supply and cause amputations (Figs. 20-13 and 20-14). It is argued by some that amniotic or fibrous bands represent secondary noncausal features in this situation, the primary cause being hemorrhage or other vascular compromise in the terminal aspect of the developing limb.90,120,121 Hemorrhage into limb bud tissues may also be a plausible explanation for the association of chorionic villus sampling and maternal thrombophilias with distal limb deficiencies.98–100,103 Thrombosis or emboli associated with maternal cocaine use or demise of a monozygous twin may cause similar terminal deficiencies without evidence of bands.106,108,109 Mild terminal deficiencies of digits have been found secondary to intrauterine exposure to warfarin and hydantoin (Fig. 2017).122,123 Usually only the terminal phalanx of one or more digits is affected, and this is accompanied by nail hypoplasia or absence. Heritable causes may be identified for limb deficiencies covering the gamut of defects found in thalidomide embryopathy and terminal transverse and unilateral defects as well. Various chromosomal aberrations and gene mutations are among these.26,60,64,65,124–128 In virtually all such circumstances, the limb deficiency is but one component of a multiple anomaly syndrome (Tables 20-2, 20-3, 20-5, and 20-6; see also Chapter 22). In most cases of heritable isolated and syndromic long bone deficiencies, the mutated genes are not known. Important exceptions may be cited: TBX5 mutations in Holt-Oram syndrome, TBX3 in ulnar-mammary syndrome, NIBPL in de Lange syndrome, CDMP1 in DuPan fibular hypoplasia-brachydactyly, SHOX in Langer mesomelic dysplasia, and NSDHL in CHILD syndrome.31,124-–128 Genomic duplications of 7q21.2–q21.3 and 10q24 have been found in type 1 and type 3 split hand/split foot malformation.60 These split hand/split foot malformation syndromes have long bone deficiency only in a minority of cases.

Fig. 20-9. Tibial deficiencies. A. Schematic shows various degrees. B and C. Male infant has tibial intercalary longitudinal meromelia. Relatively normally formed feet are inverted at the ankle. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute,

Wilmington, DE.) Radiographs (D and E) show left tibial hypoplasia (now fused to fibula) and right tibial aplasia in a father, and (F and G) left tibial aplasia and normal right tibia in his daughter. 847

848

Limbs

849

Fig. 20-11. Bowing of tibias associated with fibular agenesis in a 4-year-old male. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Limb deficiencies occur in three to eight infants of every 10,000 live births (Tables 20-7 and 20-8).11–14,74,79,129,130 Upper limbs are affected at least twice as commonly as the lower limbs, and unilateral defects are four times as common as bilateral deficiencies.11–14 Among unilateral defects, the right limbs are affected more frequently. A slight preponderance of affected males has been noted for most limb deficiencies. Limb deficiencies are often the only malformations present. When other defects are present, they are often life threatening. Among the Swedish Registry, Kallen et al.11 found 32% of infants with limb deficiencies to have at least one additional nonlimb malformation. A higher incidence (53%) of other anomalies was reported from the British Columbia Survey of live births with limb deficiencies.12 The most common associated anomalies included those of the musculoskeletal system (20%), head and neck (15%), cardiovascular system (10%), gastrointestinal (GI) system (10%), and genitourinary system (10%). Mortality is highest among infants with other defects, particularly cardiac and GI anomalies. Under 10% of infants are stillborn, and 10–15% die during infancy. Prognosis, Treatment, and Prevention

The goal of treatment of limb deficiencies is to restore function and appearance of the limb(s). Inasmuch as shortening is usually an integral part of these conditions, various methods of surgical lengthening must be weighed against amputation with prosthetic restoration. Because the shortened limb may be programmed to be short, lengthening procedures are frequently complicated and often end in failure. Upper limb deficiencies are commonly transverse,

involving the forearm, and improved function and appearance can be restored by fitting with a myoelectric prosthesis. Tibial deficiencies, if complete, are best treated by disarticulation at the knee, removing the remaining fibula and malformed foot. If the affected femur is of equal length to the contralateral femur, an appropriate growth arrest will be necessary to allow for satisfactory fitting of a prosthetic appliance. If tibial deficiency is partial, the fibula can be fused to the proximal remaining tibial segment, providing a reasonably stable knee joint. The foot is usually amputated, leaving the patient with a functional below-knee prosthesis. Fibular deficiency can be treated by fusion of the ankle and a lengthening procedure if the foot is normal, keeping in mind that there is also some residual deficiency of the ligamentous structures of the knee. When one or two of the lateral rays are missing, resulting in a narrow and short foot, amputation at the level of the ankle joint using either a Syme type of disarticulation or a Boyd amputation that retains the os calcis is the treatment of choice. Proximal femoral focal deficiency results in a shortened limb, with pathologic changes of the proximal femur and acetabulum. The method of treatment depends on the degree of shortening and on the status of the hip joint. Lengthening procedures usually fail because of the severity of the femoral shortening and the instability associated with the hip joint abnormality. Fibular deficiency often occurs in association with proximal femoral focal deficiency and adds to the leg length discrepancy. The treatment of choice in most instances is to fuse the femur and tibia (distal femoral metaphysis to proximal tibial epiphysis) to gain adequate

3

Fig. 20-10. Fibular deficiencies. A. Schematic shows varying degrees. B. 10-year-old male with mesomelic shortening of lower limb. C and D. Radiographs show marked fibular hypoplasia in infancy and at age 16 years in affected sisters. E and F. Mild mesomelic shortening of legs in 14-year-old male with short fibulas.

G. Radiograph showing unilateral fibular hypoplasia with mild tibial bowing. Note small ossified remnant of fibula (arrowhead) and shortening of all long bones of the right lower limb. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Table 20-4. Time of appearance of primary ossification centers of the limbs Prenatal Limb Ossification

Week

Postnatal Limb Ossification

Upper Limb

Month

Upper Limb

Clavicle (diaphysis)

7

Proximal humeral epiphysis

3

Scapula

8–9

Hamate

4

Humerus (diaphysis)

8

Capitate

Radius (diaphysis)

8

Distal radial epiphyses

Ulna (diaphysis)

8

Triquetrium

36

Lunate

48

Phalanges

6 12

Terminal

9

Proximal radial epiphyses

60

Basal 3 and 2

9

Trapezium

60

Basal 4 and 1

10

Scaphoid

60

Basal 5

11–12

Trapezoid

72

Middle 3, 4, 2

12

Distal ulnar epiphyses

Middle 5

13–16

Pisiform

72 120

Metacarpals 2 and 3

Lower Limb

9

4, 5, 1

10–12

Proximal femoral epiphysis

Lower Limb Ilium

9

12

Cuneiform-1

12

Distal fibular epiphysis

24

Ischium (descending ramus)

16–17

Cuneiform-3

36

Os pubis (horizontal ramus)

21–28

Proximal fibular epiphysis

48

Cuneiform-2

48

Femur (diaphysis)

8–9

Femur (distal epiphysis)

35–40

Tibia (diaphysis)

8–9

Tibia (proximal epiphysis)

Navicular

48

Patella

60

40

Fibula

9

Os calcis

21–29

Astragalus

24–32

Cuboid

40

Metatarsals 2 and 3

9

4, 5, and 1

10–12

Phalanges Terminal 1

9

Terminal 2, 3, 4

10–12

Terminal 5

13–14

Basal 1, 2, 3, 4, 5

13–14

Middle 2

20–25

Middle 3

21–26

Middle 4

29–32

Middle 5

33–36

Data from Potter and Craig72 and Wilkins.73

Table 20-5. Conditions with amelia Syndrome 83

Limbs Involved

Comment

Alcohol, prenatal

Upper and/or lower

Rare association

Amniotic bands84

Upper and/or lower

Rare association, distal transverse deficiencies are usual

Isolated amelia85

Upper and/or lower

Limb-body wall complex86 87

850

12

Distal tibial epiphysis

Upper or lower

Maternal diabetes

Upper

Roberts (SC phocomelia)9

Upper and/or lower

Splenogonadal fusion-limb deficiency88

Upper and/or lower

Thalidomide, prenatal6,7

Upper and lower

Rare association

Upper limb deficiencies more common

Fig. 20-12. Amelia in 6-week-old female infant. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Fig. 20-13. Transverse deficiency (carpal terminal transverse meromelia) in 6-year-old male with Poland-Mo¨bius syndrome. Child has facial weakness and absence of left pectoralis major in addition to the limb deficiency. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Fig. 20-14. Transverse deficiency. A 3-year-old male (at left) has phalangeal terminal transverse meromelia of left upper limb, and his 7-year-old brother has carpal terminal transverse meromelia of right upper limb. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

851

852

Skeletal System Table 20-6. Meromelias: transverse limb deficiencies Syndrome

Major Features

Causation Gene/Locus

Acheiropodia (Brazil type)95

Absent hands and feet

AR (200500)

Aglossia-adactyly96,97

Micrognathia, tongue deficiency, facial palsies, variable transverse deficiencies

Unknown (103300)

Amniotic bands

Constriction rings, transverse deficiencies of limbs, facial clefts

Sporadic

Buttiens: distal limb deficiencies23

Micrognathia, microstomia, mental retardation, distal limb deficiencies

AR (246560)

CHILD24

Congenital hemidysplasia ichthyosiform erythroderma, limb defects (variable transverse and longitudinal deficiencies)

XLD (308050) NSDHL, Xq28

Chorionic villus sampling98–

Various terminal transverse deficiencies

Injury to limb bud

Femur-fibula-ulna101

Femoral deficiency associated with various defects of upper and lower limbs

Unknown (228200)

100

Hecht: limb deficiency35

Absence or oligosyndactyly of hands and feet, heart defect

Unknown (246570)

Isolated102

None

Sporadic, may have vascular basis

Limb-body wall complex75

Limb deficiency, ventral wall defect, facial cleft

Sporadic, may have vascular or mechanical basis

Maternal thrombophilias103

Various transverse and longitudinal deficiencies often with digital nubbins, synostoses

Possible tissue hemorrhage

Poland (PolandMo¨bius)104,105

Cranial nerve palsy, unilateral symbrachydactyly or distal transverse defect of upper limb, ipsilateral pectoral muscle deficiency

Unknown, rarely familial (173750)

Prenatal cocaine106–108

Various limb deficiencies, vascular disruptions of brain and genitourinary systems, cardiac defects

Tissue thrombosis or emboli

Roberts (SC phocomelia)9

Cleft lip/palate, blond hair, short and malformed limbs, enlarged phallus

AR (268300)

Sirenomelia109

Failure of lower limbs to completely separate, anomalies of the genitalia, lower bowel and kidneys

Sporadic, vascular basis, maternal diabetes

Splenogonadal fusion-limb deficiency88

Micrognathia, abnormal dentition, splenogonadal fusion, variable transverse limb deficiencies

Unknown (183300)

a-Thalassemia110

Variable transverse limb deficiencies, cardiovascular anomalies

AR (301040)

Fig. 20-15. Upper limb intercalary transverse meromelia in 16-year-old male with prenatal thalidomide exposure. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Limbs

853

Table 20-7. Incidence of limb reduction defects Affected Infants/Births

Rate per 1000 Births

855*/1,368,024

0.62

Froster-Iskenius and Baird, 198912 British Columbia, 1966–1984 Live births

422/706,844

0.60

Czeizel et al., 1991129 Hungary, 1974–1984 Live births and stillbirths

868/1,575,904

0.55

Lin et al., 1993130 USA: New York, 1983–1987 Live births

271/720,047

0.45

Stoll et al., 199674 Europe, 1982–1991 Live births, stillbirths, terminations

432/611,158

0.71

McGuirk et al., 200179 USA: Boston, 1972–1994 Live births, stillbirths, terminations

110/161,252

0.68

CBDMP, 200313,14 USA: California, 1996–2000 Live births, stillbirths, terminations

152/281,180

0.54

MACDP, 200313,14 USA: Atlanta, 1996–2000 Live births, stillbirths, terminations

131/225,770

0.58

Kallen et al., 198411 Sweden, 1965–1979 Live births and stillbirths

Fig. 20-16. Unilateral limb deficiency in infant of a diabetic mother. The right lower limb was hypoplastic with bowed femur, proximally placed and elongated great toe, syndactyly of middle digits, and absence of one ray.

length of the ‘‘thigh’’ segment, amputate the foot, and fit an above-knee prosthesis. Prenatal diagnosis of most limb deficiencies can be made by sonographic examination during the mid trimester.131,132 Ultrasound can delineate both soft tissue and skeletal elements. Ossification of the long bones occurs according to the schedule shown in Table 20-4. Standards for prenatal measurements of the skeletal elements have been published by Elejalde and de Elejalde,133 among others.

*Includes sirenomelia (16 cases) and micromelia (19 cases).

Fig. 20-17. Digital and nail hypoplasia associated with prenatal exposure to hydantoin. Terminal phalanges may be hypoplastic or absent. (Courtesy of Dr. James W. Hanson, University of Iowa, Iowa City.)

854

Skeletal System Table 20-8. Incidence of different limb reduction defects in selected series

Froster-Iskenius and Baird, 198912 (1) Lin et al., 1993130 (1) 11

Terminal Transverse

Longitudinal

Intercalary

Hands/Feet /Digits

0.02

0.16

0.35

0.18

*

—

0.13

0.09

0.04

0.10**

0.01

0.14

0.10

0.06

0.24

Czeizel et al., 1991129 (2)

—

0.14

0.17

0.02

0.06**

McGuirk et al., 200179 (3)

0.006

0.19

0.33

0.06

*

—

0.40

0.18

0.01

0.05**

Kallen et al., 1984

(2)

Amelia

Stoll et al., 199674 (3) (1) Rate per 1000 live births.

(2) Rate per 1000 live births and stillbirths. (3) Rate per 1000 live births, stillbirths, terminations. *Reduction defect of hands, feet, and digits included in other categories. **Split hand/split foot only.

References (Limb Deficiencies) 1. Swinyard CA, Marquardt E: Equivalents in systems of nomenclature. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969. 2. Frantz CH, O’Rahilly R: Congenital skeletal limb deficiencies. J Bone Joint Surg 43A:1202, 1961. 3. Burtch RL: Classification nomenclature for congenital skeletal limb deficiencies. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969. 4. McKusick VA, Weilbaecher RG, Gragg GW: Recessive inheritance of a congenital malformation syndrome. JAMA 204:113, 1968. 5. Boehme DH, Shotar AO: A complex deformity of appendicular skeleton and shoulder with congenital heart disease in three generations of a Jordanian family. Clin Genet 36:442, 1989. 6. McCredie J, North K, De Longh R: Thalidomide deformities and their nerve supply. J Anat 139:397, 1984. 7. McCredie J, Willert HG: Longitudinal limb deficiencies and the sclerotomes. J Bone Joint Surg Br 81B:9, 1999. 8. Lenz W: A short history of thalidomide embryopathy. Teratology 38:203, 1988. 9. Freeman MVR, Williams DW, Schimke RN, et al.: The Roberts syndrome. Clin Genet 5:1, 1974. 10. Hillmann JS, Mesgarzadeh M, Revesz G, et al.: Proximal femoral focal deficiency: radiologic analysis of 49 cases. Radiology 165:769, 1987. 11. Kallen B, Rahmani TMZ, Winberg J: Infants with congenital limb reduction registered in the Swedish register of congenital malformations. Teratology 29:73, 1984. 12. Froster-Iskenius UG, Baird PA: Limb reduction defects in over one million consecutive livebirths. Teratology 39:127, 1989. 13. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: State birth defects surveillance programs directory. Birth Defects Res Part A Clin Mol Teratol 67:669, 2003. 14. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: Birth defects surveillance data from selected states, 1996-2000. Birth Defects Res Part A Clin Mol Teratol 67:729, 2003. 15. O’Rahilly R: Morphological patterns in limb deficiencies and duplications. Am J Anat 89:135, 1951. 16. Pardini AG Jr: Radial dysplasia. Clin Orthop 57:153, 1968. 17. Broudy AS, Smith RJ: Deformities of the hand and wrist with ulnar deficiency. J Hand Surg 4:304, 1979. 18. Al-Awadi SA, Teebi AS, Farag TI, et al.: Profound limb deficiency, thoracic dystrophy, unusual facies, and normal intelligence: a new syndrome. J Med Genet 22:36, 1985.

19. Pelias MZ, Superneau DW, Thurmon TF: Brief clinical report: a sixth report (eighth case) of craniosynostosis-radial aplasia (Baller-Gerold) syndrome. Am J Med Genet 10:133, 1981. 20. Harris LC, Osborne WP: Congenital absence or hypoplasia of the radius with ventricular septal defect: ventriculo-radial dysplasia. J Pediatr 68:265, 1966. 21. Brahimi L, Bacha L, Kozlowski K, et al.: Acro-mesomelic dysplasia—a new type. Report of two siblings. Pediatr Radiol 18:67, 1988. 22. Burck U: Mesomelic dysplasia with punctate epiphyseal calcifications—a new entity of chondrodysplasia punctata? Eur J Pediatr 138: 67, 1982. 23. Buttiens M, Fryns JP: Apparently new autosomal recessive syndrome of mental retardation, distal limb deficiencies, oral involvement, and possible renal defect. Am J Med Genet 27:651, 1987. 24. Falek A, Heath CW Jr, Ebbin AJ, et al.: Unilateral limb and skin deformities with congenital heart disease in two siblings: a lethal syndrome. J Pediatr 73:910, 1968. 25. Happle R, Koch H, Lenz W: The CHILD syndrome: congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr 134:27, 1980. 26. Haspeslagh M, Fryns JP, Moerman P: Severe limb malformations in 4p deletion. Clin Genet 25:353, 1984. 27. Cortada X, Kousseff BG, Matsumoto GM: Constricted maxilla and mandible, scoliosis, bowed radii, ulnar hypoplasia, acromicria and microcephaly with mental retardation—a new autosomal recessive syndrome? Birth Defects Orig Artic Ser XVIII(3B):197, 1982. 28. Ptacek LJ, Opitz JM, Smith DW, et al.: The Cornelia de Lange syndrome. J Pediatr 63:1000, 1963. 29. Whitley CB, Burke BA, Granroth G, et al.: De la Chapelle dysplasia. Am J Med Genet 25:29, 1986. 30. Di Bella D, Di Stefano G, Romeo MG, et al.: Upper limb cardiovascular syndrome with ulna agenesis (abstract). Pediatr Radiol 14:259, 1984. 31. Faiyaz-Ul-Haque M, Ahmad W, Zaidi SHE, et al.: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). Clin Genet 61:454, 2002. 32. Eaton GO, McKusick VA: A seemingly unique polydactyly syndactyly syndrome in four persons in three generations. Birth Defects Orig Artic Ser V(3):221, 1969. 33. Juhl JH: Roentgenographic findings in Fanconi’s anemia. Radiology 89:646, 1967. 34. Fuhrmann W, Fuhrmann-Rieger A, De Sousa F: Poly-, syn-, and oligodactyly, aplasia, or hypoplasia of fibula, hypoplasia of pelvis and bowing of femora in three siblings—a new autosomal recessive syndrome. Eur J Pediatr 133:123, 1980. 35. Hecht JT, Scott CI Jr: Limb deficiency syndrome in half-sibs. Clin Genet 20:432, 1981.

Limbs 36. Poznanski AK, Gall JC, Stern AM: Skeletal manifestations of the HoltOram syndrome. Radiology 94:45, 1970. 37. Ramer JC, Ladda RL: Humero-radial synostosis with ulnar defects in sibs. Am J Med Genet 33:176, 1989. 38. Hutteroth H, Spranger J: Case report 34. Synd Ident 111:15, 1975. 39. Ives EJ, Houston CS: Autosomal recessive microcephaly and micromelia in Cree Indians. Am J Med Genet 7:351, 1980. 40. Arias S, Penchaszadeh VB, Pinto-Cisternas J, et al.: The IVIC syndrome: a new autosomal dominant complex pleiotropic syndrome with radial ray hypoplasia, hearing impairment, external ophthalmoplegia and thrombocytopenia. Am J Med Genet 6:25, 1980. 41. Langer LO Jr: Mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type. Radiology 89:654, 1967. 42. Langer LO, Beals RK, Solomon IL, et al.: Acromesomelic dwarfism: manifestation in childhood. Am J Med Genet 1:87, 1977. 43. Al-Gazali LI, Bakir M, Dawodu A, et al.: Recurrence of the severe form of microgastria-limb reduction defects in a consanguineous family. Clin Dysmorphol 8:253, 1999. 44. Stewart C, Stewart M, Stewart F: Microgastria-limb reduction anomaly with total amelia. Clin Dysmorphol 11:187, 2002. 45. Hall BD: Nager acrofacial dysostosis: autosomal dominant inheritance in mild to moderately affected mother and lethally affected phocomelic son. Am J Med Genet 33:394, 1989. 46. Halal F, Herrmann J, Pallister PD, et al.: Differential diagnosis of Nager acrofacial dysostosis syndrome: report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14: 209, 1983. 47. Schinzel A, Illig R, Prader A: The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin Genet 32:160, 1987. 48. Pallister PD, Herrmann J, Spranger JW, et al.: The W syndrome. (Studies of malformation syndromes in man XXVIII). Birth Defects Orig Artic Ser X(7):51, 1974. 49. Pfeiffer RA, Stoss H, Voight HJ, et al.: Absence of fibula and ulna with oligodactyly, contractures, right-angle bowing of femora, abnormal facial morphology, cleft lip/palate and brain malformation in two sibs: a possibly new lethal syndrome. Am J Med Genet 29:901, 1988. 50. Pillay VK: Ophthalmo-mandibulo-melic dysplasia: an hereditary syndrome. J Bone Joint Surg 46A:858, 1964. 51. Sharony R, Garber A, Viskochil D, et al.: Preaxial ray reduction defects as part of valproic acid embryofetopathy. Prenat Diagn 13:909, 1993. 52. Goldblatt J, Viljoen D: New autosomal dominant radial ray hypoplasia syndrome. Am J Med Genet 28:647, 1987. 53. Moeschler J, Clarren SK: Familial occurrence of hemifacial microsomia with radial limb defects. Am J Med Genet 12:371, 1982. 54. Siegler RL, Larsen P, Buehler BA: Upper limb anomalies and renal disease. Clin Genet 17:117, 1980. 55. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development, ed 2. Oxford University Press, New York, 2002. 56. Richieri-Costa A, Opitz JM: Ulnar ray a/hypoplasia: evidence for a developmental field defect on the basis of genetic heterogeneity. Report of three Brazilian families. Am J Med Genet Suppl 2:195, 1986. 57. Savarirayan R, Cormier-Daire V, Curry CJ, et al.: New mesomelic dysplasia with absent fibulae and triangular tibiae. Am J Med Genet 94:59, 2000. 58. Schmitt E, Gillenwater JY, Kelly TE: An autosomal dominant syndrome of radial hypoplasia, triphalangeal thumbs, hypospadias, and maxillary diastema. Am J Med Genet 13:63, 1982. 59. Majewski F, Kuster W, ter Haar B, et al.: Aplasia of tibia with split-hand/ split-foot deformity. Report of six families with 35 cases and considerations about variability and penetrance. Hum Genet 70:136, 1985. 60. De Mollerat XJ, Gurrieri F, Morgan CT, et al.: A genomicrearrangement resulting in a tandem duplication is associated with split handsplit foot malformation 3 (SHFM3) at 10q24. Hum Mol Genet 12: 1959, 2003. 61. Sofer S, Bar-Ziu J, Abeliovich R: Radial ray aplasia and renal anomalies in father and son, a new syndrome. Am J Med Genet 14:151, 1983. 62. Hall JG: Thrombocytopenia and absent radius (TAR) syndrome. J Med Genet 24:79, 1987.

855 63. Schoenecker PL, Capelli AM, Millar EA, et al.: Congenital longitudinal deficiency of the tibia. J Bone Joint Surg 71A:278, 1989. 64. Phelan MC, Skinner SA, Schroer RJ, et al.: Radial aplasia in trisomy 18 and triploidy. Proc Greenwood Genet Center 10:142, 1991. 65. Christianson AL, Nelson MM: Four cases of trisomy 18 syndrome with limb reduction malformations. J Med Genet 21:293, 1984. 66. Schrander-Stumpel C, Die-Smulders C, Fryns JP, et al.: Limb reduction defects and renal dysplasia: confirmation of a new, apparently lethal, autosomal recessive MCA syndrome. Am J Med Genet 37:133, 1990. 67. Weaver DD, Mapstone CL, Yu PL: The VATER association. Analysis of 46 patients. Am J Dis Child 140:225, 1986. 68. Werner P: Ueber einen seltenen fall von zwergwuchs. Arch Gynaekol 104:278, 1915. 69. Turnpenny PD, Dean JCS, Duffty P, et al.: Weyers’ ulnar ray/ oligodactyly syndrome and the association of midline malformations with ulnar ray defects. J Med Genet 29:659, 1992. 70. MacDermot KD, Winter RM: Radial ray defect and Duane anomaly: report of a family with autosomal dominant transmission. Am J Med Genet 27:313, 1987. 71. Evans JA, Reed MH, Greenberg CR: Fibular aplasia with ectrodactyly. Am J Med Genet 113:52, 2002. 72. Potter EL, Craig JM: Pathology of the Fetus and the Infant, ed 3. Yearbook Medical Publishers, Chicago, 1975. 73. Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, ed 3. Charles C Thomas Publishers, Springfield, IL, 1965. 74. Stoll C, Calzolari E, Cornel M, et al.: A study on limb reduction defects in six European regions. Ann Ge´ne´t 39:99, 1996. 75. Evans JA, Vitez M, Czeizel A: Congenital abnormalities associated with limb deficiency defects: a population study based on cases from the Hungarian Congenital Malformation Registry (1975–1984). Am J Med Genet 49:52, 1994. 76. Goutas N, Simopoulou S, Petraki V, et al.: Limb reduction defects— autopsy study. Pediatr Pathol 13:29, 1993. 77. Parry DM, Mulvihill JJ, Tsai S, et al.: SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma. Am J Med Genet 24:653, 1986. 78. Auerbach AD, Alder B, Chaganti RSK: Prenatal and postnatal diagnosis and carrier detection of Fanconi anemia by a cytogenetic method. Pediatrics 67:128, 1981. 79. McGuirk CK, Westgate MN, Holmes LB: Limb deficiencies in newborn infants. Pediatrics 108:1, 2001. 80. Zwilling E: Abnormal morphogenesis in limb development. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969. 81. Zwilling E: Ectoderm-mesoderm relationship in the development of the chick embryo limb bud. J Exp Zoolog 128:423, 1955. 82. Harrison RG: Experiments on the development of the forelimb of Amblystoma. A self-differentiating equipotential system. J Exp Zoolog 25:413, 1918. 83. Pauli RM, Feldman PF: Major limb malformations following intrauterine exposure to ethanol: two additional cases and literature review. Teratology 33:273, 1986. 84. Fisher RM, Cremin BJ: Limb defects in the amniotic band syndrome. Pediatr Radiol 5:24, 1976. 85. Tan KL: Congenital malformations of the limbs. Br J Clin Pract 24:463, 1970. 86. Van Allen MI, Curry C, Walden CE, et al.: Limb-body wall complex: II. Limb and spine defects. Am J Med Genet 28:549, 1987. 87. Bruyere HJ Jr, Viseskul C, Opitz JM, et al.: A fetus with upper limb amelia, ‘‘caudal regression’’ and Dandy-Walker defect with an insulindependent diabetic mother. Eur J Pediatr 134:139, 1980. 88. Pauli RM, Greenlaw A: Limb deficiency and splenogonadal fusion. Am J Med Genet 13:81, 1982. 89. McCredie J, Beals RK: Dysmorphology of congenital limb defects: fifth years experience in Oregon. Birth Defects Orig Artic Ser XIX(5):186, 1983.

856

Skeletal System

90. Kennedy LA, Persaud TVN: Pathogenesis of developmental defects induced in the rat by amniotic sac puncture. Acta Anat 97:23, 1977. 91. Van Allen MI, Curry C, Walden CE, et al.: Limb-body wall complex: II. Limb and spine defects. Am J Med Genet 28:549, 1987. 92. Van Allen MI, Hoyme HE, Jones KL: Vascular pathogenesis of limb defects. I. Radial artery anatomy in radial aplasia. J Pediatr 101:832, 1982. 93. Jost A, Roffi J, Courtat M: Congenital amputations determined by the BR gene and those induced by adrenalin injection in the rabbit fetus. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969, p 187. 94. Nielsen NO: Vascular abnormalities due to hyperthermia in chick embryos. Teratology 30:237, 1984. 95. Freire-Maia A: The handless and footless families of Brazil. Lancet 1:519, 1970. 96. Hanhart E: Uber die Kombination von Peromelie mit Mikrognathie, ein neues Syndrom beim Menschen, entsprechend der Akroteriasis congenita von Wriedt und Mohr beim Rinde. Arch Julius Klaus Stift 25:531, 1950. 97. Chicarilli ZN, Polayes IM: Oromandibular limb hypogenesis syndromes. Plast Reconstr Surg 76:13, 1985. 98. Firth HV, Boyd PA, Chamberlain P, et al.: Severe limb abnormalities after chorion villus sampling at 56–66 days’ gestation. Lancet 337:762, 1991. 99. Olney RS, Khoury MJ, Alo CJ, et al.: Increased risk for transverse digital deficiency after chorionic villus sampling: results of the United States Multistate Case-Control Study, 1988–1992. Teratology 51:20, 1995. 100. Golden CM, Ryan LM, Holmes LB: Chorionic villus sampling: a distinctive teratogenic effect on fingers? Birth Defects Res Part A Clin Mol Teratol 67:557, 2003. 101. Lenz W, Zygulska M, Horst J: FFU complex: an analysis of 491 cases. Hum Genet 91:347, 1993. 102. Hoyme HE, Jones KL, Van Allen MI, et al.: Vascular pathogenesis of transverse limb reduction defects. J Pediatr 101:839, 1982. 103. Hunter AGW: A pilot study of the possible role of familial defects in anticoagulation as a cause for terminal limb reduction malformations. Clin Genet 57:197, 2000. 104. Bosch-Banyeras JM, Zuasnabar A, Puig A, et al.: Poland-Mo¨bius syndrome associated with dextrocardia. J Med Genet 21:70, 1984. 105. Collins DL, Schimke RN: Moebius syndrome in a child and extremity defect in her father. Clin Genet 22:312, 1982. 106. Hoyme HE, Jones KL, Dixon SD, et al.: Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 85:743, 1990. 107. Froster UG, Baird PA: Maternal factors, medications, and drug exposure in congenital limb reduction defects. Environ Health Perspect 101(suppl 3):260, 1993. 108. Kashiwagi M, Chaoui R, Stallmach, et al.: Fetal bilateral renal agenesis, phocomelia, and single umbilical artery associated with cocaine abuse in early pregnancy. Birth Defects Res Part A Clin Mol Teratol 67:951, 2003. 109. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 110. Lam YH, Tang MHY, Sin SY, et al.: Limb reduction defects in fetuses with homozygous a-thalassaemia-1. Prenat Diagn 17:1143, 1997. 111. Torpin R: Fetal Malformations Caused by Amnion Rupture During Gestation. Charles C Thomas Publisher, Springfield, IL, 1968. 112. Stephens TD: Proposed mechanism of action in thalidomide embryopathy. Teratology 38:229, 1988. 113. Stevenson RE: The Fetus and Newly Born Infant, ed 2. CV Mosby Co, St. Louis, 1977, p 46. 114. Becerra JE, Khoury MJ, Cordero JF, et al.: Diabetes mellitus during pregnancy and the risks for specific birth defects: a population based case-control study. Pediatrics 85:1, 1990. 115. Holmes LB: Teratogen-induced limb defects. Am J Med Genet 112:297, 2002. 116. Martinez-Frias ML: Epidemiological analysis of outcomes of pregnancy in diabetic mothers: identification of the most characteristic and most frequent congenital anomalies. Am J Med Genet 51:108, 1994. 117. Van der Horst RL, Gotsman MS: Anomalous origin of the subclavian artery associated with phocomelia. S Afr Med J 45:1397, 1971.

118. Hootnick DR, Levinsohn EM, Randall PA, et al.: Vascular dysgenesis associated with skeletal dysplasia of the lower limb. J Bone Joint Surg 62A:1123, 1980. 119. Schinzel AGL, Smith DW, Miller JR: Monozygotic twinning and structural defects. J Pediatrics 95:921, 1979. 120. Lockwood C, Ghidini A, Romero R, et al.: Amniotic band syndrome: reevaluation of its pathogenesis. Am J Obstet Gynecol 160:1030, 1989. 121. Houben JJ: Immediate and delayed effects of oligohydramnios on limb development in the rat: chronology and specificity. Teratology 30:403, 1984. 122. Shaul WL, Emery H, Hall JG: Chondrodysplasia punctata and maternal warfarin use during pregnancy. Am J Dis Child 129:360, 1975. 123. Barr MJ, Poznanski AK, Schmickel RD: Digital hypoplasia and anticonvulsants during gestation: a teratogenic syndrome? J Pediatr 84:254, 1974. 124. Packham EA, Brook JD: T-box genes in human disorders. Hum Mol Genet 12:R37, 2003. 125. Fan C, Duhagon MA, Oberti C, et al.: Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome. J Med Genet 40:e29, 2003. 126. Bamshad M, Le T, Watkins WS, et al.: The spectrum of mutations in TBX3: genotype/phenotype relationship in ulnar-mammary syndrome. Am J Hum Genet 64:1550, 1999. 127. Konig A, Happle R, Bornholdt D, et al.: Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet 90:339, 2000. 128. Zinn AR, Wei F, Zhang L, et al.: Complete SHOX deficiency causes Langer mesomelic dysplasia. Am J Med Genet 110:158, 2002. 129. Czeizel A, Vite´z M, Kodaj I, et al.: Birth prevalence of different congenital limb deficiency types in a revised, population based Hungarian material, 1975–1984. Acta Morphologica Hungarica 39:229, 1991. 130. Lin S, Marshall EG, Davidson GK, et al.: Evaluation of congenital limb reduction defects in upstate New York. Teratology 47:127, 1993. 131. Stoll C, Alembik Y, Dott B, et al.: Evaluation of prenatal diagnosis of limb reduction defects by a registry of congenital anomalies. Prenat Diagn 14:781, 1994. 132. Holder-Espinasse M, Devisme L, Thomas D, et al.: Pre- and postnatal diagnosis of limb anomalies: a series of 107 cases. Am J Med Genet 124A:417, 2004. 133. Elejalde BR, de Elejalde MM: The prenatal growth of the human body determined by the measurement of bones and organs by ultrasound. Am J Med Genet 24:575, 1986.

20.2 Synostosis Definition

Synostosis is the existence or persistence of an osseous connection between bones that are normally separate in postnatal life. Developmental synostosis arises primarily from the failure of complete segmentation of the cartilaginous template on which the osseous skeleton of the limb is patterned and from the failure of mesodermal structures or body clefts to intervene between cartilaginous plates developing in parallel (ray formation). The former results in synostoses involving bones normally separated by joint space (e.g., humeroradial synostosis, carpal-carpal coalition); the latter results in synostoses of bones of different rays in the middle or distal segments of the limbs or synostosis of bones of different limbs (e.g., radioulnar synostosis, syndactyly, symmelia). Synostoses involving long bones normally separated by a joint space are identified simply by naming the components of the compound bones (e.g., radioulnar synostosis). A variety of different terms have been used to identify synostoses involving other bones: Syndactyly (osseous): synostoses of phalanges of different digits resulting from failure of development of interdigital soft tissues and spaces

Limbs

Symphalangism: synostosis of phalanges resulting from failure of development of interphalangeal joints Coalition: synostosis of carpals or tarsals resulting from failure of intercarpal or intertarsal joints to develop Symmelia: synostoses of bones of the two members of paired limbs resulting from failure of limb anlage to be separated into paired structures In hands and feet with polydactyly, osseous connections often persist between metacarpals, metatarsals, and phalanges when the anomalous partition into rays is incomplete (see Section 21.2). Similarly, bony connections may be found in the central limb of a conjoined twin (Chapter 34). Fusion of previously separate bones can occur following trauma or inflammatory diseases of the bones and joints. Such postnatally acquired synostotic phenomena will not be considered further in this section. Synostoses involving cranial bones are discussed in Section 7.1. Diagnosis

Three clinical features (joint stiffness, absence of dermal creases, and shortening of segments involved) predominate when synostosis affects bones of the limbs. Movement between involved bones is absent or limited. Usually synostosis of long bones and phalanges occurs with the bones in extension or with only a minor degree of flexion. An exception is humeroradial synostosis, in which the elbow may be fixed at 908 or greater flexion.1 Absence of movement causes absence of flexion and extension creases over the junction of involved bones. The formation of creases over joints depends on movement at the joint stretching soft tissues over the extensor surface and compressing tissues over the flexor surface. Flexion creases on the palmar side of the digits are well-formed by week 8 postovulation, indicating that faulty partition of phalanges must predate this time if the creases are absent.2 Shortening of the limb segments or subsegments involved in a synostosis occurs but is quite variable. In the presence of the above-mentioned clinical features suggesting synostosis, radiographs must be made to document the skeletal changes. Osseous continuity between bones may be evident on radiographs taken at birth or may become evident as bony maturation progresses. Humeroradial synostosis and fifth finger symphalangism are often radiographically obvious at birth. Most transarthric synostoses, however, cannot be demonstrated at birth. The cartilaginous template, though, will be abnormal, showing underdevelopment or absence of the articular interzone in which the intervening joint normally forms. This may be reflected in a decrease in measurement between the ossified portions of the two bones involved. The age at which osseous continuity between affected bones can be demonstrated radiographically varies widely, but it may be as late as the age of normal epiphyseal fusion in the involved bones. Synostoses between different digits (syndactyly) and between bones of different limbs (symmelia) always entail obvious malformations of the affected parts. In these cases, synostosis is demonstrable at birth and does not progress. In the absence of joint stiffness or other clinical signs suggesting synostosis, synostosis may be found incidentally when radiographs are taken for unrelated reasons. Isolated carpal-carpal, tarsal-tarsal, metacarpal-metacarpal, and metatarsal-metatarsal synostoses are often asymptomatic. Although synostoses often occur simultaneously in different limb segments, only rarely do synostoses cross major limb segments. In the upper limb, metacarpophalangeal, carpometacarpal, radiocarpal, ulnocarpal, and humeroradial synostoses are distinctly rare. An analogous situation holds true for the lower limb.

857

Etiology

For the most part, synostoses represent developmental anomalies produced by gene mutations and chromosome abnormalities (Tables 20-9, 20-10, 20-11, and 20-12). The bone morphogenetic protein (TGFb-FM) antagonist noggin (NOG) has been shown to play a key role in joint formation.3–6 Mutations in NOG and in a number of other genes involved in limb development (FGFR1, FGFR2, HOXA11, HOXD13, FBLN1, ROR2, DTDST, FOP, FLNA) have been associated with synostosis with or without other skeletal anomalies.3–15 Important sporadic synostoses of unknown origin or of environmental origin are recognized, and these have no appreciable recurrence risks.16–22 Synostoses of bones normally separated by a joint space arise because of failure of joint development. Segmentation of the cartilaginous template for the skeleton of the limb begins at 5 to 6 weeks postovulation.23–25 Through processes of cell death in the articular interzone, the cartilage anlage is separated into segments that will become individual long bones. In the absence of cartilaginous segmentation, the usual limits of ossification are not confined, and union takes place. The dynamics of the processes can be seen most clearly in cases of proximal symphalangism, which can be observed through serial radiographs.2,3,26,27 Here the proximal and middle phalanges appear radiographically separate at birth. The epiphyses appear normally, but the epiphysis of the middle phalanx expands at the expense of the joint space and becomes united with the distal end of the proximal phalanx. Radiographic continuity between the bones is completed as the epiphysis fuses with the proximal end of the middle phalanx, usually at the normal time. The same process presumably applies in cases of synostoses involving the long bones and those across metacarpophalangeal or metatarsophalangeal joints. Coalition of carpals and tarsals is permitted when the network of joint spaces that partition the carpus and hindfoot fails to develop completely. Mesodermal tissues and interdigital spaces may fail to separate longitudinal rays that normally occur in the middle and distal segments of the limb.16,22,28,29 The same process is responsible for the formation of symmelia of the lower limb.17 Upper limb symmelia is precluded because the intervening cardiovascular structures are essential to embryonic development. An interruption of programmed cell death responsible for separating the limb skeleton into segments and rays is presumed to be the cause of most synostoses. In many cases isolated synostoses and synostoses associated with other anomalies are inherited (Tables 20-9, 20-10, 20-11, and 20-12). Limb synostoses associated with craniosynostoses were the first to be linked to specific genes. Mutations in fibroblast growth factor receptor 1 (FGFR1) are responsible for a minority of cases of Pfeiffer syndrome and mutations in FGFR2 cause Apert syndrome, Jackson-Weiss syndrome, and most cases of Pfeiffer syndrome.7 FGFR2 mutations also cause Crouzon syndrome, which uncommonly has carpal fusion as a limb finding. In the absence of craniosynostosis, few genes have been associated with synostosis. Mutations in NOG TGFb-FM antagonist noggin have been found in proximal symphalangism (including Fuhrmann carpal-tarsal coalition-symphalangism) and in multiple synostosis syndrome.3–6 It may be anticipated that other carpal and tarsal coalitions and symphalangism (Tables 20-9 and 20-11) may be found to be allelic. Mutations in Fibulin-1 (FBLN1) and HOXD13 have been found in synpolydactyly and mutations in HOXA11 have been demonstrated in radioulnar synostosis associated with thrombocytopenia.8–10 Synostoses also recur in several

Table 20-9. Conditions with carpal or tarsal coalitiona Condition

Major Features

32

b

Causation Gene/Locus

Banki

(C-C) Short and thin metacarpals, fifth finger clinodactyly

AD (109300)

Bersani: massive tarsal coalition33

(T-T,T-MT) Flat and stiff feet (Possibly same as multiple synostosis syndrome)

AD (186400)

Calcaneonavicular coalition, isolated34

(T-T) Flat feet

AD or sporadic

Cenani-Lenz syndactyly35

(R-U,C-C,MC-MC,T-T,MT-MT) Oligodactyly, syndactyly, brachydactyly

AR (212780)

Challis: symphalangismtalonavicular coalition36

(P-P,T-T) Flat feet, stiff feet, stiff fingers

AD (186750)

Christian: carpal and tarsal coalition-platyspondyly37

(C-C,C-MC,T-T,T-MT) Asymmetry of metacarpals and metatarsals, syndactyly, camptodactyly, platyspondyly

AD

Forney: carpal and tarsal coalition-deafness38

(C-C,T-T) Short stature, freckling, mitral insufficiency, conductive deafness, vertebral synostosis

AD (157800)

Frontometaphyseal dysplasia39

(C-C) Prominent supraorbital ridges, hearing loss, limited pronation and supination, bowed tibia and fibula

XLD (305620)

Fuhrmann: carpal and tarsal coalition-symphalangism40

(P1-P2,P2-P3,H-R,C-C,MC-MC,T-T,MT-MT) Stiff and painful varus feet

AD (186500) NOG, 17q21-q22

Gorlin: cleft palate-stapes fixation-oligodontia41

(T-T,T-MT) Cleft palate, depressed nasal bridge, deafness metaphyseal widening, vertebral anomalies, limited MP joints

AR (216300)

Grosse: acro-pectorovertebral dysplasia42

(C-C,T-T,MT-MT) Prominent sternum, spina bifida occulta, syndactyly of hands and feet, postaxial polydactyly of feet, mental impairment

AD (102510)

Hand-foot-genital43,44

(P-P,C-C,T-T) Short first ray of hands and feet, male hypospadias, duplication of female genital tract

AD (140000) HOXA13, 7p15.3

Holt-Oram45

(C-C) Radial ray limb reduction, atrioseptal or other cardiac defect

AD (142900) TBX5, 12q21.3-q22

Jackson-Weiss7,46

(T-T,MT-MT) Craniosynostosis, broad and deviated hallux, normal thumbs

AD (123150) FGFR2, 10q25.3-q26

Liebenberg: carpal coalition-brachydactylyelbow limitation47

(C-C) Brachydactyly, joint limitation of upper limb

AD (186550)

Multiple synostosis6

(P1-P2, C-C, T-T) Carpal and tarsal coalition

AD (186400) NOG, 17q21-q22

Nievergelt mesomelia48

(R-U,T-T,T-MT,MT-P) Short stature, short forearms and legs, cutaneous dimples, varus feet, valgus knees, clubfeet, long bones of forearms and legs malformed

AD (163400)

Otopalatodigital15,49

(C-C,T-T) Short stature, frontal bossing, cleft palate, deafness, short thumbs, bulbous finger tips

XLD (311300) FLNA, Xq28

Pfeiffer7

(P1-P2,P2-P3,C-C,T-T,MC-MC,MT-M-T,H-R,R-U) Craniosynostosis, brachydactyly, broad thumbs and great toes

AD (101600) FGFR2, 10q25.3-q26 FGFR1, 8p11.2-p12

Prenatal alcohol20

(C-C,R-U) Growth and mental impairment, ptosis, small palpebral fissures, smooth philtrum, thin upper lip

In utero exposure to alcohol

Proximal symphalangism2,5,6

(P1-P2,C-C,T-T,T-MT,MT-P) Hearing loss

AD (185800) NOG, 17q21-q22

Talonavicular coalition, isolated50,51 52

(T-T)

Talocalcanean coalition, isolated

(T-T) Flat feet, short stature

AD (186570)

Thalidomide19

(H-R-U,R-U,T-Fi,C-C,MC-MC,P-P) Limb deficiencies, ear malformations, visceral anomalies

Prenatal drug exposure

Van Bever: cardiac-carpal coalition53

(C-C) Cardiac septal, valvar and conduction defects, subluxed radial head, scoliosis

AD

Ventruto: craniosynostosissymphalangism54

(P1-P2,C-C,T-T) Craniosynostosis, hip dysplasia, amputation-like reductions of digits 3–5, absent or hypoplasia of middle or terminal phalanges, absent nails (similar to brachydactyly B and to proximal symphalangism)

AD

(continued)

858

Limbs

859

Table 20-9. Conditions with carpal or tarsal coalitiona (continued) Condition 55

Waardenburg: anophthalmia

Waardenburg-like (Goodman)56 WL: brachydactyly-symphalangism

57

Major Features

Causation Gene/Locus

(P-P,C-C,T-T,MT-MT,MC-MC) Anophthalmia, syndactyly, oligodactyly, camptodactyly

AR (206920)

(C-C) Deafness, white forelock telecanthus

Uncertain

(P1-P2,C-C,T-T) Hypertelorism, short metacarpals and proximal and middle phalanges (similar to brachydactyly E and Fuhrmann symphalangism)

AD (186500)

a

Single case by Rupps et al.58 (C1-C2 fusion-thrombocytopenia) not listed.

b

Bones affected indicated in parentheses.

skeletal dysplasias for which the gene basis is known (Tables 2010, 20-11, and 20-12). McCredie19 suggests that the fault in synostosis is not intrinsic to the bone or cartilage but rather is caused by impaired sensory nerves, which fail to organize correctly the mesenchymal template on which cartilage and bone will form. Silverman30 suggests that, in some cases, intrauterine pressure may cause synostosis. In only a single known circumstance does congenital synostosis represent fusion of separately formed bones into a compound bone. This is the case of distal syndactyly caused by amniotic band constriction (Fig. 20-18).18 Through some combination of pressure, hemorrhage, and vascular deprivation, soft tissues of the digits may degenerate, bringing previously formed phalanges Table 20-10. Conditions with synostosis of metacarpals or metatarsalsa,b Alopecia-contractures-mental retardation60 Apert (FGFR2, 10q25.3-q26)7,61 Cenani-Lenz syndactyly35 Diastrophic dysplasia (DTDST, 5q32-q33.1)13,62 Fuhrmann: carpal and tarsal coalition-symphalangism (NOG, 17q21-q22)5,6,40 Gonzales: pancytopenia-upper limb reduction63 Grosse: acro-pectoro-vertebral dysplasia42 Hecht: unilateral terminal hand deficiency64 Holzgreve: clefting-renal agenesis65 Jackson-Weiss (FGFR2, 10q25.3-q26)7,46 Multiple synostosis (NOG, 17q21-q22)5,6 Nievergelt mesomelia66 Pfeiffer (FGFR2, 10q25.3-q26; FGFR1, 8p11.2-p12)7 Proximal symphalangism (NOG, 17q21-q22)2–6 Sirenomelia17 Sugiura synpolydactyly-diphalangism67 Syndactyly68 Townes-Brock (SALLI, 16q12.1)69 Waardenburg anophthalmia55 Weyers acrofacial70 X-linked recessive71 a Single reports by Clayton-Smith (unusual facies-ichthyosis-limb defects),72 Figuera et al. (telecanthus-cleft palate-oral frenula-duplicated thumb-absent fibulaabsent nails),73 Martinez (mesial polydactyly-cardiac defects),74 Leiba (ocular defectshypospadias-dysplastic nails),75 Pfeiffer (deafness-hypospadias-mental retardation),76 Ramos Fuentes et al. (trigonocephaly-radial aplasia-absent thumbs-symphalangism),77 and Robinow (micrognathia-oligodactyly) not listed.78 b

Responsible gene and gene locus in parentheses.

(cartilaginous or osseous) into contact, where fusion may occur. This disruptive process may take place at any time after differentiation of the digits. Carpal Coalition and Tarsal Coalition

The failure of articular interzones and joint cavities to partition the wrist and hindfoot completely into the usual carpal and tarsal domains produces a wide variety of carpal and tarsal coalitions.3,24,25 Most frequently, only two carpals or two tarsals are involved, other carpals or tarsals being normally separated by intervening joint spaces. Massive coalition does occur, however, and can involve nearly all of the carpals and tarsals. Not uncommonly, the bones excluded from the coalition have irregular shapes. Carpal and tarsal coalitions occur as isolated phenomena, in association with synostoses elsewhere, and with other skeletal and nonskeletal features (Table 20-9, Figs. 20-19 through 20-23).3–6,15,20,30–58 Simple carpal-carpal and tarsal-tarsal coalitions may be entirely asymptomatic. Multiple carpal-carpal coalitions usually do not impair wrist function, although the wrists may be deviated. Tarsal-tarsal coalitions produce greater morphologic and functional changes. The feet may be flat and may have equinovarus angulation, and there may be limited foot movement, particularly inversion and eversion. Painful ambulation is not uncommon. The ossification centers of bones involved in carpal-carpal or tarsal-tarsal coalition appear separately and at the normal age. Absence of an intervening joint space becomes obvious as the ossification centers enlarge and coalesce. Coalition of the cartilaginous templates of carpal and tarsal bones has been demonstrated in embryos and fetuses via histologic techniques.25 Carpal-carpal coalition and tarsal-tarsal coalition may involve any adjacent bones (Figs. 20-19, 20-20, and 20-21). In the wrist, lunate-triquetrum coalition is most common, occurring in less than 1% of most populations. The incidence among West African populations was found to be 10-fold higher.59 In the foot, calcaneonavicular and talocalcanean coalitions are most common (Fig. 20-20). Nearly all carpal and tarsal coalitions have heritable bases (Table 20-9). Thalidomide exposure is a historically important environmental cause of carpal and tarsal coalitions. Trauma and inflammatory processes may lead to fusions of carpals and tarsals across previously normal joint spaces. Metacarpophalangeal and Metatarsophalangeal Synostosis

Several cases of metacarpophalangeal (MCP) synostosis involving the thumb have been reported. Temtamy and McKusick59 presume that C.S. Lewis had metacarpophalangeal synostosis, basing their presumption on the author’s description of lifelong stiffness at the MCP joint. They described an additional case. This rare synostosis apparently occurs as an isolated entity. A genetic basis has not been

Table 20-11. Conditions with symphalangism* Condition 7,61

Major Features

Causation Gene/Locus {

Apert

(P1-P2,MC-MC,R-U) Craniosynostosis, mitten syndactyly, joint limitation

AD (101200) FGFR2, 10q25.3-q26

Braham: progeroid features with craniodiaphyseal hyperostosis79

(P1-P2) Short stature, progeroid skin, developmental delay, delayed fontanelle closure, choanal atresia, diaphyseal dysplasia

Unknown

Brachydactyly A-180,81

(P2-P3) Short stature, short digits with middle phalanges most severely affected

AD (112500) IHH, 2q35-q36

Brachydactyly B12,82

(P2-P3) Irregular amputation-like shortening of digits 2–5, thumbs broad with bifid distal phalanx, nails small or absent

AD (113000) ROR2, 9q22

Brachydactyly-nail dysplasia83

(P2-P3) Irregular shortening of fingers 2–5, nail hypoplasia or aplasia, feet and thumb normal (possibly same as brachydactyly B)

AD

Diastrophic dysplasia13,62

(P1-P2,MT-MT) Short stature, cleft palate, cystic ears, short limbs, joint limitation, scoliosis, varus feet, hitchhiker thumbs

AR (222600) DTDST, 5q32-q33.1

Distal symphalangism59

(P2-P3)

AD (185700)

Distal symphalangism-absent nails84

(P2-P3) Involves only the index finger, nail may be absent

AD

Fibrodysplasia ossificans progressiva14,85

(P1-P2,P2-P3,MC-P,MT-P) Short thumbs and great toes, heterotopic calcifications in soft tissues, hearing loss

AD (135100) FOP, 4q27-q31

Fuhrmann: carpal and tarsal coalitionsymphalangism5,6,40

(P1-P2,P2-P3,H-R,C-C,MC-MC,T-T,MT-MT) Stiff and painful varus feet

AD (186500) NOG, 17q21-q22

Herrmann: symphalangism-brachydactyly (WL: brachydactyly-symphalangism)86

(P1-P2,C-C,T-T) Absence or hypoplasia of nails, elbow limitation, cutaneous syndactyly, hearing loss

AD (186500)

Kelly: microcephaly-digital anomalies87

(P2-P3) Microcephaly, short metacarpals, syndactyly of toes 2–5

AR (251255)

Kirmisson symphalangism88

(P1-P2,P2-P3,C-C,T-T,T-MT) Absence or hypoplasia of distal phalanges and nails, short first metacarpal, rigid clubfoot, platyspondyly, subluxed radial head

AD

Learman: symphalangism-syndactylybroad thumbs89

(P1-P2) Broad thumbs, hypoplasia of thenar and hypothenar eminences, syndactyly (similar to proximal symphalangism and to brachydactyly D)

AD (185750)

Lenz: progeroid features with craniodiaphyseal hyperostosis90

Same as Braham

Unknown

Multiple synostosis6

(P1-P2,C-C,T-T) Carpal and tarsal coalition

AD (186400) NOG, 17q21-q22

Pearlman5,6,48

Same as proximal symphalangism

AD (186500) NOG, 17q21-q22

Pillay: ophthalmo-mandibulomelic dysplasia91

(P1-P2,P2-P3) Corneal opacities, temporomandibular fusion, radial and ulnar deficiencies

AD (164900)

Pfeiffer7,92

(P1-P2,P2-P3,C-C,T-T,MC-MC,MT-MT,H-R,R-U) Craniosynostosis, broad thumbs and great toes

AD (101600) FGFR2, 10q25.3-q26 FGFR1, 8p11.2-p12

Proximal symphalangism2,5,6

(P1-P2,C-C,T-T,T-MT,MT-P,H-R) Conductive hearing loss

AD (185800) NOG, 17q21-q22

Sillence: distal symphalangism-tall stature-scoliosis93

(P1-P2) Tall stature: short or absent middle phalanges: short and square first phalanges of digits 1, 4, and 5; flat or malformed vertebrae; clubfeet

AD

Sorsby: macula colobomadigital anomalies94

(P1-P2) Macular coloboma, duplication of distal phalanx of thumb and hallux, small nails of fingers 2, short middle phalanx of fifth digit

AD (120400)

Ventruto: craniosynostosissymphalangism54

(P1-P2,C-C,T-T) Absent middle and distal phalanges of ulnar digits, nail absence of hypoplasia, craniosynostosis, hip dysplasia (similar to brachydactyly B)

AD

Wildervanck: symphalangismtalonavicular coalition95

(P1-P2,T-T) Accessory bones of medial midfoot free or fused to navicular (possibly same as proximal symphalangism or talonavicular)

AD

*Single case reports of Blaichman (TE fistula-symphalangism),96 Theodor et al. (accessory testis-symphalangism),97 and Sakati et al. (acrocephalopolysyndactyly-tibial hypoplasia)98 not listed. {

Bones affected indicated in parentheses.

860

Table 20-12. Conditions with synostosis of the long bonesa Condition

Major Features b

Causation Gene/Locus

Abruzzo: cleft palate-coloboma-synostosis

(R-U) Short stature, cleft palate, colobomas, hearing loss, hypospadias (similar to CHARGE syndrome)

XLD or AD (302905)

Alopecia-contractures-mental retardation60

(H-R) Short stature, microcephaly, alopecia, mental retardation, contractures, vertebral synostosis

AR (203550)

Alsing: retinal coloboma-fibular hypoplasia106

(H-R) Retinal coloboma, hip dislocation, fibular hypoplasia, renal disease

AR

Antley-Bixler1,107

(H-R) Craniosynostosis, proptosis, choanal stenosis, downslanting palpebral fissures, bowed ulnas and femurs

AR (207410) POR, 7q11.2

Apert7,61,108

(P1-P2,MC-MC,R-U) Craniosynostosis, mitten syndactyly, joint contractures

AD (101200) FGFR2, 10q25.3-q26

Berant craniosynostosis109

(R-U) Craniosynostosis (possibly same as Antley-Bixler)

AD

Blepharophimosis-radioulnar synostosis110

(R-U) Ptosis, blepharophimosis (similar to fetal alcohol syndrome)

Uncertain

Cenani-Lenz syndactyly35

(R-U,C-C,MC-MC,P-P,MT-MT) Oligodactyly, brachydactyly, syndactyly

AR (212780)

Der Kaloustian: hypotoniaradioulnar synostosis111

(R-U) Macrocephaly, mental retardation, hypotonia

AR (266255)

Facio-auriculo-radial112

(R-U) Short stature, radial oligodactyly, malformed ears, deafness, sinus arrhythmia

AD

Fuhrmann: carpal and tarsal coalition-symphalangism5,6,40

(P1-P2,P2-P3,H-R,C-C,MC-MC,T-T,MT-MT) Stiff and painful varus feet

AD (186500) NOG, 17q21-q22

Giuffre: microcephalyradioulnar synostosis113

(R-U) Microcephaly, syndactyly, cubitus valgus

AD

Humeroradial synostosis102

(H-R,H-R-U) Stiff elbow, short upper limbs, unilateral or bilateral with associated anomalies

Sporadic, AD (143050) AR (236400)

Kantaputra: mesomelic dysplasia114,143

(Ti-T,Fi-T,T-T) Short stature, short forearms, bowed radius

AD (156232) 2q24-q32

Kelly: acrofacial115

(P-P,R-U) Short stature, downslanting palpebral fissures, flat malar area, hearing loss, mental impairment, hypospadias, undescended testes

AR

Multiple pterygium (lethal)116,117

(R-U,H-U,C-C,T-T) Hydrops, fetal cystic hygroma, hypertelorism, cleft lip and palate, pulmonary and cardiac hypoplasia, multiple contractures

AR (253290)

Multiple synostosis5,6

(P1-P2,C-C,T-T) Carpal and tarsal coalition

AD (186400) NOG, 17q21-q22

Nager118

(R-U) Acrofacial dysostosis, radial ray defects

Unknown, some AD (154400)

Nievergelt mesomelia119

(R-U,T-T,T-MT,MT-P) Short stature, short forearms and legs, cutaneous dimples, varus feet, valgus knees, clubfeet, long bones of forearms and legs malformed

AD (163400)

Osteosarcoma-limb anomalieserythroid macrocystosis120

(R-U) Variable features as named in a father and offspring

Unknown

Pasma: elbow contractures101

(H-R-U-T-Fi) Elbow contractures, exostosis of femur

AD (177300)

Pfeiffer7,121

(P1-P2,P2-P3,C-C,T-T,MC-MC,MT-MT,H-R,R-U) Craniosynostosis, broad thumbs and great toes

AD (101600) FGFR2, 10q25.3-q26 FGFR1, 8p11.2-p12

Pitt122

(R-U) Prenatal and postnatal growth retardation, mental retardation, microcephaly, telecanthus, short philtrum, wide mouth

AR (262350)

Prenatal alcohol syndrome20

(C-C,R-U) Growth and mental impairment, short palpebral fissures, smooth philtrum, thin upper lip

Prenatal alcohol exposure

Prenatal fluconazole21

(H-R) Wide sutures, large nose, ear anomalies, dysplastic hips

Prenatal fluconazole exposure

Prenatal thalidomide19

(H-R,R-U,C-C,MC-MC,P-P,T-Fi) Reduction anomalies, absent or hypoplastic auricles, visceral anomalies

Prenatal exposure to thalidomide

Post fracture29

(R-U)

Trauma (continued)

861

862

Skeletal System

Table 20-12. Conditions with synostosis of the long bonesa (continued) Condition

Major Features

Causation Gene/Locus

Radioulnar synostosis, isolated

(R-U) Limited supination and pronation of forearm, usually bilateral if inherited

Sporadic or AD

Roberts123

(H-R) Limb reductions, cleft lip and palate, blonde hair, premature centromere separation

AR (268300)

Say: craniosynostosis124

(R-U) Cloverleaf skull, disorganized hand bones, polydactyly of hands and feet, ribs missing and fused, popliteal web, varus feet

Unknown

Sex chromosome aneuploidy125,126

(R-U) Variable, depending on the chromosome aberration (XYY, XXY, XXXY, XXXXY, XXYY)

Chromosomal

Sirenomelia17

(F-F,T-Fi,T-T,MT-MT) Lower limb symmelia, genital agenesis, imperforate anus, renal agenesis

Sporadic, occasionally maternal diabetes

Stiles: upper limb reduction127

(R-U) Radial oligodactyly, hypoplastic humeri, no heart defect

AD (107900)

Thrombocytopeniaradioulnar synostosis8

(R-U) Symptomatic thrombocytopenia

AR (605432) HOXA11, 7p14-7p15

Tibiofibular, distal129

(T-Fi)

Unknown

Tibiofibular, proximal128

(T-Fi) Genu varum

Unknown

(R-U,C-C,MC-MC,T-T,MT-MT) Split hand, split foot

AR (225300)

16,22,27

Verma: ectrodactyly

104

Walker acrofacial130

Probably same as Nager

AR

X-linked radioulnar synostosis131

(R-U) Females with radial defects, one male with absent radius, oligodactyly, anencephaly, renal agenesis

XLD

a Single reports by Cohen (H-R synostosis-anosmia-holoprosencephaly),132 DiBella et al. (H-R synostosis-ulnar agenesis-oligodactyly),133 Glass et al. (H-R-U synostosis-cleft palate-brain anomalies),134 Lacheretz et al. (C-C, H-R synostosiscraniosynostosis),135 Park et al. (H-U synostosis-ambiguous genitalia-symphalangism),136 Samson and Graham (R-H synostosiscraniosynostosis-hydranencephaly-absent thumbs),137 and Tamari and Goodman (R-U synostosis-heart defects )138 not listed. b

Bones involved indicated in parentheses.

documented except in fibrodysplasia ossificans progressiva, where MCP synostosis may occur in the thumb and great toe.14 Symphalangism may occur concurrently in these digits as well (Fig. 20-23). Fibrodysplasia ossificans progressiva is an autosomal dominant condition, although most cases are sporadic, perhaps representing new mutations. Proximal Symphalangism

In proximal symphalangism, the proximal interphalangeal (PIP) joints of digits 2 to 5 fail to develop or are markedly hypoplasFig. 20-18. Distal syndactyly associated with amniotic bands. This is the only circumstance in which phalanges formed separately may fuse into a syndactylous compound bone.

tic.2,5,6,26,27 The surrounding phalanges eventually unite as shown radiographically and are fixed in extension or a mild degree of flexion (Fig. 20-24). Movement of the MCP joint and the distal interphalangeal (DIP) joint occurs normally, but metatarsal-phalangeal movement may be restricted. The fifth finger appears to be involved most consistently and with greatest severity. The thumbs and great toes are not affected. Affected digits lack flexion and extension creases over the affected joint and may be shortened. Involvement is clinically obvious from birth. The toes are less commonly affected. Fusion of the middle and distal phalanges of the toes occurs more commonly than proximal symphalangism. Synostoses of bones other than the phalanges occur concurrently in proximal symphalangism. Carpal bones may have unusual configurations, and carpal-carpal coalitions are common. The first metacarpal may be short, with blunting of the distal aspect. Some patients have shortening of the distal radius. Talonavicular coalition occurs in most patients. Other tarsal-tarsal fusions and tarsal-metatarsal and metatarsal-phalangeal synostoses occur as well. Foot involvement, which occurs in almost all persons with proximal symphalangism, causes greater difficulty than does hand involvement. The feet are flat and have limited movement because of the tarsal and metatarsal synostoses. Pressure points arise over bony prominences of the medial and lateral midfoot. Gait disturbance and foot pain are not uncommon. Conduction hearing loss is a common feature in proximal symphalangism, having its onset during the first couple of years of life.2 Hearing loss is variable and is due to synostosis of the stapes and petrous bone. Serial radiographs show that the epiphyses of the middle phalanges appear at the normal time. The epiphyses expand at the

Limbs

863

Fig. 20-19. Schematics of bones of hand and foot (left) with locations of reported carpal–carpal and tarsal–tarsal coalescence indicated by solid bars (right).

expense of the joint space and unite with the proximal phalanges. Fusion of the epiphysis and its phalanx during adolescence completes the osseous union of the two phalanges. These stages of osseous union may not be obvious in digit 5, where the proximal and middle phalanges appear to unite directly, without an intervening epiphysis. The medullary canal of the compound phalanx of digit 5 may appear continuous, and the diaphysis may be remodeled to resemble a single phalanx. A vestige of the joint may persist in synostoses involving digits 2 to 4, appearing as a localized widening of the diaphysis, with cortical thinning in the distal half of the compound phalanx. In some instances, bony bridging between two phalanges never occurs, but joint movement is nevertheless restricted because of severe hypoplasia of the joint. Proximal symphalangism is an autosomal dominant condition (Fig. 20-24). The extensive pedigree published by Cushing26

and updated by Strasburger et al.2 includes 351 affected persons in 10 generations. The condition has been identified among various ethnic groups. Males and females show similar expression. Mutations in NOG have been demonstrated in a number of families.5,6 Fuhrmann carpal-tarsal coalition-symphalangism and multiple synostosis syndrome have NOG mutations as well and hence are allelic synostosis entities.5,6,40 Synostosis of the proximal and middle phalanges also occurs in several malformation syndromes (Table 20-11).2,5,6,7,61–98 No cases with prenatal environmental causation are recognized. Distal Symphalangism

Although fewer cases of distal symphalangism have been described, it appears to be a distinct entity.99 The middle and distal phalanx are involved, and the middle phalanx is usually short.

864

Skeletal System

Fig. 20-21. Carpal coalescence. Multiple carpal–carpal coalitions and carpal–metacarpal coalition in a 17-year-old male with Poland syndrome (unilateral symbrachydactyly and breast hypoplasia). (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston.)

proximal symphalangism, that is, failure of development of the DIP joint. Humeroradial Synostosis

Fig. 20-20. Tarsal coalescence. Talonavicular coalition (top, arrowhead), calcaneotalar coalition (middle, arrowhead), and cuneiform coalition (bottom, arrowhead). (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Fingers 2 and 5 are involved most commonly, but considerable variability is found (Fig. 20-25). The DIP joints are stiff from birth, although osseous continuity may not be demonstrable radiographically until the age of epiphyseal closure. Toes are also affected in distal symphalangism, but it may involve any of the phalanges. Synostosis elsewhere is not reported. Distal phalangism is inherited as an autosomal dominant condition. The pathogenesis is considered to be the same as in

Although humeroradial synostosis likely represents a segmentation defect dating from the embryonic period, it is possible that in some cases cartilaginous segmentation occurs normally but is followed by obliteration of the humeroradial joint space. The appearance of humeroradial synostosis is variable, depending on the degree of flexion at the elbow (Fig. 20-26).1,19,100–103 Synostosis in extension causes a short and rigid limb, with little demarcation of the arm and forearm. The ulna may be involved in the synostosis or may remain as a separate hypoplastic bone.100 Synostosis also occurs in various degrees of flexion. In these cases the head of the radius may appear united with the side of the distal humerus. Humeroradial synostosis is typically seen in the Antley-Bixler syndrome.1 Other features of this recessive condition include craniosynostosis with brachycephaly, midface retraction with choanal stenosis, proptosis, femoral bowing, and multiple joint contractures. Humeroradial synostosis has also been found in association with oligodactyly and as an isolated entity.19,102,103 Hunter et al.102 found that sporadic cases were more likely to be unilateral (65%), to be accompanied by ulnar hypoplasia (62%), and to entail hand anomalies including oligodactyly (77%). Dominantly transmitted cases were bilateral and often included hand anomalies without oligodactyly. Recessively transmitted humeroradial synostosis was usually bilateral (91%) and did not include hand malformations, but there was an increased incidence of anomalies elsewhere. Thalidomide was an important cause of humeroradial synostosis in the 1950s and 1960s.19 Caffey described a case of humeroradial synostosis, which he attributed to faulty fetal position.30

Limbs

865

Fig. 20-22. Tarsometatarsal synostosis (cuneiform 2–metatarsal 2 and cuneiform 3–metatarsal 3) in a 6-year-old male with otopalatodigital syndrome. Bottom radiographs show a proximal ossification center in metacarpal 2. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston.)

It appears unlikely that pressure alone could cause fusion across a joint space that was normally formed. Radioulnar Synostosis

Failure of the complete longitudinal separation of the cartilaginous bars of the embryonic radius and ulna or fusion after separation results in radioulnar synostosis. The usual site of synostosis is the proximal radioulnar joint. Bony connection between the two bones extends distally for variable distances, usually not beyond the proximal one-third of the bone (Fig. 20-27).16,22,29 In a case reported by Verma et al.,104 the radius and ulna were united along the entire length. Radioulnar synostosis may be suspected clinically from limitation of forearm supination. Longitudinal bone growth is not notably impaired. Two types of

Fig. 20-23. Synostoses of the hands and feet in a 13-year-old girl with fibrodysplasia ossificans progressiva. Top: Carpal–carpal and carpometacarpal (arrow) synostoses. Middle: Tarsal–tarsal and tarsal–metatarsal synostoses. Bottom: Symphalangism affecting digits 1, 4, and 5 of the feet.

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noted with sex chromosomal aberrations in males.125,126 Thalidomide and alcohol exposures are the only prenatal environmental insults known to produce radioulnar synostosis.19 Postnatally, trauma is a recognized cause. Males appear to be more commonly affected, even with the familial autosomal dominant variety. Bilateral involvement is more common than unilateral involvement. Tibiofibular Synostosis

Both proximal and distal synostoses of the tibia and fibula have been reported.128,129 Involvement may be unilateral or bilateral and is confined to a small segment near the ends of the bones. Proximal tibiofibular synostosis is associated with genu valgum. Tibiofibular synostosis has occurred as an isolated sporadic condition. It has also been noted commonly following prenatal thalidomide exposure. McCredie19 found tibiofibular synostosis in 20 of 59 (39%) children malformed by thalidomide. Synostoses involving other bones were common among these children. Sirenomelia

Fig. 20-24. Proximal symphalangism in a 5-year-old girl. Although symphalangism affects digits 2–5, the process appears more complete in digit 5 at this age. Eight other family members were affected with this autosomal dominant anomaly.

proximal radioulnar synostosis are discussed in the literature.29 In one type the radial head is normally placed, and in the other it is dislocated. Since both types have been seen in the same family, the causation and pathogenesis are likely the same in the two variants. This most common form of long bone synostosis may be seen as an isolated autosomal dominant anomaly, as an isolated sporadic defect, or as a component of several syndromes (Table 2012).8,16,17,19–22,27,35,60,61,105–138 A particular association has been Fig. 20-25. Distal symphalangism affecting digit 3 in an adult female.

Symmelia is a limb anomaly in which the normally paired limbs are replaced by a single midline limb.17,139 This malformation affects almost exclusively the lower limb, in which case it is also known as sirenomelia or mermaid malformation (Fig. 20-28). Symmelia of the upper limb occurs only in conjoined twins when one limb is incompletely separated.140 In an analogous situation, incomplete twinning of the caudal portion of the embryo can result in an accessory symmelic limb. These twinning anomalies are discussed in Chapter 34. The diagnosis in sirenomelia is rarely in doubt because of the central placement of the lower limb and the consistent concurrence of other anomalies. Unilateral limb agenesis or a proximal amputation results in a single lower limb, but the remaining limb is clearly lateralized in these cases. Accompanying malformations are helpful in diagnosis. Almost without exception, genitourinary and gastrointestinal malformations are present in sirenomelia, as are features secondary to oligohydramnios.17,139 The single lower limb in sirenomelia may vary markedly in morphology. In the most severe form, the limb appears as a tapering appendage, without segmentation or ray formation. In the mildest form, only a soft tissue web connects the thighs, with the morphology of the legs and feet appearing normal. Most commonly the appearance falls somewhere between these two extremes of severity (Fig. 20-28). The presence of other skeletal and nonskeletal anomalies is the rule in sirenomelia. Cardiac defects, most commonly ventriculoseptal defects, occur in one-fourth of infants.17 Lung hypoplasia is almost constant, a consequence of oligohydramnios. The lungs may be abnormally lobated, and tracheoesophageal fistula and diaphragmatic hernia have been reported. The gastrointestinal system is abnormal in all cases. One-third of all cases have upper gastrointestinal anomalies, including Meckel diverticulum, agenesis of the gall bladder, and duodenal atresia. All cases have agenesis of the terminal colon, with imperforate anus. Renal agenesis occurs in two-thirds of cases, and the balance of cases have renal dysplasia. The ureters and urinary bladder are usually absent and when present are hypoplastic. Gonads can be identified, often bilaterally, in about 80% of cases. Hands appear large and spade shaped, a configuration often seen in association with oligohydramnios. Fifteen percent of cases have reduction malformations of the upper limbs. Characteristically the umbilical cord has a single artery and major anomalies of the abdominal arterial system are present.

Limbs

Fig. 20-26. Humeroradial synostosis in a 33-month-old. Each upper limb terminates in two digits, with one appearing thumb-like. Radiograph shows humeroradial synostosis with hypoplastic ulna.

Fig. 20-27. Radioulnar synostosis. Proximal synostosis in a 4-year-old male (left) and near complete synostosis in an adult with mental retardation and congenital hip dysplasia (right). (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

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Fig. 20-28. Sirenomelia. Three infants with sirenomelia and associated defects. One infant (top left) has termination of the lower limb in two digits. One infant (top right) has gastroschisis and single foot with 10 digits. One infant (bottom) has omphalocele, lumbosacral meningocele, and incompletely separated feet.

All cases of sirenomelia are sporadic, and no genetic factors have been implicated in the causation. Sirenomelia and other anomalies of caudal development have been seen in association with maternal diabetes mellitus. Development of the caudal end of the embryo is disturbed such that pelvic structures are deficient and the lower limb forms as a single midline structure. Stevenson et al.141 attribute this to a vascular steal in which nutrients necessary to support caudal development are diverted to the placenta. Sirenomelia occurs with an incidence of one in 25,000 to 50,000 births, and male cases outnumber females. An increased frequency has been noted among monozygous twins. In most cases, only one of the twins is affected.

Virtually all infants with sirenomelia are stillborn or die in the immediate neonatal period. This is secondary to renal agenesis and lung hypoplasia. The potential for survival is present when kidneys are formed and are not severely dysplastic. In the single case of survival into childhood, the symmelic limb was separated by surgery during the 1st year of life.142 References (Synostosis) 1. Robinson LK, Powers NG, Dunklee P, et al.: The Antley-Bixler syndrome. J Pediatr 101:201, 1982. 2. Strasburger AK, Hawkins MR, Eldridge R, et al.: Symphalangism: genetic and clinical aspects. Bull Johns Hopkins Hosp 117:108, 1965.

Limbs 3. Brunet LJ, McMahon JA, McMahon AP, et al.: Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Nature 280:1455, 1998. 4. Gong Y, Krakow D, Marcelino J, et al.: Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21:302, 1999. 5. Dixon ME, Armstrong P, Stevens DB, et al.: Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med 3:349, 2001. 6. Takahashi T, Takahashi I, Komatsu M, et al.: Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet 60:447, 2001. 7. Cohen MM Jr: Fibroblast growth factor receptor mutations. In: Craniosynostosis: Diagnosis, Evaluation and Management, ed 2. MM Cohen Jr, RE MacLean, eds. Oxford University Press, New York, 2000, p 77. 8. Thompson AA, Nguyen LT: Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet 26:397, 2000. 9. Muragaki Y, Mundlos S, Upton J, et al.: Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 272:548, 1996. 10. Debeer P, Schoenmakers EFPM, Twal WO, et al.: The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. J Med Genet 39:98, 2002. 11. Kornak U, Mundlos S: Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73:447, 2003. 12. Afzal AR, Rajab A, Fenske CD, et al.: Recessive Robinow syndrome, allelic to brachydactyly type B is caused by a mutation of ROR2. Nat Genet 25:419, 2000. 13. Rossi A, Superti-Furga A: Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat 17:159, 2001. 14. Se´monin O, Fontaine K, Daviaud C, et al.: Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva. Am J Med Genet 102:314, 2001. 15. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 16. Hansen OH, Andersen NO: Congenital radio-ulnar synostosis. Report of 37 cases. Acta Orthop Scand 41:225, 1970. 17. Stocker JT, Heifetz SA: Sirenomelia: a morphological study of 33 cases and review of the literature. Perspect Pediatr Pathol 10:7, 1987. 18. Torpin R: Fetal Malformation Caused by Amnion Rupture During Gestation. Charles C Thomas Publisher, Springfield, IL, 1968. 19. McCredie J: Congenital fusion of bones: radiology, embryology, and pathogenesis. Clin Radiol 26:47, 1975. 20. Pauli RM, Feldman PF: Major limb malformations following intrauterine exposure to ethanol: two additional cases and literature review. Teratology 33:273, 1986. 21. Aleck KA, Bartley DL: Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 72:253, 1997. 22. Wilkie DPD: Congenital radioulnar synostosis. Br J Surg 1:366, 1914. 23. Swinyard CA, Pinner B: Some morphological considerations of normal abnormal human limb development. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969, p 2. 24. O’Rahilly R, Gardner E, Gray DJ: The skeletal development of the hand. Clin Orthop 13:42, 1959. 25. O’Rahilly R: A survey of carpal and tarsal anomalies. J Bone Joint Surg 35A:626, 1953. 26. Cushing H: Hereditary ankylosis of the proximal interphalangeal joints. Genetics 1:90, 1916. 27. Steinberg AG, Reynolds EL: Further data on symphalangism. J Hered 39:23, 1948.

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80. Farabee WC: Inheritance of digital malformations in man. In: Papers of the Peabody Museum of American Archeology and Ethnology, vol 3. Harvard University Press, Cambridge, 1905, p 69. 81. Gao B, Guo J, She C, et al.: Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet 28:386, 2001. 82. Fitch N: Classification and identification of inherited brachydactylies. J Med Genet 16:36, 1979. 83. Schott GD: Hereditary brachydactyly with nail dysplasia. J Med Genet 15:119, 1978. 84. Daniel GH: A case of hereditary anarthrosis of the index finger, with associated abnormalities in the proportions of the fingers. Ann Eugen 8:231, 1936. 85. Schroeder HWJ, Zasloff M: The hand and foot malformations in fibrodysplasia ossificans progressiva. Johns Hopkins Med J 147:73, 1980. 86. Herrmann J: Symphalangism and brachydactyly syndrome: report of the WL symphalangism-brachydactyly syndrome: review of literature and classifications. Birth Defects Orig Artic Ser X(5):23, 1974. 87. Kelly TE, Kirson L, Wyatt J: Microcephaly and digital anomalies: a newly recognized syndrome of recessively inherited mental retardation. Am J Med Genet 45:353, 1993. 88. Kirmisson E: Double Pied bot varus, associe´ a` des Ankyloses conge´nitales des Doigts et des Orteils chez quatre Membres d’une meˆme Famille. Rev Orthop 9:392, 1898. 89. Learman Y, Katznelson MBM, Bonne-Tamir B, et al.: Symphalangism with multiple anomalies of the hands and feet: a new genetic trait. Am J Med Genet 10:245, 1981. 90. Lenz WD, Majewski F: A generalized disorder of the connective tissues with progeria, choanal atresia, symphalangism, hypoplasia of dentine and craniodiaphyseal hyperostosis. Birth Defects Orig Artic Ser X(12): 133, 1974. 91. Pillay VK: Ophthalmo-mandibulo-melic dysplasia. J Bone Joint Surg 46A:858, 1964. 92. Vanek J, Losan F: Pfeiffer’s type of acrocephalosyndactyly in two families. J Med Genet 19:289, 1982. 93. Sillence DO: Brachydactyly, distal symphalangism, scoliosis, tall stature, and club feet: a new syndrome. J Med Genet 15:208, 1978. 94. Sorsby A: Congenital coloboma of macula, together with an account of the familial occurrence of bilateral macular coloboma in association with apical dystrophy of the hands and feet. Br J Ophthalmol 19:65, 1935. 95. Wildervanck LS, Goedhard G, Meijer S: Proximal symphalangism of fingers associated with fusion of os naviculare and talus and occurrence of two accessory bones in the feet (os paranaviculare and os tibiale extemum) in an European-Indonesian-Chinese family. Acta Genet 17: 166, 1967. 96. Blaichman S: Tracheoesophageal fistula, protruding pinnae, proximal interphalangeal symphalangism of fifth finger. A new syndrome? Am J Med Genet 13:233, 1982. 97. Theodor R, Hertz M, Goodman RM: Symphalangism, short stature, skeletal anomalies, and accessory testis: a new malformation syndrome. J Med Genet 16:159, 1979. 98. Sakati N, Nyhan WL, Tisdale WK: A new syndrome with acrocephalopolysyndactyly, cardiac disease, and distinctive defects of the ear, skin and lower limbs. J Pediatr 79:104, 1971. 99. Inman OL: Four generations of symphalangism. J Hered 15:329, 1924. 100. Hersh JH, Joyce RM, Profumo LE: Humero-radio-ulnar synostosis: a new case and review. Am J Med Genet 33:170, 1989. 101. Pasma A, Wildervanck LS: Hereditary occurrence of congenital rigidity of the elbows and knees (congenital multiple ‘pseudoarthro gryposis’). Arch Chir Neerl 8:43, 1956. 102. Hunter AGW, Cox DW, Rudd NL: The genetics of and associated findings in humero-radial synostosis. Clin Genet 9:470, 1976. 103. Ramer JC, Ladda RI: Humero-radial synostosis with ulnar defects in sibs. Am J Med Genet 33:176, 1989. 104. Verma IC, Joseph R, Bhargava S, et al.: Split-hand and splitfoot deformity inherited as an autosomal recessive trait. Clin Genet 9:8, 1976.

Limbs 105. Abruzzo MA, Erickson RP: A new syndrome of cleft palate associated with coloboma, hypospadias, deafness, short stature, and radial synostosis. J Med Genet 14:76, 1977. 106. Alsing A, Christensen C: Atypical macular coloboma (dysplasia) associated with familial juvenile nephronophthisis and skeletal abnormality. Ophthalmol Paediatr Genet 9:149, 1988. 107. Kelley RI, Kratz LE, Glaser RL, et al.: Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. Am J Med Genet 110:95, 2002. 108. Hoover GH: The hand and Apert’s syndrome. J Bone Joint Surg 52A: 878, 1970. 109. Berant M, Berant N: Radioulnar synostosis and craniosynostosis in one family. J Pediatr 83:88, 1973. 110. Jorgenson RJ, Lenz W, Uzielli MLG: Case report 110. J Clin Dysmorphol 1:14, 1983. 111. Der Kaloustian VM, McIntosh N, Silver K, et al.: Unilateral radioulnar synostosis, generalized hypotonia, developmental retardation, and a characteristic facial appearance in sibs: a new syndrome. Am J Med Genet 43:942, 1992. 112. Harding AE, Hall CM, Baraitser M: Autosomal dominant asymmetrical radial dysplasia, dysmorphic facies, and conductive hearing loss (facioauriculoradial dysplasia). J Med Genet 19:110, 1982. 113. Giuffre L, Corsello G, Giuffre M, et al.: New syndrome: autosomal dominant microcephaly and radio-ulnar synostosis. Am J Med Genet 51:266, 1994. 114. Kantaputra PN, Gorlin RJ, Langer LO Jr.: Dominant mesomelic dysplasia, ankle, carpal, and tarsal synostosis type: a new autosomal dominant bone disorder. Am J Med Genet 44:730, 1992. 115. Kelly TE, Cooke RJ, Kesler RW: Acrofacial dysostosis with growth and mental retardation in three males, one with simultaneous HermanskyPudlak syndrome. Birth Defects Orig Artic Ser XIII(3B):45, 1977. 116. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809, 1984. 117. Van Regemorter N, Wilkin P, Englert Y, et al.: Lethal multiple pterygium syndrome. Am J Med Genet 17:827, 1984. 118. Bowen P, Harley F: Mandibulofacial dysostosis with limb malformations (Nager’s acrofacial dysostosis). Birth Defects Orig Artic Ser X(5): 109, 1974. 119. Solonen KA, Sulamaa M: Nievergelt syndrome and its treatment. A case report. Ann Chir Gynaecol Fenn 47:142, 1958. 120. Mulvihill JJ, Gralnick HR, Whang-Peng J: Multiple childhood osteosarcomas in an American Indian family with erythroid macrocytosis and skeletal anomalies. Cancer 40:3115, 1977. 121. Saldino RM, Steinbach HL, Epstein CJ: Familial acrocephalosyndactyly (Pfeiffer syndrome). Am J Roentgenol Radium Ther Nucl Med 116: 609, 1972. 122. Donnai D: Brief clinical report: a further patient with the Pitt-RogersDanks syndrome of mental retardation, unusual face, and intrauterine growth retardation. Am J Med Genet 24:29, 1986. 123. Ro¨mke C, Froster-Iskenius U, Heyne K, et al.: Roberts syndrome and SC phocomelia. A single genetic entity. Clin Genet 31:170, 1987. 124. Say B, Poznanski AK: Cloverleaf skull associated with unusual skeletal anomalies. Pediatr Radiol 17:93, 1987. 125. Cleveland WW, Arias D, Smith GF: Radioulnar synostosis, behavioral disturbance, and XYY chromosomes. J Pediatr 74:103, 1969. 126. Jancu J: Radioulnar synostosis: a common occurrence in sex chromosomal abnormalities. Am J Dis Child 122:10, 1971. 127. Stiles KA, Dougan P: A pedigree of malformed upper extremities showing variable dominance. J Hered 31:65, 1940. 128. Bergmann E: Congenital tibiofibular synosteosis. J Int Coll Surg 4:359, 1941. 129. Grobelski M: Die angeborene tibiofibulare synostose am distalen Ende des Unterschenkels. Arch Orth Unfall-Chir 57:190, 1965. 130. Walker FA: Apparent autosomal recessive inheritance of the Treacher Collins syndrome. Birth Defects Orig Artic Ser X(8):135, 1974.

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131. Manouvrier S, Moerman A, Coe¨sler A, et al.: Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new X-linked dominant multiple congenital anomalies syndrome? Am J Med Genet 90:351, 2000. 132. Cohen MM Jr.: Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and syndromology. Teratology 40:211, 1989. 133. Di Bella D, Di Stefano G, Romeo MG, et al.: Upper limb cardiovascular syndrome with ulna agenesis (abstract). Pediatr Radiol 14:259, 1984. 134. Glass IA, Walford-Moore J, Chapman S, et al.: Ear anomalies, clefting and limb reduction defects: a new autosomal recessive condition? Clin Dysmorphol 3:150, 1994. 135. Lacheretz M, Walbum OW, Tourgis R: L’ Acrocephalo-synankie. A propos d’une observation avec synostoses multiples. Pediatrie 29:169, 1974. 136. Park IJ, Jones HW, Melhem RE: Nonadrenal familial female hermaphroditism. Am J Obstet Gynecol 112:930, 1972. 137. Samson G, Gardner JC: Craniosynostosis, microcephaly, hydrancephaly, humero-radial synostosis, and thumb aplasia: a new syndrome? Am J Med Genet 61:174, 1996. 138. Tamari I, Goodman RM: Upper limb-cardiovascular syndromes: a description of two new disorders with a classification. Chest 65:632, 1974. 139. Kampmeier OF: On sireniform monsters, with a consideration of the causation and the predominance of the male sex among them. Anat Rec 34:365, 1927. 140. Hamon A, Dinno N: Dicephalus dipus tribrachius conjoined twins in a female infant. Birth Defects Orig Artic Ser XIV(6A):213, 1978. 141. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 142. Savader S, Savader BL, Clark RA: Sirenomelia without Potter syndrome: MR characteristics. J Comput Assist Tomogr 13:689, 1989. 143. Fujimoto M, Kantaputra PN, Ikegawa S, et al.: The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32. J Hum Genet 43:32, 1998.

20.3 Constriction Rings Definition

Constriction rings are soft tissue depressions that encircle any portion of the limb. Congenital constriction rings usually affect multiple sites, often contain fibrous bands in their depths, and may be associated with other disruptions of the face, trunk, and limbs. Acquired constriction rings affect the digits exclusively and may be caused by infection, inflammation, and trauma. Nonconstricting rings may be associated with obesity and shortlimb skeletal dysplasias. Diagnosis

Constriction rings are diagnosed by direct examination.1–6 They are readily apparent at birth. The soft tissue depressions completely encircle the involved portion of the limb and vary from hair size to several centimeters in width (Figs. 20-29 and 20-30). Rings associated with coils of the umbilical cord or thick ropes of amnion and those of the proximal part of the limbs tend to be wider. Constriction rings occur most commonly on the digits but may also involve the proximal or middle limb segments, neck, craniofacies, and trunk. Multiple constriction rings occur more commonly than single rings, and multiple limbs are involved more often than a single limb. Other disruptions and deformations are commonly found in association with constriction rings; some of these are caused by tissue bands, and others result from oligohydramnios and fetal compression following amnion rupture (see

872

Skeletal System Table 20-13. Frequency of various anomalies associated with amniotic bands* Torpin1 (400 cases)

Patterson4 (52 cases)

Baker and Rudolph3 (13 cases)

Constriction rings (%)

—

100

77

Amputations

10

4

62

Syndactyly

26

8

38

Lymphedema

—

6

—

Clubfoot

32

19

31

Craniofacial fissure

33

8

15

9

—

0

1:5,000–15,000

1:15,000

1:10,000

Umbilical cord constriction Estimated incidence

*Frequencies given as percentages.

Fig. 20-29. Broad constriction ring encircling arm in a 5-year-old female.

Table 20-13).1,3,4 Amputations, craniofacial clefts and lobations, skin defects, autotransplanted tags, body wall defects, syndactyly, and club-foot may be seen. Rarely, the ear or penis is involved. In one-third of cases with evidence of amnion rupture, craniofacial involvement can be seen.1–6 This results primarily from the swallowing of strands of amnion. With continued swallowing, the fetus may be drawn along the amniotic tether to the placenta, to which the craniofacies or other body parts may adhere, and the fetus may twist on the tether, sustaining lacerations of the face and unusual lobations of the head (Fig. 20-31). Early amnion rupture has been associated with a variety of body wall defects.1,5–9 Prenatal growth impairment, major limb deficiencies, short umbilical cord, scoliosis, and other postural deformities commonly accompany the body wall defect. Neural tube defects, facial clefts, placentofetal adhesions, and constriction rings are found in one-half of cases. Fig. 20-30. Amputations and constriction rings of digits secondary to amniotic bands. Note narrow constriction rings on left fourth finger and left third toe.

Constriction rings represent one stage in a process of pathologic compression of the limb. They may exist merely as cutaneoussoft tissue depressions, with the distal portion of the limb having normal size and function. If vascular impairment has occurred, the segment distal to the constriction may be undergrown; if lymphatic and venous obstruction is blocked, the distal segment may be swollen with tissue fluid (Fig. 20-32). Necrosis and amputation occur with further strangulation of blood supply (Fig. 20-33). The skin covering ring constrictions usually has normal microscopic appearance, although it may be thin.4 Underlying soft tissues are deficient or absent altogether. In some constriction rings, there are areas of cutaneous ulcerations and fibrosis. Abnormalities of the fetal membranes should be anticipated whenever constriction rings are found.1 The amnion may be frayed, with strands partially separated from the membrane, or the amnion may be completely separated from the chorion. In the latter circumstance, the amnion is usually collapsed about the placental attachment of the umbilical cord. Strands of amnion are easily demonstrated by immersion of the fresh placenta and membranes in a container of water. Very few findings are likely to be confused with constriction rings. In the extremely obese infant, deep skin creases may be seen along the limbs (Fig. 20-34). A related example is the so-called ‘‘Michelin Tire Baby’’ in which there may be some underlying muscle, adipose, or other soft tissue pathology.10–12 Deep creases also may separate folds of soft tissue in limbs that are unusually short. This is seen particularly in achondroplasia, thanatophoric dysplasia, and other skeletal dysplasias with rhizomelic shortening (Figs. 20-35).11 In neither circumstance do the creases completely encircle the limb, nor are they associated with fibrous bands or evidence of vascular compromise to the distal part. Hypoplastic fingers and extra digits often are constricted at their attachment to the hand, but these rarely pose diagnostic difficulties. Greater diagnostic confusion arises when facial fissures, neural tube defects, and body wall defects are a part of the clinical presentation.2,5,6 Likewise, the Adams-Oliver syndrome, an autosomal dominant condition with scalp defects and reduction anomalies of the toes, may be confused with amniotic disruptions.13 Postnatally acquired constriction rings of the digits, sometimes resulting in autoamputation, have been described as an isolated phenomenon and as a complication of a number of medical conditions. Presumably, some underlying vascular or neurologic pathology, inflammation, infection, injury, and fibrosis may be contributing factors. Isolated constriction rings, usually but not

Limbs

873

Fig. 20-31. Encephalocele, cranial lobation, and oral clefting secondary to amniotic bands in a 2-week-old female. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.) Newborn infant on right shows cranial attachment to placenta, digital amputations with bands attached to fetal membranes, and left oral cleft.

exclusively of the fifth toe, may develop in childhood or adult life.14 The underlying pathologic basis is not known, but familial recurrences are well-known as is a predilection among Brazilians of African descent. The term ‘‘ainhum’’ is best reserved for this isolated and acquired phenomenon. Acquired constriction rings of the digits have been associated with several dermatologic disorders, notably the mutilating palmoplantar keratodermas (Olmsted, Vohwinkel, Mal de Meleda, and deafness-associated types).15–18 Patients with sensory and autonomic neuropathy may develop constriction rings of the digits, presumably the result of soft tissue injury. Certain infections (leprosy, yaws, and syphilis) may also result in acquired constriction rings of the digits. Etiology and Distribution

The cause of constriction rings remains controversial. Most observers accept the view that they result from encirclement of the limb by strands of amnion.1–3 These strands arise from tears in the amniotic membrane and float freely or partially freely in the amniotic fluid. Various parts of the anatomy may become entangled in the strands, resulting in injury. Digits are most commonly affected. In the absence of vascular impairment, the limb encircled by an amniotic band continues to grow normally except for the soft tissues adjacent to the band. All of the anomalies seen in association with constriction rings have been related to amnion tears or rupture.1–6 Encircling bands may produce limb hypoplasia, edema, and amputation as well as syndactyly and pseudopolydactyly (Fig. 20-18). Strands of amnion are sometimes swallowed by the fetus. If the swallowed band is not attached, it may pass innocuously through the gastrointestinal system or can be retrieved from the infant’s mouth at

Fig. 20-32. Marked edema from obstructed venous return caused by constriction ring at the ankle in an infant with amniotic band disruptions.

birth. If the amnion is attached, the fetus becomes tethered and may sustain remarkable tissue lacerations, adhesions, and lobations of the craniofacies. Clubfoot, clubhand, and lung hypoplasia have been related to oligohydramnios following amnion rupture, and severe body wall defects have resulted from mechanical forces attending early amnion rupture.5–9 The causes of amnion rupture are not certain. The association with other pregnancy events or with maternal and fetal diseases is uncommon however (Table 20-14). Trauma may play a role in some cases. Torpin1 and Ossipoff and Hall2 found an increased incidence of nonpenetrating abdominal trauma among their cases.

874

Skeletal System

Fig. 20-33. Amputation of right leg and foot secondary to amniotic bands in a newborn infant. Amputated distal leg and foot were not found.

Although a few cases of amniotic bands have been noted in association with amniocentesis, the procedure does not appear to be a frequent cause of amnion rupture.19,20 Abnormalities of placental collagen have also been suggested as a cause of amnion rupture; such abnormalities have not been demonstrated in cases of amniotic bands and would seem unlikely because of the rarity of familial cases. This notwithstanding, several cases of epidermolysis bullosa, osteogenesis imperfecta, and Ehlers-Danlos syndrome have been associated with amniotic bands.21–24 Donnai and Winter have suggested that the mutations in the human homolog of the mouse mutant disorganization may be responsible for some cases of amnion rupture.25

Fig. 20-34. Skin creases on thighs and forearms of healthy infant. The creases do not completely encircle the limbs.

Fig. 20-35. Deep skin creases on upper limbs of infant with thanatophoric dysplasia.

Numerous investigators have denied that amniotic bands have any causal relationship to constriction rings, amputations, and other associated anomalies.4,9,26–28 Streeter26 favored the concept that the affected areas were defective from the outset of embryogenesis. Focal areas of defective tissue, he felt, sloughed during intrauterine life, leaving healed grooves and amputation stumps. Ring constrictions, amputations, and other limb anomalies have been produced in rat fetuses by artificial rupture of amnion.29–31 Houben29 demonstrated hemorrhage into the limb, with subsequent necrosis and tissue resorption, to be the sequence of changes initiated by the amnion rupture. Van Allen et al.9 favor the concept that bands and constriction rings in humans arise by adherence of amnion to the embryo in areas of posthemorrhagic necrosis. Lockwood et al.27 suggested that tissue hemorrhage is the primary event leading to constriction rings and amputations and that the fibrous bands found in association with these defects are late reparative phenomena of little or no causal importance. Constriction rings and associated anomalies have low recurrence risk. Although several familial cases have occurred, these may represent coincidence.27,32 Ossipoff and Hall2 found amniotic bands in one of every 1200 births in a San Francisco hospital over a 5-year period. Others have not found the incidence to be this high (Table 20-13).

Table 20-14. Entities associated with constriction rings of the limbs Congenital

Acquired 40

Ainhum14

Adams-Oliver

5

Palmoplantar keratosis15–18,38

Amnion rupture

21

Epidermolysis bullosa

Sensory neuropathy 24

Ehlers-Danlos syndrome

Leprosy

Osteogenesis imperfecta22,23

Syphilis

Septo-optic dysplasia35

Trauma

Abdominal trauma1,2 Human ‘‘disorganization’’25 Congenital heart defect36,37 Nonconstricting rings may be seen along the limbs in extreme obesity, the ‘‘Michelin Tire Baby,’’10,11,39 and short limb skeletal dysplasias.12

Limbs

Torpin1 reviewed all the cases of amniotic band disruptions reported between 1850 and 1967 and estimated the incidence to be between one in 5000 and 15,000 births. Kalousek33 found 12 cases among 813 spontaneously aborted fetuses, for an incidence of one in 70. The fetuses were between 10 and 20 weeks gestation. The sexes appear to be equally affected. Prognosis, Treatment, and Prevention

Little or no progression in severity of constriction rings should be anticipated following birth. In cases with compromised vascular supply, edema distal to the constriction ring may become more pronounced during early infancy. The lymphatic and venous obstruction in these cases may be relieved by Z-plasty surgical release of the constriction ring and should be performed without delay. When vascular impairment has been sufficient to cause necrosis of distal tissues, the process may continue postnatally, culminating in sloughing of the necrotic tissue during the neonatal period. Areas of cutaneous ulceration associated with constriction rings heal normally following birth. Constriction rings with normal distal structures can also be cosmetically improved with Z-plasty. The procedure is usually staged, first removing one-half the circumference of the ring and then, after healing, the second half. In cases with severe disruption of distal tissues, the anomalous segment may be amputated and the limb fitted with a prosthesis. Prenatal ultrasound diagnosis has been made by finding associated anomalies, usually amputations, craniofacial defects, or body wall defects.34 Strands of tissue in the amniotic fluid are seen in some cases. The risk of spontaneous abortion appears to be increased for fetuses affected with amniotic bands. References (Constriction Rings) 1. Torpin R: Fetal Malformations Caused by Amnion Rupture During Gestation. Charles C Thomas Publisher, Springfield, IL, 1968. 2. Ossipoff V, Hall BD: Etiologic factors in the amniotic band syndrome: a study of 24 patients. Birth Defects Orig Artic Ser XIII(3D): 117, 1977. 3. Baker CJ, Rudolph AJ: Congenital ring constrictions and intrauterine amputations. Am J Dis Child 121:393, 1971. 4. Patterson TS: Congenital ring constrictions. Br J Plast Surg 14:1, 1961. 5. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 6. Moerman P, Fryns JP, Vandenberghe K, et al.: Constrictive amniotic bands, amniotic adhesions, and limb-body wall complex: discrete disruption sequences with pathogenetic overlap. Am J Med Genet 42:470, 1992. 7. Miller ME, Graham JM Jr, Higginbottom MC, et al.: Compressionrelated defects from early amnion rupture: evidence for mechanical teratogenesis. J Pediatr 98:292, 1981. 8. Pagon RA, Stephens TD, McGillivray BL, et al.: Body wall defects with reduction limb anomalies: a report of fifteen cases. Birth Defects Orig Artic Ser XV(5A):171, 1979. 9. Van Allen MI, Curry C, Gallagher L: Limb body wall complex: I. Pathogenesis. Am J Med Genet 28:529, 1987. 10. Ross CM: Generalized folded skin with an underlying lipomatous nevus. ‘‘The Michelin Tire Baby.’’ Arch Dermatol 100:320, 1969. 11. Schnur RE, Herzberg AJ, Spinner N, et al.: Variability in the Michelin Tire syndrome. A child with multiple anomalies, smooth muscle hamartoma, and familial paracentric inversion of chromosome 7q. J Am Acad Dermatol 28:364, 1993. 12. Akaba K, Nishimura G, Hashimoto M, et al.: New form of platyspondylic lethal chondrodysplasia. Am J Med Genet 66:464, 1997. 13. Orstavik KH, Stromme P, Spetalen S, et al.: Aplasia cutis congenita associated with limb, eye, and brain anomalies in sibs: a variant of the Adams-Oliver syndrome? Am J Med Genet 59:92, 1995.

875 14. Dent DM, Fataar S, Rose AG: Ainhum and angiodysplasia. Lancet 2:396, 1981. 15. Olmsted HC: Keratodermia palmaris et plantaris congenitalis: report of a case showing associated lesions of unusual location. Am J Dis Child 33:757, 1927. 16. Lucker GPH, Steijlen PM: The Olmsted syndrome: mutilating palmoplantar and periorificial keratoderma. J Am Acad Dermatol 31:508, 1994. 17. Gibbs RC, Frank SB: Keratoderma hereditaria mutilans (Vohwinkel). Arch Dermatol 94:619, 1966. 18. Pujol RM, Moreno A, Alomar A, et al.: Congenital ichthyosiform dermatosis with linear keratotic flexural papules and sclerosing palmoplantar keratoderma. Arch Dermatol 125:103, 1989. 19. Moessinger AC, Blanc WA, Byrne J, et al.: Amniotic band syndrome associated with amniocentesis. Am J Obstet Gynecol 141:588, 1981. 20. Kohn G: The amniotic band syndrome: A possible complication of amniocentesis. Prenat Diagn 7:303, 1987. 21. Marras A, Dessi C, Macciotta A: Epidermolysis bullosa and amniotic bands. Am J Med Genet 19:815, 1984. 22. Van der Rest M, Hayes A, Marie P, et al: Lethal osteogenesis imperfecta with amniotic band lesions: collagen studies. Am J Med Genet 24:433, 1986. 23. Elejalde BR, de Elejalde MM: Prenatal diagnosis of perinatally lethal osteogenesis imperfecta. Am J Med Genet 14:353, 1983. 24. Young ID, Lindenbaum RH, Thompson EM, et al.: Amniotic bands in connective tissue disorders. Arch Dis Child 60:1061, 1985. 25. Donnai D, Winter RM: Disorganization: a model for ‘‘early amnion rupture’’? J Med Genet 26:421, 1989. 26. Streeter GL: Focal deficiencies in fetal tissues and the relation to intrauterine amputation. Contrib Embryol 22:41, 1930. 27. Lockwood C, Ghidini A, Romero R, et al.: Amniotic band syndrome: reevaluation of its pathogenesis. Am J Obstet Gynecol 160:1030, 1989. 28. Bamforth JS: Disruption sequences: embryonic vascular accident or blastogenic disruption sequence? Am J Med Genet 47:284, 1993. 29. Houben JJ: Immediate and delayed effects of oligohydramnios on limb development in the rat: chronology and specificity. Teratology 30:403, 1984. 30. Kennedy LA, Persaud TVN: Pathogenesis of developmental defects induced in the rat by amniotic sac puncture. Acta Anat 97:23, 1977. 31. Kino Y: Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology. J Bone Joint Surg 57A:636, 1975. 32. Lubinsky M, Sujansky E, Sanger W, et al.: Familial amniotic bands. Am J Med Genet 14:81, 1983. 33. Kalousek DK: Amniotic band syndrome in embryos and previable fetuses. Proc Greenwood Genet Center 5:149, 1986. 34. Chen CP, Tzen CY, Chang TY, et al.: Prenatal diagnosis of acrania associated with facial defects, amniotic bands and limb-body wall complex. Ultrasound Obstet Gynecol 20:94, 2002. 35. Pagon RA, Stephan MJ: Septo-optic dysplasia with digital anomalies. J Pediatr 105:966, 1984. 36. Van den Ende J, Van der Burgt CJAM, Jansweijer MCE, et al.: Ectrodactyly of lower limbs, congenital heart defects and characteristic facies in four unrelated Dutch patients: a new association. Clin Dysmorphol 5:1, 1996. 37. Seaver LH, Smith JM: ‘‘Never, never doubt what nobody is sure about.’’ Malformation and disruptions associated with apparent amniotic bands. Proc Greenwood Genetic Center 23:98, 2004. 38. Maestrini E, Korge BP, Ocan˜a-Sierra J, et al.: A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families. Hum Mol Genet 8:1237, 1999. 39. Kondoh T, Eguchi J, Hamasaki Y, et al.: Hearing impairment, undescended testis, circumferential skin creases, and mental handicap (HITCH) syndrome: a case report. Am J Med Genet 125A:290, 2004. 40. Keymolen K, De Smet L, Bracke P, et al.: The concurrence of ring constrictions in Adams-Oliver syndrome: additional evidence for vascular disruption as common pathogenetic mechanism. Genet Couns 10:295, 1999.

876

Skeletal System

20.4 Duplications, Excessive Partitions, and Accessory Bones

postovulation). The formation of extra joint spaces presumably occurs during this period if extra segments or subsegments are to be separated by joint spaces. Triphalangeal Thumbs

Definition

Duplications result from excessive divisions of the cartilaginous template for the limb skeleton, resulting in extra segments, extra rays, or accessory bones. The limb is normally partitioned into segments and rays during the late embryonic period.1–3 Segments are separated by joint spaces; rays are separated by soft tissues or interdigital spaces. The radius and ulna are separated proximally by a joint space and longitudinally by soft tissues. The distal segments (hands and feet) are further subpartitioned by joint spaces, soft tissues, and interdigital spaces. Most instances of extra rays, segments, or subsegments represent excessive partitions of the limb rather than duplications. Anomalies resulting from excessive partition of the skeleton make up the second most common type of limb defect. Only syndactyly occurs more commonly. Excessive segmentation (division perpendicular to the long axis) causes hyperphalangy, metacarpal hypersegmentation, and metatarsal hypersegmentation. Extra ray formation occurs as polydactyly or long bone duplication. The various types of polydactyly are discussed in Section 21.2. Long bones may also be partitioned by fracture and failure of union, producing an anomaly called pseudoarthrosis. Additionally, more or less complete extra limbs occur as a part of various types of incomplete twinning (see Chapter 34). Extra limbs possibly may also derive from very early disorganization of the limb anlage and from teratomas. In the latter two circumstances, the limb always resembles the lower limb and is usually located at the sacrum or buttocks. Perhaps such an anomaly of the upper limb is precluded because this would disturb essential cardiovascular function. Although the embryologic mechanisms leading to these anomalies are not known, they are classified herein as limb duplications. Diagnosis

Visible manifestations almost invariably accompany division of the limb into an excessive number of segments and rays. Contrary to expectation, however, extra segmentation usually results in a shortening of the major segment involved. Angulation at adjacent joints is the rule. Formation of extra rays by excessive partitioning may cause increased width of the segment involved. Polydactyly is typical. Radiographs provide the necessary evidence to conclude that excessive partitioning has occurred. Virtually all excessive segments and rays, as well as duplications, can be identified at birth. The notable exceptions are partitions of carpals or tarsals, which do not become evident until postnatal ossification occurs. Etiology and Distribution

In most cases of excessive partition of segments and rays, the process begins during embryogenesis of the limb.2 Partition of the hand and foot plates into digits is complete by the 8th embryonic week. Extra ray formation must be accomplished during this partition process, which extends about from day 41 to day 57 postovulation. The first phase of limb segmentation is the formation in the cartilaginous templates of articular interzones, where future joints will form. These interzones are identifiable during weeks 7 to 8 postovulation. Cavitation of the joint spaces generally progresses during the first 2 weeks of the fetal period (weeks 9 and 10

Morphologic and functional disturbances result when the thumb is segmented into three rather than the usual two phalanges.4–11 Two more or less distinct types of triphalangeal thumb occur (see also Section 21.2).10 In the first type, the thumb retains functional opposition to the other digits but is malformed. The metacarpal has normal configuration and a proximal epiphysis, and the extra phalanx is usually malformed and positioned between the two usual phalanges in the long axis of the digits. In type II triphalangeal thumb, the digit appears more like an index finger and is nonopposable. The metacarpal resembles metacarpals 2 to 5 and has a distal epiphysis, the thenar eminence is underdeveloped, and the extra phalanx often has the configuration of the middle phalanges of digits 2 to 5. The presence of triphalangeal thumb is usually obvious clinically. In type I, the digit typically has deviation of the distal phalanx and rarely is longer than the normal thumb. The type II digit is typically long and may have distal deviation as well. Radiographs are helpful in confirming the type based on the location of the epiphysis of the metacarpal and the configuration of the extra phalanx. In some cases of triphalangeal thumbs, particularly those associated with split hand, the metacarpal has epiphyses at both ends. Approximately 75% of cases of the triphalangeal thumbs will have associated skeletal and nonskeletal anomalies. Most isolated and syndromic cases are heritable (see Table 20-8). Thalidomide and phenytoin are the only teratogens that have been associated with triphalangeal thumbs. The incidence of triphalangeal thumbs appears to be about one in 25,000 births.7 In different surveys, triphalangeal thumb constitutes 0.5–3.0% of anomalies of the upper limb. Miura11 found opposable (type I) triphalangeal thumb to be more common than nonopposable (type II) triphalangeal thumb both in isolated cases and in cases with associated polydactyly or bifid distal phalanx. In a review of over 350 individuals with triphalangeal thumb, Wood10 found recurrence in the family in twothirds of cases. The majority of patients had bilateral involvement, and the sexes were equally affected. As an isolated defect, the opposable (type I) triphalangeal thumb appears to result from excessive segmentation of the cartilaginous template of the first ray. As indicated by the frequent concurrence of a bifid or duplicated distal phalanx, some cases may have arisen from an aborted attempt at first ray duplication, the extra phalanx representing an incompletely duplicated proximal phalanx that has assumed longitudinal alignment with the other phalanges. Many observers interpret the nonopposable (type II) triphalangeal thumb to represent duplication of the index finger and absence of the thumb. This interpretation is based on the absence of a thenar eminence, the resemblance of the metacarpal to metacarpals 2 to 5, and the configuration of the extra phalanx similar to the middle phalanges of digits 2 to 5. Treatment is directed at cosmetic and functional improvement.9,10 Surgical correction may not be indicated if the thumb can adequately oppose the other digits. Angulation caused by an abnormally shaped phalanx, inadequate thenar muscle function, polydactyly, and contracture of the thumb web require surgical correction. Simple removal of the extra phalanx or angular correction usually is not enough. Ligamentous reconstruction has not

Limbs

been universally successful, and fusion of the shortened thumb may be necessary. Stability and opposition are essential in the surgical reconstruction. The five-fingered hand with all digits in the same plane is best treated by pollicization of the first digit. Hyperphalangy

The formation of four or more phalanges in digits 2 to 5 is termed hyperphalangy. Digits 2 and 3 are most commonly affected.12–16 Typically the extra phalanx is located between the metacarpal and proximal phalanx of the digit and may be offset from the midline of the digital ray (Fig. 20-36). Invariably, the extra phalanx is malformed and short. Other phalanges of the digit commonly are short or malformed as well. Digits 2 and 3 are often affected concurrently, although either may be affected alone. Digit 4 is rarely, if ever, affected. When the extra digit is placed proximally to the first phalanx, it may ultimately fuse with this phalanx, resulting in an abnormally shaped large proximal phalanx (Fig. 20-36).16 Because of the malformation of the phalanx, the digit often deviates from the longitudinal axis, usually in an ulnar direction. When the index finger is involved, there may be deviation at the metacarpophalangeal joint toward the radius and deviation at the proximal interphalangeal joint toward the ulna. The affected digits may be flexed into the palm or may deviate across the palmar or the dorsal side of the other digits. The tendons of affected digits are commonly misplaced, resulting in nonuse of the digit and interference with the use of other digits because of the deviation and overlap. Involvement is generally bilateral, although there may be asymmetry of involvement. Males and females are affected equally, except in those cases representative of the Catel-Manzke syndrome, which is probably an X-linked condition.15,16 Only two females have been reported to have this condition. Hyperphalangy is a characteristic finding in brachydactyly C (see Section 21.3).17 The excessive segmentation usually affects the second, third, and fifth digits and uncommonly affects one or more metacarpals in this dominantly inherited entity. As with the other heritable brachydactylies, considerable variability of involvement may be seen. Metacarpal Segmentation

Segmentation of the metacarpals occurs rarely. It may be seen as a feature in brachydactyly C (see Section 21.3)17 or as an isolated anomaly. The total length of the segments may be less than that of the normal metacarpal, resulting in shortening of the corresponding digit (Fig. 20-36). Occasionally an ununited epiphysis appears at the proximal end of the second metacarpal, but this should not be interpreted as a segmentation of the metacarpal.18 Partition of Carpals and Tarsals

Two types of abnormal partition of carpals and tarsals have been described.2,19 In the first, small elements of the constant carpals and tarsals may calcify separately but eventually fuse to the large mass of the bone. These small calcified elements are considered by some to be accessory bones but are best considered as representing a subordinate center of ossification that will not remain permanently separate from the constant bone of which it is a part. The second type of abnormal partition divides a carpal or tarsal into two separate bones. A joint space separates the two parts, and the division is permanent. The incidence is low, well under 1%. In the wrist, partitions of the scaphoid, lunate, triquetrum, and trapezoid appear to be most common. In the foot, partitions of the medial cuneiform, calcaneus, and navicular bones predominate. The possibility of the contribution of trauma is raised in some

877

instances, but certainly this does not explain all cases of carpal and tarsal partition. Differentiation from fractures can be difficult. A history of trauma and pain may be as important as the radiographic appearance in this differentiation. In some cases, the diagnosis can be resolved only with sequential radiographs to demonstrate the presence or absence of changes of a healing fracture. No treatment is usually necessary for partitioned carpals or tarsals. Accessory Bones

The occurrence of accessory bones in the hindfoot is commonplace (Fig. 20-37).2,19,20 Occurrence in the wrist is less common, and in the proximal and middle segments of the limb it is rare. Certain of the more commonly seen accessory bones are called sesamoid bones. These are osseous elements that develop within tendons and occur in most persons. They may have an articular surface that relates to an adjacent bone or joint. The nonsesamoid accessory bones are well-defined separate bones occurring in addition to the normal 120 bones of the limbs. They are inconstant and do not relate to any prior pathologic condition. Cartilaginous templates for accessory bones have been found in human embryos and fetuses.2 In some cases, accessory bones appear to be a separately ossified portion of one of the constant bones of the limb. This is the case in Larsen and otopalatodigital syndromes. Eventual osseous union between the separately ossified portions will take place in many of these bones. These cases should be considered bipartition of bones or ossification centers rather than accessory ossicles. In contrast, true accessory bones do not appear to be an element of one of the constant limb bones and remain separate from them. The locations of accessory bones, including the sesamoid bones of the hands and foot, are shown in Figure 20-37. Accessory bones rarely cause symptoms. Pain in the foot has been attributed to accessory bones. This may be spontaneous or may follow minor trauma. Radiographs are necessary to demonstrate accessory bones. Multiple views may be required because of the overlapping images of the bones of the hands and feet. Shands and Wentz20 found that 26% of children 8 years of age and older had accessory bones in the feet. An incidence in this range has been found by most investigators, although incidence figures as high as 75% have been reported.2 The incidence of accessory bones in the hand appears to be much lower, perhaps in the 0.5–1.5% range. Accessory bones may be bilateral or unilateral. The occurrence of accessory bones within families has been described.21 Accessory bones of the hands and feet rarely require any form of treatment. Their presence and location are important in radiologic interpretation when fractures are suspected. In the foot, an accessory navicular or prehallux may cause discomfort, and surgical removal is sometimes necessary. The os trigonum on the posterior talus may fail to unite, or, if united, it may fracture and produce symptoms. If pain persists, surgical excision may be necessary. Bifurcation of Humerus or Femur

Complete segmentation or duplication of the humerus has not been reported. Duplication of the femur and distal bifurcation of each bone have been described, but these are extremely rare malformations (Figs. 20-37 and 20-38).22–25 Kozlowski et al.24 reported halfsibs with bilateral bifurcation of the distal humerus. The infants also had coronal clefts of the vertebrae, proximal dislocation of the ulna, shortening of the long bones of the lower limbs, clubfeet, and cardiac defects. Gollop and Coates23 reported an infant with upper limb

878

Skeletal System

Fig. 20-36. Hyperphalangy. A. Radiograph taken in neonatal period shows extra ossification between the bases of digits 2 and 3. Photograph at age 6 years shows angulation of left index finger. Right index finger has been removed because of interference with function of other digits. B. Radiograph of hands of maternal grandfather of child shown

in A, showing malformed compound first phalanx formed by fusion of the proximal phalanx with the extra bone located at the base of digit 2 bilaterally. Right index finger is angulated similar to the grandson’s; left index finger is shortened but not angulated. C. Bilateral shortening of the index finger associated with segmentation of metacarpal 2.

anomalies, including oligodactyly and union of the long bones into a single bone with a bifurcation at midshaft. These authors initially interpreted the long bone anomaly as representing bifurcation of the distal humerus but acknowledged that it might be a compound bone made up of humerus, radius, and ulna. Cornah and Dangerfield26 reported an infant with nearly complete duplication of the femur and absence of the tibia involving the right lower limb, and Weiner et al.27 reported fibular duplication with ipsilateral absence of the fibula. A single case with duplication of most of the bones of one lower limb has also been reported.28

Unilateral bifurcation of the distal femur has been noted in several families. Usually the anomaly occurs as part of a dominantly inherited split hand/split foot condition.25 The expression is extremely variable but may include tibial aplasia, ulnar hypoplasia, hallux hypoplasia, patellar aplasia, and transverse limb reduction.22,23,25 Treatment of bifurcation of the femur is largely dependent on the status of the limb distal to the bifurcation. If the distal portion of the limb is rudimentary and nonfunctional, it should be amputated, and prosthetic restoration can then be accomplished by fitting the patient with a knee disarticulation prosthesis. Flaring

Limbs

879

Fig. 20-37. Schematics showing location of sesamoid bones and accessory bones of the wrist and hindfoot. Left: Sesamoid bones are located on the palmar (solid circles) side of the metacarpals and phalanges. The accessory bones of the wrist may be palmar (solid circles) or dorsal (open circles). Right: Sesamoid bones of feet (solid circles) are located on the plantar side of the phalanges or metatarsals. Accessory bones of the hindfoot and midfoot are shown in hatched circles.

Fig. 20-38. Left: Bifid right humerus noted in the skeleton of a 35to 40-year-old man. The skeleton was excavated in Poland and dated to the 13th century. (Reprinted with permission from Mann et al.42) Middle: bifid humerus in an infant with bilateral upper limb reductions and oligodactyly. This malformation probably represents synostosis of the

humerus and radius with absence of the ulna. (Reprinted with permission from Gollop and Coates.23) Right: unilateral bifurcation of the femur in a male infant with tridactylous ectrodactyly of one upper limb and monodactyly and absent tibias of both legs. A sib and possibly a great-aunt were similarly affected. (Reprinted with permission from Gollop et al.43)

880

Skeletal System

of the distal portion of the stump provides a good opportunity for suspension of the prosthesis. If the limb below the knee is functional, alignment of the patella and reconstruction of the lateral ligaments are required to accomplish joint stability.

surgeon against inadvertent entry into other organ systems that may be involved in the malformation. Pseudoarthrosis

A number of cases of partial or complete duplication of the lower limb have been described.29–36 These infants usually have three lower limbs, but as many as five have been reported (Fig. 20-39). There appears to be a predilection for attachment of the extra limb to the sacrum or buttocks. Two limbs will have a normal relationship to the pelvis, and at least one of the two will have normal morphology and function. The aberrantly attached extra limb(s) usually has abnormal morphology. Some extra limbs appear to have sensory or motor innervation or both. Attachment may be into a rudimentary pelvis or directly into soft tissues of the buttocks. In one case, the extra limb arose from a lumbosacral meningomyelocele.32 Weisselberg et al.29 reported an infant with partial duplication of a leg and foot attached along a popliteal web of the left lower limb. Billett and Bear33 reported a similar case. Infants with extra lower limbs usually have additional anomalies as well. Neural tube defects, partial duplications of the lower genitourinary and gastrointestinal structures, and ipsilateral renal agenesis have been noted. The etiology of lower limb duplications is not known, nor is the pathogenesis understood. Recurrence within a family has not been noted. Donnai and Winter37 have pointed out the similarity of these anomalies and those seen in the mouse mutant disorganization (Ds). Some cases likely represent instances of incomplete twinning. The case of Stevenson et al.38 appears to represent amputation of the distal part of one leg, with reattachment of the severed part onto the buttocks. It is necessary to evaluate the attachment site of the accessory limb carefully in preparation for surgical removal. This protects the

Failure of union following fracture of the long bones is called pseudoarthrosis (Fig. 20-40). The nonunion persists for a period of time well beyond that required for normal healing and is permanent in many cases. The tibia is affected most frequently, but the femur, fibula, radius, ulna, and clavicle may be involved.39–41 No joint develops between the two parts of the affected bone. Pseudoarthrosis may be obvious at birth, but more commonly it develops in infancy or early childhood. Typically the infant will acquire some bowing of the tibia during the 1st year of life and thereafter will experience a spontaneous fracture or a fracture associated with osteotomy followed by nonunion. When the tibia or femur is involved, the affected limb is shortened with bowing and is weak and unsuitable for weight bearing. Stability of the leg may be maintained if the fibula alone is involved. Radiographic evidence of cysts, fibrous lesions, sclerosis, or irregular ossification predates the fracture and nonunion in the majority of cases. Neurofibromatosis is the most common condition predisposing to pseudoarthrosis. In the series reported by Andersen,39 three-fourths of cases had neurofibromatosis. Biopsy from the area of nonunion may show evidence of neurofibromatosis tissue, but this finding is uncommon. No single treatment for pseudoarthrosis is universally successful, and follow-up support of the involved bone must continue through skeletal maturity and beyond. The excision of the pseudoarthrosis with intramedullary fixation and bone grafting has led to a higher degree of success than other forms of internal fixation. Supplemental electrical stimulation is thought by some investigators to enhance healing. Reported results for microvascular transplants, usually from the fibula to the pseudoarthrosis site, have been encouraging.

Fig. 20-39. Duplication of lower limbs. Left and middle: 19-weekold fetus with three lower limbs. The left Leg (L1) arises normally and is of appropriate size. Limbs L2 and L3 arise from a conjoined parasitic twin. Dissection demonstrated duplication of the gonads, distal gut, and

external genitalia. Note also omphalocele (O). (Courtesy of Dr. Will Blackburn, Fairhope, AL.) Right: Extra lower limb arising from a perineal teratoma. (Courtesy of Janice Edwards, University of South Carolina School of Medicine, Columbia.)

Duplication of the Lower Limbs

Limbs

Fig. 20-40. Pseudoarthrosis of the tibia associated with neurofibromatosis in a 6-year-old girl. Note cafe´ au lait spots on leg. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

References (Duplications, Excessive Partitions, and Accessory Bones) 1. O’Rahilly R, Gardner E, Gray DJ: The skeletal development of the hand. Clin Orthop 12:42, 1959. 2. O’Rahilly R: Developmental deviations in the carpus and the tarsus. Clin Orthop 10:9, 1957. 3. Swinyard CA, Pinner B: Some morphological considerations of normal and abnormal human limb development. In: Limb Development and Deformity: Problems of Evaluation and Rehabilitation. CA Swinyard, ed. Charles C Thomas Publisher, Springfield, IL, 1969, p 2. 4. Wood VE: Duplication of the index finger. J Bone Joint Surg 52A: 569,1970. 5. Haas SL: Three-phalangeal thumbs. Am J Roentgenol Radium Ther Nucl Med 42:677, 1939. 6. Roberts E: Hereditary hyperphalangism of the thumb. J Hered 34:291, 1943. 7. Lapidus PW, Guidotti FP, Coletti CJ: Triphalangeal thumb. Surg Gynecol Obstet 77:178, 1943. 8. Swanson AB, Brown KS: Hereditary triphalangeal thumb. J Hered 53:259, 1962. 9. Wassel HD: The results of surgery for polydactyly of the thumb. Clin Orthop 64:175, 1969. 10. Wood VE: Treatment of the triphalangeal thumb. Clin Orthop 120:188, 1976. 11. Miura T: Triphalangeal thumb. Plast Reconstr Surg 58:587, 1976.

881 12. Wood VE: Different manifestations of hyperphalangism. J Hand Surg 13A:883, 1988. 13. Drinkwater H: Hereditary abnormal segmentation of index and middle fingers. J Anat Physiol 50:177, 1916. 14. Shoul ME, Ritvo M: Roentgenologic and clinical aspects of hyperphalangism (polyphalangism) and brachydactylism: hereditary abnormal segmentation of the hand. N Engl J Med 248:274, 1953. 15. Gewitz M, Dinwiddie R, Yuille T, et al.: Cleft palate and accessory metacarpal of the index finger syndrome: possible familial occurrence. J Med Genet 15:162, 1978. 16. Stevenson RE, Taylor HA, Burton OM, et al.: A digitopalatal syndrome with associated anomalies of the heart, face and skeleton. J Med Genet 17:238, 1980. 17. Temtamy S, McKusick V: The genetics of hand malformations. Birth Defects Orig Artic Ser XIV(3): 187, 1978. 18. Bogart FB: Variations of the bones of the wrist. Am J Roentgenol 28:638, 1932. 19. O’Rahilly R: A survey of carpal and tarsal anomalies. J Bone Joint Surg 35A:626, 1953. 20. Shands AR Jr, Wentz IJ: Congenital anomalies, accessory bones, and osteochondritis in the feet of 850 children. Surg Clin North Am 33:1643, 1953. 21. Nissen KI: A study in inherited brachydactyly. Ann Eugen 5:291, 1933. 22. Aalami-Harandi B, Zahir A: Congenital bifid femur. Acta Orthop Scand 47:419, 1976. 23. Gollop TR, Coates R: Letter to the editor: apparent bifurcation of distal humerus with oligoectro-syndactyly. Am J Med Genet 14:591, 1983. 24. Kozlowski DS, Celermajer JM, Tink AR: Humero-spinal dysostosis with congenital heart disease. Am J Dis Child 127:407, 1974. 25. Majewski F, Kuster W, ter Haar B, et al.: Aplasia of tibia with split-hand/ split-foot deformity. Report of six families with 35 cases and considerations about variability and penetrance. Hum Genet 70:136, 1985. 26. Cornah MS, Dangerfield PH: Reduplication of the femur. Report of a case. J Bone Joint Surg 56B:744, 1974. 27. Weiner DS, Greenberg B, Shamp N: Congenital reduplication of the femur associated with paraxial fibular hemimelia. J Bone Joint Surg 60A:554, 1978. 28. Srivastava KK, Garg LD: Reduplication of bones of lower extremity. J Bone Joint Surg 53A:1445, 1971. 29. Weisselberg B, Ben-Ami R, Goodman RM: Partial duplication of the lower limb with agenesis of ipsilateral kidney—a new syndrome: report of a case and review of the literature. Clin Genet 33:234, 1988. 30. McDowell DE, Talavera M: An infant with four lower limbs. J Pediatr Surg 7:338, 1972. 31. Taniguchi K, Aoki Y, Kurimoto H, et al.: Baby with a third leg. J Pediatr Surg 10:143, 1975. 32. Krishna A, Chandna S, Misra NK, et al.: Accessory limb associated with spina bifida. J Pediatr Surg 24:604, 1989. 33. Billett DM, Bear JN: Partial duplication of the lower limb. A case report. J Bone Joint Surg 60A:1143, 1978. 34. Okuboyejo A: Extra leg with anencephaly. Lancet 1:188, 1971. 35. Hagberg S, Rubenson A, Lansinger O: A case of surgically treated dipygus (caudal duplication). J Pediatr Surg 21:58, 1986. 36. Nasta R, Scibilia G, Corrao A, et al.: Surgical treatment of an asymmetric double monstrosity with esophageal atresia, omphalocele, and interventricular defect. J Pediatr Surg 21:60, 1986. 37. Donnai D, Winter RM: Disorganisation: a model for ‘‘early amnion rupture’’? J Med Genet 26:421, 1989. 38. Stevenson RE, Saul RA, Parham KJ, et al.: Limb amputation with autotransplantation in one of twins. Proc Greenwood Genet Center 2:23, 1983. 39. Andersen KS: Radiological classification of congenital pseudoarthrosis of the tibia. Acta Orthop Scand 44:719, 1973. 40. Richin PF, Kranik A, Herpe LV, et al.: Congenital pseudoarthrosis of both bones of the forearm. J Bone Joint Surg 58A:1032, 1976. 41. Dooley BJ, Menelaus MB, Patterson DC: Congenital pseudoarthrosis and bowing of the fibula. J Bone Joint Surg 56B:739, 1974.

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42. Mann RW, Wiercinska A, Scheffrahn W: Distal phocomelia of the forearm in a thirteenth-century skeleton from Poland. Teratology 45:139, 1992. 43. Gollop TR, Lucchesi E, Martins RMM, et al.: Familial occurrence of bifid femur and monodactylous ectrodactyly. Am J Med Genet 7:319, 1980.

20.5 Bowing of Long Bones Definition

Bowing of long bones is the curvature of the long bones greater than 158 from the longitudinal axis. In practice, this arbitrary definition is not used; any appreciable deviation from the long axis is considered bowing. Bowing may take the form of a gentle arc, or the bone may be more or less distinctly angulated (Fig. 2041). The curvature may cause secondary changes of the metaphysis and epiphysis of the lower limb by shifting weight bearing to a limited area of the articulation surface. Altered bone alignment also contributes to dislocation of adjacent joints in upper and lower limbs. Diagnosis

Bowing of the long bones may be suspected clinically in the presence of curvature or shortening of the proximal or middle segments of the limbs, dimpling of the skin and soft tissues, and malalignment or dislocation of joints.1,2 Curvature of the femur or humerus can be hidden by the greater muscle mass of the thigh and arm. Radiographs are necessary for definition of the bone configuration and to differentiate bowing from fractures, long bone deficiencies, and other bone abnormalities. Typically, the bowed bone has cortical thickening on the concavity of the curve and cortical thinning along the convexity of the curve (Fig. 20-41).1 Cortical thickening on the inside of the curve may be adequate to obliterate the medullary cavity. The articulating surface of the bone may be malaligned, particularly when the bowing occurs near the end of the long bone rather than in the midshaft. Long bones normally have some mild degree of bowing, generally with the concavity toward the flexor muscles. This physiologic bowing is more pronounced at birth, but some bowing of Fig. 20-41. Schematics showing varying degrees of bowing of a long bone. Note thickening of the cortex on the concave side of the bowed bone.

the long bones persists in adult life. The femur and tibia are bowed slightly anteriorly and laterally, the fibula slightly posteriorly, the distal ulna medially, and the radius medially. This normal bowing can best be demonstrated on lateral radiographs of the tibia and femur and on anterior radiographs of the radius and ulna. The fibula and humerus are the straightest of the long bones. Pathologic bowing may appear as an accentuation of the usual long bone curvature, as a localized curvature, or as a distinct angulation. Bones of the lower limbs generally are bowed more frequently and to a greater degree than bones of the upper limbs, attesting in part to the greater intrauterine folding stresses on the lower limbs (Fig. 20-42). It has been stated that the flexor muscles have greater strength than the extensor muscles during intrauterine life.3,4 This claim is hard to substantiate, because the compressive forces of the uterus tend to hold the limbs in flexion; because joint structure favors flexion; and because the extensor muscles, particularly those of the lower limbs, have little opportunity for exercise. Bowing of the long bones is a dynamic phenomenon dependent on the intrinsic quality of the bone, the mechanical stresses exerted on the bone, and the remodeling capacity of affected bones. In most cases of pathologic bowing, the degree of curvature appears worse at birth, with spontaneous improvement thereafter. The presence of cutaneous dimpling suggests, however, that bowing may have been even greater prenatally, sufficient to bring the periosteum and dermis into contact. Spontaneous improvement follows relief from the compressive forces of the uterus in most cases. Straightening is usually complete by age 2 years, but some degree of bowing may persist even into adult life.2,5 Weight bearing may maintain or increase the curvature of the long bones of the lower limbs, particularly in cases with an underlying metabolic disorder or intrinsic bone dysplasia. Developmental bowing of the long bones of the lower limbs should not be confused with tibial torsion, in which the tibia is rotated internally relative to the femur. This rotational abnormality may be established during the prenatal period and maintained postnatally by sleeping on the abdomen or sitting on the legs with the feet turned in. Tibial torsion gives the appearance of bowing of the legs, but the tibia can be shown to be straight radiographically or by correcting the femur-tibia alignment manually.6 Likewise, developmental bowing should be differentiated from Blount disease (tibia varum), which is acquired after weight bearing begins. In Blount disease, the proximal growth plate of the tibia appears to be abnormal, resulting in migration of the tibia laterally and in some bowing of the proximal tibia. This disorder may be progressive and may cause irreversible changes in the tibia, requiring surgical realignment for proper weight bearing (Fig. 20-43). Isolated bowing of one or more long bones can occur sporadically, in sibs of apparently normal parents, and in parents and children.1,5,7 Bowing of the long bones is a conspicuous skeletal feature of the campomelic syndromes, rickets, and a number of constitutional bone dysplasias (Table 20-15, Fig. 20-44; see also Chapter 22).8–90 Postnatal hyperostosis along the diaphyseal cortex (Caffey disease, sequela of prenatal syphilis) can cause a bowed appearance in the tibia (Fig. 20-45).15 Bowing may also develop during childhood in association with tumors, fibrous dysplasia,91 hereditary exostoses,92 hypercalcemia,93 and osteolytic processes.94 Mesomelic bowing often occurs when one of the two long bones of the middle segment of a limb is absent or hypoplastic (see Section 20.1). The residual bone generally bows with the concavity toward the deficiency, and dislocation or malalignment can occur at either end of the segment. Conditions with bowing due to deficiency of one of the middle segment bones are listed in Table 20-16.77,78,94–117

Limbs

Fig. 20-42. Bowing of long bones in an infant with facial hemangioma, micrognathia, and glossopalatine fusion. Note more severe bowing of bones of lower limbs than of upper limbs. (From Stevenson.89)

Fig. 20-43. Bowing of the lower limbs in a 6-year-old male with Blount disease. Note the abnormal proximal growth plate of the tibias. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

883

Table 20-15. Syndromes that include bowing of the long bonesa Clinical Findings

Radiographic Findingsb

Causation Gene/Locus

Antley-Bixler

Frontal bossing, large fontanelle, midface retraction, abnormal ears, choanal stenosis, small auditory canals, joint contractures, syndactyly, rocker-bottom feet, urogenital anomalies, often lethal

(U,F) Craniosynostosis, radiohumeral synostosis, thin ribs, narrow pelvis, fractures

AR (207410)

Astley-Kendall dysplasia9

Short limbs, small thorax, prominent abdomen

(H,R,U,F,T,Fi) Absent skull ossification; platyspondyly; short irregular ribs; fractures; short deformed long bones; stippling of carpus, tarsus, and axial skeleton; metaphyseal flaring

Uncertain

Atelosteogenesis I10

Rhizomelia, short limbs micrognathia, facial hemangioma

(U,T) Absent fibula, hypoplastic humerus and femur, deficient ossification of thoracic spine and hand bones

AD (108720)

Atelosteogenesis II11

Hypertelorism, cleft palate, small thorax, prominent abdomen, short curved limbs, wide spacing of digits 1 and 2 of hands and feet

(R,T,Fi) Short long bones with wide metaphyses, bifid distal humerus, rounded distal femur, hypoplastic cervical vertebrae, large metacarpals and metatarsals 1 and 2

AR (256050)

Axelrod: sensory neuropathy-skeletal dysplasia12

Hypotonia, sensory neuropathy, absent deep tendon reflexes

(F,T) Short long bones, metaphyseal widening

Uncertain

Bellini: wedge-shaped epiphyses of knees13

Short limbs, limited knee movement, delayed development

(F) Short bones of lower extremity with metaphyseal widening and wedge-shaped epiphyses at knees

AR

Boomerang dysplasia14

Short limbs, omphalocele, lethal

(T) Absent femur, humerus, ulna, radius; deficient ossification of cranium, vertebrae, metacarpals, phalanges, and pubis

Sporadic (112310)

Caffey disease15

Swollen and painful limbs, fever, spontaneous resolution

(R,U,T,Fi) Hyperostotic lesions of long bones, less commonly other bones

AD (114000)

Campomelic dysplasia16,17

Large head, large fontanelle, short upwardslanted palpebrae, small nose, prominent philtrum, small mouth, cleft palate, small chin, short trunk and lower extremities, heart and renal anomalies, protuberant abdomen, hip and elbow dislocations, clubfeet, sex reversal, pretibial dimples, usually lethal

(F,T) Small scapula, hypoplastic pedicles of thoracic vertebrae, absent sternal ossification, thin ribs, 11 ribs, vertebral anomalies, narrow ilia, wide spaced ischia, delayed epiphyseal ossification

AR (211970) SOX9, 17q24.3-q25.1

Campomelia-cystic kidneys (Cumming)18

Cleft palate; short limbs, cystic hygroma; hydrops; pretibial dimples; polysplenia; cysts of kidneys, liver, and pancreas

(H,R,U,F,T) Short long bones, normal scapulas

AR (211890)

Craniosynostosis-bone fragility19

Short stature, craniosynostosis, proptosis, hydrocephalus, dentinogenesis imperfecta

(F,T) metaphyseal and diaphyseal fractures, craniosynostosis

Unknown

Diaphyseal dysplasia-ichthyosis20

Abnormal gait, muscle weakness and pain, ichthyosis

(F,T) Cortical thickening of long bones

AD (122480)

Dyschondrosteosis21

Mild short stature, mesomelic limb shortening, Madelung deformity, females more severely affected, adult height 135–170 cm, normal intellect

(R,U,T) Short radius, dorsal dislocation of distal ulna, wedging of carpals between distal ulna and radius, short fibula and tibia

XLD (304990) SHOX, Xp22.3 AD (127300)

Dyschondrosteosis-like (Fasanelli)22

Flat nasal bridge, acromesomelic limb shortening, midfoot varus

(H,R,F,T) Short long bones, metaphyseal expansion, cone-shaped epiphyses

AR

Dyschondrosteosis-like (Fryns)23

Short forearm with ulna deviation of hand, clubfeet

(R,U) Short radius and ulna

Uncertain

Dyschondrosteosis-like (Ventruto)24

Mesomelic shortening of forearm, Madelung deformity

(R,U) Fused C1–C2

AD; affected with balanced t(2;8)(q32;p13)

Syndrome 8

(continued)

884

Table 20-15. Syndromes that include bowing of the long bonesa (continued) Syndrome

Clinical Findings

Radiographic Findingsb

Causation Gene/Locus

Dyssegmental dysplasia (RollandDesbuquois)25

Short limbs, micrognathia, cleft palate

(F) Metaphyseal widening, deficient and irregular ossification of vertebrae

AR (224400)

Dyssegmental dysplasia (Silverman)26

Flat face, cleft palate, prominent joints, short bent limbs, encephalocele, lethal

(T,F) Short long bones, short ribs, metaphyseal widening, coronal clefts of vertebrae varying in size and configuration, small round ilia

AR (224410) HSPG2, 1p35-p36.1

Fuhrmann27

Oligodactyly of feet, short thighs, thin legs, polydactyly of hands, hip dislocation, nail hypoplasia

(F) Hypoplasia of pelvis, absence or hypoplasia of various bones of the feet, absence of fibula

AR (228930)

Goldblatt-Behari28

Short stature

(R,F) Distal ulna hypoplasia, short femoral necks, mild platyspondyly, metaphyseal expansion

AR (271700)

Grant29

Blue sclerae, small mandible, large fontanelle, pretibial dimple, joint dislocations

(F,T) Wormian bones

AD (138930)

Grebe-like chondrodysplasia (Teebi)30

Prominent fontanel, hypertelorism, depressed bridge and bulbous tip of nose, rhizomelic limb shortening, short digits, hearing loss

(R,U,F,T) Short or hypoplastic long bones, disorganized hand and foot bones with irregular shortening and fusions

Unknown

Hypophosphatasia (mild dominant)31

Large fontanelle, broad lower extremities, premature loss of teeth, painful ambulation, fractures, decreased alkaline phosphatase

(R,U,F,T) Short or hypoplastic long bones, disorganized hand and foot bones with irregular shortening and fusions

Unknown AD (146300, 171760)

Hypophosphatasia (severe recessive)32

Globular soft head, short limbs, blue sclerae, decreased alkaline phosphatase, often lethal

Deficient skeletal ossification, fractures

AR (241500, 241510) TNSALP, 1p34-p36.1

Jansen metaphyseal dysplasia33

Prenatal and postnatal growth deficiency (adult height 120 cm), joint prominence, limited joint movement

(H,R,U,F,T,Fi) Sclerosis of base of skull, progressive metaphyseal expansion and irregularity

AD (156400) PTHR1, 3p22-p22.1

Kyphomelic dysplasia34,35

Facial hemangiomas, small chin, small mouth, thigh and leg dimple, joint enlargement and limitation, (some cases same as Schwartz-Jampel)

(H,R,F,T,Fi) Metaphyseal expansion, flared iliac wings, flat acetabular roof

AR (211350) Heterogeneous HSPG2, 1p35-p36.1

Le Marec: mesomelia36

Macrocephaly, short stature, short forearms, clubfoot, clubhand

(R) Severe hypoplasia of ulna, malformed tarsals

Uncertain

Leroy: mesomelia37

Mesomelic limb shortening

(R,U,T,F) Severe shortening and pseudoarthrosis of tibia

AD (156230)

Lohr: mesomelia38

Sparse hair, hypertelorism, micrognathia, short neck, short forearms, camptodactyly, clinodactyly

(R,U,Fi) Wormian bones, wide sutures, short ulna and radius, subluxed elbow, long and thin fibula

Uncertain

Mahloudji39

Short limbs, deafness, delayed speech

(R,U,F) Short radius and ulna

Uncertain

40

Martsolf

Prominent eyes, redundant neck skin, micrognathia, cleft palate, small mouth, rhizomelic short limbs, polydactyly of feet, short digit 2 of hands, developmental delay

(T) Short long bones, coronal vertebral clefts, flat acetabular roof, absent middle phalanx of finger 2, extra preaxial ossification center of hands and feet, postaxial polydactyly of feet

Uncertain

Maternal diabetes41

Fetal overgrowth; anomalies of limbs, spine, heart, and brain

Variable limb reduction defects with or without lower spine anomalies

Abnormal glucose metabolism

Maternal hypoparathyroidism42

Fetal hyperparathyroidism with hypercalcemia

Bowing, periosteal resorption and osteopenia of all bones, fractures

Compensatory intrauterine hyperparathyroidism

McAlister43

Macrocephaly, cleft palate, short limbs, small thorax, lethal (resembles achondrogenesis)

(R,T) Short long bones with wide metaphyses; platyspondyly; small scapula; short ilia; short tubular bones of hands; deficient ossification of vertebral pedicles, pubes, and sacrum

Uncertain

(continued)

885

Table 20-15. Syndromes that include bowing of the long bonesa (continued) Clinical Findings

Radiographic Findingsb

Causation Gene/Locus

44–46

Exophthalmos, high narrow forehead, small chin, narrow thorax, delayed fontanelle closure, bowed limbs

(T,R) Thickened and uneven cortices of long bones and ribs, metaphyseal flaring, triangular pelvis with wide iliac wings

XLD (309350) FLNA, Xq28

Melnick-Needles-like (Dereymaeker)47

Coarse hair, hypertelorism, hirsutism, short neck, polycystic kidneys

(Fi) Elongated fibula, vertebral abnormalities

Uncertain

Micromelic chondrodysplasia (Langer)48

Short limbs, micrognathia, cleft palate, small mouth, (resembles Kniest dysplasia)

(R,U,F,T,Fi) Short long bones, metaphyseal expansion, large vertebrae with coronal clefts or anterior wedging

AR (249700)

Mucopolysaccharidoses IS, IH, IH-S, II, IV, VI49

Variable clinical signs in different types: macrocephaly, coarse facies, corneal clouding, hepatosplenomegaly, cardiac valve dysfunction, joint limitation, mental deficiency

(R,U) Widespread changes of dysostosis multiplex with changes in cranium, spine, long bones, hands, and feet

AR (252800, 253000, 253200) XLR (309900)

Osteodysplastia II50

Marked prenatal and postnatal retardation, Seckel-like craniofacies, mental retardation

(R) Short forearm and leg bones, middle phalanges, first metacarpals, notched distal femur, lysis of head of femur, tall narrow pelvis, delayed ossification

AR (210720)

Osteoectasia (hyperphosphatasia)51

Large skull with bony protuberances, hypertension, angioid striae of retina, bowed and widened extremities, short trunk, pectus carinatum, painful movement, anemia, fever, hypertension, onset in early childhood, elevated alkaline phosphatase

(F,T) Cortical expansion of long bones, markedly thickened skull with uneven ossification and irregular contour, uneven ossification of all bones with irregular densities and translucencies

AR (239000)

Osteogenesis imperfecta, Bruck type52

Short stature, large joint contractures, fractures

(H,R,U,F,T,Fi) Wormian bones, vertebral wedging, long bone deformation

AR (259450), 17p12

Osteogenesis imperfecta, types I–IV53

Blue sclerae, globular head, deafness, connective tissue fragility, fractures, short limbs

(H,R,U,F,T,Fi) Variable radiographic appearance in different types: osteoporosis, fractures, bone compressions, and deformity

I, AD (166240) II–IV, AD (120160), AR (159420, 259440, 259400, 259410, 259450)

Oto-palato-digital II47,54

Prominent forehead, hypertelorism, downward-slanting palpebrae, micrognathia, microstomia, cleft palate, anomalies of digits

(H,R,U,F,T,Fi) Osteosclerosis, irregular contour of long bones and ribs, short first digital ray, hypoplasia of fibula

XLR (304120) FLNA, Xq28

Panostotic fibrous dysplasia59

Hypertelorism, depressed nasal bridge, dental abnormalities, pigmentary patches, fractures, mental delay

(T,F) Osteopenia, widespread fibrous dysplasia, cortical thinning of long bones

AR (260490)

Pfeiffer: absent fibula and ulnaoligodactyly-cleft lip/palate56

Large head, cleft lip and palate, oligodactyly of hands and feet, contractures, absence of nails of feet, Arnold-Chiari malformation, hydrocephalus (similar to Fuhrmann)

(F) Absent ulna and fibula, variable absence of bones of the hands and feet

Uncertain

Polystotic fibrous dysplasia (McCune-Albright)57

Irregular skin pigmentation, precocious puberty, bone pain

(F) Irregular sclerotic and radiolucent lesions in skull, facial bones and long bones

AD (174800) GNAS1, 20q13

Prenatal thalidomide58

Limb reduction defects, cardiac anomalies, intestinal atresias, hernias, renal anomalies

Wide variety of long bone deficiencies and synostoses

Intrauterine exposure to thalidomide

Reinhardt-Pfeiffer mesomelia59

Mesomelic limb shortening, ulna deviation of hands, short legs with lateral bowing and cutaneous dimples, adult height 150–169 cm

(R,T,F,I) Short bowed radius with dislocation, deficiency of distal ulna and proximal fibula, expanded shaft of ulna and fibula, short broad tibia

AD (191400)

Rhizomelia-severe combined immunodeficiency60

Short stature, rhizomelic bone shortening, small thorax, severe combined immunodeficiency, often lethal

(F) Short long bones, metaphyseal changes of long bones

Rickets (all types)61–63

Joint prominence, short stature

(H,R,U,F,T,Fi) Rachitic changes at metaphyses of long bones

Syndrome

Melnick-Needles

Various causes, including nutritional, renal, and hereditary (continued)

886

Table 20-15. Syndromes that include bowing of the long bonesa (continued) Clinical Findings

Radiographic Findingsb

Causation Gene/Locus

Roberts

IUGR, Scant blonde hair, facial hemangioma, cleft lip/palate, limb deficiency, joint contractures, premature centromere separation

(H,R,U,F,T,Fi) Variable deficiencies of tubular bones

AR (268300)

Round inferior femoral epiphyseal dysplasia65

Large head, narrow chest, protuberant abdomen, short limbs, lethal

(H,R,U,F,T,Fi) Short long bones with metaphyseal expansion, short ribs, hypoplastic pelvis, platyspondyly

AR

Say: cloverleaf skull-limb anomalies66

Cloverleaf skull, midface retraction, polydactyly, hydrocephaly

(R) Short angular ulna, radioulnar synostosis, abnormal rib spacing and size

Uncertain

Schinzel-Giedion67

Tall cranium with severe midface retraction, hirsutism, hypospadias, clubfoot, choanal atresia, cardiac and renal anomalies, hyperconvex nails

(T,Fi) Steep sclerotic base of skull, wide sutures, wormian bones, hypoplastic phalanges, broad ribs

AR (269150)

Schmid metaphyseal dysplasia57,68

Normal at birth, short stature obvious prior to school, bowed legs, lumbar lordosis, waddling gait, short and curved extremities, varus deformities at hip and knees (adult height 150 cm)

(F,T) Short and bowed long bones, varus hip and knees

AD (156500) COL10A1, 6q21-q22.3

Schwartz-Jampel35,69

Ptosis, blepharal phimosis, myopathic facies, small mouth, large joints

(F,T) Metaphyseal expansion

AR (255800) HSPG2, 1p35-p36.1

Schwartz-Lelek70

Large cranium, frontal bossing, scoliosis, genuvarum

(F) Sclerosis and hyperostosis of skull, tubular bones expanded, metaphyseal widening

AR (269300)

Shokeir: thumb agenesis-short stature-immunodeficiency71

Short stature, absent thumbs, immunodeficiency, anosmia ichthyosiform dermatitis, hyperkeratosis of palms and soles, sparse and brittle hair, heart defect

(R,U) Absent carpals, absent first ray of hands, bipartite patella, elbow abnormalities

AR (274190)

Short rib-polydactyly (BeemerLanger type)72

Hydrops, large head, flat face, cleft lip/ palate, omphalocele, polydactyly

(R,U) Short ribs

AR (269860)

Split hand split foot-tibial aplasia73,74

Monodactylous or split hand and foot, variable other limb deficiencies, markedly variable expression

(R,F) Absent hand bones resulting in split hand/split foot or monodactyly, absence or hypoplasia of tibia or ulna or occasionally other long bone

AD (119100)

Spondylometaphyseal dysplasia (Algerian type)75

Short stature, lumbar lordosis, genuvarum, myopia, wrist deformity

(H,T) Short long bones, metaphyseal expansion, small carpals, platyspondyly

AD (184253)

Stuve-Wiedemann dysplasia76

Short stature, bowed lower limbs, camptodactyly, malpositioned toes and feet, respiratory distress, often lethal

(F,T,Fi) Bowed lower limb long bones, metaphyseal radiolucencies and expansion

AR (601559)

Thanatophoric dysplasia type I57,77

Signs at birth, short limbs, short trunk, narrow thorax, large head, depressed nasal bridge, lethal

Short cranial base with large cranium, very flat vertebral bodies, short ilia with horizontal acetabular roofs, small scapulae, short ribs, short long bones with wide oblique metaphyses, translucent proximal femur and humerus, deficient ossification of bones of hands and feet

AD (187600) FGFR3, 4p16.3

Weismann-Netter78 (EatonMcKusick)

Short stature, mild mental retardation, elevated alkaline phosphatase

(F,T,Fi) Cortical thickening of inner and outer curvature of long bones

AD (112350)

Werner mesomelia79

Short stature with marked leg shortening, extra preaxial toes, five or six triphalangeal fingers, syndactyly, limited wrist movement, normal intelligence (adult height 120–130 cm)

(Fi) Absence or hypoplasia of patella, triphalangeal thumbs, carpal fusion, thick humerus

AD (188770)

Syndrome 64

a Does not list single reports of Akaba et al.80 (platyspondylic lethal chondrodysplasia), Cole and Carpenter81 (craniosynostosisproptosis-bone fragility), Moore et al.82 (macrocephaly-hypertelorism-bowed long bones), MacLeod and Fraser83 (short limb-myopiamental retardation), Draper et al.84 (osteosclerosis-mental retardation), Guschmann et al.85 (mesomelia-polydactyly-DandyWalker), Yolken et al.86 (hypotelorism-cleft palate-hypospadias), Al-Awadi et al.87 (polydactyly-short tibia), Langer et al.88 (brachymesomelia-renal dysplasia), Stevenson89 (campomelia-ankyloglossia), and Stevenson and Wilkes90 (atelosteogenesis-absent fibula). b

Bones affected indicated in parentheses.

887

888

Skeletal System

Fig. 20-44. Lower limb bowing in an infant with thanatophoric dysplasia (A,B), an infant with campomelia (C,D), and an otherwise normal 2-year-old child (E,F). (C–F courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

While bowing occurs rarely in association with neurologic imbalance (neural tube defects, fetal akinesia, arthrogryposis syndromes), the bowing is usually of mild degree.118,119 Etiology and Distribution

Two factors, the intrinsic quality of bone and mechanical stress, appear to be most important in the etiology of bowed bones. In most cases, these two factors collaborate to cause bowing.1–4 Many genetic conditions in which bowing occurs can be identified, but even in these cases prenatal and postnatal mechanical forces undoubtedly contribute to the altered bone configuration. In certain circumstances, intrauterine mechanical force may be sufficient to cause excessive curvature or angulation of apparently normal long bones. Such circumstances include oligohydramnios;

uterine malformations; abnormal limb folding; and intrauterine crowding due to small pelvis, fibroids, and twinning. Limited intrauterine space requires that the fetus be folded, and the requirement for folding becomes progressively greater as the fetus grows. The lower limbs are more affected by the space limitations. After about midgestation, intrauterine space is insufficient for full extension of the lower limbs. By virtue of their smaller size and location, the upper limbs have greater opportunity for movement. Throughout pregnancy, the upper limbs have space adequate for full or near-full extension. Bowing of the bones may be found before substantial compressive forces of the uterus would be anticipated.120 In these cases, one must presume that intrinsic abnormality of the bone permits bowing from the flexor pull of muscles.

Limbs

889

Fig. 20-45. Bowing of tibias associated with Caffey disease (infantile cortical hyperostosis) in a 2-week-old infant (A,B). Note more severe involvement of left leg. Mild residual bowing at 21⁄2 years in older sibling (C,D) of the infant in A and B.

Intrauterine movement offers some protection against bowing, and this may be compromised by central nervous system defects and neuromuscular diseases. Bowing related to neuromuscular impairment occurs infrequently and is not severe. Prenatal fractures may also be a cause of bowed bones. More angulated bowing of bones suggests that mechanical forces were exerted over a narrow area of the bone, that there was a localized area of weakness of bone, or that a fracture occurred, with healing in angular fashion (Fig. 20-46).1 Curves that appear at one end of the bone rather than near the midshaft of the bone suggest localized stress to that region of the bone.

Cutaneous dimpling commonly occurs over the apex of a bowed limb, especially when the long bone is more acutely angulated. Microscopic examination of dimples has shown thinning of the epidermis, absence of subcutaneous soft tissues, and fusion of the dermis and periosteum.3 Dimpling has been attributed to pressure atrophy of the soft tissues caused by compression between the bowed bone and the uterine wall (Fig. 20-47)2,3 Alternative considerations must be given to the pathogenesis of this phenomenon. With dermal-periosteal fusion at the apex of the curve, remodeling of bone would cause dimpling of the skin due to traction as the bone straightens. In some cases of bowed bone, a

890

Skeletal System Table 20-16. Syndromes that include mesomelic bowing associated with aplasia or hypoplasia of a collateral bone* Radial Bowing

Aglossia-adactyly (Hanhart)95 Burck: mesomelic dysplasia97 Cortada: scoliosis-ulnar hypoplasia99 De la Chapelle dysplasia100 Di Bella: ulnar agenesis101 Maroteaux: acromesomelia109 Pallister: ulnar-mammary (TBX3, 12q23-q24.1)111 Pallister W clefting112 Pillay: ophthalmomandibulomelic dysplasia113 Richieri-Costa: limb deficiency114 Ulnar Bowing

Buttiens: distal limb deficiencies98 Fanconi pancytopenia102 Holt-Oram (TBX5, 12q21.3-q22)106 Hutteroth: absent thumb107 IVIC108 Nager110 Richieri-Costa: limb deficiency114 Schmit: Radial hypoplasia-triphalangeal thumbs115 Sofer: radial deficiency116 Thrombocytopenia-absent radius117 Tibial Bowing

Brahimi: acromesomelia96 De la Chapelle dysplasia100 Femoral hypoplasia-unusual facies103,104 Hecht: limb deficiency105 Fibular Bowing

Split-hand/split-foot-tibial deficiency73,74 Werner mesomelic dysplasia (Eaton-McKusick tibial deficiency)79 *See also Entry 20.1.

spike of bone crests the apex of the long bone curvature or angulation. In these cases, the possibility that the dermis produces traction on the periosteum under which new bone forms cannot be dismissed (Fig. 20-46). The incidence of pathologic bowing of the various long bones is not known. Bowing occurs as part of nearly 100 entities, each of which is uncommon (Tables 20-15, 20-16). Dietary rickets, at one time the most common cause for bowed bones, has all but disappeared in the developed countries. A combined incidence for all types of osteogenesis imperfecta is about one case per 25,000 births, making it the most common skeletal dysplasia that includes bowed bones. This is roughly twice the incidence of thanatophoric dysplasia and four times the incidence of campomelic dysplasia. Prognosis, Treatment, and Prevention

Mild bowing of the long bones is corrected spontaneously with the normal remodeling activity of the bones. Bowing may be perpet-

uated or accentuated by continuation of mechanical stress on the bones. In infants and young children, sleeping on the abdomen or sitting on the legs with feet turned may perpetuate tibial bowing. Weight bearing may augment curvature in the presence of intrinsic bone disease or ongoing metabolic imbalance such as in rickets. Contractures and muscle imbalance may further delay the straightening of long bones. Although the long bones of the upper limbs are not affected by weight bearing, bowing of these bones may also worsen with time. This is seen especially in dyschondrosteosis and other bony dysplasias affecting the middle segment. Also, bowing may persist or increase when the collateral bone is absent. The contribution of muscle imbalance must be considered in these circumstances. Several constitutional disorders of bone that include bowing are lethal, with affected infants being stillborn or dying in the immediate neonatal period (Table 20-15; see also Chapter 22).57,121 A general correlation of severity of bowing with lethality can be made. Although some infants with the campomelic syndromes have lived, there has been no follow-up on the natural history of the bone curvature in these patients. Physiologic bowing, usually confined to the tibia and femur, corrects spontaneously in almost all instances. Bracing and surgery are not indicated. In Blount disease (tibia varum), the tibia is bowed and rotated medially. In the earliest stage, bracing is advisable. Upper tibial osteotomy and realignment are necessary for those cases with progressive changes that do not respond to bracing. Specific treatment may be necessary in the case of nutritional, hereditary, and renal rickets. If complete correction of the bowing is not achieved with medical management, surgery may be necessary. This usually requires multiple-level osteotomies, with some form of fixation, usually intramedullary. Osteotomies and realignment may be necessary in other conditions that include severe curvature of the bones without spontaneous straightening.122 Sonographic diagnosis of conditions with bowed long bones has been made in the mid-trimester.120,123,124 Other associated anomalies may be detected in the absence of shortening or bowing of the bones. This has importance for families among whom an infant with bowing due to an autosomal recessive gene has been found. References (Bowing of Long Bones) 1. Angle CR: Congenital bowing and angulation of long bones. Pediatrics 13:257, 1954. 2. Caffey J: Prenatal bowing and thickening of tubular bones, with multiple cutaneous dimples in arms and legs. Am J Dis Child 74:543, 1948. 3. Lazjuk GI, Shved IA, Cherstvoy ED, et al.: Campomelic syndrome: concepts of the bowing and shortening in the lower limbs. Teratology 35:1, 1987. 4. Middleton DS: Studies on prenatal lesions of striated muscle as a cause of congenital deformity. Edinburgh Med J 41:401, 1934. 5. Kapur S, Van Vlotten A: Isolated congenital bowed long bones. Clin Genet 29:165, 1986. 6. Wilkins KE: Bowlegs. Pediatr Clin North Am 33:1429, 1986. 7. Hall BD, Spranger J: Congenital bowing of the long bones. Eur J Pediatr 133:131, 1980. 8. Escobar LF, Bixler D, Sadove M, et al.: Antley-Bixler syndrome from a prognostic perspective: report of a case and review of the literature. Am J Med Genet 29:829, 1988. 9. Elcioglu H, Hall CM: A lethal skeletal dysplasia with features of chondrodysplasia punctata and osteogenesis imperfecta: an example of Astley-Kendall dysplasia. J Med Genet 35:505, 1988. 10. Maroteaux P, Spranger J, Stanescu V, et al.: Atelosteogenesis. Am J Med Genet 13:15, 1982.

Limbs

891

Fig. 20-46. A,B. Angular bowing of lower limb bones in the infant in Fig. 20-42 showing spicule of bone at apex of bowed femurs. C,D. Irregular and angular bowing in long bones due to multiple prenatal fractures in an infant with osteogenesis imperfecta. Fig. 20-47. Cutaneous dimpling over the convexity of tibial bowing in a 23-month-old female with camptomelic dysplasia. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

11. Sillence DO, Kozlowski K, Rogers JG, et al.: Atelosteogenesis: evidence for heterogeneity. Pediatr Radiol 17:112, 1987. 12. Axelrod FB, Pearson J: Congenital sensory neuropathies. Am J Dis Child 138:947, 1984. 13. Bellini F, Chiumello G, Rimoldi R, et al.: Wedge-shaped epiphyses of the knees in two siblings: a new recessive rare dysplasia? Helv Paediatr Acta 39:365, 1984. 14. Kozlowski K, Sillence D, Cortis-Jones R, et al.: Boomerang dysplasia. Br J Radiol 58:369, 1985. 15. Saul RA, Lee WH, Stevenson RE: Caffey’s disease revisited. Further evidence for autosomal dominant inheritance with incomplete penetrance. Am J Dis Child 136:56, 1982. 16. Houston CS, Opitz JM, Spranger JW, et al.: The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year old boy just reported by Maroteaux et al. in 1971. Am J Med Genet 15:3, 1983. 17. Hall BD, Spranger JW: Campomelic dysplasia: further elucidation of a distinct entity. Am J Dis Child 134:285, 1980. 18. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986.

892

Skeletal System

19. Cole DE, Carpenter TO: Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: a newly recognized type of osteogenesis imperfecta. J Pediatr 110:76, 1987. 20. Koller ME, Maurseth K, Haneberg B: A familial syndrome of diaphyseal cortical thickening of the long bones, bowed legs, tendency to fracture and ichthyosis. Pediatr Radiol 8:179, 1979. 21. Fryns JP, Van Den Berghe H: Langer type of mesomelic dwarfism as the possible homozygous expression of dyschondrosteosis. Hum Genet 46:21, 1979. 22. Fasanelli S, Iannacoone G, Bellussi A: A possibly new form of familial bone dysplasia resembling dyschondrosteosis. Pediatr Radiol 13:25, 1983. 23. Fryns JP, Hofkens G, Fabry G, et al.: Isolated mesomelic shortening of the forearm in father and daughter: a new entity in the group of mesomelic dysplasias. Clin Genet 33:57, 1988. 24. Ventruto V, Pisciotta R, Renda S, et al.: Multiple skeletal familial abnormalities associated with balanced reciprocal translocation 2:8(q32:p13). Am J Med Genet 16:589, 1983. 25. Aleck KA, Grix A, Clericuzio C, et al.: Dyssegmental dysplasias: clinical, radiographic, and morphologic evidence of heterogeneity. Am J Med Genet 27:295, 1987. 26. Handmaker SD, Robinson LD, Campbell JA, et al.: Dyssegmental dwarfism: a new syndrome of lethal dwarfism. Birth Defects Orig Artic Ser XIII(3D):79, 1977. 27. Fuhrmann W, Fuhrmann-Rieger A, De Sousa F: Poly-, syn- and oligodactyly, aplasia or hypoplasia of fibula, hypoplasia of pelvis and bowing of femora in three sibs—a new autosomal recessive syndrome. Eur J Pediatr 133:123, 1980. 28. Goldblatt G, Behari D: Unique skeletal dysplasia with absence of the distal ulnae. Am J Med Genet 28:625, 1987. 29. Maclean JR, Lowry RB, Wood BJ: The Grant syndrome: persistent wormian bones, blue sclerae, mandibular hypoplasia, shallow glenoid fossae and campomelia—an autosomal dominant trait. Clin Genet 29:523, 1986. 30. Teebi AS, Al-Awadi SA, Opitz JM, et al.: Severe short-limbed dwarfism resembling Grebe chondrodysplasia. Hum Genet 74:386, 1986. 31. Fallon MD, Teitelbaum SL, Weinstein RS: Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine 63:12, 1984. 32. Kozlowski K, Sutclijfe J, Barylak A: Hypophosphatasia: review of 24 cases. Pediatr Radiol 5:103, 1976. 33. Charrow J, Poznanski AK: The Jansen type of metaphyseal chondrodysplasia: confirmation of a dominant inheritance and review of radiographic manifestations in the newborn and adult. Am J Med Genet 18:321, 1984. 34. MacLean RN, Prater WK, Lozzio CB: Brief clinical report: skeletal dysplasia with short angulated femora (kyphomelic dysplasia). Am J Med Genet 14:373, 1983. 35. Nicole S, Davoine CS, Topaloglu H, et al.: Perlecan, the major proteoglycan of basement membranes, is altered in patients with SchwartzJampel syndrome (chondrodystrophic myotonia). Nat Genet 26:480, 2000. 36. Le Marec B, Bracq H, Picaud JC, et al.: Un syndrome malformatif complexe avec brachymesomelie. Ann Pediatr 30:721, 1983. 37. Leroy JG, De Vos J, Timmermans J: Dominant mesomelic dwarfism of the hypoplastic tibia, radius type. Clin Genet 7:280, 1975. 38. Lohr H, Wiedemann HR: Mesomelic dysplasia-associated with other abnormalities. Eur J Pediatr 137:313, 1981. 39. Mahloudji M, Zarrabi M, Emami-Ahari Z: Prenatal bowing of long bones in two sibs. Birth Defects Orig Artic Ser V(5):121, 1974. 40. Martsolf JT, Reed MH, Hunter AGW: Case report 56. Synd Ident V(1):14, 1977. 41. Williamson DAJ: A syndrome of congenital malformations possibly due to maternal diabetes. Dev Med Child Neurol 12:145, 1970. 42. Bronsky D, Kiamko RT, Moncada R, et al.: Intra-uterine hyperparathyroidism secondary to maternal hypoparathyroidism. Pediatrics 42: 606, 1968. 43. McAlister WH, Crane JP, Bucy RP, et al.: A new neonatal short limbed dwarfism. Skeletal Radiol 13:271, 1985.

44. Melnick JC, Needles CF: An undiagnosed bone dysplasia: a 2 family study of 4 generations and 2 generations. AJR Am J Roentgenol 97:39, 1966. 45. Donnenfeld AE, Conrad KA, Roberts NS: Melnick-Needles syndrome in males: a lethal multiple congenital anomalies syndrome. Am J Med Genet 27:159, 1987. 46. Robertson SP, Twigg SRF, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 47. Dereymaeker AM, Christens J, Eeckels R, et al.: Melnick-Needles syndrome (osteodysplasty). Helv Paediatr Acta 41:339, 1986. 48. Langer LOJ, Gonzalez-Ramos M, Chen H, et al.: A severe infantile micromelic chondrodysplasia which resembles Kniest disease. Eur J Pediatr 123:29, 1976. 49. Eggli KD, Dorst JP: The mucopolysaccharidoses and related conditions. Semin Roentgenol 21:275, 1986. 50. Majewski F, Ranke M, Schinzel A: Studies of microcephalic primordial dwarfism II: the osteodysplastic type II of primordial dwarfism. Am J Med Genet 12:23, 1982. 51. Dohler JR, Souter WA, Beggs I, et al.: Idiopathic hyperphosphatasia with dermal pigmentation, a twenty-year follow-up. J Bone Joint Surg 68B:305, 1986. 52. Leroy JG, Nuytinck L, DePaepe A, et al.: Bruck syndrome: neonatal presentation and natural course in three patients. Pediatr Radiol 28:781, 1998. 53. Sillence DO, Senn AS, Danks DM: Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101, 1979. 54. Andre M, Vigneron J, Didier F: Abnormal facies, cleft palate, and generalized dysostosis: a lethal X-linked syndrome. J Pediatr 98:747, 1981. 55. Cole DEC, Fraser FC, Glorieux FH, et al.: Panostotic fibrous dysplasia: a congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia. Am J Med Genet 14:725, 1983. 56. Pfeiffer RA, Stoss H, Voight HJ, et al.: Absence of fibula and ulna with oligodactyly, contractures, right-angle bowing of femora, abnormal facial morphology, cleft lip/palate and brain malformation in 2 sibs: a possibly new lethal syndrome. Am J Med Genet 29:901, 1988. 57. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development. Oxford University Press, New York, 2002. 58. Newman CGH: Teratogen update: clinical assessment of thalidomide embryopathy—a continuing preoccupation. Teratology 32:133, 1985. 59. Rheinhardt K, Pfeiffer RA: Ulno-fibulare dysplasia. Eine autosomaldominant vererbte mikromesomelie a¨hnlich dem Nievergelt syndrome. Fortschr Roentgenstr 107:379, 1967. 60. MacDermott KD, Winter RM, Wigglesworth JS, et al.: Short stature/ short limb skeletal dysplasia with severe combined immunodeficiency and bowing of the femora: report of two patients and review. J Med Genet 28:10, 1991. 61. Tapia J, Stearns G, Ponseti IY, et al.: Vitamin-D resistant rickets. A long-term clinical study of eleven patients. J Bone Joint Surg 46A:935, 1964. 62. Swischuk LE, Hayden DKJ: Rickets: a roentgenographic scheme for diagnosis. Pediatr Radiol 8:203, 1979. 63. Tieder M, Modai D, Samuel R, et al.: Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 312:611, 1985. 64. Herrmann J, Feingold M, Tuffli GA, et al.: A familial dysmorphogenic syndrome of limb deformities, characteristic facial appearance and associated anomalies: the ‘‘pseudothalidomide’’ or ‘‘SC-syndrome.’’ Birth Defects Orig Artic Ser V(3):81, 1969. 65. Maroteaux P, Stanescu R, Stanescu V, et al.: Recessive lethal chondrodysplasia, ‘‘round femoral inferior epiphysis type.’’ Eur J Pediatr 147:408, 1988. 66. Say B, Poznanski AK: Cloverleaf skull associated with unusual skeletal anomalies. Pediatr Radiol 17:93, 1987. 67. Schinzel A, Giedion A: A syndrome of severe midface retractions, multiple skull anomalies, club feet, and cardiac and renal malformations in sibs. Am J Med Genet 1:361, 1978.

Limbs 68. Lachman RS, Rimoin DL, Spranger J: Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature. Pediatr Radiol 18:93, 1988. 69. Edwards WC, Root AW: Chondrodystrophic myotonia (SchwartzJampel syndrome): report of a new case and follow-up patients initially reported in 1969. Am J Med Genet 13:51, 1982. 70. Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperosteoses: a critical analysis. Birth Defects Orig Artic Ser V(4):79, 1969. 71. Shokeir MHK: Short stature, absent thumbs, flat facies, anosmia and combined immune deficiency (CID). Birth Defects Orig Artic Ser XIV(6A):103, 1978. 72. Beemer FA, Langer LO Jr, Klep-de Pater JM, et al.: A new short rib syndrome: report of two cases. Am J Med Genet 14:115, 1983. 73. Bujdoso G, Lenz W: Monodactylous splithand-splitfoot. A malformation occurring in three distinct genetic types. Eur J Pediatr 133:207, 1980. 74. Majewski F, Kuster W, Ter Haar B, et al.: Aplasia of tibia with splithand/split-foot deformity. Report of six families with 35 cases and considerations about variability and penetrance. Hum Genet 70:136,1985. 75. Kozlowski K, Bacha L, Massen R, et al.: A new type of spondylometaphyseal dysplasia-Algerian type. Report of five cases. Pediatr Radiol 18:221, 1988. 76. Wiedemann HR, Stuve A: Stuve-Wiedemann syndrome: update and historical footnote. Am J Med Genet 63:12, 1996. 77. Maroteaux P, Stanescu V, Stanescu R: The lethal chondrodysplasias. Clin Orthop 114:31, 1976. 78. Robinow M, Johnson GF: The Weismann-Netter syndrome. Am J Med Genet 29:573, 1988. 79. Eaton GO, McKusick VA: A seemingly unique polydactyly syndactyly syndrome in four persons in three generations. Birth Defects Orig Artic Ser V(3):221, 1969. 80. Akaba K, Nishimura G, Hashimoto M, et al.: New form of platyspondylic lethal chondrodysplasia. Am J Med Genet 66:464, 1997. 81. Cole DEC, Carpenter TO: Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: a newly recognized type of osteogenesis imperfecta. J Pediatr 110:76, 1987. 82. Moore LA, Moore CA, Smith JA, et al.: Asymmetric and symmetric long bone bowing in two sibs: an apparently new bone dysplasia. Am J Med Genet 47:1072, 1993. 83. MacLeod PM, Fraser FC: Case report 2. Synd Ident 1:10, 1973. 84. Draper MW, Chafetz N, Winberg GL: Distinct form of osteosclerosis in identical twins with mental retardation. AJR Am J Roentgenol 129:1205, 1982. 85. Guschmann M, Horn D, Entezami M, et al.: Mesomelic, camptomelia, polydactyly and Dandy-Walker cyst in siblings. Prenat Diagn 21:378, 2001. 86. Yolken R, Konecny P, Effmann EL: Case report 48. Synd Ident IV(2): 13, 1976. 87. Al-Awadi SA, Naguib KK, Farag TI, et al.: Hypoplastic tibiae with postaxial polysyndactyly: a new dominant syndrome. J Med Genet 24:369, 1987. 88. Langer LO, Nishino R, Yamaguchi A, et al.: Brachymesomelia-renal syndrome. Am J Med Genet 15:57, 1983. 89. Stevenson RE: Campomelia, prenatal fractures, and ankyloglossia superior. Proc Greenwood Genet Center 1:47, 1982. 90. Stevenson RE, Wilkes G: Atelosteogenesis with survival beyond the neonatal period. Proc Greenwood Genet Center 2:32, 1983. 91. Stewart MJ, Gilmer WSJ, Edmonson AS: Fibrous dysplasia of bone. J Bone Joint Surg 44B:302, 1962. 92. Shapiro F, Simon S, Glimcher MJ: Hereditary multiple exostoses: arthropometric, roentgenographic, and clinical aspects. J Bone Joint Surg 61A:815, 1979. 93. Rosenberg E, Lohr H: A new hereditary bone dysplasia with characteristic bowing and thickening of the distal ulna. Eur J Pediatr 145:40, 1986. 94. Osterberg PH, Wallace RGH, Adams DA, et al.: Familial expansive osteolysis. A new dysplasia. J Bone Joint Surg 70B:255, 1988.

893

95. Temtamy S, McKusick VA: Synopsis of hand malformations with particular emphasis on genetic factors. Birth Defects Orig Artic Ser V(3):125, 1969. 96. Brahimi L, Bacha L, Kozlowksi K, et al.: Acro-mesomelic dysplasia—a new type. Report of two siblings. Pediatr Radiol 18:67, 1988. 97. Burck U: Mesomelic dysplasia with punctate epiphyseal calcifications—a new entity of chondrodysplasia punctata? Eur J Pediatr 138:67, 1982. 98. Buttiens M, Fryns JP: Apparently new autosomal recessive syndrome of mental retardation, distal limb deficiencies, oral involvement and possible renal defect. Am J Med Genet 27:651, 1987. 99. Cortada X, Kousseff BG, Matsumoto GM: Constricted maxilla and mandible, scoliosis, bowed radii, ulnar hypoplasia, acromicria and microcephaly with mental retardation—a new autosomal recessive syndrome? Birth Defects Orig Artic Ser XVIII(3B):197, 1982. 100. Whitley CB, Burke BA, Granroth G, et al.: De la Chapelle dysplasia. Am J Med Genet 25:29, 1986. 101. Di Bella D, Di Stefano G, Romeo MG, et al.: Upper limb cardiovascular syndrome with ulna agenesis (abstract). Pediatr Radiol 14:259, 1984. 102. Juhl JH: Roentgenographic findings in Fanconi’s anemia. Radiology 89:646, 1967. 103. Johnson JP, Carey JC, Gooch WM III, et al.: Femoral hypoplasiaunusual facies syndrome in infants of diabetic mothers. J Pediatr 102:866, 1983. 104. Bevan-Thomas WH, Millar EA: A review of proximal focal femoral deficiencies. J Bone Joint Surg 49A:1376, 1967. 105. Hecht JT, Scott CI Jr: Limb deficiency syndrome in half-sibs. Clin Genet 20:432, 1981. 106. Smith AT, Sack GHJ, Taylor GJ: Holt-Oram syndrome. J Pediatr 95:538, 1979. 107. Hutteroth H, Spranger J: Case report 34. Synd Ident III(2):15, 1975. 108. Arias S, Penchaszadeh VB, Pinto-Cisternas J, et al.: The IVIC syndrome: a new autosomal dominant complex pleiotropic syndrome with radial ray hypoplasia, hearing impairment, external ophthalmoplegia and thrombocytopenia. Am J Med Genet 6:25, 1980. 109. Langer LO, Beals RK, Solomon IL, et al.: Acromesomelic dwarfism: manifestations in childhood. Am J Med Genet 1:87, 1977. 110. Halal F, Herrmann J, Pallister PD, et al.: Differential diagnosis of Nager acrofacial dysostosis syndrome: report of four cases with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209, 1983. 111. Schinzel A, Illig R, Prader A: The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin Genet 32:160, 1987. 112. Pallister PD, Herrmann J, Spranger JW, et al.: The W syndrome. (Studies of malformation syndromes in man XXVIII). Birth Defects Orig Artic Ser X(7):51, 1974. 113. Pillay VK: Ophthalmo-mandibulo-melic dysplasia: an hereditary syndrome. J Bone Joint Surg 46A:858, 1964. 114. Richieri-Costa A, Opitz JM: Ulnar ray a/hypoplasia: evidence for a developmental field defect on the basis of genetic heterogeneity. Report of three Brazilian families. Am J Med Genet Suppl 2:195, 1986. 115. Schmitt E, Gillenwater JY, Kelly TE, et al.: An autosomal dominant syndrome of radial hypoplasia, triphalangeal thumbs and maxillary diastema. Am J Med Genet 13:63, 1982. 116. Sofer S, Bar-Ziu J, Abeliovich R: Radial ray aplasia and renal anomalies in father and son, a new syndrome. Am J Med Genet 14:151, 1983. 117. Bagnasco J, Stevenson RE: Thrombocytopenia-absent radius syndrome. Proc Greenwood Genet Center 7:36, 1988. 118. Poznanski AK, La Rowe PC: Radiographic manifestations of the arthrogryposis syndrome. Radiology 95:353, 1970. 119. Chen H, Blumberg B, Immken L, et al.: The Pena-Shokeir syndrome: report of five cases and further delineation of the syndrome. Am J Med Genet 16:213, 1983. 120. Fryns JP, van den Berghe K, van Assche A, et al.: Prenatal diagnosis of campomelic dwarfism. Clin Genet 19:199, 1981. 121. Spranger J, Maroteaux P: The lethal osteochondrodysplasias. Adv Hum Genet 19:1, 1990.

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122. Dietz FR, Weinstein SL: Spike osteotomy for angular deformities of the long bones in children. J Bone Joint Surg 70A:848, 1988. 123. Filly RA, Golbus MS, Carey JC, et al.: Short-limbed dwarfism: ultrasonographic diagnosis by measurement of fetal femoral length. Radiology 138:653, 1981. 124. Escobar LF, Bixler D, Weaver DD, et al.: Bone dysplasias: the prenatal diagnostic challenge. Am J Med Genet 36:488, 1990.

20.6 Short Stature Definition

Short stature is length or height more than 2 standard deviations (SD) below the mean during the growth period or less than 152 cm (5 feet) in the adult. To consider short stature a congenital anomaly, the birth length must be less than 2 SD below the mean. At term gestation, the mean birth length is 51 cm (20 inches), and 2 SD below the mean is 47 cm (18.5 inches).1 During the growth period, separate growth charts are used for males and females. Although mature heights are also significantly different in males and females, the convention of using 152 cm (5 feet) as the division between normal adult height and short stature is wellaccepted.2 Diagnosis

Stature makes an immediate visual impact, equivalent in attraction to facial features, general bulk, and hair style. Attention to stature is greatest when children are grouped by age, as in school and athletic settings. Anxiety about stature is particularly heightened during entry into school and at puberty, when short stature may be accompanied by the absence of secondary sexual characteristics.

Short stature must be confirmed by actual measurement of the crown-heel length or standing height and comparison with agespecific and sex-specific standards for the population.2–5 Prior to the age of standing, the crown-heel length is taken in the fully extended supine position on a firm surface. This measurement is particularly difficult to make precisely, especially in an uncooperative or active infant. A measuring board for infants and young children is helpful. Standing height is taken with feet together, shoes removed, and back against a wall-mounted measuring device with a horizontal head plate. Care must be taken to ensure accurate measurements. Flexion of joints, curvature of the trunk, shoes, and hair bulk may contribute to erroneous measurements. Radiographic assessment of bone age and bone structure is essential in the evaluation of short stature. Bone age may be adequately determined by comparing a dorsal radiograph of the hands with the standards of Pyle et al.6 If the cause of short stature is not immediately obvious, a skeletal survey including views of the skull, vertebrae, pelvis, and long bones will be helpful in determining the presence of a skeletal dysplasia or other primary skeletal disorder. In proportionate short stature, the cranium, trunk, and limb proportions appear normal, whereas in disproportionate short stature, the trunk or limbs are shortened to a greater degree than other portions of the body (Fig. 20-48).7 Platyspondyly, vertebral malformations, and spinal curvature may cause disproportionate short stature of the short trunk type. Short stature of the short limb type can be due to shortening of all segments of the lower limb or to rhizomelic (thigh) or mesomelic (leg) shortening. Short stature is a quite nonspecific feature, and diagnosis always requires consideration of other findings. The potential for finding a reversible cause for short stature is sufficient to require certain diagnostic tests on all persons with short stature in whom the cause is not immediately obvious.8–16 Such studies should

Fig. 20-48. Left: Proportionate short stature in a 3-year old male with Weil-Marchesani syndrome. Middle: Short limbs and short stature in a 5-year-old male with achondrodysplasia. Right: Short trunk and short stature in an adult with spondyloepiphyseal dysplasia.

Limbs

895

Table 20-17. Characteristics of major types of short stature Cause

Birth Length

Bone Age

Associated Anomalies

Genetic short stature

Low/normal

Normal

None

Constitutional delay of growth and development

Normal

Delay

None

Growth hormone deficiency

Normal

Delay

None

Hypothyroidism

Normal

Delay

Coarse facies, hernias

Chromosome aberrations

Low

Normal/delay

Malformations

Gonadal dysgenesis

Low/normal

Normal/delay

Malformations

Syndromes (genetic and nongenetic)

Low/normal

Normal/delay

Malformations

Skeletal dysplasias

Low/normal

Normal/delay

None/malformations, deformations

Peripheral resistance to somatomedin

Low

Normal

None

Emotional deprivation

Normal

Delay

None

Chronic illness

Normal

Delay

None

exclude renal disease with acidosis, cyanotic heart defects, and endocrine disturbances, principally hypothyroidism and growth hormone deficiency.8–11 Emotional deprivation may be suspected from the history, but this possibility requires documentation of a growth spurt on removal from the home environment for confirmation.12–14 Other equally important but nontreatable causes may be found in the evaluation. These include chromosome aberrations, prenatal trophogenic insults, skeletal dysplasias, and recognizable syndromes of known and unknown etiology (Table 20-17). The approach to evaluation of short stature depends in part on the time at which the short stature first becomes apparent and on the presence of other clinical features. Short stature obvious at birth should be evaluated by ascertainment of gestational age; review of historical and clinical evidence of prenatal environmental exposures; and clinical and laboratory investigation for chromosome aberrations, skeletal dysplasias, and recognizable syndromes (Fig. 2049). Children with short stature not evident at birth but becoming obvious prior to or during the school years must be evaluated in addition for renal, cardiac, endocrine, and metabolic disorders (Table 20-18). Emotional deprivation, malnutrition, and constitutional delay of growth and maturation are additional diagnostic considerations during this period. Short stature making its initial appearance at the age of usual puberty is less common and requires endocrine and chromosome evaluations. Etiology and Distribution

In that it is a characteristic defined by deviation from the mean, short stature occurs in 2.5% of the population as a part of nonpathologic continuous variability. Pathologic causes of short stature may be identified in an equivalent number of individuals (Tables 20-17 and 20-19). Virtually all of the skeletal dysplasias identifiable at birth include short stature as a feature. In many other skeletal dysplasias, short stature is seen later (see Chapter 22, Tables 22-2 and 22-3). The window for human growth is limited, extending through the fetal period and through only the first 20% of postnatal life. Closure of the growth window coincides with fusion of the epiphyses of the long bones, principally the femur and tibia. From the point of viability (approximately 24 weeks postovulation) until about 38 weeks postovulation, growth is nearly linear. Thereafter growth slows, presumably because of the inability of the placenta to sustain the linear growth rate. Growth rate progressively decreases postnatally until the time of puberty, when the final spurt of growth in the life-cycle takes place (Fig. 20-50).

In fetal life and thereafter, length (and height) is most affected by longitudinal growth of the long bones of the lower limbs. Growth of the cranium and vertebral column makes a less substantial contribution to length. At birth, the height of the head and face constitutes one-fourth of the total length. The craniofacies nearly doubles in height during the growth period, but at the end of growth it constitutes only one-eighth of the total height. The contribution of postnatal spine growth to overall height is likewise small. The lower limb length increases more than fourfold during postnatal growth and accounts for slightly more than one-half of mature height. At birth the lower limb accounts for about one-third of total length. Statural growth is a complex phenomenon influenced by numerous known factors and perhaps by an equally large number of factors not yet identified. Virtually all illness will slow growth and if sufficiently chronic may result in short stature.8–16 Heredity is of overwhelming importance in statural growth of most individuals. Short parents can expect to have short offspring.17 Short offspring of parents with normal or excessive height are the exceptions, and in these cases there is reason to search for pathologic causes of the short stature. In the pathologic situation, an individual genetic or environmental influence may be sufficient to cause short stature. Individuals with achondrodysplasia, for example, have short stature irrespective of parental height, nutrition, hormone production, or other factors. The same applies to individuals with certain chromosome aberrations, prenatal environmental insults, and syndromic entities. Growth appears to be driven by different factors at different ages. Insulin, growth hormone, androgens, and thyroxin are the most important hormonal growth factors.18 Under stimulation by the cerebral cortex, the hypothalamus produces growth hormonereleasing factor, which in turn results in the production and release of growth hormone by the anterior pituitary gland.19 Growth hormone serves to drive the liver’s production and release of somatomedin, an insulinlike polypeptide that directly stimulates growth of cartilage. Adequate evidence exists to consider insulin a growth-promoting hormone. Insulin and growth hormone exert synergistic effects on protein synthesis. Short stature has been noted in several insulindeficient situations, including poorly controlled diabetes mellitus and familial dysautonomia. Poor insulin production following arginine stimulation and oral glucose load has been documented in some children with constitutional delay of growth and maturation.20

896

Skeletal System

Fig. 20-49. Short stature at birth due to a skeletal dysplasia, achondroplasia, length 49.5 cm (left); the chromosome aberration trisomy 18 and inverted duplication 15, length 44.4 cm at 42 weeks gestation (middle); and a syndrome of unknown cause, Russell-Silver syndrome, 39.5 cm at 38 weeks gestation (right).

Compounds with androgenic activity are likely important for normal childhood growth in both boys and girls. These compounds are produced by the adrenal cortex and have low levels in the blood. Testosterone produced in the male testes participates prominently in the statural surge in males at puberty. In contrast, estrogens appear to play very little role in the pubertal growth Table 20-18. Time of appearance of major types of short stature Time

Principal Causes

Birth*

Genetic short stature Certain skeletal dysplasias Chromosome aberrations Prenatal environmental insults Drugs Infections Radiation Certain recognizable syndromes

Childhood

Constitutional delay of growth and maturation Hormonal deficiencies Thyroid Growth hormone Emotional deprivation Certain skeletal dysplasias Certain recognizable syndromes X and Y chromosome aberrations

Puberty

X and Y chromosome aberrations

*Inaccurate gestational age assessment may falsely suggest short length at birth.

spurt in females, androgens produced by the adrenal cortex being more important in this regard. Unfortunately, a precise chronology detailing the different growth promoters required at different ages cannot yet be made. No individual factor is known to be essential at any age inasmuch as some statural growth continues even in the total absence of individual growth promoters. The fetus appears to have a primitive growth system dependent primarily on an adequate supply of insulin and nutrients. Hormonal influences important to postnatal growth have but limited influence prenatally. Growth hormone is produced by the 3rd fetal month but does not appear essential to fetal growth, as is shown by normal growth in fetuses with anencephaly and in those with isolated growth hormone deficiency. The requirement for thyroxin for fetal growth has been argued. Although prenatal brain development and bony maturation may be impaired in athyreotic cretins, bone growth is usually normal. If not before birth, certainly after birth and throughout the growth phase, thyroxin is important to normal bone growth. Longitudinal growth of the long bones, the major contribution to postnatal growth, depends on all of these hormonal factors (Fig. 20-51). No growth factors are known to be produced in the long bones. Rather, they must be produced elsewhere and released into the circulation to reach the bones. Cartilage presumably has specific receptors that recognize the growth factors and permit their biologic activity. Thyroid and growth hormone promote growth throughout the postnatal growth period; androgen and other hormones with androgenic activity exert their influence primarily during puberty and adolescence. Nutrition greatly influences body bulk but does not have an equivalent effect on stature. In the normal child and in most children with pathologic growth impairment, height can be affected very little by increasing calories, supplementing vitamins

Limbs

897

Table 20-19. Estimates of prevalence of major types of short stature after age 1 year Percent of Persons with Short Stature

Percent of Population

Genetic (familial) short stature

50

Constitutional delay of growth and development

24

2.5 1.2

Renal, cardiac, pulmonary, and gastrointestinal disease

9

0.45

Syndromes (genetic and nongenetic)

6

0.3

Autosomal chromosome defects

4

0.2

Gonadal dysgenesis

0.8

0.04

Skeletal dysplasias

0.8

0.04

Hormone deficiencies

0.4

0.02

End organ insensitivity

<1

Very rare

Emotional deprivation

<1

Very rare

and minerals, or altering the sources of caloric intake. Denervation of limbs impedes longitudinal growth of the long bones as evidenced by short lower limbs in children with spina bifida and short upper limbs following brachial nerve injury. The growth impairment does not appear to be adequately explained by disuse or decrease in blood supply, and the possibility of a peripheral neurohumor with trophic effect has not been eliminated. Local growth factors (paracrine factors) may be important in asymmetric growth but have not been shown to play a substantial role in overall height attainment. Approximately 5% of all children will have short stature at some time during the period of growth. Boys and girls are equally affected. Nearly twice as many males as females are diagnosed as

having constitutional delay of growth and development. However, this may relate to greater anxiety about height and muscular development in males. Short stature commonly occurs as an isolated phenomenon. Genetic (familial) short stature and constitutional delay of growth and development account for the overwhelming majority of patients so affected.21 Pathologic short stature often but not invariably has other accompanying features. Congenital anomalies should be anticipated only when short stature is associated with chromosome aberrations, skeletal dysplasias, teratogenic influences, heritable syndromes, and other recognizable syndromes of unknown etiology (Table 20-20). Endocrine disturbances are among the least common causes of short stature (Table 20-19).21

Fig. 20-50. Typical supine length or height velocities for males and females. (Reprinted with permission from Tanner JM, Whitehouse RH, Takaishi M: Arch Dis Child 41:454, 1966.)

Prognosis, Treatment, and Prevention

The prognosis and treatment of short stature depends on the cause. Short stature in infancy related to premature birth, placental insufficiency, and twin pregnancy is self-limited, usually with return to the normal percentiles by age 1 year. Children with constitutional delay of growth and puberty have normal length at birth, but a portion of them fall below the normal percentiles during late

Fig. 20-51. Hormonal and other factors that influence growth of long bones.

898

Skeletal System

Table 20-20. Conditions with short stature as a common feature Syndrome

Causation

Aarskog

XLR (305400)

Acrocallosal

AR (200990)

Acrocraniofacial

AR (201050)

Acrogeria

Unknown

Alagille

AD (118450)

Alcohol, prenatal

Environmental exposure

Aminopterin, prenatal

Drug exposure

Aminopterin-like

Uncertain

Baller-Gerold craniosynostosis

Uncertain (218600)

Bardet-Biedl

AR (209900)

Bloom

AR (210900)

Bo¨rjeson-Forssman-Lehmann

XLR (301900)

Cerebrocostomandibular

Unknown (117650)

Cerebrooculofacioskeletal (COFS)

AR (214150)

Chromosome aberrations (most)

Chromosomal

Cockayne

AR (216400)

Coffin-Lowry

XLR (303600)

Coffin-Siris

Uncertain (135900)

Cranioectodermal dysplasia

Uncertain (218330)

Cytomegalovirus infection, prenatal

Prenatal infection

De Lange

AD (122470)

Dubowitz

AR (223370)

Fanconi anemia

AR (227650)

Focal femoral hypoplasia

Heterogeneous (134780)

Freeman-Sheldon

AD (193700)

GAPO

AR (230740)

Geroderma osteodysplastica

AR (231070)

Hajdu-Cheney

AD (102500)

Hallermann-Streiff

Unknown (234100)

Hypertelorism-hypospadias

AD, XLR (145410)

Jarcho-Levin spondylothoracic dysplasia

AR (277300)

Johanson-Blizzard

AR (243800)

Kabuki make-up

Del 8p (147920)

KBG

AD (148050)

LEOPARD

AD (151100)

Marden-Walker

AR (248700)

Marshall

AD (154780)

Martsolf

AR (212720)

Miller-Dieker

Del 17p

MULIBREY nanism

AR (253250)

Multiple synostosis

AD (186400)

Nager

Unknown (154400)

Neu-Laxova

AR (256520)

Noonan

AD (163950)

Oculo-palato-skeletal

AR (257920)

Opitz FG

XLR (305450)

Opitz trigonencephaly

AR (211750)

Otopalatodigital I

XLR (311300)

Pena-Shokeir hypokinesia

AR (208150)

Syndrome

Causation

Prader-Willi

Del 15q, UPD 15q

Progeria

AR (176670)

Rothmund-Thompson

AR (268400)

Rubella infection, prenatal

Environmental exposure

Rubinstein-Taybi

Del 16p13.3; AD

Russell-Silver

Unknown (270050), UPD 7p

Schinzel-Giedion

AR (269150)

Schwartz-Jampel

AR (255800)

Seckel

AR (210600)

Septo-optic dysplasia

Unknown (182230)

Skeletal dysplasias (see Chapter 22)

Heterogeneous

Spondylocostal dysplasia

AD (122600), AR(277300)

Three-M

AR (273750)

Trimethadione, prenatal

Environmental exposure

Weil-Marchesani

AR (277600)

Werner

AR (277700)

Wiedemann-Rautenstrauch

AR (264090)

Williams

AD (194050), del 7q

infancy or the childhood years.22,23 These children have delayed onset of puberty and do not experience a distinct pubertal growth spurt but continue to grow for a longer period of time than their agemates who enter puberty at the usual time. Ultimately they often reach normal height for their families, but this is not invariable. Although no treatment is necessary for constitutional delay, androgenic agents have been successfully used, especially in boys, to boost growth during the early teen years and to induce pubertal changes. Children who fail to grow because of emotional deprivation (psychosocial short stature) experience catch-up growth upon removal from the offending environment. Good control in insulin-dependent diabetes mellitus helps to maintain normal growth and prevents short stature. Nutritional therapy is helpful only in the case of nutritional rickets. Hypothyroidism and growth hormone deficiencies, the two most frequent endocrinopathies, require replacement therapy with thyroxin or human growth hormone.19,21 Historically, the limited supply of growth hormone has dictated that it be used only in the treatment of persons with demonstrable growth hormone deficiency. With the availability of a safe and abundant supply of growth hormone, this growth promoter has also been utilized in an attempt to increase stature in individuals without growth hormone (GH) deficiency. The experience has been most extensive in Turner syndrome with less experience in skeletal dysplasias and other syndromes with short stature. Long-term therapy (5 years) in Turner syndrome has resulted in an overall 5 to 6 cm increase in adult height.24–30 The response to GH appears to be consistently better during the 1st year of treatment. Final adult height exceeded 152 cm (5 feet) in about one-fourth of individuals. Some treatment regimens include combination therapy with estrogen and oxandrolone.29 Patients with Noonan syndrome may have equivalent growth gain with GH therapy, but few reach adult height above –2 SD.31,32 The response to GH therapy in children with chondrodysplasias has been mixed, depending on the type of dysplasia.33–36 Hypochondroplasia appears to show the greatest response. The growth velocity in this mild chondrodysplasia increases 2 to 4 cm per year of

Limbs

treatment.34 A significant but smaller increase in growth velocity has been noted in achondrodysplasia and metaphyseal dysplasia. No growth gain has been achieved by GH treatment in pseudoachondroplasia and spondyloepiphyseal dysplasia.36 Trials of GH in infants and children with Prader-Willi syndrome have been shown to normalize statural growth, decrease body mass index, and increase lean body mass and strength.37–40 Concerns that increased stature and strength might aggravate behavioral problems have not materialized. Deaths have occurred after starting GH therapy in patients with pretreatment respiratory impairment and morbid obesity.40 Genetic short stature without GH deficiency also responds to GH therapy, but whether the small adult height gain with this costly therapy improves self-image or provides other benefits has been questioned.30,41–43 No specific therapy can be provided for many types of short stature. Short stature related to chromosome aberrations, certain prenatal environmental insults to growth, and most recognizable syndromes that include short stature are likewise resistant to therapy. No treatment is available nor is it usually indicated in cases of neurotrophic short stature such as spina bifida. In recent years, long bone lengthening has offered hope of increasing stature to an acceptable range for patients with skeletal dysplasias. Surgical bone lengthening was devised in the 1920s as a means of equalizing lower limb length in patients with polio and osteomyelitis.44 High complication rates attended these procedures. Modification of the procedures for bone lengthening has decreased the complication rate sufficiently that they can now be recommended for patients with short stature.45,46 Many of the genes associated with skeletal dysplasias that present with short stature have been identified (Chapter 22). The causative genes for a number of other heritable conditions with short stature area also known. Interventions that target the genes or pathways involved are currently under development. Sonographic examination permits prenatal diagnosis in cases when the long bones are short and in those with certain associated anomalies. In addition to careful examination of the morphology and length of the lower limbs, evaluation of head size, facial structure, thorax configuration, heart, kidneys, and movement help in the sonographic diagnosis of many skeletal dysplasias and other syndromes that include short stature.47 Maternal serum screening (afetoprotein, human chorionic gonadotropin, estriol), chorionic villus sampling, and amniocentesis permit the early diagnosis of cytogenetic and metabolic disorders associated with short stature. Most cases of short stature are not attended with physical disability. The patients’ size, however, can place them at a psychological disadvantage, particularly in school and in the workplace. Performing daily activities in houses, cars, and public facilities built for the person of average stature can be formidable tasks for those with short stature. These individuals benefit from early efforts to assist in adjustment to a world of greater height and to structure the immediate environment to accommodate their stature.48,49 References (Short Stature) 1. Usher R, McLean F: Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks gestation. J Pediatr 74:901, 1969. 2. Gordon CC, Churchill T, Clauser CE, et al.: 1988 Anthropometric Survey of U.S. Army Personnel: Summary Statistics Interim Report. U.S. Army Natick Research, Development and Engineering Center, Natick, MA, 1989.

899 3. Saul RA, Seaver LH, Sweet KM, et al.: Growth References: Third Trimester to Adulthood. Keys Printing, Greenville, SC, 1998. 4. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 5. Ogden CL, Kuczmarski RJ, Flegal KM, et al.: Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109:45, 2002. 6. Pyle SI, Waterhouse AM, Greulich WW: A Radiograph Standard of Reference for the Growing Hand and Wrist. Press of Case Western Reserve University, Cleveland, 1971. 7. Scott CI Jr: Dwarfism. Ciba Symposia 40:1, 1988. 8. Barrett TM, Broyer M, Chantler C, et al.: Assessment of growth. Am J Kidney Dis 7:340, 1986. 9. Rizzoni G, Basso T, Setari M: Growth in children with chronic renal failure on conservative treatment. Kidney Int 26:52, 1984. 10. Mehrizi A, Drash A: Growth disturbance in congenital heart disease. J Pediatr 61:418, 1962. 11. Galler JR, Ramsey F, Salimano G: A follow up study of the effects of early malnutrition on subsequent development. I. Physical growth and sexual maturation during adolescence. Pediatr Res 19:581, 1985. 12. Powell GF, Brasel JH, Blizzard RM: Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. N Engl J Med 276: 1271, 1967. 13. Annecillo C, Money J: Abuse or psychological dwarfism: an update. Growth Genet Hormones 1:1, 1985. 14. Stanhope R, Adlord P, Hamill G, et al.: Physiological growth hormone (GH) secretion during the recovery from psychosocial dwarfism: a case report. Clin Endocrinol (Oxf) 28:335, 1988. 15. Young WF, Pringle EM: 110 children with coeliac disease, 1950-1969. Arch Dis Child 46:421, 1971. 16. Kanof ME, Lake AM, Bayless TM: Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology 95:1523, 1988. 17. Rohr RD: Comparative heights of mothers and fathers whose children are short. Am J Dis Child 144:995, 1990. 18. Mendez H: Introduction to the study of pre- and postnatal growth in humans: a review. Am J Med Genet 20:63, 1985. 19. Phillips JA III: Genetic diagnosis: differentiating growth disorders. Hosp Pract 20:85, 1985. 20. Karp M, Laron Z, Moron M: Insulin secretion in children with constitutional short stature. J Pediatr 83:241, 1973. 21. Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, ed 3. Charles C Thomas Publisher, Springfield, IL, 1965, p 174. 22. Crowne EC, Shalet SM, Wallace WHB, et al.: Final height in boys with untreated constitutional delay in growth and puberty. Arch Dis Child 65:1109, 1990. 23. Bierich JR: Constitutional delay of growth and adolescent development. Growth Genet Hormones 3:9, 1987. 24. Quigley CA, Crowe BJ, Anglin DG, et al.: Growth hormone and low dose estrogen in Turner syndrome: results of a United States multicenter trial to near-final height. J Clin Endocrinol Metab 87:2033, 2002. 25. Betts PR, Butler GE, Donaldson MDC, et al.: A decade of growth hormone treatment in girls with Turner syndrome in the UK. Arch Dis Child 80:221, 1999. 26. Rosenfeld RG, Attie KM, Frane J, et al.: Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr 132:319, 1998. 27. Johnston DJ, Betts P, Dunger D, et al.: A multicenter trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis. Arch Dis Child 84:76, 2001. 28. Price DA, Ranke MB: Growth hormone in Turner syndrome. Arch Dis Child 84:525, 2001. 29. Parvin M, Roche E, Costigan C, et al.: Treatment outcome in Turner syndrome. Ir Med J 97:12, 2004.

900

Skeletal System

30. Root AW, Kemp SF, Rundle AC, et al.: Effect of long-term recombinant growth hormone therapy in children—the National Cooperative Growth Study, USA, 1985–1994. J Pediatr Endocrinol Metab 11:403, 1998. 31. Kirk JMW, Betts PR, Butler GE, et al.: Short stature in Noonan syndrome: response to growth hormone therapy. Arch Dis Child 84:440, 2001. 32. Romano AA, Blethen SL, Dana K, et al.: Growth hormone treatment in Noonan syndrome: The National Cooperative Growth Study experience. J Pediatr 128:S18, 1996. 33. Hagenas L, Ritzen M, Eklof O, et al.: First year response of growth in short children with achondroplasia or hypochondroplasia treated with growth hormone. Pediatr Res 33(suppl):S40, 1993. 34. Key LL, Gross AJ: Response to growth hormone in children with chondrodysplasia. J Pediatr 128:S14, 1996. 35. Tanaka N, Katsumata N, Horikawa R, et al.: The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia. Endocr J 50:69, 2003. 36. Kanazawa H, Tanaka H, Inoue M, et al.: Efficacy of growth hormone therapy for patients with skeletal dysplasia. J Bone Miner Metab 21:307, 2003. 37. Lindgren AC, Ritzen EM: Five years of growth hormone treatment in children with Prader-Willi syndrome. Swedish National Growth Hormone Advisory Group. Acta Paediatr Suppl 88:109, 1999. 38. Carrel AL, Myers SE, Whitman BY, et al.: Benefits of long-term growth hormone therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab 87:1581, 2002. 39. Whitman BY, Myers S, Carrel A, et al.: The behavioral impact of growth hormone treatment for children and adolescents with PraderWilli syndrome: a 2-year, controlled study. Pediatrics 109:e35, 2002. 40. Van Vliet G, Deal CL, Crock PA, et al.: Sudden death in growth hormone-treated children with Prader-Willi syndrome. J Pediatr 144:129, 2004. 41. Finkelstein BS, Imperiale TF, Speroff T, et al.: Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 156:230, 2002. 42. Guyda HJ: Growth hormone therapy for non-growth hormonedeficient children with short stature. Curr Opin Pediatr 10:416, 1998. 43. Kawai M, Momoi T, Yorifuji T, et al.: Combination therapy with GH and cyproterone acetate does not improve final height in boys with non-GH-deficient short stature. Clin Endocrinol (oxf) 48:53, 1998. 44. Sofield HA, Blair SJ, Millar EA: Leg-lengthening. A personal follow up of foster patients some twenty years after the operation. J Bone Joint Surg 40A:311, 1958. 45. Patterson D: Leg-lengthening procedures. A historical review. Clin Orthop 250:27, 1990. 46. Paley D: Problems, obstacles, and complications of limb lengthening by the Illizarov technique. Clin Orthop 250:81, 1990. 47. Escobar LF, Bixler D, Weaver DD, et al.: Bone dysplasias: the prenatal diagnostic challenge. Am J Med Genet 36:488, 1990. 48. Scott CI Jr: Medical and social adaptation in dwarfing conditions. Birth Defects Orig Artic Ser XIII(3C):29, 1977. 49. Van Etten AM: Dwarfs Don’t Live in Doll Houses. Adaptive Living, Rochester, 1988.

20.7 Tall Stature Definition

Tall stature is length or height greater than 2.5 standard deviations (SD) above the mean for age and sex. At birth, excessive length is 56.3 cm or greater.1 Tall stature in adult males is a height of over 192 cm and in adult females a height of over 179 cm.2 Many clinicians prefer to use height greater than 2 SD above the mean to define tall stature. Using this definition, height over 189 cm in adult males and 176 cm in adult females constitutes tall stature.2

Diagnosis

For the fetus and infant, length is measured from the crown to the heel, with the lower limbs fully extended. After ambulation begins, the height is measured standing without shoes, using a rigid wallmounted tape or a stadiometer. Standardized height curves are available for determining standard deviations from the mean or, as is more commonly used in the clinical setting, height centiles.3–5 Contemporary adult height (1988) as well as a number of other measurements based on the study of 1774 males and 2258 females in military service have been reported by Gordon et al.2 Excessive length or height in boys and girls causes little concern during infancy and the early childhood years. It is the exception for isolated tall stature in males to cause major social concern at any age. Rather, it is generally looked upon as a desirable trait. Hence, tall males who are otherwise normal are usually not evaluated regardless of the projected adult height. For girls, excessive height may be less desirable. Girls who have tall stature during childhood and are projected to be tall as adults may seek evaluation and intervention to limit ultimate height.6 The prediction of adult height is usually based on the BayleyPinneau tables.7,8 The chronologic age, height, and bone age of the hand (Greulich-Pyle method) are used in these tables. Some clinicians prefer the Tanner or Roche-Wainer-Thissen methods, which use midparental height and other factors in prediction of adult height.9–11 Etiology and Distribution

The most common cause of tall stature is normal variation. One in 40 persons will have tall stature on this basis. Tall parents can be expected to have tall children. Tall stature may also occur in association with pathologic features (Table 20-21). Pathologic causes of excessive height include excess growth hormone and excess thyroid hormone production. Excess growth can also be seen in conditions that include a prolonged growing period because of lack of androgen or tissue insensitivity to androgen. Transient excess stature can be associated with precocious puberty, although the ultimate height may be normal or short. Excess length may be seen at birth in a number of conditions that include generalized macrosomia (see Table 20-22). In a number of other conditions with macrosomia at birth, growth slows postnatally, and ultimate height is normal or short. Typical of these conditions are the mucopolysaccharidoses, Bannayan-Riley-Ruvalcaba syndrome, and infants of diabetic mothers. Prognosis, Treatment, and Prevention

Isolated tall stature carries a good prognosis, although there may be an increased incidence of eye and heart complications. Treatment is rarely sought for males with isolated tall stature. Females with tall predicted adult heights may be treated with estrogen to advance closure of the epiphyseal growth plates. In general, the bone age can be increased by 1.5 or 2.5 years per year of estrogen treatment. The prognosis in the conditions shown in Table 20-21 depends on associated defects and complications. In Marfan syndrome, aortic dilation with dissection into the tunica media may be life threatening. Thrombosis may be a serious complication in homocystinuria. Ectopic lenses impair vision in both conditions. Patients with Klinefelter syndrome and androgen insensitivity are infertile. Fragile X syndrome is associated with mental retardation in males; homocystinuria, Sotos syndrome, and Klinefelter syndrome have associated mental retardation in some cases.

Limbs

901

Table 20-21. Conditions that include tall stature* Excessive Length at Birth

Causation, Gene, Locus

Syndrome

Major Features

Androgen insensitivity12

Males with female genitalia, blind vagina, undescended testes, deficient pubic and axillary hair, breast development at puberty

0

XLR (313700) DHTR, Xq11-q13

BeckwithWiedemann13

Generalized macrosomia, macroglossia, omphalocele, tumor predisposition

0

AD (130650) P57 or Pat UPD, 11p15.5

Contractural arachnodactyly14

Digital contractures, crumpled ear helices

þ

AD (121050) FBN2, 5q23-q31

Fragile X15

Tall facies, prominent forehead and lower jaw, macroorchidism, mental retardation

þ

XLD (309550) FMR1, Xq27.3

Homocystinuria16

Ectopic lenses, venous thromboses, osteoporosis, mental or behavioral problems

þ

AR (236200) CBS, 21q22

Hyperthyroidism6

Exophthalmos, goiter, tremor

0

Heterogeneous

17

Klinefelter

Small testes, gynecomastia, feminine habitus

0

Chromosomal (XXY)

Marfan18

Ectopic lenses, aortic dilation

þ

AD (154700) FBN1, 15q21.1

Nevo19

Contractures, edema, developmental delay

þ

AR (601451)

Pituitary tumor6

Acromegaly, visual field defect, enlarged sella turcica

0

Heterogeneous

Sclerosteosis20,21

Overgrowth and sclerosis of skeleton, syndactyly, cranial nerve compression

þ

AR (269500) SOST, 17q12-q21

Sexual precocity22

Early development of secondary sexual characteristics with or without gonadal maturation

0

Heterogeneous

Simpson-GolabiBehmel23

Overgrowth, wide mouth, cleft palate, inverted nipples, polydactyly, cystic kidneys

þ

XLD (312870) GPC3, Xq26

Sotos (cerebral gigantism)24

Macrodolichocephaly, hypertelorism, large hands and feet, developmental delay

þ

AD (117550) NSD1, 5q35

Weaver25

Overgrowth, camptodactyly, advanced bone age, developmental delay

þ

Sporadic (277590) Some cases have NSD1 mutations (5q35)

XYY26

Aggressive behavior in some

þ

Chromosomal (XYY)

*Single reports by Fryns et al.27 (overgrowth-vertebrae fusion) and Fryer28 (overgrowth-asymmetry) not listed.

References (Tall Stature) 1. Usher R, McLean F: Intrauterine growth of Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 74:901, 1969. 2. Gordon CC, Churchill T, Clauser CE, et al.: 1988 Anthropometric Survey of U.S. Army Personnel: Summary Statistics Interim Report. U.S. Army Natick Research, Development and Engineering Center, Natick, MA, 1989. 3. Ogden CL, Kuczmarski RJ, Flegal KM, et al.: Centers for Disease Control and Prevention 2000 growth charts for the United States. Improvements to the 1977 National Center for Health Statistics version. Pediatrics 109:45, 2002. 4. Saul RA, Seaver LH, Sweet KM, et al.: Growth References: Third Trimester to Adulthood. Keys Printing, Greenville, SC, 1998. 5. Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. Oxford University Press, Oxford, 1989. 6. Fisher M, Nussbaum M, Shenker IR, et al.: Growth problems in adolescence. II. Tall stature. J Curr Adolesc Med 2:23, 1980. 7. Pyle SI, Waterhouse AM, Greulich WW: A Radiographic Standard of Reference for the Growing Hand and Wrist. Press of Case Western Reserve University, Cleveland, 1971. 8. Bayley N, Pinneau SR: Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr 40:423, 1952.

9. Tanner JM, Whitehouse RA, Marshall WA, et al.: Assessment of Skeletal Maturity and Prediction of Adult Height (TW2 Method). Academic Press, New York, 1975. 10. Roche AF, Wainer H, Thissen D: Predicting adult stature for individuals. In: Monographs in Paediatrics, vol 3. S. Karger, Basel, 1975. 11. Zachman M, Sobractillo B, Frank M, et al.: Bayley-Pinneau, RocheWainer-Thissen, and Tanner height predictions in normal children and in patients with various pathologic conditions. J Pediatr 93:749, 1978. 12. Varrela J, Alvesalo L, Vinkka H: Body size and shape in 46,XY females with complete testicular feminization. Ann Hum Biol 2:291, 1984. 13. Cohen MM: A comprehensive and critical assessment of overgrowth and overgrowth syndromes. In: Advances in Human Genetics. H Harris, K Hirschhorn, eds. Plenum Press, New York 1989, p 202. 14. Ramos Arroyo MA, Weaver DD, Beals RK: Congenital contractural arachnodactyly. Report of four additional cases and review of literature. Clin Genet 27:570, 1985. 15. Prouty LA, Stevenson RE, Dean HJ: Fragile X syndrome II. Postnatal growth. Proc Greenwood Genet Center 7:87, 1988. 16. Mudd SH, Levy HL, Kraus JP: Disorders of transsulfuration. In: The Metabolic and Molecular Basis of Inherited Disease, vol 1, ed 8. CR Scriver, AL Beaudet, WS Sly, et al., eds. McGraw-Hill, New York, 2001, p 2007.

902

Skeletal System

Table 20-22. Limb overgrowth as a part of generalized macrosomia Syndrome

Major Features

Causation Gene/Locus

Beckwith-Wiedemann

Omphalocele, macroglossia, visceromegaly, earlobe creases, predisposition to malignancy

Most sporadic, some AD (130650) Pat UPD 11p15 KIP2, 11p15.5

Marshall-Smith15

Dolichocephaly, prominent eyes, brain anomalies, mental retardation, umbilical hernia, hirsutism, advanced bone age

Sporadic

Maternal diabetes mellitus16

Neonatal metabolic instability, increased risk for cardiac, nervous system, and skeletal anomalies

Excess glucose, ketones, and insulin in utero

Maternal obesity17

Proportional prenatal overgrowth that returns to normal postnatally in otherwise normal infant

Multifactorial

Parental overgrowth17

Proportional prenatal overgrowth that persists postnatally in otherwise normal infant

Multifactorial

Perlman18

Macrocephaly, round face, visceromegaly, hypotonia, predisposition to malignancy

AR (267000)

Simpson-Golabi-Behmel19,20

Macrocephaly, coarse facies, supernumerary nipples, polydactyly, hypotonia

XLD (312870) GPC3, Xq26

Sotos21,22

Downward-slanting palpebrae, hypertelorism, advanced bone age, reduced intellect

Most sporadic, some AD (117550) NSD1, 5q35

Storage diseases23,24

For several lysosomal storage disease (MPS IH, MPS IH/IS, MPS II) excessive prenatal and infantile growth followed by growth impairment

AR/XLR several

Weaver12,25

Joint contractures or limitation, micrognathia, spasticity, developmental delay, advanced bone age

Sporadic (277590) Some cases have NSD1 mutations, 5q35

12–14

17. Salbenblatt JA, Bender BG, Puck MH, et al.: Development of eight pubertal males with 47,XXY karyotype. Clin Genet 20:141, 1981. 18. Pyeritz RE, McKusick VA: The Marfan syndrome: diagnosis and management. N Engl J Med 300:772, 1979. 19. Nevo S, Zeltzer M, Benderly A, et al.: Evidence for autosomal recessive inheritance in cerebral gigantism. J Med Genet 11:158, 1974. 20. Beighton P: Inherited Disorders of the Skeleton, ed 2. Churchill Livingstone, London, 1988, p 195. 21. Hamersma H, Gardner J, Beighton P: The natural history of sclerosteosis. Clin Genet 63:192, 2003. 22. Kaplan SA, Ling SM, Irani NG: Idiopathic isosexual precocity. Therapy with medroxyprogesterone. Am J Dis Child 116:591, 1968. 23. Golabi M, Rosen L: A new X-linked mental retardation-overgrowth syndrome. Am J Med Genet 17:345, 1984. 24. Sotos JF, Dodge PR, Muirhead D, et al.: Cerebral gigantism in childhood: a syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder. N Engl J Med 271:109, 1964. 25. Ardinger HH, Hanson JW, Harrod MJE, et al.: Further delineation of Weaver syndrome. J Pediatr 108, 228, 1986. 26. Jacobs PA, Brunton M, Melville MM, et al.: Aggressive behaviour, mental subnormality and the XYY males. Nature 208:1351, 1965. 27. Fryns JP, Fabry G, Remans J, et al.: Progressive anterior vertebral body fusion, overgrowth and distinct craniofacial appearance. Genet Couns 4:235, 1993. 28. Fryer AE: A patient with a previously undescribed overgrowth syndrome. Clin Dysmorphol 4:255, 1995.

20.8 Limb Overgrowth Definition

Limb overgrowth is the enlargement of skeletal and soft tissue components of the limb. Although the term hypertrophy is often used to describe limb overgrowth, in most cases it is not known whether

the excessive mass is due to increased size of cells (hypertrophy) or to increased numbers of cells (hyperplasia). Limb overgrowth can be segmental, involving a single limb or part of a limb, or can be a component of hemihypertrophy or generalized macrosomia. This category of anomaly does not include excessive limb length with normal or decreased soft tissue mass, nor does it include excessive soft tissue with normal or decreased bone length. Diagnosis

Segmental limb overgrowth and hemihypertrophy cause discordance in the size of all or a part of paired limbs and can be more easily detected than proportional overgrowth (Fig. 20-52). The discordance in limb size is usually apparent at birth or in the early months of life. Surface measurements of the limb are usually adequate to demonstrate a size difference between the two sides. Circumference often provides a better discriminator than does length between bony landmarks. Radiographs of the skeleton with comparisons of bone length to age-specific and sex-specific standards may be helpful in some cases.1 The craniofacies and trunk may be involved in hemihypertrophy. Crossover hemihypertrophy with overgrowth of one part on the left and another part on the right may occur as well. In some cases of limb asymmetry, it is difficult to determine whether the smaller limb is undergrown or the larger limb is overgrown.2 Limb undergrowth and hemihypotrophy are more commonly found in association with other anomalies and mental deficiency.2–5 Russell-Silver syndrome, diploid-triploid mosaicism, and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome) are three examples. If accompanied by neurologic dysfunction, the smaller limb is usually considered atrophied. Edema from lymphatic or venous obstruction can also cause soft tissue enlargement, but this is not accompanied by bone overgrowth.

Limbs

903

Fig. 20-52. Hemihypertrophy affecting left upper and lower limb in a 21⁄2 year old boy. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

When generalized overgrowth occurs, standard measurements may be taken for comparison with age- and sex-specific norms. Radiographs are useful in demonstrating that the limb bones participate in the overgrowth and in determining the amount of growth potential remaining. Although some patients with limb overgrowth will show advanced bone age, overgrowth may occur without altering the bone age. Cutaneous and vascular anomalies commonly occur in association with limb overgrowth, particularly when the excessive growth is segmental.2,6–11 Linear pigmented nevi may be present on the affected segment (Fig. 20-53). Superficial or deep vascular malformations involving soft tissue and bone may be present in the affected segment or elsewhere (Fig. 20-54). Hemangiomas, arteriovenous fistulas, venous angiomas, lymphangiectasia, and lipomas have been reported. Malformations of the heart and major arteries have been reported as well. Massive infiltration of soft tissue with mature adipocytes has been found in some cases. Uncommonly, patients with hemihypertrophy have absence of sweating and insensitivity to pain over the affected limb. Ipsilateral cerebral enlargement with or without ventriculomegaly or vascular malformations has been noted rarely. Seizures or contralateral neurologic signs occur uncommonly, but mental retardation has been reported in 20% of cases. Limb overgrowth as a part of generalized macrosomia has been seen in several heritable syndromes (Table 20-22). In most cases, these infants are large at birth and continue to grow at an excessive rate thereafter. An exception is the Marshall-Smith syndrome in which growth dramatically decreases during infancy. Typically, infants of women with class A-C diabetes experience excessive prenatal growth. Postnatally the growth in these infants returns to the normal rate. Likewise, infants of obese women and of large parents exhibit excessive intrauterine growth. Infants of large parents often continue to grow at excessive rates postnatally, in keeping with the familial large stature. Infants with segmental limb overgrowth and hemihypertrophy exhibit limb overgrowth throughout childhood. The size

discrepancy between affected and unaffected segments may remain static or may become progressively greater until bone growth is completed. Progressive growth disparity is particularly seen in cases when the bone age is advanced in the overgrown segment. Some catch-up growth may occur in the smaller limb if the bones in the larger limb mature first. Segmental limb overgrowth and hemihypertrophy are seen in a large and causally heterogeneous group of entities (Table 20-23). Macrodactyly

Isolated overgrowth of the soft tissues and phalanges of the digits occurs uncommonly (Fig. 20-55). Several hundred cases have been reported.49–51 Bilateral involvement occurs more commonly than unilateral involvement, and multiple digits are involved more commonly than a single digit. When multiple digits are involved, they are always adjacent and may be syndactylous. Digit 2 is affected most often. The hands are affected more commonly than the feet and males more commonly than females. In the type of digit involvement termed macrodactyly simplex congenita, the digit is large at birth and does not grow disproportionately thereafter.50 This type accounts for about 10% of macrodactyly cases, involves any digit, and occurs sporadically. In a second type, macrodystrophica lipomatosa progressiva, the abnormal rate of growth continues postnatally, causing progressively greater disparity between affected and unaffected digits. This latter type is often associated with fatty infiltration of the soft tissues of the digits.50,51 Overgrowth of the palms and soles with fibrous and fatty tissue commonly accompanies macrodactyly, causing digits to appear dorsally placed rather than at the terminus of the hand or foot. Microscopically the overgrowth is characterized by deposition of adipose and fibrous tissue. Commonly the nerves are thickened. During the growth period, the overgrown digit may become angulated, usually deviating to the ulnar side at the distal phalanx. The excessive rate of growth ceases with bone maturation.

Fig. 20-53. Overgrowth of left upper limb associated with a linear nevus of the left upper limb in a girl with lipomas of the back (Proteus syndrome). The linear nevus extended from the left pectoral region to the palm. Progressive disparity of limb size occurred over the first 3 years, but bone age in the two hands remained the same (right). Fig. 20-54. Overgrowth of left upper and lower limbs associated with hemangiomas in a girl with Klippel-Trenaunay-Weber syndrome. Overgrowth is more pronounced in left lower limb as evidenced by difference in foot sizes.

904

Limbs

905

Table 20-23. Entities that include segmental or asymmetric limb overgrowth Syndrome

Major Features

Causation Gene/Locus

CHILD

Congenital hemidysplasia, ichthyosiform erythroderma, limb defects

XLD (308050) NXDH2, Xq28

Chromosome mosaicism and segment aneusomy (diploid/triploid; trisomy 18 mosaicism; 45,X mosaicism; distal dup 15q)12,26–31

Hemihypertrophy, variable other features depending on chromosome(s) involved and tissues involved

Chromosomal mosaicism

Dysplasia epiphysialis hemimelica32

Asymmetrical overgrowth of one or more epiphyses in the limb, onset at birth or first decade of life

Unknown

Fibrous dysplasia (polyostotic)33

Fibrous dysplasia involving multiple bones, skin pigmentation, endocrine disturbance, precocious menarche

Usually sporadic, occasionally AD (174800)

Fischer; hemihypertrophy-intracranial vascular malformation9

Hemihypertrophy, vascular malformation of brain, seizures

Sporadic

Isolated hemihypertrophy2,26,34–37

Increased risks for intraabdominal malignancy, mental impairment

Sporadic

Klippel-Trenaunay-Weber6,12

Cutaneous hemangiomas, varicosities, agenesis or obstruction of deep veins, limb overgrowth associated with vascular anomalies

Sporadic

Maffucci38

Enchondromas, subcutaneous hemangiomas

Sporadic (166000)

Macrodactyly (simple)39,40

Nonprogressive overgrowth of one or more digits, prenatal onset

Sporadic

5

Macrodactyly (lipomatous)

39,40

Progressive lipomatous overgrowth of one or more digits

Sporadic

Neurofibromatosis41,42

Cafe´ au lait pigmentation, fibromas and other soft tissue tumors, oncogenic potential

AD (162200) NF1, 17q11.2

Nudleman: hemihypertrophyhemihypaesthesia-hemiareflexia43

Hemihypertrophy, hemihypaesthesia, hemiareflexia

Sporadic (235000)

Ollier44

Osteochondromas, oncogenic potential

Usually sporadic (166000)

Partial gigantism45

Overgrowth of any part of the body, advanced bone age of affected part

Heterogeneous

Proteus10,46

Lipoatrophy, pigmented nevi, asymmetric overgrowth of soft tissues, lipomas, hamartomas, skull exostoses, thickened palms and soles

Sporadic PTEN mutations reported but cases questioned46

Temtamy: crossed hemihypertrophyosteochondromas47

Cutaneous and deep vascular malformations, multiple osteochondromas of craniofacial and limb bones (possibly same as Maffucci syndrome)

Unknown

Temtamy: macrodactylyhemihypertrophy-nevus48

Single case with skin thickening and depigmentation, hemihypertrophy and macrodactyly (possibly same as Proteus syndrome)

Unknown

The etiology of isolated macrodactyly has not been determined. All cases appear to be sporadic. Numerous suggestions have been offered regarding the pathogenesis. Prominent is the suggestion that localized growth factors, or a localized lack of inhibition of growth factors, or an overresponsiveness to growth factors is at work.49,50,52 The presence of thickened nerves in many cases of simple macrodactyly has suggested a neurotrophic influence. The infiltration with adipose tissue in lipomatous macrodactyly has suggested a lipotrophic factor. It is sufficient to say that the factors underlying localized overgrowth of the digits have not been determined. Although the etiology is known in some cases of syndromic macrodactyly, the pathogenesis of the overgrowth in these entities remains obscure as well (Table 20-24). Hemihypertrophy

Unilateral limb overgrowth occurs with ipsilateral overgrowth of the craniofacies and trunk in isolated hemihypertrophy.2,36 Several hundred cases have been reported. Cutaneous and vascular

anomalies do not occur and serve to distinguish isolated hemihypertrophy from overgrowth as a part of Klippel-TrenaunayWeber syndrome, Proteus syndrome, and neurofibromatosis. Increased risks for genitourinary anomalies and intra-abdominal tumors accompany the asymmetric somatic growth. The asymmetry can be detected at birth or within the first 6 months of infancy. While the size difference of the two sides persists, the disparity does not generally increase with age (Fig. 2056). Bone age usually does not differ between the two sides, but this is not invariable. Hemihypertrophy has been reported in 3% of children with Wilms tumor. Conversely, Wilms tumor develops in 4% of children with hemihypertrophy.12,17,26,34 The risk of developing Wilms tumor is greater during the initial 3 years of life, during which the child with hemihypertrophy should be monitored with ultrasound every 6 months. Other intraabdominal tumors, including adrenal carcinoma, hepatoblastoma, pheochromocytoma, and retroperitoneal sarcoma, have been found in association with

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Skeletal System

Fig. 20-55. Isolated macrodactyly in three patients involving right fingers 2 and 3 (left), right fingers 3 to 5 (center), and right toe 2 (right). (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

hemihypertrophy. Genitourinary anomalies, including inguinal hernias, cryptorchidism, medullary sponge kidney, renal cysts, and horseshoe kidney, show an increased incidence in hemihypertrophy. Intellectual impairment has been reported in 15–25% of individuals with hemihypertrophy. Beals2 found no case of mental retardation among 20 patients with hemihypertrophy. He speculated that the increased risk for mental deficiency found in other

Table 20-24. Entities that include macrodactyly Isolated, simple (macrodactyly congenita simplex) Isolated, lipomatous (macrodystrophica lipomatosa progressiva) Syndromic entities Klippel-Trenaunay-Weber Neurofibromatosis Proteus Polyostotic fibrous dysplasia Hemangiomas Ollier disease Idiopathic hemihypertrophy Temtamy: macrodactyly-hemihypertrophy-nevus Maffucci

studies may have reflected inclusion of hemihypotrophy cases in these series. The cause for isolated hemihypertrophy is not known. Familial cases are rare. Affected females have been reported more frequently than males in several series. Isolated hemihypertrophy requires differentiation from hemihypotrophy associated with several syndromes, hemiatrophy associated with neurologic impairments, and hemihypertrophy associated with certain heritable (single gene and chromosomal) and sporadic syndromes (Table 20-25). Leck et al.53 have found the incidence of hemihypertrophy to be one per 15,000 births in England. This incidence figure likely includes a heterogeneous group of disorders that include limb asymmetry. Etiology and Distribution

Both heritable and environmental causes for limb overgrowth are recognized (Tables 20-22, 20-23, and 20-25). Limb overgrowth due to these identifiable causes often is merely a part of generalized somatic overgrowth. Generalized overgrowth secondary to maternal diabetes has been attributed to excess glucose and insulin during the prenatal period. Similarly, an excessive supply of nutrients may be the cause of intrauterine overgrowth in infants of obese mothers. Genetic factors likely play a more dominant role in fetal overgrowth associated with large parents, BeckwithWiedemann syndrome, Marshall-Smith syndrome, Weaver syndrome, and certain storage disorders (Fig. 20-57). No satisfactory explanation has been found for most cases of segmental overgrowth of the limbs or hemihypertrophy. A direct

Limbs

907

Fig. 20-56. Hemihypertrophy without nevi or hemangiomas limited to the right lower limb in a 6-year-old female. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

genetic influence should be suspected in cases associated with neurofibromatosis, Proteus syndrome, and Klippel-TrenaunayWeber syndrome. The nature of the genetic influence and the reason for its regional effect in these conditions are, however, not known. Segmental overgrowth and hemihypertrophy are both good candidates for genetic mosaicism in which the genetic makeup of Table 20-25. Entities that include hemihypertrophy Chromosome 11p13 deletiona Chromosome mosaicisma Diploid/triploid Trisomy 18/normal

the affected tissues differs from the balance of the body tissues. Streeter52 and others have favored the idea that localized overgrowth represents intrinsic localized tissue defects that were overresponsive to growth factors. Others have suggested localized lack of growth inhibitors. The association with angiomas has provided a basis for thinking that overgrowth may be caused by nutrient oversupply in an area of hypervascularity. The association of nerve overgrowth gives a basis for anticipating that a neurotrophic factor is at work in these cases. The accumulation of fat suggests that the lipotrophic factors may be at work. Much remains to be learned about the pathogenesis of limb overgrowth. Only now is the technology becoming available to study some of the many growth factors, the genes responsible, and their control and tissue partition.

45,X/normal Fischer: hemihypertrophy-vascular malformation of brain

Prognosis, Treatment, and Prevention

Hanley: hemihypertrophy-jejunal web-preauricular tag-corneal opacity

Limb overgrowth represents an important clinical finding that necessitates a careful search for other less obvious associated features. These features, more than the asymmetry, may determine the prognosis and dictate therapy. Specifically, central nervous system malformations or tumors, deep tissue vascular malformations, renal malformations, and intraabdominal malignancies may occur in association with limb overgrowth. Mental retardation also occurs with increased frequency. Chromosome studies may document that mosaicism is responsible for the growth asymmetry in a minority of cases. Treatment must be directed at the limb overgrowth and at other complications.54–56 In simple macrodactyly and isolated hemihypertrophy, the growth disparity usually remains static during childhood. Shortening and debulking of digits can have satisfactory

Isolated hemihypertrophy Klippel-Trenaunay-Weber Maffucci Neurofibromatosis Nudleman: hemihypertrophy-hemihypaesthesia-hemiareflexia Partial gigantism Proteus Temtamy: macrodactyly-hemihypertrophy-nevus a Asymmetry may be caused by hemiatrophy or hemihypotrophy of small region rather than hemihypertrophy of enlarged region.

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Skeletal System

Fig. 20-57. Generalized overgrowth in an infant of a diabetic mother (upper left) and in an infant with Beckwith-Wiedemann syndrome (upper right). Localized lipomatous overgrowth of trunk in one of monozygous twins with Proteus syndrome (lower left), and verrucous overgrowth of the soft tissue of the foot in an adult with neurofibromatosis (lower right).

results. Bone lengthening of the shorter limb or epiphysiodesis of the larger limb may be used to equalize limb length. These procedures are performed more commonly on the lower limbs but can be used in upper limb asymmetry as well. Alternatively, a built-up shoe may be used to equalize the lower limbs and to help prevent scoliosis. Partial

or complete amputation of the macrodactylous toes may be necessary to permit shoe fitting. In contrast, hemihypertrophy, segmental overgrowth, and macrodactyly associated with nevi, hemangiomas, and lipomatous infiltration show progressively disparate growth and pose greater

Limbs

difficulties in treatment. Surgery consisting of joint ablation, epiphysiodesis, and partial amputation are all used but with less satisfactory results. Ligation and laser ablation of angiomas and fistulas have been successful in some circumstances. Success in debulking overgrown tissues depends on the extent of involvement and the cause. Smaller areas may be debulked with successful cosmetic results. Larger areas often require repeated removal of skin and soft tissues. Massive scarring and keloid formations may occur as complications. When there is substantial interference with function, amputation may be the treatment of choice. In the absence of generalized macrosomia or associated anomalies, prenatal diagnosis of limb overgrowth is a formidable task. Ultrasonographic evaluation provides the major means of detection. Limb asymmetry should be sought when intracranial or renal anomalies are found and when omphalocele is present. However, the disparity in limb size may be too subtle during the second trimester for convincing demonstration. References (Limb Overgrowth) 1. Maresh MM: Linear growth of long bones of the extremities from infancy through adolescence. Am J Dis Child 89:725, 1955. 2. Beals RK: Hemihypertrophy and hemihypotrophy. Clin Orthop 166: 199, 1982. 3. Tanner JM, Lejarraga H, Cameron N: The natural history of the SilverRussell syndrome: a longitudinal study of thirty-nine cases. Pediatr Res 9:611, 1975. 4. Jenkins ME, Eisen J, Sequin F: Congenital asymmetry and diploidtriploid mosaicism. Am J Dis Child 122:80, 1971. 5. Happle R, Koch H, Lenz W: The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr 134:27, 1980. 6. Lindenauer SM: The Klippel-Trenaunay syndrome. Varicosity, hypertrophy and hemangioma with no arteriovenous fistula. Ann Surg 162:303, 1965. 7. Enell H, Hahn B: Elephantiasis congenita angiomatosa. Acta Paediatr 42:416, 1953. 8. McCullough CJ, Kenwright J: The prognosis in congenital lower limb hypertrophy. Acta Orthop Scand 50:307, 1979. 9. Fischer EG, Strand RD, Shapiro F: Congenital hemihypertrophy and abnormalities of the cerebral vasculature. J Neurosurg 61:163, 1984. 10. Biesecker LG, Happle R, Mulliken JB, et al.: Proteus syndrome: Diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84:389, 1999. 11. Powell ST, Su WPD: Cutis marmorata telangiectasia congenita: report of nine cases and review of the literature. Cutis 34:305, 1984. 12. Cohen MM Jr, Neri G, Weksberg R: Overgrowth Syndromes. Oxford University Press, New York, 2002. 13. Li M, Squire JA, Weksberg R: Molecular genetics of WiedemannBeckwith syndrome. Am J Med Genet 79:253, 1998. 14. Pettenati MJ, Haines JL, Higgins RR, et al.: Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 74:143, 1986. 15. Williams DK, Carlton DR, Green SH, et al.: Marshall-Smith syndrome: The expanding phenotype. J Med Genet 34:842, 1997. 16. Horger EO, Facog M, Miller C, et al.: Relation of large birthweight to maternal diabetes mellitus: Obstet Gynecol 45:150, 1975. 17. Stevenson DK, Hooper AO, Cohen RS, et al.: Macrosomia: causes and consequences. J Pediatr 100:515, 1982. 18. Neri G, Martini-Neri ME, Katz BE, et al.: The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. Am J Med Genet 19:195, 1984. 19. Neri G, Gurrieri F, Zanni G, et al.: Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome. Am J Med Genet 79:279, 1998.

909 20. Pilia G, Hughes-Benzie RM, Mackenzie A, et al.: Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12:241, 1996. 21. Sotos JF, Dodge PR, Muirhead D, et al.: Cerebral gigantism in childhood: a syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder. N Engl J Med 271:109, 1964. 22. Turkmen SW, Gillessen-Kaesbach G, Meinecke P, et al.: Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Eur J Hum Genet 11:858, 2003. 23. Stevenson RE, Howell RR, McKusick VA, et al.: The iduronidasedeficient mucopolysaccharidoses: clinical and roentgenographic features. Pediatrics 57:61, 1976. 24. Aylsworth AS, Taylor HA, Stuart CM, et al.: Mannosidosis: phenotype of a severely affected child and characterization of a-mannosidase activity in cultured fibroblasts from the patient and his parents. J Pediatr 88:814, 1976. 25. Weaver DD, Graham CB, Thomas IT, et al.: A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly. J Pediatr 84:547, 1974. 26. Fraumeni JF Jr, Geiser CF, Manning MD: Wilms’ tumor and congenital hemihypertrophy: report of five new cases and review of literature. Pediatrics 40:886, 1967. 27. Jenkins ME, Eisen J, Sequin F: Congenital asymmetry and diploidtriploid mosaicism. Am J Dis Child 122:80, 1971. 28. Hook EB, Yunis JJ: Congenital asymmetry associated with trisomy 18 mosaicism. Am J Dis Child 110:551, 1965. 29. Brogger A, van der Hagen CB, Storen A: Mosaicism involving two karyotypes with 45 chromosomes and a new autosomal translocation in a girl with mental defect, asymmetry, congenital heart disease and other malformations. Acta Paediatr 155(suppl):44, 1965. 30. Gerloczy F, Schuler D, Letenyei K, et al.: Hemihypertrophy: 10 years follow-up and chromosomal study. Acta Paediatr Acad Sci Hung 6:423, 1965. 31. Zollino M, Tiziano F, Di Stefano C, et al.: Partial duplication of the long arm of chromosome 15q: confirmation of a causative role in craniosynostosis and definition of a 15q25-qter trisomy syndrome. Am J Med Genet 87:391, 1999. 32. Connor JM, Horan FT, Beighton P: Dysplasia epiphysealis hemimelica. A clinical and genetic study. J Bone Joint Surg 65B:350, 1983. 33. Albright F, Butler AM, Hampton AO, et al.: Syndrome characterized by osteitis fibrosa dessiminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females: report of five cases. N Engl J Med 216:727, 1937. 34. Hoyme HE, Procopio F, Crooks W, et al.: The incidence of neoplasia in children with isolated congenital hemihypertrophy. Proc Greenwood Genet Cent 6:126, 1987. 35. Ringrose RE, Jabbour JT, Keele DK: Hemihypertrophy. Pediatrics 36:434, 1965. 36. Viljoen D, Pearn J, Beighton P: Manifestations and natural history of idiopathic hemihypertrophy: a review of eleven cases. Clin Genet 26:81, 1984. 37. Harris RE, Fuchs EF, Kaempe MJ: Medullary sponge kidney and congenital hemihypertrophy: case report and literature review. Urology 126:676, 1981. 38. Sun TC, Swee RG, Shives TC, et al.: Chondrosarcoma in Maffucci’s syndrome. J Bone Joint Surg 67A:1214, 1985. 39. Pearn J, Bloch CE, Nelson MM: Macrodactyly simplex congenita. A case series and considerations of differential diagnosis and actology. S Afr Med J 70:755, 1986. 40. Thorne FL, Posch JL, Mladick RA: Megalodactyly. Plast Reconstr Surg 41:232, 1968. 41. Crawford AH: Neurofibromatosis in children. Acta Orthop Scand 57:1, 1986. 42. Riccardi VM: Neurofibromatosis. Phenotype, Natural History and Pathogenesis, ed 2. John Hopkins University Press, Baltimore, 1992. 43. Nudleman K, Andermann E, Andermann F, et al.: The hemi 3 syndrome. Hemihypertrophy, hemihypaesthesia, hemiareflexia, and scoliosis. Brain 107:533, 1984.

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44. Temtamy S, McKusick V: The genetics of hand malformations. Birth Defects Orig Artic Ser XIV(3):513, 1978. 45. Gonzalez-Crussi F, Lee SC, McKinney M: The pathology of congenital localized gigantism. Plast Reconstr Surg 59:411, 1977. 46. Cohen MM Jr, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 122A:323, 2003. 47. Temtamy S, McKusick V: The genetics of hand malformations. Birth Defects Orig Artic Ser XIV(3):519, 1978. 48. Temtamy SA, Rogers JG: Macrodactyly, hemihypertrophy and connective tissue nevi: report of a new syndrome and review of the literature. J Pediatr 89:924, 1976. 49. Barsky AJ: Macrodactyly. J Bone Joint Surg 49A:1255, 1967. 50. Pearn J, Bloch CE, Nelson MM: Macrodactyly simplex congenita. A case series and considerations of differential diagnosis and aetiology. S Afr Med J 70:755, 1986. 51. Tuli SM, Khanna NN, Sinha GP: Congenital macrodactyly. Br J Plast Surg 22:237, 1969. 52. Streeter GL: Focal deficiencies in fetal tissues and their relation to intra-uterine amputation. Contrib Embryol 22:1, 1930. 53. Leck I, Record IQ, McKeown T, et al.: The incidence of malformations in Birmingham, England, 1950-1959. Teratology 1:263, 1968. 54. Kinmoth JB, Young AE, Edwards JM, et al.: Mixed vascular deformities of the lower limbs with particular reference to lymphography and surgical treatment. Br J Surg 63:899, 1976. 55. Letts RM: Orthopaedic treatment of hemangiomatous hypertrophy of the lower extremity. J Bone Joint Surg 59A:777, 1977. 56. Dell PC: Macrodactyly. Hand Clin 1:511, 1985.

20.9 Increased Bone Density Definition

Increased bone density results from the excessive deposition or deficient resorption of calcium salts from bones. The term osteosclerosis is used to indicate increased density of bone without expansion of the bone. Hyperostosis indicates increased density of bone associated with expansion of the bone. Osteopetrosis (marble bone) also indicates increased density of the bone, but this term is best reserved for two specific heritable disorders described by Albers-Schonberg1 and by Nadolny.2 Diagnosis

Increased bone density is detected by radiographs. In practice, it is a subjective determination based on the apparent radiodensity. Measurement of the thickness of the cortex of the bones of the hands and comparison with standards provides an objective means of diagnosis.3 Alternatively, densitometry may be performed on bones using radiographs taken under standardized conditions.4 Increased bone density may be generalized, affecting all bones of the membranous and cartilaginous skeleton (Fig. 20-58). When generalized, increased bone density usually represents an important finding, indicating the presence of a systemic disorder. These conditions are rare and are usually heritable (Table 20-26).4–13 Localized areas of increased density may be seen in areas of infection, hematoma, or callous formation. The concavities of bowed bones have thickened cortices, and in some cases the cortical thickness obliterates the medullary cavity (see Section 20.5). Certain heritable conditions, metabolic derangements, and nutritional deficiencies may also cause increased bone density of a segmental or localized nature (Fig. 20-59, Table 20-27).14–24 Increased bone thickness may cause disfigurement, particularly when the craniofacial bones are involved.6,7,13,14,17,18

Curvature of the long bones or fracture may prompt radiographic studies. Musculoskeletal pain is prominent in some patients with increased bone density. Often, however, increased bone density is a finding noted on radiographs taken for unrelated reasons. Increased bone strength does not accompany increased bone density. To the contrary, in most conditions in which there is generalized increased density of the bones, an associated fragility is manifested by an increased incidence of fractures. Expansion of the cortical bone may produce anemia by encroaching on the marrow cavity and nerve damage by narrowing the bony foramina. Etiology and Distribution

Maintenance of bone mass is achieved through balancing the resorptive activity of osteoclasts and the regenerative activity of osteoblasts. Type 1 collagen and hydroxyapatite are the main constituents of bone, but a host of enzymatic, structural, and regulatory proteins are involved in bone remodeling. Mutations in any of the genes that give osteoblast activity an advantage over osteoclast activity may result in the accumulation of excessive bone mass and increased bone density. The continuous deposition and resorption of calcium are normal processes. These dynamic processes allow bone restructuring, healing, and renewal and are complex phenomena involving intrinsic cellular, hormonal, and other metabolic factors. Increased bone density is produced by excessive deposition of calcium salts in bone or by deficient resorption of calcium from bone. The organic matrix into which calcium salts are deposited consists of collagen fibers and a ground substance (proteoglycans and glycoproteins). The primary calcium salt in bone is hydroxyapatite [CAl0(PO4) (OH)2], although other calcium salts may be found in small amounts. In most cases, hyperdense bones result from calcium deposition in osteoid that is thickened. Hyperdense bones can, however, result from concentration of calcium salts in an otherwise normal cortex. Most entities with increased bone density are heritable. (Tables 20-26 and 20-27; see also Section 15 of Table 22-3 in Chapter 22). Prognosis, Treatment, and Prevention

In disorders that include generalized increased bone density, dense bones are present at birth and have been diagnosed prenatally on radiographs taken late in pregnancy. These disorders are progressive, with the bones showing increased density over time. An increased incidence of complications (anemia, bone fragility, and nerve compression) accompanies this progression. The range of symptoms in patients with bone density varies greatly. Some patients have no symptoms, the diagnosis being made on radiographs taken for unrelated reasons. This is the case for some patients with dominant osteopetrosis, diaphyseal dysplasia, and osteopoikilosis. Limb pain and muscle weakness may be prominent symptoms in patients with diaphyseal dysplasia. Pain may also occur in osteopetrosis, the craniotubular dysplasias, melorheostosis, and the cortical hyperostosis of Caffey. In conditions with cranial involvement, deafness, optic atrophy and blindness, and cranial nerve palsies from narrowing of the cranial foramina occur. Anemia is a prominent feature in recessive osteopetrosis, occurs less often and with less severity in dominant osteopetrosis and Kenny medullary stenosis, and is not to be expected in the other sclerosis conditions. Growth impairment is notable in pycnodysostosis and recessive osteopetrosis and may be present in several other conditions listed in Table 20-26 as well. Excessive stature is often present in sclerosteosis.

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Fig. 20-58. A. 4-year-old girl with osteopetrosis. Radiographs show generalized increase in bone density of long bones in osteopetrosis at age 1 year (B,C), age 10 years (D,E) and age 27 years (F,G). (A–C courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

References (Increased Bone Density) 1. Albers-Schonberg H: Rontgenbilder einer seltenen knochenerkrankung. Munchen Med Wochenschr 51:365, 1904. 2. Nadolny G: Diffuse osteosklerose im kindesalter. Jahr Kinderh 105:212, 1924. 3. Morgan DB, Spiers FW, Pulvertaft CN, et al.: The amount of bone in the metacarpal and the phalanx according to age and sex. Clin Radiol 18:101, 1967.

4. Shagam JY: Bone densitometry: an update. Radiol Technol 74:321, 2003. 5. Robinow M, Johanson AJ, Smith TH: The Lenz-Majewski hyperostotic dwarfism. J Pediatr 91:417, 1977. 6. Griffiths DL: Engelmann’s disease. J Bone Joint Surg 38B:312, 1956. 7. Kinoshita A, Saito T, Tomita H, et al.: Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet 26:19, 2000.

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Table 20-26. Conditions that include generalized increase in bone density Condition

Major Features

Causation Gene/Locus

Braham dysplasia

Growth and developmental retardation, large fontanelle, hypertelorism, deficient calcification of teeth, proximal symphalangism, loose atrophic skin, prominent veins, cryptorchidism, hyperextensible joints

Uncertain (151050)

Camurati-Engelmann6,7

Long slender extremities, decreased muscle mass and strength, leg pain, marked variability of symptoms

AD (131300) TGFB1, 19q13.1

Craniodiaphyseal dysplasia8

Progressive overgrowth of craniofacial skeleton, particularly about the nose; cranial nerve compression; late-onset mental and growth impairment; vertebral bodies spared

AR (218300)

Craniometaphyseal dysplasia9

Overgrowth of craniofacial skeleton, particularly in the frontal region; obliteration of paranasal sinuses; diaphyseal involvement in childhood; vertebral bodies spared

AD (123000) ANKH, 6q21-q22 AR (218400)

Dysosteosclerosis10

Short stature, platyspondyly, widening of metaphyses with radiolucency between diaphysis and metaphysis, optic atrophy

AR (224300)

Generalized cortical hyperostosis11

Dense skeleton with cortical widening

AD (144750) LRP5, 11q13.4

Osteopetrosis, recessive12–14

Growth and developmental impairment, pallor, sparse hair, cranial nerve compression, late eruption and early loss of teeth, hepatosplenomegaly, anemia

AR (259700) GL, 6q21 CLCN7, 16p13 TCIRG1, 11q13.4-q13.5

Osteopetrosis, dominant14–18

Cranial nerve compression, variable joint or bone pain, mild anemia

AD (166600) LRP5, 11q13.4 CLCN7, 16p13

Pycnodysostosis19

Short stature, large cranium, wide fontanelles, small mandible, brachydactyly, brittle nails, fractures

AR (265800) CTSK, 1q21

Sclerosteosis20,21

Somatic and skeletal overgrowth, cranial nerve compression, proptosis, digital anomalies

AR (269500) SOST, 17q12-q21

Van Buchem (endosteal hyperostosis)22

Short stature, mandibular and frontal overgrowth, cranial nerve compression, endosteal hyperostosis of tubular bones

AR (239100) Decreased SOST expression, 17q12-q21

5

Other skeletal dysplasias with increased bone density are listed in Table 22-4, Sections 26 and 27, Chapter 22.

8. Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperostoses. A critical analysis. Birth Defects Orig Artic Ser V(4):79, 1969. 9. Rimoin DL, Woodruff SL, Holman BL: Craniometaphyseal dysplasia (Pyle’s disease): autosomal dominant inheritance in a large kindred. Birth Defects Orig Artic Ser V(4):96, 1969. 10. Spranger J, Albrecht C, Rohwedder HJ, et al.: Die Dysosteosklerose, eine Sonderform der generalisierten osteosklerose. Fortschr Rontgenol, 109:504, 1968. 11. Worth HM, Wollin DG: Hyperostosis corticalis generalisiata congenita. J Can Assoc Radiol 17:67, 1966. 12. Frattini A, Orchard PJ, Sobacchi C, et al.: Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25:343, 2000. 13. Beighton P, Hamersma H, Cremin BJ: Osteopetrosis in South Africa. The benign, lethal, and intermediate forms. S Afr Med J 55:659, 1979. 14. Chalhoub N, Benachenhou N, Rajapurohitam V, et al.: Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 9:399, 2003. 15. Bollerslev J, Andersen PE Jr: Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis. Bone 9:7, 1988. 16. Van Hul E, Gram J, Bollerslev J, et al.: Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13. J Bone Miner Res 17:1111, 2002. 17. Benichou OD, Laredo JD, De Vernejoul MC: Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone 26:87, 2000.

18. Cleiren E, Benichou O, Van Hul E, et al.: Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the CICN7 chloride channel gene. Hum Molec Genet 10:2861, 2001. 19. Sedano HD, Gorlin RJ, Anderson VE: Pycnodysostosis. Clinical and genetic considerations. Am J Dis Child 116:70, 1968. 20. Beighton P, Durr L, Hamersma H: The clinical features of sclerosteosis: a review of the manifestations in twenty-five affected individuals. Ann Intern Med 84:393, 1976. 21. Brunkow ME, Gardner JC, Van Ness J, et al.: Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knotcontaining protein. Am J Hum Genet 68:577, 2001. 22. Van Buchem FSP, Hadders HN, Hansen JF, et al.: Hyperostosis corticalis generalisata. Report of seven cases. Am J Med 33:387, 1962. 23. Saul RA, Lee WH, Stevenson RE: Caffey’s disease revisited. Further evidence for autosomal dominant inheritance with incomplete penetrance. Am J Dis Child 136:56, 1982. 24. Spranger J, Maroteaux P: The lethal osteochondrodysplasias. Adv Hum Genet 19:1, 1990. 25. Firat D, Stutzman L: Fibrous dysplasia of bone. Review of twenty-four cases. Am J Med 44:421, 1968. 26. Bianco P, Riminucci M, Majolagbe A, et al.: Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in nonMcCune-Albright fibrous dysplasia of bone. J Bone Miner Res 15:120, 2000. 27. Gorlin RJ, Cohen MM Jr: Fronto-metaphyseal dysplasia. Am J Dis Child 118:487, 1969.

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Fig. 20-59. Left and middle: Leg swelling and curvature associated with increased density and expansion of the tibia in an infant with Caffey disease. Right: Irregular cortical density and thickening of phalanges in an adult female with melorheostosis. (Courtesy of Dr. R. I. Macpherson, Medical University of South Carolina, Charleston.)

Table 20-27. Disorders that include segmental, localized, or irregular increase in bone density Disorder

Major Features

Causation Gene/Locus

Usual infantile onset of hyperostosis of virtually any bone, most commonly affects bones of lower limbs or mandible, associated pain and swelling, spontaneous resolution

AD (114000)

Dappled diaphyseal dysplasia24

Lethal, fragmented long bones with calcified and noncalcified areas, general undermineralization of skeleton

AR

Fibrous dysplasia (polyostotic)25,26

Skin pigmentation, endocrine disturbances

AD (174800) GNAS, 20q13.2

Frontometaphyseal dysplasia27–29

Irregular densities of skull with frontal overgrowth; irregular densities of tubular bones; bowed long bones including ribs

XL (305620) FLNA, Xq28

Kenny: medullary narrowing30

Short stature, cortex of long bones thickened at expense of medullary cavity, hypocalcemia

AR (244460) Tubulin-specific chaperone E, 1q42-q43

Melnick-Needles29,31

Irregular densities and thickening of cranium, bowed bones, proptosis, high and narrow forehead

XL (309350) FLNA, Xq28

Melorheostosis32

Irregular cortical thickening affecting a single bone, limb, or side of the body; pain over site of cortical involvement

(155950)

Osteoectasia (hyperphosphatasia)33

Large cranium with irregular protuberance, expansion and irregular sclerosis of long bones, fever, anemia, bone pain, fractures

AR (239000)

Osteopoikilosis34

Spotty distribution of multiple small sclerotic plaques often in epiphyses or metaphyses of long bones, flat nevi

AD (166700)

Pachydermoperiostosis35

Digital clubbing, oiliness of skin, seborrhea, hyperhydrosis, enlarged paranasal sinuses, thickened and sclerotic cortices of long bones

AD (167100)

Paget: osteitis deformans36

Localized or widespread skeletal involvement with expansion of bone with sclerotic and lucent areas, fractures, pain

Uncertain (167250)

Caffey: cortical hyperostosis

23

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28. Zenker M, Rauch A, Winterpacht A, et al.: A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts. Am J Hum Genet 74:731, 2004. 29. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 30. Kenny FM, Linarelli L: Dwarfism and cortical thickening of tubular bones. Transient hypocalcemia in a mother and son. Am J Dis Child 111:201, 1966. 31. Melnick JC, Needles CF: An undiagnosed bone dysplasia: a 2 family study of 4 generations and 3 generations. AJR Am J Roentgenol 97:39, 1966. 32. Campbell CJ, Papademetriou T, Bonfiglio M: Melorheostosis. A report of the clinical, roentgenographic, and pathological findings in fourteen cases. J Bone Joint Surg 50A:1281, 1968. 33. Caffey J: Familial hyperphosphatasemia with ateliosis and hypermetabolism of growing membranous bone: review of the clinical, radiographic and chemical features. Prog Pediatr Radiol 4:438, 1973. 34. Melnick JC: Osteopathia condensans disseminata (osteopoikilosis). Study of a family of 4 generations. AJR Am J Roentgenol 82:229, 1959. 35. Rimoin DL: Pachydermoperiostosis (idiopathic clubbing and periostosis). Genetic and physiologic considerations. N Engl J Med 272:923, 1965. 36. Kornak U, Mundlos S: Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73:447, 2003.

leaving the bones radiolucent to radiograph. Osteoporosis is a general term used for undermineralization of bone. Osteomalacia indicates undermineralization in the presence of excess osteoid. Osteopenia indicates a decrease in bone mass due to deficient production of osteoid. In osteopenia, the mineralization may be normal. Diagnosis

Decreased mineral content of bone becomes manifest clinically as bone pain or fractures. Radiographically, the bones have increased lucency. Determination of osteoporosis is usually made subjectively from the appearance of the bones on radiographs. The simplest objective measure of decreased bone density is the thickness of the cortex in the hand bones.1 Densitometry on radiographs taken under standardized conditions may also be used.2–4 Mild degrees of osteoporosis are not symptomatic; this is usually an incidental finding on radiographs taken for other reasons. Decreased bone density may be generalized or localized (Figs. 20-60 and 20-61). Minor trauma can fracture osteoporotic bone. Etiology and Distribution

20.10 Decreased Bone Density Definition

Decreased bone density results from decreased deposition of calcium salts in the osseous skeleton or increased resorption

Maintenance of bone mass is achieved through balancing the resorptive activity of osteoclasts and the regenerative activity of osteoblasts. Type 1 collagen and hydroxyapatite are the main constituents of bone, but a host of enzymatic, structural, and regulatory proteins are involved in bone remodeling.5,6 Mutations in any of the genes that give osteoclast activity an advantage over osteoblast activity may result in decreased bone density.

Fig. 20-60. Generalized decreased density of bones in a 13-year-old girl with rickets secondary to renal disease.

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915

Tables 20-28 and 20-29 list heritable conditions that include decreased bone density. To these can be added any heritable condition that limits movement and nutrition such as the spinal muscular atrophies, muscular dystrophies, and various neuropathies. Renal diseases in which mineral is lost also cause osteoporosis and rickets. Prognosis, Treatment, and Prevention

The greatest risk for osteoporotic bone is fracture. Fractures may occur prenatally. This is the hallmark of osteogenesis imperfecta, but it may occur in other skeletal dysplasias, in arthrogrypotic conditions, and in other conditions that limit movement. Prenatal diagnosis is possible for many conditions with decreased bone density by imaging (ultrasound, radiograph, magnetic resonance imaging) or, in cases where the causative gene is known, by mutational analysis. Fig. 20-61. Localized areas of decreased skull density caused by eosinophilic granuloma.

References (Decreased Bone Density)

Osteoporosis can result from a number of chronic conditions that interfere with nutrition and activity. Chronic administration of steroids can also produce osteoporosis. Hemolytic anemia may lead to osteoporosis through expansion of the marrow cavity at the expense of the bony cortex. Rickets and scurvy also cause osteoporosis, rickets by decreased mineral uptake in the intestine and increased loss through the kidneys and scurvy by an inhibition of bone deposition. Hyperparathyroidism causes increased renal loss of calcium and phosphorus, producing osteoporosis. Most of these causes of decreased bone density are not congenital, although congenital rickets has been reported, as has congenital hyperparathyroidism secondary to maternal hypoparathyroidism.

1. Morgan DB, Spiers FW, Pulvertaft CN, et al.: The amount of bone in the metacarpal and the phalanx according to sex and age. Clin Radiol 18:101, 1967. 2. Colbert C, Spruit JJ, Davila LR: Biophysical properties of bone: determining mineral concentration from the X-ray image. Ann NY Acad Sci 30:271, 1967. 3. Van Rijn RR, van der Sluis IM, Link TM, et al.: Bone densitometry in children: a critical appraisal. Eur Radiol 13:700, 2003. 4. Shagam JY: Bone densitometry: an update. Radiol Technol 74:321, 2003. 5. Kornak U, Mundlos S: Genetic disorders of the skeleton: A developmental approach. Am J Hum Genet 73:447, 2003. 6. Rauch F, Travers R, Plotkin H, et al.: The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 110:1293, 2002.

Table 20-28. Conditions that include generalized decrease in bone density Condition

Major Features 7

Causation Gene/Locus

Arthrogryposes (all types)

Contractures, decreased muscle mass

Heterogeneous

Cerebrooculofacioskeletal (COFS)8

Growth and developmental retardation, microcephaly, contractures, hypotonia

AR (214150) Multiple loci

Hemolytic anemias

Anemia secondary to marrow expansion, thinned cortex

Usually AR

Homocystinuria9

Dislocated lens, decreased pigment, thrombosis, mental retardation or behavioral disorders

AR (236200) CBS, 21q22.3

Hypophosphatasia10,11

Globular head, fractures, bowing of long bones, often lethal

AR (241500) ALPL, 1p36.1-p34

Idiopathic juvenile osteoporosis12

Onset in teens, associated pain and fracture of limb and vertebral bones

Unknown (259750)

Lowe13

Cataract, growth and mental retardation, renal disease, hypotonia

XLR (309000) OCRL, Xq26.1

Osteogenesis imperfecta11

Short stature, prenatal fractures, blue sclerae, often lethal

Multiple loci AD (120160) (166210) AR (259410) (259420)

Pseudoglioma-osteoporosis14

Cataracts, phthisis bulbi, hyperextensible joints, fractures

AR (259770)

Rickets (all types)

Metaphyseal expansion, short stature

Heterogeneous XLD (307800) PHEX, Xp22.2-p22.1 AD (193100) FGF23, 12p13.3

Winchester15

Coarse facial features, thick skin, short stature, progressive joint deformation, osteolysis

AR (277950)

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Table 20-29. Conditions that include localized or irregular decrease in bone density Condition

Major Features

Causation

Enchondromatosis (Ollier, Maffucci)16

Malignant potential

Unknown (166000)

Polyostotic fibrous dysplasia (McCune-Albright)17

Large irregular pigmentary skin lesions, precocious puberty

Unknown (174800) GNAS, 20q13.2

Reticuloendothelioses6,18

Rash, hepatosplenomegaly, pancytopenia, growth stunting, granulomas in various tissues including skeleton

XL (312500) AR (276700)

7. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, ed 4. Mosby, St. Louis, 1996. 8. Pena SDJ, Shokeir MHK: Autosomal recessive cerebro-oculo-facioskeletal (COFS) syndrome. Clin Genet 5:285, 1974. 9. MacCarthy JMT, Carey MC: Bone changes in homocystinuria. Clin Radiol 19:128, 1968. 10. Fallon MD, Teitelbaum SL, Weinstein RS, et al.: Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine 63:12, 1984. 11. Spranger JW, Brill PW, Poznanski A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development, ed 2. Oxford University Press, New York, 2002. 12. Dent CE: Idiopathic juvenile osteoporosis (IJO). Birth Defects Orig Artic Ser V(4):134, 1969. 13. Richards W, Donnell GN, Wilson WA, et al.: The oculo-cerebro-renal syndrome of Lowe. Am J Dis Child 109:185, 1965. 14. Frontali M, Stomeo C, Dallapiccola B: Osteoporosis-pseudoglioma syndrome: report of three affected sibs and an overview. Am J Med Genet 22:35, 1985. 15. Winchester P, Grossman H, Lim WN, et al.: A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis. AJR Am J Roentgenol 106:121, 1969. 16. Bender BL, Yunis E: Fibrocartilaginous lesions of bone and hemangiomas and lipomas of soft tissue resembling Maffucci’s syndrome. J Bone Joint Surg 61A:1104, 1979. 17. Firat D, Stutzman L: Fibrous dysplasia of bone: review of twenty-four cases. Am J Med 44:421, 1988. 18. Schajowicz F, Schlullitel J: Eosinophilic granuloma of bone and its relationship to Hand-Schuller-Christian syndrome. J Bone Joint Surg 56B:545, 1973.

20.11 Osteolysis Definition

Osteolysis is the resorption of previously formed cartilage and bone. Diagnosis

Marked heterogeneity and variability among the osteolyses make for a confusing array of disruptive processes, which can affect virtually any bone of the body, begin at any postnatal age, and carry life-threatening or inconsequential implications. Osteolysis may be heralded by painful or painless swelling over the bones, which will subsequently be lysed. All osteolyses are dynamic processes that ultimately result in replacement of bone and cartilage by fibrous tissue. Attempts at regeneration is seen early in the

course in some cases. In most patients, osteolyses begin after a few years of life. In no condition has the process been documented during fetal life. Peripheral osteolyses may be anticipated from swelling of the overlying soft tissue, from progressive blunting of the terminal aspect of the digits, or from shortening and angulation at the wrists and ankles. Sequential radiographs are necessary to document the progressive loss of bone. In some cases, calcific spikes are extruded from the skin. Carpotarsal Osteolysis

Swelling and pain over the wrists and ankles at age 3 to 4 years herald the symptomatic phase of carpotarsal osteolysis.1–3 Pain may limit movement of the joints. Not uncommonly, attention is called to a preceding history of a nonspecific febrile illness or mild trauma. These findings spontaneously resolve over a period of months, to be followed by an asymptomatic period during which sclerosis and lysis of the carpals and tarsals proceed (Fig. 20-62). The lytic process may extend to the proximal metacarpals and metatarsals and to the distal radial and ulnar epiphyses. Lysis progresses over several decades, ultimately causing complete dissolution of the affected bones, with collapse of the ankle and wrist joints. Bone particles may be extruded through the skin. Biopsy has shown replacement of cartilage and bone by fibrous tissue, without evidence of inflammatory or necrobiotic changes. The arterioles may have hypertrophy of muscle layers. An associated nephropathy is commonly seen.4,5 Several different

Fig. 20-62. Carpal osteolysis in an 11-year-old male with carpotarsal osteolysis and nephropathy. (Courtesy of Dr. R. I. Macpherson, Medical University of South Carolina, Charleston.)

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Table 20-30. Syndromes that include osteolysis* Major Features

Bones involved{

Causation

Carpotarsal osteolysis

Onset age 2–7 years with swelling and pain of hands and feet, collapse of carpus, limitation at adjacent joints

(C,T) Lysis may spread to metacarpals, radius, and ulna

AD

Carpotarsal osteolysis with nephropathy4,5

Onset age 2–5 years with pain and swelling of hands, progressive nephropathy

(C,T) Lysis may extend to metacarpals, radius, and ulna

Unknown, AD (166300)

Familial expansile osteolysis6

Hearing loss, tooth loss, painful limb deformation

(R,T) Expansile lesions in long bones, especially tibia

AD 174810 TNFRSF11A, 18q22.1

Farber7

Onset in childhood, joint swelling, subcutaneous granulomas

Multiple loci of bone destruction

AR (228000)

Gorham: massive osteolysis8

Onset at any age, burns out after a few years, may be related to angiomatous lesions

Monocentric at variable sites

Unknown

Hajdu-Cheney9,10

Onset in early childhood, short stature, coarse facies, hernias, hirsutism

(P,C,T,U) Base of cranium and vertebral bodies may be involved

AD (102500)

Mandibuloacral dysplasia11

Onset in early childhood, alopecia, progeroid appearance, mandibular hypoplasia

(P) Clavicles and posterior ribs may be affected

AR (248370)

Murray-Puretic: juvenile hyaline fibromatosis12

Onset in childhood, gingival hyperplasia, skin papules and subcutaneous tumors, joint swelling

(P) Metaphyses of long bones may be affected

AR (265700)

NAO (nodulosis-arthropathy-osteolysis [allelic with Torg and possibly Winchester]13,14

Brachycephaly, coarse face, deformed and painful hands, nodules on palms and soles and over large joints

(C,T) Osteopenia, sclerotic cranial sutures, square vertebrae

AR MMP2, 16q21.21

Pachydermoperiostosis15

Thickened skin, cutis verticis gyrata, clubbed digits, enlarged hands and feet

(P) Periosteal new bone formation

Unknown (167100)

Phalangeal osteolysis, dominant16

Onset in teen years

Syndrome 1–3

Phalangeal osteolysis, recessive17

(P)

AD

(P)

AR

Pycnodysostosis18

Short stature, large cranium, small face, increased bone density

(P)

AR (265800)

Singleton: osteolysis-aortic calcification-hypodontia19

Short stature, osteoporosis, aortic calcification, dental dysplasia

(P)

Unknown (182250)

Thieffry: multicentric osteolysis (may be same as carpotarsal osteolysis with nephropathy or multicentric carpotarsal osteolysis)20

Onset in childhood, triangular facies, small mouth, prominent eyes (?same as carpotarsal osteolysis)

(C,T) May spread to metacarpals, metatarsals, and phalanges

AD

Torg: carpotarsal osteolysis (likely same as Winchester and nodulosisosteolysis-arthropathy)21

Onset age 2–5 years with swollen fingers; osteoporosis; joint restriction at wrists, elbows, hips, and knees

(C,T)

AR MMP2, 16q12-21

Winchester22

Onset at age 1 year with short stature, coarse facies, painless swelling of hands and feet, corneal opacities, joint contractures

(P,C,T)

AR (277950)

*Does not include the case reports of Sirinavin et al.23 (clubbing-hyperhydrosis-osteoporosis), Petit and Fryns24 (short staturemental retardation-osteolysis), Kozlova et al.25 (skin ulceration-osteolysis), Skinner24 (mental retardation-brachydactyly-osteolysis), Teebi et al.27 (progressive arthropathy-osteolysis), Osebold et al.28 (spondylmetaphyseal dysplasia-phalangeal osteolysis), Borrone et al.29 (coarse face-acne-camptodactyly-osteolysis), and Penttinen et al.30 (progeroid appearance-acroosteolysis). {

Bones involved are indicated in parentheses.

entities that include carpotarsal osteolysis have been identified (Table 20-30).1–30 Phalangeal Osteolysis

This phenomenon usually involves only the distal phalanges (Fig. 20-63).16,17 The lesions are progressive. Autosomal recessive and dominant forms have been described (Table 20-30).

Multicentric Osteolysis

Although multicentric osteolysis commonly affects the cranium, phalanges, carpals, and tarsals, it may affect any bone.9,10,20–22,31–33 Several syndromic forms can be differentiated (Table 20-30). The autosomal dominant Hajdu-Cheney syndrome includes coarse facies, hirsutism, hernias, blunt digits, and short stature.9,10

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Skeletal System

Fig. 20-63. Distal phalangeal osteolysis of fingers and toes in a 30-year-old woman. Her sister was similarly affected.

Osteolysis first becomes evident in the distal phalanges in early childhood (Fig. 20-64). Lysis of carpals, tarsals, base of cranium, and proximal ulna develop by the teen years. The vertebrae become osteoporotic and collapse. Fractures of the long bones are not uncommon. Biopsies of lytic areas show replacement of bone and cartilage with fibrous tissue. Winchester syndrome, an autosomal recessive condition, has onset of painless swelling of the hands and feet at about age 1 year.22 In early childhood, coarse facies develop, corneal opacities become evident, wrists and feet shorten, and contractures form at small and large joints. Pro-

gressive lysis of carpals, tarsals, and phalanges is well-established by early school age. Hollister et al.22 consider Winchester syndrome to be a nonlysosomal connective tissue disease. They have shown bone and cartilage to be replaced by hypervascular fibrous tissue. Etiology and Distribution

Osteolysis may result from a number of insults to bone, including trauma, arterial disease, infection or other inflammatory

Fig. 20-64. Distal phalangeal osteolysis in an 8-year-old male with Hadju-Cheney syndrome. Note also hypoplasia and dislocation of the proximal radius and dysplastic distal humerus. (Courtesy of Dr. R. I. Macpherson, Medical University of South Carolina, Charleston.)

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processes, tumors, and aseptic necrosis. It may also follow neurologic dysfunction. In the osteolyses described above, none of these processes appears to play a part. Rather, the osteolytic process appears to be genetically determined and may be associated with other skeletal and nonskeletal features (Table 20-30). In none of the hereditary osteolyses is the pathogenesis certain. Tyler and Rosenbaum32 have proposed that an autoimmune process is responsible in the multicentric osteolyses and carpotarsal osteolysis with nephropathy. In Gorham nonhereditary massive osteolysis, hyperemia from an adjacent angioma may initiate the lytic process.8 The osteolyses are individually and collectively rare. No sexual predilection is known. Prognosis, Treatment, and Prevention

Phalangeal osteolysis is the most benign of the hereditary osteolyses. Involvement is usually limited to the distal phalanges. In Gorham massive osteolysis, the lytic process appears benign and ceases after a few years of activity.8 The multicentric osteolyses and carpotarsal osteolyses are the most severe. They may progress to complete destruction of the bones in one area and may extend to adjacent bones. The surrounding joints are usually swollen and may eventually be the site of contractures. No specific treatments have been found to be beneficial. Steroids do not appear to impede the process. Neither are passive exercises or casting helpful. The lytic process usually becomes inactive after a variable number of years. The cause of cessation of the lytic process is no less mysterious than the cause of its onset. Many patients are left with deformations at the joint adjacent to affected areas that may limit mobility and dexterity. References (Osteolysis) 1. Erickson CM, Hirschberger M, Stickler BG: Carpal-tarsal osteolysis. J Pediatr 93:779, 1978. 2. Beals RK, Bird CB: Carpal and tarsal osteolysis: a case report and review of the literature. J Bone Joint Surg 57A:681, 1975. 3. Lemaitre L, Remy J, Smith M, et al.: Carpal and tarsal osteolysis. Pediatr Radiol 13:219, 1983. 4. Shurtleff DB, Sparkes RS, Clawson DK, et al.: Hereditary osteolysis with hypertension and nephropathy. JAMA 188:363, 1964. 5. Carnevale A, Canun S, Mendoza L, et al.: Idiopathic multicentric osteolysis with facial anomalies and nephropathy. Am J Med Genet 26:877, 1987. 6. Osterberg PH, Wallace RGH, Adams DA, et al.: Familial expansile osteolysis. A new dysplasia. J Bone Joint Surg 70B:255, 1988. 7. Antonarakis SE, Valle D, Moser HW, et al.: Phenotypic variability in siblings with Farber disease. J Pediatr 104:406, 1984. 8. Gorham LW, Stout AP: Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone). J Bone Joint Surg 37A:985, 1955. 9. Silverman FN, Dorst JP, Hajdu N: Acroosteolysis (Hajdu-Cheney syndrome). Birth Defects Orig Artic Ser X(12):106, 1974. 10. Brown DM, Bradford DS, Gorlin RJ, et al.: The acro-osteolysis syndrome: morphologic and biochemical studies. J Pediatr 88:573, 1976. 11. Toriello HV: Mandibulo-acral dysplasia: heterogeneity versus variability. Clin Dysmorphol 4:12, 1995. 12. Murray J: On three peculiar cases of molluscum fibrosum in children. Med Chir Trans 38:235, 1873. 13. Al Mayouf S, Majeed M, Hugosson C, et al.: New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. Am J Med Genet 93:5, 2000.

919 14. Martignetti JA, Al Ageel A, Al Sewairi W, et al.: Mutation for the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 28:261, 2001. 15. Guyer PB, Brunton FJ, Wren MWG: Pachydermoperiostosis with acro-osteolysis. A report of five cases. J Bone Joint Surg 60B:219, 1978. 16. Lamy M, Maroteaux P: Acro-osteolyse dominante. Arch Fr Pediatr 18:693, 1961. 17. Joseph R, Nezelof C, Gueraud L, et al.: Acro-osteolyse idiopathique famiale. Renseignments fournis par la biopse. Semin Hop 35:622, 1959. 18. Bennani-Smires CH, el Alamy NR, Bouchareb N: Pyknodysostosis. typical and atypical features and report on 7 cases. J Radiol 65:689, 1984. 19. Singleton EB, Merten OF: An unusual syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition. Pediatr Radiol 1:2, 1973. 20. Thieffry S, Sorrel-Dejerine J: D’Osteolyse essentielle hereditaire et familiale. Presse Med 66:1858, 1958. 21. Torg JS, Digeorge AM, Kirkpatrick JA, et al.: Hereditary multicentric osteolysis with recessive transmission: a new syndrome. J Pediatr 75:243, 1969. 22. Hollister DW, Rimoin DL, Lachman RS, et al.: The Winchester syndrome: a nonlysosomal connective tissue disease. J Pediatr 84:701, 1974. 23. Sirinavin C, Buist NRM, Mokkhaves P: Digital clubbing, hyperhidrosis, acro-osteolysis and osteoporosis. A case resembling pachydermoperiostosis. Clin Genet 22:83, 1982. 24. Petit P, Fryns J-P: Distal osteolysis, short stature, mental retardation, and characteristic facial appearance: delineation of an autosomal recessive subtype of essential osteolysis. Am J Med Genet 25:537, 1986. 25. Kozlova SI, Altshuler BA, Kravchenko VL: Self-limited autosomal recessive syndrome of skin ulceration, arthroosteolysis with pseudoacromegaly, keratitis, and oligodontia in a Kirghizian family. Am J Med Genet 15:205, 1983. 26. Skinner SA: Unknown cases-KAM and KEM-white female siblings. Proc Greenwood Genet Center 7:72, 1988. 27. Teebi AS, Elliott AM, Azouz EM, et al.: Progressive erosive arthropathy with contractures, multicentric osteolysis-like changes, characteristic craniofacial appearance, and dermatological abnormalities: a new syndrome? Am J Med Genet 100:198, 2001. 28. Osebold WR, Poznanski AK, Opitz JM, et al.: Previously undescribed syndrome of spondylometaphyseal dysplasia, osteocartilanginous metaplasia of long bones, and progressive osteolysis of distal phalanges. Am J Med Genet 80:187, 1998. 29. Borrone C, Di Rocco M, Crovato F, et al.: New multisystemic disorder involving heart valves, skin, bones, and joints in two brothers. Am J Med Genet 46:228, 1993. 30. Penttinen M, Niemi KM, Vinkka Puhakka H, et al.: New progeroid disorder. Am J Med Genet 69:182, 1997. 31. Hardegger F, Simpson LA, Segmueller G: The syndrome of idiopathic osteolysis. Classification, review, and case report. J Bone Joint Surg 67B:89, 1985. 32. Tyler T, Rosenbaum HD: Idiopathic multicentric osteolysis. Am J Roentgenol 126:23, 1976. 33. De Ravel TJL, Matthijs G, Holvoet M, et al.: Idiopathic multicentric osteolysis presents early and is not linked to chromosome 18q21.1. J Med Genet 37:E34, 2000.

20.12 Anomalies of the Patella The patella is a sesamoid bone contained within the quadriceps tendon. It is the largest sesamoid bone in the body and the only one of the three sesamoid bones of the knee with clinical

920

Skeletal System

Fig. 20-65. Left: Absence of patella in an 8-year-old male with nail-patella syndrome. Right: Iliac horns (arrows) in a 57-year-old female with nail-patella syndrome. (Courtesy of Dr. R. I. Macpherson, Medical University of South Carolina, Charleston.)

importance. By virtue of its location, it provides a measure of protection for the anterior aspect of the knee joint but becomes important to the function of the knee only if it is dislocated. Agenesis of the Patella

Total absence of the patella may be diagnosed clinically and radiographically (Fig. 20-65).1 The anterior aspect of the knee appears flattened, a finding accentuated with flexion of the knee. Radiographs show no patella ossification and a flattening of soft tissues over the anterior aspect of the knee. The knee may function normally without apparent loss of stability. Agenesis of the patella occurs only on a heritable basis, either as an isolated autosomal recessive or autosomal dominant defect or as a component of other entities with additional features (Table

20-31).1–21 Mutations in LMX1B, a LIM-homeodomain transcription factor, cause nail-patella syndrome, and mutations in TBX4 cause small patella syndrome. Bongers et al.6,10 have suggested that other entities with patellar abnormalities may be caused by defects in the PTX/TBX signaling cascade. Hypoplasia of the Patella

Underdevelopment of the patella is diagnosed when the ossified mass of the patella fails to reach a size 2 standard deviations (SD) below the mean size. Since patella diameter is a feature of continuous variation, the majority of small patellas represent simply the lower extreme of normal anatomic variation. In a minority of cases, underdevelopment is a feature of a multiple anomaly syndrome or skeletal dysplasia (Table 20-32).1–5,12,14,20–24

Table 20-31. Conditions that include absent patellaa Major Features

Causation Gene/Locus

Microcephaly, agenesis of corpus callosum, coarse face, genital hypoplasia

AR (606170)

Kuskokwim

Multiple joint contractures, cysts in long bones

AR (208200)

Meier-Gorlin8

Microtia, micrognathia, cryptorchidism

AR (224690)

Nail-patella9,10

Nail dystrophy, iliac horn, proteinuria

AD (161200) LMX1B, 9q34.1

Neurofibromatosis11,21

Macrocephaly, cafe´-au-lait spots, neurofibromatosis, Lisch nodules

AD (162200) NF1, 17q11.2

Patella aplasia-hypoplasia1,2

None, other than aplasia or hypoplasia of patella

AR, AD (168860)

Seckel13

Retarded growth and development, microcephaly, beaklike nose

AR (210600) ATR, 3q22-q24 SCKL2, 18p11.31-q11.2

Small patella syndrome3–5

Aplasia or hypoplasia of patellas, abnormal ossification of ischiopubic function, infraacetabular notches

AD (147891) TBX4, 17q22

Condition

Genitopatellar14 7

a Does not include syndromes of Mirkinson and Mirkinson15 (aniridia-absent patellas), Goeminne and Dujardin16 (short statureabsent patellas-skeletal anomalies), Hurst et al.17 (craniosynostosis-absent patellas), Singh et al.18 (lens opacities-absent patellasmental retardation), and Cohen19 (craniosynostosis-absent patellas).

Limbs

921

Table 20-32. Conditions that include hypoplastic patella* Condition

Major Features

Causation

Campomelic dysplasia

Micrognathia, cleft palate, bowed femora, hypoplastic scapula, sex reversal in males

AD (114290) SOX9, 17q24.3

Coffin-Siris20

Nail hypoplasia, sparse scalp hair, coarse facies

AR (135900)

Microcephaly, agenesis of corpus callosum, coarse face, genital hypoplasia

AR (606170)

12

Genitopatellar

14,24

Patella aplasia-hypoplasia1,2

Small or absent patellas

AD (168860)

Pterygium syndromes21

Contractures and webs at joints, immobile facies

AR (265000) (263650) AD (119500)

Small patella syndrome3–5

Small or absent patellas, abnormal ossification of ischiopubic function, infraacetabular notches

AD (147891) TBX4, 17q22

Spondyloepiphyseal dysplasias21

Epiphyseal dysplasias with spine involvement with or without associated anomalies

Several forms

Tall facies, narrow chest, joint contractures, plantar furrows, variable mental function

Chromosome

Trisomy 8

22

*Does not include the reports of Sandhaus et al.

23

(hypoplastic patella-skeletal anomalies).

Fig. 20-66. Schematic of various configurations of patellar anatomy that can arise from multicentric ossification. A. Normal configuration. B–D. Bipartite patellas with lateral view shown above. E–J. Marginal partitions of the patella. (After Birkner.29)

Abnormal Ossification of the Patella

The patella normally ossifies at about age 5 years. The cartilaginous template of the patella, however, is present at birth and can be palpated in the distal aspect of the quadriceps tendon. Ossification generally precedes from several foci, and the margins may be quite irregular. The smooth contour of the mature patella is achieved during the teen years. The union of separate ossification centers may likewise occur in the late teens (Fig. 20-66). Abnormalities of ossification of the patella are seen in a number of circumstances. Rarely, the patella is prematurely ossified. This phenomenon is of diagnostic assistance in the Zellweger syndrome (Fig. 20-67).25 Delayed ossification occurs in a number of skeletal dysplasias, particularly in the epiphyseal disorders (Chapter 22) and in hormonal and nonhormonal disorders that impair bone age. Irregular ossification or stippling of the patella also occurs in hypothyroidism and in other disorders that include stippled epiphyses. Dislocation of the Patella

Normally the patella rests in the diamond formed by the femorotibial junction and the concavities of the femoral and tibial epiphyses. The patella is contained within the quadriceps tendon. Movement is limited and occurs only vertically. Dislocation of the patella can occur in any direction.26–28 Patella dislocation that occurs after birth is usually not familial. In the series of Bowker and Thompson,26 75% of cases occurring

Fig. 20-67. Ossification of the patella in a newborn infant with Zellweger syndrome.

922

Skeletal System

after age 3 years were not familial. The majority of bilateral cases are familial, however. Predominant predisposing factors for patella dislocation include hypermobile patellas with or without increased joint mobility elsewhere, abnormal position of the patella in extension, thigh atrophy, abnormal patella configuration with deficiency of the trochlea, genu valgum, genu recurvatum, and hypoplasia of the patella. In association with hypermobile joints, the patella dislocates laterally. There may be recurrent dislocation with knee flexion. References (Anomalies of the Patella) 1. Bernhang AM, Levine SA: Familial absence of the patella. J Bone Joint Surg 55A:1088, 1973. 2. Mangino M, Sanchez O, Torrente I, et al.: Localization of a gene for familial patella aplasia-hypoplasia (PTLAH) to chromosome 17q21-22. Am J Hum Genet 65:441, 1999. 3. Scott JE, Taor WE: The ‘‘small patella’’ syndrome. J Bone Joint Surg 61B:172, 1979. 4. Poznanski AK: Editorial comments on the ischio-pubic-patellar syndrome. Pediatr Radiol 27:428, 1997. 5. Braun HS: Familial aplasia or hypoplasia of the patella. Clin Genet 13:350, 1978. 6. Bongers EMHF, Duijf PHG, van Beersum SEM, et al.: Mutations in the human TBX4 gene cause small patella syndrome. Am J Hum Genet 74:1239, 2004. 7. Petajan JH, Momberger GL, Aase JM: Arthrogryposis syndrome (Kuskokwim disease). JAMA 209:1481, 1969. 8. Meier Z, Poschavio J, Rothschild M: Ein fall von arthrogryposis multiplex congenita kombiniert mit dybostosis mandibulofacialis (Franceschetti syndrom). Helv Paediatr Acta 14:213, 1959. 9. Bennett WM, Musgrave JE, Campbell RA, et al.: The nephropathy of the nail-patella syndrome: clinicopathologic analysis of 11 kindreds. Am J Med 54:304, 1973. 10. Dreyer SD, Zhou G, Baldini A, et al.: Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 19:47, 1998. 11. Crawford AH Jr, Bagamery N: Osseous manifestations of neurofibromatosis in childhood. J Pediatr Orthop 6:72, 1986. 12. Mansour S, Offiah AC, McDowall S, et al.: The phenotype of survivors of camptomelic dysplasia. J Med Genet 39:597, 2002. 13. Majewski F, Goecke T: Studies of microcephalic primordial dwarfism. I. Approach to a delineation of the Seckel syndrome. Am J Med Genet 12:7, 1982. 14. Lifchez CA, Rhead WJ, Leuthner SR, et al.: Genitopatellar syndrome: expanding the phenotype. Am J Med Genet 122A:80, 2003. 15. Mirkinson AE, Mirkinson NK: A familial syndrome of aniridia and absence of the patella. Birth Defects Orig Artic Ser XI(5):129, 1975. 16. Goeminne L, Dujardin L: Congenital coxa vara, patella aplasia and tarsal synostosis: a new inherited syndrome. Acta Genet Med Gemellol 19:534, 1970. 17. Hurst JA, Winter RM, Baraitser M: Distinctive syndrome of short stature, craniosynostosis, skeletal anomalies and malformed ears. Am J Med Genet 29:107, 1988. 18. Singh SD, Chhaparwal BC, Dhanda RP, et al.: A syndrome of dwarfism, mental retardation, lens opacities, nystagmus, strabismus, cryptorchidism and absent patellae: report of 2 cases in siblings. Ind J Pediatr 37:197, 1970. 19. Cohen MM Jr, MacLean RE: Craniosynostosis. Diagnosis, Evaluation, and Management. Oxford University Press, New York, 2000, p 132. 20. Coffin GS, Siris E: Mental retardation with absent fifth fingernail and terminal phalanx. Am J Dis Child 119:433, 1970. 21. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, ed 4. Mosby, St. Louis, 1996. 22. Berry AC, Mutton DE, Lewis DGM: mosaicism and the trisomy 8 syndrome. Clin Genet 14:105, 1978.

23. Sandhaus YS, Ben-Ami T, Chechick A, et al.: A new patella syndrome. Clin Genet 31:143, 1987. 24. Goldblatt J, Wallis C, Zieff S: A syndrome of hypoplastic patellae, mental retardation, skeletal and genitourinary anomalies with normal chromosomes. Dysmorphol Clin Genet 2:91, 1988. 25. Kelley RI: Review: the cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet 16:503, 1983. 26. Bowker JH, Thompson EB: Surgical treatment of recurrent dislocation of the patella. J Bone Joint Surg 46A:1451, 1964. 27. Goldthwait JE: Slipping or recurrent dislocation of the patella. With the report of eleven cases. Boston Med Surg J 150:169, 1904. 28. Carter C, Sweetnam R: Familial joint laxity and recurrent dislocation of the patella. J Bone Joint Surg 40B:664, 1958. 29. Birkner R: Normal Radiologic Patterns and Variances of the Human Skeleton. Urban and Schwarzenberg, Baltimore, 1978.

20.13 Hypermobile Joints Definition

Hypermobile joints have an excessive range of movement because of lack of constraint by surrounding soft tissues. Diagnosis

Excessive mobility of the joints is clinically determined by the degree to which joints can be hyperextended or hyperflexed. A series of limb maneuvers has been devised by Carter and Wilkinson1 to add consistency to clinical testing for hypermobility. Multiple joints are tested in these easily administered and scored maneuvers. The commonly used adaptation for hypermobility testing2 substitutes assessment of spine flexion for dorsiflexion and eversion of the foot originally proposed by Carter and Wilkinson.1 A positive score for hypermobility is assigned for the ability to: 1. Hyperextend the wrist and metacarpophalangeal joints, permitting the fingers to be retropositioned parallel to the forearm. 2. Appose the thumb to the flexor aspect of the forearm. 3. Hyperextend the elbow 108 or more. 4. Hyperextend the knee 108 or more. 5. Flex the spine so that the palms can rest on the floor with the knees extended (Fig. 20-68). A maximum score of 9 is possible: one for each side on the limb maneuvers and one for spine flexion. A score of 4 or more is indicative of hypermobility. Hypermobile joints are part of a heterogeneous group of conditions ranging from benign variants to life-threatening entities. Benign variants with isolated joint hypermobility are most common, and these can be considered to represent one end of the spectrum of joint mobility. These individuals do have an increased incidence of soft tissue and musculoskeletal complaints, particularly hernias and joint pain. Most, however, have no symptoms related to the joints, skin, or other soft tissues. The joints appear normally formed, without abnormality of the surrounding soft tissues and skin. Although the joints usually assume normal positions in the resting state, the hypermobility may be reflected in flat feet, scoliosis, and genu valgum. Joint effusion, presumably from minor trauma, may be a recurrent but transient sign. Isolated joint hypermobility has been termed benign hypermobility syndrome and may be seen with different presentations at different ages.3–8 It appears to be inherited in an autosomal

Limbs

923

Table 20-33. Causes of the floppy infant Syndrome

Fig. 20-68. Maneuvers used to score hypermobility.

dominant manner in most families. In the infant, hypermobility may present as floppiness, with delay of motor development.6 All causes of the floppy infant must be considered when this is the presentation (Table 20-33). Normal deep tendon reflexes, normal facial movements and growth, and normal scores on nonmotor development help to differentiate the hypermobility syndrome from other causes of the floppy infant. Motor skills that are delayed from this cause can be expected to catch up to normal by age 3 years.6 In childhood, arthralgias are the major complaint in the hypermobility syndrome. Among a group of 15 symptomatic patients described by Biro et al.,4 46% had knee pain and 40% had pains in the hands and fingers. Traumatic or inflammatory joint disease must be entertained in the diagnosis. The patient with benign hypermobility of the joints often has a family history of hypermobility. Biro et al.4 found a positive family history in four of 15 patients (27%). They also found a history of degenerative joint complaints prior to age 60 years in seven of the 15 families. Others have also found that ligamentous laxity may be one factor contributing to osteoarthritis.9,10 At the severe end of the spectrum of conditions that include joint hypermobility are the Marfan (Fig. 20-69) and EhlersDanlos syndromes.11,12 These conditions are distinguished not on the basis of the degree of hypermobility but rather by the presence of other features. Patients with Marfan syndrome have dislocations of the ocular lens, dolichostenomelia, pectus carinatum or pectus excavatum, and dilation of the ascending aorta.

Causation Gene/Locus

Adrenoleucodystrophy, neonatal

AR (202370) Multiple loci: PEX1, 7q21-q12 PEX5, 12p13.3 PEX10, chromosome 1 PEX13, 2p15 Others

Allan-Herndon

XLR (309600) MCT8, 8q13.2

Benign hypermobility

AD (130020)

Bo¨rjeson-Forssman-Lehmann

XLR (301900) PHF6, Xq26.3

Canavan

AR (271900) ASPA, 17pter-p13

Cerebral anoxia

Environmental

Cerebral malformations

Heterogeneous

Cerebrooculofacioskeletal

AR (214150) Multiple loci: 19q13.2-q13.3, 13q33, 10q11

Cohen

AR (216550) 8q22-q23

Creatine transporter defects

XL SLC6A8, Xq28

De Barsy

AR (219150)

Familial dysautonomia

AR (256800)

Johanson-Blizzard

AR (243800)

Miller-Dieker

Del 17p LIS1, 17p13.3

Muscle hypoplasia

AR (159100)

Myopathies (benign congenital hypotonia, central core, nemaline, mitochondrial, myotubular, myotonic dystrophy)

Heterogeneous

Myasthenia gravis

AR (254210)

Opitz FG

XLR (305450) Multiple loci

Pompe (glycogen storage, type II)

AR (232300) GAA, 17q25.2-q25.3

Prader-Willi

Del 15q11-q13 Mat UPD 15q

Smith-Lemli-Opitz

AR (270400) DHCR7, 11q12-q13

Werdnig-Hoffmann

AR (253300) SMA1, 5q12.2-q13.3

Zellweger

AR (214100) Multiple loci: PEX1, 7q21-q22 PEX2, 8q21.1 PEX3, 6q23-q24 PEX5, 12p13.3 others

They are at risk for aortic aneurysm. Ehlers-Danlos syndrome includes a number of entities characterized by joint hypermobility, stretchable skin, and tissue fragility. Cutaneous injuries heal with thin ‘‘tissue-paper’’ scars. Excessive bruising or bleeding

924

Skeletal System

Fig. 20-69. Hypermobility of knees and feet in adult with Marfan Syndrome.

may occur. Vascular rupture, retinal detachment, and aggressive periodontia occur as complications in types IV, VI, and VIII. Joint hypermobility has been consistently associated with other features in a number of other syndromes (Table 20-34). Most are heritable. Etiology and Distribution

The range of movement in the joints is determined by the integrity of the surrounding soft tissues. Structural proteins, principally collagen, give these tissues their tensile strength. The chemical structure of collagen determines its tensile strength, but strength can be influenced by age, hormones, and use. It was anticipated that collagen or other structural proteins in individuals with joint hypermobility might have a different chemical structure than in those with less joint mobility. This has now been demonstrated. Abnormalities of fibrillin 1 are responsible for the phenotype of individuals with Marfan syndrome.12,13 Abnormalities of various collagens have been described in the EhlersDanlos syndromes, although delineation of the molecular basis of all types has not yet been accomplished.11,14 Joint hypermobility can be expected in 5–10% of school-age children and in 4–5% of adults.15–19 A larger percentage of infants and young children have joint hypermobility. Females at any age tend to have greater joint mobility than males of similar ages. Blacks have been found to have greater joint mobility than whites. Prognosis, Treatment, and Prevention

Joint hypermobility predisposes to scoliosis, joint dislocations, joint malalignment, and premature osteoarthritis. Joints of the lower limbs are particularly susceptible to damage. Hypermobile joints may be protected in a number of ways. Excessive hyperflexion or hyperextension should be avoided. Sitting ‘‘Indian style’’ places excessive stretch on the soft tissues at the ankles, knees, and hips. Standing with the knees slightly flexed prevents chronic and progressive hyperextension. Arch supports may benefit the person with flat feet. Muscle tone and strength can be improved with exercise of specific joints and with general conditioning activities such as swimming and walking.7

References (Hypermobile Joints) 1. Carter C, Wilkinson J: Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg 46B:40, 1964. 2. Beighton P, Solomon L, Soskolne CL: Articular mobility in an African population. Ann Rheum Dis 32:413, 1973. 3. Kirk JA, Ansell BM, Bywaters EGL: The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis 26:419, 1967. 4. Biro F, Gewanter HL, Baum J: The hypermobility syndrome. Pediatrics 72:701, 1983. 5. Grahame R: Joint hypermobility—clinical aspects. Proc R Soc Med 64:692, 1971. 6. Benady S, Ivanans T: Hypermobile joints: a benign cause of transitory motor delay in infancy. Clin Pediatr 17:790, 1978. 7. Sheon RP, Kirsner AB, Farber SJ, et al.: The hypermobility syndrome. Postgrad Med 71:199, 1982. 8. Jessee EF, Owen DS Jr, Sagar KB: The benign hypermobile joint syndrome. Arth Rheum 23:1053, 1980. 9. Scott D, Bird H, Wright V: Joint laxity leading to osteoarthrosis. Rheum Rehab 18:167, 1979. 10. Bird HA, Tribe CR, Bacon PA: Joint hypermobility leading to osteoarthrosis and chondrocalcinosis. Ann Rheum Dis 37:203, 1978. 11. Beighton P: Inherited Disorders of the Skeleton, ed 2. Churchill Livingstone, Edinburgh, 1988, p 409. 12. Beighton P, McKusick VA: McKusick’s Heritable Disorders of Connective Tissue. CV Mosby Co, St. Louis, 1993. 13. Biggin A, Holman K, Brett M, et al.: Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat 23:99, 2004. 14. Wenstrup RJ, Florer JB, Willing MC, et al.: COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet 66:1766, 2000. 15. Silverman S, Constine L, Harvey W, et al.: Survey of joint mobility and in vivo skin elasticity in London schoolchildren. Ann Rheum Dis 34:177, 1975. 16. Wynne-Davies R: Hypermobility. Proc R Soc Med 64:689, 1971. 17. Bird HA, Brodie DA, Wright V: Quantification of joint laxity. Rheum Rehab 18:161, 1979. 18. Gedalia A, Person DA, Brewer EJ Jr, et al.: Hypermobility of the joints in juvenile episodic arthritis/arthralgia. J Pediatr 107:873, 1985. 19. Grana WA, Moretz JA: Ligamentous laxity in secondary school athletes. JAMA 240:1975, 1978.

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Table 20-34. Conditions that include persistent joint hypermobility Condition

Causation Gene/Locus

Condition

Causation Gene/Locus

Aarskog

XLR (305400) FDG1, Xp11.21

MPS IV (Morquio)

AR (253000) GALNS, 16q24.3

Benign hypermobility

AD (130020)

Occipital horn

Bo¨rjeson-Forssman-Lehmann

XLR (301900) PHF6, Xq26.3

XLR (305450) ATP7A, Xq12-q13

Opitz FG

Chromosome disorders

Trisomy 21, deletion 5p, tetrasomy 12p, others

XLR (305450) Multiple loci

Pseudoxanthoma elasticum

AD (177850)

Coffin-Lowry

XLR (303600) RSK2, Xp22.2-p22.1

SHORT

AR (269880)

Coffin-Siris

AR (135900)

Skeletal dysplasias

Cohen

AR (216550) 8q22-q23

Dyssegmental dysplasia

AR (224400, 224410) HSPG2, 1p36.1

Cutis laxa

Heterogeneous (123700, 219100, 304150)

Hypochondroplasia

AD (146000) FGFR3, 4p16.3

De Barsy

AR (219150)

Lenz-Majewski hyperostotic dysplasia

AD (151050)

Ehlers-Danlos

Multiple loci

Megaepiphyseal dysplasia

AR (249230)

Geroderma osteodysplastica

AR (231070)

Metaphyseal dysplasia, McKusick type

Hajdu-Cheney

AD (102500)

AR (250250) RMRP, 9p21-p12

Hyperlysinemia

AR (238700)

Metatropic dysplasia

AR (250600)

AR (243800)

Osteogenesis imperfecta

Multiple loci

Laband

AD (135500)

Pseudoachondroplasia

Larsen

AD (150250) 3p21.1-p14.1 AR (245600)

AD (177150) COMP, 19p13.1

Spondyloepimetaphyseal dysplasia

AR (271640)

Spondyloepiphyseal dysplasia

AD (120140)

Trichorhinophalangeal dysplasia type II

AD (150230)

Velocardiofacial

AD (192430) Del 22q11.2

Wrinkly skin

AR (278250) 2q32

Johanson-Blizzard

Lowe

XLR (309000) OCRL, Xq26.1

Marfan

AD (154700) FBN1, 15q21.1

Data from Brighton and McKusick,12 Taybi and Lachman,20 and other sources.

20. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, ed 4. Mosby, St. Louis, 1996.

20.14 Arthrogryposis (Multiple Congenital Contractures) Judith G. Hall Definition

Arthrogryposis is multiple, nonprogressive congenital contractures in two or more body areas. Multiple congenital contractures have been recognized for hundreds of years; however, the term arthrogryposis multiplex congenita was coined early in the last century to describe infants with multiple congenital contractures in various body areas. Shortened to arthrogryposis, the term is now used as a sign rather than as a specific diagnosis. Arthrogryposis is found in a very heterogeneous group of conditions including well-known syndromes and nonspecific associations.1–12 In general, the term is appropriately used to describe infants who have congenital, nonprogressive contractures in two or more body areas. Thus, bilateral clubfeet would not be arthrogryposis, whereas a clubfoot and a dislocated hip would be

considered to be within the purview of arthrogryposis. The medical literature on congenital contractures is rather confusing because many authors have tended to lump together all the patients with congenital contractures and draw conclusions that may apply to only one subgroup of patients. Diagnosis

The diagnosis of multiple congenital contractures is very obvious at birth, but the diagnosis is now often made prenatally by ultrasound studies. It may be necessary to observe a fetus for up to 45 minutes in utero with real-time ultrasound to determine whether there is normal movement of various joints. However, it is clear that prenatal diagnosis of conditions with multiple congenital contractures can be made as early as 14 weeks by the abnormal positioning of the limb and the lack of full extension or flexion of particular joints. On the other hand, it has also become clear that the congenital contractures may not be present in early fetal life and only develop during the third trimester, depending on the particular condition involved. By definition, arthrogryposis is present at birth. The particular pattern of contractures, the specific body areas involved, the presence of flexion versus extension contractures, and involvement of the jaw and/or trunk may be very helpful in arriving at

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a specific diagnosis. There are over 300 specific conditions in which congenital contractures are regularly seen; thus, a practical approach to diagnosis is needed.1–12 Clinically, three subgroups of arthrogryposis can be distinguished based on the (1) involvement of the limbs only, (2) involvement of limbs together with other body areas, and (3) involvement of the limbs and central nervous system.1–3 This approach can help in developing the differential diagnosis and in arriving at a specific diagnosis in most cases (Table 20-35). However, in at least 30% of cases with multiple congenital contractures, no specific diagnosis can be established in the newborn period. It is particularly important in such cases to take photographs to document the position of contractures in the newborn period, since they may well change with therapy. The positioning in the newborn period is important in the differential diagnosis process as well. The specific diagnosis and prognosis may only emerge over time with repeated evaluation.

4.

5.

6.

Etiology and Distribution

Multiple congenital contractures are present whenever there has been lack of normal fetal movement (fetal akinesia). Moessinger13 coined the term fetal akinesia sequence to describe the process involved in the development of multiple congenital contractures. From work with rats, he recognized that if fetal movement was limited, for many different reasons, then contractures developed prior to birth. Fifty to sixty percent of individuals with multiple congenital contractures have all four limbs involved, 30–40% the legs only, and 10–15% the arms only. The temporomandibular joint and spine can be involved, and the hips are frequently dislocated. The skin overlying affected joints often has dimples. Swinyard14–15 developed the hypothesis that with decreased movement, increased connective tissue develops around the inactive joint, making movement even more difficult. The development of stiffness in a joint is certainly observed after birth when a normal individual is immobilized; for example, in the treatment of a fracture when a cast is applied and then removed 6 to 8 weeks later, marked stiffness is present that requires physical therapy to regain full range of motion. Similarly, contractures develop when limitation of joint movement is seen prior to birth, as in arthrogryposis. With increasing length of time of immobilization, the contractures become more severe. Thus, the earlier during in utero life immobilization begins, the more severe are the contractures at birth. There are at least seven well-recognized reasons for decreased fetal movement in utero: 1. Myopathic processes. These can be related to absent or nonfunctional muscles. It appears that if the muscles are nonfunctional early during intrauterine development, a muscle biopsy may actually look like a neuropathic process even though the original defect was myopathic. Many types of myopathic processes lead to contractures in utero. 2. Neuropathic processes. These can include failure of the central or peripheral nervous system to develop or failure of these elements to function. Occasionally, there may be in utero neurologic degeneration. Any abnormality of nervous tissue, including the motor end plate, may lead to decreased movement of limbs by the fetus and subsequent contractures. 3. Connective tissue disorders. Connective tissue disorders are best exemplified by the various types of bone dysplasia syndromes in which congenital contractures of the limbs are seen.

7.

However, there can also be abnormalities in connective tissue that involve the joint but not the bone. Abnormal connective tissue or abnormal connective tissue responses can lead to joint contractures in utero. Limitation of space and constraint. Limited space for the fetus to move due to many different etiologies may lead to a decrease in fetal movement (e.g., oligohydramnios, multiple gestations, fibroid, abnormal uterine shape, etc.). Vascular compromise. Decreased blood flow to the placenta or to the embryo/fetus during critical stages of central nervous system maturation may be associated with arthrogryposis. The observations of attempted terminations of pregnancy and maternal trauma indicate that the 8 to 14 weeks from the last menstrual period is a particularly vulnerable period for the embryo/fetus. Teratogenic exposures.10 Misoprostol, ergot, penicillamine, angiotensin-converting enzyme (ACE) inhibitors, and muscle relaxant ingestions by the mother have been associated with multiple congenital contractures in the offspring. Maternal fever, hyperthermia, acidosis, and infections are also considered risk factors and have been associated with multiple congenital contractures at birth. Early amniocentesis and chorionic villus sampling are also associated with a small risk for congenital contractures. Maternal illness. Certain maternal illnesses, including myotonic dystrophy, diabetes mellitus, myasthenia gravis, and multiple sclerosis, are associated with fetal akinesia and arthrogryposis at birth. Mothers may also develop antibodies against fetal neurotransmitter receptor subunits, which are associated with congenital contractures but preventable by maternal steroid therapy during pregnancy.2

Any of the above processes can be associated with a variety of clinical situations that lead to decreased fetal movement and secondary contractures. Moessinger13 recognized, however, that with decreased fetal movement, a number of other specific secondary deformational abnormalities are observed. These include intrauterine growth retardation, craniofacial anomalies (small chin, cleft palate, high bridge of nose, depressed tip of the nose), hypoplastic lungs, short umbilical cord, and polyhydramnios with secondary immaturity of the gastrointestinal tract. These features are seen in addition to congenital contractures of the limbs, and any combination can be observed. However, if congenital contractures are present, it is important to look for other features of fetal akinesia, and in particular hypoplastic lungs and nonfunctional gastrointestinal system, because of the need for therapeutic considerations. Approximately one in 3000 births in North America have multiple congenital contractures. Males and females are affected equally except for some rare X-linked recessive forms. Approximately one-third of children born with arthrogryposis represent various forms of lethal congenital contracture syndromes.4 Onethird have a specific entity known as amyoplasia, and about onethird consist of many other specific entities. The differentiated diagnosis is most easily organized into three clinical presentations: those primarily involving the limbs, those with limb contractures plus other body areas (such as deafness, trismus, cardiac involvement), and those with central nervous system involvement and dysfunction. (Table 20-35). Amyoplasia

Amyoplasia is the condition with multiple congenital contractures that as been referred to as classic arthrogryposis in the past.7–9

Table 20-35. Differential diagnosis of disorders with multiple congenital contractures Limbs Only

Limbs and Other Body Areas

Limbs and CNS, and/or Lethal

Absence of dermal ridges

Aase-Smith

Absence of the cerebellum with AMC

Absence of DIP creases of fingers

Abnormal uterine shape

Adducted thumbs

Amniotic bands

Abnormal uterine structure

AMC—lethal (Finland)

Amyoplasia

Adductor laryngeal paralysis

Angulation of long bone with overlying dimples and shortening of soft tissue

Asymmetric crying facies

AMC with IUGR, craniofacial, and brain anomalies

Antecubital pterygium

Camptodactyly-arthropathy-coxa varapericarditis-synovitis

AMC, renal tubular dysfunction, cholestosis (ARC)

Bruck

Camptodactyly, Guadalajara type

Anterior horn cell disease (Finnish)

Camptodactyly—congenital and general

Camptodactyly, Kilic type

Antley-Bixler (trapezoidcephaly)

Camptodactyly with arthropathy

Camptodactyly, London type

Coalition

Camptodactyly, Tel Hashomer type

Bartsocas-Papas syndrome (lethal popliteal pterygium)

Contractural arachnodactyly

Caudal deficiency and asplenia

Distal arthrogryposis type I

Clasped thumbs, congenital

Humeroradial synostosis (HRS)

Clasped thumbs and mental retardation

Blepharophimosis-joint contractures-mental retardation-Dandy-Walker malformation

Impaired pronation/supination of the forearm (familial)

Conradi-Hunermann

Bowen-Conradi

Contractures, continuous muscle discharges, and titubation

Campomelic dysplasia

Liebenberg Lower limb only (autosomal dominant, autosomal recessive, and X-linked arthrogryposis type 6)

Deafness and camptodactyly Diastrophic dysplasia

Lumbee

Distal arthrogryposis with abnormal facial movement

Mesomelic dysplasia

Distal arthrogryposis IIA (Gordon syndrome)

Patella aplasia-hypoplasia (PTLAH)

Distal arthrogryposis IIB (mitochondrial) ophthalmoplegia with firm muscles

Popliteal pterygium (autosomal dominant)

Basal ganglia disease Bixler microcephaly

Carbohydrate-deficient glycoprotein Carey-Fineman-Ziter Caudal dysgenesis Cerebrooculofacioskeletal (COFS; Pena Shokeir II) CHARGE Chondrodysplasia puncatata (rhizomelic)

Distal arthrogryposis II with cleft lip and palate, type IIC

Congenital fiber type disproportion with congenital contractures

Distal arthrogryposis with scoliosis (distal type IID)

Congenital muscular dystrophy

Distal arthrogryposis II with trismus (distal IIE)

Dyssegmental dysplasia (Rolland Desbuquois)

Symphalangism-brachydactyly

Duane’s retraction syndrome and multiple contractures

Encephalopathy-edema-hypsarrhythmia-optic atrophy (PEHO)

Symphalangism-brachydactyly, Nievergelt-Perlman type

Ectodermal dysplasia with contractures

Ear-patella-short stature

Ectodermal dysplasia with contractures and cardiomyopathy

Faciocardiomelic

Ectodermal dysplasia with cleft lip/palate and contractures

Fetal alcohol

Ectodermal involvement caudal appendage with contractures

Fryns

Poland anomaly Radioulnar synostosis Skeletal dysplasia, Saul-Wilson type Symphalangism, Cushing type Symphalangism, distal

Transient neonatal arthrogryposis X-linked resolving arthrogryposis

Focal femoral dysplasia Freeman-Sheldon (craniocarpotarsal dystrophy)

Dygvve-Melchior-Claussen

Fetal akinesia FG Fukuyama congenital muscular dystrophy (FCMD) Geleophysic dysplasia

Hand foot uterus syndrome

German

Hanhart (aglossia adactyly, hypoglossia hypodactyly)

Ives microcephaly micromelia

Haspeslagh

Leprechaunism

Holt-Oram

Lethal multiple pterygium

Hoepffner

Lissencephaly with fetal akinesia sequence

King-Denborough

Martsolf

Kniest dysplasia

MASA

Kuskokwim Larsen

Maternal antibodies to fetal acetylcholine receptors

Marden-Walker

Megalocornea and skeletal anomalies

Lenz-Majewski (hyperostotic dysplasia)

(continued)

927

Table 20-35. Differential diagnosis of disorders with multiple congenital contractures (continued) Limbs Only

Limbs and Other Body Areas

Limbs and CNS, and/or Lethal

Marfan (severe neonatal)

Meningomyelocele

Metaphyseal dysplasia (Jansen)

Mietens

Metatrophic dysplasia

Miller-Dieker (lissencephaly)

Misoprostol

Mucolipidosis

Moebius

Multiple pterygium lethal (Gillin Pryce Davis type)

Multiple pterygium, Escobar type Multiple pterygium and malignant hyperthermia

Myhre contractures with muscular hypertrophy

Multiple sclerosis

Neuromuscular disease of larynx

Multiple synostosis (severe symphalangism, WL)

Nezelof (renal-hepatic)

Myasthenia gravis

Oto-palato-digital type II

Myotonic dystrophy

Palant

Nail-patella (hereditary onychoosteodysplasia) Nemaline myopathy

Pena-Shokeir phenotype (anylosis, facial anomalies, and pulmonary hypoplasia)

Neurofibromatosis

Phosphofructokinase deficiency-infantile

Neuropathic Israeli-Arab

Potter

Neurosensory contractures-Cyprus Oculoauriculo-vertebral spectrum

Prader-Willi habitus, osteoporosis, hand contractures

Oculo-dental-digital

Ragged red fibers

Ophthalmo-mandibulo-melic dysplasia

Restrictive dermopathy

Ophthalmoplegia, retinitis pigmentosa, contracture and mental retardation

Roberts (pseudothalidomide syndrome, SC)

Oral-cranial-digital (Juberg-Hayward)

Rutledge

Oto-onchyo-peroneal

Schinzel-Giedion

Parastremmatic

Smith-Lemli-Opitz (type II—severe)

Pfeiffer cardiocranial

Sotos-like

Popliteal pterygium (fasciogenital popliteal, Gorlin type)

Spastic paraplegia

Proteus with distal arthrogryposis

Tricho-rhino-phalangeal, syndrome type II (Langer-Gidion)

Pseudodiastrophic

Neu Laxova

Oculo-dental-digital

Rudiger

Spondylospinal thoracic dysostosis

Puretic-Murray (juvenile hyaline fibromatosis)

Trigonocephaly (C-syndrome)

Sacral agenesis

Van Biervieldt chest dysplasia

Schwartz-Jampel

VSR

SED congenita Spondylospinal

Warburg (Hard ± cerebro-oculo-muscular)

Stiff man/stiff baby

Weaver

Trismus pseudocamptodactyly

Wieacker muscular atrophy and contractures

Tuberous sclerosis

Zellweger syndrome (cerebro-hepato-renal)

VATER association

X-linked arthrogryposis type 1

Waardenberg (Klein/Waardenberg syndrome) Weill-Marchesani

X-linked arthrogryposis type 1, anterior horn cell loss

Winchester

X-linked arthrogryposis type 2

X-linked moderately severe, type 3

X-linked arthrogryposis type 5

Van Benthem

47XXY/48XXXY 48XXXX and 49XXXXY Trisomy 4p Trisomy 8/trisomy 8 mosaicism Trisomy 9 Trisomy 9q (continued)

928

Limbs

929

Table 20-35. Differential diagnosis of disorders with multiple congenital contractures (continued) Limbs Only

Limbs and Other Body Areas

Limbs and CNS, and/or Lethal

Trisomy 10q Deletion 10q25 Trisomy 10p Trisomy 11q Trisomy 13 Partial trisomy 14 Trisomy 15 Trisomy 18 Abbreviations: CNS, central nervous system; DIP, distal interphalangeal; MASA, mental retardation, aphasia, shuffling gait, and adducted thumbs; SED, spondyloepiphyseal dysplasia; VATER, vertebral defects, anal atresia, tracheosophageal fistula with esophageal atresia and radial and renal anomalies. Modified from Hall.1

One-third of all patients with multiple congenital contractures in North America have amyoplasia. The term is a bit misleading but was chosen because historically it was used to describe this condition. The lack of normal muscle growth (amyoplasia) with fatty and fibrous replacement of muscle can be seen in other conditions; however, it is actually a very specific condition characterized by specific positioning at birth. The term amyoplasia should not be applied to other conditions. Amyoplasia is characterized by typical symmetric positioning of the limbs with flexed wrists, clenched hands, internal rotation of the shoulder, extended elbows, and severe equinovarus defor-

mity of the feet (Fig. 20-70). The knees and hips can be in a variety of positions. Sometimes as the child grows older the elbow becomes flexed because the bones grow but the muscle does not stretch. Early physical therapy is extremely important to loosen the contractures and to give whatever muscle tissue is present a chance to strengthen rather than atrophy. Muscle biopsy from areas affected with amyoplasia show absence of muscle with fibrotic and fatty replacement, whereas other muscle may be entirely normal. Disuse atrophy can also be seen. Approximately 20% of individuals affected with amyoplasia have only their upper limbs or only their lower limbs involved.

Fig. 20-70. Left: Midfacial hemangioma; short, upturned nose; internally rotated, narrow shoulders; extended elbows; posteriorly clenched fist; oriented hands; contractures at the knees; and severe equinovarus clubfeet in an infant with typical amyoplasia positioning. Right: 6-year-old boy with narrow shoulders, extended elbows, web neck, axillary webbing, asymmetric wrist and flexed wrist, decreased muscle mass often seen in amyoplasia; however, his ptosis is not typical.

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Skeletal System

Very rarely three limbs are involved. About 5% of cases of amyoplasia have amniotic bands or digit reduction in one or more limbs. A midfacial hemangioma or birthmark is very typically seen in affected individuals. Approximately 10% of affected individuals have abdominal structural abnormalities, including bowel atresia, gastroschisis, and abdominal wall defects. These abnormalities appear to be due to vascular accidents. Intelligence appears to be normal or high normal in these individuals, and they are usually very vigorous and motivated. Particularly in the newborn period is it obvious that they interact in a normal way, eat well, and are aware of their surroundings. There is an increased incidence of amyoplasia in one of monozygotic twins.8 The reason for this is not absolutely clear; however, for this and other reasons, amyoplasia appears to be related to a type of vascular compromise (which occurs more often in monozygotic twins than in singletons). There is apparently no recurrence risk for amyoplasia. By chance alone, one per 10,000 live births has amyoplasia. There has not been a second affected child born to parents in over 1000 personally observed cases, and affected individuals themselves have not had affected children. Distal Arthrogryposis

The term distal arthrogryposis may be inappropriate since there are many conditions in which distal involvement of the limbs is predominant.11 However, distal arthrogryposis type I is a relatively common disorder characterized by autosomal dominant inheritance and a very specific hand abnormality. In the hand there is camptodactyly of all fingers, with a clenched hand and overlapping fingers in the newborn period (Fig. 20-71). Characteristically, as the contractures are worked out, there is ulnar deviation of all the fingers. There is primarily distal involvement of the hands and feet. Usually, both hands and feet are involved. Sometimes knees and hips are involved. There are rarely nonorthopedic abnormalities, and there is quite good response to therapy, both physical and surgical. About 20% of cases represent new dominant mutations, but most cases are seen in a quite extensive pedigree of autosomal dominant inheritance with variable expression. Individuals have normal intelligence and are quite responsive and interactive as infants. Without these specific features, a condition should not be considered distal arthrogryposis type I. Bamshad16 has described several subtypes of distal arthrogryposis primarily involving the distal limbs, but also with mild facial involvement. He has found mutations in the tropomyosin genes (TNNT3 and TNN12), which are fibers present in fasttwitch muscle. Apparently, this type of muscle fiber does not usually become active until the mid trimester and primarily is involved in distal limb movement. Without normal mid-trimester fetal movement, contractures develop. Multiple Pterygium Syndrome (Escobar Type)

There are several types of arthrogryposis that have webs or pterygia across nonmoving joints.12 The multiple pterygium syndrome described by Escobar is the most common and is characterized at birth by flexion contractures thoughout.12 At birth, the webs across joints (pterygium) are usually not present, but as the joints begin to be mobilized and as the child grows, the webbing becomes more obvious, particularly in the neck, elbows, knees, and intercrural areas. Features that should alert the clinician to consider multiple

Fig. 20-71. Distal arthrogryposis type I with typical clenched fist appearance in newborn period (middle) and residual contractures and ulnar deviation in older individuals (top and bottom).

pterygium syndrome are the presence of cleft palate, vertebral segmentation abnormalities, deafness, and/or scoliosis. With age, the face develops a myopathic appearance. In most cases, there is good response to physical therapy and the hands are quite functional, although many patients require some orthopedic work on their feet, knees, and back. With aging, decreased pulmonary capacity frequently develops, as well as increasing thoracic lordosis. Individuals have normal intelligence. The condition is autosomal recessive. A particular subgroup of patients have many of the features very much like the Escobar type of multiple pterygium syndrome, but also are at risk to develop malignant hyperthermia. It is important to be aware of these individuals, since they have very severe reactions to the anesthesia used with surgery.5

Limbs

931

Fig. 20-72. Newborn female with Freeman-Sheldon syndrome. Note puckering of the mouth, H-shaped depression of the chin, and ulnar deviation of fingers when the fist is opened.

Freeman-Sheldon or Whistling Face Syndrome

Diastrophic Dysplasia

Freeman-Sheldon syndrome is also known as cranio-carpaltarsal dystrophy. Patients are born with multiple congenital contractures primarily involving the hands with similar newborn positions to distal arthrogryposis, that is, with clenched fists and overlapping fingers and ulnar deviation (Fig. 20-72). In addition, the feet are usually involved in some type of contracture. The face, eyes, and mouth also have contractures secondary to fibrosis of the facial muscles. There may be a characteristic H-shaped band on the chin, decreased facial movement, and pursing of the mouth. Occasionally, coloboma of the lateral ali nasi are seen. Patients with Freeman-Sheldon syndrome frequently develop scoliosis and ptosis. The condition usually has autosomal dominant inheritance, but there is a great deal of variability seen within families. Intelligence is normal, and affected individuals tend to respond well to physical therapy.

Diastrophic dysplasia is a chondrodysplasia involving abnormalities of the cartilage such that there is disproportionate short stature with shortening of limbs and trunk and clubbing of feet and hands. With time, the cartilage of the ear becomes calcified, and symphalangism of the fingers occurs. It appears that physical therapy is actually detrimental in this condition, since the cartilage is not normal and does not take the stress of wear and tear caused by physical therapy. Therefore, it is the one condition with arthrogryposis in which physical therapy is contraindicated. The cartilage of the trachea is involved as well, and pressure on that cartilage causes swelling and calcification; thus, intubation should be avoided with diastrophic dysplasia if possible. The congenital contractures in diastrophic dysplasia would appear to be secondary to connective tissue changes. The clubfeet and scoliosis are quite resistant to therapy. The condition is autosomal recessive and can be diagnosed prenatally. It is due to mutations in the sulfate transporter gene (DTDST).

Contractural Arachnodactyly

Contractural arachnodactyly is an autosomal dominantly inherited condition characterized by multiple congenital contractures with long, thin limbs (particularly hands and feet), kyphoscoliosis, and unusual ear shape consisting of crumpling of the top of the helix of the ear. Various deformities of the chest are seen with frequent pectus carinatum or excavatum. When a particularly severe case is seen in the newborn period, it is very frequently lethal. Careful autopsies on these infants demonstrate that a large number have involvement of the heart, in particular floppy mitral valve and aortic dilation. Advanced bone age, gastrointestinal abnormalities, and vertebral abnormalities have also been seen. These individuals have many features in common with the Marfan syndrome; however, a different fibrillin is involved. Contractural arachnodactyly is associated with defects of the fibrillin gene on chromosome 5.

Pena-Shokeir Syndrome Phenotype (Fetal Akinesia Deformation Sequence)

The Pena-Shokeir syndrome is a lethal condition characterized by multiple congenital contractures (usually in the flexion position), pulmonary hypoplasia, micrognathia, prominent bridge of the nose, and depressed tip of the nose. The clinical findings reflect severe fetal akinesia and most affected individuals die of pulmonary hypoplasia. Many families have been reported with autosomal recessive inheritance. However, there appears to be heterogeneity, and the phenotype is a sign of decreased in utero movement seen in a number of specific conditions. Autopsies have revealed a variety of additional abnormalities, particularly in the central nervous system, that are consistent within families, suggesting that there are many, many genes that can lead to de-

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creased in utero movement and give this phenotype. However, if the phenotype is present, there is a high chance of it being due to an autosomal recessive gene, and there is approximately a 20% recurrence risk to that family. The condition is almost always lethal. Prenatal diagnosis is possible utilizing real-time in utero movement and has been diagnosed in several cases prior to 20 weeks. Maternal Illness

A variety of maternal illnesses, including myasthenia gravis and myotonic dystrophy, are associated with infants who are affected with multiple congenital contractures. In view of this, when a specific diagnosis has not been made, the possibility that there is a maternal teratogen leading to the multiple congenital contractures in the embryo/fetus needs to be considered. Specifically, maternal antibodies to fetal neurotransmitter receptors can be tested for2 since that is a treatable disorder. Prognosis, Prevention, and Treatment

Although prognosis, prevention, and treatment should be addressed with regard to very specific conditions, some generalizations can be made about most types of multiple congenital contractures.1,3,19 In general, the prognosis for a child with multiple congenital contractures is favorable, since once the contractures can be mobilized, the child does well; however, the prognosis depends on the cause and severity in a given case. On the other hand, approximately one-third of the affected individuals have central nervous system dysfunction and do very poorly. This can usually be recognized in the first several months because the child is unresponsive, does not feed well, and does not interact with his or her environment. A vigorous physical therapy program should be instituted shortly after birth to give the infant an opportunity to respond. In the past, children with congenital contractures have been placed in multiple casts to stretch the joint contractures and whatever muscle tissue was present and then atrophied. It is important before immobilization that muscle tissue be preserved if possible, and this is best done by physical therapy stretching the joints for the first few months with splinting to maintain the stretch. Care must be given not to fracture bones, since immobilized bones are often osteoporotic. Response to this type of physical therapy usually occurs within the first 4 to 6 months after birth, and then there seems to be less response. At that time, surgical considerations and casting need to be considered. Night splinting is an important part of postsurgical therapy, since there is a tendency for joints that have had contractures to return to the presurgical position. With the advent of prenatal diagnosis, there may well be cases in which congenital contractures are recognized in utero. Increasing fetal movement either through maternal exercise or stimulatory medications may improve the long-term outcome for these infants. Early delivery may be considered in order to institute early physical therapy if the lungs are mature. The recurrence risk for a family and an affected individual depends on the specific type of arthrogryposis. In approximately 20% of cases, a specific diagnosis cannot be made. In those situations, empiric recurrence risks indicate there is approximately a 3–5% recurrence risk both for the parents of the child and for the affected individual.4 Prenatal diagnosis using real-time ultrasound is very useful in these situations.

A recent study of complications during affected pregnancies18 indicates that there is no good prognostic indicator during a pregnancy to anticipate that the child will be born with multiple congenital contractures, nor is there any strong evidence for environmental influences as the cause of nonspecific multiple congenital contractures. Fetal movement is often decreased. Breech presentation is more frequent than usual. The mean birth weight is decreased for age; however, this is probably related to decreased muscle mass. The height of affected individuals is usually 4 to 8 inches less than unaffected family members.19 This appears to be related to decreased use of the lower limbs. Adults with arthrogryposis seem to have an increased propensity to develop degenerative arthritis of involved joints. This may actually be related to the type of therapy used at a young age, including physical therapies and surgery to the affected joints. Thus, care involving wear and tear on affected joints is an important consideration. A parent group for the families of individual children with arthrogryposis has been extremely helpful by providing suggestions for appliances, therapies, and various support mechanisms.20 References (Arthrogryposis) 1. Hall JG: Arthrogryposes (Multiple Congenital Contractures). In: Emery and Rimoin’s Principle and Practice of Medical Genetics, vol 2, ed 4. DL Rimoin, JM Connor, RE Pyeritz, eds. Churchill Livingstone, New York, 2001, p 4182. 2. Hall JG, Vincent A: Arthrogryposis. In: Neuromuscular Diseases of Infancy, Childhood, Adolescence—A Clinician’s Approach. H Jones, DC De Vivo, BT Darris, eds. Heinemann, Amsterdam, 2002, p 123. 3. Hall JG: Arthrogryposis. In: Management of Genetic Syndromes, ed 2. SB Cassidy, JE Allanson, eds. Wiley-Liss, New York, 2005, p 63. 4. Hall JG: Genetic aspects of arthrogryposis. Clin Orthop 194:44, 1985. 5. Froster-Iskenius UG, Waterson JR, Hall JG: A recessive form of congenital contractures and torticollis associated with malignant hyperthermia. J Med Genet 25:104, 1988. 6. Reed SD, Hall JG, Riccardi VM, et al.: Chromosomal abnormalities associated with congenital contractures (arthrogryposis). Clin Genet 27:353, 1985. 7. Hall JG, Reed SD, Driscoll EP: Part I. Amyoplasia: a common, sporadic condition with congenital contractures. Am J Med Genet 15:571, 1983. 8. Hall JG, Reed SD, McGillivray BC, et al.: Part II. Amyoplasia: twinning in amyoplasia—a specific type of arthrogryposis with an apparent excess of discordantly affected identical twins. Am J Med Genet 15:591, 1983. 9. Reid CO, Hall JG, Anderson C, et al.: Association of amyoplasia with gastroschisis, bowel atresia, and defects of the muscular layer of the trunk. Am J Med Genet 24:701, 1986. 10. Hall JG, Reed SD: Teratogens associated with congenital contractures in humans and in animals. Teratology. 25:173, 1982. 11. Hall JG, Reed SD, Greene G: The distal arthrogryposes: delineation of new entities—review and nosologic discussion. Am J Med Genet 11:185, 1982. 12. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: a review and report of eleven patients. Am J Med Genet 12: 377, 1982. 13. Moessinger AC: Fetal akinesia deformation sequence: an animal model. Pediatrics 72:857, 1983. 14. Swinyard CA, Bleck EE: The etiology of arthrogryposis (multiple congenital contractures). Clin Orthop 194:15, 1985. 15. Swinyard CA. Concepts of multiple congenital contractures (arthrogryposis) in man and animals. Teratology 25:247, 1982.

Limbs 16. Bamshad M, Jorde LB, Carey JC: A revised and extended classification of the distal arthrogryposes. Am J Med Genet 65:277, 1996. 17. Sung SS, Brassington AM, Krakowiak PA, et al.: Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Am J Hum Genet 73:212, 2003.

933 18. Fahy M, Hall JG: A retrospective study of pregnancy complications among 828 cases of arthrogryposis. Genet Couns 1:3, 1990. 19. Staheli LT, Hall JG, Jaffe KM, et al.: Arthrogryposis: A Text Atlas. Cambridge University Press, Cambridge, UK, 1998. 20. Avenues: A National Support Group for Arthrogryposis Multiplex Congenita. http://sonnet1.sonnet.com/avenues/.

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21 Hands and Feet David B. Everman

M

alformations of the hands and feet have been extensively described and characterized, in large part because they occur commonly and are easily visualized by patients, family members, and physicians alike. The major categories of hand and foot malformations include short digits (brachydactyly), extra digits (polydactyly), fused digits (syndactyly), and deficient digits (oligodactyly). As with other types of malformations, hand and foot anomalies occur either in isolation or as a component feature of numerous syndromes. Many hand and foot malformations are heritable, often manifesting as isolated traits that are transmitted in families through many generations. In such instances, affected persons may not seek medical attention for the malformations themselves, simply considering them to be the normal hands or feet for the family. In cases of cosmetically or functionally significant malformations, or when they are associated with other physical or developmental abnormalities, patients typically present for evaluation by primary care physicians, geneticists, or orthopedists. Like other limb malformations, hand and foot anomalies have numerous genetic and non-genetic causes, necessitating thorough prenatal, medical, and family histories and a detailed physical examination in every case. Review of photographs, radiographs, and medical records is often helpful when the patient has already undergone surgical intervention. Examination of parents and other family members is frequently indicated to look for subtle digital abnormalities that may not be reported. The importance of having patients and their relatives remove their shoes and socks for a careful foot examination cannot be overstated. Embryology

Hand and foot malformations arise from abnormalities of limb development during the weeks 4–8 following conception. Deformations or disruptions may occur during this period or long after the limbs are formed. The limbs develop from paired upper and lower limb buds that arise from the lateral plate mesoderm at the end of week 4 (day 26 or 27), with development of the upper limb preceding that of the lower limb by 2 days (Fig. 21-1).1 The limb buds consist of a mesenchymal core covered by ectoderm and undergo growth and patterning along three axes: proximo-distal (shoulder to finger, hip to toe), dorso-ventral (dorsum of hand to palm, dorsum of foot to sole), and antero-posterior (thumb to 5th finger, hallux to 5th toe).1– 5 As the limbs grow outward, three segments (stylopod, zeugopod,

and autopod) form, corresponding to the upper limb (shoulder to elbow, hip to knee), middle limb (elbow to wrist, knee to ankle), and hand/foot. The bones and connective tissues arise from the limb bud mesenchyme originating from the lateral plate mesoderm. The skeletal elements of each limb segment and its component rays are formed as the mesenchymal cells condense into discrete structures (mesenchymal condensations) and differentiate into cartilage-forming cells (chondroblasts and chondrocytes). The condensations are converted into cartilaginous models of the future bones by week 6 as the mesenchymal cells differentiate into chondroblasts that synthesize collagen fibrils and matrix material.1 The cartilaginous precursors are ultimately transformed into bone through the process of endochondral or intracartilaginous ossification. Primary ossification centers form in the diaphyses of all of the tubular bones by week 12. Secondary ossification centers form in the epiphyses of the long bones and the tubular bones of the hands and feet, and analogous single ossification centers form within the carpal and tarsal bones during the first several years after birth. Longitudinal bone growth occurs through cell proliferation within the growth plates, which are situated between the epiphyses and diaphyses of the tubular bones, and ceases when epiphyseal– diaphyseal fusion occurs after the completion of puberty.1 Hand and foot plates are formed by week 5.1 The digital rays of the hand and foot plates appear in weeks 6 and 7, respectively, in the form of mesenchymal condensations joined by loose connective tissue. Over time, the digital condensations differentiate into cartilage and the interdigital mesenchyme degenerates through a process of programmed cell death (apoptosis), leaving the digits fully separated by week 8. The joints form during weeks 6–8 in the interzones between the ends of the skeletal elements.1 The central undifferentiated mesenchyme in these regions degenerates to form the joint space, while the peripheral mesenchyme develops into a joint capsule. The lining cells differentiate into synovial cells that produce fluid to lubricate the joint spaces. The ligaments, tendons, blood vessels, and lymphatics all arise from mesenchyme within the budding limb, while the nails originate from the overlying ectoderm.1 Invasion of the limb bud by myoblasts from the somites gives rise to the limb muscles, and a similar invasion from motor and sensory axons arising from the spinal cord gives rise to the nerve supply. 935

936

Skeletal System

Fig. 21-1. Schematics of hand and foot development, showing locations of the apical ectodermal ridge (open arrows) and zone of polarizing activity (closed arrows). A, 27 days; B, 32 days; C, 41 days; D, 46 days; E, 50 days; F, 52 days; G, 28 days; H, 36 days; I, 46 days; J, 49 days; K, 52 days; L, 56 days. (Modified from Moore KL: The Developing Human, ed 4. WB Saunders, Philadelphia, 1988.)

Developmental and Molecular Mechanisms

Specification of the ‘‘limb fields,’’ the positions along the craniocaudal axis of an embryo from which the limb buds arise, is programmed prior to limb budding and probably involves HOX gene signaling.5 Interactions between the intermediate mesoderm, lateral plate mesoderm, and overlying ectoderm are believed to be responsible for limb initiation.5 Limb outgrowth and patterning are coordinated by interactions between three cellular signaling centers within the limb buds (Fig. 21-1).3 These are the apical ectodermal ridge (AER), the ectoderm covering both sides of the limb bud, and the polarizing region or zone of polarizing activity (ZPA).3 It is thought that these centers set up a 3-dimensional coordinate system that imparts positional information to individual cells through which they are destined to contribute to particular structures, including the bones, tendons, and muscles (Fig. 21-2).3 The AER consists of a thickened ridge of ectoderm that forms along the antero-posterior axis at the tip of the limb bud. The AER separates the dorsal and ventral surfaces of the limb bud and helps to Fig. 21-2. The budding limb and its axes of development. Important growth and signaling centers in the limb bud include the apical ectodermal ridge (AER), progress zone (PZ), and zone of polarizing activity (ZPA). The fully developed hand and foot maintain the dorso-ventral, proximo-distal, and antero-posterior axes.

direct limb outgrowth and patterning. The limb bud mesenchyme is necessary for proximo-distal patterning, and the progress zone (PZ) comprises an area of proliferating undifferentiated mesenchyme lying immediately beneath the AER.2 Cells are thought to leave the PZ at specified times to form the skeletal elements in a proximo-distal sequence as the limb elongates.2–5 The progress zone model hypothesizes that cells in the PZ progressively acquire their developmental fates, with those leaving the PZ earlier forming more proximal structures, and those leaving later forming more distal structures. This model has recently been challenged with the idea that proximodistal specification may be pre-programmed within the early limb bud.2 The ectoderm covering the sides of the limb bud participates in dorso-ventral patterning through interactions with the underlying mesenchyme. The ZPA develops as a discrete area of mesenchymal cells on the posterior aspect of the limb bud and specifies development along the antero-posterior axis. The activities of each signaling center are precisely coordinated and interrelated; as an example, interactions between the AER and PZ occur in a positive feedback loop.3 The molecular signals mediating limb development have begun to be delineated through studies of animal models including the chick and mouse.3–5 Identification of genes causing limb malformations in both animals and humans has also been of central importance in characterizing the signaling pathways required for normal limb morphogenesis.3–5 Many genes contributing to human limb development and malformations have been discovered, and a number of them cause hand and foot disorders.3–5 The prevailing molecular model of human limb development is complex. Fibroblast growth factors (FGFs) and Wnt transcription factors are required for limb initiation and specification of the AER.3,4 The gene radical fringe (r-Fng) helps create a molecular boundary specifying the AER position.5 Once the limb bud has formed, the AER produces FGF4 and FGF8, which facilitate limb outgrowth along the proximo-distal axis. Patterning along this axis is also mediated by HOX genes, which are clustered genes encoding transcription factors. Genes in the HOXA and HOXD clusters (HOXA9-13 and HOXD913) are expressed in an overlapping pattern within the developing limbs, and it is thought that this graded expression permits specification of the upper, middle, and distal limb segments.4 Dorso-ventral patterning is controlled by the expression of Wnt7a in the dorsal ectoderm, Engrailed-1 (En-1) in the ventral ectoderm, and LMX1B in the dorsal mesenchyme.3,4 Patterning along the antero-posterior axis

Hands and Feet

is controlled by the ZPA, which forms before significant budding has occurred.5 The function of the ZPA has been demonstrated in animal experiments in which transplantation of this region to the anterior aspect of another limb bud results in a mirror-image duplication, or removal of this region causes digital absence.2–5 Sonic hedgehog (SHH), a transcription factor, is secreted by cells in the ZPA to specify digital identity.2 It is thought that the SHH signaling pathway and BMPs help to pattern the hands and feet along the antero-posterior axis, whereas retinoic acid, which is also highly expressed by the posterior mesenchyme, may be involved in more proximal A-P patterning.2,3 Genes from the HOXD cluster (HOXD9-13) are expressed in a nested pattern along the antero-posterior axis and also contribute to patterning of the digits.3 Specification of the upper versus the lower limbs appears to be achieved by differential expression of genes belonging to the TBX family.3,4 Once the limb is correctly patterned, development of the skeletal elements is equally complex, requiring the coordinated activities of a number of genes to promote mesenchymal condensation, chondrogenic differentiation, and endochondral ossification. Critical players in this process include the FGFs, FGF receptors (FGFRs), bone morphogenetic proteins (BMPs), growth/differentiation factor (GDF5), and Indian hedgehog (IHH), which mediate cartilage and bone formation.6 Interactions between GDF5 and its antagonist, Noggin (NOG), are essential for normal joint formation.7 For detailed discussions of the genes and molecular pathways involved in limb and skeletal development, the reader is referred to a number of excellent reviews.2–8 Classification

Molecular advances have led to new ideas about classifying limb malformations and other skeletal disorders. Older classification schemes are based on clinical and radiographic findings,9 whereas newer schemes are based on insights into molecular pathogenesis.8,10 Kornak and Mundlos8 have recently proposed a scheme based on embryology and molecular pathology, dividing skeletal disorders into problems with skeletal patterning, early differentiation, growth, and homeostasis. Molecular pathogenetic insights have also led to issues regarding nomenclature, since different genes may cause the same phenotype (genetic heterogeneity), and different phenotypes may be caused by the same gene (pleiotropy).11 In this chapter, clinical/anatomic classifications will be utilized, along with a discussion of pertinent molecular and developmental aspects of each hand and foot malformation. References 1. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, ed 7. Saunders, Philadelphia, 2003. 2. Niswander L: Pattern formation: old models out on a limb. Nat Rev Genet 4:133, 2003. 3. Tickle C: Molecular basis of vertebrate limb patterning. Am J Med Genet 112:250, 2002. 4. Gurrieri F, Kjaer KW, Sangiorgi E, et al.: Limb anomalies: developmental and evolutionary aspects. Am J Med Genet 115:231, 2002. 5. Innis JW, Mortlock DP: Limb development: molecular dysmorphology is at hand! Clin Genet 53:337, 1998. 6. Kronenberg HM: Developmental regulation of the growth plate. Nature 423:332, 2003. 7. Mariani FV, Martin GR: Deciphering skeletal patterning: clues from the limb. Nature 423:319, 2003. 8. Kornak U, Mundlos S: Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73:447, 2003. 9. Temtamy SA, McKusick VA: The genetics of hand malformations. Birth Defects Orig Art Ser XIV(3):1, 1978.

937

10. Winter RM, Tickle C: Syndactylies and polydactylies: embryological overview and suggested classification. Eur J Hum Genet 1:96, 1993. 11. Biesecker LG: Polydactyly: How many disorders and how many genes? Am J Med Genet 112:279, 2002.

21.1 The Polydactylies Definition

Polydactylies represent excessive partitioning of the hands and feet resulting in either complete or incomplete extra digital rays (Tables 21-1 and 21-2).1–4 These malformations occur in a spectrum that includes well-formed extra digits, incompletely formed extra digits that are fleshy or contain bone, and a normal number of digits with one or more having extra bones or broad/bifid tips. Polydactyly may be preaxial, postaxial, or mesoaxial, and different types can occur in the same disorder. Polydactyly is often accompanied by other types of digital malformation, particularly syndactyly. In polysyndactyly, extra digits are a consistent feature and syndactyly is a variably associated finding. Polydactyly is most commonly an isolated condition inherited as an autosomal dominant trait with incomplete penetrance and variable expression.1 Polydactyly is also seen in numerous syndromes (Tables 21-3 through 21-7).3 Postaxial Polydactyly

Postaxial polydactyly is an extra digit located on the postaxial (ulnar or fibular) side of the limb. The size and degree of develTable 21-1. Classification of the syndactylies and polydactylies on the basis of patterning Normal Patterning

Abnormal separation of digits Preaxial, F syndrome Mesoaxial, syndactyly type I Postaxial, syndactyly types III, V Total, Apert syndrome Increased number of digits (sometimes with abnormal separation) Preaxial, preaxial polydactyly type I Mesoaxial, synpolydactyly (syndactyly type II) Postaxial, postaxial polydactyly types A and B Pre- and postaxial, preaxial polydactyly type IV Decreased number of digits Preaxial, radial ray defects Mesoaxial, split hand/foot Postaxial, ulnar ray defects Abnormal Patterning

Abnormal separation of digits Cenani-Lenz syndrome Preaxial Polydactyly of an index finger (preaxial polydactyly type III) Triphalangeal thumbs (preaxial polydactyly type II) Symmetric with increased number of digits Mirror hands/feet With increased number and abnormal separation of digits Haas-type polysyndactyly (syndactyly type IV)

938

Skeletal System Table 21-2. The polydactylies: Temtamy and McKusick classification1 Type

Digits Involved

Comment

Postaxial

Postaxial extra digits

Types A and B

Preaxial type I

Duplication of thumbs/great toes

Associated with Fromont anomaly

Preaxial type II

Triphalangeal thumbs/duplication of great toes

Thumbs opposable

Preaxial type III

Absent thumbs, one or two extra preaxial digits

Preaxial digit may or may not be opposable, preaxial metacarpal has distal epiphysis

Preaxial type IV

Broad thumbs, preaxial polysyndactyly, postaxial postminimus

Overlaps with Greig syndrome

opment of the extra digit may vary. The extra digit may be relatively well formed (type A) or it may be a small, rudimentary digit or pedunculated tag (type B). Postaxial Polydactyly Type A

Postaxial polydactyly type A is an extra digit in the hand articulating with the lateral metacarpal surface (Fig. 21-3). The digit is well formed and contains a nail but may be much smaller than the normal 5th finger and contain fewer than three phalanges. The degree of function of this digit can vary. A similar extra toe may be present. The condition can be unilateral or bilateral, and when bilateral it can be symmetric or asymmetric. Hand radiographs usually demonstrate two or three phalanges in the extra finger, which articulates with the fifth metacarpal or with a bifid or duplicated metacarpal. Foot radiographs demonstrate an extra digit articulating with the 5th metatarsal or with a bifid or duplicated metatarsal. Postaxial Polydactyly Type B (Pedunculated Postminimus)

In postaxial polydactyly type B, the extra digit is rudimentary and poorly formed or consists only of soft tissue. The digit appears as a small conical projection or pedunculated tag of varying size. It may contain bone and a nail. The extra digit attaches to the lateral border of the 5th digit, usually between the proximal and distal flexion creases (Fig 21-3). Classically, the condition is restricted to the hands.1 The condition can be unilateral or bilateral. When unilateral, it preferentially involves the left hand.1 Postaxial polydactyly types A and B are traditionally classified as separate disorders, but they are not completely distinct. This is clear from families in which both phenotypes occur and from individuals with variable manifestations in different limbs.1,5 Based upon their extensive studies of postaxial polydactyly in Latin America, Castilla and colleagues consider types A and B to be arbitrary distinctions, particularly for the purpose of population-based analyses.5,6 They have also questioned the generally accepted idea that postaxial polydactyly of the hands versus feet represents the same disorder.6 Through the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), they found that among cases of isolated postaxial polydactyly, 76% were confined to the hands, 16% were confined to the feet, and 8% involved both hands and feet.6 Polydactyly was more likely to be left-sided and present in first-degree relatives when isolated to the hands or when affecting the hands and feet together.6 Castilla et al.7 found that 12% of postaxial polydactyly cases are associated with other anomalies. In one-third of these cases, the other anomalies are restricted to the limbs. There is a statistically increased frequency of syndactyly, particularly involving toes 2–3 and 4–5.7 The remaining cases are associated with known syn-

dromes or multiple congenital anomaly patterns of unknown cause. Many syndromes have postaxial polydactyly as a feature (Tables 21-3, 21-5). Among these, Castilla et al.7 found that trisomy 13 and Meckel syndrome were the most frequent. When known syndromes were excluded from their analysis, postaxial polydactyly was not positively associated with any non-limb anomaly but was negatively associated with spina bifida, hydrocephaly, congenital heart disease, and anal atresia.7 The highest frequency of associated anomalies occurs when both the hands and feet are affected.6 The inheritance pattern of postaxial polydactyly has been a subject of debate. Temtamy and McKusick1 indicated that types A and B are usually inherited as autosomal dominant traits with reduced penetrance and variable expression. Castilla et al.8 estimated the penetrance of type A as 0.68 and of type B as 0.43. Autosomal recessive inheritance has also been suggested.1,9 Studies of postaxial polydactyly at the population level suggest that it is a multifactorial trait.5 Linkage mapping studies of families with autosomal dominant postaxial polydactyly have led to the identification of at least four major gene loci. The type A phenotype was mapped to chromosomes 7p and 13q, and a mixed type A/B phenotype was mapped to chromosome 19p.10–12 GLI3 was later found to be the responsible gene on chromosome 7p.13 GLI3 encodes a zinc fingercontaining transcription factor that participates in the sonic hedgehog pathway and is involved in patterning of the limbs along the anterior-posterior axis.14 Mutations in this gene also cause Pallister-Hall syndrome, Greig cephalopolysyndactyly syndrome, and preaxial polydactyly type IV.14 Radhakrishna et al.14 subsequently discovered GLI3 mutations in three additional families with autosomal dominant postaxial polydactyly with mixed features of types A and B (type A/B). They observed phenotypic variation among the limbs of affected persons with the same family and attributed this to environmental or stochastic factors.14 They proposed that postaxial polydactyly type A or type A/B be classified among other GLI3-related disorders as ‘‘GLI3 morphopathies.’’14 A fourth locus for postaxial polydactyly type A/B has recently been mapped to chromosome 7q21-q34.15 Numerous studies have investigated the epidemiology of polydactyly. Postaxial polydactyly is the most common type and is approximately 10 times more frequent in blacks than whites. ScottEmuakpor and Madueke16 found an overall prevalence of 22.5/ 1000 in Nigerians, with a 1.5:1 male-to-female sex ratio. Bingle and Niswander17 reported an incidence of 1.07/1000 in Native Americans. Wolf and Myrianthopoulus18 found an incidence of 13.5/ 1000 in African-Americans and 1.2/1000 in Caucasian-Americans. The most extensive study was by Castilla et al.,4 who found 6912 cases of polydactyly among over 4 million births. Postaxial polydactyly accounted for the vast majority (5345) of cases with a rate of 6–15/10,000 depending on the ethnic background of the

Table 21-3. Syndromes with postaxial polydactyly Syndrome

Prominent Features

Causation (OMIM#) Gene/Locus

Acrofrontofacio-nasal dysostosis74

Hypertelorism, bifid nasal tip, cleft lip/palate, mental retardation

AR (201180)

Asphyxiating thoracic dystrophy (Jeune)75

Short ribs, trident configuration to acetabulum, short limbs, renal failure

AR (208500) 15q13

Bardet-Biedl76

Obesity, mental retardation, retinal dystrophy, renal anomalies

AR (209900) triallelic inheritance BBS1, 11q13 BBS2, 16q21 BBS4, 15q22.3 BBS6, 20p12 BBS7, 4q27 BBS8, 14q32.11 3p13, 2q31

Beckwith-Wiedemann77

Postaxial polydactyly of feet (rare), macrosomia, macroglossia, abdominal wall defect, hemihyperplasia, predisposition to develop embryonal tumors

AD (130650), imprinting-related mechanism CDKN1C (point mutations), 11p15.5 LIT1 and H19 (altered methylation), 11p15.5

Biemond, type 21

Obesity, iris coloboma, hypogenitalism, hydrocephalus

Unknown (210350)

C-trigonocephaly78

Trigonocephaly, oral frenulae, syndactyly, mental retardation

AR (211750)

Cerebrooculonasal79

Anophthalmia, abnormal nose, hypertelorism, brachycephaly, mental retardation

Unknown (605627)

Chondrodysplasia, Grebe type80

Hypoplastic digits, severe shortening of long bones

AR (200700) CDMP1/GDF5, 20q11.29

Czeizel-Brooser81

Myopia, corneal and lens opacities

AD (174310)

Dandy-Walker malformationpostaxial polydactyly82

Dandy-Walker malformation

AR (220220)

Ectrodactyly-polydactyly83

Absent digits, split-foot malformation

AR (225290)

Ellis-van Creveld84

Atrial septal defect, short ribs, acromesomelic limb shortening, oral frenulae, trident configuration to acetabulum, central polydactyly

AR (225500) EVC, 4p16 EVC2, 4p16

Esmer85

Liver fibrocystic disease, mental retardation

Unknown (605944)

Fuhrmann86

Angulated femur, hypoplastic fibula, metacarpal/metatarsal synostosis, hypoplasia of digits

AR (228930)

Garrett-Tripp87

Total alopecia, Perthes disease, exfoliative dermatitis

XLR (306050)

Goltz (focal dermal hypoplasia)88

Atrophic skin, papillomas of nose/mouth, eye colobomas, syndactyly

XLD (305600)

Guttmacher89

Hypospadias

AD (176305) HOXA13, 7p15-p14.2

Halal90

Split-hand, mu¨llerian abnormalities

AD (146160)

Hernandez91

Cortical blindness, mental retardation

AR (218010)

Holoprosencephaly-polydactyly (pseudotrisomy 13)92

Holoprosencephaly, hydrocephalus, hypotelorism, congenital heart defects

AR (264480)

Joubert93

Apnea/hyperventilation, cerebellar vermis aplasia

AR (213300) NPHP1, 9q34.3 Heterogeneous

Kaplan-Bellah94

Ulnar ray dysgenesis, oligodactyly, renal dysplasia

Unknown (604380)

McKusick-Kaufman95

Hydrometrocolpos, imperforate anus, congenital heart defects, malrotation of intestine, central polydactyly

AR (236700) MKKS, 20p12

Meckel-Gruber96

Encephalocele, cystic kidneys, microphthalmia, cleft lip/palate, hepatic fibrosis

AR (249000) 17q22-q23, 11q13, 8q24

Oliver97

Mental retardation

AR (258200)

Oral-facial-digital, Sugarman type98

See-saw winking, oral frenulas, hamartomas of tongue, supernumerary teeth, mental retardation

AR (258850) (continued)

939

940

Skeletal System

Table 21-3. Syndromes with postaxial polydactyly (continued) Syndrome

Prominent Features

Causation (OMIM#) Gene/Locus

Oto-palato-digital, type II99

Hypertelorism, micrognathia, cleft palate, overlapping fingers, dense bones

XL (304120) FLNA, Xq28

Pallister-Hall100

Hypothalamic hamartoblastoma, imperforate anus, hypopituitarism, central polydactyly

AD (146510) GLI3, 7p13

Midline cleft of upper lip

AR (174300)

Reish (BRESHECK syndrome)

Brain anomalies, growth retardation, mental retardation, Hirschsprung disease, deafness, cleft palate

XLR (300404)

Reiss (distal arthrogryposis)103

Cleft lip/palate, micrognathia, webbed neck, scoliosis

AD (108130)

Robinson (ectodermal dysplasia-deafness)104

Oligodontia, hypoplastic nails, syndactyly, deafness

AD (124480)

Rogers105

Hypoplastic or fused vertebrae, webbed neck, prognathism, abnormal teeth

AR (263540)

Sakati-Nyhan (acrocephalopolysyndactly type III)106

Craniosynostosis, short limbs, atrophic skin on scalp, alopecia, symphalangism, malformed ears, hypoplastic tibia

Unknown (101120)

Santos107

Hirschsprung disease, renal agenesis, sensorineural deafness

AR (235740)

Scalp defects-polydactyly108

Scalp defects

AD (181250)

Schinzel-Giedion109

Hypertrichosis, midface retraction, deep-set nails, broad ribs, choanal stenosis, mental retardation

AR (269150)

Short rib-polydactyly, type I (Saldino-Noonan)110

Short ribs, imperforate anus, urogenital abnormalities, congenital heart defects

AR (263530)

Short-rib-polydactyly, type II (Majewski)111

Short ribs, midline cleft of upper lip, ovoid tibia

AR (263520)

Short-rib-polydactyly, type III (Naumoff)112

Short ribs, craniofacial abnormalities

AR (263510)

Simpson-Golabi-Behmel113

Prenatal macrosomia, organomegaly, macrostomia, hypoplastic distal phalanges, mental retardation

XLR (306050) GPC3, Xq26

Smith-Lemli-Opitz114

Anteverted nares, 2-3 toe syndactyly, short thumbs, hypospadias, mental retardation

AR (270400) DHCR7, 11q12-q13

Ulnar-mammary115

Ulnar ray defects, anal atresia, hypoplastic breasts and apocrine glands, hypogenitalism

AD (181450) TBX3, 12q24.1

Urioste116

Mu¨llerian duct remnants, lymphangiectasia, prenatal growth deficiency

AR (235255)

Weyers acrofacial dysostosis117

Short limbs, oligodontia, small nails

AD (193530) EVC, 4p16

Polydactyly-cleft lip (OFD V)101 102

population.4 Orioli19 found that there was segregation distortion in postaxial polydactyly, with greater transmission of the trait to offspring of affected black fathers. Preaxial Polydactyly Preaxial Polydactyly Type I

Preaxial polydactyly type I is complete or partial duplication of a normal biphalangeal thumb. The feet may be similarly affected. There is no postaxial duplication of the limbs and no syndactyly of other digits. In this disorder, a normal biphalangeal thumb has all or some elements duplicated.1 The degree of polydactyly ranges from a broad or partially duplicated distal phalanx, to a completely duplicated distal phalanx articulating with a single proximal phalanx, to a complete, usually hypoplastic and nonfunctional, extra biphalangeal thumb (Fig. 21-4).1 Graham et al.20 described four families with an autosomal dominant phenotype of thumb polydactyly in conjunc-

tion with hypoplasia of thenar muscles and inability to adduct the thumb across the palm (Fromont anomaly). In two of these families, preaxial polydactyly type I was observed, suggesting that mild abnormalities of thumb position and thenar musculature are manifestations of the disorder. Similarly, radial deviation of the distal phalanx of the thumb has been suggested to be a mild feature of this condition.1 The feet may be affected in a similar fashion. For example, Ray21 described a family with partial or complete duplication of the halluces in all affected persons, some of whom also had thumb duplication. Orioli and Castilla22 studied differences between hand and foot involvement in 715 cases of isolated preaxial polydactyly. They found that among type I cases (which accounted for 91% of the entire group), 86% involved the hands only, 13% involved the feet only, and less than 1% involved both the hands and feet.22 They also found that thumb or hallux duplication is usually unilateral and more often right-sided.22 All of the cases reported by

Table 21-4. Syndromes with preaxial polydactyly Prominent Features

Causation (OMIM#) Gene/Locus

Hypoplastic thumbs, anemia

AR (205600)

Acrocraniofacial dysostosis

Ptosis, choanal atresis, malformed ears, craniosynostosis, preauricular pits, cleft palate

AR (201050)

Acrofrontofacionasal dysostosis, severe (NaguibRichieri-Costa)120

Hypertelorism, ptosis, shawl scrotum, hypospadias, syndactyly, midline nasal groove

AR (239710)

Acropectoral syndrome36

Syndactyly of all fingers and toes, prominent upper sternum, U-shaped sinus in chest wall

AD (605967) 7q36

Acro-renal-ocular121

Eye colobomas, Duane syndrome, ptosis, hypoplastic thumbs, renal ectopia

AD (102490) SALL4, 20q13.13-q13.2

Anophthalmia-polydactyly122

Anophthalmia

AD (607932) 14q22-q23

Biemond type 2, sensu stricto123

Duplicated thumb, hypogonadism, short stature, coloboma

AR (210350)

Congenital heart defect, syndactyly, polyhydramnios

AR (263630)

Preaxial polydactyly (rare), branchial cleft sinuses/cysts/ hemangiomas, cleft or pseudocleft lip, colobomata, premature graying of hair

AD (113620)

Braun126

Deafness, renal tract malformations, brachytelephalangy

Unknown (256200)

Curry-Jones127

Syndactyly of hands/feet, craniosynostosis, facial asymmetry, absent corpus callosum, abnormal skin

Unknown (601707)

Fanconi anemia128

Bifid or duplicated thumb (rare), hypoplastic or absent thumb/ radius, pancytopenia, short stature, microcephaly, hyperpigmented macules

AR (227650) FANCA, 16q24.3 FANCB, 13q12.3 FANCC, 9q22.3 FANCD1/BRCA2, 13q12.3 FANCD2, 3p25.3 FANCE, 6p22-p21 FANCF, 11p15 FANCG, 9p13 FANCL/PHF9, 2p16.1

Femoral-facial (femoral hypoplasia-unusual facies)129

Preaxial polydactyly of feet, femoral hypoplasia, upslanted palpebral fissures, long philtrum with thin upper lip, micrognathia, cleft palate

AD (134780), maternal diabetes

Frontonasal dysplasia130

Duplicated hallux, agenesis of nasal root, broad nose with slit-like nares, tibial aplasia

Sporadic (136760, 603671)

Hemifacial microsomiaradial defect131

Hemifacial microsomia, triphalangeal thumbs

Unknown (141400)

Howard-Young132

Microcephaly, clefting, mental retardation

Unknown (601420)

Lacrimo-auriculodento-digital133

Absent lacrimal punctas, malformed ears, deafness, hypoplastic thumbs

AD (149730)

Lambotte134

Intrauterine growth retardation, microcephaly, holoprosencephaly, anterior chamber cleavage defect

AR (245552)

Lenz microphthalmia135

Microphthalmia, colobomas, simple ears, cleft lip/palate, abnormal teeth, syndactyly

XLR (309800) Xq27-q28

Okihiro136

Radial ray dysplasia, Duane anomaly, deafness

AD (607323) SALL4, 20q13.13-q13.2

Pfeiffer137

Craniosynostosis, syndactyly

AD (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Sorsby138

Macular colobomas, brachydactyly type B

AD (120400)

Spondylocostal dysostosis139

Multiple vertebral segmentation defects, rib anomalies

AR (277300) DLL3, 19q13 MESP2, 15q26.1

Townes-Brocks140

Hypoplastic/triphalangeal thumbs, anal atresia, preauricular pits/ tags, overfolded helices, sensorineural deafness, renal agenesis

AD (107480) SALL1, 16q12.1

Varadi-Papp (oral-facialdigital type VI)101

Oral frenulas, tongue hamartomas, cleft lip/palate, cerebellar hypoplasia, central polydactyly, syndactyly

AR (277170)

WT141

Anemia, pancytopenia, leukemia, syndactyly, radius/ulna defects

AD (194350)

Syndrome

Aase118 119

Bonneau124 Branchio-oculo-facial

125

941

942

Skeletal System Table 21-5. Syndromes with preaxial and postaxial polydactyly Syndrome

Prominent Features

Causation (OMIM#) Gene/Locus

Acrocallosal142

Preaxial polysyndactyly, macrocephaly, agenesis of corpus callosum, hypertelorism, mental retardation

AR (200990) 12p13.3-p11.2

Acrocephalo-polysyndactyly type II (Carpenter)143

Preaxial polydactyly of feet, postaxial polydactyly of hands, brachydactyly, syndactyly, brachycephaly, craniosynostosis, heart defects, variable mental retardation

AR (201000)

Ectrodactyly, ectodermal dysplasia, cleft lip/palate144

Preaxial polydactyly of hands/feet (rare), postaxial polydactyly (rare), hypoplastic or absent digits, split-hand/foot malformation, syndactyly, ectodermal dysplasia, cleft lip/palate

Greig cephalopolysyndactyly50

Macrocephaly, hypertelorism, syndactyly

AD (129900 and 604292) P63, 3q27 7q21-q22 AD (175700) GLI3, 7p13

Hirschsprung disease-polydactyly145

Hirschsprung disease, congenital heart defects

AR (235750)

Holmes146

Absent/hypoplastic tibia, cleft lip, retrocerebellar arachnoid cyst, absent diaphragm

AR (601027)

Hydrolethalus147

Hydrocephaly, micrognathia, ventricular septal defect

AR (236680) 11q23-q25

Multinodular goiter-cystic renal disease-digital anomalies148

Multinodular goiter, cystic renal disease

AD (138790)

Oral-facial-digital, type I149

Midline cleft lip, cleft tongue, hamartomas of tongue, hyperplastic frenula, mental retardation, polycystic kidneys

XLR (311200) CXORF5, Xp22.3-p22.2

Oral-facial-digital, type II149

Midline cleft lip, cleft tongue, hamartomas of tongue

AR (252100)

Oral-facial-digital, type IV150

Hamartomas of tongue, cleft lip/palate, clubfoot, tibial dysplasia

AR (258860)

Syndactyly-polydactylyearlobe151

Preaxial syndactyly of feet, groove/nodule of earlobe

AD (186350)

Tibial hypoplasia-polydactyly (tibial hemimelia-polydactylytriphalangeal thumbs with fibular dimelia)33

Triphalangeal thumb, tibial aplasia, syndactyly

AD (188770)

Triphalangeal thumbpolysyndactyly30,31

Triphalangeal thumb, syndactyly

AD (190605) 7q36

Temtamy and McKusick1 and Bingle and Niswander17 involved only one hand. Radiographs of the hands and feet show varying degrees of duplication of the thumbs and/or halluces. The distal phalanges can be broad, partially duplicated and fused, or completely duplicated and separate, with or without similar changes in the proximal phalanges. The first metacarpal or metatarsal may also be short, broad, or partially or completely duplicated. The genetic contribution to preaxial polydactyly type I is complex. Most cases are sporadic, while some families demonstrate autosomal dominant inheritance with significant variation in expression and reduced penetrance.20,21 Castilla et al.8 found only two familial cases among 24 cases of thumb polydactyly. In their large study, Orioli and Castilla22 found that 14% of persons with either thumb or foot duplication had one or more affected relatives and that penetrance was 9% in the thumb duplication group under an autosomal dominant model. A chromosomal locus for this disorder has not yet been identified. Preaxial polydactyly type I is most often an isolated finding in an otherwise healthy individual. In approximately 20% of cases, it is associated with other abnormalities.7,22 It has a statistically significant association with esophageal atresia and Down syndrome.7 At least six cases of a proximally placed, duplicated hallux have been reported in infants of diabetic mothers.23 Preaxial

polydactyly is seen in a variety of other syndromes (Tables 21-4, 21-5). Orioli and Castilla22 found a prevalence of 2/10,000 for isolated preaxial polydactyly type I in South America, with a male-tofemale sex ratio of 1.5:1 for thumb duplication and 2:1 for hallux duplication. Similarly, Castilla et al.4 found a prevalence of 1.9/ 10,000 in Spain. Woolf and Myrianthopoulos18 found an equal incidence of 0.8/10,000 for preaxial polydactyly among Caucasians and African-Americans, but did not specify the proportion of type I cases in each group. There was no sex difference in their study.18 The condition appears to be much more common in the Chinese. Handforth24 reported 13 cases from among 5842 Chinese prisoners in Hong Kong (22/10,000), whereas only one prisoner had postaxial polydactyly. Bingle and Niswander17 found an incidence of 2.5/10,000 in Native Americans. They noted that the condition is 3 to 4 times more common in this population than in Caucasians or those of African descent.17 In the Chinese and Native Americans, the condition is also more common in males and is most often unilateral, nonfamilial, and restricted to the hands.17,24 Preaxial Polydactyly Type II (Polydactyly of a Triphalangeal Thumb)

Preaxial polydactyly type II is an opposable thumb with three phalanges, with or without partial or complete duplication of the

Table 21-6. Syndromes with triphalangeal thumbs Syndrome

Prominent Features

Causation (OMIM#) Gene/Locus

Aase118

Bifid/hypoplastic thumbs, anemia

Unknown (205600)

DOOR (deafnessonychodystrophy-onycholysismental retardation)152

Sensorineural deafness, hypoplastic distal phalanges, mental retardation, seizures/abnormal EEG

AR (220500)

Deafness-onychodystrophytriphalangeal thumbs153

Sensorineural deafness, hypoplastic distal phalanges, small/hypoplastic/deep-set nails

AD

Hemifacial microsomia-radial defects131

Hypoplastic thumbs, asymmetric face, preauricular tags, cleft palate, supernumerary kidneys, hypoplastic radius, malformed ears

Unknown (141400)

Holt-Oram154

Absent or hypoplastic thumbs, atrial and ventricular septal defects, absent or hypoplastic radii, reduction defects of arms

AD (142900) TBX5, 12q24.1

Hydantoin, prenatal40

Hypoplastic distal phalanges, low frontal hairline, mental retardation, microcephaly, small/hypoplastic/deep-set nails

Environmental

Lacrimo-auriculo-dentodigital133

Absent or hypoplastic thumbs, absent or stenotic nasolacrimal ducts, sensorineural deafness, hypoplastic radii, oligodontia

AD (149730)

Neuro-facio-digito-renal155

Bifid nasal tip, frontal cowlick, macrocephaly, mental retardation, seizures

Unknown (256690)

Onychonychia-acral defects (Cooks)156

Distal phalangeal hypoplasia, small/hypoplastic/deep-set nails

AD (106995)

Radioulnar synostosis-radial ray abnormalities (Manouvrier)157

Radioulnar synostosis, radial ray abnormalities, hypoplastic thumb, severe anomalies (anencephaly, renal agenesis) or prenatal lethality in males

XLD (300233)

Richieri-Costa acrofacial dysostosis158

Cleft lip/palate, malformed ears, malar hypoplasia

AR

Schmitt159

Hypoplastic radius, hypospadias, maxillary diastema

AD (179250)

Hypoplastic thumbs, anal atresia, preauricular pits/tags, overfolded helices, sensorineural deafness, renal agenesis

AD (107480) SALL1, 16q12.1

Tibial hypoplasia-polydactyly (tibial hemimelia-polydactylytriphalangeal thumbs with fibular dimelia)33

Triphalangeal thumb, tibial aplasia, syndactyly

AD (188770)

Triphalangeal thumbpolysyndactyly30,31

Triphalangeal thumb, syndactyly

AD (190605) 7q36

Triphalangeal thumbbrachyectrodactyly160

Brachydactyly, ectrodactyly

AD (190680)

Townes-Brocks

140

Table 21-7. Syndromes with central polydactyly Causation (OMIM#) Gene/Locus

Syndrome

Prominent Features

Acropectorovertebral dysplasia (F-syndrome)161

Broad/bifid thumb, duplicated index finger, syndactyly of thumb and index finger with radial deviation and ‘‘bone chain’’ configuration, duplicated hallux, bizarre appearance of toes, carpal/ tarsal synostosis, chest deformity, incomplete L5/S1 vertebral arch

AD (102510) 2q36

Ellis-van Creveld84

Atrial septal defect, short ribs, acromesomelic limb shortening, oral frenulae, trident configuration of acetabulum, postaxial polydactyly

AR (225500) EVC, 4p16 EVC2, 4p16

Holzgreve162

Congenital heart defect, renal agenesis, hypoplastic 5th digit

Unknown (236110)

Martinez

Mental retardation, short stature, preaxial polydactyly of feet, facial dysmorphism, cardiac defect

AR (249670)

McKusick-Kaufman95

Hydrometrocolpos, imperforate anus, congenital heart defects, intestinal malrotation, postaxial polydactyly

AR (236700) MKKS, 20p12

Pallister-Hall100

Hypothalamic hamartoblastoma, imperforate anus, hypopituitarism, postaxial polydactyly

AD (146510) GLI3, 7p13

Varadi-Papp (oral-facialdigital type VI)101

Oral frenulae, tongue hamartomas, cleft lip/palate, cerebellar hypopoplasia, syndactyly

AR (277170)

163

943

944

Skeletal System

Fig. 21-3. Postaxial polydactyly. Schematic shows type A postaxial polydactyly on left and type B on right. In type B, the extra digit is usually only a pedunculated tag attached to the 5th digit between the first and second flexion creases.

thumb or great toe. A triphalangeal thumb must be distinguished from polydactyly of an index finger. A triphalangeal thumb has three recognizable phalanges instead of two. It is longer than normal, oriented at an approximate 90-degree angle to the other digits, and usually opposable (Fig. 21-5).25 It should be distinguished from the first digit of a fivefingered hand, which is nonopposable, oriented in the same plane as the other digits, and does not have a normal first web space or thenar musculature.25 In preaxial polydactyly type II, the triphalangeal thumb may be isolated or accompanied by partial or complete duplication of the thumb and/or hallux.1,25,26 Radiographs reveal a middle phalanx of the thumb that is often rudimentary or delta shaped but can be fully developed. There can also be various degrees of complete or partial duplication of the phalanges of the thumb and the first metacarpal. An important radiographic clue to a triphalangeal thumb versus a duplicated index finger is the presence of a normal proximal epiphysis on the first metacarpal.25 The hallux and first metatarsal may also be duplicated to varying degrees. Accessory ossifications can be found near the metacarpal-phalangeal and metatarsal-phalangeal joints.

Fig. 21-4. Preaxial polydactyly type I. Schematic and radiograph show partial duplication of a biphalangeal thumb. Photos show a patient with a broad thumb and partially duplicated hallux.

Hands and Feet

945

Fig. 21-5. Preaxial polydactyly type II (triphalangeal thumb). Schematic shows three phalanges in thumb that is opposable. Radiograph shows opposable triphalangeal thumb on right hand of 7-year-old male. Distal phalanx of left hand is abnormally formed. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

In addition to families with classical preaxial polydactyly type II, there are a number of reports of families with more complex phenotypes involving the hands, feet, and long bones. In some kindreds, there is a mixed picture of preaxial polydactyly type II (with triphalangeal, opposable thumbs and extra preaxial digits) and preaxial polydactyly type III (with duplicated, non-opposable index fingers and extra preaxial digits) that has been called ‘‘PPDII/ III’’.27,28 In other families, preaxial polydactyly type II is associated with syndactyly and postaxial polydactyly of the hands and feet. In the Dutch families described by Zguricas et al.,29 the mixed PPDII/ III phenotype without hallux duplication was accompanied by rudimentary postaxial polydactyly and occasional 4–5 syndactyly of the hands and/or feet. A more complex phenotype involving triphalangeal thumbs, duplicated preaxial and postaxial digits, and syndactyly has been reported by Nicolai and Hamel30 and Balci et al.31 and is commonly known as triphalangeal thumb-polysyndactyly syndrome (TPT-PS) (Fig. 21-6). In the latter family, a phenotype resembling syndactyly type IV occurred in some individuals.31 Radhakrishna et al.32 reported a family with triphalangeal thumbs and a polysyndactyly phenotype characterized by extra preaxial digits or index fingers and preaxial syndactyly, with no foot abnormalities. In a member of a PPDII/III family, a severe phenotype involving polysyndactyly of the hands and feet and bi-

lateral tibial aplasia was described.30 Triphalangeal thumbs, tibial absence, and polydactyly also occur in the tibial hemimelia-polydactyly-triphalangeal thumbs with fibular dimelia syndrome (THP-TTS). Kantaputra and Chalidapong33 reported this phenotype in the daughter of a man with the TPT-PS syndrome, suggesting that these may be related conditions. Hence, the clinical distinction between preaxial polydactyly types II and III, syndactyly type IV, and various syndromes sharing these features is not completely clear. Triphalangeal thumbs are seen in a number of other syndromes (Table 21-6). Mapping studies and animal models are beginning to make sense of the complicated clinical picture described previously. Preaxial polydactyly type II and the related disorders such as PPDII/III, TPT-PS, and TH-P-TTS are all inherited as autosomal dominant traits with wide variability.25–33 The preaxial polydactyly type II, PPDII/III, and TPT-PS phenotypes in most of the families described previously have been linked to chromosome 7q36.26,28–32,34,35 An acropectoral syndrome consisting of triphalangeal thumbs, preaxial polydactyly, soft tissue syndactyly between all fingers and toes, and sternal abnormalities also maps to this locus.36 Several mouse mutants with limb abnormalities, including sasquatch (Ssq) and hemimelic extra toes (Hx), map to the homologous region of mouse chromosome 5.37 In the Ssq Fig. 21-6. Triphalangeal thumb-polysyndactyly syndrome. Note triphalangeal thumb, duplicated index finger, and extensive syndactyly. (Courtesy of Dr. Ellen Boyd, Fullerton Genetics Center, Asheville, NC.)

946

Skeletal System

phenotype, heterozygotes have preaxial polydactyly of the hindlimbs and homozygotes have preaxial polydactyly of the forelimbs and hindlimbs with variable long bone shortening.37 The Ssq phenotype was recently found to be caused by a transgenic insertion in intron 5 of the Lmbr1 gene approximately 1 megabase away from the sonic hedgehog (Shh) gene.37 The same region of LMBR1 was disrupted by a balanced chromosome translocation in a sporadic case of preaxial polydactyly type II.37 A long-range enhancer of SHH expression in the developing limbs was subsequently identified within intron 5 of LMBR1, and point mutations in this enhancer were found in four families with preaxial polydactyly type II and in the Hx mouse.37 Based upon animal studies, the preaxial polydactyly phenotype is thought to result from misexpression of SHH in the anterior region of the developing limb bud.37 LMBR1 (also called C7orf2) is partially deleted in the disorder acheiropodia, in which the hands and feet are absent.38 The normal distal phalanx of the thumb is postulated to represent the fusion of the middle and ungual phalangeal ossification centers, which are present in the embryo.39 It has also been suggested that a triphalangeal thumb results from the integration of

part of a duplicated proximal or distal phalanx between the middle and distal phalanges. While misexpression of SHH may be responsible for some cases of triphalangeal thumb, other genes, such as SALL1 in Townes-Brocks syndrome, and TBX5 in Holt-Oram syndrome, are also associated with this malformation. Hence, triphalangeal thumb represents a final common pathway of abnormalities affecting different genes involved in limb development. Triphalangeal thumb has also been reported with prenatal hydantoin and thalidomide exposures.40,41 Lapidus et al.42 estimated the prevalence of triphalangeal thumbs to be 1/25,000 in a study of military draftees. Castilla et al.4 found a prevalence of preaxial polydactyly type II of 0.7/100,000 in Latin America and Spain. There is no known sex or racial variation for this disorder. Preaxial Polydactyly Type III (Polydactyly of an Index Finger)

Preaxial polydactyly type III is duplication of the index finger with or without an additional biphalangeal or triphalangeal thumb (Fig. 21-7). Hence, if there are a normal number of digits, all are

Fig. 21-7. Preaxial polydactyly type III (polydactyly of index finger). Schematic and top photograph show a five-finger hand with a triphalangeal first digit. Photograph below shows opposable thumbs as well as duplication of the second finger. (Bottom photograph courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Hands and Feet

triphalangeal and the radial most digit (which may be called a ‘‘thumb’’) is in the plane of the other fingers and may or may not be opposable.1,43 The distal phalanx of the duplicated index finger may be partially duplicated.1 Alternatively, the hand may have six digits, with the duplicated index finger situated between the normal index finger and a normal, rudimentary, hypoplastic, or partially duplicated thumb.1,44,45 Buck-Gramcko46 referred to preaxial polydactyly type III as a form of thumb duplication and differentiated this condition from true duplications of the index finger, which are a rare form of central polydactyly. As noted previously, some families show a mixed picture of preaxial polydactyly type II and preaxial polydactyly type III that has been called ‘‘PPDII/ III’’.27,28 One important clinical feature of a duplicated index finger is the presence of an extra ‘‘a’’ digital triradius and A digital line.1,44 The toes can be normal, or the hallux or 2nd toe may be duplicated.1,44 Radiographs reveal three phalanges in the duplicated finger. A constant radiographic finding is a distal epiphysis for the metacarpal of the accessory digit, which also has the configuration of the normal metacarpals 2–5.1,43 Preaxial polydactyly type III is inherited as an autosomal dominant trait with high penetrance.1,43–45 As described previously, linkage studies have mapped the mixed PPDII/III phenotype to a region of chromosome 7q36 implicated in the regulation of sonic hedgehog expression in the developing limbs. The differential diagnosis includes tibial hemimelia-polydactylytriphalangeal thumbs with fibular dimelia (TH-P-TPT) syndrome. This disorder features a five-fingered hand with preaxial polydactyly or mirror-image duplication of the feet.47 A mother and three daughters, reported by Say et al.,48 had mild short stature, borderline

947

intelligence, recurrent dislocation of the patellae, and polydactyly of the hands and feet with no recognizable thumbs or halluces. Preaxial polydactyly type III is a rare condition. Bingle and Niswander17 did not observe any cases of the condition among their study of polydactyly in over 44,000 Native Americans. Castilla et al.8 found one sporadic case of the disorder with unilateral involvement among 188 cases of polydactyly ascertained from 185,704 live births. In their large epidemiologic study of polydactyly in Latin America and Spain, Castilla et al.4 found 39 cases of 2nd digit duplication with a birth prevalence of 1 per 100,000. However, only 4 of 39 cases had findings consistent with a diagnosis of preaxial polydactyly type III.4 Many of the remaining cases had duplications of the 2nd toe, which were more often unilateral.4 Preaxial Polydactyly Type IV (Polysyndactyly)

Preaxial polydactyly type IV is duplication of preaxial digits associated with variable syndactyly of the other digits. Crossed polydactyly type I is probably the same disorder. In the hands, the thumbs are usually broad, bifid, radially deviated, or flattened (‘‘spade-like’’) (Fig. 21-8).1 There may be pedunculated postminimi (postaxial polydactyly type B), and there is occasional cutaneous syndactyly of fingers 3 and 4.1 In contrast, the feet are more severely affected, demonstrating complete or partial duplication of the first or second toes and syndactyly of toes 2–5, most commonly toes 2 and 3 (Fig. 21-8).1 Hallux varus may be present due to short, tibially deviated first metatarsal bones.1 Postaxial polydactyly of the feet can also occur.49 Radhakrishna et al.14 reported a family with the disorder in which some persons had well-developed extra postaxial digits on both the hands and feet.

Fig. 21-8. Preaxial polydactyly type IV (polysyndactyly). The upper photos show partial duplication of the halluces with syndactyly involving toes 2–3 and fingers 3–4. The lower photos show the broad thumbs and typical craniofacial features seen in Greig polysyndactyly syndrome.

948

Skeletal System

Hand radiographs usually demonstrate broad or bifid distal phalanges of the thumbs without more significant degrees of duplication. These phalanges may also be dysplastic with a central hole.49 Foot radiographs demonstrate varying degrees of duplication of the halluces and often show short, tibially deviated metacarpals.1 The condition is inherited as an autosomal dominant trait with clinical variability and high penetrance. Identical limb abnormalities occur in Greig cephalopolysyndactyly syndrome (GCPS) (Fig. 21-8), and the clinical distinction between the two disorders is not always clear.50 Preaxial polydactyly type IV was shown to be allelic to GCPS when a GLI3 mutation was identified in a family with this disorder.14 Findings similar to those of preaxial polydactyly type IV are also seen in the acrocallosal syndrome. The findings in some cases of preaxial polydactyly type IV represent crossed polydactyly, in which the extra digits are found on opposite sides of the hands relative to the feet.51 Crossed polydactyly is divided into type I (postaxial in hands, preaxial in feet) and type II (preaxial in hands, postaxial in feet).51 Crossed polydactyly is usually syndromic but can occur as an isolated disorder with or without syndactyly of toes 2–5.51,52 Castilla et al.4 observed 30 isolated cases of crossed polydactyly (types I and II) in their large Latin-American series and classified these as the same disorder as preaxial polydactyly type IV, giving an incidence of 0.007/10,000. Woolf and Myrianthopoulos18 found one case of crossed polydactyly type I among 25,126 AfricanAmericans and no cases among 24,153 Caucasians. Mesoaxial (Central) Polydactyly

Mesoaxial (central) polydactyly is partial or complete duplication of the 2nd, 3rd, or 4th finger. Beyond duplication of the index finger associated with preaxial polydactyly type III, this malformation is not described in Temtamy and McKusick’s1 classification of polydactyly. Most duplications of the 4th finger occur as a feature of syndactyly type II (synpolydactyly).46 In this disorder, there is syndactyly of fingers 3–4 and toes 4–5, with a partially duplicated digit in the syndactylous web (Fig. 21-9).1,46 Mesoaxial duplications do occur as isolated malformations not classified elsewhere, although they are frequently accompanied by other hand or foot abnormalities. Most of the information about this type of central polydactyly comes from the orthopedic literature. Buck-Gramcko46 distinguishes true duplications of the index

finger from preaxial polydactyly type III, which he classifies as a form of thumb duplication. In true duplications of the 2nd or 3rd fingers, there is usually a complete duplication of one or more phalanges.46 The extra phalanges often articulate with a normal underlying phalanx or metacarpal bone. In some cases, there is distal separation of duplicated phalanges with a synostotic or bifid appearance to the more proximally placed phalanx on hand radiographs. In other cases, all phalanges of a given digit are duplicated and articulate with a bifid or Y-shaped metacarpal bone. Rarely, the entire digit and metacarpal are completely duplicated. In the most rudimentary form, there is an extra soft tissue mass with no skeletal components.53 Syndactyly is often found between the involved digits and the adjacent normal digits. When the middle finger is duplicated with syndactyly on either side, the distal hand has a ‘‘cleft’’ appearance.46 Interestingly, in some cases of central polydactyly, there is a contralateral cleft hand.46,47 Polydactyly or syndactyly of the toes can also occur. In their analysis of rare polydactylies, Castilla et al.4 observed 34 cases of 2nd digit duplication, 11 cases of 3rd digit duplication, and 19 cases of 4th digit duplication. The latter group was separate from cases classified as synpolydactyly, and none of these duplications was accompanied by other non-limb anomalies. The feet were more frequently affected than the hands for 2nd and 3rd digit duplications. Only four cases of 2nd digit duplication were classified as preaxial polydactyly type III.4 Some of the cases in this series were familial as are some cases described in the orthopedic literature.46 However, information in the genetics literature concerning the inheritance of central polydactyly is lacking. The differential diagnosis includes preaxial polydactyly type III and syndactyly type II (synpolydactyly). The latter condition is usually caused by expansion of a sequence encoding a polyalanine tract in the gene HOXD13, which participates in limb patterning across the antero-posterior axis.54 Interestingly, different mutations in HOXD13 can cause several other phenotypes featuring mesoaxial polydactyly. Goodman et al.55 reported two families with an autosomal dominantly inherited, novel foot malformation characterized by bilateral partial duplication of the bases of the 2nd metatarsals and occasionally the 4th metatarsals. This was accompanied by broad halluces, short metatarsals, brachydactyly and symphalangism of the toes, and more classical manifestations of syndactyly type II in some persons. The condition was caused by intragenic deletions of Fig. 21-9. Central polydactyly associated with syndactyly (synpolydactyly). Radiographs demonstrate variable bilateral duplications of the phalanges of the 4th fingers and soft tissue syndactyly of the 3rd and 4th fingers. Also note partial duplication of the left third metacarpal and an accessory bone between the distal right 3rd and 4th metacarpals.

Hands and Feet

HOXD13 in both cases.55 Kan et al.56 detected a splice-site mutation in HOXD13 in a family with a similar phenotype but without classic features of syndactyly type II except for one person with unilateral syndactyly of fingers 3–4. Caronia et al.54 detected a missense mutation in the HOXD13 homeodomain in an autosomal dominant phenotype comprised of brachydactyly affecting the distal finger phalanges, middle toe phalanges, and 3rd–5th metacarpals and metatarsals. Two family members also had bilateral partial duplications of the 4th fingers. Mesoaxial polydactyly also occurs in several syndromes (Table 21-7). From the study of Castilla et al.,4 mesoaxial polydactyly appears to be a very rare malformation. Mirror Hands and Feet

The term mirror hands and feet describes polydactyly of a hand or foot with the appearance of a mirror-image duplication around

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the midline axis of the arm or leg in the absence of a recognizable thumb or great toe. In this malformation, there is a high degree of polydactyly associated with abnormalities of the long bones.1 In the typical mirror hand, also called ulnar dimelia, there are 7 or 8 fingers and no thumbs (Fig. 21-10).1,57 The axis of the duplication occurs along the middle of the 2nd finger, which has been postulated to divide the radial and ulnar rays.1 In addition, the wrist and elbow are thick, and the forearm is shortened.57 On radiographs, there are triphalangeal digits only, mirror-image duplications of the carpal bones, absence of the radius, and duplication of the ulna.57 Light57 indicates that most cases are sporadic and unilateral. Although extremely rare, a similar isolated form of mirror foot can occur. The pattern of duplication is analogous to that seen in the hand, with 7–8 toes, duplication of the tarsal bones and fibula, and absence of the tibia. The foot is fixed in an equinus position.

Fig. 21-10. Mirror hands. Duplication of ulnar digits with absence of a recognizable thumb. The ulna is also duplicated and the radius absent. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

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Bayram et al.58 described a unilateral case of this malformation and noted a previous report of the same malformation associated with a sacrococcygeal teratoma. Rivera et al.59 provided a detailed description of the internal anatomy of a mirror foot. Temtamy and McKusick1 noted that mirror-image polydactyly occurs as a component feature of several heritable conditions affecting the limbs. As originally described, the Laurin-Sandrow syndrome features bilateral ulnar and fibular dimelia in association with mirror feet, syndactyly of the toes, and complete synpolydactyly of the hands with a mitten or ‘‘rosebud’’ appearance as seen in syndactyly type IV.60,61 Distinctive clefts along the inferior margins of the nostrils also occur.61 Several other cases of this syndrome with varying manifestations have been described, and the findings have been reviewed by Kantaputra.62 Most patients have mirror feet with 7–10 toes each and complete syndactyly of the hands with 5–10 fingers each. Ulnar and fibular dimelia are inconsistent features, with some patient having tibial or fibular hypoplasia and some having normal long bones. A range of nasal abnormalities occur, including inferior grooves of the nares, grooved columella, and scar-like tissue under the nose.62 Based upon several cases with parent-to-child transmission, autosomal dominant inheritance has been postulated. Mirror feet are also seen in the tibial hemimelia-polydactyly-triphalangeal thumbs with fibular dimelia (TH-P-TPT) syndrome.1,47 Pfeiffer and Roeskau63 described a mother and son with tibial absence, fibular dimelia, and mirror feet. Urioste et al.64 and Martinez-Frias et al.65 described four cases of a condition featuring severe limb deficiencies, vertebral hypersegmentation, and mirror feet. The pathogenesis of mirror-image polydactyly is unknown but is presumably related to abnormal patterning along the anteroposterior axis of the developing limb. This is supported by animal experiments in which the transplantation the zone of polarizing activity (ZPA) to the anterior limb bud results in a mirror-image duplication. Although the ZPA expresses sonic hedgehog (SHH), sequence analysis of SHH failed to identify mutations in patients with mirror image polydactyly phenotypes.66 One patient with mirror image polydactyly was found to have a de novo balanced translocation between chromosomes 2 and 14, and a novel gene (MIPOL1) was identified at one breakpoint.67 However, mutations in this gene were not found in two other patients with a similar phenotype.67 Mirror-image limb duplications have been observed in the Disorganization mouse mutant and in some patients with congenital anomalies postulated to represent the human counterpart of this disorder.68 Mirror-image polydactyly is a very rare malformation. Castilla et al.4 found two isolated and two syndromic cases of mirror foot among over 4 million live births. Treatment

In its simplest form, the treatment of polydactyly involves removal of extra bone and soft tissue elements. In more complicated cases, reconstructive surgery involving the bones, soft tissues, tendons, intrinsic muscle attachments, stabilizing ligaments, and neurovascular components must also be performed in order to modify one or more existing digits.57 The ultimate goal of surgery is to create an acceptable cosmetic and functional result with a normal number of fingers and an opposable thumb. Among Asian cultures, a five-digit hand is preferred for social and religious reasons over a more functional hand with fewer digits.69 The surgical approach is based upon a precise classification of the anatomy, and the schemes used by surgeons specifically denote the type and level of the duplication.57,69 The treatment of postaxial polydactyly depends upon whether it is type A or B.57,69 In its simplest form (type B), the

transection of a small skin tag attached to the digit may be all that is necessary. This can be accomplished by a simple ligation in the nursery (the usual method) or by surgical excision. Complications of suture ligation include a small scar in most cases and occasional necrosis of the digit without falling off.70 If the level of ligation is too far distal, there may be a residual nipple-like prominence on the hand that necessitates elective surgical revision.57,69,70 In cases of postaxial polydactyly type A, the surgical approach depends upon the level of the duplication. As a general rule, the extra ulnar elements are removed in favor of more well-developed radial elements.57,69 If there are osseous connections, then sufficient bone must be removed to prevent excessive prominence of the lateral side of the hand that is cosmetically unacceptable. When there is complete bone, tendon, and soft tissue attachment, reconstruction of a normal 5th finger may require transfer of the muscle attachments and ulnar collateral ligament from the excised ulnar digit in order to provide stability and function.57,69 In preaxial polydactyly (duplicate thumb), surgical correction is nearly always necessary, and the type and amount of surgery depends on the classification of the defect and whether a triphalangeal component is present. In the frequently used classification scheme of Wassel,71 bifid or duplicated biphalangeal thumbs are classified as types I–VI, depending on the level of the duplication, and triphalangeal thumbs are type VII. Thumb polydactyly is usually corrected between 1 and 2 years of age.72 Simple excision of one of the thumbs is rarely satisfactory and can be applied in only a very few cases. For a partially duplicated, biphalangeal thumb, excision of the radial component with reconstruction of the ulnar portion is usually preferred. Care must be taken to align the bony elements, create a normal 1st web space, narrow excessively broad articular surfaces, reconstruct the supporting collateral ligaments to prevent angular deformity, and reattach muscles to provide balanced forces around the joints and promote optimal function.57,71 Parents should be advised that the resulting thumb will not appear completely normal.71 Combining duplicate distal phalanges by wedge excision and synostosis of the distal phalanx (the Bilhaut-Cloquet procedure) provides a satisfactory cosmetic and functional result in mild cases.57,70,71 Sophisticated surgical techniques are required to correct duplications that occur at more proximal levels. Angular deformity, instability, and loss of joint mobility are the most common complications, and up to 25% of children require additional surgery as they grow.71 The treatment of thumb polydactyly with a triphalangeal component is more complex and usually requires multiple procedures, beginning between 6 and 24 months of age.57 When a triphalangeal thumb is preserved, surgery may be required to correct angular deformity caused by an abnormal shape of the extra phalanx.57 The surgical treatment of central polydactyly is highly complex, and multiple operations may be required to obtain a satisfactory functional result.69 Correction is recommended around 6–12 months of age.57,69 Syndactyly and neurovascular anomalies frequently complicate the removal of extra bony elements, and digital ischemia can occur during surgery.57 Angular deformities, such as flexion contractures, of the residual digits are another complicating factor and may only become apparent after excision of an adjacent digit.57 In some instances, because of growth and vascular problems, the creation of a more functional hand with a thumb and three fingers may be advisable.69 Correction of mirror hand is also extremely complex. The aim of hand surgery in this disorder is to select one preaxial digit for pollicization (in which it is shortened and rotated to function as a

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thumb) and remove the other supernumerary digits.57,69 In cases of ulnar dimelia, the elbow and wrist require procedures to reduce associated deviation and improve flexion and extension. References (The Polydactylies) 1. Temtamy SA, McKusick VA: The genetics of hand malformations. BDOAS XIV(3)1, 1978. 2. Winter RM, Tickle C: Syndactylies and polydactylies: embryological overview and suggested classification. Eur J Hum Genet 1:96, 1993. 3. Biesecker LG: Polydactyly: how many disorders and how many genes? Am J Med Genet 112:279, 2002. 4. Castilla EE, da Fonseca RL, de Garcia Dutra M, et al.: Epidemiological analysis of rare polydactylies. Am J Med Genet 65:295, 1996. 5. Feitosa MF, Castilla EE, da Graca Dutra M, et al.: Lack of evidence of a major gene acting on postaxial polydactyly in South America. Am J Med Genet 80:466, 1998. 6. Castilla EE, da Graca Dutra M, Lugarinho da Fonseca R, et al.: Hand and foot postaxial polydactyly: two different traits. Am J Med Genet 73:48, 1997. 7. Castilla EE, Lugarinho R, de Garcia Dutra M, et al: Associated anomalies in individuals with polydactyly. Am J Med Genet 80:459, 1998. 8. Castilla EE, Paz J, Mutchinick O, et al.: Polydactyly, a genetic study in South America. Am J Hum Genet 25:405, 1973. 9. Mollica F, Li Volti S, Sorge G: Autosomal recessive postaxial polydactyly type A in a Sicilian family. J Med Genet 15:212, 1978. 10. Radhakrishna U, Blouin J-L, Mehenni H, et al.: Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis. Am J Hum Genet 60:597, 1997. 11. Akarsu AN, Ozbas F, Kostakoglu N: Mapping of the second locus of postaxial polydactyly type A (PAP-A2) to chromosome 13q21-q32. Am J Hum Genet 61(suppl):A265, 1997. 12. Zhao H, Tian Y, Breedveld G: Postaxial polydactyly type A/B (PAPA/B) is linked to chromosome 19p13.1-13.2 in a Chinese kindred. Europ J Hum Genet 10:162, 2002. 13. Radhakrishna U, Wild A, Grzeschik K-H, et al.: GLI3 mutations in postaxial polydactyly type A. Am J Hum Genet 61(suppl): A48, 1997. 14. Radhakrishna U, Bornholdt D, Scott HS, et al.: The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations. Am J Hum Genet 65:645, 1999. 15. Galjaard RJ, Smits AP, Tuerlings JH, et al.: A new locus for postaxial polydactyly type A/B on chromosome 7q21-q34. Eur J Hum Genet 11: 409, 2003. 16. Scott-Emuakpor AB, Madueke E-D: The study of genetic variation in Nigeria. II. The genetics of polydactyly. Hum Hered 26:198, 1976. 17. Bingle GJ, Niswander JD: Polydactyly in the American Indian. Am J Hum Genet 27:91, 1975. 18. Woolf CM, Myrianthopoulos NC: Polydactyly in American Negroes and whites. Am J Hum Genet 25:347, 1973. 19. Orioli IM: Segregation distortion in the offspring of Afro-American fathers with postaxial polydactyly. Am J Hum Genet 56:1207, 1995. 20. Graham JM Jr, Brown FE, Hall BD: Thumb polydactyly as a part of the range of genetic expression for thenar hypoplasia. Clin Pediatr 26:142, 1987. 21. Ray AK: A pedigree with bilateral preaxial polydactyly from India. J Genet Hum 35:267, 1987. 22. Orioli IM, Castilla EE: Thumb/hallux duplication and preaxial polydactyly type I. Am J Med Genet 82:219, 1999. 23. Slee J, Goldblatt J: Further evidence for preaxial hallucal polydactyly as a marker of diabetic embryopathy. J Med Genet 34:261, 1997. 24. Handforth JR: Polydactylism of the hand in Southern Chinese. Anat Rec 106:119, 1950. 25. Merlob P, Grunebaum M, Reisner SH: Familial opposable triphalangeal thumbs associated with duplication of the big toes. J Med Genet 22:78, 1985. 26. Hing AV, Helms C, Slaugh R, et al.: Linkage of preaxial polydactyly type 2 to 7q36. Am J Med Genet 58:128, 1995. 27. Radhakrishna U, Multani AS, Solanki JV, et al.: Polydactyly: a study of a five generation Indian family. J Med Genet 30:296, 1993.

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28. Zguricas J, Heus H, Morales-Peralta E, et al.: Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36. J Med Genet 36:32, 1999. 29. Zguricas J, Snijders PJLM, Hovius SER, et al.: Phenotypic analysis of triphalangeal thumb and associated hand malformations. J Med Genet 31:462, 1994. 30. Nicolai J-P, Hamel BCJ: A family with complex bilateral polysyndactyly. J Hand Surg 13A:405, 1988. 31. Balci S, Demirtas M, Civelek B, et al.: Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome linked to chromosome 7q36. Am J Med Genet 87:399, 1999. 32. Radhakrishna U, Blouin J-L, Solanki JV, et al.: An autosomal dominant triphalangeal thumb-polysyndactyly syndrome with variable expression in a large Indian family maps to 7q36. Am J Med Genet 66:209, 1996. 33. Kantaputra PN, Chalidapong P: Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family. Am J Med Genet 93:126, 2000. 34. Heutink P, Zguricas J, van Oosterhout L, et al.: The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nat Genet 6:287, 1994. 35. Tsukurov O, Boehmer A, Flynn J, et al.: A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nat Genet 6:282, 1994. 36. Dundar M, Gordon TM, Ozyazgan I, et al.: A novel acropectoral syndrome maps to chromosome 7q36. J Med Genet 38:304, 2001. 37. Lettice LA, Heaney SJH, Purdie LA, et al.: A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Molec Genet 12:1725, 2003. 38. Ianakiev P, van Baren MJ, Daly MJ, et al.: Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene. Am J Hum Genet 68:38, 2001. 39. Qazi Q, Kassner EG: Triphalangeal thumb. J Med Genet 25:505, 1988. 40. Kouseff BG, Stein M: Fetal hydantoin syndrome. Am J Dis Child 135:370, 1981. 41. Lenz W, Knapp K: Thalidomide embryopathy. Arch Environ Health 5:100, 1962. 42. Lapidus PW, Guidotti FP, Colletti CJ: Triphalangeal thumb. Report of 6 cases. Surg Gynecol Obstet 77:178, 1943. 43. Swanson AB, Brown KS: Hereditary triphalangeal thumb. J Hered 53:259, 1962. 44. Atasu M: Hereditary index finger polydactyly: phenotypic, radiological, dermatoglyphic, and genetic findings in a large family. J Med Genet 13:469, 1976. 45. Warm A, Di Pietro C, D’Agrosa F, et al.: Non-opposable triphalangeal thumb in an Italian family. J Med Genet 25:337, 1988. 46. Buck-Gramcko D: Central Polydactyly. In: Congenital Malformations of the Hand and Forearm. Buck-Gramcko D, ed. Churchill Livingstone, London, 1998, p 237. 47. Vargas FR, Pontes RL, Llerena JC Jr., et al.: Absent tibiae-polydactylytriphalangeal thumbs with fibular dimelia: variable expression of the Werner (McKusick 188770) syndrome? Am J Med Genet 55:261, 1995. 48. Say B, Field E, Coldwell JG, et al.: Polydactyly with triphalangeal thumbs, brachydactyly, camptodactyly, congenital dislocation of the patellas, short stature, and borderline intelligence. Birth Defects Orig Artic Ser XII(5):279, 1976. 49. Reynolds JF, Sommer A, Kelly TE: Preaxial polydactyly type 4: variability in a large kindred. Clin Genet 25:267, 1984. 50. Baraitser M, Winter RM, Brett EM: Greig cephalopolysyndactyly: report of 13 affected individuals in three families. Clin Genet 24:257, 1983. 51. Ishikiriyama S, Sawada H, Nambu H, et al.: Crossed polydactyly type I in a mother and son: an autosomal dominant trait? Am J Med Genet 40:41, 1991. 52. Nathan PA, Keniston RC: Crossed polydactyly: case report and review of the literature. J Bone Joint Surg Am 57:847, 1975. 53. Tada K, Kurisaki E, Yonenobu K, et al.: Central polydactyly—a review of 12 cases and their surgical treatment. J Hand Surg 7A:460, 1982.

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54. Caronia G, Goodman FR, Zappavigna V, et al.: An I47L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function. Development 130:1701, 2003. 55. Goodman F, Giovannucci-Uzielli M-L, Hall C, et al.: Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families. Am J Hum Genet 63:992, 1998. 56. Kan S, Johnson D, Giele H, et al.: An acceptor splice site mutation in HOXD13 results in variable hand, but consistent foot malformations. Am J Med Genet 121A:69, 2003. 57. Light TR: Polydactyly. In: Green’s Operative Hand Surgery, 4th Ed. Green DP, Hotchkiss RN, Pederson WC, eds. Churchill Livingstone, London, 1999, p 432. 58. Bayram H, Herdem M, Temocin AK: Fibular dimelia and mirror foot without associated anomalies. Clin Genet 49:311, 1996. 59. Rivera RE, Hootnick DR, Gingold AR, et al.: Anatomy of a duplicated human foot from a limb with fibular dimelia. Teratology 60:272, 1999. 60. Laurin CA, Favreau JC, Labelle P: Bilateral absence of the radius and tibia with bilateral reduplication of the ulna and fibula. J Bone Joint Surg Am 46:137, 1964. 61. Sandrow RE, Sullivan PD, Steel HH: Hereditary ulnar and fibular dimelia with peculiar facies. A case report. J Bone Joint Surg Am 52:367, 1970. 62. Kantaputra PN: Laurin-Sandrow syndrome with additional manifestations. Am J Med Genet 98:210, 2001. 63. Pfeiffer RA, Roeskau M: Agenesis of the tibia, duplication of the fibula and mirror foot in mother and child [in German]. Z Kinderheilkd 111:38, 1971. 64. Urioste M, Lorda-Sanchez I, Blanco M, et al.: Severe congenital limb deficiencies, vertebral hypersegmentation, absent thymus and mirror polydactyly: a defect expression of a developmental control gene? Hum Genet 97:214, 1996. 65. Martinez-Frias ML, Arroyo I, Bermejo E, et al.: Severe limb deficiencies, vertebral hypersegmentation, and mirror polydactyly: two additional cases that expand the phenotype to a more generalized effect on blastogenesis. Am J Med Genet 73:205, 1997. 66. Vargas FR, Roessler E, Gaudenz K, et al.: Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly. Hum Genet 102:387, 1998. 67. Kondoh S, Sugawara H, Harada N, et al.: A novel gene is disrupted at a 14q13 breakpoint of t(2;14) in a patient with mirror-image polydactyly of hands and feet. J Hum Genet 47:136, 2002. 68. Robin NH, Abbadi N, McCandless SE, et al.: Disorganization in mice and humans and its relation to sporadic birth defects. Am J Med Genet 73:425, 1997. 69. Graham TJ, Ress AM: Finger polydactyly. Hand Clin 14:49, 1998. 70. Watson BT, Hennrikus WL: Postaxial type-B polydactyly. Prevalence and treatment. J Bone Joint Surg 79A:65, 1997. 71. Wassel HD: The results of surgery for polydactyly of the thumb. Clin Orthop 64:175, 1969. 72. Cohen MS: Thumb duplication. Hand Clin 14:17, 1998. Cohen MS: Thumb duplication. Hand Clin 14:17, 1998. 73. Online Mendelian Inheritance in Man. Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2004. Available from: URL:http://www.ncbi.nlm.nih.gov/omim/ 74. Richieri-Costa A, Colletto GMDD, Gollop TR: A previously undescribed autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/palate, limb hypoplasia, and postaxial poly-syndactyly. Am J Med Genet 20:631, 1985. 75. Morgan NV, Bacchelli C, Gissen P, et al.: A locus for asphyxiating thoracic dystrophy, ATD, maps to chromosome 15q13. J Med Genet 40: 431, 2003. 76. Katsanis, N: The oligogenic properties of Bardet-Biedl syndrome. Hum Mol Genet 13(Suppl 1):R65, 2004. 77. Elliott M, Maher ER: Beckwith-Wiedemann syndrome. J Med Genet 31: 560, 1994. 78. Opitz JM, McCreadie SR, Smith DW, et al.: The C syndrome of multiple congenital anomalies. BDOAS V(2):161, 1969.

79. Guion-Almeida ML, Kokitsu-Nakata NM, Richieri-Costa A: Clinical variability in cerebro-oculo-nasal syndrome: report on two additional cases. Clin Dysmorphol 9:253, 2000. 80. Costa T, Ramsby G, Cassia F, et al.: Grebe syndrome: clinical and radiographic findings in affected individuals and heterozygous carriers. Am J Med Genet 75:523, 1998. 81. Czeizel A, Brooser G: A postaxial polydactyly and progressive myopia syndrome of autosomal dominant origin. Clin Genet 30:406, 1986. 82. Pierquin G, Deroover J, Levi S, et al.: Dandy-Walker malformation with postaxial polydactyly: a new syndrome? Am J Med Genet 33:483, 1989. 83. Regemorter NV, Milaire J, Ramet J, et al.: Familial ectrodactyly and polydactyly: variable expressivity of one single gene—embryological considerations. Clin Genet 22:206, 1982. 84. McKusick VA, Egeland JA, Eldridge R, et al.: Dwarfism in the Amish. I. The Ellis-van Creveld syndrome. Bull Johns Hopkins Hosp 115:306, 1964. 85. Esmer C, Alvarez-Mendoza A, Lieberman E, et al: Liver fibrocystic disease and polydactyly: proposal of a new syndrome. Am J Med Genet 101:12, 2001. 86. Fuhrmann W, Fuhrmann-Rieger A, De Sousa F: Poly-, syn- and oligodactyly, aplasia or hypoplasia of fibula, hypoplasia of pelvis and bowing of femora in three sibs—a new autosomal recessive syndrome. Eur J Pediatr 133:123, 1980. 87. Garrett C, Tripp JH: Unknown syndrome: mental retardation with postaxial polydactyly, congenital absence of hair, severe seborrheic dermatitis, and Perthes’ disease of the hip. J Med Genet 25:270, 1988. 88. Temple IK, MacDowall P, Baraitser M, et al.: Syndrome of the month. Focal dermal hypoplasia (Goltz syndrome). J Med Genet 27:180, 1990. 89. Guttmacher A.E: Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias. Am J Med Genet 46:219, 1993. 90. Halal F: A new syndrome of severe upper limb hypoplasia and Mullerian duct anomalies. Am J Med Genet 24:119, 1986. 91. Hernandez A, Garcia-Esquival L, Reynoso MC, et al.: Cortical blindness, growth and psychomotor retardation and postaxial polydactyly: a probably distinct autosomal recessive syndrome. Clin Genet 28:251, 1985. 92. Cohen MM Jr, Gorlin RJ: Pseudo-trisomy 13 syndrome. Am J Med Genet 39:332, 1991. 93. Egger J, Bellman MH, Ross EM, et al.: Joubert-Bolthauser syndrome with polydactyly in siblings. J Neurol Neurosurg Psychiatr 45:737, 1982. 94. Kaplan BS, Bellah RD: Postaxial polydactyly, ulnar ray dysgenesis, and renal cystic dysplasia in sibs. Am J Med Genet 87:426, 1999. 95. Chitayat D: Delineation of the McKusick-Kaufman syndrome. Am J Dis Child 141:1133, 1987. 96. Fraser FC, Lytwyn A: Spectrum of anomalies in the Meckel syndrome, or: ‘‘maybe there is a malformation syndrome with at least one constant anomaly.’’ Am J Med Genet 9:67, 1981. 97. Oliver CP: Recessive polydactylism associated with mental deficiency. J Hered 31:365, 1940. 98. Sugarman GI, Katakia M, Menkes J: See-saw winking in a familial orofacial-digital syndrome. Clin Genet 2:248, 1971. 99. Fitch N, Jequier S, Papageorgiou A: A familial syndrome of cranial, facial, oral, and limb anomalies. Clin Genet 10:226, 1976. 100. Graham J Jr, Saunders R, Fratkin J, et al.: A cluster of Pallister-Hall syndrome cases (congenital hypothalamic hamartoblastoma syndrome). Am J Med Genet Suppl 2:53, 1986. 101. Toriello HV: Heterogeneity and variability in the oral-facial-digital syndromes. Am J Med Genet Suppl 4:149, 1988. 102. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/ BRESHECK): new X-linked syndrome? Am J Med Genet 68:386, 1997. 103. Reiss JA, Sheffield LJ: Distal arthrogryposis type II: a family with varying congenital abnormalities. Am J Med Genet 24:255, 1986. 104. Robinson GC, Miller JR, Bensimon JR: Familial ectordermal dysplasia with sensorineural deafness and other anomalies. Pediatrics 30:797, 1962. 105. Rogers JG, Levin LS, Dorst JP, et al.: A postaxial polydactyly-dentalvertebral syndrome. J Pediatr 90:230, 1977.

Hands and Feet 106. Sakati N, Nyhan WL, Tisdale WK: A new syndrome with acrocephalopolysyndactyly, cardiac disease, and distinctive defects of the ear, skin, and lower limbs. J Pediatr 79:104, 1971. 107. Santos H, Mateus J, Leal MJ: Hirschsprung disease associated with polydactyly, unilateral renal agenesis, hypertelorism and congenital deafness: a new autosomal recessive syndrome. J Med Genet 25:204, 1988. 108. Buttiens M, Fryns JP, Jonckheere P, et al.: Scalp defect associated with postaxial polydactyly: confirmation of a distinct entity with autosomal dominant inheritance (case report). Hum Genet 71:86, 1985. 109. Schinzel A, Giedion A: A syndrome of severe midface retraction, multiple skull anomalies, clubfeet, and cardiac and renal malformations in sibs. Am J Med Genet 1:361, 1978. 110. Saldino RM, Noonan CD: Severe thoracic dystrophy with striking micromelia, abnormal osseous development, including the spine, and multiple visceral abnormalities. Am J Roentgen 114:257, 1972. 111. Majewski F, Pfeiffer RA, Lenz W, et al.: Polysyndaktylie, verkuerzte gliedmassen, und genitalfehlbildungen: kennzeichen eines selbstaendigen syndrome? Z. Kinderheilk. 111:118, 1971. 112. Naumoff P, Young LW, Mazer J, et al.: Short-rib-polydactyly syndrome type III. Radiology 122:443, 1977. 113. Cohen M, Jr: A comprehensive and critical assessment of overgrowth and overgrowth syndromes, Simpson-Golabi-Behmel syndrome. Adv Hum Genet 18:262, 1989. 114. Penchaszadeh VB: Invited editorial comment: the nosology of the Smith-Lemli-Opitz syndrome. Am J Med Genet 28:719, 1987. 115. Schinzel A, Illig R, Prader A: The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene. Clin Genet 32:160, 1987. 116. Urioste M, Rodriguez JI, Barcia JM, et al.: Persistence of mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet 47:494, 1993. 117. Roubicek M, Spranger J: Syndrome of polydactyly, conical teeth and nail dysplasia. Am J Med Genet 20:205, 1985. 118. Aase JM, Smith DW: Congenital anemia and triphalangeal thumbs: a new syndrome. J Pediatr 74:417, 1969. 119. Kaplan P, Plauchu H, Fitch N: A new acro-cranio-facial dysostosis syndrome in sisters. Am J Med Genet 29:95, 1988. 120. Teebi A S: Naguib-Richieri-Costa syndrome: hypertelorism, hypospadias, and polysyndactyly syndrome. (Letter) Am J Med Genet 44:115, 1992. 121. Halal F, Homsy M, Perreault G: Acro-renal-ocular syndrome: autosomal dominant thumb hypoplasia, renal ectopia, and eye defect. Am J Med Genet 17:753, 1984. 122. Ahmad ME, Dada R, Dada T, et al: 14q(22) deletion in a familial case of anophthalmia with polydactyly. Am J Med Genet 120A:117, 2003. 123. Verloes A, Temple IK, Bonnet S, et al.: Coloboma, mental retardation, hypogonadism, and obesity: critical review of the so-called Biemond syndrome type 2, updated nosology, and delineation of three ‘new’ syndromes. Am J Med Genet 69:370, 1997. 124. Rajab A: Bonneau syndrome: a further case report. Clin Dysmorphol 6: 85, 1997. 125. McGaughran J: Another case of preaxial polydactyly and white forelock in branchio-oculo-facial syndrome. Clin Dysmorphol 10:67, 2001. 126. Braun FC, Bayer JF: Familial nephrosis associated with deafness and congenital urinary tract anomalies in siblings. J Pediatr 60:33, 1962. 127. Temple IK, Eccles DM, Winter RM, et al.: Craniofacial abnormalities, agenesis of the corpus callosum, polysyndactyly and abnormal skin and gut development—the Curry Jones syndrome. Clin Dysmophol 4:116, 1995. 128. Tischkowitz MD, Hodgson SV: Fanconi anemia. J Med Genet 40:1, 2003. 129. Sabry MA, Obenbergerova D, Al-Sawan R, et al: Femoral hypoplasiaunusual facies syndrome with bifid hallux, absent tibia, and macrophallus: a report of a Bedouin baby. J Med Genet 33: 165, 1996. 130. Prescott KE, Sheridan-Pereira M, Manchester DK, et al.: The median cleft face/skeletal syndrome (frontonasal dysplasia): a distinct subgroup with nasal agenesis, tibial aplasia, hallucal polydactyly and mental retardation. Am J. Hum Genet Suppl 45:A59, 1989. 131. Moeschler J, Clarren SK: Familial occurrence of hemifacial microsomia with radial limb defects. Am J Med Genet 12:371, 1982.

953

132. Howard FM, Young ID: Unknown syndrome: microcephaly, facial clefting and preaxial polydactyly. J Med Genet 25:272, 1988. 133. Thompson E, Pembrey M, Graham JM: Phenotypic variation in LADD syndrome. J Med Genet 22:382, 1985. 134. Verloes A, Dodinval P, Beco L, et al.: Lambotte syndrome: microcephaly, holoprosencephaly, intrauterine growth retardation, facial anomalies, and early lethality—a new sublethal multiple congenital anomaly/ mental retardation syndrome in four sibs. Am J Med Genet 37:119, 1990. 135. Traboulsi EI, Lenz W, Gonzales-Ramos M, et al.: The Lenz microphthalmia syndrome. Am J Ophthalmol 105:40, 1988. 136. Kohlhase J, Heinrich M, Schubert L, et al.: Okihiro syndrome is caused by SALL4 mutations. Hum Molec Genet 11: 2979, 2002. 137. Pfeiffer RA: Dominant erbliche Akrocephalosyndaktylie. Z Kinderheilkd 90:301, 1964. 138. Thompson EM, Baraitser M: Sorsby syndrome: a report on further generations of the original family. J Med Genet 25:313, 1988. 139. Murr MM, Waziri MH, Schelper RL, et al.: Case of multivertebral anomalies, cloacal dysgenesis and other anomalies presenting Prenatally as cystic kidneys. Am J Med Genet 42:761, 1992. 140. Powell CM, Michaelis RC: Townes-Brocks syndrome. J Med Genet 36:89, 1999. 141. Gonzalez CH, Curkin-Stamm MV, Giemer NF, et al.: The WT syndrome—a ‘‘new’’ autosomal dominant pleiotropic trait of radial/ ulnar hypoplasia with high risk of bone marrow failure and/or leukemia. BDOAS XIII(3B):31, 1977. 142. Hendriks HJE, Brunner HG, Haagen TAM, et al.: Acrocallosal syndrome. Am J Med Genet 35:443, 1990. 143. Cohen DM, Green JG, Miller J, et al.: Acrocephalopolysyndactyly type II—Carpenter syndrome: clinical spectrum and an attempt at unification with Goodman and Summitt syndromes. Am J Med Genet 28:311, 1987. 144. Roelfsema NM, Cobben JM: The EEC syndrome: a literature study. Clin Dysmorphol 5:115, 1996. 145. Laurence KM, Prosser R, Rocker I: Hirschsprung’s disease associated with congenital heart malformation, broad big toes, and ulnar polydactyly in sibs: a case for fetoscopy. J Med Genet 12:334, 1975. 146. Holmes LB, Redline RW, Brown DL, et al.: Absence/hypoplasia of tibia, polydactyly, retrocerebellar arachnoid cyst, and other anomalies: an autosomal recessive disorder. J Med Genet 32:896, 1995. 147. Salonen R, Herva R: Hydrolethalus syndrome. J Med Genet 27: 756, 1990. 148. Daneman D, Davy T, Mancer K, et al.: Association of multinodular goiter, cystic renal disease, and digital anomalies. J Pediatr 107:270, 1985. 149. Anneren G, Arvidson B, Gustavson KH, et al.: Oro-facio-digital syndromes I and II: radiological methods for diagnosis and the clinical variations. Clin Genet 26:178, 1984. 150. Toriello HV, Carey JC, Suslak E, et al.: Six patients with oral-facialdigital syndrome IV: the case for heterogeneity. Am J Med Genet 69:250, 1997. 151. Goldberg MJ, Pashayan HM: Hallux syndactyly-ulnar polydactylyabnormal ear lobes: a new syndrome. BDOAS XII(5):255, 1976. 152. Patton MA, Krywawych S, Winter RM, et al.: DOOR syndrome (deafness, onycho-, osteodystrophy, and mental retardation): elevated plasma and urinary 2-oxoglutarate in three unrelated patients. Am J Med Genet 26:207, 1987. 153. Goodman RM, Lockareff S, Gwinup G: Hereditary congenital deafness with onychodystrophy. Arch Otolaryngol 90:474, 1969. 154. Newbury-Ecob RA, Leanage R, Raeburn JA, et al.: Holt-Oram syndrome: a clinical genetic study. J Med Genet 33:300, 1996. 155. Freire-Maia N, Pinheiro M, Opitz JM: The neurofaciodigitorenal (NFDR) syndrome. Am J Med Genet 11: 329, 1982. 156. Cooks RG, Hertz M, Bat Miriam Katznelson M, et al.: A new nail dysplasia syndrome with onychonychia and absence and/or hypoplasia of distal phalanges. Clin Genet 27:85, 1985. 157. Manouvrier S, Moerman A, Coeslier A, et al.: Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new

954

Skeletal System

158.

159.

160.

161.

162.

163.

X-linked dominant multiple congenital anomalies syndrome? Am J Med Genet 90:351, 2000. Richieri-Costa A, Gollop TR, Colletto GMDD: Syndrome of acrofacial dysostosis, cleft lip/palate, and triphalangeal thumb in a Brazilian family. Am J Med Genet 29:875, 1988. Schmitt E, Gillenwater JY, Kelly TE, et al.: An autosomal dominant syndrome of radial hypoplasia, triphalangeal thumbs, and maxillary diastema. Am J Med Genet 13:63, 1982. Zenteno JC, Aguinaga M, Chavez V, et al.: Triphalangeal thumb and brachyectrodactyly syndrome: an uncommon entity with evidence of geographic distribution. Clin Genet 50:152, 1996. Camera G, Camera A, Pozzolo S, et al.: F-syndrome (F-form of acropectoro-vertebral dysplasia): report on a second family. Am J Med Genet 57:472, 1995. Legius E, Moerman PH, Fryns JP, et al.: Holzgreve-Wagner-Rehder syndrome: Potter sequence associated with persistent buccopharyngeal membrane. A second observation. Am J Med Genet 31:269, 1988. Martinez RMY, Corona-Rivera E, Martinez MJ: A new probably autosomal recessive cardiomelic dysplasia with mesoaxial hexadactyly. J Med Genet 18:151, 1981.

21.2 The Syndactylies

Syndactyly Type I (Zygodactyly)

Definition

The syndactylies are a heterogeneous group of anomalies in which the digits fail to separate completely.1–3 Syndactyly may be cutaneous (involving the soft tissue) or osseous (involving the bones), complete or partial, and isolated or part of a syndrome. It is often accompanied by other digital malformations, including polydactyly, brachydactyly, or camptodactyly. In synpolydactyly, syndactyly is consistently present, whereas polydactyly is a variable feature. In symbrachydactyly, syndactyly is associated with shortening of the digits. Osseous syndactyly involving separate digits is easily distinguished from symphalangism, in which osseous fusion of phalanges within a given digit occurs (see Section 20.2, Table 20-11). Temtamy and McKusick1 classified the isolated syndactylies on the basis of anatomic findings (Table 21-8), while Winter and Tickle2 proposed a scheme based on the patterning of the hands and feet during development (Table 21-1). Syndactyly is usually genetic in origin, although a well-recognized exception is pseudosyndactyly. True syndactyly represents a failure of normal digit patterning or separation during development and always starts at the bases of the digits. In contrast, pseudosyndactyly arises from constrictive forces (e.g., amniotic bands) that interfere with normal digit separation4 and may selectively involve the tips of the digits (Fig. 21-11). Isolated syndactyly is usually inherited as an autosomal dominant trait with variable clinical expression. Table 21-8. Syndactylies: Temtamy and McKusick1 classification Fingers Involved

Toes Involved

I

3–4

2–3

II

3–4

4–5

III

4–5

–

Overlaps with oculo-dento-digital syndrome

Type

Comment

Frequent mesoaxial polydactyly

IV

1–5

–

Polydactyly common

V

4–5*

2–3, 4–5

Variable cutaneous syndactyly of fingers

*Metacarpals

Fig. 21-11. Pseudosyndactyly in a fetus with amniotic band disruption complex. Note that a probe can be passed between the fingers proximal to the level of soft tissue fusion. (Courtesy of Dr. Laurie Seaver, Greenwood Genetic Center, Greenwood, SC.)

Syndactyly type I is complete or partial cutaneous syndactyly of the 3rd and 4th fingers and 2nd and 3rd toes (Fig. 21-12).1 Bony fusion of the distal phalanges of fingers 3–4 can occur.1,5 The syndactyly occasionally occurs in variant patterns, such as fingers 2–3, 3–5, 2–5, and toes 2–4, 1–4, or 1–5.1,5,6 Clinodactyly and camptodactyly have been described.6 The syndactyly can affect the hands, the feet, or both, and it can be unilateral or bilateral. The feet are more often affected than are the hands. Isolated involvement of toes 2–3 is about four times as common as isolated involvement of fingers 3–4.3 Mild syndactyly between toes 2 and 3 involving up to 1/3 of the web space is generally considered a common anatomical variant not indicative of a significant abnormality of limb morphogenesis. Dermatoglyphic analysis frequently reveals an interdigital triradius at the base of the fused fingers rather than separate triradii for each finger.1 A reduced distance between the b and c digital triradii or a single interdigital triradius in the absence of syndactyly have been interpreted as mild manifestations of the condition.1 Radiographs demonstrate soft tissue webbing and occasional fusion of the distal phalanges of fingers 3–4. Isolated cases of syndactyly type II, syndactyly type V, and polysyndactyly can present with the appearance of syndactyly type I due to variability of expression. Pavone et al.7 described a patient with findings of syndactyly type I associated with unusual facies, congenital cataracts, thinning of the lower legs, and mental retardation. Many syndromes involve syndactyly (Table 21-9). Syndactyly type I is usually inherited as an autosomal dominant trait with considerable variability in expression within and between families. In some families, isolated involvement of toes 2–3 occurs, while in other families, toes 2–3 and fingers 3–4 are involved.8 Some authors have distinguished these forms of the condition as types Ia and Ib, respectively.8 Incomplete penetrance has been described.1,5,8 A gene locus for syndactyly type I has been mapped to chromosome 2q34-q36 in two unrelated families.5,6 While several candidate genes involved in limb development map to this region, the causative gene has not yet been identified. In a family segregating syndactyly type I with isolated toe involvement, consanguineous matings between affected persons produced offspring with complete syndactyly of fingers 3–4 and hypoplasia of the thumbs and halluces.9 The authors hypothesized that this

Hands and Feet

955

Fig. 21-12. Syndactyly I. Schematic (A) and photographs (B–D) show syndactyly of fingers 3 and 4 and toes 2 and 3.

severe phenotype may represent homozygosity for a gene mutation causing syndactyly type I.9 Webbing of fingers 3–4 and of toes 2–3 are the most common forms of isolated hand and foot syndactyly, respectively.3 Syndactyly type I is also the most frequent type of heritable syndactyly, with many families having been reported. In a Latin-American population, Castilla et al.3 estimated the frequency of finger 3–4 syndactyly to be 3/100,000, of toe 2–3 syndactyly to be 12/100,000, and of all cases that would fit into the syndactyly type I category to be 17/100,000. They also found a 2.5:1 ratio of males to females with isolated 2–3 toe syndactyly.3 Similarly, in familial cases of isolated 2–3 toe syndactyly, Woolf and Cone8 found a 2:1 ratio of affected males to females. In contrast to the findings of Castilla et al., Marden et al.10 found an incidence of isolated toe syndactyly of 16/10,000 among 4,412 American (predominantly Caucasian) newborns, and Rogala et al.11 found an incidence of 1.3/10,000 among over 52,000 births in Scotland. Woolf and Cone8 found that segregation distortion, with increased transmission of the trait from affected fathers to their sons, occurs in families with

isolated syndactyly of either toes 2–3 or toes 2–3 combined with fingers 3–4.8 Syndactyly Type II (Synpolydactyly)

Syndactyly type II typically involves fingers 3–4 and toes 4–5 (Fig. 21-13).1,12,13 The condition is a form of synpolydactyly in that a complete or partial extra digit is often present within the syndactylous web.1,12,13 Thus, the polydactyly is mesoaxial in location. In both the hands and feet, the findings can range from partial soft tissue syndactyly to complete digit reduplication.12,13 Other hand manifestations include brachydactyly, clinodactyly, or camptodactyly of the 5th fingers, 4–5 syndactyly, and, in the mildest cases, isolated brachydactyly of the 4th fingers.1,12,13 Other foot manifestations include variable clinodactyly, syndactyly, and brachydactyly of toes 2–5 with underdeveloped or absent middle phalanges.12,13 The mildest foot findings are 2–3 syndactyly, 5th toe brachydactyly, and overriding 4th or 5th toes.12,13 The condition can involve one to four limbs, and asymmetric findings are common.12,13

Table 21-9. Syndromes featuring syndactyly* Prominent Features

Ackerman74

Pyramidal molar roots, absent cupid’s bow of lip, entropion, glaucoma

3–4

Unknown (200970)

Acrocephalo-polysyndactyly type IV75

Acrocephaly, brachydactyly, postaxial polydactyly

2–5

AR (201020)

Acro-fronto-facio-nasal dysostosis76

Hypertelorism, bifid nasal tip, cleft lip/palate, mental retardation, polydactyly

2–4

AR (201180)

Acropectorovertebral dysplasia (F syndrome)77

Broad/bifid thumb, duplicated index finger, syndactyly of thumb and index finger with radial deviation and ‘‘bone chain’’ configuration, duplicated hallux, bizarre appearance of toes, carpal/tarsal synostosis, chest deformity, incomplete L5/S1 vertebral arch

1–2

AD (102510) 2q36

Amniotic bands78

Amputation defects, craniofacial clefts, body wall defects

Anophthalmia, type Waardenburg79

Anophthalmia, oligodactyly, talipes equinovarus

2–5

AR (206920)

Apert46

Cranisynostosis, mental retardation

1–5

AD (101200) FGFR2, 10q26

Bartsocas-Papas80

Popliteal pterygium, cleft lip/palate, ankyloblepharon, absent thumbs

2–5

AR (263650)

Double eyebrows, synophrys, hyperextensible skin

2–4

Unknown (227210)

Blepharo-naso-facial

Telecanthus, lower lid coloboma, fleshy nose, midface hypoplasia, dystonia, mental retardation

2–4

Unknown (110050)

Blepharophimosis-ptosissyndactyly83

Blepharophimosis, ptosis, short stature

2–3 (toes)

AR (210745)

C-trigonocephaly84

Trigonocephaly, oral frenulae, postaxial polydactyly, mental retardation

2–4

AR (211750)

Camptodactyly (Tel-Hashomer)85

Camptodactyly, thin fingers, talipes equinovarus, myopathy, hypertelorism

3–4

AR (211960)

Carpenter86

Preaxial polydactyly of feet, postaxial polydactyly of hands, brachydactyly, brachycephaly, craniosynostosis, heart defects, variable mental retardation

2–5

AR (201000)

Crane-Heise87

Cleft lip and palate, absence of clavicles and cervical vertebrae, dislocated radial heads

2–4

AR (218090)

Ectrodactyly-ectodermal dysplasia-cleft lip/palate88

Split-hand/foot malformation, ectodermal dysplasia, cleft lip/palate

Various

Filippi89

Short stature, microcephaly, mental retardation, high nasal bridge

3–4

AR (272440)

Fraser90

Cryptophthalmia, renal agenesis, hypospadias, laryngeal stenosis

2–5

AR (219000) FRAS1, 4q21

Goltz (focal dermal hypoplasia)91

Atrophic skin, papillomas of nose/mouth, eye colobomas, polydactyly

3–4

XLD (305600)

Greig cephalopolysyndactyly92

Macrocephaly, hypertelorism, preaxial and postaxial polydactyly

3–4

AD (175700) GLI3, 7p13

Hypoglossia-hypodactyly93

Hypoplastic tongue, absent digits, terminal transverse defects of limbs

2–5

Sporadic (103300)

Jackson-Weiss94

Craniosynostosis, midface hypoplasia, 2-3 toe syndactyly, broad hallux

3–4

AD (123150) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Klein-Waardenburg95

Blepharophimosis, telecanthus, iris heterochromia, white forelock, deafness, flexion deformities

2–5

AD (148820) PAX3, 2q35

Lenz-Majewski96

Prominent veins, loose skin, choanal atresia, hypospadias, sclerotic bones and skull, brachydactyly

2–5

Unknown (151050)

Mo¨bius65

6th and 7th cranial nerve palsy, oligodactyly, brachydactyly, absent pectoral muscles

2–5

Sporadic, AD (157900) 13q12.2-q13 3q21-q22 10q21.3-q22.1

Laurin-Sandrow97

Mirror feet, tibial absence, fibular duplication, nasal grooves

1–5

AD (135750)

Multiple pterygium98

Ptosis, webbed neck, multiple pterygia, talipes equinovarus

2–4

AR (265000)

Berkenstadt81 82

Digits

Causation (OMIM#) Gene/Locus

Syndrome

Various

Sporadic (217100)

P63, 3q27 7q21-q22

(continued)

956

Hands and Feet

957

Table 21-9. Syndromes featuring syndactyly* (continued) Digits

Causation (OMIM#) Gene/Locus

Syndrome

Prominent Features

Naguib-Richieri-Costa (Acrofrontofacionasal dysostosis, severe)99

Hypertelorism, ptosis, shawl scrotum, hypospadias, preaxial polydactyly, midline nasal groove

3–4

AR (239710)

Neu-Laxova100

Microcephaly, absent eyelids, joint contractures, edema, cataracts

2–5

AR (256520)

Oculodentodigital31

Microphthalmia, pinched nose, enamel hypoplasia

3–5

AD (164200) GJA1, 6q21-q23.2

Oral-facial-digital, type 1101

Midline cleft lip, cleft tongue, hamartomas of tongue, hyperplastic frenula, mental retardation, polycystic kidneys, polydactyly

2–5

XLR (311200) CXORF5, Xp22.3-p22.2

Oral-facial-digital, type 2101

Midline cleft lip, cleft tongue, hamartomas of tongue, polydactyly

2–4

AR (252100)

Oral-facial-digital, type 4102

Hamartomas of tongue, cleft lip/palate, clubfoot, tibial dysplasia, polydactyly

2–5

AR (2258860)

Oto-palato-digital, type 2103

Hypertelorism, micrognathia, cleft palate, overlapping fingers, dense bones, postaxial polydactyly

2–4

XL (304120) FLNA, Xq28

Pfeiffer104

Craniosynostosis, broad thumbs and halluces

2–4

AD (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Poland65

Aplasia of pectoralis major, symbrachydactyly

2–5

Sporadic (173800)

Popliteal pterygium105

Cleft lip/palate, lower lip pits, popliteal web

2–4

AD (263650) IRF6, 1q32-q41

Roberts106

Hypertelorism, cleft lip/palate, limb reduction defects, oligodactyly

2–4

AR (268300)

Saethre-Chotzen107

Craniosynostosis, ptosis, facial asymmetry

2–4

AD (101400) TWIST, 7p21 FGFR2, 10q26 FGFR3, 4p16.3

Schilbach-Rott108

Hypotelorism, submucous cleft palate, hypospadias, blepharophimosis

3–4

AD (164220)

Sclerosteosis109

Macrocephaly, prognathism, sclerosis of bones

2–3

AR (269500) SOST, 17q12-q21

Smith-Lemli-Opitz110

Anteverted nares, 2-3 toe syndactyly, short thumbs, hypospadias, mental retardation

2–3 (toes)

AR (270400) DHCR7, 11q12-q13

Tibial hypoplasia-polydactyly (tibial hemimeliapolydactyly-triphalangeal thumbs with fibular dimelia)38

Triphalangeal thumb, tibial aplasia, polydactyly

1–5

AD (188770)

Triphalangeal thumbpolysyndactyly37

Triphalangeal thumb, polydactyly

3–5

AD (190605) 7q36

Triploidy111

Intrauterine growth retardation, congenital heart defect, brain anomalies, miscarriage or early lethality

3–4

69,XXX, 69,XXY, or 69,XYY

Zlotogora-Ogur112

Cleft lip/palate, pili torti, ectodermal dyplasia, mental retardation

2–4

AR (225000) PVRL1, 11q23-q24

*It is sometimes impossible to classify the type of syndactyly in many multiple congenital anomaly syndromes, as the pattern of syndactyly does not fit exactly into the classification of isolated syndactylies.

Radiographs reveal varying degrees of polydactyly with partial or complete duplication of phalanges at different levels. The extra digit can arise from a separate metacarpal/metatarsal bone or share a broad or partially duplicated metacarpal/metatarsal with an adjacent digit. The duplication can start more distally with a broad or bifid proximal phalanx. Middle and distal phalanges of digits contained in the syndactylous web can be hypoplastic or absent.

Occasionally, the polydactyly is represented only by a partial duplication of one phalanx, giving the appearance of an extra wedge of bone. In the absence of polydactyly, the condition can resemble syndactyly type I, especially in the hands. Radiographs are necessary to look for subtle degrees of partial duplication of the phalanges of digits 3 and 4. Although 3–4 finger syndactyly can occur in Greig

958

Skeletal System

Fig. 21-13. Syndactyly II. Schematic (A) shows syndactyly and polydactyly of central digits of the hand and lateral digits of the foot. Photograph of hands (B) show affected female twin before surgery on the left. Brother and other twin on the right are

after surgery. Hand radiographs of 4-month-old female who has central syndactyly and polydactyly (C, D). Her brother and father were similarly affected. Postaxial syndactyly and polydactyly of foot (E) are also shown.

cephalopolysyndactyly syndrome, the pattern of polydactyly is quite different, consisting of preaxial polysyndactyly, especially in the feet, and postaxial postminimi. Ellis-van Creveld syndrome can occasionally present with a mesoaxial polydactyly together with heart defects and characteristic skeletal abnormalities, although the polydactyly is more usually postaxial. Mesoaxial polydactyly can also be part of the Varadi-Papp and the Kaufman-McKusick syndromes. Inheritance of syndactyly type II is autosomal dominant with highly variable expression and incomplete penetrance.1,12,13 The causative gene for this condition is HOXD13 on chromosome 2q31. The locus was initially mapped in a large Turkish family14 and mutations in HOXD13 were later discovered in multiple families.12,13,15 HOXD13 is a transcription factor expressed in the limb bud and involved in digital patterning and growth.13

Most mutations causing syndactyly type II are expansions of an imperfect trinucleotide repeat normally encoding 15 successive alanine residues.12,13 Expansions resulting in 7 to 14 extra alanines have been described in persons with syndactyly type II.12,13 They are thought to interfere with normal HOXD13 signaling through a gain of function mechanism and remain stable through many generations, in contrast to other trinucleotide repeat expansions associated with human disease.12,13 Increasing expansion size correlates with the degree of penetrance and more severe clinical manifestations, including combined hand and foot involvement, the presence of duplicated digits, and a more proximal level of digit duplication.12 Males with the largest expansions (14 extra alanine residues) also have hypospadias.12,13 A severe limb phenotype is also seen in these individuals, including the most severe findings of syndactyly type II accompanied by broad and radially

Hands and Feet

deviated thumbs with short metacarpals, enlarged capitate bones, and broad halluces.12 More severe hand and foot abnormalities have also been described in persons who are homozygous for smaller expansions in HOXD13.12,13,16 Other types of mutations involving HOXD13 can result in a variety of different hand and foot abnormalities. Missense mutations in the homeodomain have been described in families with novel autosomal dominant forms of brachydactyly and polydactyly17,18 and in families with features of brachydactyly types D and E.19 Loss of HOXD13 function caused by intragenic deletions or a specific missense mutation in the homeodomain causes an autosomal dominantly inherited, novel foot malformation characterized by bilateral partial duplication of the bases of the 2nd metatarsals and occasionally the 4th metatarsals, broad halluces,

959

short metatarsals, brachydactyly and symphalangism of the toes, and more classical manifestations of syndactyly type II in some persons.20,21 Larger deletions involving the HOXD gene cluster have recently been found to cause syndactyly type II in one family and severe limb reduction defects in two unrelated patients.22 The incidence of syndactyly type II is uncertain. Mutations in HOXD13 have been identified in over 20 families.13 Syndactyly Type III

Syndactyly type III is variable cutaneous or osseous syndactyly of the 4th and 5th fingers, with or without involvement of the 3rd fingers. There is a varying degree of fusion between fingers 4–5 or 3–5 (Fig. 21-14).1,23,24 The findings range from partial cutaneous webbing to complete syndactyly with osseous fusion of the distal

Fig. 21-14. Syndactyly III. Schematic (A) shows typical involvement of fingers 3–5. Affected child has syndactyly of fingers 3–5 on left hand and fingers 4–5 on right hand (B). Hand radiograph (C) demonstrates hypoplasia of the middle 5th phalanx and fusion of the distal phalanges of fingers 4–5. Photograph (D) shows the typical facial features of oculodentodigital dysplasia.

960

Skeletal System

phalanges and concomitant fusion of the nails. The 5th fingers are usually short with underdeveloped or absent middle phalanges, and the 4th fingers have camptodactyly when extensively fused to the 5th fingers. The mildest manifestation may be radial deviation of the distal phalanges of the 5th fingers.24 Patients who have undergone surgery have radial deviation and shortening of the 5th fingers and ulnar deviation of the 4th fingers. The hand findings are usually bilateral and often symmetric. In isolated type III syndactyly, the toes are not typically involved. Radiographs may show fusion of the terminal phalanges in complete syndactyly (Fig. 21-14). The middle phalanx of the 5th finger is frequently hypoplastic or absent, and the distal phalanges of the affected fingers may be deviated. When evaluating a patient with type III syndactyly, the major syndrome to consider is oculodentodigital dysplasia (ODDD). In this disorder, an identical pattern of hand abnormalities occurs, in addition to microcornea, microphthalmia, a pinched nose with hypoplastic alae nasi, and small teeth with hypoplastic enamel (Fig. 21-14).25 Variable toe syndactyly and hypoplasia or absence of the middle toe phalanges can also occur. Neurologic manifestations, including white matter abnormalities and spasticity, are an increasingly recognized feature of the disorder.26 The typical facial characteristics of ODDD have been observed in some persons with syndactyly type III, suggesting that the two disorders represent different ends of the same clinical spectrum.1,27,28 Both syndactyly type III and ODDD are inherited as autosomal dominant traits. Linkage studies in a number of families with ODDD identified a locus on chromosome 6q22-q24.29,30 The responsible gene, GJA1 or connexin 43, was subsequently identified.31 It encodes a transmembrane protein that participates in the assembly of gap junctions permitting cell-to-cell transfer of ions and small molecules.31 Mutations in this gene were identified in all 17 families tested, including some with features of syndactyly type III, supporting allelism of the latter condition with ODDD.31 The majority of mutations are missense changes that are thought to cause the syndactyly and other manifestations through a dominant negative effect.31 A homozygous GJA1 mutation was recently identified in a patient with some features of Hallerman-Streiff syndrome, which has some clinical overlap with ODDD.32 Syndactyly type III is rare. Castilla et al.3 estimated the frequency to be 0.3/100,000 in a South American population. Over 240 patients with ODDD have been described in over 70 literature reports.31 Syndactyly Type IV (Haas-type Polysyndactyly)

Syndactyly type IV is complete cutaneous syndactyly of the fingers and thumbs associated with preaxial or postaxial polydactyly in the hands and sometimes in the feet. The characteristic finding is complete cutaneous syndactyly of the thumbs and all fingers, giving the hands a cup-shaped ‘‘rosebud’’ appearance (Fig. 21-15).1,33–35 In the hands, there are usually six or more digits of preaxial, postaxial, or indeterminate origin fused into a mass with up to eight nails.33–35 In the sporadic case reported by Miura et al.,35 all digits of the left hand were completely fused, while on the right hand the most radial digit was hypoplastic and triphalangeal but was not involved in the web. The hand findings are bilateral. The feet are usually normal but may have pre- or postaxial polydactyly.34 Hand radiographs typically demonstrate complete syndactyly of all digits with six metacarpals and varying numbers of extra phalanges. The syndactyly may be non-osseous, or some of the distal phalanges may be fused. The thumbs may be triphalangeal.

Foot radiographs demonstrate supernumerary metatarsals and phalanges in some cases. Unilateral absence of the tibia has been observed in one affected member of a family segregating syndactyly type IV.36 A phenotype suggesting syndactyly type IV has also been described in the triphalangeal thumb-polysyndactyly syndrome and the tibial-hemimelia-polysyndactyly-triphalangeal thumb syndrome.37,38 Complete synpolydactyly of the hands with a ‘‘rosebud’’ appearance also occurs with mirror feet in the Laurin-Sandrow syndrome.39 Complete syndactyly is a major feature of Apert syndrome, but craniosynostosis occurs in this condition. Inheritance of Haas-type polysyndactyly is presumed to be autosomal dominant, based upon a few reports of familial cases and evidence of male-to-male transmission.1,33,34,36 The genetic basis of this condition is unknown. The disorder was reported in 1/300,000 newborns in Latin America.3 Syndactyly Type V

Syndactyly type V is metacarpal and metatarsal fusion associated with variable syndactyly. Variable synostosis of metacarpals 4 and 5 is the most characteristic feature of this condition (Fig. 21-16).40 The fusion may be complete or partial and unilateral or bilateral, and metacarpals 4 and 5 can also be short.40 When fingers 4 and 5 arise from completely fused metacarpals, they are usually flexed in a ‘‘claw like’’ deformity.40 Cutaneous syndactyly can occur between fingers 2–3, 3–4, and/or 4–5.1,40 Other features in the hands include camptodactyly, brachydactyly, distal phalangeal hypoplasia, absence of the distal interphalangeal flexion creases, and swelling of the interphalangeal joints.40 In the feet, there may be synostosis of metatarsals 3 and 4 and variable syndactyly of toes 2–5.1,40 Other foot manifestations include varus deformities of the metatarsals, valgus deformities of the toes, hypoplasia of metatarsals 3–5, short toes with abnormal or fused phalanges, and overlapping or plantar-flexed toes.1,40 Radiographs demonstrate the characteristic metacarpal or metatarsal synostosis and other bony changes. The hand and foot anomalies can be highly variable within families, leading to difficulties with classification.1,40,41 For example, an affected member of the family reported by Temtamy and McKusick1 had 3–4 syndactyly of the fingers, which would have been classified as syndactyly type I if considered in isolation and without the aid of radiographs. The appearance has also been misclassified as split hand.1 Robinow et al.27 speculated whether urogenital abnormalities are part of the clinical spectrum, since one of their patients had a hypoplastic kidney with bilateral ureteric reflux and one of the patients reported by Temtamy and McKusick1 had exstrophy of the bladder. Syndactyly type V is an autosomal dominant trait. Only a few families have been described,1,40,41 and the causative gene is unknown. Debeer et al.42 reported a family with variable hand and foot malformations including fusion of metacarpals 4–5 and metatarsals 3–4, and syndactyly of fingers 3–4 with partial digit duplication. The findings segregated with a balanced reciprocal translocation between chromosomes 12p and 22q.42,43 The latter breakpoint was found to disrupt the fibulin-1 (FBLN1) gene, which encodes a glycoprotein expressed in the developing limb.43 Fusion of metacarpals 4 and 5, without other anomalies of the digits, is a distinct condition inherited as an X-linked recessive trait.1,44,45 In this disorder, metacarpals 4 and 5 are fused with hypoplasia of the 5th metacarpals and fixed ulnar deviation of the

Hands and Feet

961

Fig. 21-15. Syndactyly IV (Haas type polysyndactyly). Schematic (A) shows complete syndactyly of polydactylous hand. Radiographs (B, C) and photograph (D) of affected infant show complete syndactyly of left hand and exclusion of first digit from syndactyly of right hand.

Palmar view (E) of affected 7-month-old female shows folding of hand into ‘‘rosebud’’ configuration. (C and D reprinted with permission from Miura et al.: J Hand Surg 15-A:445, 1990. E courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

5th fingers.1,44,45 Autosomal dominant inheritance of this disorder has also been suggested in some families.1,44,45 The incidence of syndactyly type V is unknown.

drome. The characteristic appearance of the hands gives them a ‘‘mitten’’ appearance (Fig. 21-17). Cohen and Kreiborg46 described three subtypes of syndactyly (named types 1, 2, and 3) affecting the hands and feet in this disorder. In type 1, there is a mid-digital mass with syndactyly of digits 2–4, separate digits 1 and 5, and flat palms. There is usually some degree of soft tissue webbing between the 5th finger and the hand mass. The thumbs and great toes are short, broad, and medially deviated. In type 2, there is fusion between digits 2–5 with spoon-shaped palms. In type 3, there is complete syndactyly between all five digits with cup-shaped palms. Nail fusion (synonychia) occurs in the hands,

Complete Syndactyly

This disorder involves complete syndactyly of digits 2–5, sometimes also including the thumb. Complete syndactyly may be confused with syndactyly type IV and mainly occurs in Apert syndrome in association with craniosynostosis. As noted by Cohen and Kreiborg,46 a number of authors have studied the hand and foot findings in Apert syn-

962

Skeletal System

Fig. 21-16. Syndactyly V. Schematic (A) shows syndactyly of metacarpals 4–5 and metatarsals 4–5. The claw-like positioning of the fingers in the photograph (B) and radiographs (C, D) occurs when the metacarpals are completely fused. Less digital clawing is

evident when the metacarpal fusion is incomplete, as in the radiograph at the right in D. (B [photograph of hands] courtesy of Dr. Meinhart Robinow; D courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

but not in the feet. Different patterns of hand and foot involvement may occur in the same individual. Radiographs of the hands and feet in Apert syndrome reveal proximal delta phalanges in the thumbs and great toes that fuse with the distal phalanges over time, proximal symphalangism involving fingers 2–4, and progressive synostosis of the carpals, tarsals, and metatarsals.46 Cohen and Kreiborg46 point out that the progressive bone fusions noted on radiographs represent ossification of cartilaginous models that have failed to separate. Complete syndactyly rarely occurs as an isolated finding. Miura et al.35 published photographs of an isolated case without craniofacial abnormalities. In the right hand there was complete syndactyly with a separate thumb, and in the left hand there was cutaneous syndactyly between digits 3, 4, and 5. Coombs and Mutimer47 also described a patient with an isolated mitten hand anomaly. Complete syndactyly with a cup-shaped palm appears similar to syndactyly type IV, but polydactyly occurs in that condition. Cenani-Lenz syndactyly is easily distinguished from the syndactyly of Apert syndrome. Apert syndrome is an autosomal dominant condition caused by recurrent missense mutations in the fibroblast growth factor receptor 2 gene (FGFR2).48 The cause of isolated cases of complete

syndactyly is unknown. Complete syndactyly of fingers 2–5 and toes 2–5 was the most severe expression of syndactyly type I in one reported family whose phenotype maps to a locus on chromosome 2q.5 The frequency of complete syndactyly is unknown. The prevalence of Apert syndrome has been estimated at 15.5/1,000,000 births.49 Cenani-Lenz Syndrome

The syndactyly of Cenani-Lenz syndrome involves all elements of the digits, often with fusion of the radius and ulna. As first described in siblings by Cenani and Lenz,50 this condition represents a type of complete syndactyly with fused and disorganized hand and foot bones. The hand may have a ‘‘spoon’’ shape and appear as a mass of digits, or, in more severe cases, as a fused tubular mass with a variable number of separate digits represented by their distal and middle elements (Fig. 21-18).50–55 Dermatoglyphic patterns are strikingly abnormal.51,52,54 The feet can have a similar appearance to the hands,56 a reduced number of toes,53 or variable toe syndactyly.50–56 In some cases, the feet are normal. Radiographs reveal normal or reduced numbers of metacarpals, metatarsals, and phalanges, fusion of the carpals, metacarpals

Hands and Feet

963

Seven et al.54 described a patient with typical hand and foot abnormalities associated with thoracic hemivertebrae, scoliosis, diastematomyelia, abnormal ribs, and mixed hearing loss. Bacchelli et al.55 described a patient with Cenani-Lenz syndrome and bilateral renal hypoplasia. Temtamy et al.56 reported mild facial dysmorphism in two unrelated patients with Cenani-Lenz syndrome. The atypical features included a high, broad, and prominent forehead, hypertelorism, downslanting palpebral fissures, short nose, prominent philtrum, and malar hypoplasia. A patient with Cenani-Lenz syndrome and Kabuki syndrome has been described.57 The severe disorganization of hand and foot bones found in Cenani-Lenz syndrome, and the associated forearm and elbow abnormalities, help to distinguish this condition from the complete syndactyly of Apert syndrome. Syndactyly type IV has similarities to Cenani-Lenz syndrome but also has polydactyly. Cenani-Lenz syndrome is presumed to be an autosomal recessive trait, based upon its occurrence among siblings and in the offspring of consanguineous parents.50–56 Temtamy et al.56 reported the condition in a father and daughter. They attributed this to ‘‘quasidominant’’ inheritance because the father’s parents were first cousins, and the father and mother of the daughter were doubly related as maternal and paternal first cousins. A causative gene for Cenani-Lenz syndrome has not been identified. The phenotype resembles that seen in the recessive mouse mutant, limb deformity (ld), which also has renal malformations and is caused by mutations in Formin.55,56 However, Bacchelli et al.55 did not detect homozygosity by descent involving FORMIN or its downstream target, GREMLIN, in a patient with Cenani-Lenz syndrome who was born to consanguineous parents. Cenani-Lenz syndrome is a rare condition, with fewer than 20 cases having been described in the literature. Symbrachydactyly

Fig. 21-17. Complete syndactyly. Schematic (A) shows syndactyly of hand excluding the thumb. The thumb may be included in the syndactyly, as evident on the left hand of the patient with Apert syndrome (B). The great toe is usually included in syndactyly of the foot (C). (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

of variable length that may be fused, and fused or poorly segmented phalanges with the appearance of symphalangism or osseous syndactyly.50–56 Incomplete or complete radioulnar synostosis, radial head dislocation, and/or short forearms are seen in some patients.50,51,54–56

Symbrachydactyly is shortening of the digits in association with cutaneous syndactyly. Distal symphalangism is frequently part of the condition. Symbrachydactyly is usually seen unilaterally in the hand. It may occur in isolation,58,59 but is most often associated with ipsilateral absence of the sternal head of the pectoralis major muscle. As noted by Temtamy and McKusick,1 this combination was first described in 1841 by Poland and is given the eponym Poland syndrome. There is usually cutaneous syndactyly and hypoplasia of the phalanges or all components of the hand (Figs. 21-19 and 21-20). The central digits are generally most involved.59 The syndactyly is cutaneous and may be complete or partial. It varies in location but often involves the 2nd and 3rd fingers.1 The brachydactyly generally involves the middle phalanges, which may be absent or hypoplastic.1,59 The distal phalanges are less severely affected and may be fused to the middle phalanges leading to restricted flexion. The thumb is least severely affected. De Smet and Fabry59 noted that a spectrum of abnormalities occurs in symbrachydactyly, ranging from the typical findings described here to an atypical cleft hand, monodactyly, or adactyly. In Poland syndrome, the pectoralis muscle abnormality manifests as absence of the anterior axillary fold.1 Ipsilateral absence of other muscles, hypoplasia of the nipple or breast, rib abnormalities, Sprengel deformity, and shortening of the arm may also occur.1 Hand radiographs reveal varying degrees of phalangeal hypoplasia and distal symphalangism. Karnak et al.60 reported a child with bilateral absence of the pectoralis major muscles, hypoplastic breasts and nipples, prominence of the anterior chest

Fig. 21-18. Cenani-Lenz syndactyly. Schematic (A) shows irregular mass of malformed, incompletely separated bones and digits. Photographs and radiographs (B) show clinical and radiographic appearance of hands and feet of siblings. (Reprinted with permission from Dondival P: Hum Genet 48:183, 1979.)

964

Hands and Feet

Fig. 21-19. Symbrachydactyly. This unilateral hand anomaly may be associated with ipsilateral pectoral hypoplasia.

wall, and bilateral hand brachydactyly with cone-shaped epiphyses. The authors considered this to be the first report of a bilateral Poland anomaly. Symbrachydactyly may also affect the feet.59,61–63 The findings are similar to those in the hands, with hypoplasia of the digits and variable toe syndactyly. Hallux valgus and metatarsus varus may also occur.61 Several instances of lower leg hypoplasia and foot symbrachydactyly, with or without gluteal hypoplasia, have been described as the ‘‘lower extremity counterpart’’ of Poland syndrome.61 Combined hand and foot symbrachydactyly with normal chest and gluteal muscle development has also been described.62 Symbrachydactyly of the foot associated with ipsilateral chest wall abnormalities was also reported.63 Symbrachydactyly and/or Poland syndrome have been described in association with a variety of other anomalies, including Klippel-Feil syndrome.59 Symbrachydactyly has also been observed in several other conditions, including Turner syndrome and DiGeorge syndrome.59 The most consistent association is with the Mo¨bius syndrome, in which congenital cranial nerve palsy and orofacial malformations also occur.64

965

The Poland anomaly is usually a sporadic occurrence. Bouwes, Bavinck, and Weaver65 hypothesized that the Poland and Mo¨bius syndromes arise from vascular disruptions involving the subclavian artery. Similarly, symbrachydactyly of the foot has been attributed to reduced blood flow in the lower extremity.61 One study suggested that maternal smoking during pregnancy may increase the risk for Poland syndrome.66 Some families with two or more individuals affected with Poland syndrome have been described. As reviewed by Happle,67 different theories have been proposed to explain such cases. Happle67 proposed an alternative hypothesis of ‘‘paradominant inheritance’’ in which the condition is caused by the combination of germline and somatic mutations in the same gene. McGillvray and Lowry68 estimated the incidence of Poland syndrome in British Columbia to be 1/32,000, and their review of the literature suggests a similar incidence in other studies. In Hungary, Czeizel et al.58 reported a birth prevalence of 1 in 87,550 births for typical Poland syndrome and 1 in 52,530 births when isolated cases of symbrachydactyly were included. De Smet and Fabry59 noted a 2:1 excess of males and left-sided involvement in a group of patients with symbrachydactyly ranging from mild involvement to digital absence. Treatment

Treatment of syndactyly is aimed at maintaining or improving function and appearance of the hand.69–71 The major goal is to maximize the number of functional digits while minimizing the number of procedures and complications.69 Ezaki70 emphasizes that treatment of syndactyly is a reconstructive procedure rather than a simple separation of the fingers and should be explained to parents in this way. Multiple surgeries are required in some cases. The successful surgical correction of syndactyly depends on the nature and location of digital involvement and on timing. In cases of simple, complete, or incomplete webbing, surgical separation may be delayed until the child reaches age 12–18 months, which reduces the technical difficulty involved, minimizes risks of anesthesia, and permits growth of bone and soft tissue.69,70 In complex cases in which there is bony connection or involvement of digits of significantly different length (e.g., thumb-2nd finger or 4th–5th

Fig. 21-20. Symbrachydactyly. Hands of 17-year-old male with left symbrachydactyly (A, B) and absence of left pectoralis major muscle and facial paresis (C) (Poland-Mo¨bius syndrome).

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finger), it is advised to operate before 6 months to prevent secondary deformation due to tethering of the adjacent digit from unequal growth.69–71 There are many patterns of surgical separation, depending on the experience of the individual surgeon. The basic surgical approach involves establishment of a wide and deep commissure at the base of the digits, separation of digits by a zig-zag incision, creation of skin flaps for appropriate commissure repair, division of bone and nail connections, and application of skin grafts to cover areas that cannot be reached with residual digit skin.69–71 Full-thickness skin grafts are always used to prevent contraction of the scar.69–71 Complications of surgery include scar formation with progression along the web (‘‘web creep’’), infection, nail defects, and digital necrosis resulting from vascular compromise.69–71 In order to prevent the latter problem, both sides of a digit are never corrected during the same surgery.69–71 Correction of polysyndactyly (as in syndactyly type II) typically requires multiple procedures. In some cases, portions of two or more digits are used to reconstruct a functional finger. Correction of complex syndactyly (as in Apert syndrome) is even more complicated, and the goal is to create a three-fingered hand with an opposable thumb.71 Despite surgery, patients with Poland syndrome are often left with functional deficits in the corrected hand compared to the normal hand.72 References (The Syndactylies) 1. Temtamy SA, McKusick VA: The genetics of hand malformations. BDOAS XIV(3):1, 1978. 2. Winter RM, Tickle C: Syndactylies and polydactylies: embryological overview and suggested classification. Eur J Hum Genet 1:96, 1993. 3. Castilla EE, Paz JE, Orioli-Parreiras IM: Syndactyly: frequency of specific types. Am J Med Genet 5:357, 1980. 4. Jones KL, Smith DW, Hall BD, et al.: A pattern of craniofacial and limb defects secondary to aberrant tissue bands. J Pediatr 84:90, 1974. 5. Bosse K, Betz RC, Lee Y-A, et al: Localization of a gene for syndactyly type 1 to chromosome 2q34-q36. Am J Hum Genet 67:492, 2000. 6. Ghadani M, Majidzadeh-A K, Haerian B-S, et al: Confirmation of genetic homogeneity of syndactyly type 1 in an Iranian family. Am J Med Genet 104:147, 2001. 7. Pavone L, Fiumara A, Rizzo R, et al.: Syndactyly type 1 with cataracts and mental retardation. Clin Dysmorphol 2:257, 1993. 8. Woolf CM, Cone DL: Problem of sex ratio in cases of type I syndactyly. J Med Genet 14:108, 1977. 9. Percin EF, Percin S, Egilmez H, et al: Mesoaxial complete syndactyly and synostosis with hypoplastic thumbs: an unusual combination or homozygous expression of syndactyly type I? J Med Genet 35:868, 1998. 10. Marden PM, Smith DW, McDonald MJ: Congenital anomalies in the newborn infant, including minor variations. J Pediatr 64:357, 1964. 11. Rogala EJ, Wynne-Davies R, Littlejohn A, et al.: Congenital limb anomalies: frequency and aetiological factors. J Med Genet 11:221, 1974. 12. Goodman FR, Mundlos S, Muragaki Y, et al: Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Proc Natl Acad Sci 94:7458, 1997. 13. Goodman FR: Limb malformations and the human HOX genes. Am J Med Genet 112:256, 2002. 14. Sarfarazi M, Akarsu AN, Sayli BS: Localization of the syndactyly type II (synpolydactyly) locus to 2q31 region and identification of tight linkage to HOXD8 intragenic marker. Hum Mol Genet 4:1453, 1995. 15. Muragaki Y, Mundlos S, Upton J, et al: Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 272:548, 1996. 16. Akarsu AN, Akhan O, Sayli BS, et al.: A large Turkish kindred with syndactyly type II (synpolydactyly). 2. Homozygous phenotype? J Med Genet 32:435, 1995.

17. Goodman FR, Bacchelli C, McKeown CME, et al.: An amino acid substitution in the HOXD13 homeodomain causes a novel brachydactylypolydactyly syndrome. Eur J Hum Genet (Suppl) 9:179, 2001. 18. Caronia G, Goodman FR, Zappavigna V, et al.: An I47L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function. Development 130:1701, 2003. 19. Johnson D, Kan S, Oldridge M, et al.: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. Am J Hum Genet 72:984, 2003. 20. Goodman F, Giovannucci-Uzielli M-L, Hall C, et al.: Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families. Am J Hum Genet 63:992, 1998. 21. Debeer P, Bacchelli C, Scambler PJ, et al.: Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13. J Med Genet 39:852, 2002. 22. Goodman FR, Majewski F, Collins AL, et al: A 117-kb deletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly. Am J Hum Genet 70:547, 2002. 23. Johnston O, Kirby VV Jr.: Syndactyly of the ring and little finger. Am J Hum Genet 7:80, 1955. 24. McKiernan MV, McCann JJ: Familial syndactyly type III—report of a large pedigree. Clin Genet 44:270, 1993. 25. Gorlin RJ, Meskin LH, St. Geme JW: Oculodentodigital dysplasia. J Pediatr 63:69, 1963. 26. Loddenkemper T, Grote K, Evers S, et al.: Neurological manifestations of the oculodentodigital dysplasia syndrome. J Neurol 249:584, 2002. 27. Brueton LA, Huson SM, Farren B, et al.: Oculodentodigital dysplasia and type III syndactyly: separate genetic entities or disease spectrum? J Med Genet 27:169, 1990. 28. Schrander-Stumpel CTRM, De Groot-Wijnands JBG, Die-Smulders CD, et al.: Type III syndactyly and oculodentodigital dysplasia: a clinical spectrum. Genet Counsel 4:271, 1993. 29. Gladwin A, Donnai D, Metcalfe K, Et al.: Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-24. Hum Mol Genet 6:123, 1997. 30. Boyadjiev SA, Jabs EW, LaBuda M, et al.: Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-23. Genomics 58:34, 1999. 31. Paznekas WA, Boyadjiev SA, Shapiro RE, et al.: Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408, 2003. 32. Pizzuti A, Flex E, Mingarelli R, et al.: A homozygous GJA1 mutation causes a Hallerman-Streiff/ODDD spectrum phenotype. Hum Mutat 23:286, 2004. 33. Haas SL: Bilateral complete syndactylism of all fingers. Am J Surg 50: 363, 1940. 34. Gillesen-Kaesbach G, Majewski F: Bilateral complete polysyndactyly (Type IV Haas). Am J Med Genet 38:29, 1991. 35. Miura T, Nakamura R, Horii E, et al.: Three cases of syndactyly, polydactyly, and hypoplastic triphalangeal thumb (Haas’s malformation). East Afr Med J 59:835, 1982. 36. Rambaud-Cousson A, Dudin AA, Zuaiter AS, et al.: Syndactyly type IV/ hexadactyly of feet associated with unilateral absence of the tibia. Am J Med Genet 40:144, 1991. 37. Balci S, Demirtas M, Civelek B, et al.: Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome linked to chromosome 7q36. Am J Med Genet 87:399, 1999. 38. Kantaputra PN, Chalidapong P: Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family. Am J Med Genet 93:126, 2000. 39. Kantaputra PN: Laurin-Sandrow syndrome with additional manifestations. Am J Med Genet 98:210, 2001. 40. Robinow M, Johnson GF, Broock GJ: Syndactyly type V. Am J Med Genet 11:475, 1982. 41. Kemp T, Ravn J: Ueber erbliche Hand-und Fussdeformitaeten in einem 140-loepfigen Geschlecht, Nebst einigen Bemerkungen ueber

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42.

43.

44. 45. 46. 47. 48.

49. 50. 51. 52.

53. 54. 55.

56.

57. 58. 59. 60. 61. 62. 63. 64.

65.

66.

67. 68.

Poly-und Syndaktylie beim Menschen. Acta Psychiat Neurol Scand 7:275, 1932. Debeer P, Schoenmakers EFPM, De Smet L, et al.: Co-segregation of an apparently balanced reciprocal t(12,22)(p11.2;q13.3) with a complex type of 3/3’/4 synpolydactyly associated with metacarpal, metatarsal and tarsal synostoses in three family members. Clin Dysmorphol 7:225, 1998. Debeer P, Schoenmakers EFPM, Twal WO, et al.: The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. J Med Genet 39:98, 2002. Holmes LB, Wolf E, Miettinen OS: Metacarpal 4-5 fusion with Xlinked recessive inheritance. Am J Hum Genet 24:562, 1972. Anneren G, Amilon A: X-linked recessive fusion of metacarpals IV and V and hypoplastic metacarpal V. Am J Med Genet 52:248, 1994. Cohen MM Jr., Kreiborg S: Hands and feet in the Apert syndrome. Am J Med Genet 57:82, 1995. Coombs CJ, Mutimer KL: Tissue expansion for the treatment of complete syndactyly of the first web. J Hand Surg Am 19:968, 1994. Wilkie AO, Slaney SF, Oldridge M, et al.: Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165, 1995. Cohen MM Jr., Kreiborg S, Lammer EJ, et al.: Birth prevalence study of the Apert syndrome. Am J Med Genet 42:655, 1992. Cenani A, Lenz W: Totale syndaktylie und totale radioulnare synostose bei zwei brudern. Z Kinderheilk 101:181, 1967. Pfieffer RA, Meisel-Stosiek M: Present nosology of the Cenani-Lenz type of syndactyly. Clin Genet 21:74, 1982. Elcioglu N, Atasu M, Cenani A: Dermatoglyphics in patients with Cenani-Lenz type syndactyly: studies in a new case. Am J Med Genet 70:341, 1997. Nezarati MM, McLeod DR: Cenani-Lenz syndrome: report of a new case and review of the literature. Clin Dysmorphol 11:215, 2002. Seven M, Yuksel A, Ozkilic A, et al.: A variant of Cenani-Lenz type syndactyly. Genet Counsel 11:41, 2000. Bacchelli C, Goodman FR, Scambler PJ, et al.: Cenani-Lenz syndrome with renal hypoplasia is not linked to FORMIN or GREMLIN. Clin Genet 59:203, 2001. Temtamy SA, Ismail S, Nemat A: Mild facial dysmorphism and quasidominant inheritance in Cenani-Lenz syndrome. Clin Dysmorphol 12:77, 2003. Elliott AM, Reed MH, Evans JA, et al.: Cenani-Lenz syndactyly in a patient with features of Kabuki syndrome. Clin Dysmorphol 13:143, 2004. Czeizel A, Vitez M, Lenz W: Birth prevalence of Poland sequence and proportion of its familial cases. Am J Med Genet 36:524, 1990. De Smet L, Fabry G: Characteristics of patients with symbrachydactyly. J Pediatr Orthop B 7:158, 1998. Karnak I, Tanyel FC, Tuncbilek E, et al.: Bilateral Poland anomaly. Am J Med Genet 75:505, 1998. Silengo M, Lerone M, Seri M, et al.: Lower extremity counterpart of the Poland syndrome. Clin Genet 55:41, 1999. De Smet L, Fabry G, Fryns JP: Symbrachydactyly involving both the hand and foot. Genet Counsel 9:23, 1998. Silva EO, Leal GF, Carvalho VN: Poland anomaly with foot symbrachydactyly. Am J Med Genet 109:333, 2002. Larrandaburu M, Schuler L, Ehlers JA, et al.: The occurrence of Poland and Poland-Moebius syndromes in the same family: further evidence of their genetic component. Clin Dysmorphol 8:93, 1999. Bouwes Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Moebius anomalies. Am J Med Genet 23:903, 1986. Martinez-Frias ML, Czeizel AE, Rodriguez-Pinilla E, et al.: Smoking during pregnancy and Poland sequence: results of a population-based registry and a case-control registry. Teratology 59:35, 1999. Happle R: Poland anomaly may be explained as a paradominant trait. Am J Med Genet 87:364, 1999. McGillivray BC, Lowry RB: Poland syndrome in British Columbia: incidence and reproductive experience of affected persons. Am J Med Genet 1:65, 1977.

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69. Dao KD, Shin AY, Billings A, et al.: Surgical treatment of congenital syndactyly of the hand. J Am Acad Orthop Surg 12:39, 2004. 70. Ezaki M: Syndactyly. In: Green’s Operative Hand Surgery, ed. 4. Green DP, Hotchkiss RN, Pederson WC, eds. Churchill Livingstone, London, 1999, p 414. 71. Jobe MT, Wright PE: Congenital anomalies of hand. In: Campbell’s Operative Orthopedics, ed. 10. Canale ST, ed. Mosby, Philadelphia, 2003, p 3860. 72. Kramer RC, Hildreth DH, Brinker MR, et al.: A comparison of patients with different types of syndactyly. J Pediatr Orthop 18:233, 1998. 73. Online Mendelian Inheritance in Man. Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2004. Available from: URL:http://www.ncbi.nlm.nih.gov/omim/ 74. Ackerman JL: Taurodont, pyramidal, and fused molar roots associated with other anomalies in a kindred. Am J Phys Anthropol 38:681, 1973. 75. Goodman RM, Sternberg M, Shem-Tov Y, et al.: Acrocephalopolysyndactyly type IV: a new genetic syndrome in 3 sibs. Clin Genet 15:209, 1979. 76. Richieri-Costa A, Colletto GMDD, Gollop TR: A previously undescribed autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/ palate, limb hypoplasia, and postaxial poly-syndactyly. Am J Med Genet 20:631, 1985. 77. Camera G, Camera A, Pozzolo S, et al.: F-syndrome (F-form of acropectoro-vertebral dysplasia): report on a second family. Am J Med Genet 57:472, 1995. 78. Jones KL, Smith DW, Hall BD, et al.: A pattern of craniofacial and limb defects secondary to aberrant tissue bands. J Pediatr 84:90, 1974. 79. Richieri-Costa A, Gollop TR, Otto PG: Autosomal recessive anophthalmia with multiple congenital abnormalities—type Waardenburg. Am J Med Genet 14:607, 1983. 80. Papadia F, Zimbalatti F, Gentile La Rosa C: The Bartsocas-Papas syndrome: autosomal recessive form of popliteal pterygium syndrome in a male. Am J Med Genet 17:841, 1984. 81. Berkenstadt M, Zahavie H, Goodman RM: Partial duplication of the eyebrows with other congenital malformations: a new syndrome. Clin Genet 33:207, 1988. 82. Pashayan H: A family with blepharo-naso-facial malformation. Am J Dis Child 125:389, 1973. 83. Frydman M, Cohen HA, Karmon G, et al.: Autosomal recessive blepharophimosis, ptosis, V-esotropia, syndactyly and short stature. Clin Genet 41:57, 1992. 84. Opitz JM, McCreadie SR, Smith DW, et al.: The C syndrome of multiple congenital anomalies. BDOAS V(2):161, 1969. 85. Goodman RM, Katznelson BM, Hertz M, et al.: Camptodactyly with muscular hypoplasia, skeletal dysplasia, and abnormal palmar creases: Tel Hashomer camptodactyly syndrome. J Med Genet 13:136, 1976. 86. Cohen DM, Green JG, Miller J, et al.: Acrocephalopolysyndactyly type II–Carpenter syndrome: clinical spectrum and an attempt at unification with Goodman and Summitt syndromes. Am J Med Genet 28:311, 1987. 87. Crane JP, Heise MD: New syndrome in three affected siblings. Pediatrics 68:235, 1981. 88. Roelfsema NM, Cobben JM: The EEC syndrome: a literature study. Clin Dysmorphol 5:115, 1996. 89. Filippi G: Unusual facial appearance, microcephaly, growth and mental retardation, and syndactyly. A new syndrome? Am J Med Genet 22:821, 1985. 90. Ramsing M, Rehder H, Holzgreve W, et al.: Fraser syndrome (cryptophthalmos with syndactyly) in the fetus and newborn. Clin Genet 37:84, 1990. 91. Temple IK, MacDowall P, Baraitser M, et al.: Syndrome of the month. Focal dermal hypoplasia (Goltz syndrome). J Med Genet 27:180, 1990. 92. Baraitser M, Winter RM, Brett EM: Greig cephalopolysyndactyly: report of 13 affected individuals in three families. Clin Genet 24:257, 1983. 93. Herrmann J, Pallister PD, Gilbert EF, et al.: Studies of malformation syndromes of man XXXXIB. Nosologic studies in the Hanhart and the Moebius syndrome. Eur J Pediatr 122:19, 1976.

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94. Jackson CE, Weiss L, Reynolds WA, et al.: Craniosynostosis, midfacial hypoplasia, and foot abnormalities: an autosomal dominant phenotype in a large Amish kindred. J Pediatr 88:963, 1976. 95. Goodman RM, Lewithal I, Solomon A, et al.: Upper limb involvement in the Klein-Waardenburg syndrome. Am J Med Genet 11:425, 1982. 96. Chrzanowska KH, Fryns JP, Krajewska-Walasek M, et al.: Skeletal dysplasia syndrome with progeroid appearance, characteristic facial and limb anomalies, multiple synostoses, and distinct skeletal changes: a variant example of the Lenz-Majewski syndrome. Am J Med Genet 32:470, 1989. 97. Kantaputra PN: Laurin-Sandrow syndrome with additional manifestations. Am J Med Genet 98:210, 2001. 98. Thompson EM, Donnai D, Baraitser M, et al.: Multiple pterygium syndrome: evolution of the phenotype. J Med Genet 24:733, 1987. 99. Teebi A S: Naguib-Richieri-Costa syndrome: hypertelorism, hypospadias, and polysyndactyly syndrome. (Letter) Am J Med Genet 44:115, 1992. 100. Mueller RF, Winter RM, Naylor CPE: Neu-Laxova syndrome: two further case reports and comments on proposed subclassification. Am J Med Genet 16:645, 1983. 101. Anneren G, Arvidson B, Gustavson KH, et al.: Oro-facio-digital syndromes I and II: radiological methods for diagnosis and the clinical variations. Clin Genet 26:178, 1984. 102. Toriello HV, Carey JC, Suslak E, et al.: Six patients with oral-facialdigital syndrome IV: the case for heterogeneity. Am J Med Genet 69: 250, 1997. 103. Fitch N, Jequier S, Papageorgiou A: A familial syndrome of cranial, facial, oral, and limb anomalies. Clin Genet 10:226, 1976. 104. Pfeiffer RA: Dominant erbliche Akrocephalosyndaktylie. Z Kinderheilkd 90:301, 1964. 105. Froster-Iskenius UG: Syndrome of the month. Popliteal pterygium syndrome. J Med Genet 27:320, 1990. 106. Van Den Berg DJ, Francke U: Roberts syndrome: a review of 100 cases and a new rating system for severity. Am J Med Genet 47:1104, 1993. 107. Reardon W, Winter RM: Saethre-Chotzen syndrome. J Med Genet 31: 393, 1994. 108. Schilbach U, Rott H-D: Ocular hypotelorism, submucosal cleft palate, and hypospadias: a new autosomal dominant syndrome. Am J Med Genet 31:863, 1988. 109. Hamersma H, Gardner J, Beighton P: The natural history of sclerosteosis. Clin Genet 63:192, 2003. 110. Kelley RI, Hennekam RCM: The Smith-Lemli-Opitz syndrome. J Med Genet 37:321, 2000. 111. Niemann-Seyde SC, Rehder H, Zoll B: A case of full triploidy (69, XXX) of paternal origin with unusually long survival time. Clin Genet 43:79, 1993. 112. Zlotogora J: Syndactyly, ectodermal dysplasia, and cleft lip/palate. J Med Genet 31:957, 1994.

21.3 The Brachydactylies Definition

Brachydactyly refers to shortening of the digits due to underdeveloped, absent, or abnormally shaped phalanges, metacarpals, and metatarsals (Table 21-10).1–3 Single or multiple bones of individual digits, single bones of multiple digits, or multiple bones of different digits may be involved. All digits may be proportionately short, or there may be asymmetric shortening. Symphalangism, syndactyly, and digital deviation are features of certain brachydactylies. Specific terms that indicate the bones affected in the brachydactylies may also be used. Brachymetacarpia and brachymetatarsia denote short metacarpals and metatarsals, respectively. Terms for phalanges do not specify hand or foot but are most commonly used for the hand phalanges. Brachyphalangy

Table 21-10. Bell’s classification2 of brachydactyly and comparison with the Fitch classification1 Type A: Brachymesophalangy

Type A-1: Brachymesophalangy II-V: brachybasophalangy I (Fitch type 9) Type A-2: Brachymesophalangy II (Fitch type 2) Type A-3: Brachymesophalangy V (Fitch type 3) Type B

Aplasia terminal phalanges, II-V Hypoplasia middle phalanges, II-V Broad, bifid distal phalanges, I (Fitch type 8) Type C

Brachymesophalangy II, III, V Hypersegmentation, proximal phalanges, II, III (Fitch type 11) Type D

Short, broad thumb distal phalanx (Fitch type 1) Type E

Brachymetacarpia Brachymetatarsia Fitch type 4: Brachymetacarpia II Fitch type 5: Brachymetacarpia IV Fitch type 6: Brachymetatarsia IV Fitch type 7: Brachymetacarpia IV; brachymetatarsia IV Fitch type 10: Short stature; brachymetacarpia; brachytelephalangy

is shortening of the phalanges. Brachybasophalangy indicates short proximal phalanges; brachymesophalangy, short middle phalanges; and brachytelephalangy, short distal phalanges. Terms for short deviated phalanges are brachyclinodactyly for medial or lateral curvature and brachycamptodactyly for flexion. Brachysymphalangism denotes short digits with phalangeal synostosis, and brachysyndactyly denotes short webbed digits. Roman numerals are used to indicate the specific digit that is shortened. For example, brachymesophalangy V is a short middle phalanx of the 5th finger. Mild degrees of brachydactyly are incidental or insignificant findings. More severe degrees cause cosmetic concerns and functional problems. Brachydactyly may be recognized at birth or later in childhood after failure of normal ossification of affected digital components. It may pose no difficulty for the individual or only the inconvenience of fitting gloves or shoes. In other cases, manual dexterity and hand grip may be impaired by gross shortening of digits, deviation of digits, syndactyly, or symphalangism. In the familial brachydactylies, short stature or other skeletal features may also be present. Different types of brachydactyly are classified based upon their clinical and radiographic patterns of phalangeal and metacarpal/ metatarsal involvement. Classification is aided in some cases by metacarpophalangeal pattern profile (MCPP) analysis, in which

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bone lengths measured on routine radiographs are used to generate plots that facilitate pattern identification and comparison of patient findings to known standards.4 The earliest and most widely used system is the Bell classification, which delineates five major types of brachydactyly (A–E) and three subtypes of type A (A1–A3) (Table 21-10).1 The primary sites of bony underdevelopment are the middle phalanges in types A and C, middle and distal phalanges in type B, distal phalanges of the thumbs and halluces in type D, and metacarpal/metatarsal bones in type E. A subsequent classification scheme proposed by Fitch described several additional subtypes.3 All types of isolated brachydactyly are inherited as autosomal dominant traits, and all have significant clinical variability. Brachydactyly is also a feature of many conditions, including a large variety of chromosome abnormalities, syndromes, and skeletal dysplasias (Tables 21-11 and 21-12). Brachydactyly Type A1 (Farabee Type)

Brachydactyly type A1, as described by Farabee in 1903, was the first human anomaly recognized to have a mendelian pattern of inheritance.2 Drinkwater also reported several families with this disorder in the early 1900s.2 The condition is principally characterized by variable hypoplasia or aplasia of the middle phalanges of digits 2–5 in the hands and/or feet (Fig. 21-21). The proximal phalanges of the thumbs and halluces are also involved. There is often fusion between the underdeveloped middle phalanges and the distal phalanges, producing pawn-shaped bones. Temtamy and McKusick2 noted that apparent absence of the middle phalanges is caused by hypoplasia of these bones with fusion to the distal phalanges (terminal symphalangism). The distal flexion creases are often absent, and there may be single palmar creases. Shortening of distal phalanges has also been reported.5 Shortening of the metacarpals and metatarsals, particularly in digits 4–5, may also occur.2,3,6 Radial clinodactyly of fingers 4–5 and ulnar clinodactyly of fingers 2–3 are often observed.3 The fingers may be hyperextensible.2 The degree and pattern of shortening in brachydactyly type A1 are variable, but the usual relative lengths of the digits are preserved and the findings are typically symmetric in a given individual.2 Fitch3 noted that more severe shortening and distal symphalangism involve the digits in the sequence 5-2-4-3. On radiographs, the middle phalanges of the fingers and toes and the proximal phalanges of the thumbs and halluces appear small or absent. The epiphyses of affected phalanges may be absent, coned, prematurely fused, or accessory.2,3,6 Metacarpophalangeal pattern profile analysis can be particularly helpful in diagnosing mild cases.6 A number of other findings have been described in association with this condition. Absolute short stature, or short stature relative to that of unaffected family members, are commonly seen in brachydactyly type A1.2,3 Other skeletal manifestations include sloping of the distal radius, ulna, and tibia, absence or hypoplasia of the ulnar styloid process, and variations of the femoral head and acetabulum and of the humeral head and glenoid fossa.2 Temtamy and McKusick2 described a family with brachydactyly type A1 and talipes valgus, with one member also having mild scoliosis and congenital nystagmus. The latter patient was very similar to a case described by Slavotinek and Donnai7 who belonged to a family originally reported by Drinkwater. Raff et al.8 reported a family with brachydactyly type A1 associated with abnormal knee menisci and scoliosis segregating as an autosomal dominant trait. Tsukahara et al.9 described a patient with brachydactyly type A1, short

969

limbs, scoliosis, microcephaly, and mental retardation. Piussan et al.10 reported a three-generation family with brachydactyly type A1, stiff thumbs, and mental retardation. Brachydactyly type A1 is an autosomal dominant trait with wide clinical variability. Some cases are caused by heterozygous missense mutations in the gene Indian hedgehog (IHH), which mediates the growth, condensation, and differentiation of cartilage during the formation of skeletal elements.13 Mutations in this gene were initially identified in three Chinese families after a locus was mapped to chromosome 2q35-q36.5,11 The same mutation was later identified in descendants of two British families described by Drinkwater in the early 1900s, and they were shown to share a common haplotype suggesting descent from a common ancestor.12 Mutations have been identified in two additional families with brachydactyly type A1,13,14 and alterations in the same amino acid residues have been demonstrated in several unrelated families. The mutations occur within the signaling domain of the IHH protein, but it is unclear whether they act through a loss or gain of function mechanism.11–14 Heterogeneity of brachydactyly type A1 has been demonstrated with the mapping of an additional gene locus to chromosome 5p13.3p13.2 and exclusion of linkage to this region and the IHH locus in one family.13,15 Another locus has been suggested in a patient with brachydactyly type A1 and Klippel-Feil anomaly associated with a balanced translocation involving 5q11.2 and 17q23.16 Homozygous missense mutations differing from those found in brachydactyly type A1 have been identified in two consanguineous families with acrocapitofemoral dysplasia.17 This condition is characterized by short stature, short limbs, brachydactyly with shortened middle phalanges and other tubular hand bones, relative macrocephaly, chest deformities, and cone-shaped epiphyses in the hands and proximal femurs.17 Hence, the hand and foot findings of brachydactyly type A1 represent one end of a spectrum of skeletal involvement caused by the IHH gene. The population frequency of brachydactyly type A1 is unknown. Bell1 reviewed 23 pedigrees, and a number of other families have been described. Brachydactyly Type A2 (Brachymesophalangy II; Mohr-Wriedt Type)

The characteristic findings are short, radially deviated 2nd fingers and/or short, tibially deviated 2nd toes due to malformed middle phalanges (Fig. 21-22).1,2,18–20 The shape of the short middle phalanges on radiographs is described as triangular, trapezoidal, or rhomboidal (Fig. 21-23) and causes the 2nd fingers and 2nd toes to deviate medially. The triangular, or delta, phalanx has a continuous epiphysis along the short side.2 The index finger may have a single flexion crease.2 Findings may occur in the hands only, feet only, or hands and feet.18 Temtamy and McKusick2 and Freire-Maia et al.18 reviewed several reported pedigrees. They noted several other features in some cases, including 5th finger clinodactyly, fibular deviation of the great toes, and underdeveloped middle phalanges of the other toes with tibial deviation. A member of the family described by Temtamy and McKusick,2 whose parents were related, was severely affected; he had very short 2nd fingers with duplicated proximal phalanges, partial syndactyly of the thumbs and 2nd fingers, and short 3rd fingers. Freire-Maia et al.18 described synostosis between the distal phalanges of fingers 3–4, and Lehmann et al.20 reported camptodactyly and 2–3 toe syndactyly. Meiselman et al.21 described a family with combined features of brachydactyly types A and D and other digital features not typically seen in heritable brachydactylies.

Table 21-11. Syndromes with brachydactyly Causation (OMIM#) Gene/Locus

Syndrome

Prominent Features

Aarskog73

Short stature, hypertelorism, shawl scrotum, brachyphalangy

XL (305400) FGD1, Xp11.21

Acrodysostosis74

Mental deficiency, brachymelic short stature, short saddle nose, brachyphalangy, brachymetacarpia, brachymetatarsia Cutis aplasia, terminal transverse defects

AD (101800)

Adams-Oliver75

AD, AR (100300)

Albright hereditary osteodystrophy64

Short stature, mental retardation, obesity, round face, brachymetacarpia, brachymetatarsia, receptor defect for parathyroid hormone

AD (103580) GNAS1, 20q13.2

Anonychia-brachydactyly Bectrodactyly35

Anonychia, onychodystrophy, brachydactyly B, hypoplastic or absent metacarpals and metatarsals

AD (106990)

Anophthalmia, type Waardenburg76

Anophthalmia, oligodactyly, syndactyly, talipes equinovarus

AR (206920)

Apert77

Craniosynostosis, mental retardation, complete syndactyly

AD (101200) FGFR2, 10q26

Baller-Gerold78

Craniosynostosis, acrocephaly, radial hypoplasia/aplasia, aplasia of phalanges and metacarpals, clinodactyly V

AR (218600)

Bardet-Biedl79

Obesity, mental retardation, retinal dystrophy, renal anomalies, postaxial polydactyly

AR-triallelic inheritance (209900) BBS1, 11q13 BBS2, 16q21 BBS4, 15q22.3 BBS6, 20p12 BBS7, 4q27 BBS8, 14q32.11 3p13, 2q31

Basal cell nevus80

Basal cell nevi, broad facies, cysts of mandible and maxilla, ectopic calcifications, rib anomalies, brachymetacarpia IV

AD (109400) PTCH, 9q22.3

Biemond, type I2

Cerebellar ataxia, nystagmus, brachymetacarpia IV, brachymetatarsia IV

AD (113400)

Bloom81

Short stature, sister chromatid exchange, facial telangiectasia, erythema, clinodactyly V

AR (210900) RECQL3, 15q26.1

Borjeson-ForssmanLehmann82

Mental retardation, obesity, microcephaly, coarse facies, hypogenitalism, hypoplastic middle and distal phalanges

XLD (301900) PHF6, Xq26.3

Bork83

Uncombable hair, retinal pigmentary dystrophy, cataract, oligodontia, brachymetacarpia

AD (191482)

Borrone84

Thick skin, gingival hypertrophy, acne conglobata, coarse face, kyphoscoliosis, brachydactyly, joint contractures

AR or XLR (211170)

Brachydactyly A2microcephaly22

Microcephaly, seizures, brachydactyly A2, hypoplastic thumbs and halluces

AR (211369)

Brachydactyly-distal symphalangism85

Brachydactyly, distal symphalangism, scoliosis, clubfoot

Unknown (113450)

Brachydactyly-ectrodactylyfibular aplasia (Genuardi)86

Brachydactyly, ectrodactyly, fibular aplasia or hypoplasia

AD (113310)

Brachydactyly E-atrial septal defect67

Short stature, round face, atrial septal defect, brachydactyly E

AD (113301)

Brachydactyly-hallux varusthumb abduction87

Hallux varus, broad abducted thumbs, brachymetacarpia I

AD (112450)

Brachydacytly-hypertension66

Hypertension, brachymetacarpia, brachyphalangy

AD (112410) 12p12.2-p11.2

Brachydactyly, long thumb type88

Brachyphalangy, long thumb, cardiac conduction defects

AD (112430)

Brachydactyly-mental retardation65

Short stature, mental retardation, brachymetacarpia, brachymetatarsia

AD (600430) 2q37

Brachydactyly-ventricular septal defect-deafness89

Brachymesophalangy II and V, accessory phalanx II, ventricular septal defect, sensorineural deafness

Unknown (602561)

Brachymetapody-anodontiahypotrichosis-albinoidism90

Anodontia, short stature, brachymetacarpia, brachymetatarsia, hypotrichosis, albinoidism, ocular abnormalities

AR (211370) (continued)

970

Table 21-11. Syndromes with brachydactyly (continued) Syndrome

Prominent Features

Causation (OMIM#) Gene/Locus

Brachytelephalangycharacteristic faciesKallman91

Brachytelephalangy, hypogonadotrophic hypogonadism, hyposmia

AD (113480)

Camptobrachydactyly92

Distal and proximal interphalangeal finger contractures, broad short hands, brachymetacarpia, brachymetatarsia, supernumerary metatarsals

AD (114150)

Carpenter93

Preaxial polydactyly of feet, postaxial polydactyly of hands, brachydactyly, syndactyly, brachycephaly, craniosynostosis, heart defects, variable mental retardation

AR (201000)

C-trigonocephaly94

Trigonocephaly, oral frenulae, syndactyly, postaxial polydactyly, mental retardation

AR (211750)

Cerebro-costo-mandibular95

Growth deficiency, microcephaly, micrognathia, posterior rib gaps, clinodactyly V

AD, AR (117650)

Cockayne96

Growth failure, mental retardation, microcephaly, peripheral neuropathy, retinitis pigmentosa, thin photosensitive skin, short and broad phalanges/metacarpals/metatarsals, ivory epiphyses

AR (216400, 216411) ERCC6, 10q11 ERCC8, 5q12.1

Coffin-Siris97

Growth deficiency, mental retardation, coarse facies, hypoplastic nails, 5th finger and toe distal phalangeal aplasia/hypoplasia

Uncertain (135900)

Cohen98

Short stature, obesity, mental retardation, prominent upper central incisors, narrow hands and feet, brachymetacarpia, brachymetatarsia

AR (216550) COH1, 8q22-q23

Coloboma of macula-type B brachydactyly (Sorsby)38

Macular coloboma, brachydactyly B, broad or bifid distal phalanx of thumb, absent kidney

AD (120400)

Cooks36

Onychodystrophy, anonychia, brachytelephalangy, digitalized thumbs

AD (106995)

Cornelia de Lange99

Mental retardation, growth retardation, microbrachycephaly, hirsutism, small/upturned nose, ulnar deficiency, brachymetacarpia I, clinodactyly V

AD (122470) NIPBL, 5p13.1

Corneo-dermato-osseous100

Corneal dystrophy, palmoplantar hyperkeratosis, short stature, brachydactyly, brachytelephalangy, onycholysis

AD (122440)

Cranioectodermal dysplasia101

Short stature, dolichocephaly, sparse/fine hair, dental anomalies, rhizomelia, brachydactyly

AR (218330)

Cranio-fronto-nasal dysplasia102

Brachycephaly, hypertelorism, broad/bifid nasal tip, short 5th fingers, digital hypoplasia, clinodactyly V

XLD (304110) EFNB1, Xq12 Xp22

Cryptomicrotiabrachydactyly103

Cryptomicrotia, brachytelomesophalangy, toenail hypoplasia, bifid scrotum

AD or XLD (123560)

Digital arthropathybrachdactyly104

Brachymesophalangy, brachytelephalangy, arthropathy

AD (606835)

Digitorenocerebral105

Brachytelephalangy, cystic renal dysplasia, dilated cerebral ventricle, seizures

AR (222760)

DOOR (deafnessonychodystrophyonycholysis-mental retardation)106

Sensorineural deafness, hypoplastic distal phalanges, triphalangeal thumb, mental retardation, seizures/abnormal EEG

AR (220500)

Dubowitz107

Mental retardation, growth deficiency, microcephaly, ptosis, eczema, clinodactyly V

AR (223370)

Exostoses-anetodermiabrachydactyly E108

Multiple exostoses, anetodermia, brachydactyly E

AD (133690)

Fibular hypoplasia-complex brachydactyly54

Fibular aplasia/hypoplasia, brachymesophalangy, brachymetacarpia

AR (228900) GDF5, 20q11.2

Fibrodysplasia ossificans progressiva109

Fibrous dysplasia with ossification of muscles and subcutaneous tissues, brachymetacarpia I, brachymetatarsia I, short halluces

AD (135100) 4q27-q31

Fitzsimmons-Guilbert69

Spastic paraplegia, dysarthria, mental retardation, cone-shaped epiphyses, brachydactyly E

Unknown (270710)

Floating Harbor110

Short stature, mild mental retardation, triangular facies, large nose, brachyphalangy, clinodactyly V

Unknown (136140) (continued)

971

Table 21-11. Syndromes with brachydactyly (continued) Syndrome

Prominent Features

Causation (OMIM#) Gene/Locus

Gelb111

Patent ductus arteriosus, bicuspid aortic valve, brachymetacarpia V

Unknown (604381)

Grange

Multiple arterial stenoses, bone fragility, congenital heart defects, brachysyndactyly, learning disabilities

Unknown (602531)

Hand-foot-genital113

Genital abnormalities, small feet, brachymetacarpia I, brachymetatarsia I

AD (140000) HOXA13, 7p15-p14.2

Heart-hand, Spanish type114

Brachymesophalangy, hyperphalangly of index fingers, cardiac conduction defect

AD (140450)

Hirschsprung diseasebrachydactyly D59

Hirschsprung disease, brachydactyly D

XLR (306980)

Holt-Oram115

Absent/hypoplastic/triphalangeal thumbs, brachymetacarpia I, atrial and ventricular septal defects, absent or hypoplastic radii

AD (142900) TBX5, 12q24.1

Juberg-Hayward116

Microcephaly, cleft lip/palate, thumb abnormalities, brachyphalangy, brachymetacarpia

AR (216100)

Kabuki117

Kabuki actor facies, mental retardation, short stature, brachymesophalangy V

Unknown (147920)

Keutel118

Hearing loss, midface hypoplasia, depressed nasal bridge, brachytelephalangy, peripheral pulmonary stenosis, diffuse calcification of cartilage

AR (245150) MGP, 12p13.1-p12.3

Liebenberg119

Dysplastic elbow, carpal fusion, brachytelephalangy, nail hypoplasia

AD (186550)

Mo¨bius120

Sixth and seventh cranial nerve palsy, oligodactyly, brachydactyly, absent pectoral muscles

Sporadic, AD (157900) 13q12.2-q13 3q21-q22 10q21.3-q22.1

Muenke121

Uni- or bicoronal craniosynostosis, brachydactyly, thimble-shaped middle phalanges, carpal and tarsal fusion, deafness

AD (602849) FGFR3, 4p16.3

Multiple synostoses122

Proximal symphalangism, brachymesophalangy, brachymetacarpia, carpal/tarsal coalition, conductive deafness, hemicylindrical nose, hypoplastic alae nasi

AD (186500) NOG, 17q22

Noonan123

Short stature, hypertelorism, webbed neck, downslanted palpebral fissures, pectus deformity, lymphedema, pulmonic stenosis, brachymetacarpia

AD (163950) PTPN11, 12q24.1

ODED124

Microcephaly, short palpebral fissures, brachymesophalangy and clinodactyly II and V, syndactyly of toes II/III and IV/V, esophageal/duodenal atresia

AD (164280) 2p24-p23

Odonto-tricho-ungualdigital-palmar125

Natal teeth, trichodystrophy, transverse palmar creases, brachymetacarpia I, brachymetatarsia I, brachytelephalangy of toes

AD (601957)

Oral-facial-digital, type I126

Midline cleft lip, cleft tongue, hamartomas of tongue, hyperplastic frenula, mental retardation, polycystic kidneys, polydactyly

XLR (311200) CXORF5, Xp22.3-p22.2

Oral-facial-digital, type II126

Midline cleft lip, cleft tongue, hamartomas of tongue, polydactyly

AR (252100)

Oto-palato-digital, type I127

Short stature, prominent supraorbital ridges, broad nasal root, conductive deafness, cleft palate, short and broad thumbs/halluces

XL (311300) FLNA, Xq28

Oto-palato-digital, type II128

Hypertelorism, micrognathia, cleft palate, overlapping fingers, dense bones, postaxial polydactyly, short thumbs/halluces, hypoplastic metacarpals/metatarsals

XL (304120) FLNA, Xq28

Pallister-Hall129

Hypothalamic hamartoblastoma, imperforate anus, hypopituitarism, central/postaxial polydactyly, brachymetacarpia IV

AD (146510) GLI3, 7p13

Peters-plus130

Peters anomaly, short stature, short limbs, round face, thin upper lip, smooth philtrum, micrognathia, tapering brachydactyly, brachyclinodactyly V

AR (261540)

Pfeiffer131

Craniosynostosis, broad thumbs and halluces, syndactyly, brachymesophalangy

AD (101600) FGFR1, 8p11.2-p11.1 FGFR2, 10q26

Aplasia of pectoralis major, symbrachydactyly

Sporadic (173800)

Popliteal web, cleft lip/palate, lower lip pits

AD (119500) IRF6, 1q32-q41

112

Poland120 132

Popliteal pterygium

(continued)

972

Table 21-11. Syndromes with brachydactyly (continued) Causation (OMIM#) Gene/Locus

Syndrome

Prominent Features

Prader-Willi133

Mental retardation, short stature, hypotonia, obesity, hypogonadism, small hands and feet

AD (176270) Imprinting-related defect 15q11-q13

Robinow41,42

Short stature, acromesomelia, costovertebral anomalies, fetal face, hypertelorism, hypogenitalism

AD (180700) AR (268310) ROR2, 9q22

Rothmund-Thomson134

Short stature, poikiloderma, cataract, brachymetacarpia, brachyphalangy, hypoplastic/absent thumbs

AR (268400) RECQL4, 8q24.3

Rubinstein-Taybi135

Mental retardation, short stature, downward-slanted palpebral fissures, beaked nose, broad and radially angulated thumbs

AD (180849) CREBBP, 16p13.3

Russell-Silver136

Short stature, triangular face, asymmetry, brachymesophalangy V, clinodactyly V

Unknown (180860) 7p11.2 (uniparental disomy)

Saethre-Chotzen137

Craniosynostosis, ptosis, facial asymmetry, syndactyly, duplicated hallux, brachydactyly, hypoplastic distal phalanges, clinodactyly V

AD (101400) TWIST, 7p21 FGFR2, 10q26 FGFR3, 4p16.3

Schinzel-Giedion138

Mental retardation, midface retraction, cardiac defects, renal defects, brachymetacarpia I, hypoplastic distal phalanges

AR (269150)

Seckel139

Mental retardation, short stature, microcephaly, beaked nose, clinodactyly V

AR (210600) ATR, 3q22.1-q24 18p11-q11 4q

Sjogren-Larsson140

Mental retardation, spasticity, short stature, ichthyosis, brachymetacarpia, brachymetatarsia

AR (270200) 17p11.2

Smith-Magenis141

Short stature, mental retardation, hoarse voice, brachycephaly, midface hypoplasia, brachydactyly, sleep disturbance, characteristic behavior

AD (182290) RAI1, 17p11.2 Microdeletion

Sparse hair-mental retardation142

Mental retardation, sparse scalp hair, brachydactyly, prominent lower lip

Unknown (601358)

Stiff thumbs-brachydactyly A1developmental delay10

Stiff thumbs, brachydactyly A1, mental retardation

AD or XLD (188201)

Sugarman143

Malaligned halluces, proximal symphalangism, brachybasophalangy

Unknown (272150)

Tabatznik144

Cardiac arrhythmias, sloping shoulders, brachymetacarpias IV and V, brachytelephalangy

AD

Tarsal-carpal coalition145

Proximal symphalangism, tarsal and carpal coalition, humeroradial synostosis, brachymetacarpia of thumbs

AD (186570) NOG, 17q22

Temtamy preaxial brachydactyly146

Facial dysmorphism, mental retardation, sensorineural deafness, talon cusps of maxillary central incisors, preaxial brachydactyly, hyperphalangism, radial/tibial deviation of digits

Unknown (605282)

Terminal osseous dysplasiapigmentary defects147

Brachydactyly, camptodactyly, clinodactyly, digital fibromas, pigmentary lesions on face and scalp

XLD (300244) Xq27.3-q28

Tonoki37

Short stature, mental retardation, brachydactyly B

Unknown (603396)

Trichorhinophalangeal, type I148

Sparse and thin hair, bulbous nose, coned phalangeal epiphyses, brachymetacarpia and brachymetatarsia IV and V

AD (190350) TRPS1, 8q24.12

Trichorhinophalangeal, type II149 (Langer-Giedeon)

Mental retardation, bulbous nose, sparse scalp hair, exostoses, cone-shaped phalangeal epiphyses, brachymetacarpia

AD (150230) Deletion of TRPS1 and EXT1, 8q24.11-q24.13

Triphalangeal thumbsbrachyectrodactyly150

Triphalangeal thumbs, brachydactyly, ectrodactyly of feet

AD (190680)

Williams151

Mental retardation, short stature, supravalvular aortic stenosis, anteverted nares, long philtrum, prominent lips, clinodactyly V

AD (194050) ELN, 7q11.2 Microdeletion

973

974

Skeletal System Table 21-12. Skeletal dysplasias with brachydactyly Achondrogenesis

Lenz-Majewski hyperostotic dwarfism

Achondroplasia

Metaphyseal chondrodysplasia (McKusick)

Acrodysostosis

Metaphyseal dysplasia with exocrine pancreatic insufficiency and cyclic neutropenia

Acrodysplasia with retinitis pigmentosa and nephropathy

Metatropic dysplasia

Acromesomelic dysplasia, CampaillaMartielli

Moerman lethal short limb dwarfism with brain anomalies

Acromesomelic dysplasia, Maroteaux

Multiple epiphyseal dysplasia

Acromicric dysplasia

Nance-Sweeney dwarfism

Asphyxiating thoracic dystrophy

Opsismyodysplasia

Atelosteogenesis

Osebold-Remondini

Campomelic dysplasia

Osteoglophonic dwarfism

Cephaloskeletal dysplasia

Osteosclerosis, Stanescu

Chondrodysplasia punctata

Oto-palato-digital

Chondrodysplasia, Grebe type

Pseudoachondroplasia

Chondrodysplasia, Hunter-Thompson type

Pycnodysostosis

Cleidocranial dysplasia

Robinow

Cranioectodermal dysplasia

Ruvalcaba

Deafness and metaphyseal dysostosis

Schneckenbecken dysplasia

Diastrophic dysplasia

Short rib-polydactyly

Dyggve-Melchior-Clausen

Spondyloepimetaphyseal, Irapa type

Dyschondrosteosis

Spondyloepiphyseal dysplasia congenital

Dyssegmental dysplasia

Spondylometaphyseal dysplasia, Kozlowski

Ellis-van Creveld

Spondyloperipheral dysostosis

Enchondromatosis

Thantophoric-clover leaf skull

Fibrochondrogenesis

Thanatophoric dysplasia

Geleophysic dysplasia

Tricho-rhino-phalangeal syndrome

Hypochondroplasia

Weill-Marchesani syndrome

Larsen

Brachydactyly type A2 is an autosomal dominant trait with high penetrance and variable expression. However, Graham22 reported affected siblings whose parents were second cousins. In addition to brachydactyly type A2, both had microcephaly and one had diet-controlled diabetes, seizures, and learning disabilities. Studies of two German families with brachydactyly type A2 led to the identification of missense mutations in the gene encoding bone morphogenetic protein receptor 1B (BMPR1B) in both kindreds.20 The BMPR1B protein is a transmembrane serine-threonine kinase receptor.20 It is activated by bone morphogenetic proteins and growth/differentiation factor 5 (GDF5) and participates in cartilage condensation and bone formation in the developing digits.20 The mutations are thought to act through a dominant negative mechanism and were shown to adversely affect cartilage differentiation when expressed in vitro and in vivo.20 Brachydactyly type A2 is a rare condition, with few families having been described. Brachydactyly Type A3 (Brachymesophalangy V)

In brachydactyly type A3, the middle phalanges of the 5th fingers are short, and the distal phalanges of the 5th fingers may be radially deviated due to slanting of the distal articular surface of the middle phalanges (Figs. 21-23 and 21-24).1,2,23 A single finger flexion crease can be present, and on radiograph the 5th middle

phalanx may have a cone-shaped epiphysis.2,24 Garn et al.24 concluded that brachymesophalangy V with and without cone-shaped epiphyses are distinct traits. Hersh et al.23 noted characteristic indentations in the distal radial aspect of this phalanx on radiographs in some affected persons and postulated that abnormal ossification underlies the disorder. The 5th toes may also be affected.2 Short and/or radially deviated 5th fingers are seen commonly as an isolated finding or in various syndromes, such as Down syndrome. Radial deviation of the distal phalanx of the 5th finger without shortening or malformation of the middle phalanx may be a mild manifestation of brachydactyly type A3 or may be a distinct condition.25,26 In contrast, radial deviation of the distal phalanx of the 5th finger resulting from an abnormal shape of the distal rather than the middle phalanx is a distinct condition known as Kirner anomaly, or dystelephalangy.2 Brachydactyly type A3 is an autosomal dominant trait with incomplete penetrance.2,23 The molecular basis of this condition is not well established. Debeer et al.27 reported a missense mutation in the homeodomain of HOXD13 in a family with findings of syndactyly type II and variable foot abnormalities. Thirteen of seventeen mutation carriers had isolated bilateral 5th finger clinodactyly, suggesting that HOXD13 mutations may cause brachydactyly type A3.27

Hands and Feet

975

Fig. 21-21. Brachydactyly type A1. Schematics show variation of middle phalanx in brachydactyly A1. Photograph and radiograph of hands show shortening of all digits due to shortening of the middle phalanges. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Brachymesophalangy V is a common variant observed at differing frequencies in various ethnic groups. Its prevalence is less than 1% in the United States, 1–10% in various South-American countries, 5% in Hong Kong, and 21% in Japan.23,28,29 Brachydactyly Type B (Apical Dystrophy)

The hallmark features of brachydactyly type B are severely hypoplastic or absent distal phalanges and nails of digits 2–5 in the hands and feet (Fig. 21-25).1–3,30–32 The tips of the digits have an appearance that resembles distal amputation.3 The middle phalanges of these digits may also be short. The thumbs are often flat, spatulate, broad, or bifid. Symphalangism may affect the proximal or distal interphalangeal joints.2 Cutaneous syndactyly involving fingers 3–4 or 2–4 and between toes 2–3 and 3–4 has been described, leading some to call this condition symbrachydactyly.2,31,33 The findings are usually symmetric with more severe involvement of the hands and of the ulnar and fibular digits.2,3 Hand and foot radiographs characteristically show underdeveloped or absent distal phalanges of digits 2–5.1–3,30–32 The middle phalanges may also be short but resemble distal phalanges

in their appearance.3 Symphalangism is often noted. The distal phalanges of the thumbs are notched, bifid, or duplicated.1–3,30–32 Proximal digital phalanges may have an hour-glass shape with thin diaphyses, and carpal fusions can occur.2,3 Brachydactyly type B is most often an isolated finding. However, Houlston and Temple30 noted a characteristic facial phenotype that has subsequently been described in other families.31,32 The distinctive features include increased eye spacing, high nasal bridge, prominent nose with a bulbous tip and hypoplastic alae, and a short philtrum.30–32,34 Several other hand and foot disorders overlapping with brachydactyly type B have also been reported. Temtamy and McKusick2 classified a previously reported case of middle phalangeal absence with nail hypoplasia and bifid thumbs as brachydactyly type A4, but they noted significant overlap with type B. Santos34 described a family with brachydactyly type B in which absent thumbnails and hypoplastic or absent toenails were consistent features.31 Kumar and Levick35 described a family with absent/dystrophic nails, hypoplastic distal phalanges, and long broad thumbs. One individual was missing the 5th finger, and another individual was missing fingers 2, 3, and 5 in both hands.

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Skeletal System

Fig. 21-22. Brachydactyly A2. Schematic and radiographs show phalangeal involvement of digit 2. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

The term ‘‘Cooks syndrome’’ has been used to describe several families with findings of brachydactyly type B, characteristic facies, and bulbous digital tips, but this may not be a distinct disorder.36 Two families have been described with a dominant phenotype of brachydactyly type B, characteristic facies, microcephaly, and mental retardation.37 Sorsby syndrome was originally described by Sorsby in 1935 as an autosomal dominant condition comprising brachydactyly type B and bilateral macular colobomas in all affected persons.38 Follow-up of this family suggests that genitourinary malformations may also be a feature of the condition.38 Some findings in brachydactyly type B overlap with those of symbrachydactyly, amniotic band sequence, and Adams-Oliver syndrome. Brachydactyly type B is an autosomal dominant condition with high penetrance and significant clinical variability, particularly between families.1–3,30–33 The condition is caused by heteroFig. 21-23. Three configurations of short middle phalanges: shortening without angulation (left), shortening with angulation of distal portion (middle), and delta configuration (right). These configurations are seen in brachydactyly A2 involving digit 2, in brachydactyly A3 involving digit 5, and in triphalangeal thumb. (Schematic drawn after Wood: Clin Orthol Rel Res 120:188, 1976.)

zygous mutations in the gene ROR2, which maps to chromosome 9q22 and encodes an orphan receptor tyrosine kinase.31–33 The role of this gene in skeletal development was initially demonstrated in the Ror2 knockout mouse, which has severe diffuse skeletal defects.33 ROR2 mutations have been identified in a number of large families with brachydactyly type B.33,39,40 The mutations are nonsense or frameshift changes that are thought to adversely affect digital development through a dominant negative mechanism.33,40 In contrast, homozygous missense or nonsense mutations in ROR2 have been found to cause autosomal recessive Robinow syndrome, which is characterized by short stature, short limbs and digits, characteristic facies, and genital abnormalities.41,42 The mutations are predicted to truncate the ROR2 protein and cause the phenotype through a loss of function mechanism.41,42 Of note, another locus for brachydactyly type B was suggested by failure to demonstrate linkage to chromosome 9q22 in one family.31 In addition, a ROR2 mutation was not identified in the family with Sorsby syndrome.40 The frequency of brachydactyly type B is unknown, but a number of families have been described. Brachydactyly Type C

In this condition the middle phalanges of fingers 2, 3, and 5 and the metacarpals of the thumbs are shortened (Fig. 21-26).1–3,43–46 The 4th finger is unaffected or least affected and is typically the longest finger or equal in length to the 3rd finger. The 2nd and 3rd fingers often deviate to the ulnar side, while the 5th fingers deviate to the radial side.3 The distal flexion creases of fingers 2, 3, and 5 may be absent, and flexion at these joints may be reduced.3 The feet can be normal or exhibit variable shortening of the middle phalanges. As noted by Temtamy and McKusick2 and Fitch,3 a variety of other hand and foot findings have been described. These include macrophalangy, arachnodactyly, symphalangism, camptodactyly, postaxial polydactyly, hallux valgus, and talipes valgus or varus.

Fig. 21-24. Brachydactyly A3. Schematic shows involvement of middle phalanx of digit 5.

Fig. 21-25. Brachydactyly B. Schematic shows variable changes with shortening or absence of the distal and middle phalanges. The changes are reminiscent of amputations since the nails may be absent and the digits blunted. The thumbs may be broad with duplication of the distal phalanx. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

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Fig. 21-26. Brachydactyly C. Schematics show variable shortening and hypersegmentation involving proximal and middle phalanges of digits 2, 3, and 5. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, DE.)

Hand radiographs demonstrate shortening of the middle phalanges of fingers 2, 3, and 5 with little or no involvement of the 4th fingers. In milder cases, only fingers 2 and 3 are involved. The first metacarpal is typically short, and other metacarpals or distal phalanges may also be short.3 There may be two bones in the region of the proximal phalanges of fingers 2 and/or 3. The terms hypersegmentation, hyperphalangy, and pseudoepiphysis have been used to describe this appearance.2,3,43–45 Typically, the extra bone is abnormally shaped and situated between the metacarpal and proximal phalanx. It does not contain a growth plate and represents an enlarged epiphysis.44 This bone later fuses to the proximal phalanx and results in a radial protuberance of this phalanx and ulnar deviation of the involved finger.44 A sclerotic line may be present at the site of fusion.44 Foot radiographs may show variable shortening or absence of the middle phalanges and metatarsals and hallux valgus.2,3,45,46 As in brachydactyly type A1, persons with brachydactyly type C may have absolute or relative short stature.43,47 Elbow and forearm abnormalities, including short ulnae, subluxation of the ulna and radius, irregularity of the distal radius, and Madelung deformity can occur with brachydactyly type C.2,3,44 Developmental dysplasia of the hips has been reported.47,48 Savarirayan et al.48 de-

scribed spinal changes noted on radiographs in persons with brachydactyly type C, including spondylolysis, spondylolisthesis, and premature vertebral end-plate disease. Rowe-Jones et al.49 reported a family with brachydactyly type C, short broad halluces, and cupped ears. The findings of brachydactyly type C are often distinctive but can be mild or overlap with those of brachydactyly type A1. However, the metacarpal bone, rather than the proximal phalanx, of the thumb is shortened in type C, and hypersegmentation of the proximal phalanges does not occur in type A1.3 Metacarpophalangeal pattern profile analysis can be helpful in distinguishing between these types and in detecting mildly affected individuals. Brachydactyly type C is an autosomal dominant trait with highly variable expression. Incomplete penetrance has been described.50 The disorder is caused by heterozygous mutations in the growth/differentiation factor 5 (GDF5) gene, also known as cartilage-derived morphogenetic protein 1 (CDMP1), on chromosome 20.46,50 This gene is a member of the transforming growth factor-b (TGF-b) superfamily of secreted signaling molecules. It encodes a protein with structural and functional similarity to the bone morphogenetic proteins (BMPs) that participate in the

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growth and patterning of axial skeletal elements.46,50 GDF5 was the first gene found to cause human brachydactyly following the identification of mutations in the mouse homologue (Gdf5) in brachypodism, a recessive phenotype characterized by severe digital and limb shortening.46 Like other TGF-b molecules, the GDF5 protein has a carboxy-terminal prodomain and an aminoterminal signaling domain, which are separated by a consensus cleavage site.50–52 Two protein chains normally dimerize via their prodomains, form a disulfide linkage between the two signaling domains, and undergo proteolytic cleavage to release the active dimeric signaling molecule.50–52 The majority of patients with brachydactyly type C have frameshift or nonsense mutations in the GDF5 prodomain, leading to functional haploinsufficiency of GDF5 protein.50 Locus heterogeneity of brachydactyly was previously hypothesized based upon linkage mapping in the large kindred reported by Haws,43 but this family was later found to have a GDF5 mutation.50 GDF5 mutations also cause a variety of more severe skeletal phenotypes. Prior to its association with brachydactyly type C, GDF5 was found to cause two autosomal recessive acromesomelic chondrodysplasias, the Grebe and Hunter-Thompson syndromes.51,52 A heterozygous missense mutation affecting the proteolytic cleavage site was identified in two families with brachydactyly type C and fibular hypoplasia.53 GDF5 mutations have also been identified in the autosomal recessive DuPan syndrome, which is characterized by severe brachydactyly and fibular hypoplasia.54 Hence, as with brachydactyly type A1 associated with IHH mutations, brachydactyly type C represents one end of a spectrum of generalized skeletal abnormalities attributable to different mutations in the same gene in either the heterozygous or homozygous state. Brachydactyly type C is a rare condition of unknown frequency in the general population. Brachydactyly Type D (Stub Thumb)

The main feature of this condition is a short broad thumb on one or both hands (Fig. 21-27).1–3,55–56 The nails are also short and broad, and there is an increased frequency of whorl thumbprint patterns.55 Asymmetric involvement is common.1 In families with unilateral involvement, Goodman et al.55 observed that the same

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hand was always involved. The halluces may also appear short and broad.2 Goodman et al.55 noted that the most frequently associated anomaly was a significantly short 4th toe due to shortening of the metatarsal and proximal phalanx. Syndactyly involving toes 2– 3 or all fingers of both hands has been rarely noted.55 Hand radiographs demonstrate short broad distal phalanges of the thumbs. The bases of these phalanges are typically wider than the proximal phalanges with which they articulate.2 Temtamy and McKusick2 observed that the distal phalanges of the 3rd fingers may be short and broad, as had been previously described by Stecher.2,56 The 4th or 5th metacarpals may also be short.2 Foot radiographs reveal short, broad distal phalanges of the great toes. The metatarsals and proximal phalanges of the 4th toes may be short.55 Robin et al.57 noted shortened first metatarsals and variable degrees of shortening involving other hand and foot bones in a family with brachydactyly type D studied by metacarpophalangeal pattern profile analysis. Brachydactyly type D is most often isolated but appears in several syndromes, most notably Rubinstein-Taybi syndrome.2 It has also been associated with cardiac arrhythmias in the Tabatznik syndrome.2 Viljoen et al.58 reported three sisters with a syndrome characterized by brachydactyly type D, microcephaly, short stature, dysmorphic features, and profound mental retardation. Reynolds et al.59 reported a pedigree of two brothers and two maternal uncles with brachydactyly type D, hypoplastic or absent nails on the thumbs and great toes, and Hirschsprung disease. Brachydactyly type D is inherited as an autosomal dominant trait with reduced penetrance and clinical variability. Goodman et al.55 calculated a penetrance of approximately 40% in either sex. Gray and Hurt60 studied the inheritance of this condition in 38 pedigrees and calculated the penetrance to be 100% in females and 62% in males. Brachydactyly type D is thought to arise from premature fusion of the distal phalangeal epiphysis of the thumb. This observation is based on radiographic findings of early epiphyseal closure in the affected thumbs of persons with unilateral involvement.2,55 The molecular basis of this condition is not well understood. Robin et al.57 did not find evidence of linkage to six loci-containing genes involved in limb development, and genome-wide linkage has not been performed. Johnson et al.61 identified a missense mutation in HOXD13 in a family with a variable phenotype including short

Fig. 21-27. Brachydactyly D. Schematic shows shortening of distal phalanx of the thumb.

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distal phalanges of the thumbs, short or long distal phalanges of other digits, short metacarpals and metatarsals, and carpal fusions. They considered this family to have features of brachydactyly types D and E.61 Mixed features of brachydactyly types D and E have been observed in other families.3 Temtamy and McKusick2 summarized studies of the frequency of brachydactyly type D. Stecher56 found the condition in 0.4% of Caucasians and 0.1% of African-Americans. In Japan, the frequency is approximately 3% in females and 1.2–1.6% in males.2 Goodman found a prevalence of 3% in Arabs and 1.6% in Jews, with no appreciable sex difference.55 Bracydactyly Type E (Brachymetacarpy; Brachymetapody)

The digital shortening in this disorder primarily involves the metacarpals and metatarsals (Fig. 21-28).1–3 Mild degrees of metacarpal shortening are best appreciated by examining the knuckles at

the metacarpal-phalangeal joints with the hands fisted. The 4th and 5th metacarpals and metatarsals are characteristically affected, although any or all may be affected.2,3,62,63 Brachydactyly type D can be an associated finding.3,62 Hypermobility of the fingers and other joints may be seen.2 The findings are frequently asymmetric.2 Short stature is frequently associated with brachydactyly type E.2,62 Radiographs demonstrate the shortened metacarpals and metatarsals. Distal phalanges, especially of the thumbs, and middle phalanges of the 2nd or 5th fingers may also be short.2,62 Cone epiphyses can be seen in some cases.62 Brachydactyly type E may be isolated or a component feature of a number of conditions, including Turner syndrome, acrodysostosis, and basal cell nevus syndrome.2,62 It is a cardinal feature of Albright hereditary osteodystrophy (AHO), in which short stature, round face, mental retardation, and pseudo- or pseudopseudohypoparathyroidism occur. De Sanctis et al.64 studied the variability of brachydactyly in Albright hereditary osteodystrophy. An AHO-like

Fig. 21-28. Brachydactyly E. Schematics show variable shortening of metacarpals (usually metacarpal 4). Metatarsals may also be involved, again with metacarpal 4 being affected most often and most severely. Radiograph shows shortening of digits 4 and 5. Photograph shows proximal positioning of toe 4 because of shortening of metatarsal 4.

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phenotype has also been described with microdeletions involving chromosome 2q37.65 These patients have brachydactyly type E, short stature, round face, and moderate mental retardation but no endocrine abnormalities.65 An autosomal dominant phenotype of brachydactyly with hypertension has been described. The brachydactyly is characterized by shortening of the metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses.66 Families have also been described with brachydactyly type E in association with atrial septal defect,67 multiple impacted teeth,68 and spastic paraplegia.69 Isolated brachydactyly type E occurs as an autosomal dominant trait with variable expression.1–3,62,63 Temtamy and McKusick2 postulated that the condition arises from hypoplasia and premature fusion of the metacarpal epiphyses as noted on radiographs in children. Autosomal dominant inheritance of isolated 4th metatarsal shortening was described as a common trait in India and may be a distinct condition.70 The molecular basis of brachydactyly type E has been sought in several families. Linkage to the locus for Albright hereditary osteodystrophy on chromosome 20q13 and to chromosome 2q37 has been excluded in one family.63 Brachydactyly type E with hypertension has been mapped to a locus on chromosome 12.71 Missense mutations in HOXD13 were recently described in three families with some features of brachydactyly type E, suggesting that this may be the responsible gene in other cases.61 The population frequency of brachydactyly type E is unknown. Prognosis, Prevention, and Treatment

Treatment for brachydactyly is not usually indicated, unless there are significant functional deficits. Surgical separation of syndactyly, osteotomy for deviated digits, or bone grafting for short digits may be indicated to enhance function. References (The Brachydactylies) 1. Bell J: On brachydactyly and symphalangism. Treasury Hum Inherit 5:1, 1951. 2. Temtamy SA, McKusick VA: The Genetics of Hand Malformations. BDOAS XIV(3):1, 1978. 3. Fitch N: Classification and identification of inherited brachydactylies. J Med Genet 16:36, 1979. 4. Poznanski AK, Gartman S: A bibliography covering the use of metacarpophalangeal pattern profile analysis in bone dysplasias, congenital malformation syndromes, and other disorders. Pediatr Radiol 27:358, 1997. 5. Yang X, She C, Guo J, et al: A locus for brachydactyly type A-1 maps to chromosome 2q35-q36. Am J Hum Genet 66:892, 2000. 6. Armour CM, Bulman DE, Hunter AGW: Clinical and radiological assessment of a family with mild brachydactyly type A1: the usefulness of metacarpophalangeal profiles. J Med Genet 37:292, 2000. 7. Slavotinek A, Donnai D: A boy with severe manifestations of type A1 brachydactyly. Clin Dysmorphol 7:21, 1998. 8. Raff ML, Leppig KA, Rutledge JC, et al.: Brachydactyly type A1 with abnormal menisci and scoliosis in three generations. Clin Dysmorphol 7:29, 1998. 9. Tsukahara M, Azuno Y, Kajii T: Type A1 brachydactyly, dwarfism, ptosis, mixed partial hearing loss, microcephaly, and mental retardation. Am J Med Genet 33:7, 1989. 10. Piussan C, Lenaerts C, Mathieu M, et al.: Dominance reguliere d’une ankylose des pouces avec retard mental se transmettant sur trois generations. J Genet Hum 31:107, 1983. 11. Gao B, Guo J, She C, et al.: Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet 28:386, 2001. 12. McCready ME, Sweeney E, Fryer AE, et al.: A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved. Hum Genet 111:368, 2002.

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13. Kirkpatrick TJ, Au K-S, Mastrobattista JM, et al.: Identification of a mutation in the Indian Hedgehog (IHH) gene causing brachydactyly type A1 and evidence for a third locus. J Med Genet 40:42, 2003. 14. Giordano N, Gennari L, Bruttini M, et al.: Mild brachydactyly type A1 maps to chromosome 2q35-q36 and is caused by a novel IHH mutation in a three generation family. J Med Genet 40:132, 2003. 15. Armour CM, McCready ME, Baig A, et al.: A novel locus for brachydactyly type A1 on chromosome 5p13.3-p13.2. J Med Genet 39:186, 2002. 16. Fukushima Y, Ohashi H, Wakui K, et al.: De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly. Am J Med Genet 57:447, 1995. 17. Hellemans J, Coucke PJ, Giedion A, et al.: Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am J Hum Genet 72: 1040, 2003. 18. Freire-Maia N, Maia NA, Pacheco CAN: Mohr-Wriedt (A2) brachydactyly: analysis of a large Brazilian kindred. Hum Hered 30:225, 1980. 19. Edelson PJ: Brachydactyly type A2 in an American Negro family. Clin Genet 3:59, 1972. 20. Lehmann K, Seemann P, Stricker S, et al.: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. PNAS 100:12277, 2003. 21. Meiselman SA, Berkenstadt M, Ben-Ami T, et al.: Brachydactyly type A-7 (Smorgasbord): a new entity. Clin Genet 35:261, 1989. 22. Graham JM Jr: New syndrome of type A2 brachydactyly, microcephaly, and diabetes in siblings born to consanguineous parents. Am J Hum Genet Suppl 45:A76, 1989. 23. Hersh AH, DeMarinis F, Stecher RM: On the inheritance and development of clinodactyly. Am J Hum Genet 5:257, 1953. 24. Garn SM, Poznanski AK, Nagy JM, et al.: Independence of brachymesophalangia-5 from brachymesophalangia-5 with cone mid-5. Am J Phys Anthropol 36:295, 1972. 25. Stiles KA, Schalck J: A pedigree of curved forefingers. J Hered 26:211, 1945. 26. Dutta P: The inheritance of the radially curved little finger. Acta Genet 15:70, 1965. 27. Debeer P, Bacchelli C, Scambler PJ, et al.: Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13. J Med Genet 39:852, 2002. 28. Hertzog KP: Shortened fifth medial phalanges. Am J Phys Anthropol 27:113, 1967. 29. Garn SM, Fels SL, Israel H: Brachymesophalangia of digit five in ten populations. Am J Phys Anthropol 27:205, 1967. 30. Houlston RS, Temple IK: Characteristic facies in type B brachydactyly? Clin Dysmorphol 3:224, 1994. 31. Oldridge M, Temple IK, Santos HG, et al.: Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity. Am J Hum Genet 64:578, 1999. 32. Gong Y, Chitayat D, Kerr B, et al.: Brachydactyly type B: clinical description, genetic mapping to chromosome 9q, and evidence for a shared ancestral mutation. Am J Hum Genet 64:570, 1999. 33. Oldridge M, Fortuna AM, Maringa M, et al.: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24:275, 2000. 34. Santos HG: Characteristic facies in type B brachydactyly? Clin Dysmorphol 4:274, 1995. 35. Kumar D, Levick RK: Anonychia-onychodystrophy with brachydactyly type B and ectrodactyly. Clin Genet 30:219, 1986. 36. De Ravel TJL, Berkowitz DE, Wagner JM, et al.: Brachydactyly type B with its distinct facies and ‘Cooks syndrome’ are the same entity. Clin Dysmorphol 8:41, 1999. 37. Sorge G, Baieli S, Mauceri L, et al.: Short stature, brachydactyly, nail dysplasia, and mental retardation: further observation of the Tonoki syndrome. Am J Med Genet 80:403, 1998. 38. Thompson EM, Baraitser M: Sorsby syndrome: a report on further generations of the original family. J Med Genet 25:313, 1988.

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39. Schwabe GC, Tinschert S, Buschow C, et al.: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. Am J Hum Genet 67:822, 2000. 40. Goodman F: ROR2 is mutated in hereditary brachydactyly with nail dysplasia, but not in Sorsby syndrome. Clin Genet 64:263, 2003. 41. Van Bokhoven H, Celli J, Kayserili H, et al.: Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet 25:423, 2000. 42. Afzal AR, Rajab A, Fenske CD, et al.: Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat Genet 25:419, 2000. 43. Haws DV: Inherited brachydactyly and hypoplasia of the bones of the extremities. Ann Hum Genet 26:201, 1963. 44. Robin NH, Gunay-Aygun M, Polinkovsky, et al.: Clinical and locus heterogeneity in brachydactyly type C. Am J Med Genet 68:369, 1997. 45. Galjaard RJH, van der Ham LI, Posch NAS, et al.: Differences in complexity of isolated brachydactyly type C cannot be attributed to locus heterogeneity alone. Am J Med Genet 98:256, 2001. 46. Polinkovsky A, Robin NH, Thomas JT, et al.: Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nat Genet 17:18, 1997. 47. Fitch N, Jequier S, Costom B: Brachydactyly C, short stature, and hip dysplasia. Am J Med Genet 4:157, 1979. 48. Savarirayan R, White SM, Goodman FR, et al.: Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. Am J Med Genet 117A:136, 2003. 49. Rowe-Jones JM, Moss ALH, Patton MA: Brachydactyly type C associated with shortening of the hallux. J Med Genet 29:346, 1992. 50. Everman DB, Bartels CF, Yang Y, et al.: The mutational spectrum of brachydactyly type C. Am J Med Genet 112:291, 2002. 51. Thomas JT, Lin K, Nandedkar M, et al.: A human chondrodysplasia due to a mutation in a TGF-b superfamily member. Nat Genet 12: 315, 1996. 52. Thomas JT, Kilpatrick MW, Lin K, et al.: Disruption of human limb morphogenesis by a dominant negative mutation in CMDP-1. Nat Genet 17:58, 1997. 53. Robin NH, Everman DB, Hecht J, et al.: Brachydactyly with fibular hypoplasia is associated with a dominant mutation in CDMP1. Am J Hum Genet Suppl 65:A70, 1999. 54. Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, et al.: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). Clin Genet 61:454, 2002. 55. Goodman RM, Adam A, Sheba C: A genetic study of stub thumbs among various ethnic groups in Israel. J Med Genet 2:116, 1965. 56. Stecher RM: The physical characteristics and heredity of short thumbs. Acta Genet (Basel) 7:217, 1957. 57. Robin NH, Hurvitz J, Warman ML, et al.: Clinical and molecular studies of brachydactyly type D. Am J Med Genet 85:413, 1999. 58. Viljoen DL, Kallis J, Voges S, et al.: An apparently new mental retardation syndrome in three elderly sisters. Clin Genet 40:6, 1991. 59. Reynolds JF, Barber JC, Alford BA, et al.: Familial Hirschsprung disease and type D brachydactyly: a report of four affected males in two generations. Pediatrics 71:246, 1983. 60. Gray E, Hurt VK: Inheritance of brachydactyly type D. J Hered 75:297, 1984. 61. Johnson D, Kan S, Oldridge M, et al.: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. Am J Hum Genet 72:984, 2003. 62. Riccardi VM, Holmes LB: Brachydactyly, type E: hereditary shortening of digits, metacarpals, metatarsals, and long bones. J Pediatr 84:251, 1974. 63. Oude Luttikhuis MEM, Williams DK, Trembath RC: Isolated autosomal dominant type E brachydactyly: exclusion of linkage to candidate regions 2q37 and 20q13. J Med Genet 33:873, 1996. 64. De Sanctis L, Vai S, Andreo MR, et al.: Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients. J Clin Endocrinol Metab 89:1650, 2004.

65. Phelan MC, Rogers RC, Clarkson KB, et al.: Albright hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals. Am J Med Genet 58:1, 1995. 66. Bilginturan N, Zileli S, Karacadag S, et al.: Hereditary brachydactyly associated with hypertension. J Med Genet 10:253, 1973. 67. Czeizel A, Goblyos P: Familial combination of brachydactyly, type E and atrial septal defect, type II. Europ J Pediat 149:117, 1989. 68. Gorlin RJ, Sedano HO: Cryptodontic brachymetacarpalia. BDOAS VII(7): 200, 1971. 69. Fitzsimmons JS, Guilbert PR: Spastic paraplegia associated with brachydactyly and cone shaped epiphyses. J Med Genet 24:702, 1987. 70. Ray AK, Haldane JBS: The genetics of a common Indian digital abnormality. PNAS 53:1050, 1965. 71. Schuster H, Wienker TF, Bahring S, et al.: Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. Nat Genet 13:98, 1996. 72. Online Mendelian Inheritance in Man. Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2004. Available from: http://www.ncbi.nlm.nih.gov/ omim/ 73. Aarskog D: A familial syndrome of short stature associated with facial dysplasia and genital anomalies. BDOAS VII(6):235, 1971. 74. Steiner RD, Pagon RA: Autosomal dominant transmission of acrodysostosis. Clin Dysmorphol 1:201, 1992. 75. Kuster W, Lenz W, Kaariainen H, et al.: Congenital scalp defects with distal limb anomalies (Adams-Oliver syndrome): report of ten cases and review of the literature. Am J Med Genet 31:99, 1988. 76. Richieri-Costa A, Gollop TR, Otto PG: Autosomal recessive anophthalmia with multiple congenital abnormalities—type Waardenburg. Am J Med Genet 14:607, 1983. 77. Cohen MM Jr., Kreiborg S: Hands and feet in the Apert syndrome. Am J Med Genet 57:82, 1995. 78. Ramos Fuentes FJ, Nicholson L, Scott, CI Jr: Phenotypic variability in the Baller-Gerold syndrome: report of a mildly affected patient and review of the literature. Europ J Pediatr 153:483, 1994. 79. Katsanis, N: The oligogenic properties of Bardet-Biedl syndrome. Hum Mol Genet 13(Suppl 1):R65, 2004. 80. Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine 66:98, 1987. 81. Van Kerckhove CW, Ceuppens JL, Vanderschueren-Lodeweyckx M, et al.: Bloom’s syndrome: clinical features and immunological abnormalities of four patients. Am J Dis Child 142:1089, 1988. 82. Turner G, Lower KM, White SM, et al.: The clinical picture of the Borjeson-Forssman-Lehmann syndrome in males and heterozygous females with PHF6 mutations. Clin Genet 65:226, 2004. 83. Silengo M, Lerone M, Romeo G, et al.: Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly: report of a new patient with additional findings. Am J Med Genet 47:931, 1993. 84. Borrone C, Di Rocco M, Crovato F, et al.: New multisystemic disorder involving heart valves, skin, bones, and joints in two brothers. Am J Med Genet 46:228, 1993. 85. Sillence DO: Brachydactyly, distal symphalangism, scoliosis, tall stature, and club feet: a new syndrome. J Med Genet 15:208, 1978. 86. Genuardi M, Zollino M, Bellussi A, et al.: Brachy/ectrodactyly and absence or hypoplasia of the fibula: an autosomal dominant condition with low penetrance and variable expressivity. Clin Genet 38:321, 1990. 87. Sharma AK, Haldar A, Phadke SR, et al.: Preaxial brachydactyly with abduction of thumbs and hallux varus: a distinct entity. Am J Med Genet 49:274, 1994. 88. Hollister DW, Hollister WG: The ‘long-thumb’ brachydactyly syndrome. Am J Med Genet 8:5, 1981. 89. Camera G, Costa M: Unusual type of brachydactyly associated with intraventricular septal defect and deafness: a new condition? Clin Dysmorphol 6: 31, 1997. 90. Tuomaala P, Haapanen E: Three siblings with similar anomalies in the eyes, bones and skin. Acta Ophthalmol 46:365, 1968.

Hands and Feet 91. Hunter AGW, Feldman W, Miller, J: Characteristic craniofacial appearance and brachytelephalangy in a mother and son with Kallmann syndrome in the son. Am J Med Genet 24:527, 1986. 92. Edwards JA, Gale RP: Camptobrachydactyly: a new autosomal dominant trait with two probable homozygotes. Am J Hum Genet 24:464, 1972. 93. Cohen DM, Green JG, Miller J, et al.: Acrocephalopolysyndactyly type II–Carpenter syndrome: clinical spectrum and an attempt at unification with Goodman and Summitt syndromes. Am J Med Genet 28:311, 1987. 94. Opitz JM, McCreadie SR, Smith DW, et al.: The C syndrome of multiple congenital anomalies. BDOAS V(2):161, 1969. 95. James PA, Aftimos S: Familial cerebro-costo-mandibular syndrome: a case with unusual prenatal findings and review. Clin Dysmorphol 12: 63, 2003. 96. Silengo MC, Franceschini P, Bianco R, et al.: Distinctive skeletal dysplasia in Cockayne syndrome. Pediatr Radiol 16:264, 1986. 97. Fleck BJ, Pandya A, Vanner L, et al.: Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study. Am J Med Genet 99:1, 2001. 98. Young ID, Moore JR: Intrafamilial variation in Cohen syndrome. J Med Genet 24:488, 1987. 99. Allanson JE, Hennekam RCM, Ireland M : De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes. J Med Genet 34:645, 1997. 100. Stern JK, Lubinsky MS, Durrie DS, et al.: Corneal changes, hyperkeratosis, short stature, brachydactyly, and premature birth: a new autosomal dominant syndrome. Am J Med Genet 18:67, 1984. 101. Young ID, Moore JR: Syndrome of the month. Cranioectodermal dysplasia (Sensenbrenner’s syndrome). J Med Genet 26:393, 1989. 102. Sax CM, Flannery DB: Craniofrontonasal dysplasia: clinical and genetic analysis. Clin Genet 29:508, 1986. 103. Tonoki H, Ohura T, Niikawa N: Cryptomicrotia and short, stubby fingers with excess fingertip arch patterns in a mother and son. Am J Med Genet 29:857, 1988. 104. Amor DJ, Tudball C, Gardner RJM, et al.: Familial digital arthropathybrachydactyly. Am J Med Genet 108:235, 2002. 105. Le Merrer M, David A, Goutieres F, et al.: Digito-reno-cerebral syndrome: confirmation of Eronen syndrome. Clin Genet 42:196, 1992. 106. Patton MA, Krywawych S, Winter RM, et al.: DOOR syndrome (deafness, onycho-, osteodystrophy, and mental retardadtion): elevated plasma and urinary 2-oxoglutarate in three unrelated patients. Am J Med Genet 26:207, 1987. 107. Winter RM: Syndrome of the month. Dubowitz syndrome. J Med Genet 23:11, 1986. 108. Mollica F, Li Volti S, Guarneri B.: New syndrome: exostoses, anetodermia, brachydactyly. Am J Med Genet 19:665, 1984. 109. Connor JM, Evans DAP: Genetic aspects of fibrodysplasia ossificans progressiva. J Med Genet 19:35, 1985. 110. Robinson PL: A unique association of short stature, dysmorphic features, and speech impairment (Floating-Harbor syndrome). J Pediatr 113:703, 1988. 111. Gelb BD, Zhang J, Sommer RJ, et al.: Familial patent ductus arteriosus and bicuspid aortic valve with hand anomalies: a novel heart-hand syndrome. Am J Med Genet 87:175, 1999. 112. Grange DK, Balfour IC, Chen S, et al.: Familial syndrome of progressive arterial occlusive disease consistent with fibromuscular dysplasia, hypertension, congenital cardiac defects, bone fragility, brachydactyly, and learning disabilities. Am J Med Genet 75:469, 1998. 113. Halal F: The hand-foot-genital syndrome (hand-foot-uterus): family report and update. Am J Med Genet 30:793, 1988. 114. Ruiz de la Fuente S, Prieto F: Heart-hand syndrome. III. A new syndrome in three generations. Hum Genet 55:43, 1980. 115. Newbury-Ecob RA, Leanage R, Raeburn JA, et al.: Holt-Oram syndrome: a clinical genetic study. J Med Genet 33:300, 1996. 116. Juberg RC, Hayward JR: A new familial syndrome of oral, cranial, and digital anomalies. J Pediatr 74:755, 1969. 117. Niikawa N, Kuroki Y, Kajii T, et al.: Kabuki make-up syndrome: a study of 62 patients. Am J Med Genet 31:565, 1988.

983

118. Cormode EJ, Dawson M, Lowry RB: Keutel syndrome: clinical report and literature review. Am J Med Genet 24:289, 1986. 119. Liebenberg F: A pedigree with unusual anomalies of the elbows, wrists and hands in five generations. S Afr Med J 47:745, 1973. 120. Bouwes Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Moebius anomalies. Am J Med Genet 23:903, 1986. 121. Muenke M, Gripp KW, McDonald-McGinn DM, et al.: A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet 60:555, 1997. 122. Hurvitz SA, Goodman RM, Hertz M, et al.: The facio-audiosymphalangism syndrome: report of a case and review of the literature. Clin Genet 28:61, 1985. 123. Mendez HMM, Opitz JM: Noonan syndrome: a review. Am J Med Genet 21:493, 1985. 124. Brunner HG, Winter RM: Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia. J Med Genet 28:389, 1991. 125. Mendoza HR, Valiente MD: A newly recognized autosomal dominant ectodermal dysplasia syndrome: the odonto-tricho-ungual-digital-palmar syndrome. Am J Med Genet 71:144, 1997. 126. Anneren G, Arvidson B, Gustavson KH, et al.: Oro-facio-digital syndromes I and II: radiological methods for diagnosis and the clinical variations. Clin Genet 26:178, 1984. 127. Pazzaglia UE, Beluffi G: Oto-palato-digital syndrome in four generations of a large family. Clin Genet 30:338, 1986. 128. Brewster TG, Lachman RS, Kushner DC, et al.: Oto-palato-digital syndrome, type II—an X-linked skeletal dysplasia. Am J Med Genet 20:249, 1985. 129. Graham J Jr., Saunders R, Fratkin J, et al.: A cluster of Pallister-Hall syndrome cases (congenital hypothalamic hamartoblastoma syndrome). Am J Med Genet Suppl 2:53, 1986. 130. Cabral de Almeida JC, Reis DF, Llerena J Jr, et al.: Short stature, brachydactyly, and Peters’ anomaly (Peters’-plus syndrome): confirmation of autosomal recessive inheritance. J Med Genet 28:277, 1991. 131. Pfeiffer RA: Dominant erbliche Akrocephalosyndaktylie. Z Kinderheilkd 90:301, 1964. 132. Froster-Iskenius UG: Syndrome of the month. Popliteal pterygium syndrome. J Med Genet 27:320, 1990. 133. Butler MG, Meaney FJ: Metacarpophalangeal pattern profile analysis in Prader-Willi syndrome. A follow up report on 38 cases. Clin Genet 28:27, 1987. 134. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985. 135. Berry AC: Syndrome of the month. Rubinstein-Taybi syndrome. J Med Genet 24:562, 1987. 136. Herman TE, Crawford JD, Cleveland RH, et al.: Hand radiographs in Russell-Silver syndrome. Pediatrics 79:743, 1987. 137. Reardon W, Winter RM: Saethre-Chotzen syndrome. J Med Genet 31:393, 1994. 138. Schinzel A: Midface retraction, multiple radiologic anomalies, renal malformations, and hypertrichosis. Hum Genet 62:382, 1982. 139. Poznanski AK, Iannaccone G, Pasquino AM, et al.: Radiological findings in the hand in Seckel syndrome (bird-headed dwarfism). Pediatr Radiol 13:19, 1983. 140. Jagell S, Karl-Henrik G, Holmgren G: Sjogren-Larsson syndrome in Sweden. A clinical, genetic and epidemiologic study. Clin Genet 19:233, 1981. 141. Smith ACM, McGavran L, Robinson J, et al.: Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet 24:393, 1986. 142. Nicolaides P, Baraitser M: An unusual syndrome with mental retardation and sparse hair. Clin. Dysmorphol 2:232, 1993. 143. Sugarman GI, Hager D, Kulik WJ: A new syndrome of brachydactyly of the hands and feet with duplication of the first toes. BDOAS X(5):1, 1974.

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144. Temtamy S, McKusick VA: Heart-hand syndrome II (Tabatznik syndrome). BDOAS XIV(3):241, 1978. 145. Dixon ME, Armstrong P, Stevens DB, et al.: Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med 3:349, 2001. 146. Temtamy SA, Meguid NA, Ismail SI, et al.: A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol 7:249, 1998. 147. Bacino CA, Stockton DW, Sierra RA, et al.: Terminal osseous dysplasia and pigmentary defects: clinical characterization of a novel male lethal X-linked syndrome. Am J Med Genet 94: 102, 2000. 148. Jorgenson RJ, Salinas CF, Sujansky E, et al.: Heterogeneity in the trichorhinophalangeal syndromes. BDOAS IXX(1):167, 1983. 149. Langer LO, Krassikoff N, Laxova R, et al.: The tricho-rhino-phalangeal syndrome with exostoses (or Langer-Giedion syndrome): four additional patients without mental retardation and review of the literature. Am J Med Genet 19:81, 1984. 150. Silengo MC, Biagioli M, Bell GL, et al.: Triphalangeal thumb and brachyectrodactyly syndrome. Confirmation of autosomal dominant inheritance. Clin Genet 31:13, 1987. 151. Burn J: Syndrome of the month. Williams syndrome. J Med Genet 23:389, 1986.

21.4 The Oligodactylies Definition

Oligodactyly is the severe underdevelopment or absence of one or more digits. The digital absence involves one or more limbs, can be symmetric or asymmetric, and may or may not occur in a recognizable pattern. In some cases, the deficiency preferentially involves the medial or lateral rays, the central digits, or all of the digits on a given limb. In severe cases, it may be difficult or impossible to determine which digits are missing because of disordered limb patterning or severely disrupted development. The deficiency may be isolated to the phalanges, or it may involve the metacarpal, carpal, metatarsal, or tarsal bones. The long bones of the limbs may also be hypoplastic or absent in association with oligodactyly. For example, an ulnar ray deficiency may involve absence of the ulna and one or more digits on the ulnar side of the hand. The terminology used to describe absence anomalies of the hands and feet is confusing. As used here, the term oligodactyly generally refers to all types of digital absence. Hence, it includes terminal transverse deficiencies principally involving the hands and feet, as well as hand and foot deficiencies associated with underdeveloped or absent long bones. Other terms for oligodactyly are hypodactyly, adactyly (absent digits), and aphalangy (absent phalanges). Acheiria refers to absence of the hand, apodia to absence of the foot, and acheiropody to absence of the hand and foot. Monodactyly refers to the presence of a single digit. Ectrodactyly is often used synonymously with split-hand/foot malformation to describe absence of the central digital rays. However, ectrodactyly is in fact a nonspecific term for digital deficiency that, from its Greek roots, literally means ‘‘abortion of the finger, or digit.’’1 Temtamy and McKusick1 defined ectrodactyly as partial or total absence of distal hand segments with essentially normal proximal limb segments. Under this definition, ectrodactyly represents one type of terminal transverse deficiency ranging from absent phalanges to total absence of the hand.

Oligodactyly occurs as an isolated finding and as a feature of many syndromes (Table 21-13). In some cases the condition is clearly genetic, while in other cases it results from a sporadic developmental abnormality or disruptive process. Teratogenic insults, impaired blood flow, and amniotic bands are important causes of oligodactyly. Associated hand or foot abnormalities (e.g., polydactyly, syndactyly, brachydactyly, constriction rings), long bone deficiencies, and extra-skeletal findings are important clues for generating a differential diagnosis. A positive family history and/or the pattern of involvement within or among the limbs often provide critical clues to a possible causative mechanism. For example, the sporadic occurrence of isolated unilateral digital absence is typically a non-genetic phenomenon with a low chance of recurrence in the siblings or children of an affected person.2 However, the significant clinical variability associated with oligodactyly often makes it difficult to distinguish a genetic versus non-genetic mechanism in sporadic cases. Terminal Transverse Deficiency

Terminal transverse deficiency represents a wide spectrum of hand and foot abnormalities, with absence of one or more phalanges, digits, or the entire hand or foot. The appearance typically resembles a partial or complete amputation of the distal limb (Fig. 21-29). The bony absence can assume almost any pattern within the hand or foot and can be unilateral or bilateral. In more severe cases, the deficiency occurs at the level of the long bones of the arm or leg (peromelia).2 Absence of the limb (amelia) represents the most extreme form of the condition.2 In some cases of hand absence (acheiria), there are small soft tissue nubbins arranged in a pattern suggesting rudimentary digits (Fig. 21-29). Some terminal transverse deficiencies resemble brachydactyly type B because of the uniform and symmetric appearance of the underdeveloped digits (Fig. 21-30). Syndactyly, brachydactyly, clinodactyly, or camptodactyly can be associated features. Rarely, clubfoot is associated with terminal transverse deficiency of an upper limb.2 Radiographs correlate with the clinical findings in demonstrating underdeveloped or absent bones (Fig. 21-30). Most cases of terminal transverse deficiency occur sporadically as an isolated abnormality of one hand or foot in an otherwise healthy individual. Czeizel et al.2 identified 218 cases of terminal transverse deficiency, ranging from aphalangy to amelia, among 1,575,904 total births in Hungary (birth prevalence of 1.4/ 10,000). Of these, 195 (89%) were isolated, and 96% of the isolated deficiencies were confined to a single limb. Overall, the upper limbs were involved almost 9 times more often than the lower limbs, and upper limb involvement was more often leftsided with an excess of female cases. Within the upper limbs, peromelia accounted for almost half of the cases (75/169), while acheiria, aphalangy, and adactyly followed in respective frequency. The latter three defects restricted to the hands comprised 89 of 169 cases. Within a given hand, deficiencies were uniformly distributed among digits 2 through 5, with infrequent involvement of the thumbs. In the lower limbs, absence of the feet, toes, or phalanges accounted for 8 of 9 total cases, and digital involvement was roughly equal. Evans et al.3 identified 38 cases of terminal transverse deficiency associated with other anomalies in the same Hungarian population. Some of these anomalies involved the limbs (e.g. clubfoot, syndactyly, and ring constrictions), while others involved other body areas. The authors did not find a strong association between any particular malformation and terminal transverse

Table 21-13. Selected entities with oligodactyly or adactyly Causation Gene, Locus

Entity

Fingers Only

Fingers or Toes

Toes Only

Acheiropodia (Brazil type)31

A

A

A

AR (200500) LMBR1, 7q36

Acro-dermato-ungual-lacrimaltooth (ADULT)55

M

M,M

M

AD (103285) TP63, 3q27

Adactyly, isolated unilateral1

A,R,M,U

Adams-Oliver8

R,M,U

R,M,U,T,M,Fi

T,M,Fi

AD, ?AR (100300)

Aglossia-adactyly7

R,M,U

R,M,U,T,M,Fi

T,M,Fi

Unknown (103300)

102

Unknown (?vascular)

U,T(?),Fi(?)

Al-Awadi: limb deficiencies

AR (276820)

Amniotic bands5

A,R,M,U

Baller-Gerold103

R

Buttiens: distal limb deficiency104

R,M,U

R,M,U,T,M,Fi

T,M,Fi

AR (246560)

CHILD105

M,U

M,U,M,T

M,T

XLD (308050) NSDHL, Xq28

Chorionic villus sampling (CVS)10

R,M,U

R,M,U,T,M,Fi

T,M,Fi

Mechanical disruption

Cornelia de Lange106

U,M

Ectrodactyly-ectodermal dysplasia-clefting (EEC)49

M

M,M

M

AD (129900) TP63, 3q27

Ectrodactyly-ectodermal dysplasia-macular dystrophy (EEM)52

M

M,M

M

AR (225280)

Fanconi anemia107

R

Femur-fibula-ulna88

R,M,U

R,M,U,T,M,Fi

T,M,Fi

Unknown (228200)

Fibular aplasia-ectrodactyly43

M,U

M,U,T,M,Fi

T,M,Fi

AD (225280)

Fi

Unknown

R,M,U

R,M,U,T,M,Fi

T,M,Fi

XLD (305600)

Gollop-Wolfgang complex

M

M,T,M

M,T

AD (119100), AR (228250)

Hand-foot-genital81

R

R,T

T

AD (140000) HOXA13, 7p15-p14.2

A,R,M,U,T,M,Fi

44

Hecht: limb deficiency109

Sporadic AR, ?AD (218600) TWIST, 7p21

AD (122470) NIPBL, 5p13.1

AR (227650) FANCA, 16q24.3 FANCB, 13q12.3 FANCC, 9q22.3 FANCD1, BRCA2, 13q12.3 FANCD2, 3p25.3 FANCE, 6p22-p21 FANCF, 11p15 FANCG, 9p13

Fibular deficiency, isolated83 Goltz108

A,T,Fi,M

R,M,U,T,M,Fi

Unknown (246570)

Holt-Oram86

R

AD (142900) TBX5, 12q24.1

Humeroradioulnar synostosis-oligodactyly110

U(?),M

AR (236400)

Ives-Houston111

R

Limb-body wall complex112

R,M,U

R,M,U,T,M,Fi

T,M,Fi

Unknown (?vascular)

Limb-mammary55

M

M,M

M

AD (603543) TP63, 3q27

Karsch-Neugebauer51

M

M,M

M

AD (183800)

Misoprostol exposure, prenatal10

R,M,U

R,M,U,T,M,Fi

T,M,Fi

Teratogen

113

AR (251230)

Nager

R

AD (154400) 9q32

Okihiro114

R

AD (607323) SALL4, 20q13.13-q13.2 (continued)

985

986

Skeletal System

Table 21-13. Selected entities with oligodactyly or adactyly (continued) Entity

Fingers Only

Fingers or Toes

Patterson-StevensonFontaine50

Toes Only

Causation Gene, Locus

M

AD (183700)

Poland (Poland-Mo¨bius)6

M,U

Unknown (173750)

Radial aplasia, isolated

R

Unknown

Radial deficiency-choanal stenosis115

R

AD (179270)

Radial ray deficiency, X-linked85

R

XLR (300378)

Roberts116

U

R,M,U,T,M,Fi

Robinow, autosomal recessive form117

M

M,M

M

AR (268310) ROR2, 9q22

Split-hand/foot malformation55

M

M,M

M

AD, XL (119100) TP63, 3q27 7q21-q22, Xq26, 10q24, 2q31

Split-hand/foot-sensorineural hearing loss54

M

M,M

M

AD (605617) 7q21-q22

A

Sporadic

M,T

Heterogeneous (119100)

Sirenomelia118 Split-hand/foot-long bone deficiency

M,U

Sofer: radial deficiency119

R

Thalidomide exposure, prenatal10

R

M,U,M,T

AR (268300)

AD (179280) R,T

Tibial deficiency, isolated42

Teratogen T

Unknown

Triphalangeal thumbbrachyectrodactyly38

M

M,M

M

AD (190680)

Trisomy 181

R

R,T

T

Chromosomal

Ulnar deficiency, isolated87

U,M

Unknown

Ulnar-mammary

U

AD (181450) TBX3, 12q23-q24.1

VACTERL association120

R

Valproic acid exposure, prenatal10

R

Weyers ulnar rayoligodactyly91

R,U

93

R,T,Fi

T,Fi

Sporadic (192350, 276950) XLR (314390) Teratogen

R,U,Fi

Fi

?AD (602418)

A, all; R, radial; M, middle; U, ulnar; T, tibial; Fi, fibular.

deficiency.3 The overall frequency of associated anomalies was 10% to 19% based on their findings and the results of other studies.3 The same authors found an association of asymmetric digital deficiencies (as seen in amniotic band disruption) with ring constrictions, syndactyly, encephalocele, cleft lip, scoliosis, and body wall defects.3 Rosano et al.4 identified 176 cases of transverse limb deficiencies associated with major congenital anomalies using data collected from 11 birth defect registries. They found significant associations with muscular defects, ring constrictions/amniotic bands, craniofacial defects, and micrognathia. They also identified 26 cases in which there were multiple associated malformations. Using different statistical methods, they found that transverse deficiencies were associated with certain combinations of malformations, including genital defects combined with anorectal atresia, and either cleft palate, micrognathia, or syndactyly combined with other craniofacial anomalies.4 The differential diagnosis of terminal transverse deficiency is extremely broad (Table 21-13). Amniotic band disruption

Fig. 21-29. Terminal transverse deficiency involving the entire hand (acheiria). Note presence of digital ‘‘nubbins’’ at the wrist and unilateral nature of the malformation.

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Fig. 21-30. Terminal transverse deficiency involving the phalanges (aphalangy). Note bilateral hypoplasia of toes 2 through 5 with absent nails. The nail of one hallux is also absent. Radiographs demonstrate absence of the middle and distal phalanges. The findings resemble brachydactyly type B.

complex is a frequent cause of this condition3 and should be carefully considered in every case. The presence of constriction rings, tissue strands, pseudosyndactyly, or bizarre patterns of deficiency suggest the disruption of normal digits by amniotic bands (Fig. 21-31). Craniofacial and body wall defects caused by aberrant tissue bands are frequently associated with the limb abnormalities.5 Vascular insufficiency from internal causes can also lead to oligodactyly. The finding of symbrachydactyly in combination with abnormalities of the ipsilateral chest wall and/or limited extraocular and facial movements suggests the Poland or Poland-Mo¨bius syndromes, which are hypothesized to result from vascular disruption (Fig. 21-31).6 Underdevelopment of the mandible and tongue are associated with terminal transverse deficiency in the oromandibular limb hypogenesis complex (aglossiaadactyly). This condition occurs sporadically and may also have a vascular cause, although the possibility of a genetic mechanism has not been excluded.7 In Adams-Oliver syndrome, terminal transverse deficiency is associated with cutis aplasia, warranting a careful examination of the scalp in patients with oligodactyly.8 Terminal transverse deficiency has been observed in homozygous alphathalassemia.9 Teratogens are another important cause of terminal transverse deficiency. Holmes10 recently reviewed limb abnormalities associated with teratogenic exposures. Maternal use of misoprostol, a prostaglandin E1 analog, has been associated with oligodactyly, digital nubbins, constriction rings, syndactyly, and Mo¨bius

syndrome.10 This agent is prescribed for gastric protection from the effects of nonsteroidal anti-inflammatory drugs, but it has also been used in Brazil as an abortifacient because of its ability to stimulate uterine contractions.10 Misoprostol is presumed to cause limb defects through a vascular disruptive mechanism.10 Terminal transverse deficiencies occurring at various levels of the limbs have been reported in some cases of prenatal cocaine exposure.10–12 However, an association between cocaine and limb deficiencies has not been conclusively demonstrated.10–12 Froster and Baird13 identified six cases of similar terminal transverse deficiencies involving the right arm or hand in children born to mothers who consumed alcohol heavily during pregnancy. The increased frequency of limb deficiency in the alcohol-exposed group relative to the general population suggested a causal association, but this has not been verified in other studies.10 Digital abnormalities occur in the phenytoin embryopathy, but they usually consist of mild clinical changes such as nail hypoplasia, an excess of arch patterns, and stiffness of the distal interphalangeal joints.10 Hand radiographs often demonstrate hypoplastic distal phalanges, short metacarpals, and coned epiphyses.10 A few cases of more severe deficiencies associated with phenytoin exposure, including absence of the hand with digital nubbins, have also been reported.10,14 Chorionic villus sampling (CVS) has been well established as a cause of limb deficiency in multiple studies since 1991.10,15 Terminal transverse deficiencies with or without residual nubbins, Poland anomaly, distal digital absence, and amniotic band

Fig. 21-31. Oligodactyly associated with vascular disruption. In the amniotic band disruption complex (A), digital shortening and absence occur in an asymmetric pattern. Note the constriction ring of the right thumb. In the Poland-Mo¨bius syndrome (B), digital absence is associated with symbrachydactyly.

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disruptions (including syndactyly, constriction rings, and fibrous strands attached to the tips of digits) have all been reported.15,16 CVS is thought to cause vascular disruption of the limbs, possibly through secondary effects of hemorrhage from injured chorionic villi.15 Increased frequency and greater severity of CVS-associated limb defects are correlated with procedures done earlier in pregnancy, and the risk of terminal transverse defects associated with CVS is estimated at 1 in 1,000–3,000.10,16 Golden et al.15 reviewed the CVS-associated limb abnormalities in published cases relative to the limb deficiencies identified in a large control population. They found that typical forms of transverse deficiency involving all digits of a given limb are less common than specific patterns of deficiency among the CVS-exposed infants. The third finger is most often affected, followed by the second through fourth fingers together. The authors noted the similarity of this pattern to that seen in the amniotic band disruption complex.15 Isolated cases of terminal transverse deficiency are usually attributed to sporadic developmental or disruptive causes, and the chance of recurrence is minimal.1 Czeizel et al.2 found no evidence of familial occurrence in their large study of isolated terminal transverse defects. They also pointed out that discordance among monozygotic twins argues against a genetic origin for this condition.2 These and earlier data from Hungary17 corroborated the findings of Birch-Jensen18 in Denmark. Vascular disruption has been hypothesized to cause most cases of isolated terminal transverse deficiency.2,19,20 Hoyme et al.19 studied four cases of unilateral terminal transverse defects below the elbow, and identified a brachial artery thrombus in one case and placental thrombi in three cases. In the latter cases, the authors hypothesized that placental thromboemboli occluded circulation to the affected limbs.19 They also noted the occurrence of similar transverse limb deficiencies in children with a monozygotic twin that died in utero, and in animal fetuses given vasoactive drugs.19 Van Allen20 proposed a model for different types of limb reduction defects caused by vascular disruption, noting the importance of the marginal vein in relation to the apical ectodermal ridge of the limb bud.20 The author postulated that rupture of this vein would lead to oligodactyly and transverse limb defects, with the severity and level of the deficiency depending upon the size of the resultant hematoma and the gestational timing of the insult.20 Similarly, amniotic band sequence is generally a sporadic condition with a low recurrence risk.1 Different hypotheses have been proposed to explain the limb deficiencies, ring constrictions, adherent tissue strands, and other findings that occur in this disorder. These include entanglement of structures within the amnion, attachment of structures to bands or strands of amniotic tissue, vascular disruption from various causes, and interference with normal embryonic development at an early stage.20–22 Despite the sporadic nature of most terminal transverse deficiencies, there have been at least 18 reports of familial recurrences of this condition with varying degrees of relatedness between the affected persons.23,24 In only half of the cases, the affected individuals had involvement of the same anatomical region.24 Autosomal dominant inheritance is supported in some families. For example, Pauli et al.23 reported father-to-son transmission of digital absence involving the left hand. Graham et al.25 reported a family in which unilateral adactylia with thumb hypoplasia occurred in the left hand of the proband, the right hand of her mother, and the left hand of the mother’s twin sister. Neumann et al.24 described a father with complete absence of metacarpals and digits on the left hand and his daughter with absence of fingers and a rudimentary thumb on the right hand.24 Recessive inheritance has

been proposed in two cases, including the report by Hecht and Scott.23,26 In most of the families, there is not a clear pattern of single gene transmission, leading to hypotheses of irregular autosomal dominant inheritance, multifactorial inheritance, or chance occurrence.23 Similarly, familial instances of limb deficiencies consistent with amniotic band sequence have also been reported.27,28 Such cases support the idea that genetic factors are involved in some cases of terminal limb deficiency. To determine whether inherited forms of thrombophilia may be associated with terminal limb reduction defects, Hunter29 tested 24 affected children and their mothers for a number of genetic predispositions to thrombosis. The author found a higher frequency of anticardiolipin IgG in the mothers, and a higher frequency of protein S deficiency in both the mothers and affected children relative to the general population.29 A variety of other abnormalities, including the Factor V Leiden mutation and the Prothrombin G20210A and methylene tetrahydrofolate reductase (MTHFR) C677T variants were observed in some of the children and their mothers.29 The results suggested that thrombophilia may contribute to a subset of terminal limb deficiencies.29 Acheiropody (acheiropodia) denotes absence of the hands and feet in which the limbs end in stumps. This occurs as an autosomal recessive disorder, primarily in Brazil, in association with absence of the forearm, elbow joint, fibula, and distal tibia.30 Recent discovery of the responsible gene has provided molecular insight into terminal limb deficiency. The condition is caused by partial deletion of the gene LMBR1 (also called C7orf2) on chromosome 7q36.31 This gene may be involved in regulating the expression of sonic hedgehog (SHH ) in the developing limb.31 Many studies of limb reduction defects have determined the prevalence of terminal transverse deficiency. Birch-Jensen18 found a birth prevalence of 1 in 65,000 for acheiria, 1 in 90,000 for aphalangia and adactylia, 1 in 22,000 for amputation of the forearm, and 1 in 270,000 for amputation of the upper arm in a Danish population. In Hungary, Czeizel et al.2 found a birth prevalence of 1.4/10,000 for terminal transverse deficiency, ranging from aphalangy to amelia; the birth prevalence was 1.19/1000 when only single limbs were involved. Froster-Iskenius and Baird32 found an incidence of 1.8/10,000 among over 1 million livebirths in British Columbia from 1952 to 1984. They classified defects as transverse only if they involved the entire width of the limb. The incidence of terminal longitudinal deficiencies, which included some cases of adactylia and aphalangia, was 3.3/10,000.32 Czeizel et al.33 found a birth prevalence of 0.085/1000 for isolated amniogenic limb deficiency in Hungary. Froster and Baird34 found a birth incidence of 0.19/10,000 for limb deficiency associated with amniotic band sequence. McGuirk et al.35 found a prevalence of 0.22/1000 for limb defects attributed to vascular disruption. Split-Hand/Foot Malformation

Split-hand/foot malformation (SHFM), often called ‘‘ectrodactyly,’’ is underdevelopment or absence of the central phalanges, metacarpal, and metatarsal bones associated with median clefts of the hands and feet. It comprises a highly variable spectrum of malformations that occur in both sporadic and familial forms. SHFM typically presents with hypoplasia or aplasia of one or more central digital rays (rays 2–4), accompanied by median clefts of the hands and/or feet and syndactyly of the remaining digits (Figs. 2132 and 21-33).1,36 This appearance has been called a ‘‘lobster-claw’’ or ‘‘ostrich foot’’ deformity. Shortening of one or more central digits represents the mildest end of the SHFM spectrum, while the presence of a single digital ray (monodactyly) represents the most

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severe end (Fig. 21-33).1,36 The malformation may be symmetric or asymmetric and can affect one or both hands, one or both feet, or the hands and feet together. The variability of the malformation is striking, even among the limbs of a given individual (Fig. 21-33). Other hand or foot abnormalities, such as preaxial polydactyly, triphalangeal thumb, brachydactyly, and nail hypoplasia, can accompany SHFM.1,37,38 Radiographs demonstrate varying degrees of digital, metacarpal, and metatarsal underdevelopment (Fig. 21-32, middle). The carpal or tarsal bones may also be abnormal. In some cases, all components of one or more rays are absent; in other cases, digits are completely or partially absent with normal proximal bony elements. Radiographs in these cases can show unusual articulations of remaining phalanges with neighboring bones.

Fig. 21-32. Typical split-hand/foot malformation with absence of central digital rays, median clefts of the hands and feet, and syndactyly of the remaining digits, in two different individuals.

Fig. 21-33. Clinical variability of split-hand/foot malformation. The severity of the malformation ranges from the classic appearance (top) to monodactyly (middle) to mild hypoplasia of a central digit (bottom). Note the variability of the phenotype within the limbs of a given individual (top and middle). The foot photograph (bottom) is from the individual whose hands are shown in Figure 21-32.

SHFM has been divided into typical and atypical forms as reviewed by Temtamy and McKusick1 and Czeizel et al.36 Typical SHFM has a classic appearance, involves multiple limbs, and has a clear-cut genetic basis. Atypical SHFM is unilateral, isolated, and sporadic. This form almost always involves the hands, and hypoplasia of the marginal digital rays is a characteristic feature (Fig. 21-34). However, the significant clinical variability of SHFM can make it difficult to distinguish typical from atypical forms in sporadic cases. SHFM occurs either as an isolated skeletal malformation (nonsyndromic SHFM) or in association with other extraskeletal

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Fig. 21-34. Atypical split-hand malformation. Note unilateral occurrence, lack of classic appearance, and underdevelopment of marginal digits.

findings (syndromic SHFM). Nonsyndromic SHFM has been divided into two subtypes, depending upon whether the malformations are limited to the hands and feet (type I), or whether other limb abnormalities are present (type II).39 The latter subtype includes underdevelopment or absence of the tibia, fibula, femur, radius, or ulna.39–43 The tibia is most often involved.39 Various forms of this condition have been described, including tibial aplasia with ectrodactyly and fibular aplasia with ectrodactyly, but it is not clear whether these and other conditions featuring SHFM and long bone deficiency are genetically distinct entities. Preaxial polydactyly of the hands, hypoplastic or absent hallux, aplastic patellae, and absence of an entire limb are often seen with SHFM and long bone deficiency.40–42 Distal bifurcation of the femur also occurs with SHFM in association with tibial aplasia and in the Gollop-Wolfgang complex, which are most likely related entities.44 Czeizel et al.36 studied the characteristics of isolated SHFM in the Hungarian population and found that 54 of 94 total cases (58%) were isolated. One limb was affected in 42 (78%) of the isolated cases, with 40 of these involving the upper limbs. The authors observed a 1.67:1 ratio of males to females and a 2:1 ratio of right-sided to left-sided involvement among the 54 isolated cases. When the cases were divided into typical (39%) and atypical (61%) forms, there was a right sided excess only in typical cases. Of the typical cases, 57% involved more than one limb and 85% were male.

A number of malformations and syndromes are associated with SHFM (Table 21-13). As with isolated SHFM, the syndromic conditions are often variable. The most common syndromic form of SHFM is the EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome, which includes ectodermal abnormalities (dry skin, abnormal teeth, thin hair and nails, lacrimal duct stenosis, and hypoplastic nipples) and cleft lip/palate.45–48 Several other conditions with SHFM or other limb anomalies, including limb-mammary syndrome, acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome, and lacrimo-auriculo-dento-digital (LADD) syndrome, overlap significantly with the EEC syndrome.49 Other conditions, such as the Hay-Wells and Rapp-Hodgkin syndromes, feature ectodermal dysplasia and clefting without limb anomalies.49 Splitfoot malformation with mandibulofacial dysostosis occurs in the Patterson-Stevenson-Fontaine syndrome.50 SHFM with congenital nystagmus occurs in Karsch-Neugebauer syndrome.51 SHFM is also a feature of the EEM (ectrodactyly-ectodermal dysplasiamacular dystrophy) and HHE (holoprosencephaly-hypertelorismectrodactyly) syndromes.52,53 SHFM is also associated with sensorineural hearing loss as an autosomal dominant trait.54 Duijf et al.55 provided a summary of these and other syndromes associated with SHFM. The central rays can also be deficient from various forms of vascular disruption, and are preferentially affected in CVS-related limb defects and amniotic band sequence.15,33 Not surprisingly, Evans et al.3 found a significant association of central ray deficiency with ectodermal abnormalities. The authors also found an association with tongue anomalies (in cases of oral-facial-digital syndrome type I or Hanhart anomaly) and hydronephrosis.3 Rosano et al.4 found an association between SHFM and encephalocele. Both nonsyndromic and syndromic forms of SHFM are most commonly inherited in an autosomal dominant fashion.1 Autosomal recessive inheritance has been described or suggested in some kindreds.56–58 X-linked inheritance was demonstrated in one family.59 SHFM in association with tibial aplasia and other long bone deficiencies is also typically an autosomal dominant trait,39–43 although autosomal recessive inheritance has also been hypothesized.60–62 Familial SHFM is often characterized by irregularities in inheritance, including reduced penetrance, appearance of the trait in remotely related persons within the same pedigree, and segregation distortion, in which there is increased transmission of SHFM from affected males to their sons.1,39,63,64 Irregular inheritance is frequently seen in the context of associated long bone deficiency. Zlotogora39 calculated a penetrance of 96% for isolated SHFM (type I) and 66% for SHFM associated with other limb anomalies (type II). SHFM occurs naturally in some animals,1,55 and a mouse mutant called Dactylaplasia (Dac) has made it possible to study the embryology and pathogenesis of SHFM in detail.65–68 The mouse phenotype bears striking similarity to typical human SHFM, with absence of central digits, underdevelopment or absence of metacarpal/metatarsal bones, and syndactyly.67,68 Dac is inherited as an autosomal semidominant trait, with the more severe phenotype (i.e., monodactyly) occurring in homozygotes.67,68 Studies of the developing limbs in these mice have demonstrated abnormalities affecting the apical ectodermal ridge (AER).65,66 The current model thus holds that human SHFM results from a failure to maintain the normal AER in the central region of the developing limb bud.55 Multiple gene loci causing SHFM have been identified, reflecting its genetic heterogeneity. Mapping of SHFM genes has been achieved through studies of chromosome rearrangements in both sporadic and familial SHFM cases and through linkage

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studies of large kindreds. Established loci include SHFM145,54 on chromosome 7q21-q22, SHFM269 on Xq26, SHFM370,71 on 10q24, SHFM472,73 on 3q27, and SHFM574 on 2q31. A locus on chromosome 6q has also been suggested by chromosome rearrangements in several patients with syndromic SHFM.75 Although tibial deficiency has occurred with some cases of SHFM mapping to the above loci, a major gene locus for SHFM and long bone deficiency has not yet been identified. The gene TP63 at the SHFM4 locus is the only causative gene for human SHFM thus far identified.55 TP63 encodes a transcription factor involved in the development of limbs, craniofacial structures, and epidermal derivatives.49,72,73 The protein contains transactivating (TA), DNA binding, and tetramerization domains, as well as a sterile alpha motif (SAM) that mediates protein– protein interactions. TP63 mutations cause the vast majority EEC syndrome cases but only a minority of nonsyndromic SHFM cases.49,55,71,72,76 Mutations in this gene also cause a number of related conditions, including the limb-mammary, ADULT, and Hay-Wells syndromes.49,55 Studies have demonstrated a significant genotype-phenotype correlation; most EEC and SHFM mutations affect the DNA-binding, while those causing Hay-Wells syndrome affect the SAM domain.49,55 The form of SHFM mapping to the SHFM3 locus on chromosome 10q24 is nonsyndromic but can be associated with triphalangeal thumb. The Dac phenotype is considered to be the mouse model of this condition, because the causative gene for Dac maps to the syntenic region of mouse chromosome 19.68 The Dac phenotype is thought to result from two different rearrangements that disrupt the Dactylin (Dac) gene.68 Dac is a novel member of the F-box WD-40 gene family, whose members encode subunits of ubiquitin ligases that present phosphorylated protein targets to ubiquitin-containing enzymes for degradation.68 Since the AER degenerates during limb development in Dac mice, it has been proposed that dactylin normally promotes polyubiquitination and destruction of a suppressor of AER proliferation.68 Hence, impaired dactylin function would lead to persistence of the suppressor and failure to maintain the AER.68 The human homologue, DACTYLIN (DAC) (also called SHFM3), has been mapped to the SHFM3 critical region and is the leading candidate gene for human SHFM at this locus. To date, mutations in DAC have yet to be identified in sporadic SHFM patients or families whose phenotype maps to the SHFM3 locus. However, large recurrent tandem duplications affecting the SHFM3 locus were recently identified in multiple families whose SHFM3 maps to this region.77 The smallest common duplication contains part of DAC and several other genes, but how the rearrangements cause limb abnormalities is not clear at the present time.77 The SHFM1 locus was identified through studies of patients with chromosome rearrangements and balanced translocations affecting the 7q21-q22 region.45,55 Both isolated and syndromic forms of SHFM have been associated with this locus.45 SHFM with sensorineural hearing loss has also been mapped to this region in two families by linkage studies.54 Three candidate genes (DSS1, DLX5, and DLX6) reside in the critical interval, but mutations in these genes have not been identified in SHFM patients, and none is consistently disrupted by translocations.55 Mice in which both Dlx5 and Dlx6 are knocked out have SHFM, craniofacial defects, and inner ear malformations, suggesting that loss of expression of both genes may cause human SHFM phenotypes.55 Hence, abnormalities at the SHFM1 locus may lead to SHFM through a position effect mechanism on the expression of both DLX5 and DLX6.

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Causative genes have not been identified at the SHFM2 and SHFM5 loci. The SNX3 gene was found to be disrupted in a patient with a rare SHFM phenotype known as MMEP (microcephalymicrophthalmia-ectrodactyly-prognathism) syndrome and a balanced chromosome translocation.75 Birch-Jensen18 found an incidence of about 1 in 90,000 for typical split-hand and 1 in 150,000 for atypical split-hand. Czeizel et al.36 identified 94 cases of SHFM among over 1.5 million births in Hungary, for a birth prevalence of 0.6/10,000. Froster-Iskenius and Baird32 found an incidence of 0.9/10,000 for central ray defects among over 1.2 million consecutive livebirths in British Columbia. Preaxial Deficiency

Preaxial deficiency is underdevelopment or absence of the radial or tibial rays. Preaxial deficiencies of the upper limbs involve the thumb, thenar muscles, first metacarpal bone, radial carpal bones (scaphoid and trapezium), and radius to varying degrees. As summarized by De Smet et al.,78 different classifications of thumb hypoplasia and radial dysplasia have been used. Temtamy and McKusick1 and Czeizel et al.79 discussed the range of abnormalities that occur in preaxial deficiency (Fig. 21-35). At the mildest end of the spectrum, there is hypoplasia of the thenar muscles, thumb phalanges, or first metacarpal bone. In more pronounced cases, the first metacarpal is absent and there is a small thumb attached to the index finger by soft tissue (floating thumb). With increasing severity, there is complete absence of the thumb and first metacarpal combined with radial hypoplasia or absence. In some cases, there is an intercalary deficiency of the radius with a clubhand deviated to the radial side of the wrist. In the most severe form, there is pronounced shortening of the forearm, giving the appearance of a seal limb (‘‘phocomelia’’).1 Other fingers may be underdeveloped or webbed, and radioulnar synostosis can occur.1 Radiographs demonstrate varying degrees of hypoplasia or aplasia of thumb phalanges, the first metacarpal, and the radius. Fused, underdeveloped, or absent carpal bones, particularly the scaphoid and trapezium, are found in some cases. Preaxial deficiencies of the lower limbs involve the hallux, first metatarsal bone, tarsal bones, and tibia to varying degrees, and are collectively known as tibial hemimelias.42 The clinical findings range from a short or absent hallux to complete absence of the tibia, first metatarsal, and hallux with a bowed leg, dislocated knee, and clubfoot. Syndactyly of the hallux and second toe may occur.44,80 Radiographs demonstrate variable hypoplasia or aplasia of the hallucal phalanges, the first metatarsal, and the tibia. Absence or fusion of tarsal bones can be seen. Czeizel et al.79 studied a group of patients with congenital radial and tibial deficiencies. Of 131 cases ascertained in their population study in Hungary, 40 (30%) were isolated.79 They found that 25 cases involved a single upper limb, 11 involved both upper limbs, 1 involved a single lower limb, 1 involved a single upper and lower limb, and 2 involved all of the limbs.79 Hence, upper limb involvement was far more common, and in the unilateral cases the right side was affected four times as often.79 Radial and tibial deficiencies rarely occur together.1 As noted above, there is a high rate of associated malformations with radial and tibial deficiencies, particularly because these abnormalities occur in a variety of syndromes (Table 21-13).79 Important causes of radial ray deficiency are the Fanconi pancytopenia and Holt-Oram syndromes, VACTERL association, and trisomy 18.1 Prenatal thalidomide and valproic acid exposure are associated with preaxial deficiencies.10 Evans et al.3 found different patterns of anomalies associated with unilateral versus bilateral

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and great toes occurs with Mullerian duct and urinary tract malformations in the hand-foot-genital syndrome.81 Isolated preaxial deficiencies appear to be multifactorial in origin.1 In the series of Czeizel et al.,79 most cases were radial ray deficiencies that occurred sporadically. Van Allen et al.82 reviewed the vascular development of the upper limbs and detected abnormal vascular anatomy in 12 fetuses with radial defects. The authors postulated that abnormal vascular development leads to radial ray defects in some cases.82 Lewin and Opitz hypothesized that there are distinct tibial and fibular developmental fields, with the tibial field represented by the distal femur, tibia, and hallux.83,84 Genetic factors clearly underlie some cases of isolated radial ray deficiency, because autosomal dominant inheritance with reduced penetrance and variable clinical expression have been reported in some families (Fig 21-35).1,79 X-linked recessive transmission of radial ray deficiency has also been described.85 Molecular discoveries, such as the finding of mutations affecting HOXA13 in the hand-foot-genital syndrome81 and TBX5 in the Holt-Oram syndrome,86 have made it clear that specific genes are critical to the normal development of the radial and tibial rays. The incidence of preaxial deficiency was 0.8/10,000 births in Hungary.79 Froster-Iskenius and Baird found an incidence of 0.8/ 10,000 livebirths for preaxial hand defects and 0.1/10,000 livebirths for preaxial foot defects in British Columbia.32 Postaxial Deficiency

Fig. 21-35. Preaxial deficiency. Variability in this malformation includes absence of the thumb (top), absence of the thumb and index finger with radial hypoplasia (middle), and mild thumb hypoplasia (bottom). The individual in the middle photo is the daughter of the individual in the bottom photo. (Top photo courtesy of Dr. R. Curtis Rogers, Greenwood Genetic Center, Greenwood, SC.)

involvement. Unilateral radial-tibial defects were associated with facial asymmetry, microtia, cervicothoracic and lumbosacral vertebral anomalies, sternal and rib anomalies, esophageal atresia, and bilateral renal agenesis. These findings reflected the association of radial deficiencies with Goldenhar syndrome and VACTERL association. Bilateral deficiencies were associated with esophageal atresia/tracheoesophageal fistula, VSD, ASD, and hydrocephalus. Rosano et al.4 found significant associations with esophageal atresia, anotia/microtia, other axial skeletal anomalies, unilateral renal dysgenesis, heart defects, and anorectal atresia. Tibial ray deficiencies are associated with split-hand/foot malformation in the tibial aplasia-ectrodactyly syndrome.40-42 Bifurcation of the distal femur occurs with tibial ray deficiency in the latter condition and in the Gollop-Wolfgang complex.44 Hypoplasia of the thumbs

Postaxial deficiency is the underdevelopment or absence of the ulnar or fibular rays. Postaxial deficiencies of the upper limbs involve one or more ulnar digital rays and/or the ulna to varying degrees. Different classifications of ulnar deficiency have been used.78 Temtamy and McKusick1 and Czeizel et al.87 discussed the variable findings that occur in postaxial deficiency (Fig. 21-36). The mildest end of the spectrum includes hypoplastic or aplastic ulnar digits, with or without involvement of the underlying metacarpals. More severe defects manifest with absent ulnar digital rays and partial or total absence of the ulna with radial curvature.1 In extreme cases, the ulna is absent, the radial head is dislocated, and there is humeroradial synostosis with flexion or extension at the elbow.1 The most severe form is ulnar phocomelia with pronounced shortening of the arm.1 Digital involvement may be limited to the 5th finger or may also involve the 4th and 3rd fingers. Radiographs demonstrate varying degrees of hypoplasia or aplasia of ulnar digital phalanges, their underlying metacarpals, and the ulna. Absence of the ulnar carpal bones (pisiform, hamate, triquetrum, and capitate) may be seen.1 Postaxial deficiencies of the lower limbs involve one or more fibular digital rays and/or the fibula to varying degrees. Lewin and Opitz83 provided an extensive review of fibular deficiencies (which they termed ‘‘fibular a/hypoplasia’’) and hypothesized the existence of a fibular developmental field that explains the observed patterns of deficiency. This proposed field includes the pubic portion of the pelvis, proximal femur, patella, anterior cruciate ligament, talus and cuboid bones, and second to fifth digital rays.83 Czeizel et al.87 described the range of findings observed in a series of patients with isolated fibular ray deficiencies. As with ulnar deficiencies, the mild end of the spectrum involves underdevelopment or absence of one or more fibular digits, with or without metatarsal involvement. More severe forms manifest as absence of one or more complete digital rays and fibular hypoplasia or aplasia. Lewin and Opitz83 reviewed eight case series of fibular a/hypoplasia from the orthopedic literature and noted that there is usually, though not always, a reduced number of toes.

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Fig. 21-36. Postaxial deficiency. Note bilateral absence of the 5th finger rays. (Courtesy of Dr. R. Curtis Rogers, Greenwood Genetic Center, Greenwood, SC.)

They also noted that anterior tibial bowing is usually present in unilateral fibular defects, while the legs are usually straight with bilateral defects.83 Radiographs demonstrate variable hypoplasia or aplasia of the lateral digital rays and fibula. Lewin and Opitz83 discussed the frequently associated findings of talocalcaneal fusion, absent cuboid, hypoplastic or absent patella, absent femoral condyles, and shortening of the femur. A well-known disorder in which ulnar and fibular ray deficiencies occur together is the femur-fibula-ulna (FFU) complex, which overlaps the condition known as proximal focal femoral deficiency.88 Temtamy and McKusick1 noted from their review of the literature that ulnar defects are usually sporadic and more commonly right-sided and unilateral. Czeizel et al.87 studied 114 cases of isolated ulnar and fibular deficiencies. They found 76 cases involving one limb (including 12 cases of the FFU complex), 26 cases involving two limbs, 10 cases involving three limbs, and 2 cases involving all four limbs. The most common clinical presentation was absence of the digital rays accompanied by partial or complete absence of the ulna or fibula. Upper and lower limbs were equally affected, with more frequent involvement on the right side. Males outnumbered females by almost 2.5:1. In their review of the literature on fibular a/hypoplasia, Lewin and Opitz83 concluded that the complete form is more common than the incomplete form, that unilateral involvement occurs 70% of the time, that the ratio of right-sided to left-sided involvement is 2:1, and that the condition may be slightly more common in males. Unlike preaxial deficiencies, postaxial deficiencies are uncommonly associated with non-limb abnormalities. Czeizel et al.87

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found that only 18% of cases of ulnar or fibular deficiencies coincided with other malformations. Evans et al.3 reviewed these cases and found no specific patterns of malformation. Rosano et al.4 found an association of postaxial defects with hypospadias. Some syndromes are associated with postaxial deficiencies (Table 21-13). In addition to the FFU complex, they include Cornelia de Lange syndrome (in which ulnar phocomelia may occur),1 ulnar aplasia-ectrodactyly,89 fibular aplasia-ectrodactyly,43 and postaxial acrofacial dysostosis. In the ulnar-mammary syndrome, variable postaxial deficiencies of the hands and feet are associated with hypoplasia of the apocrine glands, mammary glands, and nipples.90 In Weyer ulnar ray/oligodactyly syndrome, ulnar and radial ray deficiency are combined with midline defects, including single central maxillary incisor, hypotelorism, congenital heart disease, and urogenital anomalies.91 Lewin and Opitz83 emphasized that most cases of fibular a/hypoplasia are isolated, and reviewed known syndromes with this as a feature. When isolated, the vast majority of postaxial deficiencies are sporadic.1,83,87 Their etiology is largely unknown but appears to be heterogeneous and related to the final common pathways of specific ulnar and fibular developmental fields.83,87,92 In their series of cases with isolated postaxial deficiency, Czeizel et al.87 found only one familial recurrence in which two siblings had absent fifth rays of the left hand. Nonetheless, discovery of mutations in the gene TBX3 in the autosomal dominant ulnar-mammary syndrome indicate a critical role for a single gene in development of the postaxial rays.93 Wulfsberg et al.94 reported findings in a mother and three children with isolated postaxial oligodactyly involving all four limbs. The pedigree included at least ten other affected individuals in four generations and was compatible with autosomal dominant inheritance. It is not known whether this phenotype could be caused by a TBX3 mutation or perhaps another gene involved in the same developmental pathway. Morava et al.95 reported a threegeneration family with a variable phenotype consisting of postaxial deficiency in the upper and lower limbs, brachydactyly, and short stature. The pedigree was suggestive of autosomal dominant inheritance, and linkage of the phenotype to the ulnar-mammary syndrome locus was excluded.95 Czeizel et al.87 reviewed the prevalence of ulnar and fibular deficiencies, noting variation in rates between different countries from Europe and elsewhere. The rates ranged from 0.01/1,000 births in Denmark, England, Wales, and New Zealand to a rate of 0.072/1,000 for isolated postaxial defects in Hungary. The authors noted that the differences may be attributable to a combination of actual differences and technical factors related to ascertainment, diagnosis, and classification.87 Lewin and Opitz commented that fibular aplasia is the most common of the four types of hemimelia.83 Froster-Iskenius and Baird32 found an incidence of 0.5/10,000 livebirths for postaxial hand defects and 0.2/10,000 livebirths for postaxial foot defects in British Columbia. Prognosis, Prevention, and Treatment

The prognosis and management of the oligodactylies depend upon the nature and extent of the digital deficiency and the presence of associated abnormalities, such as syndactyly, deviation of the hand, and long bone anomalies.96 As with other congenital limb abnormalities, the major issues to consider are the function and appearance of the limbs, especially the hands. Surgery for upper limb oligodactyly involves a variety of procedures, including syndactyly release, creation of a normal first web space, excision of non-functional digital remnants, and digital reconstruction through phalangeal transfer, microvascular toe to hand transfer, or

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creation of a thumb (pollicization) from a normal finger.96,97 Surgery for lower limb oligodactyly is not typically necessary, unless there is an associated foot deviation or long bone deficiency. The use of prosthetic devices is helpful in certain situations, and some patients may require training in the use of a normal or more functional limb to compensate for deficiencies in other limbs.96 Psychological support is critical for children with limb deficiency and their families. Management of terminal transverse deficiencies proximal to the wrist is generally non-surgical.96 In contrast, digital absence or hypoplasia with intact carpal and metacarpal bones is amenable to treatment with digital transfer. Free phalangeal transfer involves the transfer of toe phalanges to the hand and must be done before 15 months of age.96 Microvascular toe transfer involves the transfer of one or more toes to the hand to correct transverse finger or thumb deficiency.96 This technique is generally used before age 1 year, and follow-up surgeries are often completed before school age.96 It cannot be used for longitudinal deficiencies or transverse deficiencies proximal to the distal carpus.96 The goal of both procedures is to improve or create a grasping (prehensile) function.96 Amniotic band disruption sequence may require correction of syndactyly, creation or revision of the 1st web space, and early release of constriction rings if they are causing distal edema and impaired circulation.96 Surgery for split-hand/foot malformation may be indicated in certain circumstances. For instance, removal of transversely oriented bones and syndactyly release may help to prevent progressive deformity or widening of the cleft.96 Procedures can also be used to narrow clefts within the hands.96 Surgery is not usually indicated for the feet unless there is difficulty fitting shoes or associated duplication or deviation of the border digits.96 Radial and ulnar deficiencies pose particular challenges because of associated hand and wrist deformity in severe cases. In this situation, the initial treatment focuses on stretching, splinting, and/or serial casting. This is followed by surgery to realign the hand and wrist and supplement deficient bone in the distal radius or ulna.96 When the thumb is absent, pollicization is indicated to create a functional thumb from the adjacent finger.97 This surgery should be delayed until at least 1 year of age.97 Prevention of oligodactylies relies primarily on reducing the chance of recurrence and detecting abnormalities prenatally. Some forms of digit deficiency, particularly those with long bone anomalies, are detectable by prenatal ultrasound.98,99 Accurate diagnosis and genetic counseling for affected individuals and their family members is critical to understanding and modifying potential recurrence risk in future children. Some studies show promising evidence that multivitamin supplements can reduce the occurrence of limb deficiencies by approximately 50%.100 It is hoped that improved understanding of the oligodactylies at the molecular and pathogenetic levels will lead to better preventive strategies in the future. References (The Oligodactylies) 1. Temtamy SA, McKusick VM: The genetics of hand malformations. BDOAS XIV(3):1, 1978. 2. Czeizel AE, Vitez M, Kodaj I, et al.: A morphological and family study on isolated terminal transverse type of congenital limb deficiency in Hungary, 1975–1984. Teratology 48:323, 1993. 3. Evans JA, Vitez M, Czeizel A: Congenital abnormalities associated with limb deficiency defects: a population study based on cases from the Hungarian Congenital Malformation Registry (1975–1984). Am J Med Genet 49:52, 1994. 4. Rosano A, Botto LD, Olney RS, et al.: Limb defects associated with major congenital anomalies: clinical and epidemiological study from

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the International Clearinghouse for Birth Defects Monitoring Systems. Am J Med Genet 93:110, 2000. Jones KL, Smith DW, Hall BD, et al.: A pattern of craniofacial and limb defects secondary to aberrant tissue bands. J Pediatr 84:90, 1974. Bouwes Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Moebius anomalies. Am J Med Genet 23:903, 1986. Robertson SP, Bankier A: Oromandibular limb hypogenesis complex (Hanhart syndrome): a severe adult phenotype. Am J Med Genet 83: 427, 1999. Kuster W, Lenz W, Kaariainen H, et al.: Congenital scalp defects with distal limb anomalies (Adams-Oliver syndrome): report of ten cases and review of the literature. Am J Med Genet 31:99, 1988. Chen CP: Severe terminal transverse limb reduction defects in homozygous Southeast-Asian alpha-thalassaemia-1. Clin Dysmorphol 10:71, 2001. Holmes LB: Teratogen-induced limb defects. Am J Med Genet 112:297, 2002. Hoyme HE, Jones KL, Dixon SD, et al: Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 85:743, 1990. Marles SL, Reed M, Evans JA: Humeroradial synostosis, ulnar aplasia and oligodactyly, with contralateral amelia, in a child with prenatal cocaine exposure. Am J Med Genet 116A:85, 2003. Froster UG, Baird PA. Congenital defects of the limbs and alcohol exposure in pregnancy: data from a population based study. Am J Med Genet 44:782, 1992. Sabry MA, Farag TI: Hand anomalies in fetal-hydantoin syndrome: from nail/phalangeal hypoplasia to unilateral acheiria. Am J Med Genet 62: 410, 1996. Golden CM, Ryan LM, Holmes LB: Chorionic villus sampling: a distinctive teratogenic effect on fingers? Birth Defects Research (Part A) 67:557, 2003. Olney RS, Khoury MJ, Alo CJ, et al.: Increased risk for transverse digital deficiency after chorionic villus sampling: results of the United States multistate case-control study, 1988-1992. Teratology 51:20, 1995. Czeizel A, Bod M, Lenz W: Family study of congenital limb reduction abnormalities in Hungary 1975–1977. Hum Genet 65:34, 1983. Birch-Jensen A. Congenital deformities of the upper extremities. Ejnar Munksgaard, Copenhagen, 1949. Hoyme HE, Jones KL, Van Allen MI, et al.: Vascular pathogenesis of transverse limb reduction defects. J Pediatr 101:839, 1982. Van Allen MI: Structural anomalies resulting from vascular disruption. Pediatr Clin North Am 39:255, 1992. Van Allen MI, Siegel-Bartelt J, Dixon J, et al.: Constriction bands and limb reduction defects in two newborns with fetal ultrasound evidence for vascular disruption. Am J Med Genet 44:598, 1992. Bamforth JS: Amniotic band sequence: Streeter’s hypothesis reexamined. Am J Med Genet 44:280, 1992. Pauli RM, Lebovitz RM, Meyer RD: Familial recurrence of terminal transverse defects of the arm. Clin Genet 27:555, 1985. Neumann L, Pelz J, Kunze J: Unilateral terminal aphalangia in father and daughter – exogenous or genetic cause? Am J Med Genet 78:366, 1998. Graham JM Jr, Brown FE, Struckmeyer CL, et al.: Dominantly inherited unilateral terminal transverse defects of the hand (adactylia) in twin sisters and one daughter. Pediatrics 78:1986, 103. Hecht JT, Scott CI Jr: Recurrent unilateral hand malformations in siblings. Clin Genet 20:225, 1981. Lubinsky M, Sujansky E, Sanger W, et al.: Familial amniotic bands. Am J Med Genet 14:81, 1983. Etches PC, Stewart AR, Ives EJ: Familial congenital amputations. J Pediatr 101:448, 1982. Hunter AGW: A pilot study of the possible role of familial defects in anticoagulation as a cause for terminal limb reduction malformations. Clin Genet 57:197, 2000. Freire-Maia A: Historical note: the extraordinary handless and footless families of Brazil—50 years of acheiropodia. Am J Med Genet 9:31, 1981. Ianakiev P, van Baren J, Daly MJ, et al.: Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene. Am J Hum Genet 68:38, 2001.

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59. Ahmad M, Abbas H, Haquie S, et al.: X-chromosomally inherited splithand/split-foot anomaly in a Pakistani kindred. Hum Genet 75:169, 1987. 60. Kohn G, El Shawwa R, Grunebaum M: Aplasia of the tibia with bifurcation of the femur and ectrodactyly: evidence for an autosomal recessive type. Am J Med Genet 33:172, 1989. 61. Zlotogora J, Nubani N: Is there an autosomal recessive form of the split hand and split foot malformation? J Med Genet 26:138, 1989. 62. Majewski F, Goecke T, Meinecke P: Ectrodactyly and absence (hypoplasia) of the tibia: are there dominant and recessive types? Am J Med Genet 63:185, 1996. 63. Jarvik GP, Patton MA, Homfray T, et al.: Non-Mendelian transmission in a human developmental disorder: split hand/split foot. Am J Hum Genet 55:710, 1994. 64. Ozen RS, Baysal BE, Devlin B, et al.: Fine mapping of the split-hand/ split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion. Am J Hum Genet 64:1646, 1999. 65. Seto ML, Nunes ME, Macarthur CA, et al.: Pathogenesis of ectrodactyly in the Dactylaplasia mouse: aberrant cell death of the apical ectodermal ridge. Teratology 56:262, 1997. 66. Crackower MA, Motoyama J, Tsui L-C: Defect in the maintenance of the apical ectodermal ridge in the Dactylaplasia mouse. Dev Biol 201:78, 1998. 67. Chai CK: Dactylaplasia in mice: a two-locus model for developmental anomalies. J Hered 72:234, 1981. 68. Sidow A, Bulotsky MS, Kerrebrock AW, et al.: A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant. Nat Genet 23:104, 1999. 69. Faiyaz ul Haque M, Uhlhaas S, Knapp M, et al.: Mapping of the gene for X-chromosomal split-hand/split-foot anomaly to Xq26-q26.1. Hum Genet 91:17, 1993. 70. Nunes ME, Schutt G, Kapur RP, et al.: A second autosomal split hand/ split foot locus maps to chromosome 10q24-q25. Hum Mol Genet 4:2165, 1995. 71. Gurrieri F, Prinos P, Tackels D, et al.: A split hand-split foot (SHFM3) gene is located at 10q24 ! 25. Am J Med Genet 62:427, 1996. 72. Celli J, Duijf P, Hamel BC, et al.: Heterozygous germline mutations in the p53 homolog P63 are the cause of EEC syndrome. Cell 99:143, 1999. 73. Ianakiev P, Kilpatrick MW, Toudjarska I, et al.: Split-hand/split-foot malformation is caused by mutations in the TP63 gene on 3q27. Am J Hum Genet 67:59, 2000. 74. Goodman FR, Majewski F, Collins AL, et al.: A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly. Am J Hum Genet 70:547, 2002. 75. Vervoot VS, Viljoen D, Smart R, et al.: Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype. J Med Genet 39:893, 2002. 76. De Mollerat XJ, Everman D, Clarkson K, et al.: TP63 mutations are not a major cause of non-syndromic SHFM. J Med Genet 40:55, 2003. 77. De Mollerat XJ, Gurrieri F, Morgan CT, et al.: A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24. Hum Molec Genet 12:1959, 2003. 78. De Smet L, Fabry G, Fryns JP: Radial ray deficiency and ulnar ray deficiency in two sibs. Genet Counsel 3:95, 1992. 79. Czeizel AE, Vitez M, Kodaj I, et al: A family study on isolated congenital radial and tibial deficiencies in Hungary, 1975–1984. Clin Genet 44:32, 1993. 80. Stevens CA, Moore CA: Tibial hemimelia in Langer-Giedion syndrome— possible gene location for tibial hemimelia at 8q. Am J Med Genet 85:409, 1999. 81. Mortlock DP, Innis JW: Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet 15:179, 1997. 82. Van Allen MI, Hoyme HE, Jones KL: Vascular pathogenesis of limb defects. I. Radial artery anatomy in radial aplasia. J Pediatr 101:832, 1982. 83. Lewin SO, Opitz JM: Fibular a/hypoplasia: review and documentation of the fibular developmental field. Am J Med Genet (Suppl 2):215, 1986.

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84. Pavano L, Viljoen D, Ardito S, et al.: Two rare developmental defects of the lower limbs with confirmation of the Lewin and Opitz hypothesis on the fibular and tibial developmental fields. Am J Med Genet 33:161, 1989. 85. Galjaard RJH, Kostakoglu N, Hoogeboom JJM, et al.: X-linked recessive inheritance of radial ray deficiencies in a family with four affected males. Eur J Hum Genet 9:653, 2001. 86. Basson CT, Bachinsky DR, Lin RC, et al.: Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15:30, 1997. 87. Czeizel AE, Vitez M, Kodaj I, et al.: Causal study of isolated ulnar-fibular deficiency in Hungary, 1975–1984. Am J Med Genet 46:427, 1993. 88. Lenz W, Zygulska M, Horst J: FFU complex: an analysis of 491 cases. Hum Genet 91:347, 1993. 89. van den Berghe H, Dequeker J, Fryns JP, et al.: Familial occurrence of severe ulnar aplasia and lobster claw feet: a new syndrome. Hum Genet 42:109, 1978. 90. Schinzel A: Ulnar-mammary syndrome. J Med Genet 24:778, 1987. 91. Turnpenny PD, Dean JCS, Duffty P, et al.: Weyer’s ulnar ray/ oligodactyly syndrome and the association of midline malformations with ulnar ray defects. J Med Genet 29:659, 1992. 92. Richieri-Costa A, Opitz JM: Ulnar ray a/hypoplasia: evidence for a developmental field defect on the basis of genetic heterogeneity. Report of three Brazilian families. Am J Med Genet (Suppl 2):195, 1986. 93. Bamshad M, Lin RC, Law DJ, et al.: Mutations in human TBX3 alter limb, apocrine, and genital development in ulnar-mammary syndrome. Nat Genet 16:311, 1997. 94. Wulfsberg EA, Mirkinson LJ, Meister SJ: Autosomal dominant tetramelic postaxial oligodactyly. Am J Med Genet 46:579, 1993. 95. Morava E, Czako M, Karteszi J, et al.: Ulnar/fibular ray defect and brachydactyly in a family: a possible new autosomal dominant syndrome. Clin Dysmorphol 12:161, 2003. 96. Ezaki M, Kay SPJ, Light TR, et al.: Congenital Hand Deformities. In: Green’s Operative Hand Surgery, ed 4. Green DP, Hotchkiss RN, Pederson WC, eds. Churchill Livingstone, London, 1999, p 325. 97. Kleinman WB, Strickland JW: Thumb reconstruction. In: Green’s Operative Hand Surgery, ed 4. Green DP, Hotchkiss RN, Pederson WC, eds. Churchill Livingstone, London, 1999, p 2068. 98. Makhoul IR, Goldstein I, Smolkin T, et al.: Congenital limb deficiencies in newborn infants: prevalence, characteristics, and prenatal diagnosis. Prenat Diagn 23:198, 2003. 99. Kevern L, Warwick D, Wellesley D, et al.: Prenatal ultrasound: detection and diagnosis of limb abnormalities. J Pediatr Orthop 23:251, 2003. 100. Botto LD, Olney RS, Erickson JD: Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet 125C:12, 2004. 101. Online Mendelian Inheritance in Man. Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for

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22 Skeletal Dysplasias Ju¨rgen Spranger

T

he skeletal dysplasias are a heterogeneous group of heritable disorders with disturbance of the growth, density, and organization of cartilage and bone. In many cases, molecular defects causing dysplasias are prenatally expressed causing neonatally recognizable disorders. Other defects manifest only in early childhood or even later. However, all defects causing bone dysplasias continue to affect skeletal growth and development postnatally. In that respect they differ from dysostoses, i.e., malformations of single bones, alone or in combination, which are caused by spatiotemporally limited disturbances during early embryogenesis. In some disorders, the molecular defects are expressed during early embryogenesis and in later life resulting in disorders that combine malformative and dysplastic bone changes. Examples of such ‘‘dysosto-dysplasias’’ are cleidocranial dysostosis, fibrodysplasia ossificans, and the Ellis-van Creveld syndrome. The differentiation between dysostoses and dysplasias is not only of theoretical interest but may have therapeutic significance in the future. For dysostoses, such as ectrodactyly or hemivertebrae, the time window to correct the causative process is limited to a few weeks after conception; whereas dysplasias such as Morquio disease or multiple epiphyseal dysplasia can be influenced until the end of the postnatal growth period. The large number of genes involved in the development of the skeleton explains the multitude of chondroosseous dysplasias. Their diversity is accentuated by allelic mutations of each of these genes, which disturb their expression in many ways. Often, a common phenotypic pattern can be recognized in families of pathogenetically related disorders, such as the type 2 collagenopathies. Different mutations of the same gene result in phenotypically divergent disorders such as Jansen metaphyseal dysplasia and Blomstrand dysplasia. Some disorders, such as dyschondrosteosis, may be heterozygous manifestations of more severe diseases, e.g., Langer mesomelic dysplasia. The same is true for minor anomalies such as brachydactyly C, the heterozygous manifestation of Grebe dysplasia. Numerous classification systems have been devised, including grouping the dysplasias according to age of usual recognition, natural history, portion(s) of body affected, histology, and inheritance. Based on the growing knowledge about the molecular basis of skeletal development and its disruptions, causally oriented classifications have evolved.1,2 Whereas these classifications

are intellectually more satisfying, they are by necessity incomplete as long as the molecular basis of all clinically recognizable disorders is not known. Also, the widely variable expression of single gene defects limits the clinical usefulness of strictly causal classifications. For clinical use, the classification of the International Working Group on Constitutional Disorders of Bone is preferred.3 It groups skeletal disorders with similar morphologic patterns, i.e., with similar deviations of form and/or structure of the skeleton. Recognition of these patterns assists the diagnostic process by eliminating large numbers of diagnostically less probable disorders. Since patterns of abnormal skeletal form and/or structure often reflect common pathogenic mechanisms, the classification proposed in this book incorporates both morphologic and pathogenic concepts. Prevalence

Population-based prevalence data are available for neonatally manifesting skeletal dysplasias. The figures given in Table 22-1 are minimal values because an unknown proportion of cases is not recognized at birth or has been lost during pregnancy. Skeletal dysplasias manifesting after birth are not systematically registered and there are no reliable prevalence figures. Based on the data given in Table 22-1, the overall prevalence of skeletal dysplasias is at least 2/10,000. In countries with an inbred high-risk population, this ratio can rise to 9.4/10,000.10 Etiopathogenesis

Skeletal development starts with pattern formation, the determination of cells according to a plan delineating size and shape of the cartilaginous template.1 This plan becomes evident with the migration of predetermined mesenchymal precursor cells to and their condensation in the sites of skeletogenesis (Fig. 22-1). Errors of patterning usually lead to dysostoses such as spondylocostal dysostosis, synpolydactyly, or nail-patella syndrome. The next step in skeletal development is the proliferation of precursor mesenchymal cells, their differentiation into chondrocytes in areas of endochondral bone formation or into osteoblasts in regions of membranous bone formation. Campomelic dysplasia results from an error of chondrocyte differentiation and cleidocranial dysplasia from an error of osteoblast differentiation. Apoptosis is part of this early stage of skeletal development, and 997

998

Skeletal System Table 22-1. Estimated prevalence of the most common skeletal dysplasias* Skeletal Dysplasia

Prevalence

Stickler syndrome

1:15,000

Osteogenesis imperfecta

1:27,000

Mucopolysaccharidoses

1:30,000

Achondroplasia

1:36,000

Hypochondroplasia

1:50,000

Multiple epiphyseal dysplasia

1:50,000

Thanatophoric dysplasia

1:60,000

Dyschondrosteosis

1:100,000

Chondrodysplasia punctata

1:128,000

Asphyxiating thoracic dysplasia

1:190,000

Campomelic dysplasia

1:212,000

Diastrophic dysplasia

1:270,000

Achondrogenesis

1:322,000

Cleidocranial dysplasia

1:320,000

Ellis-van Creveld syndrome

1:333,000

Spondyloepiphyseal dysplasia congenita

1:660,000

Short-rib/polydactyly syndromes

1:660,000

Others

1:25,000

Minimal overall prevalence of skeletal dysplasias 1:5000 *Estimates from Orioli et al.,4 Taybi and Lackman,5 Cobben et al.,6 Stoll et al.,7 Connor et al.,8 and Kallen et al.9

mutations of genes affecting apoptosis may result in dysplasias such as the multiple synostosis syndrome.18 A third step in skeletal development comprises growthrelated factors. To a minor degree, growth occurs through the proliferation of mesenchymal cells and their direct transformation to osteoblasts. This so-called ‘‘desmal ossification’’ is limited to the base of the skull, clavicles, and the periosteal bone formation. Most of the skeleton is formed by enchondral bone formation, in which a cartilage template is replaced by bone. Central to this process is the growth plate in which chondrocytes proliferate in perpendicular columns, hypertrophy, degenerate, and are replaced

Fig. 22-1. Stages of skeletal development and stage-related diseases.

by osteoblasts (Fig. 22-2). Differentiation of precursor cells into osteoblasts and osteoclasts continues throughout life. Defects in this stage result from disturbances of cell proliferation/degeneration due to defective signaling pathways or due to disturbances of cell function. Achondroplasia is an example of disease due to disturbed cell proliferation; spondyloepiphyseal dysplasia congenita is an example of a disease caused by defective cell function. The final step has to do with homeostasis, the lifelong restructuring of bone by a balanced process of resorption and accretion of osseous tissue. Bone mass reaches its maximum during early adulthood and is subject to numerous intrinsic and extrinsic factors. A balanced equilibrium between osteoblast and osteoclast activity is required to adapt bone mass and bone structure to changing mechanical and metabolic needs. Hereditary defects of osteoblast and osteoclast function lead to skeletal dysplasias characterized by deficient or excessive bone mass, such as osteogenesis imperfecta and various forms of osteopetrosis. With the rapidly increasing knowledge about gene function, a molecular/pathogenetic nosology of skeletal dysplasias has been produced2 classifying disorders in categories similar to those used for classification of proteins in Saccharomyces cerevisiae and Caenorhabditis elegans, adapted to disease-related human genes.11 Examples of pathogenetic pathways and associated bone dysplasia families are presented in Figures 22-3 through 22-5. Prenatal Diagnosis

Prenatally, a skeletal dysplasia is usually first suspected when ultrasound scanning at 18–22 weeks gestation shows abnormally short limbs. Other suggestive signs are long bone angulation, narrow thorax due to short ribs, polydactyly, mineralization, nasal hypoplasia, nuchal swelling, altered bone echo density, and other abnormalities found in a few specific disorders. Sonographic measuring technique, normal values, and diagnostic signs have been published.15 Although even in experienced hands a specific diagnosis is reached in only 31–65% of cases, correct prognostication,

Fig. 22-2. Chondrocyte proliferation and bone formation in the growth plate; selection of expressed genes and examples of locally expressed genes and related diseases. COL2A1, type 2 collagen a1; SOX 9, sex determining region Y-box 9; PTHR1, parathyroid hormone receptor; FGFR 3, fibroblast growth factor receptor 3; COL10A, type 10 collagen a1; IHH, Indian hedge hog; VEG, vascular epithelial growth factor; MMP13, matrix metalloproteinase 13 (collagenase); COL1A1, type 1 collagen a1.

Skeletal Dysplasias

Fig. 22-3. Scheme showing the FGFR3-related signaling pathways, consequences of FGRF3 mutations, and therapeutic targets. The receptor is activated by ligand-induced dimerization leading to autophosphorylation of tyrosin residues in its intracellular portion. Phosphorylated tyrosin residues are binding sites for signal transduction molecules that initiate the STAT and the MAP-kinase signaling pathways. Activation of the STAT signaling pathway suppresses the proliferation and differentiation of chondrocytes in the growth plate. Activation of the MAPK pathway reduces the production of extracellular matrix. Mutations in achondroplasia and related conditions result in a constitutive, ligandindependent dimerization and activation of the signaling pathways. The mutations also disrupt c-cbl mediated ubiquination of the receptors impairing their targeting for lysosomal degradation, resulting in an

Fig. 22-4. Mutations in various parts of the FGFR3 gene and resulting disorders. HCH, hypochondroplasia; ACH, achondroplasia; TD1/TD2, thanatophoric dysplasia type I/type II; PLSD-SD, platyspondylic lethal dysplasia, San Diego type; SADDAN, severe achondroplasia, developmental delay, acanthosis nigricans; CAN, Crouzon syndrome with acanthosis nigricans; CCS, coronal craniosynostosis (Muenke syndrome); CATSHL, congenital anomalies, tall stature, hearing loss. (Courtesy of B. Zabel, Mainz, Germany.)

999

increased signaling capacity. The overall result of the mutations is the excessively suppressed proliferation, differentiation, and function of chondrocytes in the growth plates characterizing achondroplasia and other FGFR3-related disorders. Speculative target sites of therapeutic intervention: (1) Inhibition of ligand-associated receptor activation by ligand antagonists or neutralizing antibodies; (2) Inhibition of dimerization by specific receptor antibodies; (3) Suppression of autophosphorylation by tyrosine kinase inhibitors; (4) Modulation of signal transduction by specific inhibitors or alternative pathways; (5) Suppression of FGFR3 expression; (6) Inhibition of the MAP-kinase pathway by natriuretic peptide C (CNP) activating a guanylyl-cyclase (GC-B) to provide messenger cyclic guanine monophosphate (cGMP). (Courtesy of B. Zabel, Mainz, Germany.)

the main goal of prenatal diagnosis, can be achieved in nearly all instances.16,17 Sonographic findings suggesting a poor prognosis include polyhydramnios, hydrops, and narrow chest. Three-dimensional ultrasound imaging18 and transvaginal sonography19 allow for earlier and more refined diagnosis. If a living family member is affected by a disorder with a known molecular defect, prenatal diagnosis can be achieved by specific molecular or metabolic tests in cultured amnion cells or in material from a chorion biopsy. Skeletal dysplasias that are manifesting at birth and can be detected prenatally are listed in Table 22-2. If detected, differentiation between lethal, severe, and moderately severe or mild conditions is required. Postnatal Diagnosis and Care

The clinician has immediate and long-term responsibilities in the care of the child with a skeletal dysplasia. In order to provide accurate prognostic and genetic counsel, a specific diagnosis must be made whenever possible. Only with a firm diagnosis can attention be directed at the prevention and treatment of long-term complications that accompany many of the skeletal dysplasias. The future psychomotor and intellectual development and, in particular, the prospective height is of great concern to the parents, who will have to adapt to the special appearance, function, and needs of their child.

1000

Skeletal System

developmentally homologous sites such as epiphyses, metaphyses, and membranous bones throughout the skeleton. Others affect predominantly single sites such as the spine, or the middle or distal segments of the limbs. Atlases and computer programs are available for diagnostic help.20,21 The classification of skeletal dysplasias used in this book modifies the classification of the International Working Group on Constitutional Disorders of Bone by grouping etiologically and pathogenetically related disorders, reducing the number of groups while maintaining the morphologically oriented radiodiagnostic approach (Table 22-3). References Fig. 22-5. Regulatory pathways in endochondral bone formation and their mutation-induced disorders. Left side: Indian hedgehog (IHH), expressed in distal prehypertrophic and proximal hypertrophic chondrocytes, regulates the site of hypertrophic differentiation. It induces parathyroid hormone related peptide (PTHrP) which is bound to the PTHrP-receptor (PTHrP-R). This receptor is expressed in the distal proliferating and proximal prehypertrophic chondrocytes, proximal to IHH. It suppresses hypertrophic maturation, thus forming a feedback loop regulating the rate of chondrocyte differentiation. Right side: Bone morphogenic proteins (BMP) promote the proliferation of chondrocytes, increase the domain of IHH expression, and delay the maturation of differentiated hypertrophic chondrocytes. Alternatively, IHH signaling up-regulates BMP2 and BMP4 in the growth plate. The net effect of this signaling loop is to promote chondrogenesis. The fibroblast growth factor receptors (FGFRs) are activated by fibroblast growth factors (FGF18 and others). FGFR3 is expressed in proliferating chondrocytes, FGFR1 in prehypertrophic and hypertrophic chondrocytes, and FGFR2 in developing endochondral bone, osteoblasts, and periosteal cells. Activation of FGFR3 limits chondrocyte proliferation and differentiation by direct signaling and by down-regulating the expression of the IHH/PTHrP/BMP signaling pathways. (1) Achondroplasia group, (2) Pfeiffer syndrome, other craniosynostosis syndromes, (3) Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, other craniosynostosis syndromes, (4) Acrocapitofemoral dysplasia, brachydactyly A1, (5) Blomstrand syndrome, Jansen metaphyseal dysplasia.

In most cases, the diagnosis can be reached from an analysis of clinical and radiographic findings. In doubtful cases, the diagnosis can be confirmed or ruled out by metabolic and molecular studies. Clinically, most skeletal dysplasias result in dwarfism with disproportionate shortness of body segments. The recognition of associated features is diagnostically helpful and prognostically significant. Abnormalities such as cleft palate, impaired vision, hearing defects, narrow thorax, herniae, increased or restricted joint mobility, and dislocations may be related manifestations of the primary defect. Others, such as bowing or fractures, may be secondary phenomena resulting from a weakened bone structure. Craniofacial abnormalities including frontal prominence, depressed nasal bridge, hypoplastic midface, and micrognathia characterize some bone dysplasias. Intelligence is usually normal but may be deficient in some complex disorders. Radiographs are essential in the diagnosis of skeletal dysplasias. A minimal diagnostic program requires an anteroposterior (AP) babygram and lateral spine film in newborns, and AP films of the pelvis, knees, hands and a lateral film of the spine in older children. Many skeletal dysplasias are symmetrical, affecting

1. Kornak U, Mundlos S: Genetic disorders of the skeleton: A developmental approach. Am J Hum Genet 73:447, 2003. 2. Superti-Furga A, Bonafe L, Rimoin DL: Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet 106:282, 2001. 3. Hall CM: International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 113:65, 2002. 4. Orioli IM, Castilla EE, Barbosa-Neto JG: The birth prevalence for the skeletal dysplasias. J Med Genet 23:328, 1986. 5. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders and Skeletal Dysplasias, ed 3. Year Book Medical Publishers, Chicago, 1990. 6. Cobben JM, Cornel MC, Dijkstra I, et al.: Prevalence of lethal osteochondrodysplasias. Am J Med Genet 36:377, 1990. 7. Stoll C, Dott B, Roth MP, et al.: Birth prevalence rates of skeletal dysplasias. Clin Genet 35:88, 1989. 8. Connor JM, Connor RAC, Sweet EM, et al.: Lethal neonatal chondrodysplasias in the West of Scotland 1970–1983 with description of a thanatophoric dysplasia-like, autosomal recessive disorder, Glasgow variant. Am J Med Genet 22:243, 1985. 9. Kallen B, Knudsen LB, Mutchinick O, et al.: Monitoring dominant germ cell mutations using skeletal dysplasias registered in malformation registries: an international feasibility study. Int J Epidemiol 22:107, 1993. 10. Al-Gazali LI, Bakir M, Hamid Z, et al.: Birth prevalence and pattern of osteochondrodysplasias in an inbred high risk population. Birth Defects Res Part A Clin Mol Teratol 67:125, 2003. 11. Jimenez-Sanchez G, Childs B, Valle D: The effect of Mendelian disease on human health. In: The Metabolic and Molecular Bases of Inherited Disease, vol 1. Scriver CR, Beaudet AL, Valle D, et al., eds. McGrawHill, New York, 2001, p 164. 12. Langer LO, Brill PW, Afshani E, et al.: Craniometadiaphyseal dysplasia, wormian bone type. Skeletal Radiol 20:37, 1991. 13. Chen H, Blackburn WR, Wertelecki W: Fetal akinesia and multiple perinatal fractures. Am J Med Genet 55:472, 1995. 14. Marcelino J, Sciortino CM, Romero MF, et al.: Human disease-causing NOG missense mutations: Effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Proc Natl Acad Sci USA 25:11353, 2001. 15. Romero R, Pilu G, Jeanty P, et al.: Prenatal Diagnosis of Congenital Anomalies. Appleton & Lange, Norwalk, CT, 1988. 16. Gaffney G, Manning N, Boyd SA, et al.: Prenatal sonographic diagnosis of skeletal dysplasias—a report of the diagnostic and prognostic accuracy in 35 cases. Prenat Diagn 18:357, 1998. 17. Parilla BV, Leeth EA, Kambich MP, et al.: Antenatal detection of skeletal dysplasias. J Ultrasound Med 22:255, 2003. 18. Krakow D, Williams J, Poehl M, et al.: Use of three-dimensional ultrasound imaging in the prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol 21:467, 2003. 19. Severi FM, Bocchi C, Sanseverino F, et al.: Prenatal ultrasonographic diagnosis of diastrophic dysplasia at 13 weeks of gestation. J Matern Fetal Neonatal Med 13:282, 2003. 20. Spranger J, Brill P, Poznanski A: Bone Dysplasias, ed 2. Oxford University Press, New York, 2002.

Table 22-2. Skeletal dysplasias recognizable by fetal sonography Prominent Feature

Major Discriminating Feature

Gene (OMIM)

Thanatophoric dysplasia I (L)*

Bowed femora

FGFR3 (187600)

Thanatophoric dysplasia II (L)

Cloverleaf skull

FGFR3 (187601)

Metatropic dysplasia (L, S)

Metaphyseal flare

(156530)

Very short limbs

Fibrochondrogenesis (L)

Metaphyseal flare

(228520)

Schneckenbecken dysplasia (L)

Metaphyseal flare

(269250)

Sedaghatian dysplasia (L)

Flat vertebral bodies

(250220)

Achondrogenesis IA (L)

Unossified vertebral bodies

(200600)

Achondrogenesis IB (L)

Unossified vertebral bodies

DTDST (600972)

A/hypochondrogenesis II (L)

Unossified vertebral bodies

COL2 (200610)

De la Chapelle dysplasia (L)

Hitch-hiker thumb

DTDST (256050)

Opsismodysplasia (S)

Hypoplastic vertebral bodies

(258480)

Achondroplasia (M)

Macrocephaly

FGFR3 (100800)

Cartilage-hair-hypoplasia (M)

Sometimes bowed femora

MRMP (250250)

Torrance-Luton chondrodysplasia (M, S)

Severe platyspondyly

COL2 (151210)

Kniest dysplasia (M)

Sometimes cleft palate

COL2 (156550)

Spondyloepiphyseal dysplasia congenita (M)

Sometimes cleft palate

COL2 (183900)

Diastrophic dysplasia (M)

Cleft palate, club feet

DTDST (222600)

Short limbs

Ellis-van Creveld syndrome (M)

Polydactyly

EVC, EVC2 (225500)

Spondyloepimetaphyseal dysplasia: joint laxity (M)

Dislocated hips, clubfeet

(271640)

Spondyloepimetaphyseal dysplasia: leptodactyly (M)

Dislocated hips, elbows

(603546)

SMED, short limb, abnormal calcification (M)

Flat vertebral bodies

(271665)

SMED, Pakistani type (M)

PAPSS2 (603005)

Anauxetic dysplasia (M)

(607095)

Jansen metaphyseal dysplasia (M)

PTHR (156400)

Disproportionately short humeri and femora (rhizomelia)

Atelosteogenesis/Boomerang dysplasia (L)

Cleft palate, club feet

(108720)

Chondrodysplasia punctata, AR (S)

Vertebral bodies coronal clefts

PEX7 (215100)

Chondrodysplasia punctata, AR (S)

Vertebral bodies coronal clefts

DHPAT (222765)

Chondrodysplasia punctata, AR (S)

Vertebral bodies coronal clefts

AGPS (600121)

Omodysplasia (M)

(258315)

Disproportionately short forearms and shanks (mesomelia)

Langer mesomelic dysplasia (M)

Parental dyschondrosteosis

SHOX (249700)

Nievergelt mesomelic dysplasia (M)

Restricted elbow motility

(163400)

Grebe/Hunter-Thompson/DuPan syndrome (M)

Very short digits

CDMP1 (200700)

Robinow syndrome (M)

Costovertebral anomalies

ROR2 (268310)

Mesomelic dysplasia-synostoses syndrome (M)

Club feet/synostoses

(156232)

Osebold-Remondini syndrome (M)

A/hypoplasia of middle phalanges

(112910)

Thick bones/dense bones

Raine dysplasia (L)

Hypoplastic nose

(259775)

Blomstrand dysplasia (L)

Very short limbs

PTHR1 (215045)

Osteopetrosis, infantile (S)

TC1RG1, CLCN1 (259700)

Mucolipidosis II (S) Cortical hyperostosis (M)

GNPTA (252500) Bowed femora

(114000)

Lenz-Majewski dysplasia (M)

Undermineralized calvaria

(151050)

Craniometadiaphyseal dysplasia16 (M)

Undermineralized calvaria

— (continued)

1001

1002

Skeletal System Table 22-2. Skeletal dysplasias recognizable by fetal sonography (continued) Prominent Feature

Major Discriminating Feature

Gene (OMIM)

Osteocraniostenosis (L, S)

Fractures, dyscephaly

(602361)

Fetal hypokinesia17 (L, S)

Bowing, fractures

—

Osteogenesis imperfecta (M)

Fractures, bowing

COL1 (166200)

Bruck syndrome (M)

Fractures, immobile joints

TLH (259450)

Thin bones

Discontinuous (‘‘spotted’’) ossification/stippling

Greenberg dysplasia (L)

Short limbs

LBR (215140)

Pacman dysplasia{ (L)

Short limbs

(167220)

CHILD syndrome (M)

Asymmetric limb length

NSDHL, EBP (308050)

Chondrodysplasia punctata XLD (M)

Asymmetric limb length

EBP (302960)

Dyssegmental dysplasia: Rolland-Desbuquois (L)

Anarchic vertebral bodies

(224400) PLC (224410)

Prominent femoral bowing

Dyssegmental dysplasia: Silverman-Handmaker (L)

Anarchic vertebral bodies

Cumming dysplasia (L)

Polycystic kidneys

(211890)

Campomelic dysplasia (L, S)

Hypoplastic scapula

SOX9 (114290)

Osteogenesis imperfecta II (L)

Unossified calvaria, fractures

COL1 (116210)

Osteogenesis imperfecta III (S)

Unossified calvaria, fractures

COL1 (259420)

Hypophosphatasia, infantile (L)

Unossified calvaria

ALPL (241500)

Oto-palato-digital syndrome I, II (L, M)

Cleft palate

FLNA (304120)

Schwartz-Jampel syndrome (M)

Decreased fetal movements

PLC (255800)

Antley-Bixler syndrome (M)

Brachycephaly, fixed elbows

(207410)

Femoral-facial syndrome (M)

Sometimes cleft palate

(134780)

Short rib (polydactyly) syndrome I, III (L)

Very short limbs

(263510)

Short rib (polydactyly) syndrome II (L)

Very short tibia, ?cleft lip

(263520)

Short rib (polydactyly) syndrome IV (L)

Very short limbs, ?cleft lip

(269860)

Asphyxiating thoracic dysplasia (S, M)

Short limbs

(208500)

Narrow thorax

A/hypoplastic clavicles

Cleidocranial dysplasia (M) Yunis-Varon dysplasia (M)

CBFA1 (119600) Absent thumb and hallux

(216340)

Only well-recognized osteochondrodysplasias are listed. Dysostoses may produce similar sonographic appearances and, with few exceptions, are not included in the table. They are often asymmetric and/or limited to single sites. *The prognosis is given in parentheses: (L) ¼ lethal, (S) ¼ severe, increased lethality, (M) ¼ mild to moderate, normal life. {

Pacman dysplasia may be the fetal manifestation of ML II (I-cell disease).

21. Hall C, Washbrook J: Radiological Electronic Atlas of Malformation Syndromes and Skeletal Dysplasias. Oxford University Press, New York, 2000. 22. Beals RV, Piatt JH, Yonana J: Cranio-facial conodysplasia. J Pediatr Orthopaed 15:633, 1995. 23. Campailla E, Martinelli B: Statural deficiency with micromesomelia. Minerva Orthop 22:180, 1971. 24. Ferraz FG, Maroteaux P, Sousa JP, et al.: Acromesomelic dwarfism: a new variation. J Pediatr Orthop B 6:27, 1997. 25. Ohba K, Ohdo S, Sonoda T, et al.: Acromesomelic dysplasia in a father and son: autosomal dominant inheritance. Acta Paediatr Jpn 31:595, 1989. 26. Glorieux FH, Rauch F, Plotkin H, et al.: Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 15:1650, 2000. 27. Glorieux FHB, Ward LM, Rauch F, et al.: Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 17:30, 2002.

28. Ward LM, Rauch F, Travers R, et al.: Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 31:12, 2002. 29. Jurenka SB, Van Allen MI: Mixed sclerosing bone dysplasia: small stature, seizure disorder and mental retardation: a syndrome? Am J Med Genet 57:6, 1995. 30. Elcioglu N, Hall CM: A lethal skeletal dysplasia with features of chondrodysplasia punctata and osteogenesis imperfecta; an example of Astley-Kendall dysplasia. J Med Genet 35:505, 1998. 31. Frydman M, Bar-Ziv J, Preminger-Shapiro RR, et al.: Possible heterogeneity in spondyloenchondrodysplasia: quadriparesis, basal gangliacalcifications, and chondrocyte inclusions. Am J Med Genet 36:279, 1990. 32. Freisinger P, Finidori G, Maroteaux P: Dysspondylochondromatosis. Am J Med Genet 45:460, 1993. 33. Colby RS, Saul RA: Is Jaffe-Campanacci syndrome just a manifestation of neurofibromatosis type I? Am J Med Genet 123:60, 2003.

Table 22-3. Classification of bone dysplasias A. Generalized Endochondral Dysplasias

Fig. 22-6. (A, B) Multiple epiphyseal dysplasia in a 10-year-old child. Note the flattened epiphyseal ossification centers. (C–E) Pseudoachondroplasia in a 6-year-old girl. Note normal head and short-limb dwarfism (C); small capital femoral epiphyses and hypoplastic lower ilia (D); and epiphyseal flattening and wide metaphyses with irregular margins (E).

1. Dysplasias with Predominantly Epiphyseal Involvement (Fig. 22-6) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

1.01

Multiple epiphyseal dysplasia

AD (132400)

COMP COL9A1 COL9A2 COL9A3 MATN3

9p12-13.1 6q13 1p23.2-33 20q13.3 2p23-24

Cartilage oligomeric Collagen 9a1 Collagen 9a2 Collagen 9a3 Matrilin

1.02

Pseudoachondroplasia

AD (177170)

COMP

9q12-13.1

Cartilage oligomeric

1.03

Familial hip dysplasia (Beukes)

AD (142669)

1.04

Greenberg dysplasia (lethal)

AR (215140)

1.05

Astley-Kendall dysplasia (lethal)

AR

4q35 LBR

1q42.1

Lamin B receptor (continued)

1003

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

1.06

Chondrodysplasia punctata Rhizomelic type

AR (215100) AR (222765)

PEX7 DHPAT

6q22-24 1q42

AR (600121)

AGPS

2q31

Protein

PTS2 receptor (OH)2 acetone acyltransferase Alkyl(OH)2 acetoneP-synthase

1.07

Chondrodysplasia punctata ConradiHu¨nermann type

XLD (302960)

EBP

Xp11.23-11.22

Emopamil-binding

1.08

Chondrodysplasia punctata X-linked recessive type

XLD (302950)

ARSE

Xp22.3

Arylsulfatase E

1.09

Chondrodysplasia punctata Tibia-metacarpal type

(118651)

1.10

CHILD syndrome (limb reduction/ ichthyosis)

XLD (308050)

NSDHL

Xp11

NAD(P)H steroid dehydrogenase-like

Fig. 22-7. (A–C) Thanatophoric dysplasia I in a newborn. Note shortened, bowed long bones and H-shaped vertebrae. (D) Schmid-type metaphyseal dysplasia in a 2-year-old child. Note marked metaphyseal irregularity and varus position of proximal femur. (E) Cartilage-hair hypoplasia in a 3-year-old child. Note mild femoral bowing and metaphyseal irregularities of the distal femoral and proximal tibial metaphyses.

2. Dysplasias with Predominantly Metaphyseal Involvement (Fig. 22-7)

No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

2.01

Thanatophoric dysplasia I (lethal)

AD (187600)

FGFR3

4p16.3

Fibroblast growth factor receptor 3

2.02

Thanatophoric dysplasia II (lethal)

AD (187601)

FGFR3

4p16.3

Fibroblast growth factor receptor 3

Protein

(continued)

1004

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

2.03

Achondroplasia

AD (100800)

FGFR3

4p16.3

Fibroblast growth factor receptor 3

2.04

Hypochondroplasia

AD (146000)

FGFR3

4p16.3

Fibroblast growth factor receptor 3

2.05

SADDAN

AD (134934)

FGFR3

4p16.3

Fibroblast growth factor receptor 3

2.06

Blomstrand dysplasia (lethal)

AR (215045)

PTHR1

3p22-21.1

Parathyroid hormone/PH related protein receptor

2.07

Jansen metaphyseal dysplasia

AD (156400)

PTHR1

3p22-21.1

Parathyroid hormone/PH related protein receptor

2.08

Schmid metaphyseal dysplasia

AD (156500)

COL10A1

6q21-22.3

Type 10 collagen

2.09

Cartilage hair hypoplasia

AR (250250)

RMRP

9p13

Ribonuclein-RNA

2.10

Ellis–van Creveld syndrome

AR (225500)

LBN

4p16

Limbin

2.11

Short rib (polydactyly) syndromes 1. Asphyxiating thoracic dysplasia

Protein

AR (208500)

2. Saldino/Noonan (lethal)

AR (263530)

3. Verma-Naumoff (lethal)

AR (263510)

4. Beemer-Langer (lethal)

AR (269860)

5. Majewski (lethal)

AR (263520)

6. Cumming (lethal)

AR (211890)

2.12

Metaphyseal anadysplasia (heterogeneous)

AR (309645)

2.13

Shwachman-Diamond syndrome

AR (260400)

SBDS

7q11

SBDS protein

2.14

Adenosine deaminase deficiency

AR (102700)

ADA

20q13.11

Adenosine deaminase

2.15

Acroscyphodysplasia (heterogeneous)

AR (250215)

Fig. 22-8. (A) Diastrophic dysplasia in a 3-year-old. Note misshapen short tubular bones with absent epiphyseal ossification centers and irregular metaphyses; very flat epiphysis of the distal radius; and globular metacarpal I. (B) Mild diastrophic dysplasia (multiple epiphyseal dysplasia, recessive type) in a 9-year-old. Note the flattened epiphyses and bulbous expansion of the ends of metacarpals 2–5.

3. Dysplasias with Predominantly Epimetaphyseal Involvement (Fig. 22-8)

No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

3.01

Achondrogenesis IB (lethal)

AR (600972)

DTDST

5q32-33.1

Sulfate transporter

3.02

De la Chapelle dysplasia (lethal)

AR (256050)

DTDST

5q32-33.1

Sulfate transporter

3.03

Diastrophic dysplasia

AR (222600)

DTDST

5q32-33.1

Sulfate transporter

3.04

Multiple epiphyseal dysplasia, recessive

AR (226900)

DTDST

5q32-33.1

Sulfate transporter (continued)

1005

Table 22-3. Classification of bone dysplasias (continued)

Fig. 22-9. (A–C) Spondyloepiphyseal dysplasia congenita. (A) Ovoid, immature vertebral bodies in a 15-month-old child. (B) Absent ossification of femoral heads and flat vertebrae in an 11-month-old baby. (C) Unossified femoral heads and necks with upward displacement of femora in a 14-year-old child. (D–F) Mucopolysaccharidosis. (D) MPS-II in a

4-year-old child. Note coarse facial features, thick hair, limited joint mobility. (E) MPS-I in a 2-year-old child. Note the immature, ovoid vertebral bodies with hook-shaped deformity of L1 and L2. (F) Same patient. Widened tubular bones without epiphyseal ossification centers, bullet-shaped phalanges and proximal pointing of metacarpals.

4. Dysplasias with Predominantly Spondyloepiphyseal Involvement (SED) (Fig. 22-9) Inheritance (MIM)

Gene

Chromosome localization

Protein

Achondrogenesis II (lethal)

AD (200610)

COL2A1

12q13.1-q13.3

Type II collagen

Hypochondrogenesis (lethal)

AD (200610)

COL2A1

12q13.1-q13.3

Type II collagen

4.03

SED, Torrance type

AD (151210)

COL2A1

12q13.1-q13.3

Type II collagen

4.04

SED congenita

AD (183900)

COL2A1

12q13.1-q13.3

Type II collagen

4.05

Spondyloperipheral dysplasia

AD (271700)

COL2A1

12q13.1-q13.3

Type II collagen

4.06

Kniest dysplasia

AD (156550)

COL2A1

12q13.1-q13.3

Type II collagen

4.07

Stickler arthroophthalmopathy I

AD (108300)

COL2A1

12q13.1-q13.3

Type II collagen

4.08

Late-onset SED

COL2A1

12q13.1-q13.3

Type II collagen

4.09

Stickler arthroophthalmopathy II

AD (604841)

COL11A1

1p21

Collagen 11 a1

4.10

Marshall syndrome

AD (154780)

COL11A1

1p21

Collagen 11 a1

No.

Dysplasia

4.01 4.02

(continued)

1006

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

4.11

Weissenbacher-Zweymu¨ller syndrome

AD (184840)

COL11A2

6p21.3

Collagen 11 a2

4.12

AR (215150)

COL11A2

6p21.3

Collagen 11 a2

4.13

OSMED (otospondylomegaepiphyseal dysplasia) SED tarda XL

XLD (313400)

SEDL

Xp22.2-22.1

Sedlin

4.14

SED tarda AD

AD (184100)

4.15

SED tarda AR

AR (609223)

4.16

Wolcott-Rallison dysplasia

AR (226980)

EIF2AK3

2p12

Translation initiation factor 2-a kinase

4.17

SPONASTRIME dysplasia

AR (271510)

4.18

SED, Omani type

AR (608637)

CHTS3

10q21.1

Carbohydrate sulfotransferase 3

4.19

Mselini (Handigodu) dysplasia

4.20

Dysostosis Multiplex Group 1. Mucopolysaccharidosis IH

AR (252800)

IDA

4p16.4

a-L-iduronidase

2. Mucopolysaccharidosis IS

AR (252800)

IDA

4p16.4

a-L-iduronidase

3. Mucopolysaccharidosis II

XLR (309900)

IDS

Xq27.3-28

Iduronate-2-sulfatase

4. Mucopolysaccharidosis IIIA

AR (252900)

HSS

17q25.3

Heparan sulfate sulfatase

5. Mucopolysaccharidosis IIIB

AR (252920)

NAGLU

17q21

N-Ac-aglucosaminidase

6. Mucopolysaccharidosis IIIC

AR (252930)

Chr.14

Ac-CoA:a-gluc-actransferase

7. Mucopolysaccharidosis IIID

AR (252940)

GNS

12q14

N-Ac-gluc-6-sulfatase

8. Mucopolysaccharidosis IVA

AR (253000)

GALNS

16q24.3

Galactose-6-sulfatase b-galactosidase

AR (253010)

GLB1

3p21.33

10. Mucopolysaccharidosis VI

9. Mucopolysaccharidosis IVB

AR (253200)

ARSB

5q13.3

Arylsulfatase B

11. Mucopolysaccharidosis VII

AR (253220)

GUSB

7q21.11

b-glucuronidase

12. Fucosidosis

AR (230000)

FUCA

1p34

a-fucosidase a-mannosidase

13. a-mannosidosis

AR (248500)

MAN

19p13.2-12

14. Aspartylglycosaminuria

AR (208400)

AGA

4q23-27

15. b-galactosidosis

AR (230500)

GLB1

3p21-14.2

b-galactosidase

16. Sialidosis

AR (256550)

NEU

6p21.3

a-neuraminidase

17. Sialic acid storage disease

AR (269920)

SIC17A5

6q14-15

Sialin

18. Galactosialidosis

AR (256540)

PPGB

20q13.1

b-galactosidase protective protein

19. Multiple sulfatase deficiency

AR (272200)

SUMF1

3p26

Sulfatase-modifying factor

20. Mucolipidosis II, IIIA (GNPTA ¼ ab-subunit)

AR (252500) AR (252600)

GNPTA

4q21-23

N-Ac-glucosamine-P transferase

21. Mucolipidosis III (GNPTAG ¼ g-subunit)

AR (252605)

GNPTAG

16p

N-Ac-glucosamine-P transferase (continued)

1007

Table 22-3. Classification of bone dysplasias (continued)

Fig. 22-10. Spondylometaphyseal dysplasia, Kozlowski type, in 10year-old. (A) Flat and broad vertebral bodies: platyspondyly. (B) Short femoral necks in varus position; irregular metaphyseal margins.

5. Dysplasias with Predominantly Spondylometaphyseal Involvement (SMD) (Fig. 22-10)

No.

Dysplasia

Inheritance (MIM)

5.01

SM dysplasia, Sedaghatian type (lethal)

AR (250220)

5.02

Opsismodysplasia

AR (258480)

5.03

SM dysplasia, Kozlowski type

AD (184252)

5.04

SM dysplasia, Schmidt type

AD (184253)

5.05

SMD Sutcliffe type (corner fracture)

AD (184255)

5.06

SMD Algerian type

AD (184253)

5.07

Odontochondrodysplasia (Goldblatt)

AR (184260)

5.08

SMD with cone-rod dystrophy

AR (608940)

Gene

Chromosome localization

Protein

(continued)

1008

Table 22-3. Classification of bone dysplasias (continued)

Fig. 22-11. Spondyloepimetaphyseal dysplasias. (A, B) Lethal metatropic dysplasia in a newborn. Note narrow chest, short, mushroomed tubular bones, halberd-shaped ilia, and wafer-thin vertebral bodies. (C) Metatropic dysplasia in a newborn. Note relatively long trunk.

(D) Same child at 2 years. The proportions have changed to a relatively short trunk. (E) Metatropic dysplasia in a 2-year-old child: shortened tubular bones with flared metaphyses and small, irregular epiphyses.

6. Spondyloepimetaphyseal Dysplasias (SEMD) (Fig. 22-11) Gene

Chromosome localization

Protein

AR (156530)

PLC

1q36-39

Perlecan

Silverman-Handmaker dyssegmental dysplasia (lethal)

AR (224400)

PLC

1q36-39

Perlecan

6.08

Schwartz-Jampel syndrome

AR (224410)

PLC

1q36-39

Perlecan

6.09

Progressive pseudorheumatoid dysplasia

AR (255800)

WISP3

6q22-23

WNT1-inducible signaling pathway 3

No.

Dysplasia

Inheritance (MIM)

6.01

Achondrogenesis 1A (lethal)

AR

6.02

Fibrochondrogenesis (lethal)

AR (200600)

6.03

Schneckenbecken dysplasia (lethal)

AR (228520)

6.04

Metatropic dysplasia, lethal

AR (269250)

6.05

Metatropic dysplasia, nonlethal

AD (250600)

6.06

Rolland-Desbuquois dyssegmental dysplasia (lethal)

6.07

(continued)

1009

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

6.10

Immuno-osseous dysplasia

AR (208230)

SMARCAL1

2q34-36

Chromatin modeling

6.11

Dyggve-Melchior-Clausen dysplasia

AR (242900)

FLJ90130

18q21-21.1

Dymeclin

6.12

Smith-Cort dysplasia

AR (223800)

FLJ90130

18q21-21.1

Dymeclin

6.13

Desbuquois syndrome (heterogeneous)

AR (697326)

6.14

Pseudodiastrophic dysplasia

AR (251450)

6.15

SEMD with joint laxity

AR (264180)

6.16

SEMD with leptodactyly

AR (271640)

6.17

SEMD Pakistani type

AR (603546)

PAPSS2

10q22-24

Phosphosulfate synthase

6.18

SEMD short limb/abnormal calcification

AR (603005)

6.19

Anauxetic dysplasia

AR (271665)

6.20

SEMD Missouri type

AD (607095)

Fig. 22-12. Diaphyseal dysplasias. (A, B) MelnickNeedles dysplasia. Note irregular contours of femur and tibia, coxa valga, bowing of the tibia, and coarse trabeculation. (C, D) Osteodysplastic primordial dwarfism. Note thin diaphyses (nonspecific).

7. Diaphyseal Dysplasias (Fig. 22-12) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

7.01

Melnick-Needles syndrome (osteodysplasty)

XLD (309350)

FNLA

Xq28

Filamin A

7.02

Otopalatodigital syndrome I

XLD (309350)

FNLA

Xq28

Filamin A

7.03

Otopalatodigital syndrome II (lethal)

XLD (311300)

FNLA

Xq28

Filamin A (continued)

1010

Table 22-3. Classification of bone dysplasias (continued) Inheritance (MIM)

Gene

Chromosome localization

Protein

Frontometaphyseal dysplasia

XLD (304120)

FNLA

Xq28

Filamin A

terHaar dysplasia

AR (305620)

7.06

Gracile bone dysplasia (osteocraniostenosis, lethal)

AR (249420)

7.07

Kenny-Caffey syndrome I

AR (602361)

TBCE

1q42-43

Tubulin-specific chaperone E

7.08

Kenny-Caffey syndrome II

AD (244460)

7.09

Microcephalic osteodysplastic dysplasia I

AR (127000)

7.10

Microcephalic osteodysplastic dysplasia II

AR (210710)

7.11

Microcephalic osteodysplastic dysplasia, Saul-Wilson type

AR (210720)

7.12

3-M syndrome

AR (210730) AR (273750)

No.

Dysplasia

7.04 7.05

B. Localized Dysplasias

Fig. 22-13. Brachyolmia, Hobaek type, in a 6-year-old. (A) Flattened vertebral bodies with narrow disc spaces. (B) Coxa valga without distinct epi-metaphyseal abnormalities.

8. Axial Dysplasias (Fig. 22-13)

No.

Dysplasia

Inheritance (MIM)

8.01

Brachyolmia, dominant

AD (113500)

8.02

Brachyolmia, recessive (Hobaek)

AR (271530)

Gene

Chromosome localization

Protein

(continued)

1011

Table 22-3. Classification of bone dysplasias (continued)

Fig. 22-14. Atelosteogenesis I in a newborn. (A) Rhizomelic shortening, club feet, external rotation and abduction of the legs. (B) Shortened, distally tapered humeri and femora. (C) Squared, globular phalanges. (Courtesy of E. J. Ives, Edmonton Alberta, Canada.)

9. Rhizomelic Dysplasias (Fig. 22-14) Inheritance (MIM)

Gene

Chromosome localization

Protein

Atelosteogenesis I (lethal)

AD (108720)

FNLB

3p21.1-14.1

Filamin B

Atelosteogenesis III (lethal)

AD (108721)

FNLB

3p21.1-14.1

Filamin B

9.03

Larsen syndrome, dominant

AD (150250)

FNLB

3p21.1-14.1

Filamin B

9.04

Spondylocarpotarsal synostosis

AR (272460)

FNLB

3p21.1-14.1

Filamin B

9.06

Omodysplasia, recessive

AR (258315)

9.07

Omodysplasia, dominant

AD (164745)

9.08

Larsen syndrome, recessive

AR (245600)

No.

Dysplasia

9.01 9.02

(continued)

1012

Table 22-3. Classification of bone dysplasias (continued)

Fig. 22-15. Dyschondrosteosis in a 16-year-old. (A) Bowed radius with ulnar slant of distal radial join surface. (B) Dorsal subluxation of the distal ulna.

10. Mesomelic Dysplasias (MD) (Fig. 22-15) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

10.01

Dyschondrosteosis

AD (127300)

SHOX

Xpter-p22.32

SHOX transcription factor

10.02

Langer mesomelic dysplasia

AR (249700)

SHOX

Xpter-p22.32

SHOX transcription factor

10.03

Robinow dysplasia, dominant

AD (180700)

10.04

Robinow dysplasia, recessive (see 12.15.4)

AR (268310)

ROR2

9q22

Orphan receptor tyrosine kinase

10.05

MD Nievergelt type

AD (163400)

10.06

MD Kozlowski-Reardon type

AR

10.07

MD Reinhard-Pfeiffer type

AD (191400)

10.08

MD Werner type

AD (188770)

10.09

MD with synostoses

AD (600383)

10.10

MD Kantaputra type

AD (156232)

10.11

MD Verloes type

AD (600383)

10.12

MD Savarirayan type

(605274)

Protein

2q24-32

Fig. 22-16. Acromesomelic dysplasia, Maroteaux type, in 3-year-old. (A) Flattened vertebral bodies with anterior tonguing. (B) Shortened, well-modeled metacarpals, short and broad phalanges. (C) Rounded ilia, well-developed proximal femora. 11. Acromesomelic Dysplasias (AMD) (Fig. 22-16)

No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

11.01

AMD Maroteaux type

AR (602875)

NPR2

9p13-p12

Natriuretic peptide receptor B

11.02

AMD Grebe type

AR (200700)

CDMP1

20q11.2

Cartilage-derived morphogenic 1

Protein

(continued)

1013

Table 22-3. Classification of bone dysplasias (continued) Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

AMD Hunter-Thompson type (see 12.15.5)

AR (201250)

CDMP1

20q11.2

Cartilage-derived morphogenic 1

AMD Du Pan type

AR (228900)

CDMP1

20q11.2

Cartilage-derived morphogenic 1

11.03

Cranioectodermal dysplasia

AR (218330)

11.04

AMD Osebold-Remondini type

AD (112910)

No.

Protein

Fig. 22-17. Trichorhinophalangeal syndrome. (A) Type 1, 10-month-old baby. Note the sparse eyebrows, bulbous nose, and prominent upper lip. (B) Adult, mother of baby in view A. Note delta-shaped articular surface of middle phalanx 2, short middle phalanx 1. (C) Type 2, 7-year-old child. Note the shortened middle phalanges, delta-shaped metaphyses of proximal phalanges 2 and 5, and multiple exostoses. 12. Acromelic Dysplasias (Fig. 22-17)

No.

Dysplasia

Inheritance (MIM)

12.01

Acromicric dysplasia

AR (102370)

12.02

Geleophysic dysplasia

AR (231050)

12.03

Myre dysplasia

(139210)

12.04

Weill-Marchesani

Gene

Chromosome localization

Protein

Dominant type

AD (608328)

FBN1

15q21.1

Fibrillin 1

Recessive type

AR (277600)

ADAMTS10

19p13.3-13.2

Metalloproteinase

12.05

Trichorhinophalangeal dysplasia I

AD (190351) (190350)

TRPS1

8p24.12

Zn finger, transcription

12.06

Trichorhinophalangeal dysplasia II

AD (150230)

TRPS1/EXT1

8q24.11-q24.13

8q24.1 del

12.07

Acrocapitofemoral dysplasia (see 12.15.1)

AR (607778)

IHH

2q33-35

Indian hedgehog signaling

12.08

Pseudohypoparathyroidism (Albright osteodystrophy)

AD (103580)

GNAS1

20q13.2

Stimulatory Gsa of adenylate cyclase

12.09

Acrodysostosis

AD (101800)

12.10

Saldino-Mainzer dysplasia

AR (266920)

12.11

Angel-shaped epiphyseal dysplasia

AD (105835)

12.12

Brachydactyly-hypertension dysplasia, Bilginturan

AD (112410)

12.13

Camptodactyly/arthropathy

AR (208250)

PRG4

1q24-25

Proteoglycan 4

AD (186500) AD (186570)

NOG

17q22

Noggin polypeptide

12p12.2-p11.2

Coxa vara/pericarditis (CACP) 12.14

Multiple synostosis syndrome

(continued)

1014

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

12.15

1. Brachydactyly A1 (see 12.7)

AD (112500)

IHH

2q33-35

Indian hedgehog signaling

2. Brachydactyly A2

AD (112600)

BMPR1B

4q23-24

Bone morphogenetic receptor 1B

3. Brachydactyly A3

AD (112700)

4. Brachydactyly B (see 10.4)

AD (113000)

ROR2

9q22

Orphan receptor tyrosine kinase

5. Brachydactyly C (see 11.2)

AD (113100)

GCDMP1

20q11.2

Cartilage derived morphogenic

6. Brachydactyly D

AD (113200)

HOXD13

2q31-32

Homeobox D13

7. Brachydactyly E

AD (113300)

HOXD13

2q31-32

Homeobox D13

8. Christian brachydactyly

AD (112450)

Protein

Fig. 22-18. Cleidocranial dysplasia. (A) 7-year-old child with narrow shoulders, relatively large head. (B) 5-year-old child with absent clavicles. (C) 5-year-old with delayed ossification, extra ossification centers of 2nd and 5th metacarpals, brachymesophalangism V.

13. Membranous bone dysplasias (Fig. 22-18)

No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

13.01

Cleidocranial dysplasia

AD (119600)

CBFA1

6p21

Core-binding factor a1 subunit

13.02

Yunis-Varon dysplasia

AR (216340)

13.03

Campomelic dysplasia

AD (114290)

SOX9

17q24.3-25.1

SRY-box 9

Protein

(continued)

1015

Table 22-3. Classification of bone dysplasias (continued) C. Dysplasias with Abnormal Bone Density

Fig. 22-19. Osteogenesis imperfecta. (A) Type I in a newborn. Note blue sclerae. (B, C) Type III in a 7-yearold. Note osteopenic, thin, severely bowed tubular bones. (D) Type 1 in an adult. Note tam-o’-shanter skull with basilar impression and platybasia. (Courtesy of P. Beighton, Cape Town, South Africa.)

14. Dysplasias with Decreased Bone Density (Fig. 22-19) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

14.01

Osteogenesis imperfecta I

AD (166200)

COL1A1 COL1A2

17q21.31-q22 7q22.1

a(1) polypeptide of collagen I a(2) polypeptide of collagen I

14.02

Osteogenesis imperfecta II (lethal)

AD (166210)

COL1A1 COL1A2

17q21.31-q22 7q22.1

a(1) polypeptide of collagen I a(2) polypeptide of collagen I

14.03

Osteogenesis imperfecta III

AD (259420)

COL1A1 COL1A2

17q21.31-q22 7q22.1

a(1) polypeptide of collagen I a(2) polypeptide of collagen I

14.04

Osteogenesis imperfecta IV

AD (166220)

COL1A1 COL1A2

17q21.31-q22 7q22.1

a(1) polypeptide of collagen I a(2) polypeptide of collagen I

14.05

Osteogenesis imperfecta, recessive (IIC)

AR (259440)

14.06

Stu¨ve-Wiedemann syndrome

AR (601559)

LIFR

5q13.1

Leukemia inhibitory factor receptor (continued)

1016

Table 22-3. Classification of bone dysplasias (continued) Chromosome localization

Protein

PLOD 2

7p12 3q23-q24

Telopeptide lysyl hydroxylase

LRP5

11q13.4

Lipoprotein-receptor related 5

AR (241500)

TNSALP

1p36.1-p34

Tissue-nonspecific alkaline phosphatase

AD (146300)

TNSALP

1p36.1-p34

Tissue-nonspecific alkaline phosphatase

XLD type

XLD (307800)

PHEX

Xp22.-p22.1

P-regulating endopeptidase

AD type

AD (193100)

FGF23

12p13.3

Fibroblast growth factor 23

Vitamin D dependent rickets I

AR (264700)

CYP27B1

12q14

25a(OH) calciferol-1hydroxylase

Vitamin D dependent rickets II

AR (277420)

VDR

12q12-14

1,25(OH)2 Vitamin D3 receptor

Neonatal hyperparathyroidism

AR (239200)

CASR

3q13.3-21

Calcium sensor

No.

Dysplasia

Inheritance (MIM)

Gene

14.07

Bruck syndrome, type 1 type 2

AR (259450) AR (609220)

14.08

Osteoporosis-pseudoglioma syndrome

AR (259770)

14.09

Geroderma osteodysplasticum

AR (231070)

14.10

Cole-Carpenter syndrome

(112240)

14.11

Singleton-Merten syndrome

AD (182250)

14.12

Idiopathic juvenile osteoporosis

SP (259750)

14.13

Hypophosphatasia, infantile

14.14

Hypophosphatasia, adult

14.15

Hypophosphatemic rickets,

14.16

14.17

(continued)

1017

Table 22-3. Classification of bone dysplasias (continued)

Fig. 22-20. Osteopetrosis. (A, B) Infantile type in 4-week-old. Sclerosis of the cranial and tubular bones; wide metaphyses with irregular margins. (C, D) Delayed form, type I, in 6-year-old. Sclerosis of the cranial base and vault. Sclerosis of the tibiae and fibula without metaphyseal expansion. (Courtesy of H. U. Boll, W. Mosbach, and W. Neumann, Hof.)

15. Dysplasias with Increased Bone Density (Fig. 22-20) No.

Dysplasia

15.01

Raine dysplasia (lethal)

AR (259775)

15.02

Caffey infantile hyperostosis

AD (114000)

15.03

Osteopetrosis (OP) 1. OP infantile forms (lethal)

Inheritance (MIM)

AR (259700)

Gene

Chromosome localization

TCIRG1

11q13.4-13.5

Vacuolar proton pump a3

CLCN7

16p13

Chloride channel 7

OSTM1

6q21

Transmembrane 1

Protein

2. OP with infantile. neuroaxonal dysplasia

AR (600329)

3. OP delayed form type I

AR (607634)

LRP5

11q13.4

Lipoprotein receptor related

4. OP delayed form type 2

AD (166600)

CLCN7

16p13

Chloride channel 7

5. OP mild recessive form

AR (259710)

6. OP with renal tubular acidosis

AR (259730)

CA2

8q22

Carboanhydrase 2

7. OP with renal tubular acidosis and deafness

AR (267300)

ATP6V1B1

2cen-q13

Apical proton pump subunit B1

ATP6V0A4

7q33-34

ATPase pump

8. OP with ectodermal dysplasia and immune deficiency

XL (300301)

IKBKG (NEMO)

Xq28

NF-kB essential modulator

15.04

Dysosteosclerosis

AR (224300)

15.05

Osteomesopyknosis

AD (166450)

15.06

Cranial osteosclerosis and bamboo hair (Netherton)

AR (256500)

SPINK5

5q32

Serine protease inhibitor 5 (continued)

1018

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

15.07

Pyknodysostosis

AR (265800)

CTSK

1q21

Cathepsin K

15.08

Osteosclerosis, Stanescu type

AD (122900)

15.09

Osteopathia striata/melorheostosis

AD (155950) AD (166700)

LEMD3

12q14

Inner nuclear membrane protein MAN antigen

15.10

Osteopathia striata with cranial hyperostosis

AD (166500) XLD (3003783)

15.11

Camurati-Engelmann dysplasia

AD (131300)

TGFb1

19q13.1

Transforming growth factor b1

15.12

Diaphyseal dysplasia with anemia (Ghosal)

AR (231095)

15.13

Craniodiaphyseal dysplasia

AD (122860) AR (218300)

15.14

Lenz-Majewski dysplasia

AD (151050)

15.15

Endosteal hyperostosis

AD (144750)

LRP5

11q13.4

Lipoprotein receptor related 5

15.16

Van Buchem generalized hyperostosis/sclerosteosis

AR (239100) AR (269500)

SOST

17q12-21

Sclerostin

15.17

Sclerosteocerebellar dysplasia

AR (213002)

15.18

Osteoectasia with hyperphosphosphatasia (juvenile Paget)

AR (239000)

TNFRSF11B

8q24

Tumor necrosis factor receptor 11B

15.19

Diaphyseal medullary stenosis with bone malignancy

AD (112250)

15.20

Oculodento-osseous dysplasia

AD (164200) ?AR (257850)

GJA1

6q21-23.2

Connexin 43

15.21

Trichodento-osseous dysplasia

AD (190320)

DLX3

17q21.3-22

Distal-less homeobox 3

15.22

Pyle dysplasia

AR (265900)

15.23

Craniometaphyseal dysplasia

AD (123000) AR (218400)

ANKH

5p15.2-14.1

Pyrophosphate channel

15.24

Metaphyseal dysplasia Braun-Tinschert type

AD (605946)

9p22-21

D. Disorganized Development of Cartilaginous and Fibrous Components of the Skeleton

Fig. 22-21. (A) Multiple cartilaginous exostoses in a 14-year-old boy. (B,C) Enchondromatosis, Ollier type, in a 14-year-old girl. Irregular radiolucencies and dense streaks in the right proximal femur, punched-out lesions in the right ilium, proximal and middle phalanx of the 4th finger. (Courtesy of B. Albrecht, Essen, Germany.)

16. Disorders with Disorganized Development of Cartilaginous and Fibrous Components of the Skeleton (Fig. 22-21)

No.

Dysplasia

Inheritance (MIM)

16.01

Dysplasia epiphysealis hemimelica

SP (127800)

16.02

Carpotarsal enchondromatosis

AD (127820)

Gene

Chromosome localization

Protein

(continued)

1019

Table 22-3. Classification of bone dysplasias (continued) No.

Dysplasia

Inheritance (MIM)

Gene

Chromosome localization

Protein

16.03

Multiple cartilagineous exostoses

AD (133700)

EXT1

8q24.11-24.3

Exostosin 1

AD (133701)

EXT2

11p12-11

Exostosin 2

AD (600209)

EXT3

19p

16.04

Enchondromatosis (Ollier/Maffucci syndrome)

SP (166000)

16.05

Spondyloenchondromatosis

AR (271550)

16.06

Spondyloenchondromatosis, þ 2-hydroxy glutaric aciduria

SP (600721)

16.07

Genochondromatosis

AD (166000)

16.08

Metachondromatosis

AD (156250)

16.09

Dysspondyloenchondromatosis

SP

16.10

Cheirospondyloenchondromatosis

16.11

Metaphyseal dysplasia Pena/Spahr type

AR (250300, 250400)

16.12

Osteoglophonic dysplasia

AD (166250)

FGFR1

8p11.2-11.1

Fibroblast growth factor receptor 1

16.13

Fibrous dysplasia (McCune- Albright syndrome)

SP (174800)

GNAS1 (activating)

20q13.2

Stimulatory Gsa of adenylate cyclase

16.14

Jaffe-Campanacci fibrous dysplasia

16.15

Fibrodysplasia ossificans progressiva

AD (135100)

16.16

Cherubism

AD (118400)

SH3BP2

4p16.3

SH3 domain binding

16.17

Cherubism and gingival fibromatosis

AD (135300)

SOS1

2p22-21

Guanine nucleotide exchange factor

Gene

Chromosome localization

MMP2

16q13

Matrix metalloproteinase 2

4q27-31?

E. Osteolyses

Fig. 22-22. Carpotarsal osteolysis. (A) 12-year-old with deformed, sclerotic carpal bones, undermineralized tubular bones, thin metacarpals. (B) Adult with partially destroyed and fused osteopenic bones. 17. Disorders with Osteolysis (Fig. 22-22)

No.

Dysplasia

17.01

Multicentric carpotarsal osteolysis

AD (166300)

17.02

Winchester-Torg syndrome

AR (277950) AR (259600) AR (605156)

17.03

Hajdu-Cheney syndrome

AD (102500)

17.04

Mandibuloacral dysplasia A

AR (248370)

LMNA

1q21.2

Lamin A

Mandibuloacral dysplasia B

AR (608612)

ZMPSTE24

1p34

Zn-Metalloproteinase

17.05

Familial expansile osteolysis

AD (174810)

TNFRSF11A

18q22.1

Receptor activator of NF-kB

17.06

Juvenile hyaline fibromatosis (Puretic syndrome)

AR (228600)

CMG2

4q21

Anthrax toxin receptor 2

1020

Inheritance (MIM)

Protein

23 Part VI Gastrointestinal and Related Structures

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23 Ventral Wall of the Trunk Cynthia Curry, Ellen Boyd, and Roger E. Stevenson

A

s the neural plate elevates, folds, and fuses dorsally in the embryonic week 4, folding also occurs ventrally to form the body tube. It is this ventral folding process by which the body cavities are positioned, thoracic and abdominal viscera are internalized, the embryo becomes enveloped within the amniotic cavity, and the body stalk becomes an elongated vascular lifeline. It appears that closure of the neural tube and closure of the body tube occur by very different mechanisms: neural tube closure by zippering along the dorsal midline; body tube closure by circumferential convergence in purse string fashion that brings folds from all directions toward a midpoint, the umbilicus. The complex and incompletely understood process of body wall formation may be simply viewed as ventral folding at the periphery of the embryo that converts the relatively flat embryonic disc into a near-cylindrical body tube (Fig. 23-1). Cranial folding brings the oropharyngeal membrane, cardiac primordium, and septum transversum from a position beyond the cephalic neural folds to a position ventral to the developing brain.1–9 Caudal folding brings the cloacal membrane, the allantois, and connecting stalk to a comparable ventral position at the opposite end of the embryo. Lateral folds incorporate a portion of the coelom to form the thoracic and abdominal cavities. The ventral body wall is, thus, a mosaic comprised of the original cephalic, caudal, and lateral folds converging toward the umbilicus (Fig. 23-2).3–5,9 Cranial folding is encouraged by the dorsal overgrowth of the developing brain. Caudal folding occurs as the gastrulation process results in caudal lengthening of the embryo and may be related to concurrent tethering of the connecting stalk. In the process of ventral body wall formation, the cranial portion of the endoderm is converted into foregut by the cephalic fold, the caudal portion of the endoderm into hindgut by the caudal fold, and the central portion into midgut by the two lateral folds. Coincident with embryogenesis of the ventral wall, the primitive connecting stalk is vascularized and, along with the yolk sac stalk it becomes the umbilical cord as the primitive umbilical ring narrows and the amniotic cavity enlarges. The muscular and skeletal components of this region are derived from paraxial and lateral plate mesoderm, respectively. With respect to the muscles, the lower cervical and the thoracic somites (paraxial mesoderm) contribute the mesodermal populations that migrate ventrally and form the pectoral, intercostals,

and abdominal musculature. Since the ventral midline is the farthest point from the source of this mesoderm, it is most vulnerable to migration-dependent disturbances. By the time the embryonic period ends (by the end of week 8 post-conception), the various muscle groups are established. Their maturation continues through the fetal period. Although mutations in several genes (RIEG, KIP2, HLXB9) have been associated with ventral wall defects in humans, little can be said about molecular pathways involved in ventral body wall

Fig. 23-1. Schematic showing circumferential approximation of embryonic disc margins brought about, in part, by dorsal overgrowth of the neural tube. The ventral body wall will be composed of cephalic (c), lateral, and caudal (t) folds as they converge about the yolk sac and body stalk. (Reprinted with permission from Moore KL: The Developing Human, ed 4. WB Saunders, Philadelphia, 1988.)

1023

1024

Gastrointestinal and Related Structures

Fig. 23-2. Mosaic nature of the ventral body wall. Left: in the primordial stage (28-30 days postfertilization), the cephalic, lateral, and caudal folds are converging on a prominent body stalk (BS). Right: by 10 weeks the lateral folds dominate the ventral wall topography, the cephalic and caudal folds are represented by midline structures, and the body stalk is represented by relatively small umbilicus.

formation. Studies in mice by Brewer and Williams10 indicate that the transcription factor, AP-2a, may reside ‘‘near the top’’ of a molecular hierarchy that controls ventral body wall formation. AP2a-null mice have thoracoabdominoschisis, a severe failure of body wall formation that involves all four body folds and is characterized by excess cell death adjacent to the umbilical ring and deficient mesodermal components in the body wall. Less severe body wall defects in mice have been associated with mutations in Igf-II, Bmp1, Turin, and Myogenin, with hoxb2 and hoxb4 knockouts, and with Tgfb2/Tgfb3 double mutants.10 Ventral wall defects can be caused by a number of pathogenetic mechanisms, which are not mutually exclusive.6,11–20 The first is primary failure of formation of the ventral wall primordia during the early embryonic period (weeks 3 and 4). An example would be failure of thoracic somites to form. The second is failure of maturation of the primordia during later embryonic or fetal stages (late week 4 and beyond). Examples of this second pathogenic mechanism are failure of ventral migration of mesoderm from the somites; failure of in situ differentiation into skin, skeletal muscle, or cartilage; and failure of internal reorganization, i.e., in alignment of the rectus muscles to restrict the linea alba, migration and fusion of the sternal bands, or formation of the pubic symphysis. A third mechanism involves secondary injury to the intrinsically normal ventral wall during the primordial stage of morphogenesis or later. One such cause might be a vascular incident which impairs nutrition to the tissues of the body wall. Stevenson et al.21 have suggested that space limitation in the abdominal cavity caused by a short trunk or spinal retroflexion might predispose to ventral wall defects. Cephalic fold failure may give rise to a particularly serious spectrum of defects, since the somatic layer of the lateral plate mesoderm of this fold gives rise to the framework of the midventral thoracic and epigastric body wall, the diaphragm (septum transversum), the parietal layer of the pericardium, and the sternum.15,22–25 The visceral layer forms the epimyocardium. Thus, incomplete cephalic fold formation leads to multisystem malformations, exemplified by the Cantrell pentalogy.

Lateral fold failure is usually considered to cause the typical abdominal omphalocele. Lateral fold failure alone, however, is probably insufficient to produce omphalocele, since the body wall would be left with a median septum formed by the cephalic and caudal folds. Rather, omphalocele results from combined deficiency of the lateral and cephalic and/or caudal folds.6,11,12 Caudal fold failures are complicated by the close relationship of the centrally converging disc margin, the allantoic stalk, and the cloacal membrane.17–19,26 Normally, in the initial phase of body wall closure, the advancing edge of the caudal fold is closely associated with the cloacal membrane, which almost reaches the caudal margin of the body stalk. This phase, in which the cloacal membrane dominates the anatomy of the caudal fold, is soon reversed, however, by migration of lateral plate mesoderm from the caudal end of the primitive streak, resulting in progressive lengthening of the subumbilical ventral body wall. Concurrently, there is formation of the paired genital tubercles, which fuse in the midline, and are located just cranial to the cloacal membrane. Malformations of the caudal fold include bladder and cloacal exstrophy, both of which may result from abnormal lateral plate or paraxial mesoderm development at the lower thoracic or upper lumbar levels. The timing and severity of developmental failure obviously play important roles in the resulting abnormalities. The earlier the insult occurs, the more severe the structural defects. Earlier defects in the caudal fold lead to cloacal exstrophy, later defects lead to bladder exstrophy, and still later defects lead to infraumbilical omphalocele. This principle is also true for the cephalic fold where earlier defects may lead to the Cantrell pentalogy, later defects to simple omphalocele. References 1. Seno T: An experimental study on the formation of the body wall in the chick. Acta Anat 45:60, 1961, 2. Christ B. Jacob M, Jacob HJ: On the origin and development of the ventrolateral abdominal muscles in the avian embryo. Anat Embryol 166:87, 1983.

Ventral Wall of the Trunk 3. Wybum OM: The development of the infraumbilical portion of the abdominal wall, with remarks on the aetiology of ectopia vesicae. J Anat 71:201, 1937. 4. Wybum OM: The development of the supraumbilical portion of the anterior abdominal wall. J Anat 72:365, 1938. 5. Wybum OM: The formation of the umbilical cord and the umbilical region of the anterior abdominal wall. J Anat 73:289, 1939. 6. Duhamel B: Embryology of exomphalos and allied malformations. Arch Dis Child 38:142, 1963. 7. O’Rahilly R, Mu¨ller F: Human Embryology Teratology, ed 3. WileyLiss, New York, 2001. 8. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams & Wilkins, Philadelphia, 2004. 9. Moore KL, Persaud TVN: The Developing Human. Clinically Oriented Embryology, ed 6. WB Saunders Co, Philadelphia, 1998, p 78. 10. Brewer S, Williams T: Loss of AP-2a impacts multiple aspects of ventral body wall development and closure. Dev Biol 267:399, 2004. 11. Hutchin P: Somatic anomalies of the umbilicus and anterior abdominal wall. Surg Gynecol Obstet 120: 1075, 1965. 12. Pagon RA, Stephens TD, McGillivray BC, et al.: Body wall defects with reduction limb anomalies: a report of fifteen cases. BDOAS XV(5A):175, 1979. 13. Miller ME, Graham JM, Higginbottom MC, et al.: Compressionrelated defects from early amnion rupture: evidence of mechanical teratogenesis. J Pediatr 98:292, 1987. 14. Herva R, Karkinen-Jaaskelainen M: Amniotic adhesion malformation syndrome: fetal and placental pathology. Teratology 29:11, 1984. 15. Kaplan LC, Matsuoka R, Gilbert EF, et al.: Ectopia cordis and cleft sternum: evidence for mechanical teratogenesis following rupture of the chorion or yolk sac. Am J Med Genet 21:187, 1985. 16. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 17. Straub E, Spranger J: Etiology and pathogenesis of the prune belly syndrome. Kidney Int 20:695, 1981. 18. Hoagland MH, Hutchins GM: Obstructive lesions of the lower urinary tract in the prune belly syndrome. Arch Pathol Lab Med 111:154, 1987. 19. Lattimer JK: Congenital deficiency of the abdominal musculature and associated genitourinary anomalies: a report of 22 cases. J Urol 79:343, 1958. 20. Reid COMV, Hall JG, Anderson C, et al.: Association of amyoplasia with gastroschisis, bowel atresia, and defects of the muscular layer of the trunk. Am J Med Genet 24:701, 1986. 21. Stevenson RE, Seaver LH, Collins JS, et al.: Abdominal wall defects and other anomalies associated with NTD’s: pleiotropy or secondary phenomena? Proc Greenwood Genet Center 21:53, 2002. 22. Seno T: The origin and evolution of the sternum. Acta Anat 110:97, 1961. 23. Klima M: Early development of the human sternum and the problem of homologization of the so-called suprasternal structures. Acta Anat 69:473, 1968. 24. Cantrell JR, Haller JA, Ravitch MM: A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium and heart. Surg Gynecol Obstet 107:602, 1958. 25. Major JW: Thoracoabdominal ectopia cordis. J Thorac Surg 50:405, 1986. 26. Marshall VF, Meucke EC: Variations in exstrophy of the bladder. J Urol 88:766, 1962.

23.1 Sternal Defects Definition

Sternal defects are abnormalities in the fusion of the sternal bars, causing malformations termed cleft sternum, sternal fissure, asternia, and bifid sternum. Ectopia cordis and Cantrell pentalogy

1025

are not considered among these defects and are discussed in Section 23.2. Diagnosis

In the early literature, clefts of the sternum were classified as one feature of conditions involving ectopia cordis.1,2 Most modern authorities, however, reserve the term ectopia cordis for those cases in which the heart is displaced either superiorly or inferiorly. In sternal clefting, the thoracic viscera are covered only by soft tissue, and they may be bulging and pulsatile, but the heart and lungs are normally positioned anatomically and do not require repair when the sternal defect is closed. Sternal defects are classified as superior, inferior, or complete. A superior cleft may be U-shaped, with a defect ending at the level of the fourth costal cartilage, or V-shaped if it extends to the xiphoid process (Fig. 23-3). Inferior or distal clefts are very rare and are usually seen in association with other characteristic abnormalities of midline fusion as in Cantrell pentalogy (Section 23.2). A striking example of a U-shaped cleft of the sternum was that of a Mr. E.A. Groux of Hamburg, Germany, who exhibited himself throughout Europe in the 1850s and was reported several times in the contemporary literature.3 Sternal defects range from a notch in the manubrium to a defect recognized at birth because of protrusion of soft tissue over the sternal midline. Depending on the degree of failure of fusion of the sternal bars, there may be an unstable chest wall, which allows the thoracic viscera to move paradoxically with respiration. Cyanosis and dyspnea may result, although some patients are relatively asymptomatic. The clavicles and nipples may be widely separated. Atrophic, midline, linear raphes extending completely or partially from the umbilicus to the sternal notch or occasionally onto the neck may accompany the sternal defects (Fig. 23-3). The scars either may be thin, paper-like, translucent defects or may resemble keloids.4 Other patients with sternal defects present as having atypical pectus excavatum or carinatum.

Fig. 23-3. V-shaped cleft of the sternum with raphe extending to the umbilicus. (Courtesy of Dr. Joseph H. Hersh, University of Louisville School of Medicine.)

1026

Gastrointestinal and Related Structures

Superior sternal clefts and complete sternal clefts are generally isolated abnormalities. There is one report of a woman with a 47,XXX karyotype and a sternal cleft, but this finding may be coincidental, since no other instances of chromosomal aneuploidy with sternal clefting have been reported.5 One patient with a short sternum and a supraumbilical raphe, multiple skeletal anomalies, and mental retardation had been exposed in utero to isotretinoin.6 Gorlin et al.7 reviewed the association of sternal defects with supraumbilical raphe and found 42 examples in the literature from 1842 to 1992. No sex predilection was noted in this group, which did not have facial hemangiomas. A second group of 31 patients reported between 1880 and 1994 had a marked female predominance (29F;2M) and had facial hemangiomas appearing within the first weeks of life, an association first recognized by Hersh et al.4 Within this second group is an apparent syndrome, recently termed PHACE syndrome, which includes the association of posterior fossa brain abnormalities (typically Dandy-Walker malformation), hemangiomas, arterial malformations, coarctation of the aorta, cardiac malformations, and eye malformations.8,9 As in the sternal malformation/hemangioma cases, there is an excess of females with this neurocutaneous syndrome, and the overlap of features suggests that they represent a single spectrum of abnormalities. Hypoplastic ossification centers, multiple ossification centers, and premature fusion of the segments of the sternum seem to have a distinct etiology. Approximately 20% of patients with these defects have associated congenital heart disease.10 Conversely, in children with congenital heart disease, approximately 20–50% have associated premature fusion of the sternal body segments. Multiple manubrial ossification centers occur in 6–20% of all children and are particularly common in Down syndrome.10 Etiology and Distribution

During embryonic development, the sternum arises independently of the ribs from paired mesenchymal bars present by 6 weeks gestation. These parallel bars migrate to the midline, where they undergo chondrification and fusion by 9 weeks gestation. The fusion process occurs in a cephalo-caudal direction and is followed by approximation of the ventrally growing ribs. Independent of the development of the sternal bands, a single midline condensation of mesenchyme develops, which later forms the manubrium. Sternal defects result from failure of fusion of the sternal bands. This process appears to be distinct from that leading to cephalic body wall closure. The etiology of inferior sternal clefts associated with other defects of the cephalic fold and abnormal development of the septum transversum, such as Cantrell pentalogy, is not well understood. It is clear that inferior clefts are embryologically different from superior and complete clefts. Sternal clefts are extremely rare, and because of this their exact incidence is unknown. In the largest series of 47 cases reported by Ravitch,4 16 were superior and 31 were complete. Cases have been reported from all parts of the world, with a seemingly high frequency of reports from the Middle East.11 The etiology of sternal clefts is not at all clear. The majority of cases are sporadic. Haque11 noted nutritional deficiency in the mothers of several of his patients and postulated that riboflavin deficiency might have been responsible for the skeletal defects. However, it is of interest that two of his families were consanguineous, and in one there was a recurrence, suggesting that rarely this condition is inherited in an autosomal recessive manner. Gorlin et al. reported sisters, both with nonunion of the sternum, with a teardrop shaped umbilicus in the first and hemangiomas in the second.7

Prognosis, Treatment, and Prevention

The prognosis for children with sternal clefts is quite excellent, and early repair has been advocated repeatedly. In general, patients tend to be asymptomatic; however, the cosmetic aspects of the malformation are disturbing to parents and physicians alike, and there is also concern about vulnerability of the underlying heart and great vessels. It is advocated that surgical repair be undertaken early in infancy, preferably in the first few weeks of life, since approximation of the sternal bands becomes progressively more difficult with time and may in fact become impossible. A number of operative techniques have been employed, which, when performed early in infancy, usually involve suturing of the two sternal segments together after excision of the distal fused portion. If repair is carried out later, it may require the use of Teflon, stainless steel mesh, autologous bone, or cartilage grafts. Significant risk of thoracic and cardiac compression is associated with later repair. In children with the midline skin raphes, excision of this area is recommended, and care should be taken to avoid the pericardium, which may be adherent. There are few data on long-term follow-up of children with sternal clefts, although the data available suggest that the prognosis is excellent, with normal growth of the repaired chest wall. The sequelae of mild pectus excavatum not requiring surgical correction was noted in one 8-year follow-up study.12 Currently, the etiology of sternal clefts remains, in most cases, unknown. The high frequency of cases from the Middle East and the report of consanguinity and recurrence in at least one family suggest that an autosomal recessive gene is rarely responsible for this defect, and this issue should be considered in genetic counseling. Since the thoracic viscera are covered, detection by elevations in maternal serum a-fetoprotein would not be likely. Ultrasound prenatal diagnosis of this defect has not been reported, probably because of the extreme rarity of the condition. Ultrasound prenatal diagnosis of sternal abnormalities associated with complete ectopia cordis and inferior clefts associated with Cantrell pentalogy of course have been reported, but these are apparently of a different embryologic origin. References (Sternal Defects) 1. Weese C: Des Cordis Ectopia, Inaugural Dissertation, vol 1. Starck, Berolini, 1818. 2. Breschet G: Memorie sur L ‘ectopie de L ’appareil de la circulation, et particulierement sur Celle du coeur. E Duverger, Paris, 1826, p 1. 3. Ravitch M: Sternal clefts. In: Congenital Deformities of the Chest Wall and Their Operative Correction. WB Saunders Co, Philadelphia, 1977, p 1. 4. Hersh JG, Waterfill D, Rutledge R, et al.: Sternal malformations/ vascular dysplasia associations. Am J Med Genet 21:177, 1985. 5. Stoll C, Vidier M, Renaud R: to the editor: A supraumbilical midline raphe with sternal cleft in a 47,XXX woman. Am J Med Genet 27:229, 1987. 6. Rizzo R, Lammer EJ, Parano E, et al.: Limb reduction defects in humans associated with prenatal isotretinoin exposure. Teratology 44:599, 1991. 7. Gorlin RJ, Kantaputra P, Aughton DJ, et al.: Marked female predilection in some syndromes associated with facial hemangiomas. Am J Med Genet 52:130, 1994. 8. Metry DW, Dowd CF, Barkovich AJ, et al.: The many faces of PHACE syndrome. J Pediatr 139:117, 2001. 9. James PA, McGaughran J: Complete overlap of PHACE syndrome and sternal malformation—vascular dysplasia association. Am J Med Genet 110:78, 2002. 10. Lees R, Cardicott WJH: Sternal anomalies and congenital heart disease. Am J Roentgenol Rad Ther Nucl Med 124:423, 1975. 11. Haque KN: Isolated asternia: an independent entity. Clin Genet 25:362, 1984. 12. Acastello E, Majluf R, Garrido P, et al.: Sternal cleft: a surgical opportunity. J Pediatr Surg 38:178, 2003.

Ventral Wall of the Trunk

23.2 Ectopia Cordis, Including Cantrell Pentalogy Definition

Ectopia cordis is location of the heart outside of the thoracic cavity, either lying on the outer surface or displaced superiorly to the neck or inferiorly to the abdomen (Fig. 23-4). Diagnosis

Ectopia cordis was first described by Haller in the English literature in 1706, although this malformation was recorded in the cuneiform records of Babylonia.1 Ectopia cordis has been classified into four types based on location of the heart: 1) thoracic, in which the heart lies anterior to the sternum; 2) cervical, with the heart displaced into the neck; 3) abdominal, with the heart located intraabdominally; and 4) thoracoabdominal, in which the heart is located between the thorax and the abdomen. The thoracoabdominal type of ectopia cordis is usually found in association with diaphragmatic, pericardial, and abdominal wall defects and is termed the Cantrell pentalogy. In a 1989 review of 219 cases, Leca et al.2 reported that the sternum was usually abnormal in patients with ectopia cordis. The most frequent defect is the absence of the lower one-third of the sternum. Other less common abnormalities include complete absence of the sternum, bifid sternum, and segmental defects limited to the manubrium, body, or xiphoid process. Associated abdominal wall defects are part of the Cantrell pentalogy (thoracoabdominal form of ectopia cordis) but are also seen in other forms of ectopia cordis. These defects include omphalocele, diastasis recti, abdominal wall eventration, and umbilical hernia. The heart is rarely normal structurally. Ventricular septal defect is the most common lesion, although atrial septal defects, tetralogy of Fallot, double-outlet right ventricle, diverticulum of the left ventricle, and transposition of the great vessels have been reported in all series with some frequency.2–5 The thoracoabdominal form of ectopia cordis requires further elaboration. As originally described in 1958 by Cantrell, Haller, and Ravitch, 6 criteria for this diagnosis included (1) a supraumbilical midline abdominal wall defect, (2) a defect of the lower sternum, (3) deficiency of the anterior diaphragm, (4) a defect in the diaphragmatic pericardium, and (5) congenital heart defects. There

Fig. 23-4. Ectopia cordis of thoracic type.

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clearly is marked clinical variability in the severity and presentation of this pentalogy. Many patients do not fulfill all five criteria yet seem to have a similar alteration of morphogenesis, thought to reflect a defect in the embryogenesis of the septum transversum occurring at about 14–18 embryonic days. Among 61 cases reviewed by Toyama,7 only 59% had the complete pentalogy. Cardiac anomalies varied from dextrorotation to tetralogy of Fallot, and the abdominal wall defect presented as an omphalocele or wide diastasis of the rectus muscles. Eight patients with structurally normal hearts otherwise fulfilled the criteria for this diagnosis. Seventeen cases in the literature could not be adequately classified because of incomplete documentation. Toyama7 states that the various manifestations of ectopia cordis are probably all closely related defects differing mainly in severity and location. Additional major malformations have been reported to occur rather infrequently. There appear to be definite but low-frequency associations between ectopia cordis and chromosomal aneuploidy. The association of Cantrell pentalogy with trisomy 18 has been reported in at least four instances (reviewed in 4). A few other chromosome anomalies including Down syndrome and triploidy have been reported. Therefore, chromosome analysis should be included as part of the evaluation of infants with ectopia cordis. In their report of three cases and an accompanying comprehensive review of the literature, Carmi and Boughman4 suggest a definite association of oral clefting with both isolated ectopia cordis and Cantrell pentalogy. Including their own cases, they found a total of 15 cases in the literature of cleft lip/palate and ectopia cordis with or without Cantrell pentalogy. Their review also recognized an association with neural tube defects in eight cases, although three with occipital encephalocele had trisomy 18. They suggest that the co-occurence of these defects supports the concept of a midline developmental field. Ectopia cordis has also been reported in limb body wall complex due to early amnion rupture.8 Etiology and Distribution

The embryology of ectopia cordis is complex, involving the interrelated development of the heart, the sternum, and the abdominal wall. Experimental data indicate that the defects derive from altered mesodermal development of the cephalic fold at about 14–18 days of embryonic life, prior to or immediately after the differentiation of the mesoderm into splanchnic and somatic layers. Ectopia cordis is causally heterogeneous. Despite the associations noted previously, most cases do not appear to occur in association with other non-cardiac abnormalities. Chromosomal aneuploidy and amniotic band disruption sequence are nonetheless important diagnostic considerations in the evaluation of these infants. Among the literature on ectopia cordis cases reviewed by Leca et al.,2 28% were classified as cervical, 37% as thoracic, 36% as thoracoabdominal (Cantrell pentalogy), and 11% as abdominal; 8% could not be adequately classified due to lack of information. In this series, the sex ratio was 2:1 male:female; one-third were stillborn, and one-third were born prematurely. Between 1968 and 1986, the Metropolitan Atlanta Congenital Defects Program found four cases of ectopia cordis, for a rate of 0.79 per 100,000 births.9 All were female. A similar figure was found in the BaltimoreWashington Infant Study of congenital heart malformations from 1981–1989, where five cases of Cantrell pentalogy were ascertained for a regional prevalence of 0.59/100,000 live births.4 They did not observe a skewed sex ratio.

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Gastrointestinal and Related Structures

Prognosis, Treatment, and Prevention

Long-term survival with ectopia cordis still remains exceptional, but the type of ectopia cordis, the presence or absence of associated anomalies, and the intracardiac anatomy significantly influence prognosis. There have been no survivors with the cervical type, but several patients with the abdominal type have lived to adulthood and reproduced. Until recently almost all survivors have had either normal cardiac anatomy or a repairable or functionally insignificant cardiac defect. Numerous potential problems attend surgical attempts at repair of thoracic ectopia cordis. These include the small chest cavity, with potential crowding and kinking of great vessels and a lack of skin above the heart. Lobectomy, removal of ribs, and prosthetic coverings have all been utilized, but overall results have remained quite poor. There are, however, several reported successful repairs of Cantrell pentalogy. A 1997 review of 59 cases described five longterm survivors.10 A long-term follow-up of 10 patients from 1982 to 1995 with ectopia cordis at the Hospital for Sick Children in Toronto revealed that five patients survived beyond infancy, one with thoracic and four with thoracoabdominal ectopia cordis. Three had successful repair of their cardiac defect (VSD with double outlet R ventricle; tetralogy of Fallot; double outlet R ventricle, pulmonary stenosis, total pulmonary venous return) and two others had single ventricle palliation. None of the survivors had significant extra cardiac anomalies, whereas all who died had large omphaloceles and pulmonary hypoplasia.5 Since ectopia cordis is an early embryonic defect, prenatal diagnosis with ultrasound has been accomplished as early as 9 weeks gestation, but is more usual in the second trimester.11 Maternal serum a-fetoprotein screening may detect infants with ectopia cordis without a skin covering and those who have an associated abdominal wall defect. The possibility of thoracoabdominal ectopia cordis should be considered in all infants diagnosed with omphalocele and pericardial effusion, since this diagnosis strongly influences prognosis.12 Amniocentesis for fetal karyotyping is indicated in those infants with ectopia cordis and abdominal wall defects because of the association with chromosome abnormalities, particularly trisomy 18. Fetal echocardiography may be helpful in identifying patients with lesions most amenable to surgical correction. It may also aid in helping parents make decisions regarding continuation or termination of pregnancy. Among parents electing aggressive treatment, cesarean delivery does not seem to offer any unequivocal advantages. Delivery in a tertiary care center, however, is recommended. With the exception of those infants with chromosome abnormalities, genetic mechanisms or teratogens have rarely been implicated in ectopia cordis or Cantrell pentalogy, and the recurrence risk for all types seems to be exceedingly low. However, Martin et al.13 reported three boys in one family with midline defects, suggesting a single familial gene. The first boy had bilateral absence of the diaphragm, and the second and third had Cantrell pentalogy. The boys are distinct in that they had a far more extensive diaphragmatic defect than the usual infant with Cantrell pentalogy. An X-linked recessive gene is likely responsible for this rare disorder. Cantrell pentalogy has also been reported in two monozygotic twin pairs; in one the affected twin also had a cloacal defect.14 In the other set the affected twin also had sirenomelia.15 In the latter case the authors speculate that rarely the etiology of Cantrell pentalogy may be a vascular disruptive event secondary to monozygotic twinning.

References (Ectopia Cordis, Including Cantrell Pentalogy) 1. Ballantyne JW: The teratological records of Chaldea. Teratologia 1: 132, 1894. 2. Leca F, Thibert M, Khoury W, et al.: Extrathoracic heart (ectopia cordis). Report of two cases and review of the literature. Int J Cardiol 22:221, 1989. 3. Bittman S, Ulus H, Springer A: Combined pentalogy of Cantrell with tetralogy of Fallot, gallbladder agenesis and polysplenia: a case report. J Pediatr Surg 39:107, 2004. 4. Carmi R, Boughman JA: Pentalogy of Cantrell and associated midline anomalies: A possible ventral midline developmental field. Am J Med Genet 42:90, 1992. 5. Hornberger LK, Colan SD, Lock JE, et al.: Outcome of patients with ectopia cordis and significant intracardiac defects. Circulation Suppl II 94:32. 1996. 6. Cantrell JR, Haller JA, Ravitch MM: A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium and heart. Surg Gynecol Obstet 107:602, 1958. 7. Toyama WM: Combined congenital defects of the anterior abdominal wall, sternum, diaphragm, pericardium and heart: a case report and review of the syndrome. Pediatrics 50:778, 1972. 8. Kaplan LC, Matsuoka R, Gilbert EF, et al.: Ectopia cordis and cleft sternum: evidence for mechanical teratogenesis following rupture of the chorion or yolk sac. Am J Med Genet 21:187, 1985. 9. Khoury MJ, Cordero JF, Rasmussen S: Ectopia cordis, midline defect and chromosome abnormalities: an epidemiologic perspective. Am J Med Genet 30:811, 1988. 10. Fernandez MS, Lopez A, Vila JJ, et al.: Cantrell’s pentalogy. Report of four cases and their management. Pediatr Surg Int 12:428, 1997. 11. Tongsong T, Wanapirak C, Sirivatanapa P, et al.: Prenatal sonographic diagnosis of ectopia cordis. J Clin Ultrasound 27:440, 1999. 12. Siles C, Boyd PA, Manning N, et al. : Omphalocele and pericardial effusion: possible sonographic markers for the Pentalogy of Cantrell or its variants. Obstet Gynecol 87:840, 1996. 13. Martin RA, Cuniff C, Erickson L, et al.: Pentalogy of Cantrell and ectopia cordis, a familial developmental field complex. Am J Med Genet 42:839, 1992. 14. Baker ME, Rosenberg ER, Trofatter KF, et al.: The in utero findings in twin pentalogy of Cantrell. J Ultrasound Med 3:525, 1984. 15. Egan JF, Petrikovsky BM, Vintzileos AM, et al.: Combined pentalogy of Cantrell and sirenomelia: a case report with speculation about a common etiology. Am J Perinatol 10:327, 1993.

23.3 The Umbilicus: Congenital Anomalies and Variations in Configuration and Placement Definition

Congenital anomalies of the umbilicus include patent omphalomesenteric duct (vitelline intestinal tract), urachal abnormalities, and variations in the position or shape of the umbilicus. Some characteristic abnormalities may be helpful in the diagnosis of specific syndromes. The umbilicus is a frequently ignored structure, usually considered insignificant despite its paramount importance in intrauterine life. Diagnosis

Alterations in the development and maturation of the umbilical cord may be seen later as congenital anomalies of the umbilicus or as variations in umbilical size, placement, or shape. The umbilicus is usually situated at about the level of the top of the iliac crest opposite

Ventral Wall of the Trunk

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Table 23-1. Some conditions associated with abnormalities of the umbilicus Aarskog syndrome (protruding, pouting) Rieger syndrome (broad, prominent, and redundant periumbilical skin) Robinow syndrome (high placement, broad and poorly epithelialized scar) Exstrophy and epispadias complex (low set) Achondroplasia (low set)

Fig. 23-5. Anatomic landmarks of the umbilicus placement on the abdominal wall. The manubrium-to-umbilicus measurement is normally about three times the umbilicus-to-pubis measurement. M, manubrium; P, symphysis pubis (see Section 35.15 for further details on placement of the umbilicus).

the third or fourth lumbar vertebrae. Cullen states that the umbilicus may contain four parts, although all four are usually not present (Fig. 23-5).1 These include the depression, the mamelon (which represents the solid portion of the umbilical cord), the cicatrix or scar overlying the site of exit from the exocelom, and the cushion, surrounding all or part of the depression. The morphology of the umbilicus is highly variable. Cullen, in his 1916 monograph, described 60 umbilical varieties, which he divided into nine types depending on shape, depth, size of the base, and presence or absence of the mamelon. The umbilicus is generally larger in infancy than it is later. A somewhat button-like umbilicus is frequent in small

children but is uncommon in adults, among whom depression of the umbilicus is the norm. As an aid to improved cosmetic results in the repair of omphalocele, a study of normal umbilical position was performed in 50 infants.2 The authors found that the normal umbilicus is placed 60% of the way between the xiphoid process and the superior rim of the pubic symphysis. In another study of 136 subjects, the authors disproved the common belief that the umbilicus is a truly midline structure. In over 50% of subjects it was more than 2% off the midline and in nearly 100% it was not exactly midline.3 Because of the very wide range of normal variation in umbilical shape and size, determination of what constitutes an abnormal umbilicus is difficult, and most anomalies of the umbilicus are rare. Surprisingly little attention has been given to the morphology of the umbilicus. Friedman4 pointed out the importance of including the umbilicus in the dysmorphic examination. He emphasizes the characteristic appearance of the umbilicus in Aarskog syndrome, Rieger syndrome, and Robinow syndrome (Table 23-1, Fig. 23-6). In these syndromes, specific and characteristic abnormalities may be helpful diagnostically, and surely there are other syndromes, e.g., achondroplasia (Fig. 23-7), in which specific umbilical variations have escaped the attention of clinicians to date. Variations in placement of the umbilicus may result from abnormalities in the formation of the abdominal wall and are seen consistently in the spectrum of the exstrophic abnormalities, in which there is deficiency of the caudal fold. Occasionally, a low-lying umbilicus is the only clue to abnormalities of the caudal fold. A case report of two siblings suggests that deficiencies of the caudal fold rarely may have genetic determinants and that a low-lying umbilicus, especially if associated

Fig. 23-6. Appearance of umbilicus in Robinow syndrome (A), Aarskog syndrome (B), and Rieger syndrome (C). Compare appearance with description in Table 23-1. (Reprinted with permission from Friedman JM: Clin Genet 28:343, 1985.)

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Gastrointestinal and Related Structures

A partially patent omphalomesenteric duct is more common, and, if the duct is patent near the periphery, an umbilical sinus draining mucous secretions may be attached to the distal bowel by a fibrous band. When an intermediate portion of the duct is obliterated, a cyst-like structure termed a vitelline cyst or enterocyst will form, which can be located in the wall of the ileum, in the abdominal cavity, or within the umbilicus. Omphalomesenteric duct mucosal remnants, which are also called umbilical polyps or nodules, may appear as red, oozing nodules within the umbilical depression. They secrete mucus but do not have a central canal, differentiating them from a partially patent omphalomesenteric duct.7 Any unusual thickening of the cord at the base should alert the obstetrician and/or pediatrician to the possibility of one of these anomalies. Furthermore, the failure of an apparent umbilical granuloma to respond to silver nitrate cauterization should prompt referral to a pediatric surgeon for assessment and probable excision. In 46 symptomatic patients with omphalomesenteric duct abnormalities managed and reported by Moore,6 approximately one-third became symptomatic before age 1 year, one-third between 1 and 10 years, and one-third after age 11 years. Twenty-eight percent of the patients presented with intestinal obstruction, 28% with abdominal pain, 28% with gastrointestinal bleeding, and 10% with invagination of the distal ileum onto the anterior abdominal wall. As in other series of omphalomesenteric anomalies, boys predominated. 23.3.2 Urachal Abnormalities

Fig. 23-7. Low placement of umbilicus in adult male with achondroplasia.

The urachus forms from the allantois as an outgrowth from the hindgut into the body stalk and has been thought to be vestigial in man. The urachal lumen is normally obliterated by week 15 of gestation, with a resultant fibrous cord, the median umbilical

with cranial displacement of the phallus or deficient foreskin, should prompt investigation of the urinary tract.5

Table 23-2. Omphalomesenteric duct abnormalities* Defect

Incidence

Diagnostic Features

23.3.1 Omphalomesenteric Duct Anomalies

Partially patent omphalomesenteric duct

Rare (.0067%)

Fecal discharge from umbilical lesion; contrast studies reveal communication with bowel

Partially patent omphalomesenteric duct/umbilical sinus

Rare, but more common than above

Umbilical sinus draining mucus; contrast studies do not reveal communication with bowel

Vitelline cyst/ enterocyst

Rare

Palpable subumbilical mass; surgical excision allows for diagnosis

Meckel diverticulum

2%

Abdominal pain, bleeding, intussusception; most asymptomatic

Omphalomesenteric duct remnants/ umbilical nodules

Rare

Clinical diagnosis, radiographs not usually helpful, secrete mucus, have no central canal

Abnormal development of the yolk sac may result in anomalies of the omphalomesenteric duct, including completely patent omphalomesenteric duct and a variety of less severe remnants including partially patent omphalomesenteric duct, cysts, fibrous cords connecting the umbilicus to the distal ileum, and mucosal omphalomesenteric duct remnants at the umbilicus (Table 23-2).6,7 The most common of the omphalomesenteric duct anomalies is the Meckel diverticulum which occurs in 2–3% of the population. This is a simple diverticulum with patency of the proximal portion of the omphalomesenteric duct into the small bowel. Although mostly asymptomatic, it can present with painless rectal bleeding from ectopic gastric mucosa and may also act as the lead point for intussusception in neonates and infants.8 The completely patent omphalomesenteric duct is a rare congenital anomaly characterized by the formation of a fistula between the small bowel and the umbilicus, arising from the antimesenteric surface of the small intestine, usually from the terminal portion of the ileum. The umbilical cord appears thicker than normal at birth, and, after sloughing of the cord, the umbilical depression is occupied by a bright red nodule representing the inverted end of the patent duct. Usually, this is covered with intestinal mucosa, but it may also consist of gastric mucosa or pancreatic tissue.6

*See also Section 35.4.

Ventral Wall of the Trunk

ligament, running from the dome of the bladder to the umbilicus. As has been recently demonstrated by ultrasound, a urachal remnant is almost invariable present at the time of birth. By age 3–5 months, regression is demonstrable; it is still visible and remains visible in two-thirds of children less than age 16 years, one-third of 35-year-olds, and 3% of adult autopsies (reviewed by Cappele et al.10). At least in the published literature, pathologic variants are rare. Among 315 cases reported between 1550 and 1971, complete fistula was most common (47%), followed by cyst (30%), sinus (18%), and diverticulum (3%).10 Failure of the urachal lumen to close results in a completely or partially patent urachus, urachal remnants, or urachal cysts. A completely patent urachus is a rare abnormality that is occasionally recognized prenatally in the presence of urinary tract obstruction. In this situation, the patent urachus may serve as a means of urinary tract decompression. After birth, a patent urachus may be recognized when there is drainage of urine from a fistulous tract at the umbilicus. A partially patent urachus drains clear mucinous secretions at the umbilicus and does not communicate with the bladder. Urachal cysts result from patency of an intermediate portion of the urachus (similar to the vitelline cyst). The cysts may be asymptomatic or may enlarge and present as an abdominal mass. Cysts that drain into the bladder may cause few symptoms. With obstruction, however, infection, abscess formation, urinary tract infection, and an enlarging abdominal mass may be observed.7 Rarely stone formation, voiding difficulties, and malignancy are reported.10 The presence of a urachal abnormality should always prompt thorough evaluation of the kidneys and urinary tract, since coexisting malformations are frequent. Computerized tomography and ultrasound appear to be the imaging modalities of choice in following urachal abnormalities and determining appropriate management.11,12 Umbilical granulomas are not congenital defects but are by far the most common umbilical lesion of infancy. Frequently confused with omphalomesenteric duct and urachal abnormalities, they occur as an inflammatory reaction in the healing umbilical stump. Treatment with topical silver nitrate should lead to healing. If this does not occur, dye studies may be necessary to exclude the possibility of a more serious lesion, and in some cases surgical excision is necessary. A distinctive lesion termed the fibrous umbilical polyp has been delineated among granuloma-like lesions and seems unrelated to either an omphalomesenteric or urachal anomaly. A marked male predominance has been noted.13 Etiology and Distribution

Variations in the size and shape of the umbilicus are extremely common but have not been well classified. It is likely that numerous syndromic associations other than those mentioned previously exist but have yet to be recognized by clinicians. Urachal abnormalities are extremely rare. Persistent omphalomesenteric duct is more common but is still unusual. Persistence of the omphalomesenteric duct occurs when the vitelline duct fails to degenerate after about week 6 of embryonic development. Urachal abnormalities are significantly more common among males (2:1) and occur due to failure of obliteration of the urachal lumen prior to 15 fetal weeks. As noted, persistence of ultrasonographically visible urachal remnants is common in childhood and without pathologic implication. Recurrence rates for persistent omphalomesenteric duct and urachal cysts appear to be exceedingly low. Two unlike sex siblings with urachal sinus abnormalities have been reported.14 In conditions associated with specific umbilical abnormalities, such as

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the Aarskog syndrome, the recurrence risk depends upon the underlying condition. Prognosis, Treatment, and Prevention

The prognosis for abnormalities of the omphalomesenteric duct depends on an accurate and timely diagnosis, since surgical treatment is indicated and the consequences of delayed diagnosis include infection and bowel obstruction. Infection can also complicate urachal abnormalities, and the diagnosis may be delayed until middle childhood or even adulthood. Abnormalities in configuration and placement of the umbilicus by themselves have no effect on the general health of the individual. However, an underlying condition may indicate the need to search for associated anomalies, which may affect prognosis. References (The Umbilicus) 1. Cullen TS: Embryology, Anatomy and Diseases of the Umbilicus Together with Disease of the Urachus. WB Saunders Co, Philadelphia, 1916. 2. Williams AM, Brain JL: The normal position of the umbilicus in the newborn: an aid to improving the cosmetic result in exomphalos major. J Pediatr Surg 36:1045, 2001. 3. Rohrich RH, Sorokin ES, Brown SA, et al.: Is the umbilicus truly midline? Clinical and medicolegal implications. Plast Reconstr Surg 112: 259, 2003. 4. Friedman JM: Umbilical dysmorphology. Clin Genet 28:343, 1985. 5. Aase JM: Caudal displacement of the umbilicus: implications for diagnosis of genitourinary anomalies. Proc Greenwood Genet Center 10:120, 1991. 6. Moore TC: Omphalomesenteric Duct Malformations. Semin Pediatr Surg 5:116, 1996. 7. Pomeranz A: Anomalies, abnormalities and care of the umbilicus. Pediatr Clin North Am 51:819, 2004. 8. O’Donnell KA, Glick PL, Caty MG: Pediatric umbilical problems. Pediatr Clin North Am 45:791, 1998. 9. Jona JZ: Congenital hernia of the cord and associated patent omphalomesenteric duct: a frequent neonatal problem? Am J Perinatol 13:223, 1996. 10. Cappele O, Sibert L, Descargues J, et al.: A study of the anatomic features of the duct of the urachus. Surg Radiol Anat 23:229, 2001. 11. Yu JS, Kim KW, Lee HJ, et al.: Urachal remnant diseases: Spectrum of CT and US findings. Radiographics 21:451, 2001. 12. Ueno T, Hashimoto H, Yokoyama H, et al.: Urachal anomalies: ultrasonography and management. J Pediatr Surg 38:1203, 2003. 13. Vargas SO: Fibrous umbilical polyp: a distinct fasciitis-like proliferation of early childhood with a marked male predominance. Am J Surg Pathol 25:1438, 2001. 14. Kubota K, Nomura S, Kawahara M, et al.: Familial urachal sinus associated with a possible congenital malformation: report of a case. Surg Today 33:237, 2003.

23.4 Umbilical Hernia Definition

Umbilical hernia is a skin-covered protrusion of the umbilicus secondary to a defect in closure of the umbilical ring. Diagnosis

Umbilical hernia and its treatment by ligature or strapping were described in the first century; this has been reviewed by Woods.1 Umbilical hernia is a second-trimester event, occurring after the return of the midgut and obliteration of the extraembryonic coelom at about week 10 of gestation. Since the abdominal

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Gastrointestinal and Related Structures

contents are fixed, the hernia sac contains (if anything) only loops of mobile bowel. The superior portion of the umbilicus between the umbilical vein and the upper margin of the umbilical ring is the weakest area, and herniation occurs here most frequently.2 Defects of the linea alba and diastasis recti may accompany umbilical hernia. The diagnosis of umbilical hernia is usually not difficult. The skin-covered protrusion at the umbilicus is obvious (Fig. 23-8), and an enlarged umbilical ring can be palpated. Pressure on the abdomen or having the patient cough may facilitate palpation of the peritoneal bulge, which can be helpful in obese patients. Umbilical hernia must be distinguished from omphalocele in which abdominal contents herniate into the cord and are covered by peritoneum rather than skin. The umbilical ring is enlarged or defective in both. Gastroschisis is a paraumbilical defect with no amniotic, peritoneal, or cutaneous covering and with herniation of intestinal loops into the amniotic cavity. Omphalomesenteric or urachal remnants may produce cystic masses within the umbilicus, as can metastatic tumor nodules (Sister Joseph nodules).3 An obliterated umbilical artery abscess may also simulate incarceration of an umbilical hernia.4 Supraumbilical hernias occur in the linea alba above the umbilical ring. Umbilical hernias are associated with a variety of known conditions and syndromes, many of which have in common increased abdominal girth, hypotonia, or both, and which may either have prenatal or a postnatal onset. Some of these conditions are listed in Table 23-3. Incarceration of umbilical hernia is rare in children, as is rupture or skin breakdown. One study of 590 children noted a 5% incidence of such complications.5 In other studies, the incidence was even lower. In contrast, adult umbilical hernia has a higher incidence of incarceration, and the surgical morbidity and mortality are significant.6 This is due in part to the underlying conditions predisposing to adult umbilical hernia such as cirrhosis, severe obesity, and multiple pregnancies. It is not clear whether umbilical hernias in adults represent persisting hernias of infancy or whether they occur spontaneously as the result of increased abdominal distension.

Fig. 23-8. Umbilical hernia, showing skin-covered protrusion at the umbilicus. (Courtesy Dr. Will Blackburn, Fairhope, Alabama)

Etiology and Distribution

After week 10, the physiologically herniated midgut returns to the enlarging abdominal cavity from the exocoelom included in the cord. This leads to collapse of the exocoelom and closure of the porthole linking the intraembryonic coelom and the extraembryonic coelom. The mesodermal condensations around the umbilicus grow to reinforce the ring and to increase the strength of the periumbilical skin. Interference with fascial reinforcement before birth or inadequate umbilical scar formation after birth can lead to hernia. The incidence of umbilical hernia in children is strongly dependent on birth weight, age, and race. Low-birth-weight babies have a higher incidence of this defect than do normal weight infants. Umbilical hernia occurs in 84% of infants weighing under 1500 g versus 21% of infants weighing over 2500 g.7 Black race predisposes strongly to umbilical hernia. A 32% prevalence was observed among black infants under age 6 weeks versus a 4% prevalence among white infants. At age 1 year, black infants show a 12% prevalence and white infants a 2% prevalence.7 In a recent study of 4052 individuals in Nigeria, 23% of children from 1 month to 18 years had umbilical hernia, as did 8% of those over 18 years. This suggests that some spontaneous closure of umbilical hernia occurs late in childhood.8 The strong influence of ethnicity suggests the major importance of genetic factors in the causation of umbilical hernia. Umbilical hernia is significantly more common among families in which omphalocele has occurred. Genetic factors have been recognized as important in umbilical hernias in cattle, where they occur in 4–15% of calves, especially in Holstein Friesian cattle. Evaluation of umbilical hernia in over 53,000 German Fleckvieh calves suggested that more than one genetic locus controls expression of this defect in cattle.9 Prognosis, Prevention, and Treatment

Multiple studies on the natural history of umbilical hernia in children have demonstrated that most small defects close spontaneously prior to age 4 years. Heifetz et al.10 reported that the umbilical ring contracts in area by approximately 18% per month once closure starts. In their study of 78 patients, 31 rings had closed within the first year and 72 within the first 4 years. Upright posture, ambulation, and increased strength of the rectus abdominus muscles achieved with growth contribute to umbilical ring closure. Factors predicting spontaneous closure include the age and race of the child, the size of the fascial defect, and the amount of protruding skin. Spontaneous closure can be anticipated in most children by age 3–5 years, especially in Caucasians. In children in whom the defect is greater than 1.5 cm in diameter or where there is a large proboscis-like defect, the chances for spontaneous closure are low.11 The operative approach that most advocate includes resection of the hernia sac, and this may be done as an outpatient procedure for most children. Primary repair is associated with about a 10% rate of recurrence. Increasingly, laparoscopic repair using mesh has been advocated, as it reduces recurrence and postoperative complications.12 Adult umbilical hernia should be repaired prophylactically because of the high morbidity and mortality rates associated with incarceration, and current data favor laparoscopic repair.13 Strangulation rarely occurs in childhood, but has been reported in about 1/1500 hernias. It is usually associated with small hernias less than 1.5 cm in diameter, and patients present with umbilical pain, periumbilical tenderness, and erythema.11,14

Table 23-3. Representative conditions/syndromes associated with umbilical hernia Condition

Findings (in addition to umbilical hernia)

Causation Gene/Locus

Aspartylglucosaminuria

Mental retardation, coarse features, sagging cheeks, diarrhea, angiofibromas, angiokeratoma

AR (208400) Deficiency of N-aspartylbeta-glucosaminidase

Beare-Stevenson cutis gyrata

Cutis gyrata, acanthosis nigricans, skin and mucosal tags, ear defects, craniosynostosis, anogenital anomalies

Sporadic (123790) FGFR2, 10q26

Beckwith-Wiedemann

Macrosomia, typical face, increased tumor risk, omphalocele, hemihypertrophy

Sporadic, AD, UPD (130650) Dup or UPD 11p15.5 KIP2, 11p15.5

Carpenter

Acrocephaly, syndactyly, preaxial polydactyly, obesity, hearing loss

AR (201000)

Down

Typical phenotypic findings, omphalocele rare

Trisomy 21 (94%) Mosaicism and translocations (6%)

Ehlers-Danlos VIIC

Very fragile skin, blood vessel fragility, bleeding, micrognathia, large fontanelle

AR (225410) Type 1 procollagen Nproteinase deficiency (gene on 5q23) causes abnormal type 1 collagen formation

GAPO

Growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy

AR (230740)

Gorlin-Chaudhry-Moss

Slightly coarse features, short distal phalanges, hearing loss, sparse hair, hirsutism, short stature, normal IQ

AR (233500)

Hennekam

Lymphedema, unusual face, small ears, lymphangiectasia

AR (235510)

Malpuech

Cleft lip/palate, hypertelorism, shawl scrotum, GU abnormalities

AR (148340)

Melnick-Needles

Short stature, full cheeks, small chin, distinctive skeletal changes

XLD (309350) FLNA, Xq28

Mucopolysaccharidoses I-VII

Variable: short stature, dysostosis multiplex, hepatosplenomegaly

AR (252800) IDUA, 4p16.3 XLR (309900) IDS, Xq28 AR (252940) GNS, 12q14 AR (253000) GALNS, 16q24.1 AR (253200) ARSB, 5q11-q13 AR (253220) GUSB, 7q21.11

Rieger

Anterior segment dysgenesis, dental anomalies

AD (180500) PITX2, 4q25-q26 additional locus at 13q14

Shprintzen-Goldberg

Marfanoid habitus, craniosynostosis, exophthalmus, mental retardation

AD (182212) FBN1 (15q21.1) in some cases

Trisomy 13

Cleft lip/palate, scalp defects, cardiac defects, other typical features

Trisomy 13

Trisomy 18

Clenched hands, short sternum, cardiac defects, other typical features

Trisomy 18

Uniparental disomy for chromosome 6

Transient neonatal diabetes, hypertelorism, macroglossia

(601410) Paternal UPD 6

Van der Woude

Cleft lip/palate plus lip pits/sinuses

(119300) IRF6, 1q32-q41

Weaver

Accelerated growth and osseous development, camptodactyly, hoarse voice

(277590) A few cases have had mutations in NSD1 (5q35)

Williams

Infantile hypercalcemia, cardiac defects, typical face and personality

AD (194050) Haploinsufficiency for genes at 7q11.2 including LIMK and ELN

1033

1034

Gastrointestinal and Related Structures

Following repair of umbilical hernia, a large amount of redundant skin may remain, and restoration of a more normal umbilicus has been a surgical challenge. Umbilicoplasty using various techniques has been successful, and Tamir and Kurzbart’s report of repair in identical twins is of interest.15 References (Umbilical Hernia) 1. Woods GE: Some observations on umbilical hernia in infants. Arch Dis Child 28:450, 1953. 2. Harmel RP Jr: Umbilical hernia. In: Hernia. LM Nyhus, RE Condon, eds. JB Lippincott Co, Philadelphia, 1989, p 354. 3. Sharaki M, Abdel-Kader M: Umbilical deposits from internal malignancy (the Sister Joseph’s nodules). Clin Oncol 7:351, 1981. 4. Mares AJ, Siplovich L: Obliterated umbilical artery abscess simulating a strangulated umbilical hernia: a late complication of neonatal umbilical artery catheterization. Israel J Med Sci 20:1197, 1984. 5. Lasaletta L, Fonkalsrud EW, Tovar JA, et al.: The management of umbilical hernia in infancy and childhood. J Pediatr Surg 10:405, 1975. 6. Morgan WW, White JJ, Stumbaugh S, et al.: Prophylactic umbilical hernia repair in childhood to prevent adult incarceration. Surg Clin North Am 50:839, 1970. 7. Evans AG: Comparative incidence of umbilical hernias in colored and white infants. J Natl Med Assoc 33:158, 1944. 8. Meier DE, Olaolorun DA, Omodele RA, et al.: Incidence of umbilical hernia in African children: redefinition of ‘‘normal’’ and reevaluation of indications for repair. World J Surg 25:645, 2001. 9. Herrmann R, Utz J, Rosenberger E, et al.: Risk factors for congenital umbilical hernia in German Fleckvieh. Vet J 162:233, 2001. 10. Heifetz CJ, Vilsel ZT, Gaus WW: Observations on the disappearance of umbilical hernias of infancy and childhood. Surg Gynecol Obstet 116: 469, 1963. 11. Katz DA: Evaluation and management of inguinal and umbilical hernias. Pediatr Ann 30:12, 2001. 12. Wright BE, Beckerman J, Cohen M, et al.: Is laparoscopic umbilical hernia repair with mesh a reasonable alternative to conventional repair? Am J Surg 84:505, 2002. 13. Lau H, Patil NG: Umbilical hernia in adults. Surg Endosc 17:2016, 2003.

14. Okada T, Yoshida H, Iwai J, et al.: Strangulated umbilical hernia in a child: report of a case. Surg Today 31:546, 2001. 15. Tamir G, Kurzbart E: Umbilical reconstruction of large umbilical hernia: the ‘‘lazy M’’ and omega flaps. J Pediatr Surg 39:226, 2004.

23.5 Omphalocele Definition

Omphalocele is a defect in the ventral abdominal wall, with herniation of abdominal viscera through a widened umbilical ring. The defect is covered by a sac consisting of amnion and lined by peritoneum. The umbilical cord inserts into the sac. Omphalocele is also called exomphalos or amniocele. Diagnosis

The first descriptions of infants with omphalocele date from Lycosthenes’ Chronicon of 1557 and Pare’s writings of the same century.1,2 Williams described the first surgical repair of omphalocele in 1930.3 In 1948, Gross developed a staged skin flap procedure, which yielded improved results and survival.4 The clinical appearance of omphalocele is usually quite distinct from that of the infant with gastroschisis (Section 23.6). The abdominal wall defect, which may vary between 2 and 15 cm, may contain small and large intestines, stomach, liver, spleen, bladder, uterus, and ovaries (Fig. 23-9). The abdominal cavity is small, and bowel malrotation is frequently present. In contrast to the case in gastroschisis, the bowel in omphalocele appears normal because it has been protected by the covering sac. Intrauterine rupture of an omphalocele sac occurs rarely, leaving sac remnants, and in this situation thickening and edema of the bowel wall may occur. Associated anomalies are extremely frequent in infants with omphalocele, with prevalence figures in the recent literature varying from 50–75%.5–7 Cardiac abnormalities are found in about 30% of cases, and neural tube defects in 15%.5,6 Two-thirds of infants with

Fig. 23-9. Omphalocele. Left: lateral view of intact omphalocele (O) showing sharp demarcation of skin and membrane (arrows). Middle: dissection shows liver (L) and gallbladder (GB) as only contents. Right: larger omphalocele containing most of the abdominal organs. (Courtesy Dr. Will Blackburn, Fairhope, Alabama.)

Ventral Wall of the Trunk

1035

omphalocele and congenital heart defects have additional anomalies, often constituting a specific syndrome. In series of infants with congenital heart disease and omphalocele without other major anomalies, frequent cardiac defects include tetralogy of Fallot, atrial and ventricular septal defects, and coarctation of the aorta.8 Chromosomal abnormalities occur in 10–40% of liveborn infants with omphalocele and are more frequent in prenatally ascertained cases. Looking at pooled data from three studies, it is clear that in the presence of additional anomalies identified on ultrasound, the chance of an abnormal karyotype is very high (87%); even in the absence of other detectable anomalies, the risk for a chromosomal abnormality remains significant (22%).9 Associated chromosomal abnormalities are most commonly trisomy 13 and 18, although omphalocele has also been seen in a large variety of other chromosome abnormalities. Of particular interest is the association of omphalocele with duplication 3q, which has been reported in several patients. A small region of interest with respect to omphalocele has been further localized to distal 3qter using BAC clones, suggesting a localization for gene(s) important in abdominal wall formation.10 The association of omphalocele with Down syndrome has been a subject of recent debate.11–13 If present, the association is of interest since the exonic sequence sim in Drosophila controls early mid-line central nervous system development in the fly and is conserved on human chromosome 21. Transgenic mouse work with sim suggests a pathogenetic mechanism for behavioral abnormalities and perhaps for midline abnormalities, such as omphalocele, in Down syndrome.14 There is a significant association with genetic syndromes, particularly the Beckwith-Wiedemann syndrome (BWS). Investigators have generated a mouse model for BWS with two different imprinting mutations; one a null mutation in p57 kip2 and the other with a loss of IGF2 imprinting. The mice have many characteristics of BWS including omphalocele. The two imprinted genes appear to act antagonistically, which helps explain why mutations in either gene can produce the syndrome.15 A number of other rare syndromes include omphalocele as a clinical feature (Table 23-4). Conditions in which omphalocele had been reported at least twice were included, although there are a few syndromes seemingly limited to a single family. Familial recurrences of omphalocele are reported somewhat more frequently than recurrences of gastroschisis. Obviously, in disorders such as the Beckwith-Wiedemann syndrome, which may occur as an autosomal dominant condition, the recurrence risk may be as high as 50%. Recurrence of omphalocele has been reported in at least 15 families.40 DiLiberti suggests that recurrence is more likely when omphalocele is isolated, i.e., not associated with other non-gastrointestinal malformations, and when there is a positive family history of abdominal wall hernias.40 He speculates that the basis for the recurrence may be an autosomal dominant defect of muscle or connective tissue differentiation. Kanagawa reported an additional family with nine individuals in three generations including male-to-male transmission supportive of autosomal dominant inheritance.41 Additional large population-based studies are needed to accurately determine the recurrence risk for isolated omphalocele.

lethal conditions. Approximately 45% of liveborn children with this defect die without surgery, usually due to the presence of associated anomalies. Prematurity occurs less often in association with isolated omphalocele (11%) than in association with isolated gastroschisis. However, with multiple anomalies, the incidence of prematurity is high (43% including stillbirths). Low birth weight (< 2500 g) occurs in patients with isolated defects and in 50% of those with multiple anomalies. The maternal age-specific rate for omphalocele is stable until approximately age 40 years, at which time it increases coincident with the increase in chromosomal aneuploidy.42 The embryologic explanation for the occurrence of omphalocele is a subject of some controversy, and the actual term omphalocele may have contributed to this confusion; a preferable term might be amniocele.43–45 There appears to be arrest of progression of the amnioectodermal junction toward the umbilicus. The amnion bridges the gap between the arrested amnioectodermal junction and the umbilicus and thus makes an extraembryonic contribution to the ventral abdominal wall. This amniotic patch, unlike the somatopleure, is unable to support migration and/or stabilization of migrating mesoderm from the somites. The patch stops abruptly at the displaced amnioectodermal junction and, therefore, does not mature into normal body wall. The patch remains as an avascular thin membrane, which is easily stretched by increasing intraabdominal pressure, giving rise to a membrane covered hernia, i.e., an ‘‘amniocele.’’ Visceral herniation is retroamniotic going into the exocoelom, lined internally by flat mesothelium, which is an extension of the intraembryonic peritoneum. This explains why the omphalocele membrane consists of amnion on the outside and peritoneum on the inside. A failure of lateral fold formation is commonly considered to cause the typical abdominal omphalocele, but this cannot be so since the omphalocele would be bifid, with the median septum of normal body wall formed from the cephalic and caudal folds. Thus, the supraumbilical or infraumbilical omphalocele is characterized by a defect in which the cord inserts either caudally or cranially, respectively, and results from the combined deficiency of the lateral folds and the cephalic and/or caudal folds. The funnel-shaped central omphalocele with the cord inserted into the apex can only result from the circumferential failure of all folds to reach the umbilicus. The site of cord insertion into the sac thus depends on the degree of involvement of the four folds. The timing of this defect is, therefore, somewhat earlier than that of gastroschisis, occurring during weeks 2–4 of gestation. As was discussed previously, omphalocele is commonly associated with other malformations as part of chromosomal defects, syndromes, and other recognized associations (Table 23-4). Two teratogens have emerged as potential associations in omphalocele. At least two children exposed prenatally to valproic acid have been reported with omphalocele.46 Omphalocele is also part of a spectrum of anomalies that may follow use of misoprostol as a failed abortifacient.47 Omphalocele can be seen as part of the early amnion disruption sequence, although gastroschisis is more frequent. Supraumbilical omphalocele is seen as part of Cantrell’s pentalogy, and infraumbilical omphalocele as part of the exstrophy of the cloaca.

Etiology and Distribution

Prognosis, Treatment, and Prevention

The incidence of omphalocele is about 2.5/10,000 livebirths and, unlike the rate of gastroschisis which has increased in the last decade, the rates for omphalocele are stable.42 Only 75% of infants with omphalocele are liveborn, reflecting the high association with

A meta-analysis of mode of delivery in abdominal wall defects analyzed in 15 studies by Segal et al. looked at rate of primary repair, incidence of neonatal sepsis, neonatal mortality, time to first feed, and length of hospitalization.48 She found no significant

Table 23-4. Syndromes with omphalocele Syndrome

Prominent Features

Causation Gene/Locus

Beckwith-Wiedemann

Macrosomia, typical face, increased tumor risk, hemihypertrophy

Sporadic, AD, (130650) UPD Dup 11p15.5; mutation of the p57(KIP2) gene CDKN1C

Pallister-Killian17

Coarse features, deafness, hyperpigmented streaks, temporofrontal balding, profound MR

(601803) Mosaicism tetrasomy 12p

OEIS18

Omphalocele, exstrophy, imperforate anus, spinal defects (cloacal exstrophy), variable spectrum, increased in MZ twinning

Sporadic, rare AR (258040)

Prune belly and omphalocele19

Absent abdominal musculature, hydronephrosis, sternal ossification defects; 7 cases reported

Sporadic

Cantrell pentalogy20

Diaphragmatic and ventral hernias, hypoplastic lungs, cardiac defects, sternal fusion defects, ectopia cordis

Sporadic, rarely XL (313850)

Cantrell pentalogy and sirenomelia21

Associated with vascular steal, MZ twinning

Sporadic

Hydrolethalus22

Postaxial polydactyly hands; preaxial polydactyly feet, hallux duplex, key hole foramen magnum, AV canal, cleft palate, diaphragmatic hernia, lung hypoplasia

AR (236680) 11q23-q25

Acrocallosal23

Macrocephaly, duplex hallux, postaxial polydactyly, absent corpus callosum, anencephaly, cranial cysts

AR (may be alleleic with hydrolethalus) (200990)

Meckel24

Renal cysts, CNS defects (usually encephalocele), hepatic ductal dysplasia and cysts, and polydactyly

AR (249000) MKS2, 11q MKS3, 8q

Miller-Dieker25

Lissencephaly, characteristic face, failure to thrive, microcephaly, seizures, death before age 2

AD (601545) Del 17p13 LIS1, 17p13

Fryns26

Coarse face, corneal clouding, camptodactyly with hypoplastic nails, diaphragmatic hernia, GU abnormalities, cystic hygroma, MR

AR (229850)

CHARGE27

Coloboma, heart anomaly, choanal atresia, retardation of growth and mental development, genital and ear anomalies; facial palsy

AD (214800) CHD7, 8q12

Fibrochondrogenesis28

Lethal rhizomelic chondrodysplasia; broad long-bone metaphyses, pear-shaped vertebral bodies, unique interwoven fibrous septa and fibroblastic dysplasia of chrondrocytes, severe micrognathia and bifid tongue

AR (228520)

Acrocephalopolysyndactyly type II (Carpenter)29

Craniosynostosis, brachydactyly, a syndactyly in the hands, preaxial polydactyly and syndactyly in feet

AR (201000)

Melnick-Needles30

Typical face, flared metaphyses and bowing long bones, ribbon-like ribs, pectus, club feet, cleft palate, failure to thrive

XLD (309350) FLNA, Xq28

Otopalatodigital, type I31

Bone dysplasia, conductive deafness, cleft palate, characteristic facies, broad nasal root, pugilistic appearance, toe spacing resembles tree frog

XLD (311300) FLNA, Xq28

Otopalatodigital, type II32

Cleft palate, midface hypoplasia, downward-slanting palpebral fissures, small thorax, bowed limbs with absent fibulae. Heterozygous females are more mildly affected

XL semi-dominant (304120)

C33

Unusual facies, trigonencephaly, postaxial polydactyly, cardiac abnormality, 50% die in first year

AR, most sporadic (211750)

Manitoba oculotrichoanal (MOTA)34

Hypertelorism, anomalous scalp hair, eye malformations, anal anomalies

AR (248450)

Brachial amelia, forebrain defects and facial clefts35

Holoprosencephaly, anterior encephalocele, oligodactyly, CL/P, amelia

Sporadic (601357)

Gershoni-Baruch36

Radial ray defects, agenesis of diaphragm, cardiac defects vertebral defects, abnormal lung lobation

AR

Donnai-Barrow37

Diaphragmatic hernia, absent corpus callosum, hypertelorism, myopia, hearing loss

AR

Shprintzen omphalocele38

One family; scoliosis, learning disabilities; pharyngeal and laryngeal abnormalities

AD (182210)

Omphalocele-cleft palate39

One family; 3 girls; lethal; cleft palate, GU abnormalities and hydrocephalus in one

AR (258320)

16

1036

Ventral Wall of the Trunk

differences between these factors in those delivered by cesarean section versus those delivered vaginally. Thus, except in unusual circumstances, there is no convincing evidence to support a policy of routine cesarean section delivery for these infants. Neonatal management of the child with omphalocele is similar to that for gastroschisis. Assessment and treatment of respiratory distress is important, as is close monitoring of serum glucose because of the association of omphalocele with Beckwith-Wiedemann syndrome. Further investigation of the infant with omphalocele should optimally involve consultation with a geneticist and cardiologist prior to surgical repair. The outlook for children with omphalocele is highly dependent on the presence or absence of additional congenital abnormalities. For prenatally diagnosed omphalocele, 20–50% of patients have chromosomal abnormalities, and many of these infants abort or die in utero.6 However, the prognosis for infants with isolated omphalocele in which primary closure is possible is excellent and, in experienced hands, survival approaches 100%. Factors involved in improved survival include rapid neonatal transport and vigorous resuscitation, improved infant ventilators and anesthesia, and the use of postoperative total parenteral nutrition. Improved surgical techniques have also contributed greatly to survival and reduced morbidity. During surgical repair, assessment of respiratory status is critical and will often determine whether the surgeon can perform a primary closure or must utilize a Silastic silo for staged reduction. These issues are reviewed in recent papers by Weber et al. and Wakhlu and Wakhlu.49,50 About 60% of omphaloceles can be closed primarily and 40% require the use of a silo. Staged procedures overcome many of the cardiac and respiratory problems associated with large defects; however, in those with ruptured omphalocele, there may be prolonged ileus and other surgical complications. Construction of the silo eliminates the occurrence of dehiscence, decreases angulation which may cause vascular compromise of the bowel, and appears to improve outcome. Patients with giant omphalocele represent a significant challenge; they are more likely to have associated abnormalities and, even in the absence of these conditions, have a mortality rate of 50%. Death in those with giant omphalocele may be related to pulmonary hypoplasia and underlying respiratory failure. In one center’s experience, use of resorbable polyglycan mesh to stabilize the defect followed by split thickness skin grafting met with recent success although tracheotomy was required in several patients for 1 to 2 years.50 Saxena and Willital report significant success with human dural grafts in those large defects which cannot be closed primarily. This approach avoids the need for multiple surgeries in infancy. A single surgery is followed by a cosmetic repair at age 2 to 3 years and is an alternative to the silo.52 Prenatal diagnosis of omphalocele is possible with ultrasound and maternal serum a-fetoprotein (MS-AFP) screening. The detection rate for omphalocele is significantly lower than that for gastroschisis because of the presence of a covering membrane. It has been reported that approximately 42% of omphaloceles will be detected with MS-AFP screening. In one series, median values for MS-AFP for omphalocele were 4.18 times the median.53 The ultrasound differential diagnosis of omphalocele is chiefly from gastroschisis. Omphaloceles are midline, the umbilical cord enters the hernia, and the eviscerated organs are enclosed by a membrane. The stomach and liver are much more likely to be extruded through the anterior ventral wall in omphalocele. Chromosomally abnormal fetuses are significantly less likely to have liver present in the omphalocele sac.8 Similarly, cardiac defects and other anoma-

1037

lies associated with chromosome problems are more likely in those with omphalocele. Utilizing 3-D ultrasound, the prenatal diagnosis of omphalocele, suspected on a two- dimensional study, was confirmed at 12 weeks gestation.54 Fast MRI has allowed for evaluation of the extent, location, and severity of the abdominal wall defect adding to the information available from ultrasound.55 Unfortunately, MRI should not be used in the first trimester. Generalized overgrowth with visceromegaly may suggest the diagnosis of Beckwith-Wiedemann syndrome. Although complications with the bowel itself, e.g., thickening and edema, are much less common in those with omphalocele, fetuses should have serial ultrasound monitoring because of the occasional occurrence of ascites, which may be related to cord constriction. In addition to amniocentesis for fetal karyotype, fetal echocardiography is strongly indicated when the prenatal diagnosis of omphalocele has been made because this may influence parents’ decisions regarding continuation or termination of the pregnancy. In the presence of a normal karyotype and a normal high-resolution ultrasound examination, including fetal echocardiography, parents can be given reassurance of a generally favorable prognosis for their child. A recent small case control study from the Metropolitan Atlanta Congenital Defects Program found a 60% reduction in risk associated with periconceptional multivitamin use and the risk for non-syndromic omphalocele.56 If this study is replicated and confirmed, supplementation would provide additional reassurance to families, and if widely adopted, lower the risk for this serious birth defect. The study also supports the view that omphalocele shares developmental pathways with other defects impacted by multivitamins or alternatively suggests that multivitamins have a pleiotropic effect on many malformations with varying etiologies. References (Omphalocele) 1. Ballantyne JW: Manual of Antenatal Pathology and Hygiene. The Embryo. William Green and Sons, Edinburgh, 1904, p 513. 2. Pare A: The Workes of that Famous Chirurgeon. Ambrose Parey, translated by T. Johnson. T Cotes, R. Young, London, 1634, p 59. 3. Williams C: Congenital defects of the anterior abdominal wall. Surg Clin North Am 10:805, 1930. 4. Gross RE: A new method for surgical treatment of large omphaloceles. Surgery 24:277, 1948. 5. Axt R, Quijano F, Boos R, et al.: Omphalocele and gastroschisis: prenatal diagnosis and peripartal management: A case analysis of the years 1989-1997 at the Department of Obstetrics and Gynecology, University of Homburg/Saar. Eur J Obstet Gynecol 87:47, 1999. 6. Boyd, PA, Bhattacharjee A, Gould S, et al.: Outcome of parentally diagnosed anterior abdominal wall defects. Arch Dis Child Fetal Neonatal Ed 78:F209, 1998. 7. Stoll C, Alembik Y, Dott B, et al.: Risk factors in congenital abdominal wall defects (omphalocele and gastroschisis): a study in a series of 265,858 consecutive births. Annales de Genetique 44:201, 2001. 8. Gibbin C, Touch S, Broth RE, et al.: Abdominal wall defects and congenital heart disease. Ultrasound Obstet Gynecol 21:334, 2003. 9. DeVeciana M, Major CA, Porto M: Prediction of an abnormal karyotype in fetuses with omphalocele. Prenat Diagn 14:487, 1994. 10. Yatsenko SA, Mendoza-Londono R, Belmont JW, et al: Omphalocele in Trisomy 3q: further delineation of phenotype. Clin Genet 64:404, 2003. 11. Reddy VN, Aughton DJ, DeWitte DB, et al.: Down syndrome and omphalocele: an underrecognized association. Pediatrics 93:514, 1994. 12. Torfs CP, Honore LH, Curry CJR: Is there an association of Down syndrome and omphalocele? Am J Med Genet 73:400, 1997. 13. Mastroiacovo P, Robert E, Kallen B: Is there an association of Down syndrome and omphalocele? Am J Med Genet 82:443, 1999. 14. Chen H, Chrast R, Rossiser C, et al.: Single-minded and Down syndrome? Nat Genet 10:9, 1995.

1038

Gastrointestinal and Related Structures

15. Caspary T, Cleary MA, Perlman EJ, et al.: Oppositely imprinted genes p57kir2 and Igf2 interact in mouse model for Beckwith Wiedemann syndrome. Genes Dev 13:3115, 1999. 16. Weksberg R, Smith AC, Squire J, et al.: Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 12 Spec No 1:R61, 2003. 17. Kanagawa SL, Begleiter ML, Ostlie DJ, et al.: Omphalocele in three generations with autosomal dominant transmission. J Med Genet 39: 184, 2002. 18. Keppler-Noreuil KM: OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases. Am J Med Genet 99: 271, 2001. 19. Carmi R, Boughman JA: Pentalogy of Cantrell and associated midline anomalies: a possible ventral midline developmental field. Am J Med Genet 42:90, 1992. 20. Carmi R, Boughman JA: Pentaology of Cantrell and associated midline anomalies: a possible ventral midline developmental field. Am J Med Genet 42:90, 1992. 21. Egan JF, Petrikovsky BM, Vintzileos AM, et al.: Combined pentaology of Cantrell and sirenomelia: a case report with speculation about a common etiology. Am J Perinatol 10:327, 1992. 22. Salonen R, Herva R: Hydrolethalus syndrome. J Med Genet 27:756, 1990. 23. Koenig R, Bach A, Woelki U, et al.: Spectrum of the acrocallosal syndrome. Am J Med Genet 108:7, 2002. 24. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 25. Chitayat D, Toi A, Babul R, et al.: Omphalocele in Miller-Dieker syndrome: expanding the phenotype. Am J Med Genet 69:293, 1997. 26. Cunniff C, Jones KL, Saal HM, et al.: Fryns syndrome: an autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia. Pediatrics 85:499, 1990. 27. Tellier AL, Cormier-Daire V, Abadie V, et al.: CHARGE syndrome: report of 47 cases and review. Am J Med Genet 76:402, 1998. 28. Hunt NC, Vujanic GM: Fibrochondrogenesis in a 17-week fetus: a case expanding the phenotype. Am J Med Genet 75:326, 1998. 29. Gershoni-Baruch R: Carpenter syndrome: marked variability of expression to include the Summitt and Goodman syndromes. Am J Med Genet 35:236, 1990. 30. Kristiansen M, Knudsen GP, Soyland A, et al.: Phenotypic variation in Melnick-Needles syndrome is not reflected in X inactivation patterns from blood or buccal smear. Am J Med Genet 108:120, 2002. 31. Biancalana V, LeMarec B, Odent S, et al.: Oto-palato-digital syndrome type I: further evidence for assignment of the locus to Xq28. Hum Genet 88:228, 1991. 32. Holder SE, Winter RM: Otopalatodigital syndrome type II. J Med Genet 30:310, 1993. 33. Glickstein J, Karasik J, Caride DG, et al.: ‘‘C’’ trigonocephaly syndrome: report of a child with agenesis of the corpus callosum and tetralogy of Fallot, and review. Am J Med Genet 56:215, 1995. 34. Marles SL, Greenberg CR, Persaud TV, et al.: New familial syndrome of unilateral upper eyelid coloboma, aberrant anterior hairline pattern, and anal anomalies in Manitoba Indians. Am J Med Genet 42:793, 1992. 35. Froster UG, Briner J, Zimmermann R, et al.: Bilateral brachial amelia, facial clefts, encephalocele, orbital cyst and omphalocele: a recurrent fetal malformation pattern coming into focus. Clin Dysmorphol 5:171, 1996. 36. Franceschini P, Guala A, Licata D, et al.: Gershoni-Baruch syndrome: report of a new family confirming autosomal recessive inheritance. Am J Med Genet 122A:174, 2003. 37. Chassaing N, Lacombe D, Carles D, et al.: Donnai-Barrow syndrome: four additional patients. Am J Med Genet 121A:258, 2003. 38. Shprintzen RJ, Goldberg RB: Dysmorphic facies, omphalocele, laryngeal and pharyngeal hypoplasia, spinal anomalies, and learning disabilities in a new dominant malformation syndrome. Birth Defects Orig Artic Ser 15(5B):347, 1979. 39. Czeizel A: New lethal omphalocele-cleft palate syndrome? Hum Genet 64:99, 1983.

40. DiLiberti JH: Familial omphalocele: analysis of risk factors and case report. Am J Med Genet 13:263, 1982. 41. Kanagawa SL, Begleiter ML, Ostlie DJ, et al.: Omphalocele in three generations with autosomal dominant transmission. J Med Genet 39:184, 2002. 42. Torfs C, Curry C, Roeper P: Gastroschisis. J Pediatr 116:1, 1990. 43. Duhamel B: Embryology of exomphalos and allied malformations. Arch Dis Child 38:142, 1963. 44. De Vries P: The pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 15:245, 1980. 45. Margoris L: Omphalocele (amniocele). Am J Obstet Gynecol 49:695, 1945. 46. Boussemart T, Bonneau D, Levard G: Omphalocele in a newborn baby exposed to sodium valproate in utero. Eur J Pediatr 154:220, 1995. 47. Genest DR, DiSalvo D, Rosenblatt MJ, et al.: Terminal transverse limb defects with tethering and omphalocele in a 17 week fetus following first trimester misoprostol exposure. Clin Dysmorphol 8:53, 1999. 48. Segal SY, Marder SJ, Parry S: Fetal abdominal wall defects and mode of delivery: a systematic review. Obstet Gynecol 98:867, 2001. 49. Weber TR, Au-Fliegner M, Downard CD, et al.: Anatomy and embryology. Curr Opin Pediatr 14:491, 2002. 50. Wakhlu A, Wakhlu AK: The management of exomphalos. J Pediatr Surg 35:73, 2000. 51. Bawazir OA, Wong A, Sigalet DL, et al.: Absorbable mesh and skin flaps or grafts in the management of ruptured giant omphalocele. J Pediatr Surg 38:725, 2003. 52. Saxena AK, Willital GH: Omphalocele: clinical review and surgical experience using dura patch grafts. Hernia 6:73, 2002. 53. Saller DN Jr, Canick JA, Palomaki GE, et al.: Second-trimester maternal serum alpha-fetoprotein, unconjugated estriol, and hCG levels in pregnancies with ventral wall defects. Obstet Gynecol 84:852, 1994. 54. Anandakymar C, Badruddin MN, Chua TM, et al.: First trimester prenatal diagnosis of omphalocele using three-dimensional ultrasonography. Ultrasound Obstet Gynecol 20:635, 2002. 55. Verswijvel G, Gyselaers W, Grieten M, et al.: Omphalocele: prenatal MR findings. JBR-BTR 85:200, 2002. 56. Botto LD, Mulinare J, Erickson JD: Occurrence of omphalocele in relation to maternal multivitamin use: a population-based study. Pediatrics 109:904, 2002.

23.6 Gastroschisis Definition

Gastroschisis is an abdominal wall defect lateral to the umbilicus usually to the right, with herniation of the abdominal contents directly into the amniotic cavity without any protective membrane. The term gastroschisis (from Greek for gastro ¼ belly, schism ¼ separation) was used in the early teratology literature for the condition now called omphalocele. Taruffi, in 1894, subclassified gastroschisis into seven categories, although his nomenclature was never widely accepted.1 Ballantyne, in 1904, used the term gastroschisis to designate all abdominal defects with the exception of umbilical hernia.2 Diagnosis

Gastroschisis has been regarded as an entity distinct from omphalocele since the classification of abdominal wall defects proposed by Moore and Stokes in 1953.3 Gastroschisis is a paramedian defect usually located on the right side of the cord (Fig. 23-10). The umbilical cord is intact arising lateral to the defect usually with an intervening normal bridge of skin. These anatomic characteristics, along with epidemiologic features, serve to distinguish gastroschisis from omphalocele (Table 23-5).

Ventral Wall of the Trunk

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Fig. 23-10. Gastroschisis in an infant with sirenomelia (top) and in a 20-week-old fetus without other anomalies (bottom). Note that the defect arises separately and to the left of the umbilical cord in the 20-week-old fetus. All of the small intestines and the proximal half of the colon were herniated in the infant with sirenomelia; only a portion of the ileum was herniated in the fetus.

In two recent series, 5 of 26 (19%) and 22 of 70 (31%) patients had additional anomalies.4,5 A higher incidence in the larger study reflects the inclusion of children with gastrointestinal anomalies. The majority of the associated anomalies in gastroschisis involve agenesis or disruption of a structure. Most are defects in which there is strong evidence supporting the pathogenetic importance of in utero vascular compromise. These defects include renal agenesis, porencephaly, and atresia of the gall bladder. A small, but

significant number of patients with gastroschisis have arthrogryposis of the amyoplasia type. Among patients with congenital contractures of this type, approximately 12% have been found to have gastroschisis, bowel atresia, and/or lateral defects in the trunk wall musculature.6 It seems unlikely that this association is a coincidence, and in a series from the California Birth Defects Monitoring Program (CBDMP), 3 of 135 cases were found to have amyoplasia.7

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Gastrointestinal and Related Structures Table 23-5. Features distinguishing gastroschisis from omphalocele Gastroschisis

Omphalocele

Location of defect

Usually right of umbilicus

Within umbilical ring

Umbilical cord

Normal insertion

Inserts into defect

Sac

No

Yes

Bowel

Matted, atresias and stenosis common

Usually normal

Organs extruded

Bowel, stomach, bladder, uterus, rarely liver

Bowel and liver commonly

Other birth defects

Approximately 20%, usually vascular disruptions

Approximately 75% (heart defects, trisomies, syndromes)

Maternal age

Young mothers, highest incidence in those under age 20 years

Age not a factor until þ35 years (associated with higher risk of trisomies)

Recent attention has focused on possible differences between gastroschisis occurring antenatally, which is presumably long standing, and perinatal lesions where herniation of the abdominal content may be a late phenomenon and surgical repair significantly less complicated. Experimental work on the chicken embryo has produced a successful animal model for gastroschisis.8 Data from the chicken and from human fetuses suggest that edema of the bowel and enmeshment of the intestines in a dense gelatinous matrix are most likely related to exposure to fetal urine (amniotic fluid) after the 30th week of gestation.9 Work in a fetal rabbit model has suggested that the size of the defect makes little difference in the degree of ischemic damage, or severity of bowel wall edema.10 There are several examples in the ultrasound literature suggesting that, even in experienced hands, gastroschisis may be missed and that in these cases of late herniation, the bowel often appears quite normal without thickening or matting at the time of delivery.11 These data suggest that although the defect is an early event, onset of herniation can be variable and that in some defects, the evisceration is probably a late phenomenon occurring only with fetal growth and increased intra-abdominal pressure. Etiology and Distribution

During the past two decades there has been an apparent increase in the incidence of children born with gastroschisis in several countries in Europe, as well as in the United States. The increasing incidence of gastroschisis does not appear to be completely explained by reporting artifacts or enhanced awareness of the appropriate classification of abdominal wall defects. It occurs almost exclusively in infants of mothers younger than 25 years of age. Although the overall rate is about 1/10,000 births, the rate for mothers under 20 years of age may reach 7/10,000.7 In 19 registries worldwide reporting on 2073 cases of gastroschisis, the overall prevalence was 0.29/10,000 births, with nine registries reporting an increasing incidence beginning in the late 1980s. This suggests an epigenetic or environmental influence.12 This age distribution is distinctly different from that of omphalocele. Almost 45% of infants with isolated gastroschisis are born prematurely, especially when gastroschisis is associated with atresias, stenosis, perforations, or volvulus.13 This is significantly higher than the incidence observed in isolated omphalocele. Low birth rate is also significantly more common than in omphalocele, occurring in 38% of cases,7 and is, again, more frequent in those with complex lesions.13,14 Approximately 90% of infants with gastroschisis are liveborn and relatively few die shortly after birth. Surprisingly, a relatively high percentage of families in a European registry chose elective termination despite the relatively good prognosis for gas-

troschisis.15 Most of the mortality in gastroschisis is related to the complexity of the lesion and the severity of surgical complications and ranges from approximately 3–30%.13,14 Consequently, most liveborn infants with gastroschisis undergo surgery versus only 37% of those with omphalocele.7 These distributions explain why recent surgical case series report a higher proportion of infants with gastroschisis than of infants with omphalocele. The pathogenesis of gastroschisis is, as yet, imperfectly understood. It has been ascribed to failure of maturation of the primordial body wall which is followed by rupture when abdominal pressure rises. Full thickness rupture leads to herniation of viscera. deVries proposed that gastroschisis occurs when there is premature atrophy or abnormal persistence of the right umbilical vein leading to mesenchymal damage and failure of the epidermis to differentiate at that site; this hypothesis is supported by the report of two cases of left-sided gastroschisis in which the left rather than the right umbilical vein had atrophied.16 Hoyme et al. has proposed that most cases of gastroschisis can be explained by intrauterine disruption of the right omphalomesenteric artery.17 Interruption of this artery lead concurrently to the frequent association of intestinal atresia or stenosis and explains the preferential involvement of the right side of the umbilicus and the high concurrence rate of other disruptive events thought to be the result of in utero vascular accidents. One fact arguing against this hypothesis is that the developing vessel wall receives its blood supply from parietal arteries and not from the omphalomesenteric artery. Furthermore, healing and resorption of tissues on the margin of the defect occur following the disruption, restoring the normal appearance of the skin and umbilical ring medial to the defect, and yet typical cases of gastroschisis have been seen in early second trimester abortuses. Shaw proposed a unitary hypotheses of omphalocele and gastroschisis.18 He suggested that gastroschisis is a ruptured hernia of the cord occurring after formation of the abdominal wall but before complete formation of the umbilical ring. He proposed that after rupture of the umbilical hernial sac, skin grows in from the edges of the defect and grows about the base of the cord, accounting for the skin bridge between the defect and the umbilicus. Shaw stated that gastroschisis is the result of intrauterine rupture of the membrane covering the umbilicus during its normal phase of development (5–10 weeks) or later in cases of abnormal formation of the umbilical ring. Confusion between the condition of omphalocele and umbilical hernia may explain the rare case in which there has been documented intrauterine rupture of an omphalocele with an appearance identical to that of gastroschisis at birth.

Ventral Wall of the Trunk

Timing of the defect of gastroschisis is also controversial. Most embryologists suggest that the defect occurs between weeks 5 and 10 of gestation. However, examples of this defect in early embryos have not been reported, suggesting that herniation does not occur until increasing abdominal pressure stretches the weak body wall. Whatever the underlying mechanism for the causation of gastroschisis, the clinical and epidemiologic evidence clearly separates gastroschisis from omphalocele. Gastroschisis is not associated with any known chromosomal or genetic syndromes. Infants with limb-body wall complex secondary to early amnion rupture sequence may be incorrectly classified as having gastroschisis. Such cases should be removed from analyses of cases with isolated gastroschisis, since the pathogenesis of this defect is clearly different. The association of gastroschisis and amyoplasia has been confirmed and may be related by a common vascular pathogenetic mechanism. Gastroschisis has been seen in association with schizencephaly and in a surviving twin with a deceased monozygotic co-twin, again supporting a vascular pathogenesis for gastroschisis.19 One recent case report of gastroschisis in a carbimazole-exposed pregnancy is of interest, as this agent is associated with scalp cutis aplasia and there may be as many as three other abdominal wall defects in the literature associated with this exposure.20 Ten case control studies have examined risk factors for gastroschisis, and those factors with significant odds ratio in one or more studies were maternal smoking, pseudoephedrine, aspirin, solvent exposure, and cocaine.21–23 In the literature, there are 11 reports of families in which gastroschisis has recurred, and some authors have suggested that gastroschisis may be related to other abdominal wall herniations and represents variable expressions of the same genotype.24 Supporting this view are reports of two families in which one sibling had an omphalocele and another a gastroschisis. A study of 127 families from the CBDMP found an empiric sibling recurrence risk of 3.5%.24 Prognosis, Treatment, and Prevention

The prognosis for infants with gastroschisis has improved dramatically from approximately a 90% mortality rate in 1967 to an average mortality ranging from 3–8% in 2001–02. In recent studies, however, mortality in surgically complex cases can still approach 30%.13,14 Factors affecting prognosis include the degree of prematurity, the presence or absence of associated anomalies, and, perhaps most important, the degree of bowel dilation and mural thickening which may compromise functional recovery. The timing of delivery remains controversial. Some investigators have advocated routine preterm delivery to minimize the period of exposure of the bowel wall to amniotic fluid. Bond et al. reported that of 57 antenatally diagnosed patients with gastroschisis, those delivered at term had earlier closure of their defects and shorter times to first and full feedings.25 There seems to be fairly convincing evidence that the chemically irritating effects of amniotic fluid cause the dilation and fibrous coating of the bowel and that the degree of damage increases with advancing gestational age. However, the clinical significance of these findings is not at all clear.26 The mode of delivery also remains controversial. Some investigators advocate the use of routine cesarean section, suggesting that it reduces the likelihood of injury to the abdominal organs during labor and birth as well as avoiding contamination and improving outcome. Others have shown no benefit of cesarean versus vaginal delivery.28,29 Scheduled cesarean delivery

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after confirmation of lung maturity may allow for delivery in a more controlled environment with the availability of the pediatric surgeon and possibly a shortened hospital stay. At this time, retrospective studies on the best mode of delivery suggest that there is no significant difference in outcome for infants delivered vaginally versus cesarean section.27,28 The type of surgical repair has also been the topic of some controversy. The original technique of flap closure described by Gross in 1948 carried a mortality rate of 67%.29 Shuster described the use of polyethylene film and Teflon, and later investigators have utilized silastic prosthetic materials. Recent literature has favored stretching the abdominal wall and primary closure or silastic sac closure using a combination of techniques. Recently, excellent results have been achieved using either primary closure or a preformed silo to provide coverage for the exposed viscera and allow a gradual reduction into the abdominal cavity.30 The prenatal diagnosis of gastroschisis is now a common event and is based on the ultrasound findings of freely floating eviscerated organs usually located to the right of the umbilicus with a normally inserted cord. Rarely, an omphalocele may rupture in utero and simulate a gastroschisis. The liver and stomach are much more likely to be herniated in omphalocele. Intrauterine growth retardation and hydramnios are common in gastroschisis as are dilated, thickened loops of bowel. Studies have confirmed the accuracy of ultrasound in distinguishing omphalocele and gastroschisis.31 Defects may occasionally be missed ultrasonographically depending on operator experience and/or equipment15 when there is coexisting oligohydramnios or when the evisceration occurs late in the pregnancy. MS-AFP screening is extremely valuable in the detection of ventral wall defects, particularly gastroschisis. The median MSAFP level in gastroschisis reported by Saller et al. is 9.42 MoM.32 Amniotic fluid acetylcholinesterase is also positive in the vast majority of pregnancies with gastroschisis. The prenatal diagnosis of gastroschisis by ultrasound should prompt a careful ultrasound evaluation for other anomalies which might indicate poor outcome for the infant, e.g., findings suggestive of early amnion rupture. Chromosome analysis has been suggested in all abdominal wall defects, although there are no reports of unbalanced karyotypes reported with gastroschisis. Nonetheless, the amniocentesis may provide parental reassurance in diagnostically confusing cases. The presence of a positive acetylcholinesterase band may help confirm the diagnosis of gastroschisis. Serial prenatal monitoring by ultrasound is recommended in order to monitor for polyhydramnios, intrauterine growth retardation, and progressive bowel dilation. References (Gastroschisis) 1. Taruffi C: Storia della teratologia. Regia Tipografia, Bologna, 1894. 2. Ballantyne JW: Manual of Antenatal Pathology and Hygiene: The Embryo. Edinbourgh, 1904. 3. Moore TC, Stokes GE: Gastroschisis: report of two cases treated by a modification of the Gross operation for omphalocele. Surgery 33:112, 1953. 4. Durfee S, Downard CD, Benson CB, et al.: Postnatal Outcome of Fetuses with the prenatal diagnosis of gastroschisis. J Ultrasound Med 21:269, 2002. 5. Saxena, AK, Hulskamp G, Schleef J, et al.: Gastroschisis: a 15 year, single-center experience. Pediatr Surg Int 18:420, 2002. 6. Reid COMV, Hall JG, Anderson C, et al.: Association of amyoplasia with gastroschisis, bowel atresia and defects of the muscular layer of the trunk. Am J Med Genet 24:701, 1986. 7. Torfs C, Curry C, Roper P: Gastroschisis. J Pediatr 116:1, 1990. 8. Kluck P, Tibboel D, Van der Camp AW, et al.: The effect of fetal urine on the development of the bowel in gastroschisis. J Pediatr Surg 18:47, 1983.

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Gastrointestinal and Related Structures

9. Tibboel D, Vermey-Keers C, Kluck P, et al.: The natural history of gastroschisis during fetal life: Development of the fibrous coating on the bowel loop. Teratology 33:267, 1986. 10. Albert A, Sancho MA, Julia V, et al.: Intestinal damage in gastroschisis is independent of the size of the abdominal defect. Pediatr Surg Int 17:116, 2001. 11. Knott PD, Colley NV: Can fetal gastroschisis always be diagnosed prenatally? Prenat Diagn 7:607, 1987. 12. DiTanna GL, Rosano A, Mastroiacovo P: Prevalence of gastroschisis at birth: retrospective study. BMJ 325:1389, 2002. 13. Molik KA, Gingalewski KW, West FJ: Gastroschisis: A Plea for Risk Categorization. J Pediatr Surg 36:51, 2001. 14. Baerg J, Kaban G, Tonita J, et al.: Gastroschisis: a Sixteen-Year review. J Pediatr Surg 38:771, 2003. 15. Barisic I, Clementi M, Hausler M, et al.: Evaluation of prenatal ultrasound diagnosis of fetal abdominal wall defects by 19 European registries. Ultrasound Obstet Gynecol 18:309, 2001. 16. deVries PA: The pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 15:245, 1980. 17. Hoyme HE, Jones MC, Jones KL: Gastroschisis: abdominal wall disruption secondary to early gestational interruption of the omphalomesenteric artery. Semin Perinatol 7:294, 1983. 18. Shaw A: The myth of gastroschisis. J Pediatr Surg 10:235, 1975. 19. Curry CJ: Personal communication. 20. Guignon AM, Mallaret MP, Jouk PS: Carbimazole related gastroschisis. Ann Pharmacother 38:829, 2003. 21. Torfs CP, Katz EA, Bateson TF, et al.: Maternal medications and environmental exposures as risk factors for gastroschisis. Teratology 54:84, 1996. 22. Kozer,E, Nikfar S, Cosei A, et al.: Asperin consumption during the first trimester of pregnancy and congenital abnormalities: A meta-analysis. Am J Obstet Gynecol 187:1623, 2002. 23. Werler MM, Sheehan JE, Mitchell AA: Association of vasoconstrictive exposures with risks of gastroschisis and small intestinal atresia. Epidemiology 14:349, 2003. 24. Torfs CP, Curry CJ: Familial cases of gastroschisis in a population based registry. Am J Med Genet 15:465, 1993. 25. Bond SJ, Harrison MR, Filly RA, et al.: Severity of intestinal damage in gastroschisis: Correlation with prenatal sonographic findings. J Pediatr Surg 23:520, 1988. 26. Huang J, Kurkchubasche AG, Carr SR: Benefits of term delivery in infants with antenatally diagnosed gastroschisis. Obstet Gynecol 100:695, 2002. 27. Strauss RA, Balu R, Kuller JA, et al.: Gastroschisis: the effect of labor and ruptured membranes on neonatal outcome. Am J Obstet Gynecol 189:1672, 2003. 28. Singh SJ, Fraser A, Leditschke JF, et al.: Gastroschisis: determinants of neonatal outcome. Pediatr Surg Int 19:260, 2003. 29. Gross RE: A new method for surgical treatment of large omphaloceles. Surgery, 24:277, 1948. 30. Schlatter M: Preformed silos in the management of gastroschisis: New progress with an old idea. Curr Opin Pediatr 15:239, 2003. 31. Salihu HM, Boos R, Schmidt W: Omphalocele and gastroschisis. J Obstet Gynecol 22:489, 2002. 32. Saller DN Jr, Canick JA, Palomaki GE, et al.: Second-trimester maternal serum alpha-fetoprotein, unconjugated estriol, and hCG levels in pregnancies with ventral wall defects. Obstet Gynecol 84:852, 1994.

23.7 Exstrophy of the Bladder Definition

Exstrophy of the bladder is a defect in the lower abdominal wall in which the posterior bladder wall mucosa is exposed. The umbilicus is inferiorly displaced and located close to the exstrophic bladder.

Diagnosis

Bladder exstrophy was described in the cuneiform tablets of Chaldea dating from 2000 BC.1 Scheuke von Graefenberg reports of a child treated in 1597 (reviewed in ref. 2). Reports from the Englishlanguage literature dating from the 18th century have been reviewed by Ballantyne3. In boys, characteristics of bladder exstrophy most commonly include an open urinary tract along the dorsal aspect of the penis through the anterior aspect of the bladder neck and bladder to the level of the umbilicus (epispadias) (Fig. 23-11). It may involve all or part of the penile shaft, and the penis tends to be broad and short. In female epispadias, the labia may hide the bifid clitoris and the larger urethral opening, sometimes obscuring the exposed bladder mucosa. The clitoris may be split and there may be a bifid uterus and a duplicate or exstrophic vagina. There is separation of the rectus abdominus muscles, rectus fascia, and symphysis pubis. The umbilicus is much lower than its usual mid-abdominal position, and the anus may be displaced anteriorly. The clinical picture of bladder exstrophy is striking and not likely to be confused with that of other entities except perhaps for exstrophy of the cloaca, in which the bowel is involved in the anomaly. Cloacal exstrophy includes imperforate anus and spinal defects, either open or closed, and usually an omphalocele. There may be associated duplication of Mu¨llerian duct structures. In exstrophy of the bladder, the upper urinary tract is usually normal, although unilateral renal agenesis, horseshoe kidney, and megaureter have been reported. The ureters enter the bladder such that reflux is invariable following repair. Indirect inguinal hernias are frequent, because abnormal muscle attachments lead to a short inguinal canal, with enlarged internal and external rings. Sponseller and colleagues4 have described the pelvic anatomy and secondary skeletal problems using CT scanning in 24 patients with bladder exstrophy, revealing that there is a 12-degree outward rotation of the posterior pelvis on each side, retroversion of the acetabuli, a 30% shortening of the pubic rami, and progressive diastasis of the symphysis pubis. These changes are thought to contribute to the short pendular penis. The outward rotation and lateral displacement of the innominate bones account for the increased distance between the hips and the outward rotation of the Fig. 23-11. Exstrophy of the bladder in a male infant. The penis was short and broad with epispadias. (Courtesy of Dr. Sami Elhassani, Spartanburg, SC.)

Ventral Wall of the Trunk

lower limbs which cause little disability. The waddling gait results from the external rotation of the lower limbs resulting from the posterolateral position of the acetabulum. The feet are externally rotated but correct spontaneously during childhood. These findings have been confirmed in studies using 3-D CT5 and have led to insights on the deformation of the bony pelvis and pelvic ring which may improve the surgical outcome of pelvic osteotomies. In a series of 81 patients with bladder exstrophy, there was a relatively low association with malformations outside the genitourinary system, with scoliosis, sacral agenesis, and hindgut duplications reported occasionally.6 Genital malformations, particularly epispadias, are a uniform feature of bladder exstrophy. The penile abnormality may appear to be so severe to necessitate consideration of gender reassignment in the neonatal period. However, recent data from Johns Hopkins suggests that genetic sex may be more important than anatomic sex in determining the sex of rearing.7 Often, genital reconstruction can permit near-normal sexual function. In females, successful pregnancies have been reported after reconstructive surgery, although uterine prolapse can be a serious problem both during and after pregnancy.2 Lack of urinary continence is a serious concern with this disorder. It now seems to be generally accepted that primary bladder closure in the early neonatal period followed by bladder neck reconstruction offers the best chance for eventual continence, which may approach 90% in experienced hands.2 Urinary tract infections are common with all forms of treatment due to reflux and hydronephrosis. Urinary tract infections appear to be most common in those who have undergone internal diversion with ureterosigmoidostomy and ileal conduits. Anal incontinence may occur due to anterior displacement of the anus. The literature indicates that malignant lesions of the bladder mucosa occurred in about 8% of patients with untreated bladder exstrophy between the third and fifth decades. About 80% of these tumors were adenocarcinomas and were probably related to the acute and chronic inflammatory changes associated with exposure and infection. Squamous cell carcinomas, accounting for 7% of bladder tumors, are a risk in exstrophied bladders that are left everted.8 The malignant risk associated with bladder exstrophy

closed at birth has been difficult to estimate because of lack of long-term follow-up studies. In one series of 28 patients with a low risk of malignancy because of early bladder closure, two patients had cancer (bladder and kidney) between ages 40 and 44.9 These data suggest that careful surveillance of exstrophy patients is warranted. Variants of exstrophy of the bladder are rare and, interestingly, these variants appear to be significantly more common among females in contrast to the usual male predominance in typical bladder exstrophy.10 These variants are summarized in Table 23-6. Alterations in timing and position of cloacal membrane rupture explain the clinically observed variants of bladder exstrophy. If the in-growth of mesoderm between the two layers of the cloacal membrane occurs before rupture, there is no exstrophy and the body wall is intact, with or without secondary hernia formation. This variant is characterized by the musculoskeletal defects typical of exstrophy and is termed pseudoexstrophy. If the ingrowth of mesoderm follows rupture of the cloacal membrane, the clinical picture is modified by the degree of ‘‘repair’’ accomplished by this in-growth. If the repair is complete, there is no exstrophy, but the typical musculoskeletal defects are present. This variant is known as duplicate exstrophy. In duplicate exstrophy, a small portion of exstrophied bladder remains exposed on the abdominal surface, with an intact urinary tract beneath (Fig. 23-12). In patients with exstrophy variants, a low lying umbilicus is common, as are umbilical hernias and large ventral hernias. Genital abnormalities occur in all patients; the male usually has a bifid scrotum and a small, short penis. The prognosis for eventual continence seems somewhat better for these patients, but reflux and secondary renal damage remain a significant concern. Etiology and Distribution

The etiology of bladder exstrophy is still not perfectly understood, partly because exstrophy of the bladder and exstrophy of the cloaca do not occur as normal embryologic events and no similar defects comparable to the human exstrophies occur in animals. Although they are the subject of some debate, the embryologic

Table 23-6. Variants of bladder exstrophy Variant Form

Musculoskeletal Finding

Distinguishing Features

Superior vesical fistula or fissure

þ

Normal bladder communicates to skin via fistula with small exstrophied portion visible below abnormal umbilicus, continence usual, to be differentiated from urachal fistula

Closed exstrophy

þ

No exstrophy, usually bifid bladder with or without a vesicointestinal fistula, presumed to occur after cloacal membrane rupture with secondary ‘‘repair’’

Duplicate exstrophy

þ

Occurs when superior vesicle fistula is present but fuses in embryonic life, exposed bladder mucosa just beneath low lying umbilicus, may have fistulous connection with underlying bladder, usually normal urinary tract

Pseudoexstrophy

þ

Delayed ingrowth of mesoderm before cloacal membrane rupture, normal urinary tract, cloacal membrane persists as a triangular linea alba, bladder bulges when full, simulating ventral hernia

Inferior vesicle

þ

Small defect in bladder neck, mucosa protrudes with increased intraabdominal pressure, epispadias, incontinence

Penopubic epispadias Balanic penile epispadias

þ/ 

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Epispadias extends through the vesicle sphincter, continence variable Involvement of only the glans or extension beyond coronal sulcus onto the penile shaft

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Gastrointestinal and Related Structures

Fig. 23-12. Schematic of duplicate exstrophy showing a small portion of the bladder on the abdominal surface with an otherwise normal lower urinary tract.

interpretations of Marshall and Mueke10 are widely quoted. In the 4-mm crown-rump length embryo (approximately 24 days), the cloacal membrane extends to the body stalk, forming the anterior wall of the cloaca. Between the end of weeks 4 and 5 (4–8 mm crown–rump length), the cloacal membrane is progressively obliterated by migration of mesodermal cells from the primitive streak between the two-layered structure. The membrane forms the anterior wall of the lower two-thirds of the cloaca by 6 mm, and, by 8 mm crown–rump length, it begins to form the floor of the developing genital tubercle (Fig. 23-13). The mesoderm ‘‘wedges’’ itself between the two cloacal membrane layers, forming paired genital folds, which fuse superiorly to form the genital tubercle. The cloacal membrane is pushed down and forward, forming the floor of the primitive phallus or clitoris. If this flow of mesoderm is delayed or incomplete because of an enlarged cloacal membrane, the cloacal membrane will remain as a weak twolayered membrane subject to rupture (Fig. 23-14). The genital folds then fuse inferiorly, with the cloacal membrane as a roof rather than as a floor. As a consequence, musculoskeletal structures are held apart, the pelvic girdle is widened, and the urethral groove lies anteriorly. If the defect occurs prior to urorectal septation, the more extensive defects of exstrophy of the cloaca occur, in which the hindgut prolapses between two hemibladders (see Section 23.8). Alternatively, the mesoderm may fail to grow between the ectoderm and the endoderm causing its premature rupture.11 Many authors agree with Gearhart and Jeffs,2 who

consider that exstrophy of the bladder represents a slightly later abnormality in embryogenesis than does exstrophy of the cloaca.12 Although exstrophy of the bladder is most often a sporadic event, 17 families have now been reported in which exstrophy and/or epispadias have been present in at least two family members. Reutter and colleagues13 review these data and report seven families recruited through an Internet-based support group, including one consanguineous family with an affected child, two siblings, two 3rd-degree cousins, and two uncle–nephew pairs. In addition, there have now been 22 twin pairs reported; 11 were monozygotic with half of these concordant for the defect, and nine were dizygotic pairs, all discordant for the defect. Concordance in twins, some familial recurrences, and lack of a pattern of mendelian inheritance suggests that this may be a multifactorial disorder with some genetic susceptibility plus environmental risk factors. Bladder exstrophy is an uncommon anomaly, occurring in between 1:30,000 and 1:50,000 live births; but is much more frequent than cloacal exstrophy.12 The sex ratio of 2.3:1 suggests that, in the complete form, it is primarily a defect of male development (reviewed in 12). Variants of bladder exstrophy represent about one-half of all cases. There was a barely significant association with young maternal age in a 1987 report from the International Clearinghouse for Birth Defects Monitoring System.14 Prognosis, Treatment, and Prevention

The prognosis for bladder exstrophy has improved quite significantly in recent years, but the care and repair of exstrophy remains a formidable challenge which is best handled in a tertiary care center experienced in the care of this condition. Historically, surgical repair frequently failed, and the problem of incontinence, chronic renal damage, and inadequate urogenital reconstruction plagued these unfortunate patients. Internal urinary diversion via anastomosis of the urinary tract with the bowel solved the problem of continence but was unacceptable because of damage to the upper urinary tract and frequent electrolyte problems. External urinary diversion via ileal or colonic conduits was effective in providing continence; however, this was also often unacceptable to patients and did not prevent deterioration of the upper urinary tract. Recent management techniques are significantly more encouraging with respect to achievement of continence, normal sexual function, and normal renal function. Under the management scheme proposed by Gearhart and Jeffs,2 primary bladder closure is

Fig. 23-13. Schematic showing obliteration of the portion of the cloacal membrane adjacent to the body stalk as the genital tubercle forms.

Ventral Wall of the Trunk

1045

Fig. 23-14. Schematics showing formation of exstrophy of the bladder by rupture of the cloacal (urogenital) membrane. (A) Transverse section. (B) Sagittal section.

undertaken in the first 72 hours of life. The need for osteotomy remains a controversial issue, depending on the degree of pubic diastasis and the timing of repair. If there is any doubt, most experts seem to conclude it should be performed.15 It is thought that this very early closure as well as the positioning of the urethra and the bladder neck deep in the pelvis are extremely important with respect to the achievement of later continence.15 Immobilization of the infant in traction appears to offer the best chances for primary healing, which takes place over a period of 3–4 weeks. Complications, even in experienced hands , are common. Recently, attempts have been made to utilize uroepithelium for augmentation of the bladder by using a reconfigured piece of the patient’s own ureter as a bladder patch. Functional bladder tissue has also been engineered in vitro, and experiments in a lamb and canine model of exstrophy are encouraging with respect to this eventual approach to bladder augmentation in the exstrophic patient.16 Aggressive measures to control infection and to prevent reflux are implemented during the first 2.5–3 years of the child’s life, and urologic assessments, including measurement of bladder capacity, are made prior to bladder neck reconstruction. Between age 2.5 and 5 years, bilateral ureteroneocystostomy, bladder neck reconstruction, and epispadias repair can be undertaken. In patients in whom early bladder closure has not been undertaken, it may be necessary to consider internal or external diversion, but this would be an exception with current treatment. Recent results from major centers indicate a high rate of success, with continence and normal renal function in 75–90% of cases.17 Social adjustment in patients with bladder exstrophy is considered to be fairly satisfactory. Mental retardation is not part of this condition, and many patients have married and borne children.2 Accurate prenatal diagnosis of exstrophy of the bladder is possible via ultrasound, and this condition may as well produce an elevation in MS-AFP. On ultrasound, abnormal-appearing geni-

talia and failure of normal bladder filling are suggestive of this diagnosis. The exstrophic bladder may mimic omphalocele.18 Exposure of the bladder mucosa to the amniotic fluid will result in elevation of the MS-AFP. Closed and pseudoexstrophy variants will not result in elevation of MS-AFP, since bladder mucosa is not exposed to amniotic fluid. Prenatal diagnosis allows parents to make a rational choice regarding the pregnancy. They should optimally meet with an individual experienced in this disorder in order to make an informed decision. Considering the complexity of care and the critical nature of the initial surgery with respect to long-term prognosis, referral to a tertiary medical center with experience in the multidisciplinary care of these children would seem appropriate. References (Exstrophy of the Bladder) 1. Ballantyne JW: The teratological records of Chaldea. Teratologia 1:132, 1894. 2. Gearhart JP, Jeffs RD: Exstrophy-epispadias complex and bladder anomalies. In: Campbell’s Urology, ed 7. Walsh PC, Retik AB, Vaughan ED, et al., eds. WB Saunders, 1998, p 1948. 3. Ballantyne JW: Manual of Antenatal Pathology and Hygiene. The Embryo. William Green & Sons, Edinburgh, 1904. 4. Sponseller PD, Bisson LJ, Gearhart JP, et al.: The anatomy of the pelvis in the exstrophy complex. J Bone Joint Surg Am 77:177, 1995. 5. Stec AA, Pannu HK, Tadros YE, et al.: Evaluation of the bony pelvis in classic bladder exstrophy by using CT: further insights. Urology 58: 1030, 2001. 6. de la Hunt MN, O’Donnell H: Current management of bladder exstrophy: ABAPS collective review from 8 centers of 81 patients born between 1975 and 1985. J Pediatr Surg 24:584, 1989. 7. Reiner WG, Gearhart JP: Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 350:333, 2004. 8. Kandzari SJ, Majid A, Ortega AM, et al.: Exstrophy of the bladder complicated by adeno carcinoma. Urology 3:496, 1974.

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Gastrointestinal and Related Structures

9. Smeulders N, Woodhouse CR: Neoplasia in adult exstrophy patients. BJU Int 87:623, 2001. 10. Marshall VF, Muecke EC: Variations in exstrophy of the bladder. J Urol 88:766, 1962. 11. Thomalla JV, Rudolph RA, Rink RC, et al.: Induction to cloacal exstrophy in the check embryo using the CO2 laser. J Urol 134:991, 1985. 12. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261, 2001. 13. Reutter H, Shapiro E, Gruen JR: Seven new cases of familial isolated bladder exstrophy and epispadias complex (BEEC) and review of the literature. Am J Med Genet 120A:215, 2003. 14. International Clearinghouse for Birth Defects Monitoring System: Epidemiology of bladder exstrophy and epispadias: A communication from the International Clearinghouse for Birth Defects Monitoring System. Teratology 36:221, 1987. 15. Poli-Merol ML, Watson JA, Gearhart JP: New basic science concepts in the treatment of classic bladder exstrophy. Urology 60:749, 2002. 16. Atala A: Future trends in bladder reconstructive surgery, Semin in Pediatr Surg 11:134, 2002. 17. Chan D, Jeffs RD, Gearhart JP: Determinants of continence in the bladder exstrophy population: predictors of success? Urology 57:774, 2001. 18. Cacciari A, Pilu GL, Mordenti M, et al.: Prenatal diagnosis of bladder exstrophy: what counseling? J Urol 161:259, 1999.

6.

7.

8.

9. 23.8 Exstrophy of the Cloaca Definition

Exstrophy of the cloaca is an extensive lower abdominal wall defect that includes exstrophy of the bladder and the associated musculoskeletal defects, frequent spinal defects with or without meningomyelocele, imperforate anus, and often omphalocele. Other terms used to describe this anomaly are vesicointestinal fissure, OEIS complex, and extrophia splanchnica. Diagnosis

Exstrophic conditions were described by several observers in the 17th and 18th centuries, but clear distinction between exstrophy of the cloaca and exstrophy of the bladder was not made.1–3 Exstrophy of the cloaca is an extensive defect, which presents a remarkable clinical picture consisting of the following: 1. Exstrophy of the bladder. Usually the bladder is separated into two halves (hemibladders) by the hindgut plate representing the cecum. 2. Ileocecal fistulas. A poorly developed hindgut intussuscepts into the middle of the defect through the ileocecal valve, with the characteristic appearance of an ‘‘elephant trunk.’’ Distally, there is usually an opening into the rudimentary hindgut. 3. Double appendiceal diverticula are located laterally. These anomalies present as one or two additional ostia on the upper portions of the exstrophied intestine. 4. Anal and colonic atresia. Imperforate anus is constant, and the rudimentary hindgut ends blindly. 5. Lumbosacral spine defects. These are defects in the neural arches that are occasionally asymmetrical and lead to protrusion of a soft, skin-covered mass, which in most cases consists of a terminal myelomeningocele with a localized cystic dilation of the spinal cord. The cord is low lying and tethering is frequent. Occasionally, a true open meningomyelocele or covered

lipomeningocele is present. Lower vertebral defects including extra vertebrae, missing vertebrae, and hemivertebrae have been present in about 50–60% of cases.4,7,8 Omphalocele. This anomaly is present in 65–90% of cases. It can be absent in an otherwise typical presentation.3–6 The omphalocele may be small or extremely large and may include the liver, small bowel, and spleen and is more caudally located than the usual omphalocele. Other gastrointestinal defects include single umbilical artery, duplicated colon, and malrotation.3,5–8. Genital anomalies. In males, genital malformations generally involve separation of the two halves of the phallus as well as the prostatic and urethral tissues. In the Soper and Kilger series4 of 29 males, 8 had agenesis of the penis, 19 had agenesis of the scrotum, 15 had diphallus, and 8 had bifid scrotum; among 24 females, the clitoris was absent in 14 and bifid in 7, the vagina was absent in 6 and duplicated in 14. Duplication of the uterus is common. Rarely, in both sexes, there is a smooth perineum, without any identifiable genital parts.6 Renal malformations. Various anomalies are seen in about one-half of the patients reviewed in several series.3–8 These include unilateral renal agenesis, multicystic kidney, renal dysplasia, pelvic kidney, crossed renal ectopia, and ureteral atresia. Other anomalies. Defects distant from the abdominal wall are uncommon but are somewhat more frequent than in bladder exstrophy. Cardiac defects have been reported with some frequency by Gearhart and Jeffs.3 The rarer anomalies such as limb deficiencies, oral clefts, ectopia cordis, severe scoliosis, and missing diaphragm may be the consequence of a broader pattern of defects secondary to early amnion disruption sequence, and these infants seldom survive. In the series by Carey et al.,9 two patients had polydactyly. In Keppler-Noreuil’s6 series of 14 patients, one had 4-limb arthrogryposis with a small cerebellum and another had distinct thumb hypoplasia. Two out of 37 patients in the Johns Hopkins7 series had surgery for craniosynostosis.

Exstrophy of the cloaca can be differentiated from the less severe exstrophy of the bladder by the consistent presence of imperforate anus and an abnormal hindgut (Fig. 23-15). Spinal defects are generally not seen in bladder exstrophy. Although the defects are extremely similar, their epidemiologic characteristics are distinctive, supportive of a difference in embryologic timing. Cloacal exstrophy occurs before partitioning of the cloaca by the urorectal septum, and bladder exstrophy occurs following urorectal septation. Variants in cloacal exstrophy are common, representing slightly less than one-half of all cases. Alterations in the timing of the breakdown of the cloacal membrane and the degree of urorectal septation explain the wide spectrum of defects. These variations are generally secondary to delayed, but not entirely absent, mesodermal invasion of the cloacal membrane. The terms given to variants of cloacal exstrophy are similar to those used for the variants of bladder exstrophy. Pseudoexstrophy occurs when the abdominal wall closes before cloacal membrane rupture; closed exstrophy occurs when mesodermal infiltration partially or completely repairs the defect caused by cloacal rupture (Fig. 23-16). Etiology and Distribution

The generally accepted theory of the etiology of cloacal exstrophy is that by the end of week 6–7 of gestation, the urorectal septum

Ventral Wall of the Trunk

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Fig. 23-15. Exstrophy of the cloaca. Left: note extension of defect to umbilicus, separation of genital structures, and imperforate anus. Right: note omphalocele and prolapse of the ileum and appendix onto the exstrophied cloaca.

divides the primitive cloaca into two parts; the anterior urogenital sinus and the posterior rectum. The cloacal membrane then ruptures normally before the end of week 8. The development of cloacal exstrophy is represented in Figure 23-17. Abnormal mesodermal migration between the ectodermal and endodermal layers of the cloacal membrane or failure of mesodermal migration are postulated to cause its premature perforation.10,11 Two different embryonic events (cloacal membrane perforation and failure of urorectal septation) appear to account for the anomalies seen in this defect, or alternatively early rupture of the cloacal membrane may occur before the septum has had time to develop. This latter explanation is thought to be more likely. It is the general consensus that it is the stage of development when the ‘‘hit’’ or abnormality occurs that determines whether the defect is cloacal exstrophy or bladder exstrophy, with cloacal exstrophy representing an earlier disturbance in embyogenesis and bladder exstrophy occurring later.5 These timing differences could easily account for the observed epidemiologic differences in the two conditions. However, an interesting case of female dizogotic twins followed by serial ultrasound challenges this commonly accepted

Fig. 23-16. Pseudoexstrophy in which the abdominal skin covers the defect. The labia and symphysis pubis are separated.

theory. One twin had a small omphalocele at 18 weeks; the other had a complex cloacal abnormality, oligohydramnios, and hydronephrosis with an intact anterior membrane. At 24 weeks gestation, the amniotic fluid had returned to normal and the urinary tract obstruction had resolved with disappearance of the anterior membrane. Clearly the cloacal membrane had ruptured between weeks 18–24 of gestation. Typical exstrophy of the cloaca was present at birth.12 The incidence of exstrophy of the cloaca has been estimated in the literature to be about 1/200,000. This figure was confirmed in the recent population-based study from the Spanish Collaborative Study of Congenital Malformations in a population of 1,601,860 livebirths.5 In the past, cases may have been underascertained and misclassified. This has certainly been the experience in the California Birth Defects Monitoring Program (CBDMP).13 Usually, the more obvious defects such as omphalocele and bladder exstrophy are listed as the diagnosis, but the overall pattern of exstrophy of the cloaca is not recognized. Unlike the case with bladder exstrophy, most series of cloacal exstrophy patients report equal involvement of males and females.3,5–8 In a CBDMP series of 18 cases of classical and variant cloacal exstrophy ascertained between 1983 and 1986, there were 6 males and 11 females, and in 1 the sex was not determined. Most series, including that from the CBDMP, indicate a slight tendency toward prematurity and low birth rate.13 The causes of cloacal exstrophy are heterogeneous. Cases from the literature and the CBDMP series indicate that early amnion rupture is a much more common cause of this anomaly than previously appreciated. Findings suggestive of early amnion rupture include amniotic attachments of the ventral body wall to the placenta and severe and characteristic scoliosis, which results in highly abnormal positioning of the lower limbs. Typical constriction rings or amputations usually associated with amniotic bands may or may not be seen. Absence of internal organs such as kidneys and gallbladder is not rare.3,6,8,9 Two of the CBDMP cases appear to be associated with early amnion rupture.13 Three of the six cases reported by Gosden and Brock14 showed attachment of the ventral abdominal wall to the placenta, and at least five of the six had other anomalies consistent with early amnion rupture. One of the cases reported by Carey9 had amnion rupture. Infants with this spectrum of abnormalities are underrepresented in surgical series because they usually die immediately after birth or

1048

Gastrointestinal and Related Structures

Fig. 23-17. Schematic showing development of exstrophy of the cloaca.

because the severe nature of their anomalies precludes their transport to a tertiary care center. Chromosome studies are generally normal in cloacal exstrophy patients, as they were in 10 of the 10 cases in the CBDMP study.13 There is, however, one report of this anomaly associated with trisomy 18.9 Prenatal exposures are reported in two women; one to Dilantin was reported in the series by Carey et al.,9 and one significant exposure to diazepam was reported by Lizcano-Gil et al.15 Multiple sets of both concordant and discordant dizgotic and monozygotic twins have been reported with cloacal exstrophy (reviewed by Martinez-Frias et al.5). In their population-based series, over one-third of cloacal exstrophy cases were twins; this high incidence seems supportive of a developmental defect early in embryogenesis and is interesting as this incidence is not observed in bladder exstrophy. Although the recurrence risk is thought to be generally very low, cloacal exstrophy has been observed, perhaps coincidentally, in selected single gene syndromes including Opitz/BBB and Goltz syndrome. A family with a mitochondrial 12sRNA mutation and aminoglycoside-induced deafness and pigmentary abnormalities had a child with cloacal exstrophy, whereas several other family members had spinal defects.16 In one of the families reviewed by Keppler-Noreuil, there was a three-generation history of variable defects of the cloaca.6 Sibling recurrence has been reported with bladder exstrophy but not in cloacal exstrophy. Prognosis, Treatment, and Prevention

The first successful surgical correction of cloacal exstrophy was reported by Rickham in 1960.17 Although originally associated with high mortality and morbidity rates, a multidisciplinary approach to the repair of this lesion has led to the survival of most patients and to an improved quality of life. The primary surgical challenges remain formidable; avoidance of short bowel syndrome, achievement of urinary continence, preservation of renal function, fecal continence, and effective functioning of the lower limbs.3,18,19 Immediate management is directed toward stabilization of the neonate and assessment of associated abnormalities. When omphalocele is present, repair of this defect is an immediate surgical necessity. Usually, the repair of the omphalocele, with concomitant diverting ileal stoma colostomy, is done initially. Occasionally, primary bladder closure can be achieved at the same time. Preservation of all bowel possible is critical; short bowel syndrome is a primary cause of death and morbidity in this condition. Advances in parenteral

and enteral nutrition have improved survival in these children. Usually children require a bowel management program similar to those used with other myelodysplasia patients, although continence can sometimes be achieved. Urinary tract reconstruction depends a great deal on the bladder capacity. Most centers advocate early bladder closure in the first 48 hours followed by bladder neck reconstruction, suspension, and bilateral ureteral reimplantation at 3–6 years of age. Achievement of urinary continence with either the Young-DeesLeadbetter technique or the Mitrofanoff-type reconstruction seem highly dependent on the presence of coexisting neurologic impairment.18 Recently some centers have reported encouraging short-term results with a one-stage reconstruction between 72 hours and 2 years of life, although the long-term outlook for continence is unclear.20 When one-stage closure of the pelvis is not possible, staged pelvic osteotomies have resulted in good function.19 Appropriate gender assignment requires early and careful consideration and remains an area of much research interest. The severe phallic insufficiency in genetic males has led in the past to the general recommendation for female sex assignment and early gonadectomy. However, recent data on 14 males from 5–16 years of age followed in the Johns Hopkins exstrophy clinic who were reassigned a female sex, showed that eight had declared themselves as male and all 14 had orientations and interests typical of male children.21 A recent study in the UK evaluated six genetic males raised as females and found neither differences in quality of life nor behavioral distress as compared with the controls who also had cloacal abnormalities but no genital ambiguity.22 Further evaluation of this critical issue is needed as it does appears that the genetic sex may be more important than the external genitalia in determining the sex of rearing. MS-AFP screening and the increasing use of high-resolution prenatal ultrasound have led to identification of this defect prenatally with the major criteria being nonvisualization of the fetal bladder, an infraumbilical abdominal wall defect, omphalocele, and lumbosacral defects.23,24 Rarely, persistence of the cloacal membrane beyond the first trimester as noted by Bruch et al.12 can confuse the ultrasound picture. The characteristic ultrasound appearance of severe scoliosis in association with the abnormalities of cloacal exstrophy should alert the clinician to the possibility of early amnion rupture. Early prenatal diagnosis gives the parents the option of continuation or termination of affected pregnancies.

Ventral Wall of the Trunk

If delivery is planned, coordination utilizing a team approach and early involvement of a pediatric surgeon, pediatric urologist, and neonatologist is advised. In view of the very complicated nature of the surgical intervention, maternal transport to a tertiary care center with a multidisciplinary team experienced in the management of such cases is advocated. References (Exstrophy of the Cloaca) 1. Taruffi C: Storia della teratologia, vol 7. Regia, Bologna, 1894. 2. Ballantyne JW: Manual of Antenatal Pathology and Hygiene. The Embryo. William Green and Sons, Edinburgh, 1904. 3. Gearhart JP, Jeffs RD: Exstrophy of the bladder, epispadias and other bladder anomalies. In: Campbell’s Urology, ed 7. PC Walsh, A Retik, ED Vaughn, et al. eds. WB Saunders Co, Philadelphia, 1998, p 1971. 4. Soper RT, Kilger K: Vesico-intestinal fissure. J Urol 92:490, 1964. 5. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261, 2001. 6. Keppler-Noreuil KM: OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases. Am J Med Genet 99:271, 2001. 7. Mathews RI, Jeffs RD, Reiner WG, et al.: Cloacal exstrophy—improving the quality of life: the Johns Hopkins experience. J Urol 160:2452, 1998. 8. Meglin AJ, Balotin RJ, Jelinek JS, et al.: Cloacal exstrophy: radiologic findings in 13 patients. Am J Roentgenol 155:1267, 1990. 9. Carey JC, Greenbaum B, Hall BD: The OEIS complex (omphalocele, exstrophy, imperforate-anus, spinal defects). Birth Defects Orig Artic Ser XIV(6B):253, 1978. 10. Moore PL, Persaud TV: The Developing Human: Clinically Oriented Embryology, ed 6. WB Saunders, Philadelphia, 1998. 11. Thomalla JV, Rudolph RA, Rink RC, et al.: Induction of cloacal exstrophy in the chick embryo using the CO2 laser. J Urol 134:991, 1985.

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12. Bruch SW, Adzick S, Goldstein RB, et al.: Challenging the embryogenesis of cloacal exstrophy. J Pediatr Surg 5:901, 1996. 13. Curry CJR, Yarborough MK, Yang SP, et al.: Exstrophy of the cloaca and its variants. Proc Greenwood Genet Cntr 10:50, 1991. 14. Gosden C, Brock DJH: Prenatal diagnosis of exstrophy of the cloaca. Am J Med Genet 8:95, 1981. 15. Lizcano-Gil LA, Garcia-Cruz D, Sanchez-Corona J: OmphaloceleExstrophy-Imperforate Anus-Spina Bifida (OEIS) complex in a male prenatally exposed to Diazepam. Arch Med Res 26:95, 1995. 16. Nye JS, Hayes EA, Amendola M, et al.: Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA mutation, aminoglycoside-induced deafness, pigmentary disturbances, and spinal anomalies. Teratology 61:165, 2000. 17. Rickam PO: Vesico-intestinal fissure. Arch Dis Child 35:97, 1960. 18. Schober JM, Carmichael PA, Hines M, et al.: The ultimate challenge of cloacal exstrophy. J Urol 167:300, 2002. 19. Silver RI, Sponseller PD, Gearhart JP: Staged closure of the pelvis in cloacal exstrophy: first description of a new approach. J Urol 161:263, 1999. 20. El-Sherbiny MT, Hafez AT, Ghoneim MA: Complete repair of exstrophy: further experience with neonate and children after failed initial closure. J Urol 168:1692, 2002. 21. Reiner WG, Gearhart JP: Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 350:333, 2004. 22. Baker-Towell DM, Towell AD: A preliminary investigation into quality of life, psychological distress and social competence in children with cloacal exstrophy. J Urol 169:1850, 2003. 23. Austin PF, Homsy YL, Gearhart JP, et al.: The prenatal diagnosis of cloacal exstrophy. J Urol 160:1179, 1998. 24. Hamada H, Takano K, Shiina H, et al.: New ultrasonographic criterion for the prenatal diagnosis of cloacal exstrophy: elephant trunk-like image. J Urol 162:2123, 1999.

Breasts Ellen Boyd and Roger E. Stevenson Mammals’ superior method of supplying nutrition for their offspring played a large part in their rapid proliferation after their appearance some 160 million years ago.1 The placenta permitted prenatal nutrition and avoidance of a prolonged period of exposure of the egg to a hazardous environment. The mammary glands provided a ready supply of nutrition once offspring were born. The evolution of the mammary tissue can be followed through the species. The female duck-billed platypus expels milk through two openings onto its hairs where the infant can lick the milk.2 The beginning of nipple formation occurs in marsupials, and certain species of marsupials have 25 pairs of nipples.1 Each species has a predictable number of nipples; most primates have a single pair.1 The mammary glands are specialized apocrine sweat glands.3 The glands develop as ingrowths from the ectoderm that form ducts and alveoli. The supporting connective tissue and vascular structure are derived from mesenchyme. During week 5 of human embryogenesis, thickened ridges of ectoderm form on the ventrolateral body wall, extending from the axillas to the inguinal regions (Table 23-7, Fig. 23-18).4,5 These mammary ridges (milklines) persist for only a few days, after which the caudal two-thirds of the ridges rapidly regress. If the normal pattern of regression does not occur, accessory nipples (polythelia) or accessory mammary glands (polymastia) occur along the original milkline. A small portion of

each milkline normally persists in the pectoral region, and a single pair of glands usually develops at these sites. This pair of protuberances is present in the 50-day-old embryo.2 At this site, rapid division of specialized epithelial cells leads to formation of the mammary bud, which invaginates into the underlying mesenchyme Table 23-7. Stages of development of the human mammary gland* Mammary Development

Age of Embryo (Days)

Length of Embryo (mm)

Mammary ridge

35

6

Mammary bud

49

20

Nipple formation

50

22

Primary sprouts

84

68

Secondary sprouts

100

110

Myoepithelial cells

140

160

Canalization of primary sprouts

150

170

Milk ducts

260

320

*From Brumstead and Riddick.2

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Gastrointestinal and Related Structures

Fig. 23-18. Schematic of ventral view of embryo at about day 28 showing mammary ridges (A) and at about day 46 showing regression of the ridges except at the midthoracic level when nipples normally develop (B). (Adapted from Moore KL: The Developing Human, ed 4. WB Saunders, Philadelphia, 1988.)

(Fig. 23-19). By 84 days of development, 15–20 buds extend into the connective tissue.2,5 These primary mammary sprouts determine the number of galactophores or openings per nipple. These ducts open into a shallow epithelial depression, the mammary pit.4 As the outgrowths proliferate and develop, the surface epithelium is raised and differentiates into a discrete nipple. Failure of adequate proliferation of the underlying mesenchyme results in an inverted nipple.1 Secondary outgrowths branch from each primary sprout, and the secondary sprouts branch to form tertiary outgrowths. Lumens develop in the outgrowths beginning at the proximal and distal ends of each sprout, resulting in the formation of primary and secondary milk ducts.2 The milk-producing organs or alveoli form at the ends of the tertiary sprouts.2 Each alveolus is lined by a single layer of secretory epithelium. These cells are surrounded by myoepithelial cells, which contract under oxytocin stimulation to express milk from the alveolus and ducts.2 The mesenchymal matrix that supports development of mammary glands is made primarily of adipose tissue and vascular elements. The adipose tissue may provide local growth-promoting factors necessary for differentiation of mammary-producing epithelial cells.2 The rudimentary breasts of males and females do not differ at birth. The nipple may be difficult to see at birth, and the areola is not prominent. However, most term infants have a palpable breast nodule beneath the areola. Only the main milk ducts are formed at birth, and the mammary gland remains undeveloped until puberty. When mature, breast tissue extends from the level of the second and third ribs at the superior margin to the sixth or seventh rib at the

lower margin.1 The medial border reaches the edge of the sternum, and laterally the breast tissue extends to the anterior axillary line. A thin layer of mammary tissue may extend to the midline of the sternum and to the anterior edge of the latissimus dorsi laterally. Breast tissue can also extend laterally to the axilla, superiorly to the clavicle, and inferiorly onto the anterior abdominal wall. The areola and nipple are more deeply pigmented than normal skin and are pigmented more in brunettes than in blondes.1 This pigmentation is also related to the estrogen level and is more marked in younger females. The skin of the nipple is hairless and contains large numbers of sebaceous glands, which are grouped around openings of the milk sinuses. The areola has lanugo-type hair follicles around the periphery and does not have the welldeveloped dermal papillae of the nipple. The areola contains three types of specialized sweat glands, which project above the skin’s surface. The human breast has a unique protuberant, conical form.1 Other primates have relatively flat mammary glands even during pregnancy and lactation. The female breast’s conical form is most marked in younger nulliparous females. With obesity, the breasts become enlarged and pendulous. With advancing age, female breasts become flattened, pendulous, and less firm. References (Breasts) 1. Haagensen CD: Diseases of the Breast, ed 3. WB Saunders Co, Philadelphia, 1988. 2. Brumstead JR, Riddick DH: The nonlactating human breast. In: Gynecology and Obstetrics, vol V. JJ Sciara, ed. JB Lippincott, Philadelphia, 1990, p 1.

Fig. 23-19. Schematic showing development of the mammary gland between week 7 and term gestation. (Adapted from Moore KL: The Developing Human, ed 4. WB Saunders, Philadelphia, 1988.)

Ventral Wall of the Trunk 3. Dehner LP: Breast. In: Pathology of Infancy and Childhood, ed 2. JM Kissane, ed. CY Mosby Co, St Louis, 1975, p 1172. 4. Moore KL, Persaud TVN: The Developing Human. Clinically Oriented Embryology, ed 6. WB Saunders Co, Philadelphia, 1998, p 520. 5. Bland KI, Romrell U: Congenital and acquired disturbances of breast development and growth. In: The Breast. KI Bland, EM Copeland III, eds. WB Saunders Co, Philadelphia, 1991, p 69.

23.9 Amastia and Hypomastia Definition

Amastia is total absence of breast tissue, and hypomastia is underdevelopment of breast tissue. Amastia is usually accompanied by athelia (absence of the nipple). In hypomastia, the nipple is usually present. Diagnosis

In infancy and childhood, the breasts are inconspicuous in both males and females. During this time, the nipples and areolas serve as topographic landmarks indicating the location of future breast development. Absence of the nipple(s), while not always identified at birth, usually is noted in early life. Breast hypoplasia may become obvious in girls only following puberty. Athelia or breast hypoplasia is more obvious when there is involvement of the chest and shoulder musculature (Fig. 23-20). When the musculature of the chest is deficient, breast hypoplasia is usually present and the nipple is typically located more medially and in a higher position than on the opposite, normal side.1,2 Poland anomaly is a variable spectrum of unilateral defects, which includes breast hypoplasia, nipple hypoplasia or athelia, absence of the pectoralis major muscle, rib defects, variable involvement of

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the upper limb, and occasional vertebral or renal anomalies. It has an incidence of 1/20,000, usually involves the right side, occurs more commonly among males, and perhaps has a vascular etiology.3 Bavinck and Weaver4 suggest that the anomaly is due to interruption of the subclavian artery proximal to the origin of the internal thoracic artery but distal to the origin of the vertebral artery. The nipple, areola, and ductal system are derived from ectoderm. Hypoplasia or absence of these structures is a variable feature of the ectodermal dysplasias. Amastia and hypoplastic breasts have been found also in association with various renal malformations and dysplasias. Table 23-8 lists syndromes in which amastia, breast hypoplasia, and athelia have been described. Etiology and Prevalence

Amastia may occur bilaterally or unilaterally and results from failure of development or complete regression of the pectoral portion of the mammary ridges.31 Development of breast tissue without a nipple is difficult to explain embryologically. Histologic verification of aberrant breast tissue without nipples has been confirmed only in the axilla, where it probably represents an extension or separation of the tail of normal breast tissue.32 The supportive connective tissue of the breast is derived from mesenchyme during week 6 of embryogenesis.33 These mesenchymal cells later become adipose tissue and stroma, which in a fully developed breast account for variation in size. The adipose and fibrous connective tissues are the components responsible for the reduced breast volume in hypomastia. Variations in breast size may be determined during week 6 of embryogenesis even though they are not manifested until puberty in response to hormonal stimulation. Rosenberg et al.33 noted an association between hypomastia and mitral valve prolapse and hypothesized that their

Fig. 23-20. Left: bilateral absence of nipple and breast in a male. Middle: unilateral absence of the nipple and breast in a male with Poland-Mo¨bius syndrome. Right: unilateral hypoplasia of the breast and reduction defect of ipsilateral hand in female with Poland anomaly. (Courtesy of Dr. Vazken Der Kaloustian, The Montreal Children’s Hospital, Montreal.)

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Gastrointestinal and Related Structures

Table 23-8. Conditions associated with absent or hypoplastic breasts, areolas, or nipples Syndrome

Prominent Features

Mammary Finding*

Causation Gene/Locus

Al Awadi/RaasRothschild6

Cleft lip/palate, low ears, short neck, low umbilicus, bladder exstrophy, amelia

AN, AB

AR

Amastia, isolated7

None

AB, HB, AN, HN

Amastia-ureteral replication8

Low-set ears, ptosis, epicanthal folds with antimongoloid slant and hypertelorism, mitral valve prolapse, umbilical hernia, syndactyly, skeletal anomalies, ureteral triplication

AB

AD (104350)

Athelia9–13

Joint laxity, syndactyly of digits, unusual hair whorl/pattern

AN, AB

AD (113700) AR

Becker melanosis14,15

Hypermelanosis and hypertrichosis of shoulder, hypoplasia of ipsilateral breast, ipsilateral extremity shortening, skeletal anomalies, ‘‘organoid hyperplasia’’

HB

Unknown

de Lange16

Low birth weight, microcephaly, synophrys, short nose, anteverted nares, long philtrum, midline beak of thin upper lip, hirsutism, upper limb defects, mental retardation

HN

(122470) NIBPL, 5p13.1

Chromosomal trisomy 4p, trisomy 18, trisomy 20, 45,X

Features dependent on underlying chromosome aberration

HN, HB

Chromosomal

Ectodermal dysplasia, anhidrotic17,18

Defect in sweating, alopecia, hypodontia, low nasal bridge, prominent lips

AB, HB

AR (224900) 2q11-q13

Ectodermal dysplasia, euhidrotic20

Hypotrichosis, hypodontia, linear hypoplasia tip of nose, hyperpigmentation, mild hearing loss

AB, AN

AD (129510)

Ectodermal dysplasia, hypohidrotic18–21

Defect in sweating, alopecia, hypodontia, low nasal bridge, prominent lips

AB, HB

XLR (305100) ED1, Xq12-q13.1

EEC22

Ectrodactyly, ectodermal dysplasia, cleft lip/palate

HN

AD (129900) p63, 3q27

Escobar23

Multiple pterygium, ptosis, downslanting palpebral fissures, hypertelorism, micrognathia, downturned mouth, sad emotionless face, camptodactyly, syndactyly

HN

AR (265000)

Methimazole embryopathy24

Aplasia cutis of scalp, athelia, umbilical defects

AN

Teratogen

Poland25

Unilateral absence of portions of pectoralis major, ipsilateral hand reduction malformation, ipsilateral rib defects

AB, AN

Uncertain (173800)

Progeria26

Alopecia, thin skin, hypoplasia of nails, loss of subcutaneous fat, periarticular fibrosis, skeletal hypoplasia and degeneration, delayed dentition, atherosclerosis

AB, AN

Unknown (176670) LMNA, 1q21

Ulnar ray defects, hypoplasia of aprocrine glands, hypogonadism, renal anomalies

AB, HB, HN

AD (181450) TBX3, 12q24.1

TE fistula-amastia27 Ulnar-mammary28,29

*AB ¼ absent breast, AN ¼ absent nipples, HB ¼ hypoplastic breast, HN ¼ hypoplastic nipples. Does not include the case of Amesse et al.30 (vaginal and uterine agenesis, amastia, 8q:13q translocation).

association may be related to the common mesenchymal origin and simultaneous embryologic differentiation during week 6 of fetal life. Breast hypoplasia may be initiated by therapeutic manipulation or injury to the rudimentary breast tissue in the male or female. Trauma, incisions, infectious lesions, or radiation therapy to the breast bud during the prepubertal period can result in maldevelopment and hypoplasia.34 The risk of breast neoplasms during childhood and adolescence is extremely small, but breast masses should be regarded cautiously.1 Incisional or excisional biopsy techniques should be avoided if possible, since damage to the breast bud may result in breast hypoplasia

or amastia. When thoracotomy tubes were inserted between the third and fourth intercostal spaces, the majority of children had a greater than 20% difference in breast volume because of the breast hypoplasia caused by the chest tube insertion.35 It is recommended that chest tubes be inserted below the seventh or eighth rib and that during surgery of the chest wall the pectoralis major muscle be elevated as a unit and not divided. Radiation between 1500 and 2000 rads prior to puberty can impair breast development. Radiation exposure greater than 3000 rads arrests breast growth and causes fibrosis and hypoplasia.1 When possible, portals for radiation that pass through the nipple-areola complex should be avoided in children being treated for intrathoracic malignancy.

Ventral Wall of the Trunk

Prognosis, Treatment, and Prevention

The presence and size of breasts have been associated with femininity in the postpubertal female in most cultures. The Song of Solomon (chapter 8, verse 8) records an early reference to the importance of breast development in females: ‘‘We have a little sister, and she hath no breasts: what shall we do with our sister in the day when she shall be spoken for?’’ There is little doubt that construction of breasts in an adolescent girl with amastia is desirable. When absence of breasts is not associated with other major anomalies, early reconstruction is desirable. Construction of nipples should be considered during childhood before the defect causes distress for the child or parents. Breast construction is advised in the adolescent period. Mammary asymmetry causes more distress in patients than does bilateral hypomastia.34 Unilateral development of breast tissue in adolescence may represent nonisometric growth at puberty, with ultimate breast development being symmetrical. References (Amastia and Hypomastia) 1. Bland KI, Romrell LJ: Congenital and acquired disturbances of breast development and growth. In: The Breast. KI Bland, EM Copeland III, eds. WB Saunders Co, Philadelphia, 1991, p 69. 2. Merlob P: Congenital malformations and developmental changes of the breast: a neonatological view. J Pediatr Endocrinol Metab 16:471, 2003. 3. Jones KL: Smith’s Recognizable Patterns of Human Malformations, ed 5. WB Saunders Co, Philadelphia, 1997, p 302. 4. Bavinck JNB, Weaver DD: Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil and Mo¨bius anomalies. Am J Med Genet 23:903, 1986. 5. Breslau-Siderius EJ, Toonstra J, Baart JA, et al.: Ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia: a second case of the AREDYLD syndrome. Am J Med Genet 44:374, 1992. 6. Mollica F, Mazzone D, Cimino G, et al.: Severe case of Al Awadi/RaasRothschild syndrome or new, possibly autosomal recessive facioskeleto-genital syndrome. Am J Med Genet 56:168, 1995. 7. Wilson MG, Hall EB, Ebbin AJ: Dominant inheritance of absence of the breast. Humangenetik 15:268, 1972. 8. Rich MA, Heimler A, Waber L, et al.: Autosomal dominant transmission of ureteral triplication and bilateral amastia. J Urol 137:102, 1987. 9. Goldenring H, Crelin S: Mother and daughter with bilateral congenital amastia. Yale J Biol 33:466, 1961. 10. Greenberg F: Brief clinical report: choanal atresia and athelia: methimazole teratogenicity or a new syndrome? Am J Med Genet 28: 931, 1987. 11. Kowlessar M, Orti E: Complete breast absence in siblings. Am J Dis Child 115:91, 1968. 12. Nelson MM, Cooper CKN: Congenital defects of the breast: an autosomal dominant trait. South Afr Med J 61:434, 1982. 13. Trier WC: Complete breast absence: case report and review of the literature. Plast Reconstr Surg 36:431, 1965. 14. Glinick SE, Alper JC, Bogaars H, et al.: Becker’s melanosis: associated abnormalities. J Am Acad Dermatol 9:509, 1983. 15. Moore JA, Schosser RH: Becker’s melanosis and hypoplasia of the breast and pectoralis major muscle. Pediatr Dermatol 3:34, 1985. 16. Ptacek LJ, Opitz JM, Smith DW, et al.: The Cornelia de Lange syndrome. J Pediatr 63:1000, 1963. 17. Anton-Lamprecht I, Schleiermacher E, Wolf M: Autosomal recessive anhidrotic ectodermal dysplasia: report of a case and discrimination of diagnostic features. BDOAS XXIV(2):183, 1988. 18. Burck U, Held KR: Athelia in a female infant heterozygous for anhidrotic ectodermal dysplasia. Clin Genet 19:117, 1981. 19. Clarke A, Phillips DIM, Brown R, et al.: Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 62:989, 1987. 20. Tsakalakos N, Jordaan FH, Taljaard JJ, et al.: A previously undescribed ectodermal dysplasia of the Tricho-odonto-onychial subgroup in a family. Arch Dermatol 122:1047, 1986.

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21. Lowry RB, Robinson GC, Miller JR: Hereditary ectodermal dysplasia: symptoms, inheritance patterns, differential diagnosis, management. Clin Pediatr 5:395, 1966. 22. Brill CR, Hsu LYF, Hirschhorn K: The syndrome of ectrodactyly, ectodermal dysplasia and cleft lip and palate: report of a family demonstrating a dominant inheritance pattern. Clin Genet 3:295, 1972. 23. Escobar V, Bixler D, Gleiser S, et al.: Multiple pterygium syndrome. Am J Dis Child 132:609, 1978. 24. Greenberg F: Choanal atresia and athelia: methimazole teratogenicity or a new syndrome? Am J Med Genet 28:931, 1987. 25. Stevenson RE: The Poland-Mo¨bius syndrome. Proc Greenwood Genet Center 1:26, 1982. 26. DeBusk FL: The Hutchinson-Gilford progeria syndrome. J Pediatr 80: 697, 1972. 27. Kumar V, Apte AV, Gangopadhyay AN, et al.: Tracheoesophageal fistula and amastia with other anomalies: an unusual association. Ped Surg Int 20:378, 2004. 28. Meinecke P, Stier U, Blunck W: Normal hands and feet in the ulnarmammary syndrome. Dysmorphol Clin Genet 3:61, 1989. 29. Schinzel A: Ulnar-mammary syndrome. J Med Genet 24:778, 1987. 30. Amesse L, Yen FF, Weisskopf B, et al.: Vaginal uterine agenesis associated with amastia in a phenotypic female with a de novo 46,XX,t(8;13) (q22.1;q32.1) translocation. Clin Genet 55:493, 1999. 31. Moore KL, Persaud TVN: The Developing Human. Clinically Oriented Embryology, ed 6. WB Saunders Co, Philadelphia, 1988, p 520. 32. Greer KE: Accessory axillary breast tissue. Arch Dermatol 109:88, 1974. 33. Rosenberg CA, Derman GH, Grabb WC, et al.: Hypomastia and mitral valve prolapse. Evidence of a linked embryologic and mesenchymal dysplasia. N Engl J Med 309:1230, 1983. 34. Juri J: Mammary asymmetry: a brief classification. Aesthet Plast Surg 13:47, 1989. 35. Cherup LL, Siewers RD, Futrell JW: Breast and pectoral muscle maldevelopment after anterolateral and posterolateral thoracotomies in children. Ann Thorac Surg 41:492, 1986.

23.10 Enlarged Breasts Definition

Enlarged breasts are caused by hyperplasia or hypertrophy of normal breast tissue. The time of appearance is usually helpful in determining the type of breast enlargement. Neonatal breast hypertrophy occurs in males and females and is etiologically related to maternal hormones. Virginal breast hyperplasia (macromastia) is rapid, massive, and permanent hypertrophy of one or both breasts that occurs at puberty.1 Breast hypertrophy of pregnancy, often referred to as gigantomastia of pregnancy, is massive breast enlargement that regresses following pregnancy.2 Breast enlargement from other etiologies also occurs and is independent of age. 23.10.1 Neonatal Breast Hypertrophy

Hypertrophy of the neonatal breast is a common physical finding in newborns of either sex. A firm subareolar mass of tissue can be palpated in most full-term infants. A relationship exists between the presence of breast nodules and the level of gestational maturity. With the exception of diabetic progeny and small-for-gestationalage newborns, the size of the breast nodule can be used as a criterion to evaluate maturity at birth. Breast nodules can be palpated in over 99% of full-term infants (Fig. 23-21)3,4 Eighty percent of clinically well premature infants of 36 weeks gestation weighing 2200–2400 g at birth have palpable breast nodules, whereas, only 3% of infants weighing less than 1500 g have palpable breast nodules.3 Breast nodules may be

1054

Gastrointestinal and Related Structures

overall body growth. There is no further lobular development prior to puberty. Neonatal breast hypertrophy is self-limited and most often resolves over a 3–4 week period. Breast nodules can persist into the second half of the first year. One case of persistent breast nodules with lactation was described in a 7.5-month-old infant.6 The cause was confirmed to be manual stimulation of the breasts. Within 2 weeks of stopping the manipulations of the breast tissue, the breasts were reduced to one-third of their previous size and eventually had the normal breast tissue for age. It has been reported that one-third of patients with premature thelarche have breast hyperplasia dating from the neonatal period (see Section 23.15). Unilateral and bilateral breast hypertrophy due to galactoceles or milk cysts have also been reported in infants.7 It appears that galactoceles are retention cysts with secretory activity of the breast epithelium that have been stimulated by prolactin and result from a nonneoplastic obstruction of breast ducts. The treatment consists of aspiration of the milk-like fluid and removal of the cysts in males. 23.10.2 Virginal Breast Hyperplasia

Fig. 23-21. Top: mean (± SE) size of breast nodules in average for gestational age infants (clear bars) and small for gestational age infants (hatched bars) at 37–40 weeks gestation. Bottom: excessive breast hypertrophy in a newborn male. The enlargement regressed over the initial months of life. (Graph reprinted with permission from McKiernan JF, Hull D: Arch Dis Child 56:525, 1981.)

absent or small in infants of diabetic mothers and in small-forgestational-age infants (Fig. 23-21).4,5 The lack of palpable breast nodules in infants of diabetic mothers and in low-birth-weight newborns may indicate that these infants are less mature than the gestational history indicates, or it may result from factors that are unknown at present.4,5 Placental estrogen and progesterone together with fetal prolactin may control the development of mammary tissue during fetallife.4 The fetus produces plasma prolactin in the pituitary by midterm, and at the time of delivery fetal prolactin concentrations are similar to maternal prolactin concentrations. The fetal ovaries are relatively inactive, and the circulating estriol, estradiol, and progesterone are produced by the placenta in both male and female fetuses. Within week 1, a fluid similar to colostrum can be secreted by the breast nodules of both male and female infants.4 This increased secretion parallels that of the maternal mammary gland and is thought to be related to the drop in placental steroids and continued high prolactin concentrations. The mammary gland remains inactive and nonsecretory during childhood when the plasma estrogen levels are low. Stromal tissue growth and elongation of ducts take place in proportion to

Macromastia due to a rapid and massive hyperplasia of one or both breasts at puberty has been termed virginal breast hyperplasia (Fig. 23-22), and usually occurs between 11–19 years of age, progresses independently of pregnancy, and does not regress with continued maturation.2 Virginal hyperplasia, as with the normal breast enlargement of adolescence, is usually symmetrical but can be unilateral or asymmetrical.8 On microscopic examination there is little abnormality, and the excessive growth appears to be connective tissue and fat.1 The etiology of virginal breast hyperplasia is uncertain. A decrease in plasma progesterone level in the presence of normal plasma estrogen and growth hormone levels has been documented in virginal breast hyperplasia.8 The decreased progesterone levels may be the cause of the abnormality;

Fig. 23-22. Virginal breast hyperplasia in a teenage girl.

Ventral Wall of the Trunk

however, it has been postulated that there is increased estrogen receptor sensitivity in the target tissues of the breast. The estrogen receptors in the ductal epithelium, collagen, and stroma of the breasts may have increased sensitivity to minimal concentrations of the estrogens and progesterone that regulate breast growth and development. Mammary tissue may continue to grow even after puberty is completed in females with virginal breast hyperplasia. The most common treatment for virginal breast hyperplasia is reduction mastectomy. Recurrent hyperplasia can follow this surgery. If this occurs, a total glandular mastectomy with augmentation may be indicated. Following reduction mammoplasty, partial success in prevention of regrowth has been achieved with tamoxifen citrate.8 23.10.3 Breast Hypertrophy of Pregnancy

Gigantomastia associated with pregnancy is a rarer condition and usually begins during the first month of pregnancy.2 The breasts may grow to several times their normal weight and size and become incapacitating. The breasts are tense and edematous, with a peau d’orange appearance and large, prominent superficial veins. Because of the extreme growth and increased skin pressure, necrosis, ulceration, infection, and hemorrhage may occur from insufficient cutaneous perfusion.2 Breast hypertrophy of pregnancy is usually a benign condition and recedes with the cessation of pregnancy and lactation.2 In most cases, treatment can be conservative and should include proper breast support and good skin hygiene. With severe pain, infection, necrosis, or hemorrhage, reduction mastectomy may be necessary. Therapeutic abortions have been chosen by some women. However, affected women should be advised that breast hypertrophy probably will recur in future pregnancies and that reduction mastectomy can be considered.2 23.10.4 Breast Hypertrophy Due to Other Causes

Breast hypertrophy has been described in adolescent and adult females following use of D-penicillamine.9 While on the medication, affected women experience an increase in breast size, which ceases when the drug is discontinued. However, there have been no changes in the menstrual patterns of these patients during treatment with D-penicillamine. D-penicillamine-induced breast gigantism has been successfully treated with danazol.10 It has been proposed that penicillamine breaks down carrier proteins for estrogen and that this results in more free hormone released into the circulation and available to produce a local effect on breast tissue.9 The same benign and neoplastic breast tumors that have been described in adults have occasionally been described in children. Fibroadenomas account for 75–90% of all unilateral breast masses in adolescent females and are unlikely to occur before puberty. These fibroadenomas are usually unilateral, isolated, rubbery, mobile masses ranging from 1–8 cm in size. An occasional fibroadenoma becomes gigantiform.11 Rapid enlargement of the breasts can also occur with cystosarcoma phyllodes. Breast hypertrophy has been noted in Cowden syndrome, which is characterized by multiple hamartomas and neoplasias. Cowden syndrome carries an increased risk of breast cancer (22%) and shows autosomal dominant inheritance.12 Unilateral or bilateral enlargement of the breasts in children is rarely caused by breast cancer. Breast cancer in adolescents is extremely rare, and it occurs even less frequently in children. The adolescent breast mass is most likely benign.

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References (Enlarged Breasts) 1. Hollingsworth DR, Archer R: Massive virginal breast hypertrophy at puberty. Am J Dis Child 125:293, 1973. 2. Moss WM: Gigantomastia with pregnancy. Arch Surg 96:27, 1968. 3. Keitel HG, Chu E: The breast nodule in the full-term infant and in infants born of mothers with diabetes mellitus. J Pediatr 68:983, 1966. 4. McKiernan JF, Hull D: Breast development in the newborn. Arch Dis Child 56:525, 1981. 5. Keitel HG, Chu E: Breast nodule in premature infant. Am J Dis Child 109:121, 1965. 6. Bluestein DD, Wall GH: Persistent neonatal breast hypertrophy. Am J Dis Child 105:292, 1963. 7. Steiner MM: Bilateral galactocele in a male infant. J Pediatr 71:240, 1967. 8. Bland KI, Romrell LJ: Congenital and acquired disturbances of breast development and growth. In: The Breast. KI Bland, EM Copeland III, eds. WB Saunders Co, Philadelphia, 1991, p 69. 9. Desai SN: Sudden gigantism of breasts: drug induced? Br J Plast Surg 26:371, 1973. 10. Taylor PJ, Cummings DC, Corenblum B: Successful treatment of o-penicillamine-induced breast gigantism with danazol. Br Med J 282: 362, 1981. 11. Dehner LP: Breast. In: Pathology of Infancy and Childhood, ed 2. JM Kissane, ed. CV Mosby Co, St Louis, 1975, p 1176. 12. Starink TM, van der Veen JPW, Arwert F, et al.: The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 29: 222, 1986.

23.11 Symmastia Medial confluence of breast tissue is called symmastia or webbed breasts. Symmastia presents as an excess of presternal soft tissue, which is not eliminated with breast support.1,2 It is uncommon and is considered a variant of hypertrophy of the female breast.l It has been seen concomitantly with rapid breast development during the breast enlargement of early adolescence. Large, heavy breasts may produce pseudowebbing between the breasts because of the inferior traction on the presternal skin. This resolves with adequate support of breast tissue.1 References (Symmastia) 1. Spence RJ, Feldman JJ, Ryan JJ: Symmastia: the problem of medial confluence of the breasts. Plast Reconstr Surg 73:261, 1984. 2. McKissock PK: Discussion of symmastia: the problem of medial confluence of the breasts. Plast Reconstr Surg 73:267, 1984.

23.12 Supernumerary Breasts and Nipples Definition

Extra breast tissue occurring as breasts (polymastia), nipples (polythelia), or rarely areolas alone (polythelia areola) are referred to as supernumerary breasts and nipples. Diagnosis

The classification of extra breasts and nipples set forth by Kajava in 1915 is still in use today.l 1. Complete breasts with nipple, areola, and glandular tissue 2. Supernumerary breasts without areola but with nipple and glandular tissue

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Gastrointestinal and Related Structures

3. Supernumerary breasts without nipple but with areola and glandular tissue 4. Aberrant glandular tissue only 5. Nipple and areola with gland replaced by fat (pseudomamma) 6. Nipple only (polythelia) 7. Areola only (polythelia areola) 8. A patch of hair only (polythelia pilosis) Diagnosis may be made by observation at birth or later. A supernumerary nipple may be mistaken for a birthmark, mole, neurofibroma, papilloma, or nevus (Fig. 23-23). It may appear as a small pigmented or pearl-colored mark or concave spot with a diameter of only 1–3 mm.2 If aberrant breast tissue is also present, this may resemble a lipoma, lymphadenopathy, or other mass. Supernumerary breast tissue may first be noted because of enlargement, tenderness, and lactation due to hormonal stimulation during puberty, menses, and pregnancy.3 Polythelia is the most common form of supernumerary breast tissue.2 The usual site for supernumerary nipples is inferior and medial to the normal breast tissue.4 Accessory nipples within a common areola have been reported.5,6 Commonly the supernumerary

Fig. 23-23. Bilateral supernumerary nipples. (A) Common location in a 12-year-old girl with Simpson-Golabi-Behmel syndrome (generalized overgrowth and mental retardation). (B) Uncommon location in the inguinal regions and on the thighs of a newborn infant. (B: Courtesy of A. Aylsworth, Chapel Hill, NC.)

mammary tissues occur along the milkline; however, occurrence in atypical locations such as the neck, face, arms, legs, buttocks, shoulders, scapula, and spine has been reported (Fig. 23-24).2,7–12 Accessory breast tissue with or without a nipple may be present in the axilla.3,13 When no nipple is present, this usually represents an enlargement or ectopic placement of breast tissue from the axillary tail of Spence.3,13 Lactation may occur through a nipple if it is present; however, when aberrant axillary breast tissue is present without a nipple, lactation produces subcutaneous lactoceles from which milk is secreted through contiguous skin pores.14 Accessory axillary breast tissue is frequently diagnosed as excess axillary fat, although this is an unusual location for fat. Lymphadenitis, lymphoma, metastatic carcinoma, and hidradenitis suppurativa may be misdiagnosed.3 After the regression of breast tissue following pregnancy and lactation, the axillary tissue is soft, with a defined border. The presence of dense, nodular masses must be evaluated for the possibility of malignancy. Various malformations have been associated with polythelia (Table 23-9). An isolated form of polymastia is inherited as an autosomal dominant condition.11 A number of investigators have reported an increased incidence of urogenital abnormalities in patients with supernumerary nipples.5,15–19 Other investigators have found no association.20–23 In 1979, Mehe´s17 found renal ultrasound and intravenous pyelogram results to be abnormal in 40% of Hungarian children with supernumerary nipples. In 1983, he revised the incidence of anomalies to 27% and drew attention to a possible association between polythelia and congenital pyloric stenosis.18 Varsano and associates19 demonstrated urinary tract anomalies in 23% of Israeli children with supernumerary nipples. Urinary tract anomalies included hydronephrosis, megaureter, ureteral duplication, polycystic kidneys, obstructive problems, and ureteral prolapse.16,19 Mimouni et al.21 and Rahbar22 found no renal anomalies among newborn infants with supernumerary nipples. Separate studies by Kenney et al.20 and Robertson et al.23 showed abnormal renal ultrasound results in 3 of 81 infants with supernumerary nipples. Only one of these infants had abnormal renal findings (partial ureteropelvic junction obstruction) on further renal evaluation.

Fig. 23-24. Sites of supernumerary nipples. Open circles indicate the most common sites, circles enclosing Xs are less common sites, and dark circles are rare sites. (Reprinted with permission from Leung AKC, Robson WLM: Int J Derm 28:429, 1989.)

Ventral Wall of the Trunk

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Table 23-9. Conditions commonly including supernumerary nipples Syndrome

Prominent Features

Causation Gene/Locus

Acrofacial dysostosis with postaxial defects31

Malar hypoplasia, small jaw, cleft lip/palate, downslanted palpebral fissures with ectropion, absence or incomplete development of fifth digital ray of all extremities

AR (263750)

Bannayan-RuvalcabaMyhre32

Macrocephaly, intestinal polyposis, genital pigmentation, mental retardation, cutaneous angiolipomas

AD(153480) PTEN, 10q23.31

Becker nevus33

Does not include the reports by Zannolli et al.45 (Char syndrome) and Halper and Rubenstein40 (syndactyly-aplasia cutis congenita-supernumerary nipples).

AD

Hay-Wells34

Ankyloblepharon, ectodermal dysplasia, cleft lip/palate

AD (106260) p63,3q27

Killian/Pallister mosaic35

Coarse facial features, broad forehead, apparent hypertelorism, droopy mouth, mental retardation

Tetrasomy 12p

Polymastia13,36-40

None

AD (163700)

Rubinstein-Taybi41

Short stature, broad thumbs, microcephaly, downslanting palpebral fissures, hypertelorism, mental retardation

Sporadic (180849) CREBBP, 16p13.3

Setleis (temporal forceps marks)42

Cutis aplasia of temporal scalp, absent or double eyelashes, upslanting eyebrow, vertical ridge of chin, facial ectodermal dysplasia

AR (227260)

Simpson-Golabi-Behmel43

Somatic overgrowth syndrome, severe mental retardation, hypertelorism, short and broad nose, large mouth, midline groove of the tongue

XLR (312870) GPC3, Xq26

Trisomy 12p44

Obesity, hypotonia, turricephaly, flat face, mental retardation

Trisomy 12p

The relationship between supernumerary nipples and urogenital anomalies remains uncertain. Studies that found a significant association involved the non-black, non-newborn population and used ultrasound or radiologic diagnostic techniques.17–19,25–27 The studies that found no association were limited to newborn infants and used clinical evaluations primarily.20–23 Supernumerary nipples have also been associated with hypertension, congenital heart and conduction defects, vertebral malformations, peptic ulcer, neuroses, epilepsy, ear anomalies, end-stage renal disease, gonadal hypoplasia, pyloric stenosis, and arthrogryposis.2,28 Goedert et al.24,25 found an association with renal and testicular cancers. The significance and evaluation of patients with supernumerary nipples are still debated. A conservative approach includes palpation of kidneys and bladder, monitoring blood pressures, urinalysis, and renal ultrasound evaluation.2 Urinary symptoms in patients with supernumerary nipples should receive prompt evaluation. Etiology and Distribution

Supernumerary breast tissues result from persistence of segments of the embryonic mammary ridges (milklines). There are cases in which the accessory breast tissue appears lateral to the axilloinguinal location of the mammary ridge, suggesting that the mammary ridge may initially have a lateral or dorsal placement, with later migration to the ventrolateral (axilloinguinal) location.5,8 One embryo has been described with two parallel mammary ridges, one in a more dorsal position, a finding that could explain the development of supernumerary breasts lateral to the axilloinguinal line.5,8 Among the anomalies of the breast, polythelia is the most frequently encountered, with an incidence of 0.2–5%.17,29 Polythelia has been reported with an incidence of 0.22% among the

eastern European population,17 1.63% among U.S. black neonates,20 3.7% among Japanese newborns,30 and 2.5% among Jewish newborns.21 The variable incidence of supernumerary nipples could be due to ethnic differences; however, it may also be related to the care with which they have been sought in various populations. Supernumerary nipples may be overlooked in an infant or may be mistaken for a birthmark or nevus. In the majority of cases, a single extra nipple is present (60–65%).2 One-third of cases have two nipples or breasts, approximately 4% have three extra nipples or breasts, and up to 2% have more than three extra nipples or breasts.2 Sex incidence is equal, as is laterality.4 Prognosis, Treatment, and Prevention

Although supernumerary nipples and breasts have a predominantly cosmetic and psychological effect, they have the potential to respond to hormones and are susceptible to the same disease processes as is normal breast tissue. The nipple or breast may enlarge, become tender, and lactate in response to puberty, menstruation, or pregnancy.3 There is no increase in the incidence of mastitis, abscesses, cystic lesions, or carcinoma in accessory breasts.2 Axillary breast tissue with only a glandular tissue and no areola or nipple is often diagnosed as a lipoma or benign neoplasm and is unnecessarily excised. The tissue is soft to palpation, with well-defined margins, and is in an unlikely location for a lipoma and therefore can be followed clinically.9 References (Supernumerary Breasts and Nipples) 1. Kajava Y: The proportions of supernumerary nipples in the Finnish population. Duodecim 31:143, 1915. 2. Leung AK, Robson WL: Polythelia. Int J Dermatol 28:429, 1989. 3. Greer KE: Accessory axillary breast tissue. Arch Dermatol 109:88, 1974.

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Gastrointestinal and Related Structures

4. Newman M: Supernumerary nipples. Am Fam Pract 38:183, 1988. 5. Brightmore T: Bilateral double nipples. Br J Surg 59:55, 1972. 6. Rintala A, Norio R: Familial intra-areolar polythelia with mammary hypoplasia. Scand J Plast Reconstr Surg 16:287, 1982. 7. Baruchin A, Rosenberg L: A supernumerary nipple in a rare site. J Dermatol Surg Oncol 7:918, 1981. 8. Castafto M: Dorsal scapular supernumerary breast in a woman. Plast Reconstr Surg 43:536, 1969. 9. DeCholnoky T: Accessory breast tissue in the axilla. NY State J Med 51:2245, 1951. 10. Tow SH, Shammugaratnam K: Supernumerary mammary gland in the vulva. Br Med J 5314:1234, 1962. 11. Brown J, Schwartz RA: Supernumerary nipples: an overview. Cutis 71: 344, 2003. 12. Schmidt H: Supernumerary nipples: prevalence, size, sex and side predilection–a prospective clinical study. Eur J Pediatr 157:821, 1998. 13. Weinberg SK, Motulsky AG: Aberrant axillary breast tissue: a report of a family with six affected women in two generations. Clin Genet 10: 325,1976. 14. Roux IP: Lactation from axillary tail of breast. Br Med J 1:28, 1955. 15. Leung AK: Familial supernumerary nipples. Am J Med Genet 31:631, 1988. 16. Meggyessy V, Me´hes K: Association of supernumerary nipples with renal anomalies. J Pediatr 111:412, 1987. 17. Mehe´s K: Association of supernumerary nipples with other anomalies. J Pediatr 95:274, 1979. 18. Mehe´s K: Association of supernumerary nipples with other anomalies. J Pediatr 102:161, 1983. 19. Varsano IB, Jaber L, Garty BZ: Urinary tract abnormalities in children with supernumerary nipples. Pediatrics 73:103, 1984. 20. Kenney RD, Flippo JL, Black EB: Supernumerary nipples and renal anomalies in neonates. Am J Dis Child 141:987, 1987. 21. Mimouni F, Merlob P, Reisner SH: Occurrence of supernumerary nipples in newborns. Am J Dis Child 137:952, 1983. 22. Rahbar F: Clinical significance of supernumerary nipples in black neonates. Clin Pediatr 21:46, 1982. 23. Robertson A, Sale PA-C, Sathyanarayan: Lack of association of supernumerary nipples with renal anomalies in black infants. J Pediatr 109: 502, 1986. 24. Goedert JJ, McKeen EA, Fraumeni JF, et al.: Polymastia and renal adenocarcinoma. Ann Intern Med 95:182, 1981. 25. Goedert JJ, McKeen EA, Javadpour N, et al.: Polythelia and testicular cancer. Ann Intern Med 101:646, 1984. 26. Hersh JH, Bloom AS, Cromer AO, et al.: Does a supernumerary nipple/renal field defect exist? Am J Dis Child 141:989, 1987. 27. Pellegrini JR, Wagner RF: Polythelia and associated conditions. Am Fam Pract 28:129, 1983. 28. Matesanz R, Teruel JL, Garcia Martin L, et al.: High incidence of supernumerary nipples in end-stage renal failure. Nephron 44:385, 1986. 29. Evans W: Polythelia in cardioarterial disease. Br Heart J 21:130, 1959. 30. Iwai T: A statistical study of the polymastia of the Japanese. Lancet 2: 753, 1907. 31. Donnai D, Hughes HE, Winter RM: Postaxial acrofacial dysostosis (Miller) syndrome. J Med Genet 24:422, 1987. 32. Hendriks YM, Verhallen JR, van der Smagt JJ, et al.: Bannayan-RileyRuvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation-positive cases. Fam Cancer 2:79, 2003. 33. Happle R, Koopman RJ: Becker nevus syndrome and supernumerary nipples. Am J Med Genet 77:78, 1998. 34. Greene SL, Michels VV, Doyle JA: Variable expression in ankyloblepharon-ectodermal defects-cleft lip and palate syndrome. Am J Med Genet 27:207, 1987. 35. Reynolds JF, Daniel A, Kelly TE, et al.: Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister-Killian syndrome): report of 11 cases. Am J Med Genet 27:257, 1987. 36. Galli-Tsinopoulou A, Krohn C, Schmidt H: Familial polythelia over three generations with polymastia in the youngest girl. Eur J Pediatr 160:375, 2001.

37. Grotto I, Browner-Elhanan K, Mimouni D, et al.: Occurrence of supernumerary nipples in children with kidney and urinary tract malformations. Pediatr Dermatol 18:291, 2001. 38. Orioli IM, Ribeiro MG, Castilla EE: Male to male transmission of supernumerary nipples. Am J Med Genet 73:100, 1997. 39. Urbani CE, Betti R: Accessory mammary tissue associated with congenital and hereditary nephrourinary malformations. Int J Dermatol 35:349, 1996. 40. Casey HD, Chasan PE, Chick LR: Familial polythelia without associated anomalies. Ann Plast Surg 36:101, 1996. 41. Rubinstein JH: The broad thumbs syndrome-progress report 1968. BDOAS V(2):25, 1969. 42. Setleis H, Kramer B, Valcarel M, et al.: Congenital ectodermal dysplasia of the face. Pediatrics 32:540, 1963. 43. Opitz JM: The Golabi-Rosen syndrome-report of a second family. Am J Med Genet 17:359, 1984. 44. DeGrouchy J, Turleau C: Clinical Atlas of Human Chromosomes, ed 2. John Wiley and Sons, New York, 1984. 45. Zannolli R, Mostardini R, Matera M, et al.: Char syndrome: An additional family with polythelia, a new finding. Am J Med Genet 95: 201, 2000. 46. Halper S, Rubenstein D: Aplasia cutis congenita associated with syndactyly and supernumerary nipples: report of a second family with similar clinical findings. Pediatr Dermatol 8:32, 1991.

23.13 Widely Spaced Nipples Nipples are normally placed along the midclavicular line. Widely spaced nipples are usually located lateral to this line. To determine if the nipples are actually widely spaced or only give the appearance of being widely spaced, the ratio of the internipple measurement to the width of the thorax can be determined and compared with controls.1 Alternatively, the internipple measurement and chest circumference can be compared on standardized graphs.2 Widely spaced nipples have importance only because of associated anomalies (Table 23-10). Fleischer found an association between lateral placement of the nipples and renal hypoplasia. The pathogenesis for lateral placement of the nipples has not been determined. The possibility that the milkline migrates to the axilloinguinal line from a more lateral position has been suggested.3 If this is the case, any interference in ventral migration of the milkline could result in widely spaced nipples. References (Widely Spaced Nipples) 1. Aeisher DS: Lateral displacement of the nipples, a sign of bilateral renal hypoplasia. J Pediatr 69:806, 1966. 2. Feingold M, Bossert WH: Normal values for selected physical parameters: an aid for syndrome delineation. BDOAS X(13):135, 1974. 3. Castan˜o M: Dorsal scapular supernumerary breast in a woman. Plast Reconst Surg 43:536, 1969. 4. Thomas IT, Frias JL, Felix V, et al.: Isolated and syndromic cryptophthalmos. Am J Med Genet 25:85, 1986. 5. Igarashi M, Uchida H, Kajii T: Supraumbilical midabdominal raphe and facial cavernous hemangiomas. Clin Genet 27:196, 1985. 6. Hill RM, Verniaud WM, Horning MG, et al.: Infants exposed in utero to antiepileptic drugs. Am J Dis Child 127:645, 1974. 7. Sidransky E, Feinstein A, Goodman RM: Ichthyosis-cheek-eyebrow (ICE) syndrome: a new autosomal dominant disorder. Clin Genet 31:137, 1987. 8. Zlotogora J, ZilbermanY, Tenenbaum A, et al.: Cleft lip and palate, pili torti, malformed ears, partial syndactyly of fingers and toes, and mental retardation: a new syndrome? J Med Genet 24:291, 1987.

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Table 23-10. Conditions commonly including widely spaced nipples Causation Gene/Locus

Syndrome

Prominent Features

Chromosomal: trisomy 8, duplication 4p, duplication 6q, duplication 9p, duplication 11q, duplication 13qter, duplication 19q, deletion 7q, deletion 8p, deletion 9p, 45,X

Features dependent on underlying chromosomal aberration

Chromosomal

Fraser cryptophthalmos4

Cryptophthalmia, defect of auricle, genital anomaly, mental retardation

AR (219000) 4q21

Hemangiomas-midline abdominal raphe5

Cavernous hemangioma, facial hemangioma, umbilical hernia, white groove between umbilicus and xiphoid

Uncertain (140850)

Hydantoin, prenatal6

Growth deficiency, hypertelorism, broad and depressed nasal bridge, short nose, bowed upper lip, cleft lip/palate, hypoplastic nails, mild mental deficiency

Intrauterine exposure to hydantoin

Ichtyhosis-cheek-eyebrow7

Ichthyosis, full cheeks, sparse eyebrows, scoliosis

AD (146720)

Zlotogora: cleft lip/palateectodermal dysplasia8

Cleft lip/palate, malformed ears, pili torti, partial syndactyly of digits, mental retardation

AR

23.14 Gynecomastia Definition

Gynecomastia is breast enlargement in the male. Diagnosis

Gynecomastia can range in magnitude from a barely detectable nodule to the form and size of the mature female breast. It is common and has many causes. It may be a normal physiologic occurrence, or it may be associated with severe disease. It can be transient or permanent. Physiologic gynecomastia can occur during the neonatal period, adolescence, or senescence. Transient neonatal hypertrophy is seen frequently in infants as a result of maternal hormones. This type of breast nodule is usually 5–10 mm in size and regresses within a few weeks, although it may persist for months (see Section 23.11). Adolescent gynecomastia is a common finding, occurring in 60–70% of pubertal boys and usually consisting of a 1–3 cm tender subareolar nodule.1 It is self-limited and generally disappears within 1 year. However, in 27% of cases studied by Nidick et al.,2 the condition persisted for up to 2 years, and in 7.7% it persisted for 3 years. Typically, adolescent gynecomastia develops in males between ages 12 and 17 years. Gynecomastia was found in 39% of all adolescent males examined and occurred within 1.2 years following an increase in testicular size, the first sign of puberty, with a peak incidence of 65% in 14- to 14.5-year-old boys.1,2 Three-fourths of those affected had bilateral involvement. The development of adolescent gynecomastia may be related to transient elevation of plasma estradiol relative to testosterone.3 Senescent gynecomastia occurs between the ages of 50 and 70 years and usually regresses spontaneously within 6–12 months.4 It appears more commonly among heavier men5 and is thought to be secondary to a decrease in androgen production, with a decrease in the androgen–estrogen ratio.6

Pseudogynecomastia is present in many obese men. The breast enlargement is caused by the deposition of adipose tissue in the pectoral area, but these men do not have glandular hyperplasia.7 Permanent breast enlargement occurring in the male at the time of puberty is a pathologic finding that requires evaluation. It generally appears at the same time as genital growth and appearance of secondary sexual characteristics. Gynecomastia may represent an isolated feature in males and may not be associated with any abnormality of the genital organs or infertility. This form appears to be inherited in an autosomal dominant manner. The lineage of the Egyptian pharaoh Amenophis III, including the boy pharaoh Tutankhamun, may have been affected with this isolated condition.8 Gynecomastia is associated with numerous heritable conditions, many of which include hypogonadism (Table 23-11). Klinefelter syndrome is the most frequent and readily identified of these entities.33 These patients may be recognized in childhood by the small testicular size, behavioral disturbances, and developmental impairment. At the time of puberty, the testes fail to enlarge, and patients have hypergonadotropic hypogonadism, with sterility secondary to azoospermia. Gynecomastia occurs in about 75% of patients.33 Niewoehner and Nuttall5 suggest the following method for evaluation of gynecomastia. With the patient in the supine position, the clinician places the examining thumb at the inferior outer quadrant of the patient’s breast and the index finger at the superior inner quadrant. The breast tissue is then elevated and compressed between the fingers. A 2-cm mass of subareolar breast tissue in the non-obese patient is considered abnormal. The consistency of the breast tissue can be compared with that of adipose tissue in the axillary folds if there is a question of whether this is glandular breast tissue or adipose tissue. Etiology and Distribution

Regardless of the etiology, the microscopic changes in gynecomastia are remarkably the same. Hyperplasia of the ductal system

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Gastrointestinal and Related Structures

Table 23-11. Conditions associated with testicular failure and gynecomastia Causation Gene/Locus

Syndrome

Prominent Features

Pathogenesis

Aromatase gynecomastia25

Gynecomastia

Increased aromatase activity (increased estradiol:testosterone ratio)

AD (107910)

Borjeson-ForssmanLehmann

Obesity, hypogonadism, tapered digits

Unknown

XLR (301900) PHF6, Xq26.3

Familial gynecomastia27,28

Hypogonadism, absence of hypospadias

Decreased leutinizing hormone, decreased Leydig cells

XLR (306500)

Hereditary gynecomastia29,30

Well-virilized, without hypogonadism

Increased aromatization of plasma carbon-19 steroids

AD, AR, XLR (139300)

Kallmann31,32

Anosmia, hypogonadism

Deficiency of gonadotropin-releasing hormone

XLR (308700) Xp22.3

Kennedy33 (Bulbospinal muscle atrophy)

Fasciculations, muscle weakness, dysphagia and wasting, spinobulbar atrophy

Involutional changes in Leydig cells, defect in androgen receptor gene

XLR (313200) AR, Xq11-q12

Klinefelter34 (47,XXY)

Hypogenitalism and hypogonadism, long limbs, dull mentality, behavioral problems

Androgen deficiency

Chromosomal

Reifenstein35–38

Hypospadias, hypogonadism

Partial androgen insensitivity

XLR (312300)

Wilson-Turner39

Obesity, tapered digits, mental retardation, emotional lability

Unknown

XLR (309585)

is present, but usually without alveolar development at the ends of the ducts.4 The hyperplastic ducts are found within a stroma of connective tissue that develops fibrosis and hyalinization. Estrogen is responsible for the growth of the tubal duct system, but the alveoli do not develop in the absence of progesterone. Excess estrogen secretion or a decreased androgen–estrogen ratio is usually responsible for gynecomastia.6 Drug exposures and systemic diseases can affect this balance.9 Gynecomastia resulting from estrogen stimulation can arise from increased estrogen production by the adrenals or testes, increased availability of substrate from peripheral conversion of androgens to estrogens, or increased aromatization in peripheral tissues.6 In true hermaphroditism, both an ovary and a testes or a gonad with histologic features of both (ovotestes) are present. At puberty, three-fourths of the individuals with true hermaphroditism develop significant gynecomastia, and about one-half menstruate in a cyclic pattern.10 Male hypogonadism is often accompanied by gynecomastia (Fig. 23-25). It results from failure of testosterone synthesis or action and is generally associated with elevation of plasma gonadotropins.11 There may or may not be a secondary increase in testicular estrogen secretion. About one-half of the patients with congenital anorchia develop gynecomastia.6 In these patients, the estradiol production is only about one-half the normal amount and is derived solely from the conversion of plasma androstenedione to estradiol. However, the ratio of the plasma production of testosterone to estradiol is markedly decreased. Therefore, the critical factor for breast tissue hypertrophy is not the absolute level of estradiol but the ratio of testosterone to estradiol. Enzyme defects that result in defective testosterone synthesis also cause incomplete virilization of the male embryo during embryogenesis. A complete or partial deficiency of 17 b-hydroxysteroid dehydrogenase may cause feminization, including gynecomastia at the expected time of puberty.5 Gynecomastia presumably results from diminished testosterone production together with normal or enhanced estrogen production and secretion.

Gynecomastia is common following secondary testicular failure from trauma, orchitis, cryptorchidism, irradiation, hydrocele, varicocele, and spermatocele.12 It is also recognized with secondary androgen deficiency in neurologic diseases with testicular atrophy, castration, and granulomatous diseases of the testes.5 There is also decreased testicular function in patients with chronic renal failure. Gynecomastia is common in these males and is found in one-half of males undergoing hemodialysis.5 An abnormality of the cytoplasmic androgen receptor protein may cause resistance to both endogenous and exogenous androgens. As a result, affected males (46,XY) develop completely or partially as phenotypic females.6 The plasma gonadotropin levels are elevated as a result of the negative feedback effect of testosterone on gonadotropin production at the hypothalamopituitary level, leading to increased estrogen secretion by the testes and elevated production of estrone and estradiol. There does not appear to be a direct relationship between the degree of feminization in these disorders and the amount of estrogen secretion. The degree of feminization is influenced by the degree of androgen resistance. Adrenal cortical neoplasms, lung carcinoma, and hepatocellular carcinoma may produce estrogen and gynecomastia.12 In addition to feminizing adrenal tumors,13 virilizing congenital adrenal hyperplasia (11 b-hydroxylase deficiency )14 can cause gynecomastia with increased estrogen production. An increased production of androstenedione results in increased availability of substrate, which is converted to estrogen in the periphery.6 Testicular tumors can also produce feminization. Most of the germinal cell tumors (seminomas, embryonal carcinomas, choriocarcinomas, and teratomas) produce human chorionic gonadotropin (hCG), which in turn stimulates estradiol and testosterone synthesis by the uninvolved areas of the testes.6,15 Increased aromatization of testosterone and androstenediol into estrogen precursors may play a role in the gynecomastia.12,16 Nongerminal gonadal stomal neoplasms of the testes, including interstitial Leydig cell, Sertoli cell, and granulosa-theca

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Fig. 23-25. Left: gynecomastia in a 13-year-old male from a family in which males have gynecomastia transmitted in an autosomal dominant manner. Middle: gynecomastia in a 15-year-old male with Klinefelter syndrome (47,XXY). Right: gynecomastia in a 15-year-old male with androgen insensitivity. (Right figure courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Institute, Wilmington, Delaware.)

tumors, can cause gynecomastia.6,12 Leydig cells are the principal source of estradiol biosynthesis, and estradiol has an inhibitory action on testosterone production.17 A variety of Sertoli cell tumors are familial and may be associated with precocious puberty, gynecomastia, and atriomyxomas.18 Sertoli cell tumors or sex cord tumors with increased aromatase activity have also been associated with the autosomal dominant disorder, Peutz-Jeghers syndrome.19,20 Isolated cases of gynecomastia in individuals with pigmented nevus, neurofibromatosis, and nonendocrine tumors of the skin have been reported, but the pathogenic association is unproved.12 Gynecomastia occurs in 20–40% of males with hyperthyroidism.21 Hypothyroidism can also result in gynecomastia as well as galactorrhea.22 Liver disease is associated with gynecomastia, which is found in 40% of men with cirrhosis.12,23 Gynecomastia has been found among populations that were starved and then were supplied with nutritious food.12,24 Gynecomastia may result from drug administration.6,9,12 The drugs are usually estrogens, but others that may mimic estrogen activity (e.g., digitalis), inhibit the action of androgens (e.g., cimetidine, spironolactone), or increase estrogen synthesis (e.g., chorionic gonadotropin).6,9 Table 23-12 lists drugs known to be associated with gynecomastia. Trauma, anxiety and stress, and human immunodeficiency virus (HIV) infection have been associated with gynecomastia.12 Syndromes associated with gynecomastia are listed in Table 23-11.

Prognosis, Treatment, and Prevention

A specific diagnosis must be established before any medical treatment for gynecomastia is attempted. When the breast tissue is less than 4 cm, the condition frequently will resolve spontaneously.l2 If the breast hypertrophy is progressive or persistent, medical or surgical treatment is indicated. Disorders that include androgen deficiency have been treated with testosterone. However, testosterone administration to patients who have increased peripheral conversion of androgen to estrogen can result in further enlargement of breast tissue. Drug treatments for gynecomastia remain investigational. Clomiphene citrate is an antiestrogen medication that has had a 95% success rate in treating pubertal adolescent gynecomastia.40 However, side effects are present in that gonadotropin secretion is also increased.12 Danazol is a derivative of the 7a-ethyl testosterone.12 This drug has no estrogenic or progestational effect and has been used successfully in the treatment of gynecomastia.41,42 Androgenic effects of muscle weakness, cramps, weight gain, and acne have been reported. Subareolar mastectomy carries little morbidity or mortality. It is indicated in permanent gynecomastia for cosmetic reasons and for avoidance of breast diseases, including malignancy. References (Gynecomastia) 1. Schydlowder M: Breast masses in adolescence. Am Fam Phys 25:141, 1982.

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Table 23-12. Drugs that can cause gynecomastia* Drugs with estrogenic or estrogen-related activity

Anabolic steroids (nandrolone, testosterone cypionate) Clomiphene citrate Diethylpropion hydrochloride Diethylstillbestrol Digitalis Estrogens Heroin Oral contraceptives Tetrahydrocannabinol (cannabis, marijuana) Drugs that inhibit the action and/or synthesis of testosterone

Antineoplastic agents (vincristine, nitrosoureas, methotrexate) Cimetidine Cyproterone acetate D-penicillamine Diazepam Flutamide Ketoconazole Medroxyprogesterone acetate Phenytoin Spironolactone Drugs that enhance estrogen synthesis by the testes

Human chorionic gonadotropin Drugs with idiopathic mechanism for induction of gynecomastia

Amiodarone Bumetanide Busulfan Domperidone Ethionamide Furosemide Isoniazid Methyldopa Nifedipine Reserpine Sulindac Theophylline Tricyclic antidepressants Verapamil *From Bland and Page.12

2. Nydick M, Bustos J, Dale JH, et al.: Gynecomastia in adolescent males. JAMA 178:449, 1961. 3. LaFranchi SH, Parlow AF, Lippe BM, et al.: Pubertal gynecomastia and transient elevation of serum estradiol level. Am J Dis Child 129:927, 1975. 4. Haagensen CD: Abnormalities of breast growth, secretion, and lactation. In: Diseases of the Breast, ed 3. CD Haagensen, ed. WB Saunders Co, Philadelphia, 1986, p 65. 5. Niewoehner CB, Nuttall FQ: Gynecomastia in a hospitalized male population. Am J Med 77:633, 1984.

6. Wilson JD, Aiman J, MacDonald PC: The pathogenesis of gynecomastia. In: Advances in Internal Medicine, Vol 25. GH Stollerman, et al.; eds. Year Book Medical Publishers Inc, Chicago, 1980, p 1. 7. Beraka GJ: Gynecomastia. In: The Breast. HS Gallagher, HP Lisa Jr, RK Snyderman, et al., eds. CV Mosby Co, St. Louis, 1978, p 435. 8. Paulshock BZ: Tutankhamun and his brothers. Familial gynecomastia in the Eighteenth Dynasty. JAMA 244:160, 1980. 9. Wilson JD: Gynecomastia, a continuing diagnostic dilemma. N Engl J Med 324:334, 1991. 10. Van Niekerk WA: True hermaphroditism. An analytic review with a report of 3 new cases. Am J Obstet Gynecol 126:890, 1976. 11. Winter JSD, Faiman C: Serum gonadotropin concentrations in gonadal children and adults. J Clin Endocrinol Metab 35:561, 1972. 12. Bland KI, Page DL: Gynecomastia. In: The Breast. KI Bland, EM Copeland III, eds. WB Saunders Co, Philadelphia, 1991, p 135. 13. Gabrilove JL, Sharma DC, Wotiz HH, et al.: Feminizing adrenocortical tumors in the male: a review of 52 cases including a case report. Medicine 44:37, 1965. 14. Maclaren NK, Migeon CJ, Raiti S: Gynecomastia with congenital virilizing adrenal hyperplasia (11-b-hydroxylase deficiency). J Pediatr 86:579, 1975. 15. Stephanas AV, Samaan NA, Schultz PN, et al.: Endocrine studies in testicular tumor patients with and without gynecomastia. Cancer 4:369, 1978. 16. Bardin CW: Pituitary-testicular axis. In: Reproductive Endocrinology. SSC Yen, RB Jaffe, eds. WB Saunders Co, Philadelphia, 1978, p 110. 17. Pearson JC: Endocrinology of testicular neoplasms. Urology 17:119, 1981. 18. Proppe KH, Scully RE: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 74:607, 1980. 19. Wilson DM, Pitts WC, Hintz RL, et al.: Testicular tumors with PeutzJeghers syndrome. Cancer 57:2238, 1986. 20. Coen P, Kuli H, Ballentine T, et al.: An aromatase-producing sex- cord tumor resulting in prepubertal gynecomastia. N Engl J Med 324:317, 1991. 21. Chopra IJ: Gonadal steroids and gonadotropins in hyperthyroidism. Med Clin North Am 59:1109, 1975. 22. Arnaout MA, Garthwaite TL, Krubsack AJ, et al.: Galactorrhea, gynecomastia, and hypothyroidism in a man. Ann Intern Med 106:779, 1987. 23. Summerskill WHJ, Davidson CS, Dible JH, et al.: Cirrhosis of the liver: a study of alcoholic and nonalcoholic patients in Boston and London. N Engl J Med 261:1, 1960. 24. Jacobs EC: Effects of starvation on sex hormones in the male. J Clin Endocrinol 8:228, 1948. 25. Hemsell DL, Edman CD, Marks JF, et al.: Massive extraglandular aromatization of plasma androstenedione resulting in feminization of a prepubertal boy. J Clin Invest 60:455, 1977. 26. Bo¨rjeson M, Forssman H, Lehmann O: An X-linked recessively inherited syndrome characterized by grave mental deficiency, epilepsy and endocrine disorder. Acta Med Scand 171:13, 1962. 27. Rosewater S, Gwinup G, Hamwi GJ: Familial gynecomastia. Ann Intern Med 63:377, 1965. 28. Wilson JD, Harrod MJ, Goldstein JL, et al.: Familial incomplete pseudohermaphroditism, type I, evidence for androgen resistance and variable clinical manifestations in a family with the Reifenstein syndrome. N Engl J Med 290:1097, 1974. 29. Berkovitz GD, Guerami A, Brown TR, et al.: Familial gynecomastia with increased extraglandular aromatization of plasma carbon-19 steroids. J Clin Invest 75:1763, 1985. 30. Ljungberg T: Hereditary gynaecomastia. Acta Med Scand 168:371, 1960. 31. Boyar RM, Finkelstein JW, Witkin M, et al.: Studies of endocrine function in ‘‘isolated’’ gonadotropin deficiency. J Clin Endocrinol Metab 36:64, 1973. 32. Hermanussen M, Sippell WG: Heterogeneity of Kallmann’s syndrome. Clin Genet 28:106, 1985. 33. Arbizu T, Santamaria J, Gomez JM, et al.: A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure. J Neurosci 59:371, 1983.

Ventral Wall of the Trunk 34. Klinefelter HF: Klinefelter’s syndrome: historical background and development. South Med J 79:1089, 1986. 35. Aiman J, Griffin JE, Gazak JM, et al.: Androgen insensitivity as a cause of infertility in otherwise normal men: The Reinfenstein syndrome revisited. N Engl J Med 300:223, 1979. 36. Amrhein JA, KIingensmith GJ, Walsh PC, et al.: Partial androgen insensitivity. N Engl J Med 297:350, 1977. 37. Bowen P, Lee CSN, Migeon CJ, et al.: Hereditary male pseudohermaphroditism with hypogonadism, hypospadias and gynecomastia (Reifenstein’s syndrome). Ann Intern Med 62:252, 1965. 38. Bremner WJ, Ott J, Moore DJ, et al.: Reifenstein’s syndrome: investigation of linkage to X-chromosomal loci. Clin Genet 6:216, 1974. 39. Wilson M, Mulley J, Gedeon A, et al.: New X-linked syndrome of mental retardation, gynecomastia, and obesity is linked to DXS255. Am J Med Genet 40:406, 1991. 40. Stephanas AV, Burnet RB, Harding PE, et al.: Clomiphene in the treatment of pubertal-adolescent gynecomastia: a preliminary report. J Pediatr 90:651, 1977. 41. Buckle R: Danazol in the treatment of gynaecomastia. Drugs 19:356, 1980. 42. Buckle R: Studies on the treatment of gynaecomastia with danazol (Danol). J Intern Med Res 5:114, 1977.

23.15 Premature Thelarche Definition

Premature thelarche is defined as precocious and isolated development of breast tissue without other signs of puberty in girls younger than age 8 years. Diagnosis

Breast development in premature thelarche resembles that of Tanner stage II or III. Pubic and axillary hair, vaginal discharge, or other signs of secondary sexual maturation do not accompany the breast enlargement. Bone age is within 2 SD of normal for chronologic age. There is no evidence of true precocious puberty detected via luteinizing hormone-releasing hormone (LHRH), nor are there signs of other underlying causes such as an estrogensecreting tumor or history of estrogen intake through drugs, ointments, or nutrition. Premature thelarche appears to be an uncommon finding in Kabuki, Rubinstein-Taybi, Mo¨bius, and Coffin-Siris syndromes.2–5 It has also been seen following growth hormone therapy.6 It has been suggested that premature thelarche is an incomplete form of precocious sexual development occurring from a partially overactivated hypothalamopituitary axis or an increased tissue responsiveness to hormones.1,7 LHRH can be used as a gonadotropic stimulation test in differentiating girls with premature thelarche from those with true precocious puberty. Girls with precocious puberty will respond with elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) plasma levels, and girls with premature thelarche will have normal LH but elevated FSH plasma levels.7 Estradiol levels are variable,8 and, although a majority of girls with premature thelarche have

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shown estrogenic activity on vaginal smears or cystograms, no good correlation with premature thelarche was found in these studies.1 No relation between premature thelarche and maternal obstetrical problems, diet, infections, or exposure to medication has been shown. Ilicki et al.7 found that 86% of the 68 girls evaluated as having premature thelarche had a height exceeding the 50th percentile. The authors found no correlation between patient’s and parents’ stature. None of the mothers had any abnormalities in sexual development, and the age at menarche was a mean of 13 ± 1.75 years. Pasquino et al.1 showed no acceleration of bone age after the appearance of premature thelarche but a gradual increase after age 8 years in girls with persistent premature thelarche. The incidence of premature thelarche in the general population is unknown. It appears to be increased among girls who had very low birth weight. Nelson reported premature thelarche in 8.7% of girls whose birth weight was less than 1000 g.9 The onset of premature thelarche occurs prior to age 2 years in 85% of cases. Approximately one-third of girls with premature thelarche have breast enlargement present from birth.7,10 Premature thelarche persists for 3–5 years in more than onehalf of cases.10 Regression is most likely when the age of onset is before 2 years.7 With onset after age 2 years, premature thelarche is most likely to persist until the girls develop other signs of early puberty at about age 8 years.1 No follow-up medical or sexual problems have been identified in girls with premature thelarche. The labia majora and labia minora remain infantile, and there is no sexual development or acne.7 Persistent premature thelarche is more likely to lead to simple early puberty or occasionally precocious puberty.1 References (Premature Thelarche) 1. Pasquino AM, Tebaldi L, Cioschi L, et al.: Premature thelarche: a follow up study of 40 girls. Arch Dis Child 60:1180, 1985. 2. Ihara K, Kuromaru R, Takemoto M, et al.: Rubinstein-Taybi syndrome: A girl with a history of neuroblastoma and premature thelarche. Am J Med Genet 83:365, 1999. 3. Ichiyama T, Handa S, Hayashi T, et al.: Premiere thelarche in Mo¨bius syndrome. Clin Genet 47:108, 1995. 4. Brunetti-Pierri N, Esposito V, et al.: Premature thelarche in CoffinSiris syndrome. Am J Med Genet 121:174, 2003. 5. Tutar HE, Ocal G, Ince E, et al.: Premature thelarche in Kabuki makeup syndrome. Acta Paediatr Jpn 36:104, 1994. 6. Carvalbo LRS, Mimura LY, Arnbold IJP, et al.: Premature thelarche in girls after growth hormone therapy. J Pediatr 138:448, 2001. 7. Ilicki A, Lewin RP, Kauli R, et al.: Premature thelarche-natural history and sex hormone secretions in 68 girls. Acta Paediatr Scand 73:756, 1984. 8. Escobar ME, Rivarola MA, Bergada´ C: Plasma concentrations of estradiol-17b in premature thelarche in different types of sexual precocity. Acta Endocrinol 81:351, 1976. 9. Nelson KG: Premature thelarche in children born prematurely. J Pediatr 103:756, 1983. 10. Mills JL, Stolley PD, Oavies J, et al.: Premature thelarche, natural history and etiologic investigation. Am J Dis Child 135:743, 1981.

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24 Upper Gastrointestinal System H. Eugene Hoyme

A

dvances in molecular biology increasingly have provided insights into mechanisms of intestinal morphogenesis. In addition, rapid progress has been made in identifying genes that regulate gastrointestinal development. Genes directing initial formation of the endoderm as well as organ-specific patterning have been identified.1–3 Signaling pathways that regulate the overall right-left asymmetry of the gastrointestinal tract 4–6 and epithelial/ mesenchymal interactions7 have been clarified. In searching for extrinsic developmental regulators, numerous candidate trophic factors have been proposed. A critical gene that initiates pancreatic development has been identified,8 as have a number of genes that regulate liver, stomach, and intestinal development.9,10 Mutations in genes affecting neural crest cell migration have been found to give rise to Hirschsprung’s disease.11,12 Integration of these data into a more complete understanding of the physiology of gastrointestinal development remains a challenge for the future. It is beyond the scope of this chapter to discuss molecular determinants of intestinal morphogenesis in their entirety; rather, those factors that play a role in morphogenesis and malformations of the upper GI tract will be highlighted. There are two major steps in development of the gastrointestinal tract: formation of the gut tube and formation of the individual organs with their specialized cell types. Genes regulating both phases have been identified and characterized. Gastrulation, during which the axes of the embryo are determined and formation of the gastrointestinal tract is initiated, is an essential early step in development of all multicellular organisms. Therefore, genes regulating gastrulation and development of the gastrointestinal tract probably arose early in evolution. Gastrulation gives rise to three germ layers, including the endoderm, the precursor to the epithelial lining of the gastrointestinal tract. Genetic regulation of formation of the endoderm is less well understood than that of the other two germ layers, but significant progress is now being made in this area.10 In Drosophila, the large family of homeotic genes is expressed in the body in a precise anterior to posterior order. Homeotic genes encode transcription factors, incorporating a conserved homeobox sequence, which regulates segmentation and pattern formation. Vertebrates display homologous hox genes that play important roles in the formation of specific regions of the brain and skeleton. Data indicate that the hox genes regulate

patterning of the gastrointestinal tract as well.10 A detailed study of the developing chick hindgut showed a correlation between the boundaries of expression of hoxa-9, -10, -11, and -13 in the mesoderm and the location of morphologic boundaries.13 Regional differences in expression of homeobox genes in the mouse intestine have also been demonstrated.14 Although functions have not been identified, the developing mouse foregut expresses hoxa1 and hoxb-1.15,16 Evidence is now accumulating that disruption of specific hox genes produces organ-specific gastrointestinal defects. For example, disruption of hoxc-4 gives rise to esophageal obstruction due to abnormal epithelial cell proliferation and abnormal muscle development.17 Alteration of the expression pattern of hox 3.1 (now hoxc-8) to a more anterior location causes distorted development of the gastric epithelium.18 Intriguingly, the intestine-specific transcription factor Cdx-2 recently has been found to be a potential regulator of hoxc-8.19 Furthermore, hoxc11 has been found to be a regulator of lactase-phlorizin hydrolase (LPH) expression, binding to the same element as Cdx-2.20 Mice with disrupted hoxd-12 and hoxd-13 genes demonstrate developmental defects in formation of the anal musculature.21 The regions affected by these alterations in hox gene expression are set forth in Table 24-1. Expression of the human homologues of a number of homeobox genes has also been shown to be region specific.22 These data indicate that the hox genes are critical early regulators of proximal to distal, organ-specific patterning in mammalian gastrointestinal development. The importance of the sonic hedgehog (SHH) pathway in gut morphogenesis, cellular differentiation, and the maintenance of a differentiated state is now well established in many vertebrate species. SHH plays a pivotal role in the regionalization and patterning of gut epithelium.23 For example, the SHH mutant mouse heterozygote exhibits various gastrointestinal defects, including intestinal transformation of the stomach, annular pancreas, and duodenal stenosis.24 The effect of SHH on the patterning of the gut may be brought about by its control of expression of Hox genes along the anterior/posterior axis.25–27 Expression or loss of expression of SHH is often a prerequisite for the specification of digestive tract–derived organs such as pancreas and lung, thus lending credence to the importance of SHH in the morphogenesis of the epithelium of the main digestive tract. In the development of the pancreas, the suppression of SHH in the presumptive 1065

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Gastrointestinal and Related Structures

Table 24-1. Mutations in homeotic genes affecting gastrointestinal development Gene

Region of Gastrointestinal Tract Affected

8.

hoxc-4

Esophageal epithelium and muscle17

9.

hoxc-8

Gastric epithelium18

hoxd-12

Anal musculature21

hoxd-13

Anal musculature21

Adapted from Montgomery et al.10

10.

11.

12.

pancreatic endoderm by the notochord specifies the area of the pancreatic bud. When SHH expression in the endoderm is suppressed by cyclopamine treatment, ectopic differentiation of endocrine and exocrine pancreatic cells is observed.28 Recent studies also have demonstrated that epithelial SHH affects the mesenchymal differentiation of the gut, especially the arrangement of connective tissue, smooth muscle, and the enteric nervous system.24,28,29 In addition to the genetic programming that leads to formation of individual differentiated cell types, multiple extrinsic factors may regulate development of the gastrointestinal tract. All cells are exposed to circulating factors in the fetal blood that change in level during development.30 When the fetal GI tract becomes patent and swallowing begins, it is exposed to trophic factors in the amniotic fluid; whereas postnatally the GI tract is exposed to trophic factors in milk.31 Localized synthesis of growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF)-a, and TGF-b may be important for directing specific regional changes. Members of the TGF-b family have been implicated in early determination of right and left asymmetry, which normally causes the stomach to be positioned on the left and liver on the right. In situs inversus, this asymmetry is reversed. A transcription factor gene has been identified as the gene mutated in a family displaying X-linked inheritance of situs abnormalities.4 Evidence from other studies suggests that this gene may function during development as part of a pathway involving growth factors of the TGF-b family,5 which regulate expression of a critical downstream transcription factor mediating right-left asymmetry.6 References 1. Henry GL, Melton DA: Mixer, a homeobox gene required for endoderm development. Science 281:91, 1998. 2. Zhu J, Hill RJ, Heid PJ, et al.: End-1 encodes an apparent Gata factor that specifies the endoderm precursor in Caenorhabditis elegans embryos. Genes Dev 11:2883, 1997. 3. Fukushige T, Hawkins MG, McGhee JD: The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine. Dev Biol 198:286, 1998. 4. Gebbia M, Ferrero GB, Pilia G, et al.: X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305, 1997. 5. Lowe LA, Supp DM, Sampath K, et al.: Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature 381:158, 1996. 6. Ryan AK, Blumberg B, Rodriguez-Esteban C, et al.: Pitx2 determines left-right asymmetry of internal organs of vertebrates. Nature 394:545, 1998. 7. Louvard D, Kedinger M, Hauri H: The differentiating intestinal epithelial cell: establishment and maintenance of functions through

13.

14. 15.

16.

17. 18. 19.

20.

21.

22.

23. 24.

25. 26.

27.

28.

29.

30.

31.

interactions between cellular structures. Ann Rev Cell Biol 8:157, 1992. Slack JM: Developmental biology of the pancreas. Development 121:1569, 1995. Zaret KS: Molecular genetics of early liver development. Ann Rev Physiol 58:231, 1996. Montgomery RK, Mulberg AE, Grand RJ: Development of the human gastrointestinal tract: Twenty years of progress. Gastroenterology 116: 702, 1999. Auricchio A, Casari G, Staiano A, et al.: Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a noninbred population. Hum Mol Genet 5:351, 1996. Angrist M, Bolk S, Thiel B, et al.: Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet 4:821, 1995. Yokouchi Y, Sakiyama J, Kuroiwa A: Coordinated expression of Abd-B subfamily genes of the HoxA cluster in the developing digestive tract of chick embryo. Dev Biol 169:76, 1995. James R, Kazenwadel J: Homeobox gene expression in the intestinal epithelium of adult mice. J Biol Chem 266:3246, 1991. Thompson JR, Chen SW, Ho L, et al.: An evolutionary conserved element is essential for somite and adjacent mesenchymal expression of the Hoxa1 gene. Dev Dyn 211:97, 1998. Huang D, Chen SW, Langston AW, et al.: A conserved retinoic acid responsive element in the murine Hoxb-1 gene is required for expression in the developing gut. Development 125:3235, 1998. Boulet AM, Capecchi MR: Targeted disruption of hoxc-4 causes esophageal defects and vertebral transformations. Dev Biol 177:232, 1996. Pollock RA, Jay G, Bieberich CJ: Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation. Cell 71:911, 1992. Taylor JK, Levy T, Suh ER, et al.: Activation of enhancer elements by the homeobox gene Cdx2 is cell line specific. Nucl Acids Res 25:2293, 1997. Mitchelmore C, Troelsen JT, Sjostrom H, et al.: The HOXC11 homeodomain protein interacts with the lactase-phlorizin hydrolase promoter and stimulates HNF1 alpha–dependent transcription. J Biol Chem 273:13297, 1998. Kondo T, Dolle P, Zakany J, et al.: Function of posterior HoxD genes in the morphogenesis of the anal sphincter. Development 122:2651, 1996. Walters JR, Howard A, Rumble HE, et al.: Differences in expression of homeobox transcription factors in proximal and distal human small intestine. Gastroenterology 113:472, 1997. Fukuda K, Yasugi S: Versatile roles for sonic hedgehog in gut development. J Gastroenterol 37:239, 2002. Ramalho-Santos M, Melton DA, McMahon AP: Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127:2763, 2000. Zhang XM, Yang XJ: Temporal and spatial effects of sonic hedgehog signaling in chick eye morphogenesis. Dev Biol 233:271, 2001. Roberts DJ, Smith DM, Goff DJ, et al.: Epithelial mesenchymal signaling during the regionalization of the chick gut. Development 125:2791, 1998. Sekimoto T, Yoshinobu K, Yoshida M, et al.: Region-specific expression of murine Hox genes implies the Hox code-mediated patterning of the digestive tract. Genes Cells 3:151, 1998. Apelqvist A, Ahlgren U, Edlund H: Sonic hedgehog directs specialized mesoderm differentiation in the intestine and pancreas. Curr Biol 7:801, 1997. Sukegawa A, Narita T, Kameda T, et al.: The concentric structure of the developing gut is regulated by sonic hedgehog derived from endodermal epithelium. Development 127:1971, 2000. Scott SM, Buenaflor GG, Orth DN: Immunoreactive human epidermal growth factor concentrations in amniotic fluid, umbilical artery and vein serum, and placenta in full-term and preterm infants. Biol Neonate 56:246, 1989. Koldovsky O: Hormonally active peptides in human milk. Acta Paediatr Suppl 402:89, 1994.

Upper Gastrointestinal System

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Pharynx General body form in the early embryo develops with the folding of the flat trilaminar embryonic disc into a cylindrical shape. Ventral folding occurs as a result of the rapid growth of dorsal structures, including the neural tube, during week 4 of gestation, occurring simultaneously at the cranial, caudal, and lateral margins of the embryo. The ventrally located endoderm thus becomes folded into the primitive gut. In the cephalic and caudal ends of the gut, blind tubes exist: the foregut and the hindgut. The midgut remains connected to the yolk sac by means of the vitelline duct (Fig. 24-1). The pharyngeal gut or pharynx extends from the buccopharyngeal membrane to the tracheobronchial diverticulum. At the end of week 3, the buccopharyngeal ruptures, thus establishing an open connection through the oral cavity between the amniotic space and the primitive gut.1 The most prominent anatomic features of the developing pharyngeal area are the branchial or pharyngeal arches (Fig. 24-2). The branchial arches appear during weeks 4–5 post-conception and consist of bars of mesenchyme, separated by clefts known as branchial clefts. At the same time the arches and clefts are developing, pharyngeal pouches appear along the lateral walls of the pharyngeal gut. The pouches gradually penetrate the overlying mesenchyme, but do not connect directly with the external clefts. The branchial arches contain paired arteries, aortic arches, nerves, and skeletal cartilages. Thus, each pharyngeal arch consists of a core mesenchymal tissue covered on the outside by surface ectoderm and inside by endoderm. Normally, this temporary branchial pattern is entirely obliterated in the human week 7 postconception.1–5 Derivatives of the pharyngeal arches, clefts, and pouches are set forth in Table 24-2.1,3

Fig. 24-1. Schematics of longitudinal sections of human embryos at (A) 22, (B) 26, and (C) 30 days. Foregut and hindgut pouches form between 22 and 26 days by cranial, caudal, and lateral folding of a portion of the yolk sac (YS) into the interior of the embryo. The connection of the midgut to the yolk sac is progressively narrowed in

Fig. 24-2. Human embryo at 5 weeks gestation. Note the relationships of the branchial arches and clefts. References (Pharynx) 1. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott, Williams and Wilkins, Baltimore, 2003. 2. Patten BM: The normal development of the facial region. In: Congenital Anomalies of the Face and Associated Structures. S Pruzansky, ed. Charles C Thomas, Springfield, IL, 1961, p 11. 3. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p.22.

purse string fashion. By 30 days, early development of the gut derivatives are evident: Al, allantois; T, thyroid; Pa, parathyroids; H, liver; L, lung bud; P, pancreas. (Adapted from Moore et al.6 and Tuchman-Duplessis et al.7)

Table 24-2. Derivatives of the pharyngeal arches, clefts, and pouches Pharyngeal Structure

Nerve

Derivatives

I. Arch (mandibular)

V. Trigeminal-mandibular division

Quadrate cartilage-incus Tragus and crus of pinna Meckel’s cartilage-malleus, anterior ligament of malleus, sphenomandibular ligament, portion of mandible Muscles of mastication Mylohyoid muscle Anterior belly of digastric muscle Tensor palatine and tensor tympani muscles Body of tongue

Cleft

External auditory canal

Pouch

Middle ear cavity Mastoid air cells

II. Arch (hyoid)

VII. Facial

Stapes

VIII. Auditory

Styloid process Stylohyoid ligament Lesser horn and upper portion of the body of the hyoid Muscles of facial expression Posterior belly of digastric muscle Stylohyoid muscle Stapedius muscle Root of tongue Foramen cecum Thyroid gland

Pouch

Palatine tonsil Supratonsillar fossa

III. Arch

IX. Glossopharyngeal

Hyoid (greater horn and part of body) Part of epiglottis Stylopharyngeus muscle Upper pharyngeal constrictor muscles

Pouch

Inferior parathyroid Pyriform fossa Thymus

IV-VI.

X. Vagus

Thyroid Laryngeal cartilages (thyroid, cricoid, arytenoid, corniculate, and cuneiform) Part of the epiglottis Crycothyroid muscle Levatopalatine muscle Constrictor muscles of the pharynx Intrinsic muscles of the larynx

Pouches

Superior parathyroid Thymus Ultimobranchial body 1

Data are from Sadler and Elias et al.

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3

Upper Gastrointestinal System 4. Lyall D, Stahl WM: Lateral cervical cysts, sinuses, and fistulas of congenital origin. Int Abstr Surg 102:417, 1956. 5. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 668. 6. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, ed 6. WB Saunders, Philadelphia, 1998. 7. Tuchmann-Duplessis H, David G, Haegel P: Illustrated Human Embryology. Springer-Verlag, New York, 1982.

24.1 Fistulas, Sinuses, and Cysts: Branchial Clefts and Pouches Definition

Abnormal persistence of remnants of the branchial apparatus results in epithelium-lined cysts, sinuses, and fistulas. Fistulas are patent, tube-like structures that have both external and internal orifices. External sinuses are blind openings extending inward from an external opening on the skin; internal sinuses are blind structures extending outward from an opening in the pharynx. Cysts are spherical structures lying along the track of a branchial pouch or cleft, having no communication with the surface, either at the skin or with the pharynx.1–7 Diagnosis

Cervicoaural fistulas extend from the angle of the mandible and usually open into the external auditory canal. These fistulas originate as remnants of the first branchial cleft. Lateral cervical fistulas extend from the lower neck anterior to the sternocleidmastoid muscle and open into the pharynx near the tonsillar fossas. These fistulas originate from the second branchial cleft and pharyngeal pouch. External branchial sinuses are blind-ending spaces that have the same external appearance as fistulas and may be derived from either the first or the second branchial cleft. Internal sinuses are usually of second pouch origin and open into the region of the tonsillar fossas, having no external openings at the skin.1–7 External sinuses or fistulas are usually found as small openings either at the corner of the mandible or near the anterior border of the sternocleidomastoid muscle in the neck. The opening of the structure may be slightly raised and/or slit-like. Application of pressure to the surrounding area may cause small quantities of fluid to escape through the orifice. Secondary infection of these structures is quite common.1–7 Internal sinuses are often asymptomatic. If the internal opening does not drain easily, infection may occur and/or there may be dysphagia or hoarseness from pressure on the laryngeal nerve. If the opening is large, the sinus may collect food particles, leading to patient complaints of foul taste or odor.1–7 Nearly all cystic remnants of the branchial apparatus are derived from the second pouch or cleft. They may be found anywhere along the pathway of a second cleft fistula. They generally present as swellings in the upper neck along the edge of the sternocleidomastoid muscle. The patient may state that the swelling has been there for years. Occasionally, they are described as fluctuating in size, probably indicating internal sinuses with small openings into the pharynx. Usually, cysts are moveable and painless. Branchial cleft cysts include squamous epithelium in 90%, respiratory epithelium in 10%, and surrounding lymphoid tissue in 80%. The cysts may contain birefringent cholesterol crystals.8 Diagnosis of these remnants generally has been based on clinical findings. However, various diagnostic studies can be per-

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formed to delineate the entire anatomy of the cyst. Contrast medium may be injected into an internal or external orifice followed by radiographic studies to delineate the exact anatomy.1,2 Alternatively, ultrasonographic, computerized tomographic (CT), and magnetic resonance imaging (MRI) studies of the soft tissues of the neck have been utilized to diagnose these malformations accurately.3,9 Neck masses are extremely difficult to diagnose. Approximately 50% of such masses are of thyroid origin. The remainder are neoplastic, inflammatory, congenital, or functional swellings. Of the non-neoplastic masses of congenital origin in the neck, 72% are cysts of the thyroglossal duct, 24% are branchial cysts, sinuses, or fistulas, and 4% are cystic hygromas. Skandalakis et al.10 found that branchial cleft anomalies accounted for less than 2% of nonthyroid neck masses in a series of 142,118 surgical admissions to Atlanta hospitals between 1954 and 1963. More recently, Kenealy et al. reported on the relative frequency of branchial cleft cysts, sinuses, and fistulas over a 5-year period at the Children’s Hospital of Philadelphia. In their series of 71 patients with branchial cleft malformations (39 males and 32 females), 23 branchial cleft cysts (30%), 50 sinuses (66%), and 3 fistulas (4%) were identified. A correct preoperative diagnosis was established in 60 (85%) of the patients, the highest being for patients with branchial cleft fistulas. Incorrect preoperative diagnoses included thyroglossal duct cyst, cervical lymphadenitis, dermoid, dermal inclusion cyst, lymphangioma, and malignant neoplasm.11 Etiology and Distribution

Most cases of congenital pharyngeal fistulas, sinuses, and cysts occur sporadically in otherwise normal families. However, autosomal dominant inheritance has been described.2 In addition, branchial fistulas, sinuses, and/or cysts may be features of the branchio-oto-renal (Melnick-Fraser) syndrome (Fig. 24-3)12–14 or the branchio-oculo-facial syndrome.13,15 Features of those disorders are set forth in Table 24-3. These anomalies are bilateral in approximately one-third of cases, the right side being affected more commonly than the left. No sex predilection has been noted.1,3,11 Prognosis, Treatment, and Prevention

Twenty-five percent of patients with these persistent embryonic structures have repeated local infections. It has also been suggested that there may be some malignant potential in persistent branchial remnants. The only effective treatment for branchial apparatus remnants is complete excision of the walls of the cyst, sinus, or fistula. These structures should be removed as early in life as possible to avoid recurrent infection.1–7 Presence of these defects should prompt the clinician to search for other abnormalities in formation of the branchial apparatus. In particular, hearing screening should be performed in infancy to rule out conductive or mixed hearing loss accompanying middle ear malformations.1–7 A renal imaging study should also be carried out in sporadic case to rule out the branchio-otorenal (Melnick-Fraser) or branchio-oto-ureteral syndromes.12–14 References (Fistulas, Sinuses, and Cysts) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 22. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 668.

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Gastrointestinal and Related Structures

Fig. 24-3. Branchio-oto-renal (BOR) syndrome. Note prominent cupped pinnae and branchial cleft sinus (arrow).

3. Friedburg J: Pharyngeal cleft sinuses and cysts, and other benign neck lesions. Pediatr Clin North Am 36:1451, 1989. 4. Soper RT, Pringle KC: Cysts and sinuses of the neck. In: Pediatric Surgery, ed 4 KG Welch, JG Randolph, MM Ravitch, et al. (eds): Year Book Medical Publishers, Chicago, 1986, p 539. 5. Doi O, Hutson JM, Myers NA, et al.: Branchial remnants: a review of 58 cases. J Pediatr Surg 23:789, 1988. 6. Noel F, Leung MD: First branchial cleft fistula: case reports and literature review. J Otolaryngol 13:247, 1987. 7. Titchener GW, Allison RS: Lateral cervical cysts: a review of 42 cases. NZ Med J 102:536, 1989.

8. Sonnino RE, Spigland N, Laberge JM, et al.: Unusual patterns of congenital neck masses in children. J Pediatr Surg 24:966, 1989. 9. McCurdy JA, Madalo LA, Yim DWS: Evaluation of extra-thyroid masses of the head and neck with gray scale ultrasound. Arch Otolaryngol 106: 83, 1980. 10. Skandalakis JE, Goodwin JT, Androulakis JA, et al.: The differential diagnosis of tumors of the neck. In: Progress in Clinical Cancer, vol. 4. JM Arial, ed, Grune & Stratton, New York, 1970, p 141. 11. Kenealy JF, Torsiglieri AJ Jr, Tom LW: Branchial cleft anomalies: A five-year retrospective review. Trans Pa Acad Ophthalmol Otolaryngol 42:1022, 1990.

Table 24-3. Syndromes with branchial cleft fistulas, sinuses, and cysts Causation Gene/Locus

Syndrome

Prominent Features

Branchio-oto-renal (Melnick-Fraser)12–14

Malformed pinnae, preauricular appendages or pits, malformed middle ear ossicles, inner ear anomalies, hearing loss, structural renal anomalies, aplasia or stenosis of lacrimal ducts, strabismus, higharched palate, cleft palate, facial asymmetry

AD (113650) EYA1, 8q13.3

Branchio-oto-facial13,15

Pseudocleft of upper lip, congenital nasolacrimal duct obstruction, small forehead, premature graying of hair, hypertelorism, anophthalmia, microphthalmia, myopia, cataracts, strabismus, coloboma, malformed pinnae, broad nasal bridge with indented nasal tip, conductive hearing loss, clinodactyly of finger 5, preaxial polydactyly, hemangiomas or aplasia cutis congenita of lateral neck

AD (113620)

Branchio-oto-uretal13

Deafness, preauricular pits or tags, cone-shaped pinnae, microtia, duplicated ureters, ureterocele, bifid renal pelves, spina bifida occulta

AD

Branchio-skeleto-genital13,16,17

Maxillary hypoplasia, dentigenous cysts, unerupted teeth, prognathism, dentin dysplasia, bifid uvula, cleft palate, mastoid hypoplasia, broad nasal bridge, wide nasal tip with flared alar cartilages, hypertelorism, strabismus, ptosis, nystagmus, brachycephaly, cervical vertebral fusion, pectus excavatum, penoscrotal hypospadias, mental retardation, seizures

AR

Upper Gastrointestinal System 12. Heimler A, Lieber E: Branchio-oto-renal syndrome: reduced penetrance and variable expressivity in four generations of a large kindred. Am J Med Genet 25:15, 1986. 13. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford Press, London, 2001, p 668. 14. Fraser FC: Autosomal dominant duplication of the renal collecting system, hearing loss, and external ear anomalies: a new syndrome? Am J Med Genet 14:473, 1983. 15. Fujimoto A, Lipson M, Lacro RV, et al.: New autosomal dominant branchio-oculo-facial syndrome. Am J Med Genet 27:943, 1987. 16. Elsahy NI, Waters WR: The branchio-skeletal-genital syndrome. A new hereditary syndrome. Plast Reconstr Surg 58:542, 1971. 17. Wedgwood DK: Craniofacial and dental anomalies in the branchioskeletal-genital syndrome with suggestions for more appropriate nomenclature. Br J Oral Surg 21:94, 1983.

24.2 Congenital Pharyngeal Diverticula Congenital pharyngeal diverticula are congenital pouches of the lateral or posterior walls of the pharynx and may be asymptomatic. However, if they are large, the affected individual can present with swelling of the neck, respiratory embarrassment, and/or dysphagia. Diagnosis is made by video- or cineradiographic contrast techniques1 and/or pharyngoesophagoscopy.2 Although lateral pouches are considered remnants of the third or fourth branchial clefts, posterior pharyngeal pouches or diverticula may be of heterogeneous etiology. The majority of these posterior diverticula are most likely acquired, presenting in later life.1–4 However, many of these diverticula are of early gestational onset (accompanying a congenital defect between the muscle layers in the pharyngoesophageal segment1) as evidenced

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by the fact that there is an association of such structures with congenital cervical vertebral fusion defects.5 Pharyngeal diverticula have also been seen in association with the severe autosomal recessive form of cutis laxa.6 In infants, large posterior pharyngeal diverticula can simulate atresia of esophagus.2–4 Over time, pharyngeal pouches or diverticula may enlarge to recurrent distention with food particles. The affected individual may have hoarseness, difficulty breathing, and/or dysphagia. Patients may complain of regurgitation of portions of undigested food into the mouth. When the opening of the diverticulum is located above the superior esophageal sphincter, there is no barrier to prevent spontaneous episodes of aspiration pneumonitis. Carcinoma has also been observed as a complication of pharyngeal diverticulum.2–4 In general, any diverticulum arising in the pharyngoesophageal region and producing symptoms warrants treatment. Surgical diverticulectomy is the recommended course of treatment.2–4 References (Congenital Pharyngeal Diverticula) 1. Ekberg O: New surgical and pathological aspects of Zenker’s diverticulum. Diagnostic imaging and analysis of function. Chirurg 70:747, 1999. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 679. 3. Raven RW: Pouches of pharynx and esophagus. Br J Surg 21:235, 1933. 4. Kaufman SA: Lateral pharyngeal diverticula. AJR Am J Roentgenol 75:238, 1956. 5. Baeyer EV: Zenker’s diverticulum and cervical block vertebra. AJR Am J Roentgenol 84:1037, 1960. 6. Janik JS: Cutis Laxa and hollow viscus diverticula. J Pediatr Surg 17:318, 1982.

Esophagus At approximately 4 weeks postconception, a small outgrowth appears at the ventral wall of the foregut at the border with the pharyngeal gut. This outgrowth, termed the respiratory or laryngotracheal diverticulum, is sequentially separated from the dorsal part of the foregut through a septation process resulting in an esophagotracheal septum. The foregut therefore becomes divided into a ventral portion from which the respiratory tract develops and a dorsal portion, the esophagus (Fig. 24-4).1,2 Initially, the esophagus is quite short; however, as it further develops, it elongates more rapidly that the embryo as a whole. Final length of the esophagus is not attained until approximately 7 weeks, at which time the abdominal portion of the esophagus is relatively longer than in the adult. The musculature of the esophagus is formed by surrounding mesenchymal elements, being striated in the upper two-thirds and innervated by the vagus nerve, and being smooth in the lower one-third and innervated by splanchnic plexus.1,2 The esophageal lumen is initially rounded, but becomes flattened dorsoventrally in the upper esophagus and laterally in the lower esophagus during week 5. Extensive longitudinal folding of the wall then begins to occur in humans. However, as the result of anomalous development, complete occlusion of the lumen can be observed.1,2

At 10 weeks, ciliated columnar epithelium appears. Stratified squamous epithelium replaces it at around 20–25 weeks, a process that begins in the midesophagus and proceeds in both the cephalic and caudal directions.3 Development of human fetal esophageal mucosa has been investigated in vitro. Human fetal esophageal explants at 12 and 16 weeks’ gestation demonstrate accelerated maturation, with formation of stratified squamous epithelium after 15 days in culture.3 At 10 weeks, proliferating cells are abundant throughout the epithelium. As the explants develop, mitotic activity becomes restricted to the basal zone.4 The regulation of this accelerated maturation is unknown. Hitchcock et al. have studied the esophageal musculature and innervation of the esophagus in fetuses of 8–20 weeks’ gestation, and in newborn infants.5 The circular muscle is present at 8 weeks, but the longitudinal muscle does not appear until approximately 13 weeks of gestation. In fetuses, the thickness of the muscularis externa increases linearly from 8 weeks to term, then growth slows postnatally. Neurons can be recognized concomitantly with circular muscle at 8 weeks. The density of neurons peaks at 16–20 weeks, decreases rapidly in the second trimester, and is reduced further toward adult levels in the newborn infant. Maximal numbers of ganglion cells and nerve fibers in the myenteric plexus are also observed at 16–20 weeks. Their density decreases with increasing

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Gastrointestinal and Related Structures

Fig. 24-4. Partitioning of the foregut into the esophagus and trachea during embryonic stages 11–16. Lower figures show abnormal partitioning, resulting in esophageal atresia and tracheoesophageal fistula.

gestational age to 30 weeks, thereafter becoming constant despite further esophageal growth.5 Fetal swallowing can be detected as early as 11 weeks of gestation, with sucking movements observed between 18 and 20 weeks.6 The swallowing of amniotic fluid begins very slowly at a few milliliters per day and increases to 450 ml/day in the third trimester.4 In animal models, fetal swallowing defects have been correlated with failure of growth of the gastrointestinal tract as well as ultrastructural abnormalities.7,8 Careful studies of human fetuses are not available; however, human infants with esophageal atresia appear to have normal gastrointestinal function after correction of their lesions.9 The significance of morphologic changes in animals as a consequence of the exclusion of growth factors from the fetal luminal environment during development remains to be delineated. The locations of the malformations of the esophagus are depicted in Figure 24-5, and a summary of their characteristics is set forth in Table 24-4.2 References (Esophagus) 1. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott, Williams and Wilkins, Baltimore, 2003. 2. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 89.

Fig. 24-5. Locations of malformations of the esophagus. (Adapted from Elias et al.2)

Upper Gastrointestinal System

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Table 24-4. Anomalies of the esophagus Onset of Malformation

Age at Diagnosis

Sex Preponderance

Esophageal atresia/stenosis, tracheoesophageal fistula

21–34 Days

Birth

Equal

1:3000 live births

Esophageal webs/rings

Week 7

Any age

Male

Rare

May remain asyptomatic

True duplications

Week 7

Any age

Unknown

Very rare

May remain asyptomatic

Enterogeneous cysts

End of Week 3

Any age

Female

Rare

Diverticula

Beyond Month 5

Any age

Male

Uncommon

Muscular weakness may exist without herniation occurring

Heterotopic mucosa

Beyond Month 5

Any age

Equal

Common

May remain asyptomatic

Congenital short esophagus

Week 7

Any age

Male

Rare

May remain asyptomatic

Achalasia

Week 6

Infancy

Equal

Uncommon

Adult onset cases are acquired, not malformations

Chalasia

Week 6

Early infancy

Equal

Uncommon

Anomaly

Frequency

Remarks

Adapted from Elias et al.2

3. Menard D, Arsenault P: Maturation of human fetal esophagus maintained in organ culture. Anat Rec 217:348, 1987. 4. Arsenault P, Menard D: Autoradiographic localization of [3H]thymidine incorporation in developing human esophagus. Anat Rec 220:313, 1988. 5. Hitchcock RJ, Pemble MJ, Bishop AE, et al.: Quantitative study of the development and maturation of human oesophageal innervation. J Anat 180:175, 1992. 6. Dumont RC, Rudolph CD: Development of gastrointestinal motility in the infant and child. Gastroenterol Clin North Am 23:655, 1994. 7. Trahair JF, Harding R: Ultrastructural anomalies in the fetal small intestine indicate that fetal swallowing is important for normal development: an experimental study. Virchows Archiv A Pathol Anat Histopathol 420:305, 1992. 8. Trahair JF, Harding R: Restitution of swallowing in the fetal sheep restores intestinal growth after midgestation esophageal obstruction. J Pediatr Gastroenterol Nutr 20:156, 1995. 9. Foglia RP: Esophageal disease in the pediatric age group. Chest Surg Clin North Am 4:785, 1994.

24.3 Esophageal Stenosis, Atresia, and Tracheoesophageal Fistula Definitions

Esophageal stenosis is a congenital narrowing of the lumen of the esophagus. Esophageal atresia is a congenital complete discontinuity of the lumen of the esophagus. Tracheoesophageal (TE) fistula is an anomalous connection between a portion of the esophagus and the tracheobronchial tree. TE fistula is a frequent concomitant of esophageal atresia or stenosis. 1–4 Diagnosis

Esophageal stenosis usually is diagnosed later than atresia. Symptoms and signs of esophageal stenosis consist of regurgitation of food, dysphagia, food impaction, and/or growth failure. Occasionally the symptoms do not appear until the child is fed solid food. Due to the narrowing of the esophagus, progressive

dilation superior to the defect may result. This enlargement of the esophagus above the level of obstruction may partially obstruct the trachea or bronchi and produce respiratory embarrassment. Esophageal stenosis may be diagnosed by barium swallow radiographic study or esophagoscopy.1–4 Endoscopic ultrasonography may be an additional useful diagnostic adjunct.5 Atresia of the esophagus generally presents within the first few hours of life. Excessive salivation and drooling during the first day of life should suggest this diagnosis. If an affected child eats, he or she usually eats hungrily; however, coughing, gagging, vomiting, and/or cyanosis soon follow. Diagnosis of esophageal atresia may be suspected by an inability to pass a nasogastric tube beyond an upper esophageal obstruction. The radiographic appearance of a coiled nasogastric tube in an air-filled upper pouch is diagnostic of esophageal atresia. Confirmation of the diagnosis may be made by instilling a small amount of radiopaque contrast material into the upper esophageal pouch and obtaining a radiograph of the chest and abdomen; the blind upper esophageal obstruction is thus revealed (Fig. 24-6). The presence of gas in the stomach or more distally in the intestine confirms the presence of a TE fistula (since there is no other way that gas could reach the bowel beyond the esophageal obstruction). If there is no gas in the intestine, the clinician may deduce that there is no fistulous connection between the trachea and the esophagus superior to the obstruction. Rarely, in less than 1% of cases of TE fistula, the fistulous connection is too small to allow air distally into the intestines in the first few hours of life.1–3 Esophageal atresia is commonly suspected prenatally by a combination of polyhydramnios, reduced intraluminal liquid in the fetal gut, and an inability to detect the fetal stomach on prenatal ultrasound.6 Diagnosis of a TE fistula without esophageal atresia is more problematic. If the fistulous connection is very small, the diagnosis is particularly difficult. Symptoms may include cyanosis and coughing with feeding, recurrent pneumonia (especially right upper lobe pneumonia), and excessive abdominal distention from large amounts of air crossing the fistulous tract and entering the intestine (particularly when the patient cries). Diagnostic

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Gastrointestinal and Related Structures

Fig. 24-6. Radiographs of an infant with esophageal atresia and distal tracheoesophageal fistula. Note dilated proximal esophageal pouch (arrows), air in the stomach, and segmentation anomalies of the dorsal vertebrae. (Courtesy of Dr. Rodney J. Macpherson, Medical University of South Carolina, Charleston.)

confirmation of this entity is best accomplished with cinefluoroscopy while feeding the prone infant or child a barium meal. A negative barium study, however, does not rule out a tracheoesophageal fistula. In a suspicious case with a negative barium study, bronchoscopy may reveal the orifice of a fistula, into which a catheter may then be inserted. Esophagoscopy is performed, and if the catheter is observed extending into the esophagus, a positive diagnosis has been made. Another method of diagnosis that has been employed has been the installation of 0.5 ml of methylene blue into the trachea while performing esophagoscopy. Appearance of the methylene blue in the esophagus is diagnostic of a TE fistula.1–3 Etiology and Distribution

Congenital esophageal stenosis is a rare disorder, observed in 1/25,000 to 1/50,000 births,7 although the birth prevalence is higher in Japan.8,9 There is no gender predisposition.4 The incidence of associated anomalies has been reported to range between 17–33%.10 Congenital esophageal stenosis most likely is etiologically related to esophageal atresia, as borne out by the fact that associated anomalies in esophageal stenosis mirror those described in association with

esophageal atresia. Esophageal stenosis may also be acquired postnatally, secondary to iatrogenic trauma to the esophagus, especially with chronic nasogastric intubation.1–3 The five types of congenital esophageal atresia and TE fistula are diagrammed in Figure 24-7. The most frequent form by far is type C, in which the upper esophagus ends as a blind pouch, and the lower segment forms a fistula with the trachea. This accounts for approximately 90% of cases. Type A, isolated esophageal atresia, accounts for 4% of cases, as does type E. H-type TE fistula without esophageal atresia, and types B and D (esophageal atresia with an upper fistula and esophageal atresia with a double fistula) account for 1% each.3 The combination of esophageal atresia and TE fistula occurs in approximately 1/3000 to 1/3500 births. There is no sex preponderance. Low birth weight frequently is observed in affected infants, and prematurity is common.11 As many as 55% of cases are associated with other malfomations.11–18 Amae et al. reported that 4.8% of patients with esophageal atresia displayed a concomitant stenosis of a different esophageal segment,4 although cooccurrence rates of esophageal atresia and esophageal stenosis ranging from 0.4–14% have been described.4,10 More commonly,

Fig. 24-7. Schematics of various types of esophageal atresia (EA) and/or tracheoesophageal fistula (TEF). (A) EA without TEF. (B) EA with proximal TEF. (C) EA with distal TEF. (D) EA with proximal and distal TEF. (E) TEF without EA.

Upper Gastrointestinal System

reported associated defects have been part of the VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula/esophageal atresia, renal anomalies, and limb defects). The frequencies of associated defects in children ascertained with the TE fistula/esophageal atresia are set forth in Table 24-5. It is important to note that the VACTERL association is not a specific diagnosis. Rather, it is a pattern of anomalies, of heterogeneous etiology, occurring together more frequently than one would expect by chance alone. VACTERL association defects are frequently observed as features of broader recognizable patterns of malformation.11–15 Representative multiple malformation syndromes associated with TE fistula/esophageal atresia are set forth in Table 24-6. Recurrence risk counseling in these instances requires that an accurate diagnosis of the overall pattern of malformation has been made. Esophageal stenosis, esophageal atresia, and/or TE fistula not part of multiple malformation syndromes are thought to be multifactorially determined, with both polygenic and poorly determined environmental factors during gestation being involved.15 An epidemiologic study of 149 cases ascertained through the British Columbia Health Surveillance Registry found no association with season, month, or trends of hepatitis, rubella, salmonella, or rubella infections.19 Recurrence risks for siblings of an affected child are low, probably less than 1%.15

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Table 24-5. Esophageal atresia and TE fistula: associated anomalies and their relative frequencies Defect

Cases Affected (%)

Cardiac anomalies

29–37

Anorectal malformations

11–17

Skeletal/vertebral defects

10–49

Genitourinary anomalies

11–28

Gastrointestinal defects

8–13

Data are from various series.11–15

Early in fetal life, the trachea and esophagus constitute a single tube. The separation of the trachea from the esophagus normally occurs during week 4 postconception. Esophageal stenosis, atresia, or TE fistula are thought to result from either a spontaneous deviation of the esophageotracheal septum in a posterior direction or from mechanical forces pushing the dorsal wall of the foregut anteriorly. Esophageal atresia results when a disproportionate amount of endoderm becomes organized into the trachea, leaving too little to form the esophagus. It has been hypothesized that the larger the communication between the trachea and the esophagus, the earlier the defect most likely occurred.1,2 Intrauterine anoxia or

Table 24-6. Patterns of malformation associated with esophageal atresia/TE fistula Syndrome

Prominent Features

Causation Gene/Locus

VACTERL association

Vertebral anomalies, anorectal defects, cardiac anomalies, renal defects, limb malformations, single umbilical artery, rib defects, genital defects

Unknown: may have multiple etiologies (192350)

CHARGE

Coloboma, heart defects, choanal atresia, growth deficiency, mental deficiency, genital hypoplasia, ear anomalies, deafness, micrognathia, cleft lip/palate, renal anomalies

AD (214800) CHD7, 8q12.1

Facio-auriculovertebral

Asymmetric hypoplasia of malar, maxillary, and mandibular areas, microtia, deafness, hemivertebrae, epibulbar dermoid, macrostomia, microphthalmia, cleft lip/palate, cardiac defects, hypoplastic lung, renal anomalies, rib defects

Unknown: (164210, 257700)

DiGeorge

Absent or hypoplastic thymus, asbent or hypoplastic parathyroids, aortic arch defects, conotruncal defects, unusual facies, mental deficiency

Del 22q (188400)

Down

Hypotonia, protuberant tongue, mental deficiency, brachycephaly, upslanting palpebral fissures, small ears, Brushfield spots, short incurved 5th fingers, cardiac defects, loose skin at posterior neck

Trisomy 21

Trisomy 18

Severe mental deficiency, prominent occiput, short palpebral fissures, camptodactyly, low arch dermal ridges, short sternum, congenital heart defects

Trisomy 18

Dyskeratosis congenita

Irregular hyperpigmentation and patchy atrophic hypopigmentation of skin, leukoplakia, nail dystrophy, pancytopenia, osteoporosis, mental deficiency

Heterogeneous XL (305000) DKC1, Xq28 AR (224230) AD (127550) TERC, 3q21-q28

Maternal phenylketonuria

Microcephaly, mental retardation, growth deficiency, congenital heart disease

Teratogenic effects of phenyketonuria

Opitz

Genital anomaly in males, hypertelorism, widow’s peak, hernias, cardiac defects, cleft lip/palate

XLD (300000) MID1, Xp22 AD (145410) 22q11.2

Data are from Jones.15

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Gastrointestinal and Related Structures

stress leading to vascular compromise also may produce focal necrosis of the esophagus, resulting in atresia or tracheoesophageal communication.20 Prognosis, Treatment, and Prevention

Prognosis in this entity has improved dramatically over the last 50 years. Prior to that time, children with esophageal atresia invariably died. Present-day surgical techniques allow for an excellent prognosis in most children with these disorders. The exact surgical technique utilized and the associated prognosis depend on the particular anatomy of the malformations. Overall mortality is 10–15%, usually in conjunction with multiple severe associated anomalies. In general, larger areas of esophageal atresia are more difficult to treat surgically. A one-step, end-to-end anastomosis of the cranial and caudal portions of the esophagus, with ligation of associated TE fistula, is feasible in all but a small number of cases. If the distance between the blind upper pouch and the lower segment of the esophagus is too great to perform an end-to-end anastamosis, stretching of the upper pouch must first be performed. Techniques to stretch the lower segment have also been employed. Rarely, if the missing esophageal segment is so large as to preclude union of the ends, an esophageal reconstruction with colonic segment or gastric tube must be performed.2,3,11–13,21,22 Long-term complications following surgical repair include stricture at the site of the anastamosis, recurrent fistulas, and a brassy cough. The cough is the result of poor cartilaginous development in the posterior trachea. Patients also have long-term complaints of dysphagia accompanying defective esophageal motility. 2,3,11–13,21,22 Presence of this malformation should prompt the clinician to search for the anomalies of the VACTERL association as well as to consider the multiple malformation syndromes of which these malformations may be a part.15 Although recurrence risks with subsequent pregnancies are likely to be very low, ultrasound studies to assess the amount of amniotic fluid and/or the dynamics of fetal swallowing and the size of the stomach may be used to assess the integrity of the fetal esophagus with the subsequent pregnancies of the parents of an affected child.6,11 References (Esophageal Stenosis, Atresia, and Tracheoesophageal Fistula) 1. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 678. 2. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 70. 3. Wrenn EL, Jr. Hollabaugh RS, Lobe TE, et al.: Pediatric surgery. In: Comprehensive Pediatrics. RL Summitt, ed. CV Mosby, St. Louis, 1990, p 1060. 4. Amae S, Nio M, Kamiyama T, et al.: Clinical Characteristics and Management of Congenital Esophageal Stenosis: A Report on 14 Cases. J Pediatr Surg 38:565, 2003. 5. Usui N, Kamata S, Kawahara H, et al.: Usefulness of endoscopic ultrasonography in the diagnosis of congenital esophageal stenosis. J Pediatr Surg 37:1744, 2002. 6. Hertzberg BS, Bowie JD: Fetal gastrointestinal abnormalities. Radiol Clin N Am 28:101, 1990. 7. Bluestone CD, Kerry R, Sieber WK: Congenital esophageal stenosis. Laryngoscope 79:1095, 1969 8. Ohkawa H, Takahashi H, Hoshino Y: Lower esophageal stenosis in association with tracheobronchial remnants. J Pediatr Surg 10:453, 1975 9. Nishina T, Tsuchida Y, Saito S: Congenital esophageal stenosis due to tracheobronchial remnants and its associated anomalies. J Pediatr Surg 16:190, 1981.

10. Fekete CN, Backer AD, Jacob SL: Congenital esophageal stenosis: A review of 20 cases. Pediatr Surg Int 2:86, 1987. 11. Wright VM: Oesophageal atresia. Br J Hosp Med 42:452, 1989. 12. Ein SH, Shandling B, Wesson D, et al.: Esophageal atresia and associated anomalies and prognosis in the 1980’s. J Pediatr Surg 24:1055, 1989. 13. Cudmore RE: Oesophageal atresia and tracheoesophageal fistula. In: Neonatal Surgery. PP Rickham, J Lister, IM Irving, eds. Butterworth’s London, 1978, p 191. 14. Chittmittrapap S, Spitz L, Kiely E, et al.: Oesphageal atresia and associated anomalies. Arch Dis Child 64:364, 1989. 15. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, pp 664, 833. 16. Narashimharao KL, Mitra SK: Esophageal atresia associated with esophageal duplication cyst. J Pediatr Surg 22:984, 1987. 17. Chuang JH, Chen MJ: Membranous atresia of esophagus associated with pyloric stenosis. J Pediatr Surg 22:988, 1987. 18. Nagar H, Grossman T, Muhlbaur B: Esophageal atresia complicating the Goldenhar anomalad. Acta Paediatr Scand 78:804, 1989. 19. Fraser C, Baird PA, Sadovnick AD: A comparison of incidence trends for esophageal atresia and tracheoesophageal fistula and infectious disease. Teratology 36:363, 1987. 20. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999. 21. Ashcroft KW, Holder TM: Pediatric Esophageal Surgery. Grune and Stratton, New York, 1986. 22. Skandalakis JE, Ellis H: Embryologic and anatomic basis of esophageal surgery. Surg Clin N Am 80:85, 2000.

24.4 Esophageal Webs and Rings Esophageal webs and rings are membranous or diaphragmatic circumferential partial obstructions of the esophageal lumen.1,2 They may be located in midesophagus, associated with a TE fistula, or may be found in an otherwise normal esophagus. These webs usually involve only mucosal elements; muscular fibers are generally absent. Just as in true esophageal stenosis, symptoms appear later than in patients affected with esophageal atresia. Affected children have repeated vomiting, food impaction, dysphagia, and growth failure. Dilation of the esophagus above the level of the obstruction can mechanically obstruct the trachea and bronchi, producing wheezing, choking, cyanosis, and pneumonia. Diagnosis is made by radiographic barium swallow studies or esophagoscopy.2–6 Most cases of esophageal webs involve congenital redundancies of mucosa, resulting during embryogenesis from excessive mucosal folding.2–6 No data exist regarding recurrence risks. However, this has not been described as a familial anomaly, nor has it been described as a recognizable part of multiple malformation syndromes. Management of these lesions has been variable. Some authors have suggested conservative management with repeated periodic dilations or endoscopic treatment.2 Others have advocated surgical excision of the membrane or diaphragm, leaving a nasogastric tube in place for several days.1 Prognosis following surgical treatment is excellent.1,2 References (Esophageal Webs and Rings) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 93. 2. Patel PC, Yates JA, Gibson WS, et al.: Congenital esophageal webs. Int J Pediatr Otorhinolaryngol 42:141, 1997.

Upper Gastrointestinal System 3. Schwartz SJ, Dale WA: Unusual tracheoesophageal fistula with membranous obstruction of esophagus. Arch Surg 85:480, 1962. 4. Schwartz SJ, Dale WA: Unusual tracheoesophageal fistula membranous obstruction of esophagus and postoperative hypertrophic pyloric stenosis. Ann Surg 42:1002, 1955. 5. Holinger PH, Johnston KC, Potts WJ: Congenital anomalies of the esophagus. Ann Otol 60:707, 1951. 6. Freidland GW, Melcher DW, Berridge FR, et al.: Debatable points in the anatomy of the lower esophagus. Thorax 21:487, 1966.

24.5 Tubular Esophageal Duplications Definition

Tubular esophageal duplications are tubular channels parallel to the esophagus, usually communicating with the main esophageal lumen or stomach. These duplications may be connected to the lumen of the intestinal tract both inferiorly and superiorly, or there may be a connection at one end only. Cystic duplications of esophageal tissue in the mediastinum without alimentary communication (enterogenous cysts) and true esophageal diverticula are excluded from this discussion.1 Diagnosis

Duplications of the esophagus are the second most common type of intestinal duplication (following ileal duplication), accounting for 15–20% of all reported intestinal duplications.2–4 Tubular duplications of the esophagus are separated form the true esophageal lumen by mucosal tissue only; no muscular fibers are found in the wall that 1–7 separates the duplicated segment from the true esophagus. The exact birth prevalence of this anomaly is unknown. Complete duplication of the esophagus is extremely rare and is often associated with gastric duplication.8 Visualization of the duplicated segment in complete esophageal duplication is often not appreciated until after diagnosis and surgical repair of associated gastric duplication.8,9 Many cases of esophageal duplication have been described coincidentally at autopsy in totally asymptomatic individuals. Alternatively, patients have been described with intermittent episodes of dysphagia accompanying inflammation of the duplicated segment and/or distention of the duplicated segment secondary to food particles becoming trapped in the blind pouch.1–7 Diagnosis may be made by radiographic barium swallow studies and/or by esophagoscopy.1–7 Etiology and Distribution

This anomaly generally occurs sporadically in otherwise normal individuals. There is no known association with recognizable multiple malformation syndromes.1–7 These intramural duplications arise by abnormal mucosal folding of the esophagus during embryogenesis.1 Prognosis, Treatment, and Prevention

The fact that many affected individuals with this disorder have been discovered serendipitously at autopsy implies that, in the absence of distention of the blind pouch and/or without inflammation of the involved mucosa, affected patients may remain asymptomatic. Patients have been described in the medical literature who remained asymptomatic for long periods of time until inflammation of the duplicated segments led to dysphagia and subsequently to diagnosis.1,7 Treatment depends on the degree of symptomatology in an affected patient. Surgical excision of the membrane separating the true from the false lumens of the esophagus has been performed.6

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References (Tubular Esophageal Duplications) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 95. 2. Macpherson RI: Gastrointestinal tract duplications: Clinical, pathologic, etiologic and radiologic considerations. Radiographics 13:1063, 1993. 3. Bower RJ, Sieber RK, Kiesewetter WB: Ailimentary tract duplications in children. Ann Surg 188:669, 1978. 4. Hocking M, Young DG: Duplications of the alimentary tract. Br J Surg 68:92, 1981. 5. Duda M, Sery Z, Vojacek K, et al.: Etiopathogenesis and classification of esophageal diverticula. Int Surg 70:291, 1985. 6. Borrie J, Wilson RLK: Oesophageal diverticula: principles of management and appraisal of classification. Thorax 35:759, 1980. 7. Frank RC, Paul LW: Congenital reduplication of the esophagus. Report or a case. Radiology 53:417, 1949. 8. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999. 9. Herman TE, Oser AB, McAlister WH: Tubular communicating duplications of esophagus and stomach. Pediatr Radiol 21:494, 1991.

24.6 Enterogenous Cysts Definition

Enterogenous cysts are mediastinal cysts of foregut origin. Intestinal duplications extending into the thorax, bronchogenic cysts, celomic cysts, and tubular duplications of the esophagus are excluded from this definition.1 Diagnosis

Duplications of the foregut may be either cystic or tubular and account for 15–20% of all alimentary tract duplications.2–4 Cystic duplications have been termed enterogenous cysts. Enterogenous cysts occur in the prevertebral portion of the superior mediastinum or in the posterior mediastinum. These anomalous structures may be lined with epithelium derived from either the alimentary tract or respiratory tract.1–6 In fact, several mucosal types frequently exist in different parts of the same cyst. For example, gastric mucosa and exocrine and endocrine pancreatic tissues have been described in enterogenous cysts.7,8 Dorsal enterogenous cysts in the thorax are usually found in association with the middle and lower thirds of the esophagus. In general, dorsal enteric cysts lie posterior to the esophagus, as opposed to true bronchogenic cysts, which lie lateral to the trachea.1–6 The most frequent anomalies found in association with posterior mediastinal enterogenous cysts are upper thoracic and lower cervical vertebral defects, occurring in about 50% of patients and leading to scoliosis. Duplication of the small intestine is also frequently associated. Some authors have suggested the existence of a related triad of anomalies, consisting of vertebral anomalies, posterior mediastinal enterogenous cyst, and intestinal duplication.1–6 Esophageal atresia has also been described in association with an enterogenous cyst.9 Radiographic appearance of a spherical or ovoid mass having smooth, clearly defined boundaries in the posterior mediastinum, together with developmental anomalies of the cervical or thoracic vertebrae leads to the specific diagnosis. Occasionally, when duplications have connections with the intestinal lumen, auscultation over the cyst may reveal peristaltic sounds. These cysts may be more clearly anatomically defined by CT, MR or ultrasound imaging.1–4,10

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Gastrointestinal and Related Structures

Etiology and Distribution

Diagnosis

It has been hypothesized that the basic error in embryogenesis leading to these cysts occurs very early in development, at the stage of the notochord and prior to the existence of the foregut. At this state, the notochord is growing in a cranial direction from the primitive knot, between the ectoderm and the endoderm of the two-layered embryo. The notochord at this time is in intimate association with the endodermal cells from which it later separates. If the notochord fails to detach itself from the endoderm, such cells will be displaced superiorly as the tissues separate. Such endodermal cells may round up to form a cyst. If they remain attached to the notochord they may also act as an impediment to later anterior fusion of the vertebral mesoderm leading to anterior spina bifida.1–6 With the exception of the association with vertebral anomalies and intestinal duplications, enterogenous mediastinal cysts have not been described as being associated with any particular multiple malformation syndrome. Recurrence risks for firstdegree relatives of affected individuals are likely quite small.

Treatment of enterogenous cysts involves surgical removal. Mortality accompanying an enterogenous cyst has been described following ulceration and perforation of the cyst associated with the presence of gastric mucosa. Surgical removal may be the only method to differentiate these structures from masses of neoplastic origin found in the posterior mediastinum.1–6

Diverticula primarily lead to dysphagia, which results only as the diverticula enlarge and retain food particles. Diverticula are demonstrated radiographically by barium swallow or by esophagoscopy.1–4 CT, MR or ultrasonographic imaging may be useful diagnostic adjuncts.5 Esophageal diverticula are of three types: congenital true diverticula, traction diverticula, and pulsion diverticula. Congenital true diverticula are very rare. In the few cases that have been described, all layers of the esophageal wall have been involved. Pulsion diverticula are herniations of the mucosa through intrinsic defects in the muscular wall of the esophagus. The muscular defects may be of embryonic origin; however, the subsequent herniation is acquired. Most of these diverticula are found anteriorly in the esophagus. Traction diverticula result from adhesions between the esophagus and an external structure leading to stretch of the external esophageal wall and diverticulum formation. They are usually not of embryonic origin, although there have been cases described with fibrous bands connecting the esophagus ant the trachea, which have been suggested to be remnants of TE fistulas that closed before birth.1–4 Diverticula usually occur sporadically in an otherwise normal individual. However, esophageal diverticula have been described in certain connective tissue disorders, Williams syndrome, the autosomal recessive form of cutis laxa, and Ehlers-Danlos syndrome type I (classical EDS).6–8

References (Enterogenous Cysts)

Etiology and Distribution

Prognosis, Treatment, and Prevention

1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 95. 2. Macpherson RI: Gastrointestinal tract duplications: Clinical, pathologic, etiologic and radiologic considerations. Radiographics 13:1063, 1993. 3. Bower RJ, Sieber RK, Kiesewetter WB: Ailimentary tract duplications in children. Ann Surg 188:669, 1978. 4. Hocking M, Young DG: Duplications of the alimentary tract. Br J Surg 68:92, 1981. 5. Duda M, Sery Z, Vojacek K, et al.: Etiopathogenesis and classification of esophageal diverticula. Int Surg 70:291, 1985. 6. Borrie, J Wilson RLK: Oesophageal diverticula: principles of management appraisal classification. Thorax 35:759, 1980. 7. Kaneko E, Kohda A, Honda N, et al.: Incomplete tubular duplication of esophagus with heterotopic gastric mucosa. Dig Dis Sci 34:948, 1989. 8. Qazi FM, Geisinger KR, Nelson JB, et al.: Incomplete tubular duplication of esophagus containing exocrine and endocrine pancreatic tissues. Am J Gastroenterol 85:65, 1990. 9. Narasimharao KL, Mitra SK: Esophageal atresia associated with esophageal duplication cyst. J Pediatr Surg 22:984, 1987. 10. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999.

24.7 Esophageal Diverticula Definition

Esophageal diverticula are outpouchings of the lumen of the esophagus. True diverticula are covered with all layers of the esophageal wall. False diverticula are covered with only mucosa and submucosa, herniated through defects in the esophageal wall.1–4

Congenital true diverticula arise embryonically either from persistence of mucosal diverticula in the embryo, or they are the result of small blind duplications that subsequently become enlarged. Pulsion diverticula are thought to result from herniation of mucosa through defects in the esophageal musculature. Traction diverticula result from external ‘‘pull’’ on the esophageal wall from an adhesion external to the esophagus.1–4 Prognosis, Treatment, and Prevention

Esophageal diverticula are best treated by surgical extirpation. Without surgery, over time, esophageal diverticula may eventually rupture. There is some risk of recurrence of the diverticula in individuals who have undergone surgical treatment.1–4 References (Esophageal Diverticula) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 99. 2. Duda M, Sery Z, Vojacek K, et al.: Etiopathogenesis and classification of esophageal diverticula. Int Surg 70:291, 1985. 3. Borrie J, Wilson RLK: Oesophageal diverticula: principles of management and appraisal of classification. Thorax 35:759, 1980. 4. Reddy ER, Smith I, Clarke H: Esophageal diverticula. J. Can Assoc Radiol 40:306, 1989. 5. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999. 6. Toyohara T, Keneko T, Araki H, et al.: Giant epiphrenic diverticulum in a boy with Ehlers-Danlos syndrome. Pediatr Radiol 19:437, 1988. 7. Morris CA: The natural history of Williams syndrome: physical characteristics. J Pediatr 113:118, 1988. 8. Goltz RW: Cutis laxa, a manifestation of generalized elastolysis. Arch Dermatol 92:373, 1965.

Upper Gastrointestinal System

24.8 Heterotopic Gastric Mucosa in the Esophagus Ectopic gastric mucosa is sometimes present in the esophagus, and should be differentiated from congenital short esophagus with thoracic stomach.1 The presence of gastric mucosa in the esophagus may be related to heterotopic patches of gastric mucosa. Patients with associated symptomatology complain of epigastric pain. Diagnosis may be made by esophagoscopy. If ulcers are present they may be seen on radiographic barium swallow studies.2 No specific malformation syndromes have been described in association with this anomaly. The incidence of ectopic gastric mucosa in the esophagus has been variously reported as 0.7% to as much as 70%. The greater number of these patches of gastric mucosa have been found in the upper portion of the esophagus. Heterotopic gastric mucosal islets show a male-to-female sex ratio of 2:1.1 The lining of the embryonic foregut produces three main types of adult epithelium: stratified squamous epithelium normally found in the esophagus, pseudostratified ciliated epithelium in the stomach, and heterotopic gastric mucosa resulting from aberrant epithelial differentiation during embryonic life. 1 Many individuals with heterotopic gastric mucosa in the esophagus are totally asymptomatic.2 Indeed, some autopsy series have found that 70% of individuals coming to autopsy have such ectopic gastric tissue.1–3 However, if peptic ulcers result from heterotopic gastric mucosa, surgical extirpation of the aberrant area of esophagus may be necessary. Alternatively, medical therapy could be undertaken with a histamine H2 receptor antagonist. The prognosis for most patients is excellent. However, adenocarcinoma of the upper esophagus has been associated with ectopic gastric epithelium.4 References (Heterotopic Gastric Mucosa in the Esophagus) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 104. 2. Powell RW, Luck SR: Cervical esophageal obstruction by ectopic gastric mucosa. J Pediatr Surg 23:632, 1988. 3. Rector LE Connerly ML: Aberrant mucosa in the esophagus in infants and in children. Arch Pathol 31:285, 1941. 4. Carrie A: Adenocarcinoma of the upper end of the esophagus arising from ectopic gastric epithelium. Br J Surg 37:474, 1950.

24.9 Congenital Short Esophagus Congenital short esophagus is accompanied by intrathoracic location of part of the stomach. This condition should be differentiated from heterotopic gastric mucosa and hiatal hernia.1 The most common finding in individuals with congenital short esophagus is dysphagia since birth. It is usually associated with gastroesophageal reflux and vomiting, eventually resulting in esophagitis and stricture. Accompanying the frequent vomiting are high incidences of growth failure and aspiration pneumonitis. The vomitus may be frankly bloody.1–3 Diagnosis is made by radiographic barium swallow studies. Endoscopic examination is a useful adjunct.1–3

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Although most cases are sporadic, familial occurrences have been described. It has been found more commonly in males than in females. Other intestinal anomalies, including pyloric stenosis, malrotation of the intestines, and short colon, have seen in association.1,4 Cardiovascular anomalies have been noted as well.5 Recognizable multiple malformation syndromes have not been described in association with this anomaly.1 Congenital short esophagus is the result of insufficient elongation of the esophagus. Arrest of elongation before the stomach has reached its infradiaphragmatic level results in a portion of the stomach remaining in the thorax.1 Surgical treatment for congenital short esophagus is problematic. Mobilization of the esophagus to attempt to provide sufficient length has had some success. Other survival techniques have attempted to elevate the diaphragm to a position above the stomach. Data indicate that surgery performed on infants with congenital short esophagus does not lead to immediate cessation of vomiting, which may take several months to subside.1,4 References (Congenital Short Esophagus) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 105. 2. Astley R, Carre IJ: Gastroesophageal incompetence in children with special reference to minor degree of partial thoracic stomach. Radiology 62:351, 1954. 3. Carre IJ: The natural history of partial thoracic stomach (hiatus hernia) in children. Arch Dis Child 34:344, 1959. 4. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 684. 5. Williams ER: A case of right-sided aortic arch associated with congenital short esophagus and partial thoracic stomach. Br J Radiol 18:323, 1945.

24.10 Achalasia Definition

Achalasia is a hypertrophy of the gastroesophageal sphincter mechanism, obstructing food from entering the stomach. Achalasia contrasts with chalasia, which is a laxity of the gastroesophageal spincter.1,2 Diagnosis

In infants and young children, achalasia may present with decreased food intake, vomiting of undigested food, and chronic cough. The diagnosis is confirmed by radiographic barium swallow studies. A massive esophagus with evidence of stricture of spasm at the gastroesophageal junction is proof of achalasia.1 Achalasia may be associated with distal esophageal pulsion diverticula. It has been seen in association with megacolon and megaureter attributable to vitamin B deficiency. Similarly, an acquired form of megaesophagus and chalasia is an accompaniment of Chagas disease. In that disorder, myenteric ganglion cells are progressively destroyed by the parasite Trypanosoma cruzi.1 Genetic and malformation syndromes associated with chalasia are summarized in Table 24-7. Etiology and Distribution

Achalasia occurs with a population frequency of 0.6–1.0/100,000 per year. It has been estimated that achalasia accounts for 18% of all esophageal lesions. Less than 5% of patients with chalasia

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Gastrointestinal and Related Structures Table 24-7. Syndromes with achalasia Causation Gene/Locus

Syndrome

Prominent Features

Riley-Day (familial dysautonomia)1

Emotional lability, autonomic dysfunction (lack of tearing, paroxysmal hypertension) lack of sweating, cold hands and feet, corneal anesthesia, erythematous blotching of skin, drooling

AR (223900) IKBKAP, 9q31

Achalasia-microcephaly3

Microcephaly, mental deficiency

AR (200450)

Allgrove (glucocorticoid deficiency-achalasia)4

Alacrima, glucocorticoid deficiency, hyperpigmentation

AR (231550)

present in childhood, 2% of whom are less than age 6. Males and females are reported to be equally affected, with no particular racial predilection noted.1 In young children who present with achalasia it is thought that, as in the case of Hirschsprung disease leading to megacolon, there is a defect in myenteric ganglion cells. Histologic studies of children with chalasia have shown a marked diminution in numbers of ganglion cells.2 Aganglionosis is not, however, present in all cases.5 Rarely, muscle fibers may be absent, as in familial pseudo-obstruction. Most cases of achalasia occur sporadically in otherwise normal families; however, familial achalasia has been described. The consanguinity demonstrated in some familial cases implies an autosomal recessive etiology in rare instances.6 Prognosis, Treatment, and Prevention

Treatment has been accomplished by esophageal dilation with bougies under hydrostatic pressure. Alternatively, a surgical myotomy of the affected area may be performed.1 Pharmacologic treatment (with long-acting nitrites or calcium channel blockers) may be a useful adjunctive mode of treatment. References (Achalasia) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 109. 2. Lendrum FC: Anatomic features of the cardiac orifice of the stomach: with special reference to cardiospasm. Arch Intern Med 59:474, 1937. 3. Hernandez A, Reynoso MC, Soto F, et al.: Achalasia microcephaly syndrome in a patient with consanguineous parents: support for a.m. being a distinct autosomal recessive condition. Clin Genet 36:456, 1989. 4. Allgrove J, Clayden GS, Grant DB, et al.: Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1:1284, 1978. 5. Rickham PP: Rupture of exomphalos and gastroschisis. Arch Dis Child 38:138, 1963. 6. Tyrhus MR, David M, Griffith, JK, et al.: Familial achalasia in two siblings: significance of possible hereditary role. J Pediatr Surg 24:292, 1989.

24.11 Chalasia Definition

Chalasia is a congenital laxity of the gastroesophageal sphincter mechanism, allowing gastroesophageal reflux. Chalasia is contrasted with achalasia, which is a hypertrophy of the gastroesophageal sphincter.1,2

Diagnosis

Chalasia usually begins in the first week of life. Affected children have effortless regurgitation, particularly while prone. Over time, reflux esophagitis with pain, chronic blood loss, and subsequent esophageal strictures develop. In infants and older children who are affected, persistent vomiting, growth failure, anemia, recurrent or chronic respiratory disease, apneic episodes, and sudden infant death syndrome may be related to chalasia. The diagnosis may be suspected on the basis of frequent regurgitation, especially after feeding and lying in a horizontal position. Radiographic barium swallow studies are usually diagnostic. Monitoring the pH of the esophagus may also be helpful.1,2 Chalasia most commonly occurs in otherwise normal children and may have a familial predisposition. Neurologically impaired infants and children frequently demonstrate chalasia as an accompanying complication.2 Etiology and Distribution

Males and females appear to be equally affected with this condition. It is described as being a very common problem in infancy. Manometric studies have suggested that in normal infants the tone of the esophageal sphincter is low during the first 2 weeks of life, slowly increasing to adult levels. Chalasia may represent a delay in the normal development of nervous control of the lower esophagus.1 Prognosis, Treatment, and Prevention

This condition generally does not require surgical intervention, and in most normal children it will improve spontaneously over time. Medical measures, including feeding the child in a semiupright position, giving frequent small, thickened feedings, and administering mild sedatives, antispasmodics, H2 secretion and/or proton pump inhibitors, and antacid medications are at times very successful.1,2 However, in a child with persistent symptomatology, particularly in those children who are severely neurologically impaired, surgery is indicated and has a high degree of success. Nissen or Thal fundoplication or similar surgical procedures have been undertaken to create a competent gastroesophageal junction.3 References (Chalasia) 1. Wrenn EL Jr, Hollanbaugh RS, Lobe TE, et al.: Pediatric surgery. In: Comprehensive Pediatrics, RL Summitt, ed. CV Mosby, St. Louis, 1990, p 1070. 2. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 112. 3. Randolph J: Experience with Nissen fundoplication for correction of gastroesophageal reflux in infants. Ann Surg 198:579, 1983.

Upper Gastrointestinal System

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Stomach Beginning in week 4 postconception, a dilation of the foregut begins to appear that will eventually become the stomach. At its first appearance, the gastric dilation is at the level of segments C3C5. The entire cranial region of the embryo is growing very rapidly at this stage and, with subsequent foregut elongation leading to the elongation of the esophagus, the gastric dilation is left near its origin. The superior growth of other structures cranial to the stomach results in the apparent ‘‘descent’’ of the stomach, so that eventually it lies at T5-T10 by the end of week 7. At this point, rotational changes in the stomach occur around both longitudinal and anterior-posterior axes. Around the longitudinal axis, the stomach rotates 90 degrees clockwise, bringing the left side anterior and the right side posterior. During this rotation, the original posterior wall of the stomach grows faster than the anterior wall, resulting in the formation of the greater and lesser curvatures of the stomach. The cephalic and caudal ends of the stomach, originally in the midline, move to the right and upward

and to the left and downward, respectively, giving rise to the pylorus and cardiac portion of the stomach.1,2 The morphologic and histologic development of the stomach is complete at term.3 Prenatal ultrasound examinations have shown that the fetal stomach grows in a linear fashion from 13 to 39 weeks and that the characteristic anatomic features (greater curvature, lesser curvature, fundus, body, and pylorus) can be identified by 14 weeks.4 Detailed studies of the development of the mouse stomach have established that the epithelial cells of the gastric pits arise from stem cells located in the neck region. As these stem cells divide, they produce cell populations that move in both cephalic and caudal directions.5 Parietal cell lineage ablation experiments suggest that the balance between parietal, pit, and zymogen cells is maintained by interactions among the cell lineages.6 Gastrin is an important factor in the differentiation of the parietal cells, which are reduced in numbers in transgenic mice bearing either a gastrin receptor knockout or a gastrin knockout.7,8 The locations of malformations of the stomach are depicted in Figure 24-8, and a summary of their characteristics is set forth in Table 24-8. References (Stomach)

Fig. 24-8. Locations of malformations of the stomach. (Adapted from Eias et al.2)

1. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott, Williams and Wilkins, Baltimore, 2003. 2. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 117. 3. Grand RJ, Watkins JB, Torti FM: Development of the human gastrointestinal tract. A review. Gastroenterology 70:790, 1976. 4. Goldstein I, Reece EA, Yarkoni S, et al.: Growth of the fetal stomach in normal pregnancies. Obstet Gynecol 70:641, 1987. 5. Karam S, Leblond CP: Origin and migratory pathways of the eleven epithelial cell types present in the body of the mouse stomach. Microsc Res Tech 31:193, 1995. 6. Li Q, Karam SM, Gordon JI: Diphtheria toxin–mediated ablation of parietal cells in the stomach of transgenic mice. J Biol Chem 271:3671, 1996.

Table 24-8. Anomalies of the stomach Anomaly

Embryonic Onset of Defect

Time of Clinical Appearance

Sex Preponderance

Frequency

Remarks

Microgastria

Week 4

Birth

?

Very rare

Gastric atresia/stenosis

Weeks 6–7

Atresia at birth; stenosis any age

Equal

Rare

Stenosis may be acquired

Pyloric stenosis

Weeks 6–7 (in some cases); Postnatal week 2 (majority of cases)

2–4 weeks after birth

Male

Very common

Most cases develop postnatally; few have embryonic origin

True gastric diverticula

Unknown

40-70 years

Equal

Rare

May be acquired

Duplication of stomach

Week 3

Any age

Female

Rare

Defects of gastric musculature

Weeks 8–10

Infancy

Unknown

Rare

Ectopic stomach

Week 10

Any age

Unknown

Rare

Mucosal heterotopia

Weeks 4–5

Any age

Equal

Common

Adapted from Elias et al.2

May be acquired

Usually asymptomatic

1082

Gastrointestinal and Related Structures

7. Langhans N, Rindi G, Chiu M, et al.: Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor– deficient mice. Gastroenterology 112:280, 1997. 8. Koh TJ, Goldenring JR, Ito S, et al.: Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology 113:1015, 1997.

24.12 Infantile Hypertrophic Pyloric Stenosis Definition

Infantile hypertrophic pyloric stenosis is hypertrophy of the muscular pyloric canal, leading to a thickening of the pyloric wall and a reduction in the size of the lumen.1–3 Diagnosis

Although originally considered to be a defect of embryonic origin, it is now believed that this defect in most instances arises in late perinatal or early postnatal life. Rollins et al., in an ultrasonographic study of 1400 consecutive newborns, found nine who later developed symptoms and signs of pyloric stenosis. None had an abnormal pyloric ultrasound at birth.4 Many cases may be of early gestational onset, however, as evidenced by associated anomalies of early embryogenesis in 6–12%.5–8 The hypertrophy of the pyloric canal involves not only the musculature but the elastic tissue of the submucosa. This swelling passes through a predictable series of evolutionary events. As the pyloric hypertrophy increases, the pylorus becomes extremely hard and solid, reaching its greatest development at 4–9 weeks. If surgical intervention is not carried out, the swelling relaxes and becomes smaller and softer, with complete healing becoming apparent by several months of age.1 The affected infant usually presents with increasingly severe bouts of vomiting beginning during the second week of life. The vomiting is described as occurring immediately after feeding and being ‘‘projectile’’ in nature. The emesis does not contain bile or blood. The infant is described as being hungry and will take the breast or the bottle immediately after vomiting. Dehydration and weight loss become increasing pronounced, and the stools become less frequent and smaller in size. Large peristaltic waves may become visible, moving left to right across the upper abdomen. In nearly all instances, the enlarged pylorus may be palpated, most easily felt immediately after emesis. This has been described in most instances as a 1.5–2.0 cm ‘‘olive’’ in the epigastrium. With further vomiting and dehydration, the patient develops a metabolic alkalosis. Confirmation of the pyloric obstruction is made by a radiographic barium study of the stomach (Fig 24-9).1–3 Ultrasound examination may also demonstrate the pyloric tumor.9

Fig. 24-9. Pyloric stenosis in early infancy. Note the pathognomonic ‘‘string sign’’ (arrow) on this barium contrast study.

for being similarly affected.10 Recurrence risks for relatives of affected patients are set forth in Table 24-9. Pyloric stenosis has been described as an autosomal dominant trait in some families.11 It has been associated with a number of chromosomal aneuploidy syndromes, including trisomy 21, trisomy 18, duplication 9q, ring 12 deletion 11q, and duplication 1q.12–13 It also has been associated with the Marden-Walker syndrome, an autosomal recessive disorder, including mental retardation, growth failure, microcephaly, immobility of facial muscles, absent reflexes, blepharophimosis, strabismus, micrognathia, pectus excavatum, muscle weakness, joint contractures, arachnodactyly, kyphoscoliosis, and altered palmar creases.14 It has been an occasional accompaniment of Apert syndrome, de Lange syndrome, FG syndrome, Smith-Lemli-Opitz syndrome, and Zellweger syndrome.15 Finally, pyloric stenosis has been described as one of the teratogeneic effects of prenatal exposure to thalidomide, hydantoins, and trimethadione.16 A summary of syndromes associated with pyloric stenosis is set forth in Table 24-10.

Table 24-9. Risks to relatives of index cases with pyloric stenosis Index Patients (% risk)

Etiology and Distribution

Relative

As noted previously, pyloric stenosis is usually not a defect of early embryonic onset. In fact, the developmental pathogenesis of pyloric stenosis remains largely unexplained. The condition is more frequent in firstborn children, and the disorder is seen much more commonly in males than in females. The overall population is approximately 3/1000 births. It has been suggested that there may be an underlying defect of the myenteric ganglia as in Hirshsprung disease.1,2 In general, it is thought that pyloric stenosis is multifactorially determined, with both polygenic influences and environmental factors during pregnancy coming into play. First-degree relatives of an affected individual with pyloric stenosis are at risk

Brother

3.8

9.2

Sister

2.7

3.8

Son

5.5

18.9

Daughter

2.4

7.0

Nephew

2.3

4.7

Niece

0.4

–

Male first cousin

0.9

0.7

Female first cousin

0.2

0.3

Male

Adapted from Carter and Evans.10

Female

Table 24-10. Syndromes associated with pyloric stenosis Causation Gene/Locus

Syndrome

Prominent Features

Trisomy 2113

Hypotonia, mental deficiency, brachycephaly, flat nasal bridge, epicanthal folds, Brushfield spots, small and overfolded pinnae, short neck, 5th finger clinodactyly, single transverse palmar crease, wide space between toes 1 and 2, cardiac defect

Trisomy for all or a large portion of chromosome 21

Trisomy 1813

Prenatal-onset growth deficiency, profound mental deficiency, prominent occiput, narrow bifrontal diameter, low-set and malformed pinnae, micrognathia, camptodactyly, short and dorsiflexed hallux, short sternum, predominance of low arch dermal patterns, cardiac defect

Trisomy for all or a large portion of chromosome 18

Duplication 1q13

Mild growth deficiency, relative megalencephaly, profound mental deficiency, hypertelorism, downslanting palpebral fissures, small malformed low-set pinnae, long fingers, cardiac defect, inguinal hernia

Trisomy for the distal long arm of chromosome 1 (1q32 ! qter)

Duplication 9q13

Growth deficiency, cleft lip, cleft palate, cardiac defect, clubbed feet, camptodactyly, mental deficiency

Trisomy for the distal long arm of chromosome 9 (9q22 ! qter)

Deletion 11q12

Trigonocephaly, upslanting palpebral fissures, ptosis, epicanthal folds, short nose, anteverted nares, 5th finger clinodactyly, cardiac defects, hydronephrosis, polydactyly

Monosomy for the distal long arm of chromosome 11

Ring 1213

Growth deficiency, microcephaly, moderate mental deficiency, 5th finger clinodactyly, camptodactyly

Ring chromosome 12

Apert15

Irregular craniosynostosis, short anteroposterior cranial diameter, flat face, shallow orbits, hypertelorism, strabismus, osseous and/or cutaneous syndactyly

AD (101200) FGFR2, 10q26

de Lange15

Profound growth and mental deficiency, low-pitched cry, microbrachycephaly, synophrys, small nose, anteverted nares, micrognathia, hirsutism, micromelia, phocomelia, oligodactyly

Unknown (122470) dup 3q25!29 yields similar phenotype NIPBL, 5q13.1

Opitz FG15

Mental deficiency, hypotonia, affable personality, short stature, prominent forehead, frontal hair upsweep, hypertelorism, small ears, imperforate anus, broad thumbs and great toes, cryptorchidism

XLR (305450) Multiple loci

Marden-Walker14

Mental deficiency, failure to thrive, microcephaly, immobility of facial muscles, absent reflexes, blepharophimosis, strabismus, joint contractures, arachnodactyly, kyphoscoliosis, altered palmar creases

AR (248700)

Smith-Lemli-Opitz15

Growth deficiency, moderate to severe mental deficiency, microcephaly, narrow forehead, ptosis, epicanthal folds, strabismus, syndactyly of toes 2 and 3, altered dermal ridge patterning, cryptorchidism, hypospadias, cardiac anomaly

AR (270400) DHCR7, 11q12-q13 Defective cholesterol biosynthesis leads to elevated plasma 7dehydrocholesterol and decreased cholesterol levels

Zellweger15 (cerebrohepato-renal)

Hypotonia, high forehead, flattened occiput, epicanthal folds, anteverted nares, loose skin at back of neck, cataracts, cloudy corneas, hepatomegaly, lissencephaly, micropachygyria, multiple cortical renal cysts

AR (214100) Multiple loci Defective peroxisomal number and/or function leads to elevated plasma very long chain fatty acid levels

1083

1084

Gastrointestinal and Related Structures

Prognosis, Treatment, and Prevention

Surgical pyloromyotomy should be performed in affected infants after careful stabilization of fluid and electrolyte balances. The prognosis following such surgical intervention is excellent, and the present mortality rate is extremely low.1 References (Infantile Hypertrophic Pyloric Stenosis) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 127. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 687. 3. Wrenn EL Jr, Hollanbaugh RS, Lobe TE, et al.: Pediatric surgery. In: Comprehensive Pediatrics RL Summitt, ed. CV Mosby, St. Louis, 1990, p 1069. 4. Rollins MD, Shields MD, Quinn RJM, et al.: Pyloric stenosis: congenital or acquired. Arch Dis Child 64:138, 1989. 5. Al-Salem AH, Grant C, Khwaja S: Infantile hypertrophic pyloric stenosis and congenital diaphragmatic hernia. J Pediatr Surg 25:607, 1990. 6. Scharli A, Suber WK, Keisewetter WB: Hypertrophic pyloric stenosis at the Children’s Hospital Pittsburgh from 1912 to 1967. J Pediatr Surg 4:108, 1968. 7. Ahmed S: Infantile pyloric stenosis associated with major anomalies of the alimentary tract. J Pediatr Surg 5:660, 19701. 8. Carle G, Davidson Al: Infantile pyloric stenosis in the Northwest of Scotland. J R Coll Surg Edinb 30:30, 1985. 9. Weiskittel DA, Leary DL, Blanc CE: Ultrasound diagnosis of evolving pyloric stenosis. Gastrointest Radiol 14:22, 1989. 10. Carter CO, Evans KA: Inheritance of congenital pyloric stenosis. J Med Genet 6:233, 1969. 11. Fried K: Probable autosomal dominant infantile pyloric stenosis in a large kindred. Clin Genet 20:328, 1981. 12. Yamamoto Y, Oguro N, Nara T, et al.: Duplication of part 9q due to maternal 12;9 inverted insertion associated with pyloric stenosis. Am J Med Genet 31:379, 1988. 13. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man. Walter de Gruyter, New York, 1984. 14. Gossage D, Perrin JM, Butler MG: A 26-month-old child with Marden Walker syndrome and pyloric stenosis. Am J Med Genet 29:915, 1987. 15. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 832. 16. Shafer KH, Kramer M: Infantile hypertrophic pyloric stenosis after prenatal exposure to thalidomide. Eur J Pediatr 146:63, 1987.

24.13 Microgastria

developed, and there was poor differentiation of the various regions of the stomach. The gastroesophageal junction was incompetent, and the esophagus was dilated. The child suffered from secondary anemia and failure to gain weight. Hypoplasia of the stomach has also been described as one feature of the Ivemark syndrome (asplenia, congenital cardiac defects, and partial situs inversus). Other associated anomalies have included congenital megacolon, abnormal lung lobations, anophthalmia, porencephalic cyst, cryptorchidism, bicornuate uterus, splenic gonadal fusion, absence of the kidney, horseshoe kidney, and cardiac defects.1,3,5 Microgastria has also been described in six sporadic cases associated with limb anomalies: radial defects, ulnar defects, and/or thenar hypoplasia.5 Etiology and Distribution

Microgastria and agastria are extremely rare disorders. The defect in embryogenesis dates back to weeks 4–5 postconception. Affected individuals have had deficient growth and rotation of the gastric anlagen.3 Prognosis, Treatment, and Prevention

Data regarding prognosis and treatment in this disorder are not readily available due to its rarity. Most of the cases previously described have had severe failure to thrive and early demise because of malnutrition and/or the severity of associated anomalies. Successful surgical treatment has been performed with formation of a double lumen Roux-en-Y jejunal reservoir.3 References (Microgastria) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 122. 2. Dorney SFA, Middleton AW, Kozlowski, K, et al.: Congenital agastria. J Pediatr Gastroenterol Nutr 6:307, 1987. 3. Velasco AL, Holcomb GW, Templeton JM, et al.: Management of congenital microgastria. J Pediatr Surg 25:192, 1990. 4. Caffey J: Pediatric X-Ray Diagnosis, ed 3. Year Book Medical Publishers, Chicago, 1956, p 327. 5. Lueder GT, Fitz-James A, Dowton SB: Congenital microgastria and hypoplastic upper limb anomalies. Am J Med Genet 32:368, 1989.

24.14 Atresia and Stenosis of the Stomach Definition

Definition

Microgastria is severe hypoplasia of the stomach. The definition includes agastria but excludes atresia and stenosis of the stomach.1 Diagnosis

This very rare malformation of the stomach should be easily diagnosable by radiographic barium swallow techniques. True agastria (with the distal esophagus directly contiguous with the proximal duodenum) has been described in one instance only.2 The other 22 reported cases are representative of cases in the spectrum of microgastria. Symptomatology should bring microgastria to clinical attention shortly after birth. Affected children would be expected to display poor feeding, vomiting, and failure to thrive.3 In an infant described by Caffey4 in 1956, a midline stomach was discovered at 6 months of age. The curvatures were not

Atresia of the stomach may be defined as complete obstruction of the gastric lumen, whereas stenosis of the stomach is associated with a partial gastric obstruction. This definition includes hourglass stomach but excludes microgastria.1 Diagnosis

Congenital atresia of the stomach is much less common than atresia of other portions of the gastrointestinal system, accounting for less than 1% of all gastrointestinal atresias. When present, it is generally limited to the antrum and pyloric regions. Atresia has been described secondary to obstruction by membranes or diaphragms consisting of only mucosa; however, more extensive obliteration of the lumen has been reported.2–4 If the membrane or the diaphragm is very thin, it may perforate partially, leading to stenosis of the stomach. Although some

Upper Gastrointestinal System

cases of stenosis of the stomach are congenital, the majority of the cases are probably the result of healing, expansion, and scarring secondary to peptic ulcer disease in postnatal life.1 The diagnosis of gastric atresia should be suspected in infants with persistent non-bilious vomiting after the first feeding, distention of the upper abdomen, and stools decreasing in quantity.1 Sixty-one percent of cases have a history of polyhydramnios during pregnancy, presumably secondary to lack of amniotic fluid absorption in the intestine. Intrauterine growth retardation is common.2 Radiographs of the abdomen show air in the stomach, with no air in the intestine distally. Stenosis of the stomach may not produce symptoms until later in life. Cardinal features associated with gastric stenosis include epigastric pain, weight loss, nausea, and vomiting. In some patients, division of the stomach into two chambers by a constricting ring has led to a characteristic radiographic appearance termed hourglass stomach. Such lesions are likely the end result of inflammatory processes; however, a few cases have been suspected to be congenital in nature.1 The diagnosis of these anomalies can be made accurately with barium swallow radiographic studies in greater than 90% of cases. Gastroscopy is a useful diagnostic adjunct.2 Etiology and Distribution

Atresia and stenosis of the stomach are rare anomalies, generally occurring sporadically in otherwise normal individuals. Males and females are equally affected.2,5 Autosomal recessive inheritance has been described.2,6 Pyloric atresia has also been noted as an occasional accompaniment of esophageal atresia.7 Association with recognizable multiple malformation syndromes has not been prominent (Table 24-11). The embryonic origin of gastric stenosis and atresia is uncertain. As opposed to the esophagus and duodenum, recanalization is not a process that normally occurs in the stomach, since there is no epithelial proliferation in the stomach that is embryologically comparable. It is possible that a localized redundancy of the endodermal tube may be the origin of a membranous diaphragm. Some cases are undoubtedly the end result of vascular disruption, inflammatory processes, or ulcerations during gestation.1–3,12 This may particularly be true if scarring is evident around the area of the lesion.l–3 Prognosis, Treatment, and Prevention

In the infant with atresia of the stomach, prompt surgical intervention to relieve the obstruction is essential. In infants in whom diagnosis has been delayed, rupture of the stomach will have

Table 24-11. Syndromes associated with pyloric atresia Causation Gene/Locus

Syndrome

Prominent Features

Carmi8,9

Extensive aplasia cutis congenita, esophageal atresia, axillary pterygia, lower lid ectropion

AR (207730)

Epidermolysis bullosapyloric atresia

Epidermolysis bullosa, ureterovesical junction obstruction, hydronephrosis

AR (226730) ITGB4, 17q11-qter

10,11

1085

occurred. Excision of the occluding diaphragm or membrane is the procedure of choice. It is often necessary to leave a stent in place through the area of obstruction in the postoperative period to prevent postoperative edematous changes from reoccluding the lumen of the stomach. If surgical intervention is prompt, prognosis for long-term survival is good.2 References (Atresia and Stenosis of the Stomach) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 123. 2. Moore CCM: Congenital gastric outlet obstruction. J Pediatr Surg 24: 1241, 1989. 3. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 686. 4. Brown RP, Hertzler JH: Congenital pre-pyloric gastric atresia: a report of two cases. Am J Dis Child 97:857, 1959. 5. Sloop RD, Montagne ACW: Gastric outlet obstruction due to genital pyloric mucosal membrane. Am Surg 165:598, 1967. 6. Bar-Maor JA, Nissan S, Nero S: Pyloric atresia. J Med Genet 9:70, 1972. 7. Friedman AP, Valeek FT, Ergin MA, et al.: Oesophageal atresia associated with pyloric atresia. Am J Med Genet 11:319, 1982. 8. Carmi R, Sofer S, Karplus M, et al.: Aplasia cutis congenital in two siblings discordant for pyloric atresia. Am J Med Genet 11:319, 1982. 9. Carey JC, Bose CL, Piepkorn MW: Aplasia cutis congenital-The Carmi syndrome; confirmation of a new neonatal generalized skin disorder. Proc Greenwood Genet Center 2:116, 1983. 10. El-Shafie M, Stidham GL, Klippel CH, et al.: Pyloric atresia and epidermolysis bullosa letalis. J Pediatr Surg 14:446, 1979. 11. Bull MJ, Norins AL, Weaver DD: Epidermolysis bullosa-pyloric atresia: an autosomal recessive syndrome. Am J Dis Child 137:449, 1983. 12. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999.

24.15 True Diverticula of the Stomach Definition

True diverticula of the stomach are gastric outpouchings containing all layers of stomach wall. This anomaly is congenital and is to be differentiated from acquired diverticula and false diverticula, which do not contain all layers of the stomach wall.1,2 The vast majority of cases of congenital true diverticula of the stomach arise on the posterior gastric wall about 2 cm below the junction of the esophagus and stomach and about 3 cm from the lesser curvature of the stomach. Most of the remainder of the diverticula of the stomach have also been associated with aberrant pancreatic tissue, hiatal hernias, ‘‘hourglass’’ stomach, or diverticula in other parts of the gastrointestinal tract.1,2 Studies have shown that the vast majority of the gastric diverticula are usually symptom-free, being found coincidentally at autopsy. When symptoms do occur, the patient generally complains of epigastric or lower chest pain. Diagnosis is confirmed by radiographic barium studies and gastroscopy. Not all true diverticula are thus visualized, however.1–3 True gastric diverticula are rare. They are thought to be rarer in the stomach than elsewhere in the alimentary tract. About 3% of all intestinal diverticula are gastric, 9% are esophageal, 68% are colonic, and the remainder occur in the small intestines. There is a near equal male-to-female sex ratio.1 The embryogenesis of gastric diverticula remains uncertain.1

1086

Gastrointestinal and Related Structures

References (True Diverticula of the Stomach) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 131. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 689. 3. Ogur GL, Kolarsick AJ: Gastric diverticula in infancy. J Pediatr 39:723, 1951.

24.16 Duplication of the Stomach Definition

This defect consists of duplication of the alimentary tract contiguous with, or in direct communication with, the stomach. The definition excludes gastric diverticula and ectopic stomach. Diagnosis

Duplications of the stomach result in signs and symptoms of high intestinal obstruction, including emesis, electrolyte abnormalities, dehydration, and a palpable epigastric mass.1–3 Duplications are extremely variable, ranging from a doubling of the entire esophagus and stomach to multiple small intramural gastric cysts. The majority of gastric duplications are located on the greater curvature of the stomach or on the anterior or posterior gastric walls. Communications between the duplicated area and the intestinal lumen may exist. These communications, when present, may open into the stomach, duodenum, or Meckel diverticulum. However, communications between the duplicated area and the stomach are uncommon; gastric duplications are most commonly cystic, spherical noncommunicating masses. Most gastric duplications are less than 12 cm in diameter; however, about 25% are larger.1,2–6 The mucosa lining the duplicated area may be of gastric, pseudostratified respiratory epithelium, or of pancreatic origin. In cystic duplications, the epithelial lining is often destroyed and atrophic.1 When there is a communication between the duplicated segment and the intestinal lumen, radiographic barium swallow studies may visualize the affected area. CT or MR imaging may reveal a well-defined cystic mass lying close to the greater curvature of the stomach.7 In other cases, abdominal ultrasound will serve as a useful adjunct to differentiate duplicated areas from other lesions leading to symptoms of high gastrointestinal obstruction, most commonly hypertrophic pyloric stenosis.1–3 Duplication of the stomach has most commonly occurred as an isolated finding in an otherwise normal individual. However, an association of esophageal intestinal duplication and vertebral anomalies has been described.3 Etiology and Distribution

Duplications of the stomach are uncommon, accounting for 7% of gastrointestinal duplications.7 About 60 affected patients have been described, with nearly twice as many females as males reported.1–6 There has been no particular preponderance of cases in any described subpopulation. A majority of cases are recognized within the first year of life, but many affected individuals have not displayed symptoms or signs of obstruction until adulthood.1 Complete tubular duplications of the pylorus are rare. A review of 281 lesions of the gastrointestinal tract at all levels revealed only a single case of complete tubular duplication of the pylorus.8 The etiology of this disorder is unknown. It is likely that there are a variety of pathogenetic mechanisms that explain gastric

duplications. Intramural gastric cysts could be explained by persistence of vacuoles within the primitive foregut epithelium. Larger intramural cystic duplications may be a result of persistence of embryonic gastric diverticula. Other duplications, particularly those outside the wall of the stomach, are most likely the result of faulty separation of endoderm and notochord in early embryonic development. According to this theory, when the amount of endodermal tissue detached from the primary endoderm sheet is large, the extra tissue may organize itself into a duplication of normal esophagus and stomach.1 References (Duplication of the Stomach) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 133. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 688. 3. Hocking M, Young DG: Duplications of the alimentary tract. Br J Surg 68:92, 1981. 4. Berg HF, Marx K: Duplication of the stomach. J Pediatr 40:334, 1952. 5. Kieswetter WB: Duplication of the stomach: A case report. Am Surg 146:990, 1957. 6. Bartels RJ: Duplication of the stomach: A case report and review of the literature. Am Surg 33:747, 1967. 7. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999. 8. Macpherson RI: Gastrointestinal duplications: clinical, pathologic, etiologic and radiologic considerations. Radiographics 13:1063, 1993.

24.17 Defects of Gastric Musculature Definition

A defect of gastric musculature is hypoplasia or aplasia of the musculature of the stomach wall. This defect is to be differentiated from gastric diverticula and from thinned stomach wall secondary to hypertrophic pyloric stenosis.1,2 Diagnosis

Defects of the gastric musculature may be manifest as general thinning of all muscular layers or, more commonly, as complete absence of the gastric musculature in a localized area. In affected areas, the wall consists of mucosa, submucosa, and serosa, the muscular layer ending abruptly at the margins of the defect. Sixtysix percent of these defects have been found on greater curvature of the stomach, most of the remainder occurring on the anterior or posterior wall.1 Rupture of the weakened area may take place anywhere from 12 hours to 12 days after birth. Symptoms and signs include sudden abdominal distention and rigidity, vomiting, and decreased bowel sounds. Limitation of movement of the diaphragm may result in shortness of breath and cyanosis.1–6 Diagnosis should be suspected with radiographic signs of free air and fluid in the abdomen on erect and supine radiographs. Such symptoms and signs necessitate immediate laparotomy and surgical exploration, at which time the diagnosis is confirmed. Most cases have occurred sporadically in otherwise normal families. Associated malformation syndromes are not prominent.1–6 Etiology and Distribution

Localized defects in the gastric musculature may be the result of deficient myoblast formation. This helps to explain why the

Upper Gastrointestinal System

majority of defects observed have been in the greater curvature of the stomach, the region of most rapid embryonic growth of gastric musculature. Alternatively, increased intragastric pressure caused by a distal congenital obstruction of the alimentary tract may cause rupture of an already mildly to moderately weakened gastric wall.1 Finally, some authors have suggested that neonatal asphyxia with resulting vascular disruption of the gastric musculature may be the cause of perforation in some cases.2 This rare anomaly accounts for approximately 25% of perinatal gastric perforations. More males than females have been reported, and patients frequently are premature. More cases have been reported among blacks than among whites.1 In addition, there appears to be an increased risk for this disorder among twins, with only one of the pair being affected. These cases may represent vascular disruptive events, in conjunction with unequal vascular exchange between monozygotic twins.4 Although most cases have generally occurred sporadically in otherwise normal families, autosomal recessive inheritance has been suggested in some instances.6 Prognosis, Treatment, and Prevention

Mortality in affected infants is the result of peritonitis following gastric rupture. Thus, the best prognosis is possible when early diagnosis and treatment are inititiated.1–6 Treatment for this anomaly requires immediate laparotomy, careful surgical exploration of the entire stomach, and closure of all defects noted. It should be pointed out that there may be several areas of perforation. Therefore, following surgical repair, the stomach should be filled with saline solution by catheter to test for leakage.1 References (Defects of Gastric Musculature) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 134. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 688.

1087

3. MacGilivray PC, Stewart AM, MacFarlane A: Rupture of stomach in newborn due to congenital defects in gastric musculature. Arch Dis Child 31:56, 1956. 4. Inouye WY, Evans G: Neonatal gastric perforation: a report of six cases and a review of 143 cases. Arch Surg 88:471, 1964. 5. Meyer JL III: Congenital defect in the musculature of the stomach resulting gin spontaneous gastric perforation in the neonatal period. J Pediatr 51:416, 1957. 6. Ozkaragoz K, Stewart CS: Spontaneous rupture of the stomach in two premature newborn siblings. Texas J Med 55:305, 1959.

24.18 Malposition of the Stomach Definition

Malposition of the stomach is abnormal positioning of the stomach within the abdominal cavity. Malposition of the stomach occurs as part of complete or partial situs inversus.1,2 Diagnosis

The stomach is most commonly malposed secondary to complete or partial situs inversus (Fig. 24-10). In complete situs inversus, the stomach appears normal, but is totally reversed, right for left. In some cases, all other internal organs show mirror-image reversal of laterality. In rare cases, only the stomach is involved in this malpositioning.1,2 In a patient with total situs inversus, the apex of the heart will be found on the right, rather than the left side of the chest wall. Auscultation and percussion of the abdomen will reveal transposition of the liver and stomach. A chest radiograph will reveal dextrocardia and a stomach bubble on the right. Partial degrees of situs inversus may be similarly suspected by plain radiographs of the chest and abdomen. Ultrasonographic examination may be a useful adjunct in such cases.1 Inversion of the stomach, in which the cardia is lower than the pylorus, may also occur. Gastric inversion is sometimes associated

Fig. 24-10. Massive gastric distention secondary to pyloric atresia associated with epidermolysis bullosa in a 3-day-old female infant. (Courtesy of Dr. Rodney J. Macpherson, Medical University of South Carolina, Charleston.)

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Gastrointestinal and Related Structures Table 24-12. Syndromes associated with malposition of the stomach Syndrome

Prominent Features

Causation

Isolated complete situs inversus4

Dextrocardia, trilobed left lung, mirror image, transposition of all abdominal organs

Unknown

Kartagener5,6

Immotile cilia, sinusitis, rhinitis, nasal polyposis bronchiectasis, reduced fertility (male and female), situs inversus (50%), chronic otitis media, hearing loss, rheumatoid arthritis, eye malformations

AR (244400)

Bilateral leftsidedness4

Polysplenia, cardiac anomalies (less severe than bilateral right sidedness)

Heterogeneous (sporadic AD, AR, XLR)

Bilateral rightsidedness (Ivemark)4

Asplenia, complex cardiac anomalies, aberrant mesenteric attachments, renal anomalies, recurrent infections (accompanying asplenia)

Heterogeneous (sporadic AD, AR, XLR)

with eventration of the left side of the diaphragm. Affected individuals may display symptoms and signs of partial or intermittent alimentary tract obstruction, including recurrent abdominal pain and emesis.1,3 Syndromes associated with malposition of the stomach are set forth in Table 24-12. Etiology and Distribution

Situs inversus occurs very early in gestation. The exact etiology and pathogenesis of this rare defect are unknown. However, embryonic symmetry is determined in the first week postconception. Partial situs inversus is associated in 80% of cases with other malformations and may have a genetic basis.4,7 Genes regulating the determination of overall right-left asymmetry of the gastrointestinal tract recently have been described, and the molecular genetic pathogenesis of cases of X-linked situs abnormalities has been delineated.8–10 Complete situs inversus in nearly all cases is sporadic and is not accompanied by other anomalies. Partial situs associated with asplenia has been described as bilateral right-sidedness; whereas partial situs inversus accompanying polysplenia has been described as bilateral left-sidedness. Some authors believe that bilateral left-sidedness with polysplenia is much more common than bilateral right-sideness.4 Inversion of the stomach occurs in early gestation as the result of deficient growth of the stomach and failure to develop normal greater and lesser curvatures beyond weeks 6–7 postconception. No particular multiple malformation syndromes have been associated with this finding.1 Prognosis, Treatment, and Prevention

The prognosis in individuals with complete situs inversus is usually excellent. Such individuals rarely have associated anomalies, and situs inversus is associated with little morbidity. An exception to the preceding statement pertains to individuals with Kartagener syndrome. Approximately 50% of patients with Kartagener syndrome manifest complete situs inversus as a consequence of immotile cilia. It has been suggested that ciliary beating in the early embryo helps to determine laterality. In the absence of normal cilia, therefore, laterality develops randomly in affected patients. Fertility is impaired in individuals of both sexes, with males being more severely affected. The major medical complication of the disorder is thick tenacious sinus and bronchial secretions leading to chronic sinusitis and bronchiectasis. The outcome in affected patients is dependent on the respiratory pathology. The malposed stomach in affected patients is not a cause

of significant morbidity.5,6 The prognosis in patients with partial situs inversus is likewise dependent on the severity of associated anomalies. In individuals with inversion of the stomach, significant symptomatology associated with intermittent upper intestinal obstruction implies the need for surgical intervention to restructure gastric shape to facilitate emptying of the stomach.1 References (Malposition of the Stomach) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, pp 138, 903. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 183. 3. Peck GA, Weber GW: Inversion of the stomach with eventration of the diaphragm. AJR Am J Roentgenol 67:63, 1952. 4. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 602. 5. Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes of the Head and Neck, ed 4. Oxford Press, London, 2001, p 1007. 6. Holmes LB, Blennerhasset JG, Audten KF: A reappraisal of Kartagener’s syndrome. Am J Med Sci 255:13, 1968. 7. Arnold GL, Bixler D, Gerod D: Probable autosomal recessive inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am J Med Genet 16:35, 1983. 8. Gebbia M, Ferrero GB, Pilia G, et al.: X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305, 1997. 9. Lowe LA, Supp DM, Sampath K, et al.: Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature 381:158, 1996. 10. Ryan AK, Blumberg B, Rodriguez-Esteban C, et al.: Pitx2 determines left-right asymmetry of internal organs of vertebrates. Nature 394:545, 1998.

24.19 Mucosal Heterotopia Definition

Mucosal heterotopias occur when mucosal types other than normal gastric mucosa occur in the stomach. Heterotopic gastric mucosa in other organs will not be included here.1 Diagnosis

Glandular structures with or without ducts are often encountered in the gastric wall. The origin of this aberrant mucosa is invariably

Upper Gastrointestinal System

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the pancreas. Heterotopic pancreatic mucosal masses vary in size from less than 1 mm to 5 cm in diameter. Masses that are symptomatic are usually 1–2 cm in diameter, and they may be spherical, ovoid, or disc shaped. The margins may be elevated, and the center depression marking opening of the duct may be large enough to be mistaken for a true diverticulum of the stomach. The majority of these heterotopias occur in the distal half of the stomach.1,2 Approximately 50% of cases are symptomatic, the remainder being discovered coincidentally. Epigastric pain is the presenting complaint in 75% of symptomatic cases. Pain may follow pylorospasm, ulceration caused by pancreatic enzymes produced, infection, or gastric outlet obstruction. Vomiting and weight loss are inevitable if these symptoms and signs are not addressed. Occasionally, the presenting sign may be massive upper gastrointestinal hemorrhage secondary to ulceration of the ectopic mucosa.1 Preoperative diagnosis is possible by means of barium contrast radiographic studies. In addition, the diagnosis may be suspected and/or confirmed by endoscopy.1

duodenum and elsewhere in the intestinal tract, in addition to being present in the stomach.1 This condition is rarely symptomatic in childhood. Approximately 62% of patients present between ages 30 and 50 years. There is a 2:1 male-to-female sex ratio.1,3

Etiology and Distribution

References (Mucosal Heterotopia)

Pancreatic mucosal heterotopias may be due to translocation of embryonic pancreatic precursor cells, or they may follow metaplasia of a localized or generalized nature in the stomach. In many cases, such metaplasia may be the result of chronic irritation from gastritis. Areas of ectopic pancreatic mucosa also may be associated with gastric diverticula.1,3 Pancreatic mucosal heterotopia is discovered in the stomach in approximately 0.2% of patients undergoing abdominal surgery. Autopsy series have reported such heterotopic areas in approximately 2% of cases. This ectopic mucosa may be found in the

Prognosis, Treatment, and Prevention

Nearly one-half of patients with ectopic pancreatic mucosa in the stomach remain asymptomatic. Therefore, cases that are discovered coincidentally may safely remain untreated or can be conservatively medically managed with relative success. In patients with symptomatology in whom medical therapy has been unsuccessful, laparotomy and direct inspection of the stomach to excise the heterotopic areas locally is most successful. In cases with massive hemorrhage or obstruction, wedge or segmental resection of the stomach is indicated.1,4,5 With proper diagnosis and treatment, morbidity and mortality risks are very low.1

1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 142. 2. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 730. 3. Palmer Ed: Benign intramural tumors of the stomach: a review with special reference to gross pathology. Medicine 30:81, 1951. 4. Nelson RS, Scott NM Jr: Heterotopic pancreatic tissue in the stomach: gastroscopic features. Gastroenterology 34: 452, 1958. 5. Martinez NS, Morlock CG, Dockerty MB, et al.: Heterotopic pancreatic tissue involving the stomach. Ann Surg 147:1, 1958.

Duodenum The primitive gut may be divided into three general regions: foregut, midgut, and hindgut. The duodenum is formed from the distal portion of the embryonic foregut and the proximal portion of the midgut. The junction of these two parts of the duodenum is located directly distal to the origin of the liver bud. As the stomach rotates, the duodenum begins to take on a C-shaped loop appearance, rotating to the right and finally assuming its postnatal position retroperitoneally.1–4 During week 6 postconception, the ventral pancreas and hepatic diverticulum are carried dorsally around the circumference of the duodenum, with the common duct adjacent to the dorsal pancreatic primordium, as the result of growth of the ventral duodenal wall. The ventral primordium is thus brought behind and to the left of the duodenum fusing with the dorsal pancreatic primordium.1–4 In the early embryo at the stage of the umbilical loop, there are two suspensory bands formed as a thickening of the dorsal mesentery at the proximal and distal ends of the loop. As the duodenum begins to attain its retroperitoneal position, the superior retention band also moves into a retroperitoneal position and becomes the duodenal suspensory ligament. Smooth muscle cells within the ligament form the suspensory muscle of Treitz. At the time of fixation of the mesoduodenum to the posterior abdominal wall, the cranial end of the suspensory ligament has reached the diaphragm and is anchored to the right medial crus of the diaphragm. The inferior retention band atrophies. By the end of week 10, the lumen

is completely restored.1–4 Since the foregut is supplied by the celiac artery and the midgut is supplied by the superior mesenteric artery, the duodenum is supplied by branches of both arteries.4 Development of the human intestine is largely completed well before birth, around the end of the first trimester. By week 22 of gestation, the absorptive epithelial cells resemble those of the adult intestine.5 Mucosal remodeling and villus formation proceed in a cranial to caudal direction beginning at weeks 9–10. The earliest indication is the appearance of subepithelial aggregations of mesenchymal cells associated with projections into the central lumen of the overlying stratified epithelium. Distinctive junctional complexes appear between cells in the deeper layers of the stratified epithelium during the period of villus formation. Within the mesenchymal invaginations, smooth muscle cells and blood vessels appear as development progresses.6 Smooth muscle–specific protein markers have been reported in the human fetal jejunum as early as 8 weeks.7 There are few data on human muscle development. However, apparent abnormalities of muscle morphogenesis in children have been reported.8 Columnar epithelium initially lines only the apices of the developing villi, but appears along the sides as the villi mature. After 10 weeks, only the intervillus epithelium remains stratified. In all levels of the stratified epithelium, mitotic figures are abundant. Occasional mitoses are observed on villi until 16 weeks, but by 10–12 weeks most mitotic figures are restricted to the intervillus regions and developing crypts. Crypts

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Gastrointestinal and Related Structures

first appear as solid cords of epithelial cells, but by 12 weeks display a small lumen lined by undifferentiated simple columnar cells.6 Between 17 and 20 weeks, the first indications of muscularis mucosa develop near the base of the crypts.9 Little information is available on mechanisms of vascularization. However, analysis of mice with a targeted gene disruption have demonstrated that a chemokine receptor is necessary for normal vascularization of the gastrointestinal tract.10 References (Duodenum) 1. Gray SW, Colborn GL, Pemberton LB, et al.: The duodenum, part I: history, embryogenesis, and histologic and physiologic features. Am Surg 55:257, 1989 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott, Williams and Wilkins, Baltimore, 2003. 3. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 154. 4. Warkany J: Congenital Malformations: Notes and Comments Year Book Medical Publishers, Chicago, 1971, p 690. 5. Trier JS, Moxey PC: Morphogenesis of the small intestine during fetal development. Ciba Foundation Symposium 70:3, 1979. 6. Montgomery RK, Mulberg AE, Grand RJ: Development of the human gastrointestinal tract: Twenty years of progress. Gastroenterology 116:702, 1999. 7. Frid MG, Shekhonin BV, Koteliansky VE, et al.: Phenotypic changes of human smooth muscle cells during development: Late expression of heavy caldesmon and calponin. Dev Biol 153:185, 1992. 8. Smith VV, Milla PJ: Histological phenotypes of enteric smooth muscle disease causing functional intestinal obstruction in childhood. Histopathology 31:112, 1997. 9. Moxey PC, Trier JS: Specialized cell types in the human fetal small intestine. Anat Rec 191:269, 1978. 10. Tachibana K, Hirota S, Iizasa H, et al: The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393:391, 1998.

24.20 Malrotation of the Duodenum Insufficient rotation of the duodenum results in failure of the duodenum to reach the region of the superior mesenteric artery before the return of the intestines to the abdominal cavity by 10 weeks postconception.1 Malrotation of the duodenum can be diagnosed by barium contrast radiographic studies of the small intestines. CT or MR imaging are additional diagnostic modalities which have proven helpful.2 Symptomatic cases present with signs of upper gastrointestinal obstruction including pain, abdominal distention, and emeis.3 This extremely rare anomaly has been seen on only a few cases. It is thought to arise secondary to failure of the normal 180 degree rotation of the duodenum to occur. Therefore the duodenum does not reach the region of the superior mesenteric artery prior to the return of the intestines to the abdominal cavity by 10 weeks. The duodenum then becomes prematurely fixed in an ectopic site by adhesions before rotation is complete. Malrotation of the duodenum usually does not interfere with subsequent rotation of the remaining intestines to the abdominal cavity.1,3 Surgery is indicated only if partial or complete obstruction of the malrotated segment of intestine is present. Since malrotation alone is only occasionally the cause of intestinal obstruction in affected patients, the entire intestinal tract must be carefully examined for congenital bands, volvulus, stenosis or atresia, giving

rise to symptoms of obstruction. No attempt should be made to replace the duodenum in a ‘‘more normal’’ position within the abdominal cavity.1 References (Malrotation of the Duodenum) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 156. 2. Zissin R, Osadchy A, Gayer G, et al.: CT of duodenal pathology. Br J Radiol 75:78, 2002. 3. Lewis E: Partial duodenal obstruction with incomplete duodenal rotation. J Pediatr Surg 1:47, 1966.

24.21 Duodenal Stenosis and Atresia Definitions

Duodenal stenosis is congenital narrowing of the lumen of the duodenum. Duodenal atresia is congenital complete discontinuity of the lumen of the duodenum.1 Diagnosis

Children with marked duodenal stenosis or atresia exhibit upper abdominal distention shortly after birth. Tenderness is generally not present unless there has been perforation. The distention is accompanied by emesis, which will be bile stained if the obstruction is distal to the ampulla of Vater. Stools are absent or decreased in frequency. Patients may also have slight elevation in temperature accompanying dehydration. Marked elevation in temperature generally indicates that perforation and peritonitis have developed.1–3 Diagnosis of duodenal stenosis or atresia with obstruction must be made within the first few hours after onset. Obstruction of the duodenum results in a double air bubble on an upright radiograph of the abdomen (Fig. 24-11). On the left, the stomach Fig. 24-11. Duodenal atresia. Note the pathognomonic ‘‘double bubble’’ sign.

Upper Gastrointestinal System

contains air; on the right, there is a smaller bubble in the dilated proximal duodenum above the obstruction.1–4 Marked stenosis or atresia presents with similar symptoms and signs immediately after birth. Mild areas of stenosis may produce no symptoms until adulthood; in fact, some cases of duodenal stenosis of a very mild nature may be found incidentally at autopsy. Persistent emesis and failure to grow may be associated with moderate duodenal stenosis.1 Polyhydramnios and prematurity are historical features in 40% and 70% of affected patients, respectively.5 Because the bowel has been obstructed for many months prenatally, the proximal duodenum may become very dilated, and the pylorus may become imcompetent.2 The differential diagnosis of acute infantile duodenal obstruction includes not only duodenal stenosis and atresia but also extrinsic compression accompanying Ladd’s bands or volvulus of the midgut loop. Duodenal stenosis often is also associated with an annular pancreas or intramural ectopic pancreatic tissue. Stenosis may represent a generalized narrowing of the muscular lumen of the duodenum, or it may be the result of a perforated duodenal web. The aperture of the stenotic area may be large enough so that functional obstruction develops only in later adult life. Duodenal atresia may be membranous or segmental, membranous being the more common.1–3,6,7 Major associated anomalies are observed in 50% of cases with duodenal atresia or stenosis. Approximately 30% of patients have Down syndrome. Other anomalies include malrotation of the small bowel, esophageal atresia, congenital heart disease, imperforate anus, small bowel atresia, biliary atresia, annular pancreas, and small bowel atresia.8–11 Associated anomalies and their frequencies are set forth in Table 24-13. Broader patterns of malformation in which duodenal stenosis or atresia are one feature are listed in Table 24-14. Etiology and Distribution

Seventy-five percent of all intestinal stenoses and 40% of all intestinal atresias are found in the duodenum.7 Duodenal atresia occurs with a birth prevalence of 1/10,000 live births. It most commonly occurs in the second portion of the duodenum. No sex

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Table 24-13. Nature and frequency of malformations (according to system) observed in association with duodenal stenosis/atresia

Malformation

Cases of Duodenal Atresia Associated with Malformation (%)

Gastrointestinal

Intestinal malrotation

37

Esophageal atresia

16

Anal atresia

16

Other bowel atresias

11

Intestinal duplications

11

Cardiovascular

Congenital heart defects

21

Muscoskeletal

Vertebral anomalies

16

Genitourinary

Structural GU defects

16

Adapted from Al-Salem et al.5

predilection has been noted. Multiple atresias are occasionally noted in the same patient.2 The pathogenesis of duodenal atresias is conjectural. The proximal portions of the duodenum are derived from the embryonic foregut, and the distal portions of the duodenum are derived from the embryonic midgut. It has been suggested that atresia or stenosis of the proximal portions of the duodenum follow a primary failure of recanalization of the solid embryonic duodenum, normally occurring between weeks 8 and 10 postconception. Other authors feel that occlusion of the proximal duodenum is the result of excessive embryonic epithelial proliferation rather than a failure of recanalization. Atresia or stenosis of the distal portion of the duodenum is most likely the result of

Table 24-14. Malformation syndromes associated with duodenal stenosis or atresia Sydrome

Prominent Features

Causation Gene/Locus

Down

Muscular hypotonia, small ears, mental retardation, brachycephaly, flat nasal bridge, upslanting fissures, loose skin at posterior neck, Brushfield spots, cardiac defect, short incurved 5th fingers (associated with 30–47% of cases of duodenal atresia)

Trisomy 21

Hydantoin, prenatal12

Growth deficiency, mild mental deficiency, broad and depressed nasal bridge, short nose, cleft lip and palate, hypoplastic distal phalanges and nails

Teratogenic effects of prenatal hydantoin exposure

Opitz12

Ocular hypertelorism, widow’s peak, posterior rotation of pinna, hypospadias, cryptorchidism, hernias, cardiac anomaly

XLD (300000) MID1, Xp22 AD (145410) 22q11.2

Townes-Brocks12

Auricular anomalies, first and second branchial arch defects, thumb anomalies, anal stenosis or atresia, renal anomalies, deafness

AD (107480) SALL1, 16q12.1

Prenatal thalidomide12

Phocomelia, facial hemangiomas, facial asymmetry, cranial nerve palsies, microphthalmia, coloboma

Teratogenic effects of prenatal thalidomide exposure

2,5,12

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intrauterine fetal ‘‘accidents.’’ The most commonly held theory is that vascular disruption of branches of the superior mesenteric artery lead to disruption of portions of the developing midgut and resultant atresia or stenosis.1,3,6,7,13 Duodenal atresia or stenosis is etiologically heterogeneous. Most cases are likely to be multifactorially determined, with both polygenetic and poorly determined environmental factors during gestation coming into play. Recurrence risks in these cases are low (probably less than 5%). Duodenal atresia has been proven to be a genetically determined disorder inherited as an autosomal recessive trait in some families. In these families, consanguinity has been frequently observed, lending further credence to an autosomal recessive etiology.14,15 Prognosis, Treatment, and Prevention

Treatment of duodenal stenosis or atresia is surgical. Duodenostomy or duodenojejunostomy are the preferred surgical procedures whereby the obstructive lesion is bypassed. With early recognition, diagnosis, and treatment, uncomplicated duodenal stenosis or atresia has a very good prognosis. In cases with severe associated anomalies, morbidity and mortality are dependent on the nature of the associated defects.1,3,4 Prevention can be attempted in subsequent siblings of an affected child by accurate diagnosis in the proband, appropriate genetic counseling, and prenatal diagnostic procedures with subsequent pregnancies. Ultrasonography has proven to be successful in the prenatal diagnosis of cases of duodenal atresia; duodenal stenosis cannot be reliably prenatally ascertained by this method, however.16,17 Long-term follow-up into adulthood of affected children who have undergone corrective surgical procedures during infancy has shown that the majority of survivors are totally symptom-free. Some patients may require surgical tapering of the dilated proximal duodenum because of a periodic vomiting syndrome. Despite a persistent radiographic abnormality of the duodenum in the majority of cases, however, most affected individuals are symptom-free in later life.2 References (Duodenal Stenosis and Atresia) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 157. 2. Nixon HH: Duodenal atresia. Br J Hosp Med 41:134, 1989. 3. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 694. 4. Wrenn EL Jr, Hollabaugh RS, Lobe TE, et al.: Pediatric Surgery. In: Comprehensive Pediatrics. RL Summitt, ed. CV Mosby, St. Louis, 1990, p 1071. 5. Al-Salem AH, Khwaja S, Grant C, et al.: Congenital intrinsic duodenal obstruction: problems in diagnosis an management. J Pediatr Surg 24:1247, 1989. 6. Gray SW, Colburn GL, Pemberton LB, et al.: The duodenum, part I: history, embryogenesis, and histologic and physiologic features. Am Surg 55:257, 1989. 7. Colburn GL, Gray SW, Pemberton LB, et al.: The duodenum, part III: pathology. Am Surg 55:469, 1989. 8. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999. 9. Donoghue V: Neonatal gastrointestinal tract. In: Carty H, Brunelle F, eds. Churchill Livingstone, New York, 1994, p 250. 10. Rhee RS, Ray CG, Kravetz MH, et al.: Cervical esophageal duplication cyst: MR imaging. Comput Assist Tomogr 12:693, 1988. 11. Bailey PV, Tracey TF, Connors RH, et al.: Congenital duodenal obstruction: A 32-year review. J Pediatr Surg 28:92, 1993.

12. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 833. 13. Louw JH, Barnard CN: Congenital intestinal atresia: observations on its origin. Lancet 2:1065, 1955. 14. Best LG, Wiseman NE, Chudley AE: Familial duodenal atresia: a report of two families and review. Am J Med Genet 32:375, 1989. 15. Mischalany HG, Der Kaloustian BM, Ghandour MH: Familial congenital duodenal atresia. Pediatrics 46:629, 1970. 16. Hancock BJ, Wiseman NW: Congenital duodenal obstruction: the impact of an antenatal diagnosis. J Pediatr Surg 24:1027, 1989. 17. Miro J, Bard H: Congenital atresia and stenosis of the duodenum: the impact of prenatal diagnosis. Am J Obstet Gynecol 158:555, 1988.

24.22 Duodenal Duplications Definition

Duodenal duplications are cystic or tubular dorsal enteric remnants lying adjacent to the duodenum. Duodenal diverticula are excluded from this definition. Diagnosis

Duodenal duplications may be classified as cystic or tubular. Cystic duplications (enteric cysts) occur throughout the entire length of the digestive tract. Fifty percent of these enteric cysts are found in association with the small intestine. The most common area in the small intestine to encounter duplications is in the ileocecal region. The second most common area is the region adjacent to the first and second portions of the duodenum. Cystic duplications tend to occur as single anomalies, although some patients have intrathoracic enteric cysts as well. Cystic duplications may be found in the submucosa, in the muscularis of the gut, in the subserosal areas in the mesentery, or in retroperitoneal regions.1–5 Intramural cystic duplications are usually small and rarely communicate with the intestinal lumen. They most commonly remain asymptomatic and may be found incidentally at autopsy. The majority of cystic duplications of the small intestine lie in the mesentery. There is usually a common muscular wall between the duplicated area and the remainder of the ‘‘normal’’ intestine. These mesenteric cysts are generally larger than the intramural cysts, ranging from 0.8 to 8 cm in length. A variety of mucosal types may be found in these enteric cysts, including that of the adjoining intestine, gastric mucosa, or pancreatic tissues.1–5 Tubular duplications may occur in either dorsal or lateral positions relative to the normal gut. Tubular duplication are observed less frequently than are enteric cysts. As opposed to cystic duplications, tubular duplications communicate with the intestinal lumen either distally or at both ends. Tubular duplications of the duodenum are extremely rare, being almost exclusively associated with the jejunum, ileum, or colon. All lie on the mesenteric side of the normal intestine. The duplicated segment and the normal intestine are usually of the same diameter. As with cystic duplications, the mucosa may or may not resemble that of the adjacent intestine.1–5 Duodenal duplications may remain asymptomatic if they are small, and particularly if they are cystic in nature. Symptomatic patients generally present with symptoms and signs of bowel obstruction, including abdominal pain, a palpable mass, bleeding, emesis, and dehydration. If the duplicated segment contains gastric mucosa, perforation within the duplication can be found.1–7 Due to their location, biliary obstruction and/or pancreatitis also may be observed.8

Upper Gastrointestinal System

Enteric cysts are usually diagnosed as extrinsic obstructive masses occluding the lumen of the intestine, observed in barium contrast radiographic studies. They also may be diagnosed by abdominal ultrasonographic, CT, or MR imaging.9–11 When a tubular duplication communicates with the normal lumen of the intestine, the duplication can occasionally be visualized with barium. Since 10–35% of duodenal duplications contain gastric mucosa, a 99 m Tc pertechnetate scan may show increased activity within the duplicated segment.1,8 Associated anomalies found in conjunction with duodenal duplications are much less common than with thoracic duplications. In particular, abnormalities of the spine and gastrointestinal and genitourinary tracts are seen much less frequently. Rarely there has been observed a trans-diaphragmatic duplication that has originated in the duodenum and has extended into the chest.1 Etiology and Distribution

The cause of duodenal duplications remains unknown. Suggested theories of origin have included defects of recanalization of the epithelial plugs in the duodenum, intrauterine vascular accidents, persistence of embryonic diverticula, and traction between adhering neural tube ectoderm or notochordal mesoderm and gut endoderm.1–7 Symptomatic duodenal duplications are rare, occurring in less than 1 in 100,000 live births.2 There is probably no sex predilection.1 Prognosis, Treatment, and Prevention

Since many duodenal duplications are asymptomatic, surgical intervention may not be necessary. However, if symptoms and signs of bowel obstruction are present, surgical resection of the duplicated segment and the adjacent small intestine with end-to-end anastamosis is indicated. If a large tubular duplication precludes removal of the entire segment, a proximal communication between the duplicated area and the normal lumen can be made, essentially creating a ‘‘double-barreled’’ intestine. With prompt diagnosis and surgical intervention, prognosis is excellent.1,4–7 References (Duodenal Duplications) 1. McAllister WH, Siegel MJ: Pediatric radiology case of the day: duodenal duplication. AJR Am J Roentgenol 152:1328, 1989. 2. Hocking M, Young DG: Duplications of the alimentary tract. Br J Surg 68:92, 1981. 3. Bower RJ, Siebel WKN, Kieswetter WB: Alimentary tract duplications in children. Ann Surg 188:669, 1978. 4. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 196. 5. Warkany J: Congenital Malformations: Notes and Comments, Year Book Medical Publishers, Chicago, 1971, p 696. 6. Gray SW, Colburn GL, Pemberton LB, et al.: The duodenum, part I: history, embryogenesis, and histologic and physiologic features. Am Surg 55:257, 1989. 7. Colburn GL, Gray SW, Pemberton LB, et al.: The duodenum, part III: pathology. Am Surg 55:469, 1989. 8. Inouye WY, Fitts WT: Duodenal duplication: Case report and literature review. Ann Surg 162:910, 1965. 9. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999. 10. Teele RL, Henshke CI, Tapper D: The radiographic and ultrasonographic evaluation of enteric duplication cysts. Pediatr Radiol 10:9, 1980. 11. Blumhagen JD, Weinberg E: Pediatric gastrointestinal ultrasonography, In: Ultrasound Annual. RC Sanders, M Hill, eds. Raven Press, New York, 1986, p 145.

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24.23 Duodenal Diverticula Definition

Outpouchings of the lumen of the duodenum. True diverticula are covered with all layers of the duodenal wall. False diverticula are covered with only mucosa and submucosa herniated through defects in the muscular duodenal wall.1,2 Diagnosis

True diverticula of the duodenum are extremely rare, occurring in between 1/9000 and 1/40,000 live births. False diverticula are more common. They are thought to represent herniations through muscular defects in the duodenal wall. Thus, the primary developmental defect in false diverticula is in the gastrointestinal musculature; the actual herniations are acquired.1 Approximately 75% of false duodenal diverticula are in the second part of the duodenum, the remainder being in the third part. The majority are on the concave pancreatic side. Most duodenal diverticula are spherical; however, they may also be conical or tubular. They are usually single anomalies; however, multiple diverticula have been observed in individual patienst.2–5 Although the majority of duodenal diverticula produce symptoms, many do not. Approximately 75% of duodenal diverticula diagnosed radiographically and 10–15% of diverticula found at autopsy produce symptoms. Pain is present in approximately 50% of patients and is described as epigastric, umbilical, infrascapular, at the costovertebral angle or in the right upper quadrant of the abdomen. Some authors believe that central abdominal pain indicates a lesion of the third part of the duodenum, whereas pain to the left of midline indicates involvement of the second portion of the duodenum. Additional symptoms can include constipation, eructation, nausea, and vomiting. Weight loss and/or growth failure may be prominent. Jaundice can occur if the diverticulum causes obstruction of the bile duct.2,6 The symptoms and signs that result from duodenal diverticula may be caused by mechanical obstruction of the duodenum itself or of the pancreatic or common bile ducts. Alternatively, symptoms may be the result of inflammation, diverticulitis, ulceration, perforation, or neoplastic change.2,6 Diagnosis of duodenal diverticula may be made by barium contrast radiographic studies. Ultrasonographic, CT, or MR imaging of the abdomen or endoscopy may be useful diagnostic adjuncts.1 Abdel-Haviz et al.1 reported a 40% incidence of associated anomalies in conjunction with duodenal diverticula. Observed malformations include annular pancreas, bile duct anomalies, choledochocele, malrotation of the intestines, superior mesenteric artery syndrome, situs inversus, congenital heart disease, imperforate anus, Hirschsprung disease, omphalocele, hypoplastic kidneys, and exstrophy of the bladder. In addition, duodenal diverticula have been noted in Down syndrome.1 Finally, in 1962, Clunie and Mason7 described a unique, apparently autosomal recessive disorder in four siblings whose parents were consanguineous. Unusual features included marfanoid hiatus, femoral or inguinal hernias, diverticula of the large and small intestines, urinary bladder diverticula, myopia, esotropia, and retinal detachment. Etiology and Distribution

False duodenal diverticula are thought to be the result of intraluminal duodenal pressure causing herniation through intrinsic

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defects in the musculature of the intestinal wall. These muscular wall defects have been hypothesized to be the result of many factors. Some authors have suggested that weakened areas represent sites of aberrant pancreatic tissue. Others have posited their occurrence at sites of transitory embryonic diverticula. The etiology of these muscular wall defects is most likely heterogenous.1–6 Autopsy series have documented duodenal diverticula in 2.7– 14.5% of cases. Radiographic studies have reported the incidence as 0.016–5.19%. Slightly more females than males may be affected. The majority of symptomatic patients with duodenal diverticula present after age 40.1,2 Prognosis, Treatment, and Prevention

Since many duodenal diverticula are asymptomatic, surgery is indicated only for symptomatic patients if conservative treatment fails. It is thought that less than 2% of cases in which duodenal diverticula are visualized on radiographic studies should require surgical treatment.2 Successful surgical procedures include excision and closure with inversion of the neck sac, Roux-en-Y diverticulojejunostomy, and end-to-end duodenojejunostomy.2 The prognosis in individuals with duodenal diverticula is dependent on associated anomalies and complications. Obviously, in asymptomatic cases the prognosis is excellent and treatment is not required. However, if perforation of the diverticulum occurs (particularly in association with the presence of gastric mucosa), mortality has been observed. There also has been an increased incidence of malignancy in such diverticula.1,2 References (Duodenal Diverticula) 1. Abdel-Havis A, Birkett DH, Ahmed MS: Congenital duodenal diverticula: a report of three cases and a review of the literature. Surgery 104:74, 1988. 2. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 191. 3. Gray SW, Colburn GL, Pemberton LB, et al.: The duodenum, part I: history, embryogenesis, and histologic and physiologic features. Am Surg 55:257, 1989. 4. Eggert A, Teichman NW, Whitman DH: The pathologic implication of duodenal diverticula. Surg Gynecol Obstet 154:62, 1982. 5. Colborn GL, Gray SW, Pemberton LB, et al.: The duodenum, part III: pathology. Am Surg 55:469, 1989. 6. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 696. 7. Clunie GJA, Mason JM: Visceral diverticula and the Marfan syndrome. Br J Surg 50:51, 1962.

24.24 Congenital Aganglionic Duodenum Definition

Congenital aganglionic duodenum is congenital enlargement of the duodenum secondary to lack of myenteric ganglion cells. Megacystis-microcolon-intestinal hypoperistalsis syndrome and megaduodenum/megacystis syndrome are excluded from this definition.1 Diagnosis

Generalized intrinsic defects in duodenal musculature or absence of myenteric ganglion cells of the duodenum can result in

congenital enlargement of the duodenum. Aganglionic duodenum is an uncommon cause of congenital duodenal enlargement. Affected children present with abdominal distention and symptoms and signs of complete or partial bowel obstruction, including pain, emesis, and decreased or absent bowel sounds.1,2 Diagnosis is made based on radiographic evidence of an enlarged duodenum and is confirmed by biopsy material from the duodenal wall that reveals absence of myenteric ganglion cells.1,2 This condition differs from two other disorders associated with generalized intrinsic defects in duodenal musculature. In 1938, Weiss3 first described an autosomal dominant disorder associated with megeduodenum in three generations. Since that time a number of families have been described with autosomal dominant transmission of a trait consisting of intestinal pseudoobstruction and megacystis. The developmental pathogenesis is consistent with a visceral myopathy. Histologic studies have shown an extensive collagen replacement of the longitudinal muscle layer. Ganglion cells have appeared normal with light and electron microscopy.4–6 A similar but distinct autosomal recessive visceral myopathy syndrome has been described: the megacystis-microcolon-intestinal hypoperistalsis syndrome. Affected children have had marked dilation of the bladder, hydronephrosis, a ‘‘prune belly’’ appearance to the abdomen, microcolon, and dilated small intestines. Ganglion cells of the myenteric plexus have been normal.7 Etiology and Distribution

Congenital absence of myenteric ganglion cells of the duodenum is a very rare disorder. The enlarged duodenum is thought to be the result of congenital absence of myenteric ganglion cells similar to that seen in Hirschsprung disease. Absence of myenteric ganglion cells in the duodenum may also be a consequence of Chagas disease (accompanying infection with Trypanosoma cruzi). No particular sex predilection has been noted.1 Prognosis, Treatment, and Prevention

Small atonic segments of duodenum are asymptomatic; however, complete aganglionosis of the duodenum results in megaduodenum and symptoms and signs of intestinal obstruction. In severely affected patients, surgical resection of the affected segment is necessary. Gastrojejunostomy alone may fail to relieve the enlarged duodenum, and a partial gastric resection, partial duodenal resection, and gastrojejunostomy may be necessary.1,2 References (Congenital Aganglionic Duodenum) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 205. 2. Fischer HW: The big duodenum. AJR Am J Roentgenol 83:861, 1960. 3. Weiss W: Zur Aetiologie des Megaduodenums. Dstch Z Chir 251:317, 1938. 4. Newton WT: Radical enterectomy for hereditary megaduodenum. Arch Surg 96:459, 1968. 5. Anuras S, Shaw A, Christensen J: The familial syndromes of intestinal pseudo-obstruction. Am J Hum Genet 33:584, 1981. 6. Schuffler ND, Rohrman NCA, Chafee RG, et al.: Chronic intestinal pseudo-obstruction: a report of 27 cases and review of the literature. Medicine 60:1173, 1981. 7. Winter RN, Knowles SAS: Megacystis-microcolon-intestinal hypoperistalsis syndrome: confirmation of autosomal recessive inheritance. J Med Genet 23:630, 1986.

Upper Gastrointestinal System

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24.25 Extrinsic Vascular Obstruction of the Duodenum Definition

Extrinsic vascular obstruction of the duodenum is duodenal obstruction secondary to extrinsic compression by a preduodenal portal vein or the superior mesenteric artery.1 Diagnosis

The hepatic portal vein normally lies posterior to the first part of the duodenum. However, in some cases, it comes to lie anterior to the duodenum. In that position, it may compress the duodenum to the point of obstruction.1 Occasionally the superior mesenteric artery may compress the third or transverse portion of the duodenum between the body of the vessel and the aorta and the vertebral column, at the level of the second or third lumbar vertebrae. Such a resulting obstruction may be chronic, acute, intermittent, partial, or complete (Figure 24-12).1–3 Extrinsic vascular constriction of the duodenum may lead to symptoms and signs of duodenal obstruction. Symptoms may be of a long-standing nature and relatively mild, or they may appear suddenly. Pain is the usual chief complaint. Attacks may be episodic. In the acute form, signs and symptoms of gastrointestinal obstruction appear suddenly with tremendous distention of the stomach and duodenum.1–5 Upright radiographs of the abdomen reveal a dilated stomach and duodenum. Barium contrast studies may help to delineate the exact site and nature of the vascular obstruction.1–5 Similarly, ultrasonographic, CT, or MR visualization of the abdomen may be a useful diagnostic adjunct.6 A paraduodenal portal vein is commonly accompanied by a number of serious malformations, including malrotation of the intestines, complete or partial situs inversus, annular pancreas, duodenal atresia, cardiac anomalies, and biliary defects,4 whereas as-

Fig. 24-12. Relationship of the superior mesenteric artery to the duodenum. Compression of the duodenum between the artery and the aorta may cause duodenal obstruction.

Fig. 24-13. Relationship of the portal vein to the duodenum. (A) Normal developmental anatomy. (B) Anomalous development. Note preduodenal portal vein anterior to the duodenum.

sociated anomalies with the superior mesenteric artery syndrome are uncommon.1–3 In the case of a preduodenal portal vein (Fig. 24-13), the obstruction of the duodenum can be surgically bypassed by duodenostomy or gastroenterostomy. In the superior mesenteric artery syndrome, medical treatment, including posture therapy and antispasmodic drugs, should be tried in adults before attempting surgical intervention. When this condition appears in infants and children, medical measures are usually ineffective and surgery is indicated. Duodenojejunostomy is the preferred surgical procedure.1 In the absence of severe associated congenital anomalies, and with appropriate and early medical or surgical intervention, prognosis for individuals with extrinsic vascular obstruction of the duodenum is good.1 References (Extrinsic Vascular Obstruction of the Duodenum) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 205. 2. Barner HB, Sherman CD: Vascular compression of the duodenum. Int Abstr Surg 117:103, 1963. 3. Rabinovitch J, Pines B, Felton M: Superior mesenteric artery syndrome. JAMA 179:257, 1962. 4. Boles ET Jr, Smith B: Preduodenal portal vein. Pediatrics 28:805, 1961. 5. Block MA, Zikria EA: Preduodenal portal vein causing duodenal obstruction associated with pneumatosis cystoides intestinalis. Ann Surg 153:5407, 1961. 6. Berrocal T, Torres I, Gutierrez J, et al.: Congenital anomalies of the gastrointestinal tract. Radiographics 19:855, 1999.

24.26 Congenital Paraduodenal Hernia through a Peritoneal Defect Definition

Congenital paraduodenal hernia through a peritoneal defect is herniation of a portion of the intestine into paraduodenal peritoneal pockets or fossae.1 Diagnosis

A number of normal peritoneal pockets or fossae are located near the fourth part of the duodenum. These fossae are extremely variable and are inconsistently found in each individual. Some

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authors have suggested that there are as many as nine of these potential spaces, while others feel that there are five.1,2 Signs and symptoms of intestinal herniation into a paraduodenal fossa are those of intestinal obstruction, namely, nausea, vomiting, abdominal pain, distention, and dehydration. The patient also becomes obstipated, with passage of neither feces nor gas. Distention becomes increasingly more severe as time passes. Visible peristaltic waves over the abdominal wall may be present. The pain is most commonly described as periumbilical in nature.1–3 Diagnosis may be suspected from clinical criteria and confirmed by radiographic and ultrasonographic findings. Etiology and Distribution

Internal hernias through paraduodenal fossae are thought to occur at the time the intestines normally return to the abdominal cavity in week 10 postconception. Both the ascending and descending colons have mesenteries at that time. These mesenteries subsequently come into contact with the posterior peritoneal wall and fuse with it, thereby fixing the position of the colon by month 5 postconception. Paraduodenal hernias are formed during this period of fixation of the ascending and descending colonic mesenteries.1–4 Paraduodenal hernias are termed right or left, depending on which direction the herniated loops pass as they enter the fossae. In more than 95% of cases, the herniated loop passes to the right.4

Thus, it is thought that the paraduodenal fossae and hernias are formed simultaneously as defects in fusion of the colonic mesentery and peritoneum during early gestation.1–4 Paraduodenal hernias are uncommon occurrences. There has been an excess of reported males with this anomaly.1 Prognosis, Treatment, and Prevention

Surgery is necessary to relieve the intestinal obstruction associated with the herniated intestinal loop. Surgery consists of reduction of the hernia and closure of the paraduodenal defect. With early diagnosis and surgical intervention, the prognosis is good. No recurrence of paraduodenal hernias has been reported following surgical reduction.1–3 References (Congenital Paraduodenal Hernia through a Peritoneal Defect) 1. Elias J, Skandalakis MD, Wood S, et al.: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects, ed 2. Lippincott, Williams and Wilkins, Baltimore, 1993, p 165. 2. Jones TW, Kyhus LM, Harkins HN: Hernia JB Lippincott, Philadelphia, 1964, p 134. 3. Laslie M, Durden C, Allen L: Concealed umbilical hernia: Papez’s concept of so-called paraduodenal hernia. Anat Rec 155:145, 1966. 4. Colborn GL, Gray SW, Pemberton LB, et al.: The duodenum, part III: pathology. Am Surg 55:469, 1989.

25 Small and Large Intestines Eberhard Passarge and Roger E. Stevenson

T

he enteric system takes form between postfertilization weeks 4 and 16.1–4 In the embryonic disc stage, the future enteric system is represented by the portion of the yolk sac that lies parallel and in contact with the ectodermal plate (Fig. 25-1). The tubular nature of the enteric system becomes apparent during the 4th week of embryogenesis (stages 10–13) as a portion of the yolk sac becomes folded inside the embryonic mass. At its cephalic extreme, the primitive foregut is limited by the oropharyngeal membrane, and at its caudal extreme the hindgut is limited by the cloacal membrane. These membranes will eventually break down, at which time the enteric system becomes open to the amniotic cavity. The initially large opening of the midgut into the yolk sac is progressively narrowed in purse string fashion by the cranial, caudal, and lateral folds of the embryo. The cranial portion of the enteric tube is characterized by ventral budding at the level of the fourth somite, which will develop into the respiratory tube. The oropharyngeal membrane breaks down between days 24 and 26 (stages 11 and 12), opening the enteric tube to the amniotic space via the oral and nasal cavities. An analogous partition takes place in the caudal end of the enteric tube. A ventral extension from the hindgut forms the urachus, which extends into the body stalk. Umbilical arteries develop along each side of the urachus and connect the fetus with the placenta. This urachal system will be partitioned from the caudal enteric system by descent of the rectovesical septum. Partition is completed by week 8 and prior to rupture of the anal membrane and the urogenital membrane. Thus, the caudal end of the enteric tube has adapted to provide nutrition and respiration for embryonic and fetal life, and the cranial end of the enteric tube adapts to take on these functions postnatally. At its midpoint, the communication between the gut and the yolk sac is narrowed progressively, forming the omphalomesenteric or vitelline duct. This communication between the yolk sac and the midgut will normally become obliterated by week 10. Growth of the enteric tube distal to the ligament of Treitz greatly outpaces growth in the balance of the tube. At term, the jejunum and ileum averages 250 to 300 cm in length and the colon 50 to 60 cm. Accommodation of this 300-cm long tube within the term abdominal cavity requires extensive folding of the enteric tube. The pattern of folding of the enteric tube is maintained in part by attachment of the bowel to the posterior abdominal wall by a mesentery.

Evidence that molecular controls over development are conserved across species and utilized in the formation of anatomically disparate systems has been advantageous in the study of gut development. Signaling between endoderm and mesoderm involved in gut development appears to be extensive, and the same molecular players involved in structures extensively studied like the limb appear to have roles in gut development.4,5 Consideration of formation of the gut along four developmental axes has been helpful. Most is known about patterning along the craniocaudal and left-right axes, less about the dorsal-ventral and radial axes.4 Homeobox genes involved in determining the overall body plan may pattern gut formation along the craniocaudal axis localizing the foregut and its derivatives in the thorax, the midgut and its derivatives in the abdomen, and the hindgut in the pelvis. Sonic hedgehog and its repressor Activin exert upstream control over a cascade of factors that determine left-right asymmetry. Dorsal-ventral patterning is especially important to the development of gut derivatives. For example, ventral signals (Pdx-1, Nkx2.1, others unknown), which inhibit Shh expression, are necessary for proper localization and formation of the thyroid, lung, pancreas, and liver. Although not yet discovered, it is to be anticipated that mutations in the genes controlling these developmental factors will be found in individuals with gut malformations.6 Differentiation

There are no gross or microscopic features that distinguish the jejunum from the ileum during embryonic and fetal life. The shorter club-shaped villi and presence of Peyer patches will later serve to identify the ileum. The presence of a vitelline duct remnant (Meckel diverticulum or atretic cord) allows the identification of the ileum at a point 40 to 50 cm proximal to the ileocecal junction. Both the location of the appendix and the saccular configuration of the cecum help to identify the beginning of the colon. The arrangement of the longitudinal muscles in three bands and the presence of goblet cells in the mucosa further identify the colon. Rotation

The midpoint of the enteric system is tethered to the umbilical cord by the vitelline duct. With linear growth of the enteric tube 1097

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Fig. 25-1. Schematic showing development of the enteric system at stages 8 (18 days), 11 (24 days), 13 (28 days), and 15 (33 days). The tubular nature of the enteric system becomes apparent between stages 8 and 11 with the folding of a portion of the yolk sac into the embryonic interior to form the foregut and hindgut. Further definition of the enteric tube progresses as the abdominal wall closed in purse string

fashion. a, allantois; c, cloaca; dp, dorsal pancreas; fg, foregut; h, liver; hd, hepatic ducts; hg, hindgut; lb, lungbud; m, metanephros; md, mesonephric duct; s, stomach; t, thyroid; tr, trachea; ugs, urogenital sinus; vd, vitelline duct; vp, ventral pancreas. (Adapted from Sadler,2 O’Rahilly and Muller,3 and Tuchmann-Duplessis and Haegel.7)

it is required to loop and rotate. Initially this growth is not accommodated in the peritoneal cavity and causes the bowel to extend into the umbilical cord. During the 6th week, the enteric tube first loops into the umbilical cord and undergoes an initial counterclockwise rotation of 908. This places the upper bowel to the right of the midline. A further 1808 counterclockwise rotation occurs during week 10, during which the intestine returns to the abdominal cavity. Completed, the bowel is spiraled around the superior mesentery artery (Fig. 25-2). The cecum lies anteriorly in the right upper quadrant, adjacent to the liver, the balance of the colon looping to the left and downward. The final positioning of the bowel is achieved by a lengthening of the ascending colon, which forces the cecum low and to the right of the umbilicus.

duplication; aberrant connections to the respiratory system, the umbilical cord, and the urinary system; and various obstructions. In addition to obstruction caused by agenesis/atresia, the bowel lumen may be occluded by external pressure from volvulus, malposition, and bands from the vitelline vasculature or the vitelline duct.

Patency

From its formation the enteric tube is patent along its entire course from the oropharyngeal membrane to the cloacal membrane. The enteric system never undergoes a solid phase, although parts of this tubular structure may be transiently occluded. This is particularly so of the duodenum. A wide variety of anomalies of the gastrointestinal system are recognized. These include areas of the intestine that fail to develop or that are secondarily ablated;

References 1. Snyder WH Jr, Chaffin L: Embryology and pathology of the intestinal tract: presentation of 40 cases of malrotation. Ann Surg 140:368, 1954. 2. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams and Wilkins, Philadelphia, 2003. 3. O’Rahilly RO, Muller F: Developmental Stages in Human Embryos. Carnegie Institution of Washington, Washington, DC, 1990. 4. Roberts DJ: Molecular mechanisms of development of the gastrointestinal tract. Dev Dyn 219:109, 2000. 5. Ramalho-Santos M, Melton DA, McMahon AP: Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127:2763, 2000. 6. De Santa Barbara P, Van den Brink GR, Roberts DJ: Molecular etiology of gut malformations and diseases. Am J Med Genet (Semin Med Genet) 115:221, 2002. 7. Tuchmann-Duplessis H, Haegel P: Illustrated Human Embryology, vol 2. Springer-Verlag, New York, 1982.

Fig. 25-2. Schematic showing rotation of the intestine. A. Appearance of enteric tube prior to coiling and rotation. B. During week 6, the intestine rotates 908 counterclockwise around the attachment of the vitelline duct (V), exhibits coiling of the portion of the bowel proximal to the vitelline duct, and herniates into the umbilical cord. C,D. A further 180o rotation occurs during week 10 as the intestine returns to the abdomen. E. The cecum migrates to the right lower quadrant of the abdomen during the final weeks of gestation.

Small and Large Intestines

25.1 Intestinal Agenesis Intestinal agenesis is failure of a portion of the enteric tube to form. Agenesis of the rectosigmoid portion of the colon is the only intestinal agenesis recognized in man. It is a rare malformation, occurring in one per 50,000 pregnancies. Males are more commonly affected, with a sex ratio of 2–3:1.1–5 This condition is always associated with major caudal anomalies. The typical malformation is sirenomelia. In this condition, the caudalmost portion of the intestine, generally that portion supplied by the inferior mesenteric artery, fails to develop, and the descending colon ends as a blind pouch.1 The lower genitourinary system is likewise absent in that all allantoic structures fail to form. It has been proposed that these patients have vitelline placentation, with the umbilical artery being derived from the superior mesenteric artery.1,5 Lesions with colonic agenesis are generally lethal. Only one infant has been surgically repaired. There is a wide spectrum of defects, from typical sirenomelia with allantoic and rectosigmoid agenesis to caudal dysgenesis, in which the lower intestinal and genitourinary systems are usually present but are functionally deficient because of impaired innervation. References (Intestinal Agenesis) 1. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 2. Kampmeier OF: On sireniform monsters, with a consideration of the causation and the predominance of the male sex among them. Anat Rec 34:365, 1927. 3. Smith DW, Bartlett C, Harrah LM: Monozygotic twinning and the Duhamel anomalad (imperforate anus to sirenomelia): a nonrandom association between two aberrations in morphogenesis. Birth Defects Orig Artic Ser XII(5):53, 1976. 4. Stocker JT, Heifetz SA: Sirenomelia: a morphological study of 33 cases and review of the literature. Perspect Pediatr Pathol 10:7, 1987. 5. Ballantyne JW: The occurrence of a non-allantoic or vitelline placenta in the human subject. Trans Edinb Obstet Soc 23:54, 1898.

25.2 Intestinal Atresia/Stenosis Definition

Intestinal atresia/stenosis is the complete or partial occlusion of the lumen of a segment of the small or large intestine. Single or multiple areas of occlusion occur. Diagnosis

The infant with intestinal atresia presents with a variety of signs, all related to obstruction.1–10 These include abdominal distention, bilious vomiting, and absent or limited meconium passage. These findings may be presaged by polyhydramnios during pregnancy and excessive gastric aspirate at birth. Polyhydramnios may be anticipated if obstruction of the esophagus, stomach, duodenum, or proximal small intestine occurs. Distal small intestine and colonic obstruction may not be associated with polyhydramnios, since adequate intestinal absorption area is present. With high intestinal obstruction, the gastric contents at birth will exceed 15 to 20 mL and will be bile stained.11 Following birth, the abdomen becomes distended with swallowed air. Radiographs will show air-dilated structures proximal to the obstruction, and the

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level of the obstruction can generally be determined by the gas pattern (Figs. 25-3 through 25-5).4,11 Intestinal atresias ultimately lead to bile-stained vomitus. This may occur in the initial hours of life if the enteric system is already distended with amniotic fluid. The higher the intestinal atresia is, the earlier the vomiting will be. Upper gastrointestinal contrast studies are generally not needed. Barium enema is recommended in all cases, since colonic atresia may coexist with proximal atresias. Other considerations in the differential diagnosis include ileus from sepsis and obstruction from volvulus, malrotation, anorectal malformation, intussusception, meconium plug, and meconium ileus. Jejunal and Ileal Atresia

Several types of atresia of the small intestine have been described. These include occlusion with a diaphragm of variable thickness (type I), occlusion over a variable length of intestine with the two blind ends connected by a solid cord (type II), and occlusion with complete separation of the two blind ends and a cleft in the connecting mesentery (type III). These types are shown schematically with intestinal stenosis and multiple atresias in Figure 25-6. Complete atresia with no connection between the two blind cords (type III) is the most common type of small intestine atresia, constituting about one-half of all cases (Fig. 25-6D). Atresia with a solid cord connecting the two patent sections of bowel (type II) is next in frequency. Twenty percent of small intestine atresias are in the form of a thin diaphragm (type I). Multiple areas of small bowel atresias are found in 6% of cases.1 Stenosis of the bowel lumen is much less common than atresia, comprising only about 5% in most series. A distinct type of jejunal atresia has been termed apple-peel atresia. It makes up about 10% or more of small bowel atresias and has been considered a variant of type III atresia.1,4 In these cases, the atresia is located in the proximal jejunum. The small intestine is short, and the portion distal to the atresia is coiled around a mesenteric remnant with its vascular supply provided via anastomoses with more distal mesenteric arteries (Fig. 25-7). These cases more commonly have low birth weight and associated anomalies. Familial cases have been reported. The incidences of jejunal and ileal atresias reported in the literature have varied widely. It would appear that they occur with near equal prevalence, about one per 1500 live births.1 Duodenal atresia (Section 24.21) occurs more commonly and colonic atresia less commonly than either (Table 25-1). An underlying cause for the atresia (malrotation, volvulus, intussusception, gastroschisis, omphalocele) can be found in onefourth of cases. The bowel is malrotated in about 10% of cases. Meconium ileus occurs in a similar percentage. Anomalies outside the gastrointestinal system are uncommon, occurring in less than 5% of cases (Table 25-2).12–21 Cardiovascular anomalies are the most common of these, occurring in 2% of cases. Down syndrome, an underlying condition found in one-third of infants with duodenal atresia, has been found in about 1% of the nonduodenal bowel atresias. Atresia of the Colon

Atresia of the colon occurs less commonly than atresias of the duodenum, jejunum, or ileum. In most series, only about 10% of intestinal atresias occur in the colon. Atresia of the colon is over 10 times as frequent as stenosis. The same types of atresias found in the small intestine occur in the colon (Fig. 25-6). Small series prior to 1970 reported near-equal incidences of types I, II, and III.6,11 Two recent series showed an

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Fig. 25-3. Left: Radiograph showing dilated stomach, duodenum, and proximal jejunum in an infant with jejunal atresia. Right: Microcolon demonstrated by barium enema in a 3-day-old infant with ileal atresia. Note also malrotation with distal ileum to right of cecum. (Courtesy of Dr. Rodney I. Macpherson, Medical University of South Carolina, Charleston.)

excess of type III lesions.10,22 Among cases with a single short segment of atresia, the sigmoid and transverse regions are most commonly affected and the hepatic and splenic flexures least commonly affected (Fig. 25-8). Long segment atresia covering two or more regions and multiple atresias make up one-third of colon atresias.6,17,22 Type III lesions tend to occur on the right side, perhaps related to a greater incidence of volvulus affecting the right colon. The descending and sigmoid colons have a greater incidence of type I lesions. All types of colon atresias are considered to be late anomalies occurring secondary to vascular compromise. Other anomalies can be found in about one-third of patients with atresia of the colon.6,10,11,22 Most of these anomalies involve the gastrointestinal system and often are contributing factors in the cause of the atresia. These include abdominal wall defects, volvulus, and malrotation. Associated vesicoenteric fistula is not uncommon. About 10–20% of cases will have jejunal atresia. Because of this, most medical centers perform a barium enema on all infants who present with features of small bowel obstruction.10 Etiology

Earlier concepts that intestinal atresias resulted from primary agenesis or from failure of the intestine to ‘‘recanalize’’ have been replaced by the concept that these defects represent vascular disruptions.23–26 Three lines of evidence have been important. First, observations on human embryos have failed to show a stage during which the intestine is solid.23,24 Rather, the intestine below the ligament of Treitz remains patent except for transient and widely distributed occlusions caused by epithelial proliferation. Second, the portion of the intestine distal to the atresia has been found to contain bile pigment, lanugo hairs, and squamous

epithelial cells, indicating that the bowel had been patent previously.26 Since bile is produced only after 11 weeks and lanugo hairs form only after 24 weeks, the atresias must occur relatively late in pregnancy. Third, ligation of the mesenteric vasculature and the production of experimental volvulus in animal fetuses have produced all of the types of intestinal atresias seen in humans.25 Prognosis, Prevention, and Treatment

Removal of bowel obstruction and restoration of bowel continuity are the major goals of atresia surgery.4,27–30 These goals can be frustrated by insufficient attention to electrolyte and fluid balance, nutrition, respiratory sufficiency, and the presence of other anomalies. The prognosis for infants with jejunal and ileal atresias depends on successful medical and surgical therapy. Removal of excessive intestine can produce the ‘‘short bowel syndrome,’’ in which there is inadequate digestion and absorption and increased transit time. Retention of the ileocecal valve and a length of bowel sufficient for nutrient absorption are fundamental. Potential for survival and adequate growth is best when the ileocecal valve and more than 40 cm of small intestine can be retained. Survival decreases to 50% when the length of remaining intestine is less than 40 cm and the ileocecal valve is intact. The prognosis is grim for those infants with less than 15 cm of small intestine remaining after surgery and for those with less than 40 cm of small intestine if the ileocecal valve is removed. Different medical centers prefer different types of anastomoses. All indicate the importance of resection of the blind ends of the bowel, particularly the dilated proximal segment, because of poor vascularization of the atretic ends. Primary end-to-end anastomosis

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Fig. 25-5. Colon atresia. Abdominal radiograph showing dilated proximal colon (arrow) and multiple loops of dilated small intestine. (Courtesy of Dr. Michael Thomason, Greenville Memorial Medical Center, Greenville, SC.) Fig. 25-4. Top: Proximal segment of small intestine from term fetus showing terminal cul de sac at area of atresia (AA). The intestine has been opened (arrowheads) so as to compare by transillumination the distribution pattern of the mural blood vessels on the serosal (S) and mucosal (M) surfaces. Notice the abnormal vascular concentrations (AVC) near the area of atresia. Bottom: Segments of small intestine (SI) with attached mesentery (M) showing multiple areas of intestinal atresia (A). Note the disrupted and abnormal vascular distribution pattern within the transilluminated mesentery (arrows). (Courtesy Dr. Will Blackburn, Fairhope, AL.)

is performed most commonly. Placement of an enterostomy is unusual and generally only a temporary procedure. Atresias of the right colon are preferentially resected with primary anastomosis performed. Ileostomy and right-sided colostomies are poorly tolerated by infants because of fluid and electrolyte imbalance. Surgical correction of atresias distal to the hepatic flexure commonly involves a colostomy during the neonatal period, followed by anastomosis late in the 1st year of life. Poor vascularity of the dilated proximal stump compromises the

Fig. 25-6. Types of intestinal stenosis and atresia. A. Stenosis. B. Type I, obstruction by a thin diaphragm. C. Type II, complete discontinuity of intestine with a solid cord connecting the two ends. D. Type III, separation of two ends of the intestine with no intervening cord and with a cleft of the mesentery. E. Multiple atresias.

1102

Gastrointestinal and Related Structures Table 25-1. Location of intestinal atresias Davis and Poynter2 (1922)

Pollock and Bergin3 (1961)

Benson et al.11 (1968)

Grosfeld et al.28 (1979)

134

28

109

30

60

26

73

28

Ileum

101*

33

—

—

Colon

39

4

22

7

Multiple areas

67

—

—

—

Duodenum Jejunum

*Includes ileum and cecum.

Fig. 25-7. Schematic showing apple peel atresia of proximal jejunum. The distal small bowel spirals around a vascular stalk originating in the region of the cecum. (Redrawn from Zerella and Martin8 and Grosfeld.31)

Table 25-2. Conditions with atresia of the intestines Condition

Prominent Features

Causation

Absence of small intestine muscle14

Absent or deficient muscular layers of the small intestine

AR

Campomelia (Cumming type)11

Large head, short and bowed long bones, cystic kidneys and liver, polysplenia

AR (211890)

Cafergot, prenatal16

None

Prenatal exposure to cafergot

Cocaine, prenatal17

Abruptio placenta, vascular defects

Prenatal exposure to cocaine

HIPO18

Hemihypertrophy, intestinal web, preauricular skin tags, corneal opacity

Unknown

Multiple intestinal atresias19

Areas of atresia affecting small and large intestines

AR (2453150) Heterogeneous

OEIS20

Omphalocele, exstrophy of the cloaca, imperforate anus, spinal defects

Sporadic, probably due to vascular mechanism

Omphalocele21

Enlargement of the umbilical ring with herniation of bowel and other abdominal contents with the umbilical cord

Heterogeneous

Sirenomelia22

Renal agenesis, agenesis of distal colon, absence of genitalia, imperforate anus, unseparated lower limbs

Sporadic, secondary to vascular steal

anastomosis, and resection of a portion of this region has improved the outcome. The small caliber of the colon distal to the atresia has been called microcolon. This segment is generally quite normal except for size. It will dilate and function normally once bowel continuity is established. Survival of patients with atresia of the colon is a phenomenon of this century. There has been steady improvement in surgical outcome, with survival below 50% during the first half of the century, 60–70% during the 1950s and 1960s, and 90% since 1970. References (Intestinal Atresia/Stenosis) 1. DeLorimer AA, Fonkalsrud EW, Hays DM: Congenital atresia and stenosis of the jejunum and ileum. Surgery 65:819, 1969. 2. Davis DL, Poynter CWM: Congenital occlusions of the intestines. Surg Gynecol Obstet 34:35, 1922. 3. Pollock WF, Bergin WF: Management of intestinal atresia at the Los Angeles Children’s Hospital. Am J Surg 102:202, 1961. 4. Dalla Vecchia LK, Grosfeld JL, West KW, et al.: Intestinal atresia and stenosis. Arch Surg 133:490, 1998. 5. Nixon HH, Tawes R: Etiology and treatment of small intestine atresia: analysis of a series of 127 jejunoileal atresias and comparison with 62 duodenal atresias. Surgery 69:41, 1971.

6. Peck DA, Lynn HB, Harris LE: Congenital atresia and stenosis of the colon. Arch Surg 87:428, 1963. 7. Zwiren GT, Andrews HG, Ahmann P: Jejunal atresia with agenesis of the dorsal mesentery (‘‘apple peel small bowel’’). J Pediatr Surg 7:414, 1972. 8. Zerella JT, Martin LW: Jejunal atresia with absent mesentery and a helical ileum. Surgery 80:550, 1976. 9. Farag TI, Teebi AS: Apple peel syndrome in sibs. J Med Genet 26:67, 1989. 10. Powell RW, Raffensperger JG: Congenital colonic atresia. J Pediatr Surg 17:166, 1982. 11. Benson CD, Lotfi MW, Brough AJ: Congenital atresia and stenosis of the colon. J Pediatr Surg 3:253, 1968. 12. Boles ET Jr, Vassy LE, Ralston M: Atresia of the colon. J Pediatr Surg 11:69, 1976. 13. Heckel NJ, Apfelbach CW: Congenital atresia of the colon. Am J Dis Child 34:1050, 1927. 14. Emanuel B, Gault J, Sanson J: Neonatal intestinal obstruction due to absence of intestinal musculature: a new entity. J Pediatr Surg 2:332, 1967. 15. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 16. Graham JM Jr, Marin-Padilla M, Hoefnagel D: Jejunal atresia associated with Cafergot ingestion during pregnancy. Clin Genet 22:226, 1983. 17. Hoyme HE, Jones KL, Dixon SD, et al.: Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 85:743, 1990.

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reported.1 Duplications have been called enteric cysts, great diverticuli, and intestinal duplex. Diagnosis

Fig. 25-8. Schematic showing location of atresias of the colon. (Percentages [numbers] shown are from data of Peck et al.,6 Heckel and Apfelbach,13 and Coran and Eraklis.30)

18. Hanley TB, Simon JW: Congenital HIPO syndrome. Ann Ophthalmol 16:342, 1984. 19. Guttman GM, Braun P, Garance PH, et al.: Multiple atresias and a new syndrome of hereditary multiple atresias involving the gastrointestinal tract from stomach to rectum. J Pediatr Surg 8:633, 1974. 20. Carey JC, Greenbaum B, Hall BD: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser XIV(6B):253, 1978. 21. Colombani PM, Cunningham D: Perinatal aspects of omphalocele and gastroschisis. Am J Dis Child 131:1386, 1977. 22. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 23. Tandler J: Zur Entwicklungsgeschichte des menschlichen Duodenum in fruhen Embryonalstadien. Morphol Jahrb 29:187, 1900. 24. Lynn HB, Espinas EE: Intestinal atresia. Arch Surg 79:357, 1959. 25. Louw JH, Barnard CN: Congenital intestinal atresia: observations on its origin. Lancet 2:1065, 1955. 26. Santulli TV, Blanc WA: Congenital atresia of the intestine: pathogenesis and treatment. Ann Surg 154:939, 1961. 27. Louw JH: Resection and end-to-end anastomosis in the management of atresia and stenosis of the small bowel. Surgery 62:940, 1967. 28. Grosfeld JL, Ballantine TVN, Shoemaker R: Operative management of intestinal atresia and stenosis based on pathologic findings. J Pediatr Surg 14:368, 1979. 29. Wilmore DW: Factors correlating with a successful outcome following extensive intestinal resection in newborn infants. J Pediatr 80:88, 1972. 30. Coran AG, Eraklis AJ: Atresia of the colon. Surgery 65:828, 1969. 31. Grosfeld JL: Jejunoileal atresia and stenosis. In: Pediatric Surgery, vol 2, ed 4. KJ Welch, MM Ravitch, CD Benson, et al., eds., Year Book, Chicago, 1986, p 838.

25.3 Duplications and Cysts Definition

Duplications and cysts are extra segments of the alimentary system attached to or adjacent to the intestinal tract. Cystic segments are usually short, measuring between 1 and 10 cm.1 Segments that communicate with the intestinal lumen are usually short, but duplications of the entire colon and part of the ileum have been

Intestinal duplications may be long segment or short segment, blind or communicating (Fig. 25-9).1–10 The walls of these structures have all the components of intestine, although the mucosa may not be the same as that of the adjacent intestine. They generally occur on the mesenteric side of the intestine. Blind duplications (cysts) enlarge because of the accumulation of mucosal secretions. They may obstruct the bowel by direct compression or by involvement in intussusception or volvulus. Clinical findings include abdominal pain, mass, and distension. Duplicated segments that communicate with the adjacent intestine may become distended if the duplicated pouch does not empty completely through this communication. The communication with the adjacent bowel may be at either end of the duplication or at both ends. Communicating duplications become symptomatic through abdominal pain, bleeding, or obstruction. Although intestinal duplications may be found incidentally in the course of radiographic studies, surgery, or necropsy, most become symptomatic in early life.1,2 One-fourth have symptoms in the 1st month of life, one-half by 6 months, and 90% by 2 years. One-third of cases of intestinal duplications will have other major anomalies. These are primarily gastrointestinal anomalies, including intestinal atresias, imperforate anus, gastroschisis, and omphalocele. Genitourinary and skeletal anomalies are also seen in a much lower frequency. Other cystic structures in the abdominal cavity may be confused with intestinal duplications. Vitelline duct remnants are generally less than a few centimeters in diameter and occur along the antimesenteric surface of the intestine near the umbilicus (Section 35.4). Mesenteric cysts are thin-walled and soft cysts within the mesentery that contain clear fluid or chyle. These cysts are separated from the bowel and involve the lymphatic system (Chapter 4). Presacral enteric cysts may persist from remnants of the tailgut (Section 17.8). Duplication of the Small Intestine

About one-half of all duplications of the gastrointestinal tract occur in the small intestine. The majority is found along the distal ileum (Figs. 25-10 and 25-11). Cysts outnumber communicating duplications by five to one. Duplications may cause obstruction by direct compression, by serving as a lead point for intussusception, and by involvement in a volvulus. The findings depend on the location, but induced vomiting, pain, and abdominal mass are common. When acid-secreting mucosa lines the duplication that communicates with normal intestine, hemorrhage and ulceration may occur. Duplication of the Colon

Duplications can occur at any location along the colon, and symptoms depend in part on the location (Fig. 25-12). Cysts behind the rectum push the rectum forward, causing constipation. Duplication that communicates with the urethra, bladder, or vagina discharges feces into these structures. Other duplications may communicate directly with the perineum via an accessory or bipartite anus. Colonic intussusception and hemorrhage have also been reported. Cysts outnumber communicating duplications by more than three to one. A distinct type of communicating duplication of the colon has been called a double barrel or double lumen colon. In these cases the colon is divided into two more or less equal conduits by a longitudinal septum. The septum may be limited to a

1104

Gastrointestinal and Related Structures

Fig. 25-10. Location of small bowel duplications. (Percentages [numbers] in duodenum, jejunum, and ileum are from Gross et al.,1 Mellish and Koop,2 and Grosfeld et al.3)

short segment of the rectum or may partition the entire colon and the distal part of the ileum. Etiology and Distribution

The incidence has not been well-documented. Gross et al.1 evaluated 45 patients over a 22-year period at Children’s Hospital in Boston, and Mellish and Koop2 evaluated 22 patients over a 10year period in Children’s Hospital of Philadelphia. Males and females are affected with near-equal frequency. A single mechanism that explains all intestinal duplications has not been found. Bremer7 proposed that incomplete recanalization of previously solid regions of the intestine could explain most types of duplications. It is now apparent that the intestine below the ligament of Treitz does not undergo a solid phase. Regional occlusion by epithelial proliferation may occur, and it is perhaps faulty recanalization in these areas that leads to short segment duplications. The development of diverticula of the intestinal tract has been described in human embryos and in animal embryos.8 It is possible that these diverticuli could elongate or become partitioned from the lumen, forming cysts. A major argument against this mechanism is the location of most diverticuli along the antimesenteric aspect of the intestine. The association with gastroschisis and intestinal atresias suggests the possibility that some duplications arise by a vascular mechanism. Some duplications, particularly those with duplication of the distal alimentary and urinary tracts, may represent incomplete twinning. Clearly, further investigation of the intestinal duplication must be made before the pathogenetic mechanism(s) can be stated with certainty. Prognosis, Prevention, and Treatment

Although a minority of intestinal duplications may remain asymptomatic throughout life, surgical treatment is recommended

Fig. 25-9. Schematic of types of intestinal duplication. A. Cystic duplication without communication with intestinal lumen. B,C. Tubular duplications that may lie adjacent to intestine or extend away from the intestine. D. Partitioning membrane in a portion of the colon. E. Partition of colon by a membrane extending the entire length of the colon.

Small and Large Intestines

1105

in all cases detected. Two major treatments are employed, complete removal and resection of intraluminal partitions.1–6 With resection, the duplication and the adjacent bowel are removed since they share mesentery and vasculature. When the bowel is partitioned by a longitudinal septum of the lumen, complete resection is not mandatory since both lumens may serve as unobstructed conduits for intestinal contents. Resection of part or all of the septum may be indicated if there is evidence of obstruction. Appropriate attention must be given to the evaluation and treatment of coexisting anomalies. With adequate attention to nutrition and fluid balance, surgical therapy is attended by a very low mortality rate. Prenatal diagnosis of enteric duplications is possible using ultrasound.9 References (Duplications and Cysts) 1. Gross RE, Holcomb GW Jr, Farber S: Duplications of the alimentary tract. Pediatrics 9:449, 1952. 2. Mellish RWP, Koop CE: Clinical manifestations of duplication of the bowel. Pediatrics 27:397, 1961. 3. Grosfeld JD, O’Neill AA, Clatworthy HW, Jr: Enteric duplications in infancy and childhood: an 18-year review. Ann Surg 172:83, 1970. 4. Wrenn E: Tubular duplication of the small intestine. Surgery 52:494, 1962. 5. Soper RT: Tubular duplication of the colon and distal ileum: case report and discussion. Surgery 63:998, 1968. 6. Ravitch MD, Scott WW: Duplication of the entire colon, bladder, and urethra. Surgery 34:843, 1953. 7. Bremer JL: Diverticula and duplication of intestinal tract. Arch Pathol 38:132, 1944. 8. Lewis FT, Thyng FW: Regular occurrence of intestinal diverticula in embryos of pig, rabbit and man. Am J Anat 7:505, 1908. 9. Weaver DD, Brandt IK: Catalog of Prenatally Diagnosed Conditions, ed 3. Johns Hopkins University Press, Baltimore, 1999. 10. Raffensperger JG: Swenson’s Pediatric Surgery, ed 5. Appleton & Lange, Norwalk, CT, 1990.

Fig. 25-11. Tubular duplication of the ileum. The duplicated segment contained gastric mucosa. (Reprinted with permission from Raffensperger.10)

25.4 Megacolon Definition

Fig. 25-12. Location of duplications of the colon. (Percentages [numbers] taken from Gross et al.1 and Mellish and Koop.2)

Megacolon is the enlargement of the diameter of part or all of the colon. Depending on the duration and cause, varying degrees of colonic dysfunction may accompany the enlargement. Diagnosis

Megacolon causes abdominal distension and obstipation. The abdomen may be grossly and progressively enlarged. Bowel movements become infrequent and large, and encopresis may occur. Excessive drying of fecal material results in concretions that may be falsely interpreted on palpation as an intraabdominal neoplasm. Two major diagnostic considerations arise when megacolon is identified. Aganglionic megacolon (Hirschsprung disease), characterized by absence of the parasympathetic ganglion cells of the bowel wall, may present at any time from birth to late childhood.1–11 Psychogenic megacolon develops from voluntary stool retention and occurs after the period of toilet training.11,12 Megacolon may also be associated with atresia or agenesis of the distal colon or anorectal area. This anatomic cause of megacolon can be readily identified with clinical and radiographic examinations during the neonatal period.

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Gastrointestinal and Related Structures

Table 25-3. Risk of recurrence of intestinal aganglionosis in sibs according to length of aganglionic segment in the proband Risk to Sibs (%) Index Patients

Brothers

Sisters

Type I

182 Males

4/73

(5.5)

1/172

(0.6)

35 Females

3/37

(8.1)

1/35

(2.85)

Type II

28 Males 15 Females

10/148 2/11

(6.75) (18.2)

3/27

(11.1)

1/11

(9.1)

Length of aganglionic segment: type I indicates absence of intestinal ganglion cells caudal to the splenic flexture; type II indicates absence of ganglion cells proximal to the splenic flexure.

Aganglionic Megacolon (Hirschsprung Disease)

The clinical presentation of aganglionic megacolon is by no means consistent. In one instance, the newborn fails to pass meconium and develops abdominal distension in the initial days of life. Bowel perforation may complicate the clinical picture. Meconium ileus and meconium plug are both diagnostic considerations with this presentation. In a second neonatal presentation, the infant may develop diarrhea secondary to enterocolitis, which may progress to ulceration, septicemia, and peritonitis. This cause occurs more commonly in large segment aganglionosis and carries a high mortality rate. The possibility of aganglionic megacolon may be easily overlooked in the course of evaluating and treating the lifethreatening complications. A third presentation with chronic constipation and abdominal protuberance as major features may be

Fig. 25-13. Hirschsprung disease. Top: Contrast enema in 3-day-old male showing constricted segment (arrowheads) in sigmoid colon. Bottom: Contrast enema in same infant at 5 months showing dilation of colon proximal to the constricted segment (arrowheads). (Courtesy of Dr. Michael Thomason, Greenville Memorial Medical Center, Greenville, SC.)

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Table 25-4. Conditions with megacolon Condition

Prominent Features

Causation Gene/Locus

Cartilage-hair hypoplasia

Short stature with metaphyseal dysplasia, sparse and fine hair, immunodeficiency, Hirschsprung disease is an uncommon feature

AR (250250) 9p21-p12

Down3,10

Short stature, brachycephaly, upward-slanting palpebral fissures, small mouth, heart defects, joint hypermobility, mental retardation

Trisomy 21

Hirschsprungbrachydactyly14

Broad distal phalanges, nail hypoplasia of thumbs and halluces

XLR (306980)

Hirschsprung-cleft palate15

Microcephaly, prominent nose with hypertelorism, synophrys, submucous cleft palate, sparse hair, mental retardation

Uncertain

Hirschsprung-coloboma16

Microcephaly, iris colobomas, hypertelorism, bulbous nose, mental retardation

AR

Hirschsprung-deafness17

Similar to Waardenburg without the white forelock

Unknown, probably heterogeneous

Hirschsprung-digit hypoplasia18

Upward-slanting palpebral fissures, micrognathia, hypoplastic distal digits and nails, growth and mental retardation

AR

Hirschsprung-Ondine curse19

Primary alveolar hypoventilation

Unknown

Hirschsprung-polydactyly20

Cardiac defect, postaxial polydactyly of hands, preaxial polydactyly of feet

Unknown (235750)

Lesch-Nyhan21

Mental retardation, self-mutilation, choreoathetosis, hyperuricemia; Hirschsprung disease is an uncommon feature

XLR (308000) HPRT, Xq26-q27.1

Megacolon, isolated aganglionic3,8,10

None

AD, AR (249200) Multifactorial

Multiple endocrine adenomatosis, type 322

Marfanoid habitus, thick lips, nodules of tongue and lips, endocrine carcinomas

AD (152300)

Pallister-Hall23

Prenatal growth deficiency, hypothalamic hamartoblastoma, laryngeal cleft, postaxial polydactyly, imperforate anus, heart defect, lethal (similar to severe Smith-Lemli-Opitz syndrome)

Sporadic (146510) GLI3, 7p13

Riley-Day24

Absent tearing, corneal ulceration, decreased pain sensation, smooth tongue with decreased taste, vomiting, fever, mental impairment

AR (223900) 1KBKAPl, 9q31

Smith-Lemli-Opitz25

Microcephaly, bitemporal narrowing, ptosis, nostril anteversion, hypotonia, incomplete genital development in males, mental retardation

AR (270400) DHCR7, 11q12-q13

Spondyloepimetaphyseal dysplasia-hypermobility26,27

Oval face, blue sclerae, lens dislocation, myopia, long philtrum, cleft palate, atrial and ventricular septal defects, spondyloepimetaphyseal changes, spatulate distal phalanges, join hypermobility

AR (271640)

Waardenburg28

Telecanthus, white forelock or piebaldism, deafness; Hirschsprung disease is an uncommon feature

AD (277580) PAX3, 2q35

13

Does not include the reports of Clayton-Smith and Donnai29 (Hirschsprung-digit-anomalies-ichthyosis), Freire-Maia and Pinheiro30 (Hirschsprung-ichthyosis-mental retardation), Passwell et al.31 (Hirschsprung-ichthyosis-mental retardation), Kaplan32 (Hirschsprung-absence of corpus callosum), Mutchinick33 (Hirschsprung-microcephaly), Santos et al.34 (Hirschsprung-polydactyly), Toriello et al.35 (Hirschsprung-macrocephaly), Hassinger et al.36 (Hirschsprung-Aarskog syndrome), Tarkatow37 (Hirschsprung-prenatal rubella), and Mahakrishnan and Srinivasan38 (Hirschsprung-piebaldism).

seen in the older infant or child. It is this presentation that can be confused with psychogenic megacolon. In most cases of aganglionic megacolon, the rectum is involved.3,9,10 The extent of involvement proximal to the rectum varies. In 80% of cases, the aganglionic segment extends to the midsigmoid. Only in 10–20% of cases is the transverse or right colon involved (Table 25-3). The entire colon is involved in 3% of cases, and extension to the small intestines is quite rare.

The colon is dilated above the aganglionic segment (Fig. 2513). The small-caliber aganglionic segment is maintained by tonic contraction of the noninnervated vasculature. Digital rectal examination is helpful in the diagnosis. Since the rectum is usually involved in aganglionic megacolon, the anal sphincter is not thickened and the rectum has small caliber without fecal contents. This contrasts with psychogenic megacolon in which the anal sphincter is hypertrophied and the rectum dilated with feces.

1108

Gastrointestinal and Related Structures

Psychogenic Megacolon

In psychogenic megacolon, the colon has normal innervation but has become dilated due to voluntary stool retention.12 Psychogenic megacolon is by far the most common type. In this condition, the child develops the habit of retaining stool, often the result of constipation and painful bowel movements. Thereafter a vicious cycle ensues. Stool retention further dilates the bowel, the dilated bowel becomes ineffective in signaling the need for evacuation, and the accumulation of a large amount of hard stool makes passage difficult. Leakage of feces around the fecal mass in the rectum usually leads to soiling of the clothes. In the school-aged child, this is often the predominant parental concern. The condition is mentioned here because of its frequency and must always be considered in the diagnosis of megacolon. In psychogenic megacolon, the bowel dilation always extends to include the rectum, and the anal sphincter is usually elongated and quite strong, reflecting the exercise of stool retention. The diagnostic process is initiated upon identification of bowel dilation due to fecal retention. The type of megacolon may be suspected on the basis of rectal examination. In Hirschsprung disease, the barium enema will typically show a transition zone at the junction of the dilated megacolon and the normal or smallcaliber aganglionic segment (Fig. 25-13).10 The typical appearance may not be seen in the 1st month or 2 of life, in older children who use repeated enemas for colon decompression, and in those with aganglionosis of the entire colon. Rectal biopsy may be necessary in these cases. Aganglionosis of the colon may occur as an isolated finding or in association with many other anomalies (Table 25-4).3,8,10,13–36 There is a particular association with entities that exhibit faulty migration of neural crest cells and with Down syndrome.3,10,13,26,36 Three percent of infants with Down syndrome have colon aganglionosis.3,10 The recurrence risk in isolated aganglionic megacolon depends on the length of the aganglionic segment (Table 25-3).3 When involvement is limited to the descending colon, sigmoid colon, and rectum (type I), the risk of recurrence is relatively low compared with the risk when the entire colon is involved (type II). The risk is similarly high when the small intestine is affected. For the type II involvement, Badner et al.39 have found evidence for autosomal dominant inheritance. Etiology and Distribution

The causes of megacolon are many. The immediate cause is always obstruction with retention of feces. The underlying cause may be abnormal innervation of musculature of the wall of the colon.6,40–42 In childhood, other causes are more common. In particular, psychogenic megacolon, the conscious and subconscious retention of feces because of fear of painful stool passage, must be considered. Aganglionic megacolon is considered to be a disorder of faulty neural crest migration. Neuroblasts destined to form the ganglia of the intestinal wall derive from cephalic neural crest. The neuroblasts migrate caudally along the vagus nerve pathways and reach the rectum by week 12 of development. Pelvic parasympathetic nerves also contribute to the formation of the ganglia of the intestine. The myenteric plexuses (Auerbach plexuses) form first and are located outside the circular muscle layer. Submucosal plexuses (Meissner plexuses) form subsequently. Both myenteric and submucosal plexuses are absent in Hirschsprung disease. Since neuroblasts that form these plexuses migrate in a cephalic-caudal direction, denervated intestine extends from the level of interruption of neuroblast migration to the rectum. Thus, segments of normally innervated

bowel interspersed between aganglionic segments are not to be anticipated. The tendency of denervated bowel to tonic contraction explains the small caliber of the aganglionic segment. Mutations in several genes that have roles in the development, migration, and survival of neuronal cells have been found in patients with Hirschsprung disease.43–45 The receptor tyrosine kinase, RET, seems most important, being responsible for half of familial cases and 15–20% of sporadic cases. Mutations in GDNF, EDNRB, EDN3, and NRTN have been found in a minority of sporadic cases. Syndromic forms of Hirschsprung disease have been associated with mutations in SIP1, EDNRB, EDN3, and SOX10.45 Not all cases of megacolon due to neuronal dysfunction have aganglionosis. Ganglionic megacolon, presumably due to an imbalance in sympathetic and parasympathetic innervation, has been seen in neurofibromatosis, intestinal neuronal dysplasia, and multiple mucosal neuroma syndrome. Major progress has been made recently in the understanding of the complex genetics of Hirschsprung disease. Sequence variations in the RET gene contribute decisively to the etiology of nonsyndromic Hirschsprung disease.46,47 One such variant affects an enhancer in intron 1. In addition, several other susceptibility regions have been identified in the human genome. Hershlag et al.48 have reported evidence that prenatal cytomegalovirus infection may produce intestinal aganglionosis. Aganglionic megacolon affects one per 5000 infants.3 Males are affected more commonly, with a 3–5:1 sex ratio. Psychogenic megacolon occurs in as many as 1–2% of preschool-aged children. Males are also more commonly affected with this acquired disorder. Prognosis and Treatment

Megacolon of neurogenic cause continues progressively, and improvement is not to be anticipated until surgical intervention.9,10 Removal of the affected segment of bowel and end-to-end anastomosis is possible in short segment aganglionosis. A colostomy is necessary in some. Psychogenic megacolon may self-correct during the course of childhood or may require a combination of laxatives, bowel retraining, and psychological support. Prenatal diagnosis of megacolon is not possible, since the colon is not normally used during the fetal period. References (Megacolon) 1. Bodian M, Carter CO: Family study of Hirschsprung’s disease. Ann Hum Genet 29:261, 1963. 2. Madsen CM: Hirschsprung’s Disease. Munksgaard, Copenhagen, 1964. 3. Passarge E: The genetics of Hirschsprung’s disease. N Engl J Med 276: 138, 1967. 4. Passarge E: Gastrointestinal tract: molecular genetics of Hirschsprung disease. Nature EHG 2:578, 2003. 5. Talbert JL, Felman AH, DeBusk FL: Gastrointestinal emergencies in the newborn infant. J Pediatr 76:783, 1970. 6. Saul RA: The nosology of megacolon. Proc Greenwood Genet Center 4:22, 1985. 7. McConnell RB: The Genetics of Gastro-Intestinal Disorders. Oxford University Press, New York, 1966. 8. Emanuel B, Padorr MP, Swenson O: Familial absence of myenteric plexus (congenital megacolon). J Pediatr 67:381, 1965. 9. Swenson O, Sherman JO, Fisher JH, et al.: The treatment and postoperative complications of congenital megacolon: a 25-year follow up. Am Surg 182:266, 1975. 10. Swenson O: Hirschsprung’s disease. In: Swenson’s Pediatric Surgery, ed 4. JG Raffensperger, ed. Appleton-Century-Crofts, New York, 1980, p 507. 11. Tobon F, Schuster M: Megacolon: special diagnostic and therapeutic features. Johns Hopkins Med J 135:91, 1974. 12. Mercer RD: Constipation. Pediatr Clin North Am 14(1):175, 1967.

Small and Large Intestines 13. Wilson WG, Aylsworth AS, Folds JD, et al.: Cartilage-hair hypoplasia (metaphyseal chondroplasia, type McKusick) with combined immune deficiency: variable expression and development of immunologic functions in sibs. Birth Defects Orig Artic Ser XIV(6A):117, 1978. 14. Reynolds JF, Barber JC, Alford BA, et al.: Familial Hirschsprung’s disease and type D brachydactyly: a report of four affected males in two generations. Pediatrics 71:246, 1983. 15. Goldberg RB, Shprintzen RJ: Hirschsprung megacolon and cleft palate in two sibs. J Craniofac Genet Dev Bio 1:185, 1981. 16. Hurst JA, Markiewicz M, et al.: Hirschsprung’s disease, microcephaly and iris coloboma: a new syndrome of defective neuronal migration. J Med Genet 25:494, 1988. 17. Weinberg AG, Currarino G, Besserman AM: Hirschsprung’s disease and congenital deafness. Hum Genet 38:157, 1977. 18. Al-Gazali LI, Donnai D, Mueller RF: Hirschsprung’s disease, hypoplastic nails and minor dysmorphic features: a distinct autosomal recessive syndrome? J Med Genet 25:758, 1988. 19. Hamilton J, Bodurtha JN: Congenital central hypoventilation syndrome and Hirschsprung’s disease in half sibs. J Med Genet 26:272, 1989. 20. Laurence KM, Prosser R, Rocker I: Hirschsprung’s disease associated with congenital heart malformation, broad big toes, and ulnar polydactyly in sibs: a case for fetoscopy. J Med Genet 12:334, 1975. 21. Mizuno T: Long-term follow-up of ten patients with Lesch-Nyhan syndrome. Neuropediatrics 17:158, 1986. 22. Carney JA, Hayles AB: Alimentary tract manifestations of multiple endocrine neoplasia. Mayo Clin Proc 52:543, 1977. 23. Hall JG, Pallister PD, Clarren SK, et al.: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly—a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47, 1980. 24. Azizi E, Berlowitz I, Vinograd O, et al.: Congenital megacolon associated with familial dysautonomia. Eur J Pediatr 142:68, 1984. 25. Curry CJR, Carey JC, Holland JS, et al.: Smith-Lemli-Opitz syndrome type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26:45, 1987. 26. Beighton P, Gericke G, Koslowski K, et al.: The manifestation and natural history of spondylo-epi-metaphyseal dysplasia with joint laxity. Clin Genet 26:308, 1984. 27. Currie ABM, Haddad M, Honeyman M, et al.: Associated developmental abnormalities of the anterior end of the neural crest: Hirschsprung’s disease-Waardenburg’s syndrome. J Pediatr Surg 21:248, 1986. 28. Omenn GS, McKusick VA: The association of Waardenburg syndrome and Hirschsprung megacolon. Am J Med Genet 3:217, 1979. 29. Clayton-Smith J, Donnai D: A new recessive syndrome of unusual facies, digital abnormalities, and ichthyosis. J Med Genet 26:339, 1989. 30. Freire-Maia N, Pinheiro M: Ectodermal Dysplasias: A Clinical and Genetic Study. Alan R Liss, New York, 1984, p 126. 31. Passwell J, Zipperkowski L, Katznelson D, et al.: A syndrome characterized by congenital ichthyosis with atrophy, mental retardation, dwarfism and generalized aminoaciduria. J Pediatr 82:466, 1973. 32. Kaplan P: X-linked recessive inheritance of agenesis of the corpus callosum. J Med Genet 20:122, 1983. 33. Mutchinick O: A syndrome of mental and physical retardation, speech disorders, and peculiar facies in two sisters. J Med Genet 9:60, 1972. 34. Santos H, Mateus J, Leal MJ: Hirschsprung disease associated with polydactyly, unilateral renal agenesis, hypertelorism and congenital deafness: a new autosomal recessive syndrome. J Med Genet 25:204, 1988. 35. Toriello HV, Komar K, Lawrence C, et al.: Syndrome identification case report 137. Macrocephaly, Hirschsprung disease, brachydactyly, vertebral defects and other minor anomalies. Dysmorphol Clin Genet 1:155, 1988. 36. Hassinger DD, Mulvihill JJ, Chandler JB: Aarskog’s syndrome with Hirschsprung’s disease, midgut rotation and dental abnormalities. J Med Genet 17:235, 1980. 37. Tarkatow IJ: The teratogenicity of maternal rubella. J Pediatr 66:380, 1965.

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38. Mahakrishnan A, Srinivasan MS: Piebaldness with Hirschsprung’s disease. Arch Dermatol 116:1102, 1980. 39. Badner JA, Sieber WK, Garver KL, et al.: A genetic study of Hirschsprung disease. Am J Hum Genet 46:568, 1990. 40. Andrew A: The origin of intramural ganglia. J Anat 108:169, 1971. 41. Huther W: Die Hirschsprung’sche Krankheit als Folge einer Entwicklungsstorung der intramuralen Ganglien. Beitr Pathol Anat Pathol 114: 161, 1954. 42. Okamoto E, Ueda T: Embryogenesis of intramural ganglion of the gut and its relation to Hirschsprung’s disease. J Pediatr Surg 2:437, 1967. 43. Robertson K, Mason I, Hall S: Hirschsprung’s disease: genetic mutations in mice and men. Gut 41:436, 1997. 44. Gath R, Goessling A, Keller KM, et al.: Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease. Gut 48:671, 2001. 45. Cacheux V, Dastot-Le Moal F, Ka¨a¨ria¨inen H, et al.: Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease. Hum Mol Genet 10:1503, 2001. 46. Emison ES, McCallion AS, Kashuk CS et al.: A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434:857, 2005. 47. Chakravarti A, Lyonnet S: Hirschsprung disease. In: The Metabolic and Molecular Bases of Inherited Disease. CR Scriver, AR Beaudet, WS Sly, et al., eds. McGraw-Hill, New York, 2001, p 6231. 48. Hershlag A, Ariel I, Lernau OZ, et al.: Cytomegalic inclusion virus and Hirschsprung’s disease. Z Kinderchir 39:253, 1984.

25.5 Malrotation Definition

Malrotation is deviation from the normal 2708 counterclockwise rotation of the intestine around its midpoint. Failure of complete rotation results in malposition of the upper intestine (jejunum and proximal ileum) relative to the lower intestine (distal ileum, cecum, and colon) and predisposes to intestinal obstruction. Diagnosis

Most infants with malrotation become symptomatic because of obstruction of the intestinal lumen.1–5 Affected infants may have vomiting, decreased stool passage, and abdominal pain. Bloody stools may be passed. The abdomen may not be distended if the level of the obstruction is high. About one-half of affected infants become symptomatic during the 1st week of life and twothirds by the end of the 1st month. As many as 15% of individuals with malrotation remain asymptomatic.6,7 In these individuals, appendicitis and other intraabdominal illnesses may present with atypical findings. The degree of malrotation can be quite variable. In the usual case, the intestine fails to rotate beyond 1808, leaving the proximal bowel to the right of the superior mesenteric artery and the lower intestine including the cecum to the left of the superior mesenteric artery. Each case, however, is different, and the risk of obstructive complications depends on the position of the bowel and mesentery. Radiographs are generally necessary to document malrotation. Barium enema will locate the cecum to the left of the midline and the small intestine to the right. Upper gastrointestinal contrast studies are helpful in identifying the location of high obstructions associated with malrotation. Three types of obstruction commonly occur with malrotation: volvulus, internal herniation, and duodenal obstruction. There exists a propensity for distal duodenal obstruction secondary to mesenteric bands and for adhesions that cross the duodenum

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Gastrointestinal and Related Structures

between the colon and liver. With the incompletely rotated intestine, the major portion of intestine is suspended on a narrow pedicle containing the superior mesenteric artery. This predisposes to volvulus, which may rapidly compromise the blood supply to all of the small intestine and most of the large intestine, resulting in necrosis. Volvulus presents with sudden onset of bilious vomiting and abdominal pain. There may be a palpable mass and abdominal distension. Bloody stool passage, rigid abdomen, and shock can ensue if diagnosis and surgical intervention are not carried out promptly. A pattern of recurrent abdominal pain and vomiting has been caused by intermittent and partial twisting of the malrotated bowel.2,4,5 Growth and development may proceed normally, and in later childhood the malrotation may become asymptomatic or lead to acute intestinal obstruction. Failure of normal intestinal rotation may be expected in infants with diaphragmatic hernia, omphalocele, and gastroschisis. Most cases of malrotation occur in infants without defects of the abdominal wall or diaphragm. They often have other associated anomalies, however. Stewart et al.2 found 19% of infants with malrotation to have anomalies other than abdominal wall and diaphragmatic defects. Most of the anomalies were of the gastrointestinal system. Certain recognizable patterns of malformations have malrotation as an inconsistent feature (Table 25-5). Familial intestinal malrotation is uncommon. Townes et al.14 have reported multiple siblings with malrotation. Both parents were normal. Malrotation in parent and child has also been reported.15 Etiology and Distribution

Malrotation of the intestine is a common anomaly, having been demonstrated as an asymptomatic finding in one in 500 radiographic studies of the gastrointestinal system.16 It is assumed that the majority of cases of malrotation will become symptomatic at some time, but an exact percentage cannot be given.6,7 Several studies have shown a male excess of 2:1.1,3 In most cases, no specific reason for the failure of complete intestinal rotation can be found. In cases with diaphragmatic or

abdominal wall defects, herniation of the intestine through these defects prevents normal rotation. A few cases with apparently Mendelian inheritance have been reported.14,15 Prognosis, Prevention, and Treatment

In a minority of cases, malrotation never becomes symptomatic and is found incidentally on radiographs or at autopsy. Most cases become symptomatic during the initial weeks of life because of intestinal obstruction. Surgery is necessary to relieve persistent obstruction (volvulus, internal hernia, peritoneal bands). Recurrence following surgery is unusual.2,3 In isolated cases of obstruction secondary to malrotation, prompt diagnosis and surgery is rewarded by a mortality rate of less than 5%.3 Mortality is higher in those who become symptomatic in the initial days of life and in those with associated anomalies. Prenatal diagnosis is possible only in cases with associated anomalies and in cases with prenatal intestinal obstruction. References (Malrotation) 1. Snyder WH Jr, Chaffin L: Embryology and pathology of the intestinal tract: presentation of 40 cases of malrotation. Ann Surg 140:368, 1954. 2. Stewart DR, Colodny AL, Daggett WC: Malrotation of the bowel in infants and children: a 15 year review. Surgery 79:716, 1976. 3. Andrassy RJ, Mahour GH: Malrotation of the midgut in infants and children. A 25-year review. Arch Surg 116:158, 1981. 4. Ford EG, Senac MO Jr, Srikanth MS, et al.: Malrotation of the intestine in children. Ann Surg 215:172, 1992. 5. Smith EI: Malrotation of the intestine. In: Pediatric Surgery, vol 2, ed 4. KJ Welch, MM Ravitch, CD Benson, et al., eds., Year Book, Chicago, 1986, p 882. 6. Houston CS, Wittenborg MH: Roentgen evaluation of anomalies of rotation and fixation of the bowel in children. Radiology 84:1, 1965. 7. Kieswetter WB, Smith JW: Malrotation of the midgut in infancy and childhood. Arch Surg 77:483, 1958. 8. Seashore JH: Familial apple peel jejunal atresia. Pediatrics 80:540, 1987. 9. DeLorimier AA, Fonkalsrud EW, Hays DM: Congenital atresia and stenosis of the jejunum and ileum. Surgery 65:819, 1969.

Table 25-5. Conditions associated with malrotation Condition

Prominent Features

Causation

Apple peel jejunal atresia

High jejunal atresia, short small intestine, mesentery deficiency, coiling of distal small bowel about a vascular stalk

AR (243600)

Diaphragmatic hernia

Defect of diaphragm allowing abdominal organs to herniate into the chest

Heterogeneous

Gastroschisis

Herniation of intestine through an abdominal wall defect

Sporadic, probably vascular in origin

Intestinal atresias9

Obstruction of the intestinal lumen by a web or atretic segment

Prenatal vascular accident

Natal teeth-intestinal pseudoobstruction10

Delayed gastric emptying, dilation of duodenum, microcolon, patent ductus arteriosus

Unknown

OEIS11

Omphalocele, exstrophy of the cloaca, imperforate anus, spine defect

Sporadic, probably secondary to vitelline vascular steal

Simpson-GolabiBehmel12

Hypertelorism, large mouth, overgrowth of tongue and lower lip, cleft palate, grooved cystic kidneys, Meckel diverticulum, variable mental function, hypoplastic distal digits

XLR (312870) GPC3, Xq26

Sirenomelia13

Renal agenesis, lower colon agenesis, absent genital structures, unseparated lower limbs

Sporadic, secondary to vitelline vascular steal

8

Small and Large Intestines 10. Harris DJ, Ashcraft KW, Beatty EC: Natal teeth, patent ductus arteriosus and intestinal pseudo-obstruction: a lethal syndrome in the newborn. Clin Genet 9:479, 1976. 11. Carey JC, Greenbaum B, Hall BD: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser XIV(6B):253, 1978. 12. Golabi M, Rosen L: A new X-linked mental retardation-overgrowth syndrome. Am J Med Genet 17:345, 1984. 13. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 14. Townes PL, Wunderlich RC Jr, Gerbasi MJ: Familial occurrence of malrotation of the intestine. J Pediatr 60:555, 1962. 15. Hadley HG: Non-rotation of the colon. Br J Radiol 13:35, 1940. 16. Kantor JL: Anomalies of the colon: their roentgen diagnosis and clinical significance. Resume of ten years’ study. Radiology 23:651, 1934.

25.6 Meckel Diverticulum Meckel diverticulum is a dilated proximal segment of the omphalomesenteric (vitelline) duct that is contiguous with the distal ileum. The diverticulum may appear as a pouch on the antimesenteric margin of the ileum. A patent omphalomesenteric duct or an atretic cord may remain attached to the apex of the diverticulum (see Section 35.4). Alternatively, the omphalomesenteric duct may be completely separated, leaving no continuity between the diverticulum and the umbilicus. The Meckel diverticulum is a common anomaly, occurring in 2–3% of the population. It usually remains asymptomatic and is discovered only at unrelated abdominal surgery or necropsy. Less than 5% ever become symptomatic, and about one-half of these do so during the first 2 years of life (Fig. 25-14).

1111

This remnant of the vitelline duct is attached to the ileum about 50 cm from the ileocecal valve. Three-fourths of cases end blindly. The remaining cases are attached to the umbilicus or other intraabdominal structure by a cord or duct.2 Gastric mucosa can be found in 30–50% of cases, and when present the likelihood increases that the diverticulum will become symptomatic. Clinical presentation of the Meckel diverticulum is quite variable, and often the diagnosis is made only at surgery.1–5 About one-third of symptomatic cases come to attention because of painless bleeding. This presentation is frequent in the preschoolaged child. The site of bleeding may be in the adjacent ileum or in the diverticulum and results from ulceration by secretion from gastric mucosa in the diverticulum. Obstruction of the diverticulum or the ileum occurs in one-third of symptomatic cases. Ileal intussusception with the diverticulum as the lead point is the major obstructive phenomenon. Volvulus, umbilical herniation, and obstruction by remnants of the vitelline duct or vitelline vessels also occur. Inflammation of the diverticulum accounts for about 20% of symptomatic cases. The presentation is similar to that of appendicitis. One-third of cases of Meckel diverticulitis will perforate before diagnosis is made. Persistence of a fistula to the umbilicus leads to the diagnosis in 10% of symptomatic cases. Resection of the Meckel diverticulum is indicated in all symptomatic cases and in those cases found incidentally but predisposed to obstruction because of attachment to vitelline duct or vitelline vessel remnants. Removal of the asymptomatic Meckel diverticulum is controversial, since most cases remain asymptomatic throughout life. Because of the incidence of Meckel diverticulum, familial cases should not be considered unusual.6,7 No heritable basis has been established. References (Meckel Diverticulum)

Fig. 25-14. Meckel diverticulum (M) in 22-month-old male. The child was treated for recurrent episodes of intestinal obstruction and ultimately required intestinal resection and colostomy (C). (Courtesy Dr. Will Blackburn, Fairhope, AL.)

1. Soltero MJ, Bill AH: The natural history of Meckel’s diverticulum and its relation to incidental removal. Am J Surg 132:168, 1976. 2. Soderlund S: Meckel’s diverticulum, a clinical and histologic study. Acta Chir Scand Suppl 248:13, 1959. 3. Moses WR: Meckel’s diverticulum, N Engl J Med 237:118, 1947. 4. Amoury RA: Meckel’s diverticulum. In: Pediatric Surgery, vol 2, ed 4. KJ Welch, MM Ravitch, CD Benson, et al., eds., Year Book Medical Publishers, Chicago, 1986, p 859. 5. McParland FA, Kisewetter WB: Meckel’s diverticulum in childhood. Surg Gynecol Obstet 106:11, 1958. 6. Lewenstein HJ, Levenson SS: Familial occurrence of Meckel’s diverticulum. N Engl J Med 268:311, 1963. 7. Michel ML, Field RJ, Ogden WW Jr: Meckel’s diverticulum. An analysis of one hundred cases and the report of a giant diverticulum and of four cases occurring in the same immediate family. Ann Surg 141:819, 1955.

25.7 Polyps Definition

Polyps are inflammatory, hamartomatous, or adenomatous growths on the mucosa of the intestine. Diagnosis

Intestinal polyps become symptomatic by bleeding, obstructing the intestinal lumen, inducing diarrhea, or undergoing malignant change. They may be suspected by other features, particularly a

1112

Gastrointestinal and Related Structures

history of intestinal polyps in first-degree relatives or the presence of mucocutaneous pigmentation, cutaneous tumors, or osteomas. Polyps are not present at birth and only juvenile polyps are common during childhood. Juvenile Polyps

Children not uncommonly have isolated inflammatory polyps in the rectum or sigmoid colon.1,2 They are not known to be present at birth but develop during the 1st or 2nd decades. The peak incidence is in the immediate preschool years. They rarely occur above the sigmoid colon and are not predisposed to malignant change. Occasionally more than one polyp will be present. The primary symptom is bleeding, which if chronic may lead to anemia. Polyps of this nature may autoamputate with subsequent healing of the mucosa. Alternatively they may be removed surgically. Juvenile polyps are considered to result from inflammation or from traction on the mucosa rather than from a neoplastic process. Multiple juvenile polyps may occur in the colon but are much rarer than single polyps. Juvenile polyposis is distinguished by the presence of more than 10 polyps, location throughout the intestinal tract, and a family history positive for polyps.3–6 Autosomal dominant inheritance is noted in some families. Although hamartomatous, the polyps carry a predisposition to cancerous change, especially when in the colon and stomach. Mutations in SMAD4 have been found in most families with juvenile polyposis. Multiple hamartomatous polyps also occur as a component of several recognized syndromes, most notably Bannayan and Cowden syndromes. Mutations in PTEN, a tumor suppressor gene, have been identified in both Bannayan and Cowden syndromes.6 Solitary Polyps

Five percent or more of the population have been found to have single or multiple polyps of the rectum and distal colon by age 35 years.7 These polyps have a predisposition to malignancy and may be found as sentinel lesions in families with hereditary predisposition to colon cancer.8 Multiple Polyps of the Colon

Familial adenomatous polyposis of the colon is an autosomal dominant condition in which innumerable polyps carpet the colon (Fig. 25-15).9–11 It is unusual for these polyps to be found in infants and young children. They generally become symptomatic during early adult life with abdominal pain, bleeding, or diarrhea. Polyps may occur elsewhere in the intestinal tract and they are predisposed to malignant change. The APC gene has been localized to the long arm of chromosome 5 and is known to be the same as the gene for Gardner syndrome (vide infra).12,13 The prevalence is about one in 10,000 individuals. Peutz-Jeghers Syndrome

Mucocutaneous pigmentation and intestinal polyps are the major features of this autosomal dominant condition (Fig. 25-16).14,15 The polyps usually occur in the small intestine but may be found elsewhere in the intestinal tract and also in the bladder and nose. Symptoms occur during the 1st decade in one-third of patients and in most by early childhood. These include recurrent abdominal pain, bleeding, and intussusception. The polyps in PeutzJeghers syndrome are hamartomatous. There appears to be a low but distinct risk of malignant change in the polyps, particularly

Fig. 25-15. Radiograph using air contrast barium enema showing multiple polyposis of the colon in a 6-year-old child. (Courtesy of Dr. Charles I. Scott, Jr, A.I. duPont Wilmington, DE.)

Fig. 25-16. Peutz-Jeghers syndrome. Intestinal polyps are associated with cutaneous and mucous membrane pigmentation. (Bottom illustration reprinted with permission from Raffensperger.25)

Small and Large Intestines

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those that occur in the colon and rectum. Dormandy15 has suggested that polyps in the small intestine do not become malignant even though the histology may appear invasive. The gene locus for Peutz-Jeghers syndrome is on chromosome 19q. Gardner Syndrome

The polyps in Gardner syndrome occur in the colon and have a high tendency to malignant change (Fig. 25-17). Soft tissue and bone tumors of benign types precede the development of polyposis. The soft tissue tumors are primarily dermoids, fibromas, and other connective tissue tumors.16 Osteomas usually involve the mandible but may occur elsewhere. The potential for colon cancer is sufficient to warrant prophylactic colon removal in early adult life. The gene has been localized to the long arm of chromosome 5 and is considered to be the same as the gene causing familial adenomatous polyposis of the colon.12,13,17,18 Other Conditions

Table 25-6 lists other entities in which intestinal polyps occur. References (Polyps) 1. Euler AR, Seibert JJ: The role of sigmoidoscopy, radiographs and colonoscopy in the diagnostic evaluation of pediatric age patients with suspected juvenile polyps. J Pediatr Surg 16:500, 1981. 2. Jarvinen H, Franssila KO: Familial juvenile polyposis coli: increased risk of colorectal cancer. Gut 25:792, 1984. 3. Agnifili A, Verzaro R, Gola P, et al.: Juvenile polyposis: case report and assessment of the neoplastic risk in 271 patients reported in the literature. Dig Surg 16:161, 1999.

Fig. 25-17. Extensive polyposis of the colon from a patient with Gardner syndrome.

Table 25-6. Conditions with intestinal polyps Condition

Prominent Features

Causation Gene/Locus

Bannayan-RuvalcabaMyhre23

Hamartomatous-C, macrocephaly, lipomas and angiolipomas, pigmented macules of glans penis (may be same as Bannayan syndrome)

AD (180890) PTEN, 10q23.1

Cowden19

Hamartomatous-C,* multiple hamartomas of the mucosa, face, hands, and feet, keratosis of the palms and soles, fibrocystic breast disease, thyroid disease

AD (158350) PTEN, 10q23.31

Cronkhite-Canada20

Juveile-S, J-I, C, hyperpigmentation of exposed areas, hair loss, nail splitting

Sporadic (175500)

Gardner12,16

Adenomatuous-C, S, J-I, soft tissue tumors, osteomas, malignancy elsewhere

AD (165300) APC, 5q21-q22 (174900)

Juvenile polyps1-6

Juvenile-R, S, none

SMAD4, 18q21.1 Heterogeneous

Juvenile polyps-pulmonary arteriovenous malformation21

Juvenile-C, I, have been found in several families

AD (175050)

Multiple polyps of colon10–13

Adenomatous-C, adult onset polyposis (same gene as Gardner syndrome)

AD (175100) APC, 5q21-q22

Peutz-Jeghers14,15

Hamartomatous-J, mucocutaneous pigmented macules, tumors of other systems

AD (175200) 19q13.3

Polyposis-exostoses22

Adenomatous-C, none

AD (175450)

Solitary polyps7,8

Adenomatous-S, R, none

Sporadic or AD (175400)

Adenomatous-C, cerebral tumors

AR (176300)

24

Turcot

*The type of polyp and its principal location are listed before the other major features. S ¼ stomach, J ¼ jejunum, I ¼ ileum, C ¼ colon, S ¼ sigmoid, R ¼ rectum.

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Gastrointestinal and Related Structures

4. Lynch ED, Ostermeyer EA, Lee MK, et al.: Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis. Am J Hum Genet 61:2254, 1997. 5. Bevan S, Woodford-Richens K, Rozen P, et al.: Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome. Gut 45:406, 1999. 6. Huang SC, Chen CR, Lavine JE, et al.: Genetic heterogeneity in familial juvenile polyposis. Cancer Res 60:6882, 2000. 7. Reed TE, Neel JV: A genetic study of multiple polyposis of the colon (with an appendix deriving a method of estimating relative fitness). Am J Hum Genet 7:236, 1955. 8. Swinton NW: Polyps of rectum and colon. JAMA 154:658, 1954. 9. Woolf CM, Richards RC, Gardner EJ: Occasional discrete polyps of the colon and rectum showing an inherited tendency in a kindred. Cancer 8:403, 1955. 10. McKusick VA: Genetic factors in intestinal polyposis. JAMA 182:271, 1962. 11. Harved RK, Williams SM: Familial polyposis coli and periampullary malignancy. Dis Colon Rectum 25:227, 1982. 12. Groden J, Thliveris A, Samowitz W, et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589, 1991. 13. Kinzler KW, Nilbert MC, Su LK, et al.: Identification of FAP locus genes from chromosome 5q21. Science 253:661, 1991. 14. Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips, and digits: a syndrome of diagnostic significance. N Engl J Med 241:993, 1949. 15. Dormandy TL: Gastrointestinal polyposis with mucocutaneous pigmentation: Peutz-Jeghers syndrome. N Engl J Med 256:1093, 1956. 16. Gardner EJ, Richards RC: Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 5:139, 1953. 17. Cachon-Gonzales MB, Delhanty JDA, Burn J, et al.: Linkage analysis in adenomatous polyposis coli: the use of four closely linked DNA probes in 20 UK families. J Med Genet 28:681, 1991. 18. Bodmer WF, Bailey CJ, Bodmer J, et al.: Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 328:614, 1987. 19. Carlson GJ, Nivatvongs S, Snover DC: Colorectal polyps in Cowden’s disease (multiple hamartoma syndrome). Am J Surg Pathol 8:763, 1984. 20. Cronkhite L Jr, Canada WJ: Generalized gastrointestinal polyposis: an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med 252:1011, 1955. 21. Cox KL, Frates R Jr, Wong A, et al.: Hereditary generalized juvenile polyposis associated with pulmonary arteriovenous malformation. Gastroenterology 70:1566, 1990. 22. Fuchs GA: Multiple kartilaginaere Exostosen bei Kolon- und Magenpolypose: Mitteilungen einer neuen, vom Gardner-syndrome abweichenden erblichen Kombinationserkrankung. Dtsch Med Wochenschr 100:2316, 1975.

23. Foster MA, Kilcoyne RF: Ruvalcaba-Myhre-Smith syndrome: a new consideration in the differential diagnosis of intestinal polyposis. Gastrointest Radiol 11:349, 1986. 24. Jarvis L, Bathurst M, Mohan D, et al.: Turcot’s syndrome. A review. Dis Colon Rectum 31:907, 1988. 25. Raffensperger JG: Swenson’s Pediatric Surgery, ed 5. Appleton & Lange, Norwalk, CT, 1990.

25.8 Vascular Anomalies Proliferation or dilation of blood vessels may occur in the wall of the intestine or mesentery. Telangiectasias are localized areas of dilated blood vessels without new blood vessel formation. Hemangiomas are discrete areas of new blood vessel formation. Vascular anomalies of the intestine become symptomatic by hemorrhage or, less commonly, by obstruction.1 Abdominal pain occurs only in the presence of obstruction. Chronic or acute bleeding may cause anemia. Melena or bright rectal bleeding occurs, depending on the location of the vascular anomaly. Hemangiomas are the most common intestinal tumors in childhood. Individual hemangiomas may be found anywhere in the intestine. In angiomatosis (miliary hemangiomas), small hemangiomas may be distributed throughout the intestine, in other viscera, in the nervous system, and on the skin and mucous membranes. Telangiectasias involving the intestine have been noted in Osler-Weber-Rendu syndrome (hereditary telangiectasias) and in Turner syndrome. Osler-Weber-Rendu syndrome is an autosomal dominant condition with telangiectasias of the face and hands, conjunctiva and mucous membranes, and respiratory, genitourinary, and gastrointestinal (GI) systems.1,2 Bird et al.2 found GI hemorrhage in 12% of patients, although a larger percentage of affected individuals are presumed to have telangiectasias. Intestinal telangiectasia has been reported in 6% of individuals with Turner syndrome.3 References (Vascular Anomalies) 1. Manley KA, Skyring AP: Some heritable causes of gastrointestinal disease. Special reference to hemorrhage. Arch Intern Med 107:182, 1961. 2. Bird RM, Hammarsten JF, Marshall RA, et al.: A family reunion. A study of hereditary hemorrhagic telangiectasia. N Eng J Med 257:105, 1957. 3. Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, ed 3. Charles C Thomas, Springfield, IL, 1965, p 272.

26 Rectum and Anus Cathy A. Stevens

A

norectal malformations are relatively common anomalies. They are usually recognized at birth and can cause lifethreatening bowel obstruction. However, with appropriate surgical intervention, the long-term prognosis is good. The historical treatment of anorectal malformations has been previously reviewed.1,2 There are a few references to anal atresia in the writings of ancient Egypt, Greece, and Rome, primarily suggesting rupturing an anal membrane with the finger. Paul of Aegina (A.D. 625–690), a Greek physician, gave the earliest account of surgical intervention for anal atresia. Following incision, dilation with bougies and application of wine and salve was recommended. Little more was written about this subject until the 17th century when Scultetus advocated anal dilation with gentian roots following the incision. Benjamin Bell (1787) of England performed perineal incision in the midline followed by dilation of the wound with the finger. If the rectal pouch was not located, a trocar was introduced to search for it. This sometimes resulted in perforation of the bladder or peritoneal cavity. Even when this type of operation was initially successful, occlusion by scar tissue often occurred, resulting in obstruction and death. Infants with rectovesical or rectourethral fistulas often died of infection or secondary to obstruction of the fistula. On the other hand, there were several reports of women with rectovaginal fistulas who were diagnosed very late since this fistula is often wide enough to allow adequate stool outflow. Duret performed the first successful colostomy for anal atresia in 1793. However, many children died after this procedure and it was not universally accepted. In 1835, a major advancement occurred when Amussat suggested incising the skin over the external sphincter, mobilizing the blind pouch of bowel and anchoring the mucosa to the anal skin with sutures. He also recommended enlarging the field of operation by excision of the coccyx. Others also resected the sacrum. Roux de Brignoles (1834) emphasized exposing the external sphincter and preserving the tissue of the perineum. By the end of the 19th century, an abdomino-perineal approach was accepted as the method of dealing with rectal atresia inaccessible by perineal incision. This was initially a two-stage procedure with temporary colostomy and later a one-stage procedure without colostomy. This methodology led to the modern surgical techniques currently used. The rectum and anus develop between the 3rd and the 10th weeks of gestation. The process of normal and abnormal develop-

ment of the hindgut is still not fully understood. The conventional theory derives from the early work of Tourneux3 and Retterer4 with the embryos of sheep, rabbits, and pigs. It states that the anorectum develops from a cloaca, which is subdivided into the urogenital and anorectal compartments by a urorectal septum. The urorectal septum fuses with the cloacal membrane, separating the cloaca from the amniotic cavity. The anorectal and urogenital membranes break down, giving rise to the anorectal and urogenital orifices. However, some recent studies utilizing rats and mice5–7 and human embryos8 did not find evidence for downgrowth of a urorectal septum or fusion of the septum with the cloacal membrane. According to these observations, a fold of mesoderm, the urorectal septum, forms between the dorsal yolk sac and the ventral allantois. The cloacal membrane extends from the genital tubercle anteriorly to the tailgroove posteriorly. Fusion of the tip of the urorectal septum and the cloacal membrane never occurs. Apoptotic cell death occurs throughout the cloacal membrane, leading to rupture at about day 49. Two openings appear, the posterior anal orifice and the anterior urogenital groove. The area in between (tip of the urorectal septum) becomes the perineum. Soon after rupture of the cloacal membrane, the lumen of the anorectal canal closes off due to adhesion of the walls. A plug of epithelial cells leads to occlusion of the anal orifice (days 50–56). Recanalization of the anal orifice is then observed by apoptotic cell death, leading to an open anal orifice by approximately 60 days.8 According to these observations, when the dorsal part of the cloacal membrane is absent or too small, the dorsal part of the cloaca will be absent. As a result, the hindgut opening becomes more anteriorly located. If the maldevelopment is severe, the hindgut will enter the urogenital sinus in a high position, while mild maldevelopment results in a lower or perineal position of the hindgut. A fistula is actually considered an ectopic anal orifice. Defective recanalization of the occluded anal orifice results in a malformed or occluded anus in the normal position. Figure 26-1 demonstrates normal and abnormal development of the caudal region of the human embryo. Recently it has been shown that the Shh-responsive transcription factors Gli2 and Gli3 are important in normal hindgut development in the mouse.7,9 Mutant mice with various defects in the Shh signaling pathway have a variety of malformations of the distal hindgut similar to anorectal malformations seen in humans. Of interest, some patients with Pallister-Hall syndrome, which is 1115

1116

Gastrointestinal and Related Structures

Diagnosis

Fig. 26-1. Sagittal schematic representations of the caudal region of a human embryo just before rupture of the cloacal membrane. A. Normal situation. cl, cloaca; cm, cloacal membrane; gt, genital tubercle; hg, hindgut; nt, neural tube; urs, urorectal septum; us, urogenital sinus. B. Anorectal malformation with ectopic anal orifice. The dorsal part of the cloacal membrane and cloaca are absent (arrow), and, as a consequence, the hindgut opening becomes more anteriorly located (arrowhead). C. Cloacal malformation. Both the dorsal and ventral part of the cloacal membrane are absent (arrows) and, as a consequence, the hindgut and urogenital opening become, respectively, more anteriorly and posteriorly located (arrowheads). Only the central part of the cloaca and cloacal membrane persist, which coincides with the common cavity and channel. (Adapted from Nievelstein.8)

due to mutations in GLI3, have anorectal malformations.10 The SALL1 gene, which is a possible target gene of Shh signaling, is mutated in Townes-Brocks syndrome. Mutations in the homeobox gene HLXB9 are seen in the majority of patients with familial Currarino syndrome.11 This gene is closely linked to SHH on chromosome 7q36. References 1. Scharli AF: Malformations of the anus and rectum and their treatment in medical history. Prog Pediatr Surg 11:141, 1978. 2. Stephens FD, Smith ED: Ano-Rectal Malformations in Children. Yearbook Medical Publishers, Chicago, 1971, p 1. 3. Tourneux F: Sur les premiers de´veloppements du cloaque du tubercle ge´nitale et de l’anus chez l’embryon de mouton. J Anat (Paris) 24:503, 1888. 4. Retterer E: Sur l’origine et l’evolution de la region anoge´nitale des mammife´res. J Anat (Paris) 26:126, 1890. 5. Kluth D, Hillen M, Lambrecht W: The principles of normal and abnormal hindgut development. J Pediatr Surg 30:1143, 1995. 6. Kluth D, Lambrecht W: Current concepts in the embryology of anorectal malformations. Semin Pediatr Surg 6:180, 1997. 7. Kimmel SG, Mo R, Hui CC, et al.: New mouse models of congenital anorectal malformations. J Pediatr Surg 35:227, 2000. 8. Nievelstein RAJ, Van der Werff JFA, Verbeek FJ, et al.: Normal and abnormal embryonic development of the anorectum in human embryos. Teratology 57:70, 1998. 9. Mo R, Kim JH, Zhang J, et al: Anorectal malformations caused by defects in sonic hedgehog signaling. Am J Pathol 159:765, 2001. 10. Kang S, Graham JM, Haskins-Olney A, et al.: GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 15:266, 1997. 11. Hagan DM, Ross AJ, Strachan T, et al.: Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene. Am J Hum Genet 66:1504, 2000.

26.1 Atresia of the Rectum and Anus Definition

Incomplete hindgut development results in imperforate anus and varying degrees of rectal atresia.

The spectrum of anorectal anomalies varies widely. The severity ranges from the relatively mild defects of anteriorly displaced anus, imperforate anal membrane, and anal stenosis to the more severe complete anal agenesis and rectal atresia. Most of these anomalies are detected at birth by visual inspection or with failure to pass meconium. Alternatively, meconium may be passed via the urethra, vagina, or a perineal fistula (Fig. 26-2). Rarely, the anus may appear normal but intestinal obstruction or ribbon stools may lead to the discovery of an internal membrane or stenotic canal. There may be other external findings such as genital malformations or the presence of a fistula. In the minority of situations, the lesion is truly imperforate; that is, there is no communication with the urinary or genital tract or the perineum.1 By examining the function of the bladder, urethral sphincters, and perineal skin, the innervation of the levator ani muscle can be assessed. Absence of response to perineal pinprick and impaired urethral function indicate defective nerve function. Normal radiographs of the lumbar spine and sacrum suggest a welldeveloped levator ani muscle.2 Ultrasound is a good tool to delineate the distance between the perineum and the distal rectum (Fig. 26-3). Voiding cystourethrogram and fistulograms help to identify the path of fistulous tracts (Fig. 26-4). Computed tomography and magnetic resonance imaging may also be used to identify the intestinal malformation specifically as well as other associated anomalies. Prior to surgery, it is important to identify the level of rectoanal atresia. This is based on its position in relation to the levator muscles, which are important for bowel continence. High lesions are those in which the atresia is above the levator muscles, while low lesions are located below the levator muscles. With intermediate lesions the atresia is within the puborectalis muscle sling of the levator ani muscle.3,4 High lesions are more common in males than in females, making up less than 20% of atresias in females (Fig. 26-5). An infant with a high lesion often has a smooth perineum without an anal pit or fistula and an absent anal wink. However, the external appearance cannot predict the level of atresia with certainty. Associated anomalies are approximately twice as common in infants with high lesions compared to those with low lesions. The most common anomalies associated with high lesions involve the urinary tract, vertebrae and sacrum.5 Forty percent of males and 48% of females with high anomalies Fig. 26-2. A. Imperforate anus with fistula on posterior fourchette. B. Low lesion of anal stenosis with so-called bucket handle appearance. (Courtesy of Dr. Michael Carr, T.C. Thompson Children’s Hospital, Chattanooga, TN.)

Rectum and Anus

Fig. 26-3. Sonogram in which transducer is placed on perineum of patient with imperforate anus. The distance measured between the electronic cursors (þ) depicts the level of the imperforate anus relative to the skin surface. Straight arrow, urinary bladder; curved arrows, meconium-filled rectum.

have urologic malformations.6 Sacral malformations are often accompanied by abnormalities of the levator ani and its nerve supply, leading to incontinence. Approximately 80% of high lesions have an associated fistula to the perineum or urinary or genital tract. In males, 60% have a rectourethral fistula, while in

1117

Fig. 26-4. Mucous fistulogram performed after double barrel colostomy demonstrates contrast placed into distal colon communicating with urethra (recto–urethral fistula). R, rectum; B, bladder; U, urethra.

50% of females a rectovaginal fistula is present. In 25% of females with high lesions, a cloacal opening is present.6 Intermediate atresias are the least common lesions (Fig. 26-6). These may be accompanied by a fistulous tract, usually to the urethra in males (20%) and the vestibule or vagina in females (90%). The perineum may be smooth or there may be an anal dimple, groove, or abnormal raphe. Low lesions (Fig. 26-7) are the most common of the three types, accounting for 55% of lesions in females and 40% of lesions in males.3,4 The most common low

Fig. 26-5. Schematic of high rectoanal atresias. A. Normal male (top) and female (bottom). B. Defect with rectourethral fistula in male (top) and without fistula in female (bottom). C. Defect with rectourethral fistula and anal pit in male (top) and high rectovaginal fistula in female (bottom). Horizontal line (pubococcygeal line) indicates upper level of puborectalis muscle, which separates high lesions from intermediate and low lesions.

1118

Gastrointestinal and Related Structures

Fig. 26-6. Intermediate rectoanal atresias. A. Without fistula. B. With rectovaginal fistula. C. With rectovaginal fistula at the vaginal outlet.

Fig. 26-7. Low rectoanal atresias. A. Anal stenosis with normally placed anus. B. Anal membrane. C. Cloacal defects with urethra, vagina, and rectum having a common opening. D. Rectoperineal fistula with anal pit posterior to the fistula.

lesion is anocutaneous fistula (covered anus). Usually the anal canal is of normal caliber and position to the level of the anal valves where it is narrowed and covered by skin. A fistula can be located anywhere on the perineum. The most common anal malformation in females is the anovestibular fistula in which the anal orifice opens within the vestibule. In this situation, sphincter function is usually normal. Another low lesion is an anteriorly located anus that usually appears otherwise normal. No treatment is required unless there is accompanying anal stenosis or chronic constipation. With imperforate anal membrane, the external appearance may be normal, but there is failure to pass meconium due to a membrane approximately 1 cm inside the anal verge. If the membrane is partially perforated, it is designated as anal membrane stenosis. This lesion may present later with chronic distention, ribbon stools, and fecal impaction. The incidence of other anomalies found in patients with anorectal malformations is approximately 50% but varies from 20–70% in different studies.5–9 This variation largely reflects the thoroughness of investigations performed. Anomalies in other organ systems are more common in those with high lesions compared to intermediate and low lesions. The anomalies may be multiple and may be serious or life threatening. Genitourinary tract anomalies of multiple types other than fistulas are the most common associated malformations and include renal aplasia or hypoplasia, hydronephrosis, megaureters, and hypospadias. Sacral defects as well as other vertebral and rib anomalies, clubfeet, and radial defects are common skeletal abnormalities. Esophageal and other gut atresias, malrotation, and volvulus are gastrointestinal malformations that may be present. Hirschsprung disease has also been reported. Table 26-1 outlines the malformations in other organ systems in one large study.7 There are also numerous syndromes in which anorectal malformations are seen (Table 26-2). Etiology and Distribution

Traditional theories suggest that anorectal malformations most likely result from a defect in the separation of the terminal hindgut

Table 26-1. Malformations associated with rectoanal atresias* Type of Anomaly

Urogenital

Percent Affected

19.6

Skeletal

13.2

Gastrointestinal

10.8

Cardiovascular

8.0

Abdominal wall

2.0

Cleft lip/cleft palate

1.6

Down syndrome

1.5

Meningomyelocele

0.5

Other

8.1

*Based on 1420 patients with rectoanal atresias as reviewed by Hasse.7

into the urogenital sinus and rectum by the urorectal septum or by failure of the anal membrane to rupture. However, according to recent observations in the embryos of animals48–50 and humans,51 the urorectal septum does not grow in the direction of the cloacal membrane, and fusion of these structures is never observed. The cloacal membrane ruptures by apoptotic cell death. A secondary occlusion of the anorectal canal occurs due to adhesions and a plug at the level of the anal orifice. Recanalization by apoptotic cell death of the occluded anal orifice then occurs. Anorectal malformations are caused by a disturbance of the normal development of the dorsal part of the cloacal membrane. When it is too small or absent, the dorsal cloaca will also be absent. As a result, the hindgut opening will be more anteriorly located, with its position dependent on the severity of the dorsal cloacal maldevelopment. If maldevelopment is severe, the hindgut will enter the urogenital sinus in a high position. With mild maldevelopment, the hindgut enters the urogenital sinus in a lower or perineal position. Fistulas are thus regarded as ectopic

Table 26-2. Syndromes that can include rectoanal atresias Syndrome

Anosacral defect

10

Prominent Features

Causation Gene/Locus

Anterior sacral meningocele, teratoma, or cyst

XLD (312800)

Asymmetric crying facies11

Unilateral agenesis or hypoplasia of anguli oris depressor muscle, cardiovascular anomalies

AD (125520)

Axial mesodermal defect12

Sacral dysgenesis; dysfunction of lower limbs, bladder, and bowel; oculo-auriculo-vertebral spectrum

Sporadic; possible AR

Baller-Gerold13

Craniosynostosis, radial defect

AR, AD (218600) TWIST, 7p21 in some cases

Bardet-Biedl14

Obesity, polydactyly, pigmentary retinopathy, hypogenitalism, mental retardation

AR (209900) BBS1, 11q13 BBS2, 16q21 BBS3, 3p12-q13 BBS4, 15q22.3 BBS5, 2q31 BBS6(MKKS), 20p12 BBS7, 4q27

Casamassima-Morton-Nance15

Costovertebral dysplasia, urogenital anomalies

AR (271520)

Cat eye16

Ocular coloboma; ear, cardiac, and renal anomalies; variable mental retardation

(115470) Marker derived from isodicentric inv dup (22) (pter!q11)

Caudal dysplasia17

Dysgenesis of lower spine; variable dysfunction of bladder, bowel, and lower limbs

Heterogeneous, maternal diabetes mellitus in some cases

Christian skeletal dysplasia18

Metopic ridge, cervical fusion, dysplastic spine, abducens palsy, mental retardation

XLR (309620) Xq28

Cryptophthalmos19

Palate, ear, renal, laryngeal, genital, digital, and eye malformations

AR (219000)

Currarino20

Sacral defect, presacral mass (teratoma, cyst, or meningomyelocele)

AD (176450) HLXB9, 7q36

Diabetes, maternal21

Fetal overgrowth; increased incidence of neural tube defects, cardiac anomalies, caudal dysgenesis, and renal defects

Exposure to abnormal glucose metabolism during pregnancy

Down22

Epicanthal folds, low nasal bridge, heart defects, hypotonia, mental retardation

Chromosomal abnormality (190685)

EEC23

Ectrodactyly, ectodermal dysplasia, clefting

AD (129900) EEC1, 7q11.2-q21.3 EEC2, 3q27 EEC3, Chr. 19

FG24

Macrocephaly, broad forehead, frontal hair upswept, hypotonia, mental retardation

XL(305450) FGS1, Xq12-q21.31 (300321) FGS2, Xq28 (300406) FGS3, Xp22.3 (300422) FGS4, Xp11.4-p11.3

Isolated imperforate anus25–28

None

Heterogeneous AR (207500) XLR (301800) AD (107100)

IVIC29

Radial defects, strabismus, thrombocytopenia, deafness

AD (147750)

Jarcho-Levin30

Rib and vertebral defects, respiratory failure in infancy

AR (277300) 19q13

Johanson-Blizzard31

Hypoplastic alae nasi, exocrine pancreatic insufficiency, deafness, hypothyroidism

AR (243800)

Kabuki32

Long palpebral fissures, arched brows, heart defects, persistent fetal fingertip pads

Most sporadic; some may be AD (147920)

Kaufman-McKusick33

Congenital heart defects, polydactyly, hydrometrocolpos

AR (236700) MKKS, 20p12 (continued)

1119

1120

Gastrointestinal and Related Structures

Table 26-2. Syndromes that can include rectoanal atresias (continued) Syndrome 34

Prominent Features

Causation Gene/Locus

Lowe

Sensorineural deafness, nephritis

AD

Meckel35

Encephalocele, polydactyly, cystic kidneys

AR (249000) MKS1, 17q22-23 (603194) MKS2, 11q13 (607361) MKS3, 8q24

OEIS36

Omphalocele, exstrophy of the bladder, imperforate anus, spinal defects

Uncertain; may have vascular causation; some may be AR (258040)

Opitz BBB/G37

Hypertelorism, hypospadias, swallowing defects, clefting

AD (145410), 22q11.2 XL (300000), Xp22

Pallister-Hall38

Hypothalamic hamartoblastoma, hypopituitarism, postaxial polydactyly

AD (146510) GLI3, 7p13

Pallister: ulnar-mammary39

Ulnar ray defects, delayed puberty, oligodactyly or polydactyly, hypoplasia of apocrine glands and breasts, genital anomalies

AD (181450) TBX3, 12q24.1

Rieger40

Ocular anterior chamber anomalies, hypodontia

AD (180500) PITX2, 4q25-q26 (601499) 13q14

Saldino-Noonan41

Short ribs, short limbs, postaxial polydactyly, visceral abnormalities, lethality

AR (263530)

Sirenomelia42

Single lower limb, renal agenesis, genital agenesis

Sporadic, based on vascular steal

Tetrasomy 12p43

Coarse face, sparse anterior scalp hair, hypertelorism, streaks of hyperand hypopigmentation, severe mental retardation, seizures

Chromosomal anomaly (601803)

Thanatophoric dysplasia44

Micromelia, platyspondyly, early death

Sporadic (187600) FGFR3, 4p16.3

Townes-Brocks45

Deafness, triphalangeal thumbs, overfolded helices

AD (107480) SALLI, 16q12.1

Vertebral, anal, cardiac, tracheoesophageal, renal, and radial limb defects

Sporadic (192350)

Heart defects, cleft palate, hypoplasia of thymus and parathyroids, developmental delay, long face, prominent nose, retrognathia

AD (192430, 188400) 22q11.2

VACTERL46 47

Velocardiofacial/DiGeorge

anal orifices. Cloacal malformations result from the cloacal membrane developing too small both anteriorly and posteriorly. This results in the hindgut opening being more anterior and the urogenital opening being more posterior than usual. Only the central part of the cloaca and cloacal membrane persist, resulting in a common opening. A malformed anus in the normal position such as those with imperforate anal membrane and anal stenosis is most likely caused by defective recanalization of the secondarily occluded anal orifice in the late embryonic period.51 The incidence of anorectal malformations is approximately one in 2500 births, with a slight male predominance. These malformations are seen in all ethnic groups. While most instances are sporadic, there are several reports of familial cases of isolated anorectal malformations. The pattern of inheritance varies and includes autosomal dominant with reduced penetrance, autosomal recessive, and X-linked recessive.28,52,53 Recurrence risk for sibs is approximately 1%.9 Approximately 4–5% of infants with anorectal malformations have a chromosome abnormality9 (most commonly Down syndrome), and therefore chromosome analysis should be considered, particularly if other anomalies are present. Teratogenic causes of anorectal malformations include thalidomide and maternal diabetes. Etretinate, retinoic acid, and adriamycin have been shown to induce anorectal malformations in mice and rats.54–57

Prognosis, Prevention, and Treatment

Surgical treatment for anorectal malformations is usually performed in the neonatal period. Infants with low lesions usually have an excellent prognosis for normal bowel function. Infants with high lesions may require colostomy initially with later reconstructive surgery. Those with high lesions have more difficulty with bowel continence. A thorough evaluation should be done in the newborn period looking for associated malformations and syndromes. The mortality rate is approximately 20% based on various large studies;6,58 however, most deaths are attributed to the associated anomalies. Anorectal malformations may be difficult to diagnose by ultrasound prenatally unless there are other anomalies present. Prenatal diagnosis of anorectal malformations has been made by demonstrating a dilated colon59 and intraluminal colonic calcifications.60 Decreased microvillar enzymes in the amniotic fluid have been demonstrated in fetuses with imperforate anus and other forms of intestinal obstruction.61 References (Atresia of the Rectum and Anus) 1. Smith ED: Incidence, frequency of types, and etiology of anorectal malformations. Birth Defects Orig Artic Ser XXIV(4):231, 1988.

Rectum and Anus 2. Smith ED, Yokoyama J, Saeki M: Procedure for identification and management of anorectal anomalies in the newborn infant. Birth Defects Orig Artic Ser XXIV(4):1, 1988. 3. Smith ED, Stephens FD: High, intermediate, and low anomalies in the male. Birth Defects Orig Artic Ser XXIV(4):17, 1988. 4. De Vries PA: High, intermediate and low anomalies in the female. Birth Defects Orig Artic Ser XXIV(4):73, 1988. 5. Smith ED, Saeki M: Associated anomalies. Birth Defects Orig Artic Ser XXIV(4):501, 1988. 6. Santulli TV, Schullinger JN, Kiesewetter WB, et al.: Imperforate anus: a survey from the members of the surgical section of the American Academy of Pediatrics. J Pediatr Surg 6:484, 1971. 7. Hasse W: Associated malformation with anal and rectal atresiae. Prog Pediatr Surg 9:99, 1976. 8. Endo M, Hayashi A, Ishihara M, et al.: Analysis of 1,992 patients with anorectal malformations over the past two decades in Japan. J Pediatr Surg 34:435, 1999. 9. Spouge D, Baird PA: Imperforate anus in 700,000 consecutive liveborn infants. Am J Med Genet Suppl 2:151, 1986. 10. Aronson I: Anterior sacral meningocele, anal canal duplication cyst, and covered anus occurring in one family. J Pediatr Surg 5:559, 1970. 11. Lin DS, Huang FY, Lin SP: Frequency of associated anomalies in congenital hypoplasia of depressor anguli oris muscle: a study of 50 patients. Am J Med Genet 71:215, 1997. 12. Russell LJ, Weaver DD, Bull MJ: The axial mesodermal dysplasia spectrum. Pediatrics 67:176, 1981. 13. Pelias MZ, Superneau DW, Thurmon TF: A sixth report (eighth case) of craniosynostosis-radial aplasia (Baller-Gerold) syndrome. Am J Med Genet 10:133, 1981. 14. Warkany J: The Laurence-Moon-Biedl-Bardet syndrome. In: Congenital Malformations. Yearbook Medical Publishers, Chicago, 1971, p 176. 15. Daikha-Dahmane F, Huten Y, Morvan J, et al.: Fetus with CasamassimaMorton-Nance syndrome and an inherited (6;9) balanced translocation. Am J Med Genet 80:514, 1998. 16. Magenis RE, McDermid H, White BN, et al.: The extra chromosome in cat eye syndrome (CES) is derived from chromosome 22: evidence from in situ hybridization of a chromosome 22 specific DNA probe. Cytogenet Cell Genet 40:685, 1985. 17. Denton JR: The association of congenital spinal anomalies with imperforate anus. Clin Orthop 162:91, 1982. 18. Christian JC, Demeyer W, Franken EA: X-linked skeletal dysplasia with mental retardation. Clin Genet 11:128, 1977. 19. Thomas IT, Frias JL, Felix V, et al.: Isolated and syndromic cryptophthalmos. Am J Med Genet 25:85, 1986. 20. Currarino G, Coln D, Votteler T: Triad of anorectal, sacral, and presacral anomalies. AJR Am J Roentgenol 137:395, 1981. 21. Eriksson UJ, Styrud J: Congenital malformations in diabetic pregnancy: the clinical relevance of experimental animal studies. Acta Pediatr Scand Suppl 320:72, 1985. 22. Torres R, Levitt MA, Tovilla JM, et al.: Anorectal malformations and Down’s syndrome. J Pediatr Surg 33:194, 1998. 23. Majewski F, Goecke T: Rectal atresia as rare manifestation in EEC syndrome. Am J Med Genet 63:190, 1996. 24. Opitz JM, Richieri-da Costa A, Aase JM, et al.: FG syndrome update 1988: note of 5 new patients and bibliography. Am J Med Genet 30:309, 1988. 25. Murken JD, Albert A: Genetic counseling in cases of anal and rectal atresia. Prog Pediatr Surg 9:115, 1976. 26. Winkler JM, Weinstein ED: Imperforate anus and heredity. J Pediatr Surg 5:555, 1970. 27. VanGelder DW, Kloepfer HW: Familial anorectal anomalies. Pediatrics 27:334, 1961. 28. Schwoebel MG, Hirsig J, Schinzel A, et al.: Familial incidence of congenital anorectal anomalies. J Pediatr Surg 19:179, 1984. 29. Arias S, Penchaszadeh VB, Pinto-Cisternas J: The IVIC syndrome: a new autosomal dominant complex pleiotropic syndrome with radial ray hypoplasia, hearing impairment, external ophthalmoplegia, and thrombocytopenia. Am J Med Genet 6:25, 1980.

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30. Devos EA, Leroy JG, Braeckman JJ, et al.: Spondylocostal dysostosis and urinary tract anomaly: definition and review of an entity. Eur J Pediatr 128:7, 1978. 31. Gershoni-Baruch R, Lerner A, Braun J, et al.: Johanson-Blizzard syndrome: clinical spectrum and further delineation of the syndrome. Am J Med Genet 35:546, 1990. 32. Matsumura M, Yamada R, Kitani Y, et al.: Anorectal anomalies associated with Kabuki make-up syndrome. J Pediatr Surg 27:1600, 1992. 33. Kaufman RL, Hartmann AF, McAlister WH, et al.: Family studies of congenital heart disease II: a syndrome of hydrometrocolpos, postaxial polydactyly and congenital heart disease. Birth Defects Orig Artic Ser VIII(5):85, 1972. 34. Lowe J, Kohn G, Cohen O, et al.: Dominant ano-rectal malformation, nephritis and nerve-deafness: a possible new entity? Clin Genet 24:191, 1983. 35. Moerman P, Verbeken E, Fryns JP, et al.: The Meckel syndrome. Pathological and cytogenetic observations in eight cases. Hum Genet 62:240, 1982. 36. Carey JC, Greenbaum B, Hall BD: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser XIV(6B):253, 1978. 37. Tolmie JL, Coutts N, Drainer IK: Congenital anal anomalies in two families with the Opitz G syndrome. J Med Genet 24:688, 1987. 38. Hall JG, Pallister PD, Clarren SK, et al.: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly—a new syndrome—parts I and II. Am J Med Genet 7:47, 1980. 39. Gonzalez CH, Herrmann J, Opitz JM: Studies of malformation syndromes of man XXXXII B. Mother and son affected with the ulnarmammary syndrome type Pallister. Eur J Pediatr 123:225, 1976. 40. Crawford RA: Iris dysgenesis with other anomalies. Br J Ophthalmol 51:438, 1967. 41. Bernstein R, Isdale J, Pinto M: Short rib-polydactyly syndrome: a single or heterogeneous entity? A re-evaluation prompted by four new cases. J Med Genet 22:46, 1985. 42. Stocker JT, Heifetz SA: Sirenomelia: a morphological study of 33 cases and review of the literature. Perspect Pediatr Pathol 10:7, 1987. 43. Reynolds JF, Daniel A, Kelly TE, et al.: Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister-Killian syndrome): report of 11 cases. Am J Med Genet 27:257, 1987. 44. Sillence DO, Rimoin DL, Lachman RS: Neonatal dwarfism. Pediatr Clin North Am 25:453, 1978. 45. Hersh JH, Jaworski M, Solinger RE, et al.: Townes syndrome: a distinct multiple malformation syndrome resembling VACTERL association. Clin Pediatr 25:100, 1986. 46. Weaver DD, Mapstone CL, Yu P–L: The VATER association: analysis of 46 patients. Am J Dis Child 140:225, 1986. 47. Enns GM, Cox VA, Golabi M, et al.: Gastrointestinal tract anomalies in velocardiofacial syndrome. Am J Med Genet 84:382, 1999. 48. Kluth D, Hillen M, Lambrecht W: The principles of normal and abnormal hindgut development. J Pediatr Surg 30:1143, 1995. 49. Kluth D, Lambrecht W: Current concepts in the embryology of anorectal malformations. Sem Pediatr Surg 6:180, 1997. 50. Kimmel SG, Mo R, Hui CC, et al.: New mouse models of congenital anorectal malformations. J Pediar Surg 35:227, 2000. 51. Nievelstein RAJ, Van der Werff JFA, Verbeck FJ, et al.: Normal and abnormal embryonic development of the anorectum in human embryos. Teratology 57:70, 1998. 52. Boocock GR, Donnai D: Anorectal malformation: familial aspects and associated anomalies. Arch Dis Child 62:576, 1987. 53. Landau D, Mordechai J, Karplus M, et al.: Inheritance of familial congenital isolated anorectal malformations: case report and review. Am J Med Genet 71:280, 1997. 54. Kubota Y, Shimotake T, Iwai N: Congenital anomalies in mice induced by etretinate. Eur J Pediatr Surg 10:248, 2000. 55. Diez-Pardo JA, Marino JM, Baoquan Q, et al.: Neural tube defects: an experimental model in the foetal rat. Eur J Pediatr Surg 5:198, 1995.

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56. Bitoh Y, Shimotake T, Kubota Y, et al.: Impaired distribution of retinoic acid receptors in the hindgut-tailgut region of murine embryos with anorectal malformations. J Pediatr Surg 36:377, 2001. 57. Thompson DJ, Molello JA, Strebing RJ, et al.: Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Teratology 17:151, 1978. 58. Kiesewetter WB, Chang JH: Imperforate anus: a five to thirty year follow up perspective. Prog Pediatr Surg 10:111, 1977. 59. Lam YH, Shek T, Tang MH: Sonographic features of anal atresia at 12 weeks. Ultrasound Obstet Gynecol 19:523, 2002. 60. Grant T, Newman M, Gould R, et al.: Intraluminal colonic calcifications associated with anorectal atresia. Prenatal sonographic detection. J Ultrasound Med 9:411, 1990. 61. Morin PR, Melancon SB, Dallaire L, et al.: Prenatal detection of intestinal obstructions, aneuploidy syndromes, and cystic fibrosis by microvillar enzyme assays (disaccharidases, alkaline phosphatase, and glutamyltranferase) in amniotic fluid. Am J Med Genet 26:405, 1987.

26.2 Rectal Duplication Definition

Rectal duplication is the double termination of the alimentary tract, often with a fistula to the rectum, bladder, vagina, or perineum. Diagnosis

Rectal duplication may be diagnosed in the newborn period, particularly if there is a visible perineal fistula or a stenotic anus. However, some cases are not detected until adulthood. Duplications are typically retrorectal and most demonstrate three characteristics: (1) contiguity with adherence to a part of the alimentary tract, (2) a smooth muscle coat, and (3) a mucosal lining consisting of one or more types of cells normally observed in the alimentary tract.1 Presenting signs of duplication include obstruction or prolapse caused by the rectal mass, constipation, tenesmus, urinary retention, infection, and carcinomatous degeneration. Heterotopic gastric mucosa may result in rectal bleeding. Fecal material may be extruded from a fistulous tract opening into the vagina, urethra, or perineum (Fig. 268). Misdiagnosis of hemorrhoids or perirectal abscess is common.2 The differential diagnosis of a mass in the presacrococcygeal space includes neurofibroma, dermoid cyst, rectal leiomyosarcoma, osteogenic sarcoma, and cloacogenic carcinoma.3 Other possibilities are sacrococcygeal teratoma and anterior meningocele. The diagnosis of rectal duplication is usually made by a combination of rectal examination, ultrasound, computed tomography, radiograms, or magnetic resonance imaging but sometimes may only be identified correctly at the time of surgery. Anorectal duplication has been reported in the caudal dysplasia syndrome.4 Etiology and Distribution

The exact mechanism of the development of rectal duplication is not known. Bremer5 proposed that defects in recanalization of the primitive gut resulted in duplications. Animal studies suggest the

Fig. 26-8. A. Sagittal section through a rectal duplication shows its anatomic relation to other structures in the pelvis. B. Sagittal section through a rectal duplication with fistula to the perianal skin in the posterior midline. (Adapted from LaQuaglia et al.2)

development of diverticula of the intestinal tract.6 Some instances of rectal duplication are accompanied by duplication of the genitourinary system and distal neural tube, which may represent incomplete twinning. The incidence of rectal duplication is not known, but it is believed to be a rare anomaly. The male to female ratio is probably equal but at least one author noted an increased prevalence in females.7 Prognosis, Prevention, and Treatment

The treatment of rectal duplication is surgical excision. Usually only the mucosal lining needs to be removed since the duplication and the normal rectum often share the muscularis layer. If malignant degeneration is suspected, excision of the normal rectum may also be necessary. Surgical treatment for other organ duplications and fistulae may be necessary. Prenatal diagnosis of enteric duplications has been performed by ultrasound.8 References (Rectal Duplication) 1. Ladd WE, Gross RE: Surgical treatment of duplication of the alimentary tract: enterogenous cysts, enteric cysts, or ileum duplex. Surg Gynecol Obstet 70:295, 1940. 2. LaQuaglia MP, Feins N, Eraklis A, et al.: Rectal duplications. J Pediatr Surg 25:980, 1990. 3. Monek O, Martin L, Heyd B, et al.: Rectal duplication in an adult: unusual case of a buttock mass. Dis Colon Rectum 42:816, 1999. 4. Al-Zaiem MM: Caudal regression syndrome and peno-scrotal transposition. Saudi Med J 22:544, 2001. 5. Bremer JL: Diverticula and duplications of the intestinal tract. Arch Pathol 38:132, 1944. 6. Lewis FT, Thyng FW: Regular occurrence of intestinal diverticula in embryos of pig, rabbit, and man. Am J Anat 7:505, 1908. 7. Tsuchida Y, Saito S, Honna T, et al.: Double termination of the alimentary tract in females: a report of 12 cases and a literature review. J Pediatr Surg 19:292, 1984. 8. Correia-Pinto J, Tavares ML, Monteiro J, et al.: Prenatal diagnosis of abdominal enteric duplications. Prenat Diagn 20:163, 2000.

27 Liver, Gallbladder, and Pancreas Ian D. Krantz and Arthur S. Aylsworth

A

timetable of events involving the development of the liver, gallbladder, and pancreas is given in Table 27-1.1–11 By the beginning of the 4th week postfertilization in the human, the three germ layers (ectoderm, mesoderm, and endoderm) have been established. The endodermal layer is continuous with the yolk sac cavity and will form the lining of the developing gut (Fig. 27-1a). The portion of the gut that lies dorsal to the heart is the foregut (Fig. 27-1c), and its endodermal lining provides the primordia of the liver, gallbladder, and pancreas. The junction between the foregut and midgut, called the anterior intestinal portal, is located at the

level of the septum transversum, a transverse mass of splanchnic mesoderm that lies just caudal to the heart at this stage of development. The septum transversum is in direct continuity with the splanchnic mesoderm of the yolk sac, contributes to the diaphragm, and is the tissue into which the developing liver grows. The Liver

By day 22 of development (approximately 19–20 somites), the liver primordium appears as a thickening of the ventral midline endoderm (the hepatic plate). The cells in the hepatic plate proliferate to

Table 27-1. Timetable of normal development Developmental Age

Size

Characteristic

Week 4 (days 22–28)

19–20 somites

Liver bud (hepatic diverticulum) begins to grow

Week 5 (days 29–35)

30þ somites (5–10 mm)

Primordium for gallbladder and cystic duct (pars cystica) develops Dorsal and ventral pancreatic buds appear Spleen begins to form

Week 6 (days 36–42)

10–14 mm

Hematopoiesis in liver begins Dorsal and ventral pancreas fuse First bile canaliculi appear First acini in dorsal pancreas

Week 7 (days 43–49)

14–20 mm

Gallbladder canalizes Splenic capsule forming

Week 8 (days 50–56)

20–30 mm

Anal membrane perforates

Week 9 (days 57–63)

30–35 mm

Return of midgut loop

Week 10 (days 64–70)

35–40 mm

Hepatic duct system complete Liver comprises one-tenth of body weight

Week 11 (days 71–77)

40–55 mm

Peristalsis in gut

Week 12 (days 78–84)

56–70 mm

Insulin can be detected in b cells of pancreas

Month 4 (weeks 13–16)

Hematopoiesis peaks in liver and spleen Hepatic glycogenesis Bile is produced

Month 5 (weeks 17–20)

Release of pancreatic enzymes into intestinal lumen Insulin secretion begins Hematopoietic function of spleen declines

Months 6–9

Hematopoietic sites in liver disappear

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Fig. 27-1. a. Mouse, day 8, eight somites. This ventral view shows the optic sulci (arrow) in the forebrain, the heart (H) in the opened pericardial cavity, and the developing fore- and hindgut regions (curved arrows). b. Mouse, day 8, eight somites. A midsagittal cut illustrates the features as labeled in the diagram in c. (From Sulik.15)

form the hepatic diverticulum that projects into the septum transversum (Fig. 27-2). The proliferating endodermal cells of the hepatic diverticulum invade the septum transversum, forming cords of hepatoblasts (liver cords) that grow out from the larger, cranial portion of the diverticulum (known as the pars hepatica) and form mesenchymal channels termed portal tracts. The hepatoblasts give rise to the parenchymal elements of the liver (the hepatocytes), the intrahepatic bile canaliculi, and the hepatic ducts. The connective tissue, hematopoietic tissue, and Kupffer cells of the liver are derived from the mesoderm of the septum transversum. The mesoderm of the septum transversum located caudal to the developing diaphragm surrounds the liver and is continuous from the lesser curvature of the stomach and duodenum to the ventral body wall, thus forming the lesser omentum (between the liver and gut), the hepatic capsule, and the falciform ligament (between the liver and anterior abdominal wall). As the liver grows it extends dorsally on either side of the midline into the peritoneal cavity and initially forms symmetric right and left lobes.12 The liver serves an important role in hematopoiesis, beginning by the 4th week and peaking in importance 5 months later. Endothelium-lined blood islands form in the mesenchyme of the septum transversum and fuse into small vascular channels between the anastomosing hepatic cords. These develop into the liver sinusoids, which become confluent with the vitelline and umbilical vasculature. Islands of hematopoiesis develop from mesoderm between the vessels and the hepatocytes. At 6 to 7 months gestation, when hepatic hematopoietic activity is at its peak, the liver mass is approximately 10% of the total body weight. After this point, hematopoiesis in the liver decreases rapidly. At birth, the liver weight is approximately 5% of the total body weight, and only a few isolated areas of hematopoiesis remain.

The Bile Ducts

The extrahepatic bile ducts (along with the gallbladder) develop from the caudal portion, or pars cystica, of the hepatic diverticulum. The cystic portion of the hepatic diverticulum is initially hollow but becomes a solid structure with the proliferation of epithelial cells. Subsequent vacuolization results in the formation of a lumen in the common bile duct by week 6. Bile secretion begins by the 4th month, giving the contents of the intestines (meconium) its characteristic dark green color.12 The intrahepatic bile ducts begin to develop when the hepatoblasts adjacent to the mesenchyme of the portal tracts differentiate into a ductal plate, a single layer of biliary epithelial cells, while the remaining parenchymal hepatoblasts, separated from the ductal plate cells by mesenchymal cells, differentiate into hepatocytes. By week 7, the ductal plate forms into a double layer of cells around the portal tract. Tubular structures form between the two cell layers of the ductal plate and become the intrahepatic bile ducts. The remaining ductal plate resorbs, leaving strands of bile ductules that connect the intrahepatic bile ducts with the liver parenchyma (Fig. 27-3). Maturation of the intrahepatic biliary tree progresses from the hilum of the liver outward to the periphery beginning at approximately 11 weeks gestational age and continues for several months after birth.13 The Gallbladder

Before the 4th week of gestation, the gallbladder and cystic duct develop from a small outgrowth of endoderm on the ventral surface of the duodenum just caudal to the hepatic diverticulum called the pars cystica or cystic diverticulum (Fig. 27-4). As the pars hepatica

Liver, Gallbladder, and Pancreas

Fig. 27-2. a. Mouse, day 9, 20 somites. The pericardium has been removed, revealing the heart and septum transversum (arrow). I, first pharyngeal arch; II, second pharyngeal arch; F, frontonasal prominence; arrowhead, otocyst; L, forelimb bud; S, somite. b. Diagram of a midsagittal section. c. Mouse, day 9, 20 somites. A midsagittal cut through the foregut region shows the liver bud as well as the first and second pharyngeal arches (I, II) and pouches

grows, the hepatic duct elongates. The gallbladder is attached to the main hepatic duct by the cystic duct, which elongates as the liver grows. The cells between the duodenum and the entrance of the cystic duct into the hepatic duct proliferate to form the common bile duct. As the duodenum rotates, the junction of the common bile duct with the duodenum rotates dorsally from its initial ventral position. The gallbladder is initially a hollow organ that becomes temporarily solid as its epithelial lining proliferates.1,14 In the 5- to 7mm embryo (mid-5th week), the gallbladder and connecting ducts are solid cords. Later in the same week, the common duct becomes canalized, followed by canalization of the hepatic ducts early in the 6th week. Finally, a definitive lumen develops into the cystic duct and the gallbladder by recanalization during the 7th week.

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(arrowheads), the heart tube (H), and the optic stalk that extends from the forebrain (curved arrow). d. Mouse; day 9, 20 somites. This coronal section illustrates the liver bud extending into the septum transversum. e. Higher magnification view of d, showing the endodermally derived liver diverticulum extending into the mesodermally derived septum transversum. (From Sulik.15)

The Pancreas

Shortly after the hepatic diverticulum appears, the pancreas originates as two endodermal buds from the caudalmost portion of the foregut (i.e., from that portion of the foregut that will form the upper duodenum), one growing dorsally and the other ventrally in the mesoduodenum (Fig. 27-4). The ventral pancreatic bud is closely related to the developing bile duct (pars cystica), and the dorsal bud arises at a point that is almost directly opposite the budding hepatic diverticulum. The dorsal bud extends in the mesogastrium to the area of the developing spleen. Differential growth and rotation of the duodenum to the right carries the ventral bud (and the common bile duct) dorsally so that by the 6th week it finally comes to lie

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Gastrointestinal and Related Structures

Fig. 27-3. Diagrammatic representation of the remodeling of the ductal plate to form the intrahepatic bile ducts. The ductal plate differentiates from the hepatoblasts that line the developing portal vein and initially forms a single layer, or sleeve, of biliary epithelial

cells that separates into a double layer of cells by week 7. Tubular structures form with resorption of the residual ductal plate. At completion of the process (which may continue for several months after birth) a single mature bile duct remains at the portal space

below and behind the dorsal bud. By embryonic day 32, the main duct of the ventral pancreatic bud connects with the proximal end of the common bile duct. Late in the 6th week the duct systems and parenchyma of the two buds fuse, as illustrated in Figure 27-5. Under normal circumstances, the proximal duct of the original

dorsal bud disappears and pancreatic enzymes enter the duodenum by way of the original ventral duct, which persists as the main pancreatic duct. The dorsal bud forms the upper part of the head, neck, body, and tail of the pancreas, whereas the ventral bud gives rise to the remainder of the head and the uncinate process.

Fig. 27-4. a. Mouse, day 10, 36 somites. L, forelimb bud; H, heart; S, somite; straight arrow, lens pit; curved arrow, olfactory pit. b. Mouse, day 10, 38 somites. Removal of the left body wall reveals the heart (H), septum transversum (arrow), and developing gut. Line, plane of section for c, d, and f. c. Mouse, day 10, 36 somites. A coronal cut along the plane indicated (b,e) shows the position of the developing pancreatic and gallbladder buds (shown at higher magnification in f) relative to the liver, gut, dorsal mesogastrium,

forelimb buds (L), and pericardial cavity (P). d. Mouse, day 10, 34 somites. A coronal section showing the gut and its derivatives, the dorsal and ventral pancreatic buds, and the gallbladder. e. Diagram. Dotted line shows plane of section for d and f. f. Higher magnification view of specimen in c. Note the thickened epithelium of the dorsal mesogastrium (arrowheads), which represents the splenic primordium. G, gallbladder bud; V, ventral pancreatic bud; arrow, duodenum; D, dorsal pancreatic bud. (From Sulik.15)

Liver, Gallbladder, and Pancreas

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27.1 Anomalies of Liver Shape and Lobation Definition

Anomalies of liver shape and lobation are variations in the size, shape, and location of the liver as a whole or of a lobe of the liver. Small masses of liver may also be found separated entirely from the major portion of the liver. Diagnosis

Fig. 27-5. a. At the 5th week, the ventral pancreatic bud is located next to the hepatic diverticulum. b. During the 6th week, the ventral pancreatic bud comes to lie next to the dorsal bud. (Reprinted with permission from Sadler.11)

References 1. Lewis FT: The development of the liver. In: Manual of Human Embryology. F Keibel, FP Mall, eds. JB Lippincott Co, Philadelphia, 1912, p 403. 2. Elias J, Skandalakis JE: Embryology for Surgeons, ed 2. SW Gray, ed. Lippincott Williams and Wilkins, Philadelphia, 1993. 3. Severn CB: A morphological study of the development of the human liver; I. Development of the hepatic diverticulum. Am J Anat 131:133, 1971. 4. Arey LB: Developmental Anatomy, ed 7. WB Saunders Company, Philadelphia, 1974, p 255. 5. Severn CB: A morphological study of the development of the human liver. II. Establishment of liver parenchyma, extrahepatic ducts and associated venous channels. Am J Anat 133:85, 1972. 6. Patten BM: Human Embryology, ed 3. McGraw-Hill Co, New York, 1968. 7. Hamilton WJ, Mossman HW: Hamilton, Boyd and Mossman’s Human Embryology: Prenatal Development of Form and Function, ed 4. Williams and Wilkins, Baltimore, 1972. 8. NA Michels: Blood Supply and Anatomy of the Upper Abdominal Organs. JB Lippincott Co, Philadelphia, 1955. 9. Tuchmann-Duplessis H, Haegel P, Hurley LS: Organogenesis. Illustrated Human Embryology, vol II. Springer-Verlag, New York, 1982. 10. Neiman RS, Orazi A: Disorders of the Spleen, ed 2. WB Saunders Company, Philadelphia, 1999. 11. Sadler TW: Langman’s Medical Embryology, ed 9. Lippincott Williams and Wilkins, Phildelphia, 2003. 12. Karpen SJ, Suchy FJ: Structural and functional development of the liver. In: Liver Disease in Children, ed 2. FJ Suchy, RJ Sokol, WF Balistreri, eds. Lippincott Williams and Wilkins, Philadelphia, 2001. 13. Crawford JM: Development of the intrahepatic biliary tree. Sem Liv Dis 22:213, 2002. 14. Boyden EA: Congenital variations of the extrahepatic biliary tract. Minn Med 27:932, 1944. 15. Sulik KK: Development of the gut with special reference to the liver, gallbladder, pancreas, and spleen: a review. Proc Greenwood Genet Center 8:91, 1989.

Although many references describe normal liver morphology by dividing the organ into four or five lobes, others have pointed out that this division is arbitrary and not anatomically meaningful.1,2 Functionally, the liver is made up of thousands of minute lobules, the organization of which is related to the underlying developmental pattern of bile ducts and vascular supply. On the basis of this intrahepatic architecture, the liver may be divided into right and left lobes, demarcated by the falciform ligament anteriorly and by the vena cava posteriorly.2 Based on this intrahepatic biliary and vascular anatomy, the left lobe appears to have medial and lateral functional segments, and the right lobe anterior and posterior ones. Knowledge of this segmental anatomy is of importance to surgeons operating in this region. The quadrate and caudate ‘‘lobes’’ are anterior and posterior, medially located regions on the ventral surface of the right lobe; they are described for convenience but do not correspond to true anatomic lobation. These areas tend to be extremely variable in size and shape. Other mammals have more distinct liver lobation, with connective tissue clearly separating the organ into discrete lobes.1 Occasionally, a human specimen may be similarly configured, and it has been suggested that some accessory lobes may be related to an atavistic retention of such a connective tissue septum.3 Evaluation of the liver by plain radiography is extremely difficult, and controversies about interpretation still exist.4 Anomalous variation in hepatic structure and shape can usually be diagnosed by noninvasive techniques.5 Hepatobiliary radionuclide imaging is commonly performed to study hepatic anatomy and physiology and is helpful in identifying liver symmetry and shape.6 Ultrasonography is especially useful in screening for biliary tract disease. Computed tomography (CT) and magnetic resonance imaging (MRI) can aid in differentiating between a benign variation in liver structure and an anomalous shape or size due to intrahepatic tumor. Laparoscopic examinations have identified structural anomalies of the liver that have been missed by other imaging techniques,7,8 but they are usually not indicated as most of the anomalies described in these studies were incidental findings during laparoscopic examination for other indications. Gross structural anomalies and variants of the liver include hypoplasia or absence of lobes, anomalous lobation, and accessory lobes or ectopic liver tissue. Mild to moderate variation of normal hepatic shape and size is common (Fig. 27-6), whereas more significant structural anomalies, manifested by true accessory lobes or marked hypoplasia or hyperplasia of hepatic tissue, are relatively rare.9,10 Unusually large lobes may present as abdominal masses and cause unnecessary surgery if the structural variant is not diagnosed.11,12 The left lobe is especially variable in size and shape. Secondary atrophy of the left lobe may be associated with chronic liver disease due to vascular, nutritional, and toxic factors.13,14 Total absence of the liver is a lethal malformation. It occurs with absence of other abdominal organs in the acardiac or amorphous twin disruption sequence due to an artery-to-artery placental shunt

1128

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the stomach and duodenum are displaced upward and to the right. The diagnosis may be made by a combination of radiographic techniques, including an upper gastrointestinal series with barium contrast, CT, 99mTc-sulfur colloid scintigraphy, and ultrasonography. The gallbladder fossa lies in the main lobar fissure between the right and left lobes. The falciform ligament, with the ligamentum teres in its free edge, is located in the intersegmental fissure of the left lobe. Absence of the left lobe may be suggested by a U-shaped folding of the stomach with a high position of the duodenal bulb as seen on an ‘‘upper GI’’ radiographic series. Absence of liver tissue to the left of the gallbladder fossa is considered diagnostic of absence of the left lobe of the liver, and failure to visualize the falciform ligament or ligamentum teres on sonography is supporting evidence. The right lobe may be of normal size or enlarged, its edge palpable in the right lower abdominal quadrant. Hypoplasia or Absence of the Right Lobe of the Liver

Fig. 27-6. Variations in normal liver configuration. A. Typical triangular-shaped liver, found in 41% of persons. B. Triangular with concave inferior border, found in 6%. C. Triangular with definite indentation or notch in the region of the porta hepatis at the midpoint of the inferior border of the liver, found in 15%. D. Square liver, caused by a relatively large left lobe, found in 12%. E. Configuration called en chapeau des gendarme (French for policeman’s hat) that is associated with a high diaphragm, found in 14%. F. Globular shape, caused by a small left lobe in combination with absence of the inferior tip of the right lobe, found in 3%. G. ‘‘Horn’’ shape with concave right lateral border due to impression of rib cage may be seen in individuals with short trunks or obesity. H. Downward extension of the right lobe, sometimes called Riedel’s lobe, found in 4%. I. Referred to as a superior accessory lobe by McAffee et al.9 and usually associated with localized eventration of the right hemidiaphragm. J. Configuration with a notch in the lower tip of the right lobe, found in l–2% and associated with a high position of the colonic hepatic flexure. K. Indentation of the inferior margin by the right kidney (stippled). L. Altered configuration of the entire right lateral margin of the liver caused by interposition of the right colon (stippled) between the liver and the lateral abdominal wall. (Reprinted with permission from McAffee et al.; copyright 1965, American Medical Association.9)

(twin reversed-arterial-perfusion or TRAP sequence).15 Warkany16 cites only one case report of agenesis of the liver with the intestinal tract present. Hypoplasia or Absence of the Left Lobe of the Liver

Absence or hypoplasia of the left lobe of the liver is a rare finding that is frequently asymptomatic and often found incidentally at autopsy.4,10,17–22 The diagnostic importance of left lobe absence is that it may suggest cirrhosis associated with a shrunken liver if

Absence of the right lobe has been found in asymptomatic individuals and in patients with symptoms of hepatobiliary tract disease.10,14,23,24 Significant hypoplasia or absence of the right lobe associated with malposition of the gallbladder may cause compression of the cystic duct with subsequent cholecystolithiasis and choledocholithiasis. Radiographic techniques helpful in diagnosis include CT, ultrasonography, scintigraphy, and cholangiography. The caudate ‘‘lobe,’’ when present, and the medial and lateral segments of the left lobe may be of normal size but usually undergo moderate to massive compensatory hypertrophy. The gallbladder has a suprahepatic position, below the posterior portion of the right hemidiaphragm and behind the medial segment of the left lobe. To interpret hepatobiliary scintigrams correctly, right lateral views must be obtained. The hepatic flexure of the colon may also be seen positioned just below the posterolateral aspect of the right hemidiaphragm, lateral to the gallbladder. Associated malformations have included agenesis of the gallbladder, partial or complete absence of the right hemidiaphragm, choledochal cyst, and intestinal malrotation. Anomalous Lobation

Variation in the size and shape of the liver is common (Fig. 276).4,9,11,12,25–27 Hypertrophied lobes may cause displacement of adjacent organs and appear to be abdominal or intrathoracic masses or enlarged, mobile kidneys. One of these, the so-called Riedel lobe, is a long, tonguelike downward extension of the right lobe (Fig. 276H). It is frequently firm and nontender, extending to the level of the umbilicus or below and moving with respiration. Similar extensions of the left lobe have been reported. Such extensions of normal anatomic lobes are sometimes referred to as sessile ‘‘accessory lobes’’ when the degree of enlargement is dramatic. One reported patient, a woman with ‘‘Turner’s syndrome’’ (not described further) and ‘‘severe oligophrenia,’’ had intermittent hyperbilirubinemia and elevated serum enzymes over a period of 20 years.28 When a mass was palpated in the right lower quadrant of the abdomen, a malignant ovarian tumor with liver metastases was suspected because of abnormal serum enzymes and liver function tests. Ultrasound and 99mTc-stannous colloid liver scintigraphy showed absence of the left lobe, a small right lobe, and a very large, pedunculated, tonguelike accessory lobe of the liver extending from the anterior lower part of the right lobe to the iliac region. This accessory lobe was very mobile, moving as far as the left lower quadrant. Anomalous or symmetric lobation of the liver is seen in those disorders with defects in the determination of laterality (referred

Liver, Gallbladder, and Pancreas

to in the literature as Ivemark syndrome, asplenia syndrome, polyasplenia syndrome, situs ambiguus, partial situs inversus, heterotaxy, heterotaxia, and laterality or isomerism sequence) (Section 5.1).29,30 The liver may be symmetric, with the edge palpable across the entire upper abdomen, or inverted, with the left lobe larger than the right. Such a liver configuration should lead one to suspect situs ambiguus with heterotaxia and possibly other anomalies in patients with signs of congenital heart disease. The liver is a relatively ‘‘malleable’’ organ, and some anomalous lobation may be acquired. The so-called corset liver appears to have an extra lobe or lobes, because a deep horizontal furrow runs across the anterior surface.31 This is thought to be acquired, because it is not seen in children but is usually found in an adult who has either a history of wearing tight-fitting clothing or a restrictive skeletal deformity. Accessory Lobes and Ectopic Tissue

Aberrant, supernumerary, or ectopic lobes are pediculated projections, usually from the ventral surface of the liver near the gallbladder, that contain hepatic tissue with normal structure but variable function.1,2,10,16,28,32–37 A classification of accessory liver lobes has been proposed based on the drainage of bile and on the presence of a common capsule: Type I refers to a separate accessory lobe whose duct drains into an intrahepatic bile duct of the normal liver; Type II to a separate accessory lobe whose duct drains into an extrahepatic bile duct of the normal liver; and Type III to the accessory lobe that is incorporated in a common capsule with the normal liver and the bile drains into an extrahepatic duct.37 Occasionally, they are discrete masses of hepatic tissue located elsewhere, especially in the gastrohepatic ligament, connected to the liver by a band of tissue that may contain blood vessels and bile ducts. In the newborn, they may be found in an omphalocele or in the thorax, protruding through a diaphragmatic hernia. The most common site for supradiaphragmatic lobes is in the right costophrenic region. Accessory liver lobes may be asymptomatic and found incidentally on radiography or at autopsy, but some are discovered at surgery for acute abdominal symptoms. A tumor or cyst may be suspected. The symptoms caused by the accessory lobe are usually due either to torsion of the lobe or to intestinal obstruction caused by the lobe or its mesentery. Accessory or ectopic hepatic tissue may also be the site of tumor metastasis. One reported example is that of a metastatic tumor in an accessory liver located in the gastrosplenic ligament.38 Ectopic liver tissue has been found in the abdominal cavity, in the thorax, in omphaloceles, and on the gallbladder. In several cases, the ectopic liver has had pathologic changes similar to those found in the main body of the liver.20 A 9-day-old baby girl was described with vomiting due to an external mass that connected with and obstructed the third portion of the duodenum.39 The mass was a multiloculated cyst that contained two nodules of mature pancreatic and liver tissue. Another patient, a newborn boy with Beckwith-Wiedemann syndrome, had symptoms from torsion of a gallbladder that was imbedded in an accessory lobe of the liver.35 This lobe was adherent to an omphalocele sac and attached to the main body of the liver by a narrow mesentery. A supernumerary lobe of the liver has been observed in a patient with gallbladder aplasia (Section 27.4).40 Malposition

Malposition of the liver is usually due to diaphragmatic hernia. 99m Tc-hepatic scintigraphy is especially useful in determining the location of the diaphragmatic defect in addition to delineating the size and shape of the liver.41

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Etiology and Distribution

Some variations in lobation may represent an emergence of a more distinctive pattern of lobation that is seen normally in other animals, including the pig, dog, and camel.1,3 On the other hand, there is evidence to suggest that, in some cases, such variants result from deformation and/or disruption sequences.19 Ectopic location of liver tissue that is unattached to the main organ may represent an accessory lobe that appears detached as a result of atrophy of the original pedicle.3 In the 9-day-old infant described above who presented with vomiting, the primary malformation may have been a duplication of the ventral portion of the hepatopancreatic bud.39 This was suggested by the presence of both hepatic and pancreatic tissue along with a duct draining into the duodenum. Warkanyl6 describes experiments that produced abnormal hepatic lobation in rats due to diaphragmatic hernia caused by maternal vitamin A deficiency. This anomaly usually occurs on the right side and is very rare on the left. Gross anomalies of liver lobation are also produced in animals with omphaloceles caused by prenatal treatment with salicylates, streptonigrin, and other agents. Developmental anomalies of the liver seem to be rare in the rat, but spontaneously occurring accessory supradiaphragmatic lobes have been observed in both the BB Wistar strain and a Gunnderived strain.42 Absence of the left lobe was observed in 1 of 19,000 autopsies by Merrill,17 who commented that only one other case had been reported prior to 1946. Aplasia or hypoplasia of the left lobe of the liver has been proposed to result from dysgenesis of the hepatic primordium during development, anomaly of the umbilical vein, insufficient growth or thromboembolism of the left branch of the portal vein, or positional anomalies of other organs.22 Absence of the right lobe also occurs rarely, having been reported in approximately 30 cases by 1987.14 There is a slight male preponderance that may not be statistically significant. In a 1989 review, Fogh et al.28 found fewer than 40 reported cases of accessory liver lobes found incidentally at autopsy and 11 cases diagnosed in living patients. In a series of 35,000 postmortem studies in domestic fowl, one instance of an accessory hepatic lobe was observed.43 Accessory, pedunculated lobes seem to be found almost exclusively in adult women and are usually associated with absence or hypoplasia of the left lobe of the liver.3,28,34 One reported case in the pediatric age group was a 15-year-old Japanese girl with hyperthyroidism.36 Her severe right upper quadrant abdominal pain with guarding and vomiting was due to acute necrosis of an olive-sized mass of liver attached to the inferior surface of the left lobe by a narrow fibrous stalk. It is not clear whether a causal association between hyperthyroidism and symptomatic accessory lobe exists. There is no good evidence that anomalies of liver structure, as described in this entry, have a particular association with any malformation syndrome. Abnormal lobation of the liver has been observed occasionally in patients with trisomy 18 and trisomy 13.44 The woman discussed above as having ‘‘Turner’s syndrome’’ and a long, pedunculated lobe was not described further. Severe mental retardation, as described in this patient, is not a feature of typical Turner syndrome. It is not clear that she actually had Turner syndrome, but she may have had another syndrome with short stature, dysmorphism, and mental retardation. In disorders with defects in the determination of laterality where anomalies in the lobation of the liver have been described, mutations in several genes have been found to be associated including ZIC3,

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NODAL, ACVR2B, EBAF (also known as LEFTYA), CFC1, and DNAH11. When the inv gene is disrupted in the mouse, lateralization defects, biliary atresia and other anomalies are seen. Mutations in the human ortholog have not been associated with similar defects, with the exception of one family in which a heterozygous splice site mutation was identified but found to be present in all affected and unaffected members of the family.45 The authors suggested that oligogenic inheritance may be an explanation or a randomization of the laterality defect. Prognosis, Prevention, and Treatment

Absence of the left hepatic lobe may present with abdominal distress due to volvulus of the stomach. This appears to be related to increased mobility of the stomach associated with absence of the left lobe.18 Surgical correction of the volvulus is indicated in such cases. Absence of the right lobe is more often symptomatic than is absence of the left lobe. Patients present with symptoms of biliary colic and/or portal hypertension with hematemesis, hypersplenism, and esophageal varices. Portal hypertension is seen only in those patients who do not have compensatory hypertrophy of the left lobe, suggesting a mechanism related to an overall reduction in the size of the intrahepatic vascular bed.12 Eight of the 10 original patients described by Riedel had cholecystitis in addition to a tongue-like extension of the right lobe down to the level of the umbilicus. Subsequent series have not confirmed this high incidence of cholecystitis, and most individuals with a ‘‘Riedel lobe’’ are probably asymptomatic.24 Torsion of an accessory lobe should be considered in any individual with a history of an abdominal wall defect who presents with abdominal pain or shock. It has been suggested that removal of known accessory lobes should be considered because of the risk for torsion.37 The patient with ‘‘Turner’s syndrome’’ and ‘‘oligophrenia’’ mentioned previously did not have surgery but remained well with continued elevation of bilirubin and serum enzymes, findings presumably caused by intermittent obstruction of her large, highly mobile, tonguelike, pedunculated accessory liver lobe.25 Other patients with similar large lobes have presented with abdominal crises due to the pedunculated lobes undergoing torsion or causing intestinal obstruction. Ectopic liver tissue on the gallbladder has been noted to develop cirrhosis.28 References (Anomalies of the Liver Shape and Lobation) 1. Cullen TS: Accessory lobes of the liver. Arch Surg 11:718, 1925. 2. Elias J, Skandalakis JE: Embryology for Surgeons, ed 2. Lippincott Williams and Wilkins, Philadelphia, 1993. 3. Clearfield HR: Embryology, malformations, and malposition of the liver. In: Bockus Gastroenterology, ed 4. HL Bockus, JE Berk, eds. WB Saunders Company, Philadelphia, 1985, p 2659. 4. Gelfand DW: Anatomy of the liver. Radiol Clin North Am 18:187, 1980. 5. Franken EA Jr, Smith WL, Siddiqui A: Noninvasive evaluation of liver disease in pediatrics. Radiol Clin North Am 18:239, 1980. 6. Polga JP, Spencer RP: Hepatobiliary imaging as an aid in determining situs in a case of polysplenia. Clin Nucl Med 9:159, 1984. 7. Sato S, Watanabe M, Nagasawa S, et al.: Laparoscopic observations of congenital anomalies of the liver. Gastrointest Endosc 47:136, 1998. 8. Orlando R, Lirussi F: Congenital anomalies of the liver: laparoscopic observations. Gastrointest Endosc 51:115, 2000. 9. McAfee JG, Ause RG, Wagner HN Jr: Diagnostic value of scintillation scanning of the liver. Arch Intern Med 116:95, 1965.

10. Champetier J, Yver R, Utoublon C, et al.: A general review of anomalies of hepatic morphology and their clinical implications. Anat Clin 7:285, 1985. 11. Battle WM, Laufer I, Moldofsky PJ, et al.: Anomalous liver lobulation as a cause of perigastric masses. Dig Dis Sci 24:65, 1979. 12. Meyers HI, Jacobson G: Displacements of stomach and duodenum by anomalous lobes of the liver. AJR Am J Roentgenol 79:789, 1958. 13. Benz EJ , Baggenstoss AH, Wollaeger EE: Atrophy of the left lobe of the liver. Proc Staff Meet Mayo Clin 28:232, 1953. 14. Radin DR, Colletti PM, RaIls PW, et al.: Agenesis of the right lobe of the liver. Radiology 164:639, 1987. 15. Kaplan C, Benirschke K: The acardiac anomaly. New case reports and current status. Acta Genet Med Gemellol 28:51, 1979. 16. Warkany J: Congenital Malformations. Year Book Medical Publishers, Chicago, 1971. 17. Merrill GG: Complete absence of the left lobe of the liver. Arch Pathol 42:232, 1946. 18. Banerjee B, Harrison DC: Radiologic diagnosis of absent left lobe of the liver. AJR Am J Roentgenol 152:894, 1989. 19. Belton RL, VanZandt TF: Congenital absence of the left lobe of the liver: a radiologic diagnosis. Radiology 147:184, 1983. 20. Ahmed AF, Bediako AK, Rai D: Agenesis of the left hepatic lobe with gastric volvulus. N Y State J Med 88:327, 1988. 21. Yamamoto S, Kojoh K, Saito I, et al.: Computer tomography of congenital absence of the left lobe of the liver. J Comput Assist Tomogr 12:206, 1988. 22. Saigusa K, Aoki Y, Horiguchi M: Hypoplasia of the left lobe of the liver. Surg Radiol Anat 23:345, 2001. 23. Faintuch J, Machado MC, Raia AA: Suprahepatic gallbladder with hypoplasia of the right lobe of the liver. Arch Surg 115:658, 1980. 24. Suneja SK, Teal JS: Scintigraphy in evaluation of the hypoplastic right hepatic lobe: a rare variant. J Natl Med Assoc 81:205, 1989. 25. Dick J: Riedel’s lobe and related partial hepatic enlargements. Guys Hosp Rep 100:270, 1951. 26. Van der Reis L, Clark AG, McPhee VG: Congenital hepatomegaly. Calif Med 85:41, 1956. 27. Reitemeier RJ, Butt HR, Baggenstoss AH: Riedel’s lobe of the liver. Gastroenterology 34:1090, 1958. 28. Fogh J, Tromholt N, Jorgensen F: Persistent impairment of liver function caused by a pendulated accessory liver lobe. Eur J Nucl Med 15:326, 1989. 29. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001. 30. Gilbert-Barness E, Debich-Spicer D, Cohen MM Jr, et al.: Evidence for the ‘‘midline’’ hypothesis in associated defects of laterality formation and multiple midline anomalies. Am J Med Genet 101:382, 2001. 31. Philips DM, LaBrecque DR, Shirazi SS: Corset liver. J Clin Gastroenterol 7:361, 1985. 32. Llorente J, Dardik H: Symptomatic accessory lobe of the liver associated with absence of the left lobe. Arch Surg 102:221, 1971. 33. Lieberman MK: Cirrhosis in ectopic liver tissue. Arch Pathol 82:443, 1966. 34. Pujari BD, Deodehare SG: Symptomatic accessory lobe of the liver with a review of the literature. Postgrad Med J 52:234, 1976. 35. Azmy A, Boddy SA, Eckstein HB: Torsion of gallbladder, embedded in an accessory lobe of liver in a neonate with Beckwith syndrome. Z Kinderchir Grenzgeb 30:277, 1980. 36. Tomooka Y, Torisu M, Fujimura T, et al.: Symptomatic accessory lobe of the liver associated with hyperthyroidism. J Pediatr Surg 23:1055, 1988. 37. Elmasalme F, Aljudaibi A, Matbouly S, et al.: Torsion of an accessory lobe of the liver in an infant. J Pediatr Surg 30:1348, 1995. 38. Gaber M: Accessory liver containing metastatic tumour. Virchows Arch [A] 385:361, 1980. 39. Gonzalez OR, Hardin WD Jr, Isaacs H Jr, et al.: Duplication of the hepatopancreatic bud presenting as pyloric stenosis. J Pediatr Surg 23: 1053, 1988. 40. Bennion RS, Thompson JE Jr, Tompkins RK: Agenesis of the gallbladder without extrahepatic biliary atresia. Arch Surg 123:1257, 1988.

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41. Sty JR, Starshak RJ: The role of radionuclide studies in pediatric gastrointestinal disorders. Semin Nucl Med 12:156, 1982. 42. Wright JR Jr, Sharma HM, Yates AJ, et al.: Supradiaphragmatic accessory lobe of the liver in BB Wistar rats. Teratology 27:117, 1983. 43. Grewal GS, Brar RS: Three congenital anomalies of domestic fowl. Poultry Sci 68:1019, 1989. 44. Warkany J, Passarge E, Smith LB: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502, 1966. 45. Schon P, Tsuchiya K, Lenoir D, et al.: Identification, genomic organization, chromosomal mapping and mutation analysis of the human INV gene, the ortholog of a murine gene implicated in left-right axis development and biliary atresia. Hum Genet 110:157, 2002.

27.2 Liver Dysplasias/Ductal Plate Malformations Definition

Liver dysplasias/ductal plate malformations are a complex group of disorders, also known as the fibrocystic cholangiopathies, with disorganization of liver tissue, including dilation of the intrahepatic bile ducts (Caroli disease), congenital hepatic fibrosis, and polycystic liver disease. Recently, these disorders have been linked etiologically, the result of lack of remodeling of the ductal plate that in turn results in the persistence of embryonic bile duct structures. This group of disorders is now termed the ductal plate malformation (DPM) disorders.1,2 Cystic dysplasia of the liver may occur with or without renal and pancreatic involvement. Related anomalies are discussed in Sections 27.3 (intrahepatic biliary duct atresia and hypoplasia) and 27.6 (cysts of the gallbladder).

Fig. 27-7. Diagrammatic depiction of the developing biliary tree. The positioning of the different ductal plate disorders indicates the approximate size of the associated affected bile ducts. (Adapted from Desmet.1)

Diagnosis

The nosology of the hepatic dysplasias is confusing. As is true in many areas of medicine, classification schemes can be based on anatomic and histologic considerations, inferred mechanisms of cause or pathogenesis, inheritance patterns, association with other abnormalities, or any combination thereof. Considerable overlap occurs among the various forms of hepatic dysplasia. Renal cystic dysplasia frequently coexists with hepatic cystic dysplasia, and patients may present with primary symptoms of either liver disease or renal disease. An overview of the hepatic dysplasias and their special relationships to other malformations and syndromes is given in this entry. The basic underlying lesion in all forms of intrahepatic biliary cystic disease is the DPM. Because DPM can affect any and all levels of the intrahepatic biliary tree, a wide range of clinical entities and presentations have been described depending on which segment of the biliary tree is involved (Fig. 27-7). Congenital hepatic fibrosis (CHF), a progressive destruction of the immature intrahepatic bile ducts by a nonspecific inflammatory process, is an associated finding in some of these disorders.1 Intrahepatic biliary cystic dysplasia can present with symptoms at any age. Caroli3 described congenital, nonobstructive dilation of the segmental intrahepatic bile ducts associated with recurrent cholangitis and lithiasis. Segmental saccular ectasia of the intrahepatic ducts usually causes only moderate enlargement of the liver (Fig. 27-8). Large cysts may also occur. When primary cystic ectasias of the larger intrahepatic bile ducts become symptomatic, the manifestations are those of cholangitis, cholestasis, and lithiasis. Patients may have abdominal pain, fever, jaundice, and pruritus. Progressive liver disease can eventually lead to cirrhosis, although this is not the presenting manifestation. Such a pathologic pattern occurs rarely in the absence of other abnormalities. Bernstein4 suggests that the term Caroli disease be reserved for these rare

instances of isolated, nonobstructive biliary ectasia and cyst formation unassociated with dysplastic changes in the liver, kidney, or other organs. Others, however, commonly use the term to refer to the characteristic histologic pattern when it is seen, both with and without other anomalies. Such a cystic dilation of the bile ducts is usually associated with other dysplasias such as congenital hepatic fibrosis and cystic renal disease, as was true of the patient shown in Figure 27-8. Caroli3 differentiated between two types of segmental dilation of the intrahepatic bile ducts. His ‘‘simple’’ type is characterized by fever, inspissated bile, cholangitis, and pain associated with lithiasis but not periportal fibrosis, cirrhosis, or portal hypertension.3,5 The second, more common type involves the smaller terminal ducts, is usually seen in children, and is associated with CHF, hepatosplenomegaly, and portal hypertension with esophageal varices.3,5,6 Symptoms of jaundice and cholangitis are typically not present. The combined form of ectasias of the intrahepatic bile ducts in association with CHF is now referred to as Caroli syndrome.1 The two phenotypes described by Caroli and others represent different manifestations in a continuous spectrum of dysplastic disease, likely caused by the extent of involvement of the intrahepatic biliary tree. In Caroli disease, DPM of the larger intrahepatic bile ducts likely explain the phenotype, while in Caroli syndrome, the factors leading to arrest of remodeling of the ductal plates not only affect bile duct development early in embryogenesis but also affect the development of the more distal ducts later resulting in CHF as well.1 The diagnosis of intrahepatic ductal dilation may be assisted by arteriography, endoscopic cholangiopancreatography, ultrasound, operative cholangiography, and percutaneous transhepatic cholangiography.3,7 Diagnosis is confirmed by biopsy; a specimen

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Fig. 27-8. Radiograph of the liver of a young adult male with polycystic liver and kidney disease taken during endoscopic retrograde cholangiopancreatography (ERCP) study. Injection of the pancreatic duct showed no abnormality. There is filling of the intrahepatic tree, showing multiple areas of cystic ectasia and pooling of radiopaque material. This is the radiographic appearance that is frequently referred to as Caroli disease. (Courtesy of Dr. Matt Mauro, Department of Radiology, University of North Carolina Hospitals, Chapel Hill, NC.)

may need to be obtained surgically so that a large number of portal areas can be examined.8,9 CHF presents with hepatosplenomegaly and portal hypertension in childhood.9 It is characterized histologically by portal fibrosis, absence of central portal ducts, and fibrous obliteration of portal vasculature. Biliary dysgenesis uniformly occurs, characterized by apparent bile duct proliferation due to saclike DPM.2,8,10,11 These immature bile duct structures are destroyed and replaced with increasing periportal fibrosis. The rate of this destructive cholangitis is variable, ranging from rapidly progressive to a slow chronic process, while in some cases it ceases completely, accounting for the wide range of clinical presentations.1 Relatively large intrahepatic cysts occasionally occur. This picture is also referred to as Caroli syndrome by some authors, but patients are rarely jaundiced. Liver function is usually normal. The histologic picture of hepatic fibrosis occurs typically in patients who present with symptoms due to autosomal recessive ‘‘infantile’’ polycystic kidney disease.12,13 Similar renal and hepatic findings are the most consistent features in Meckel syndrome.11,14,15 Biliary dysgenesis also has been reported in patients with many other genetic syndromes that include renal dysplasia, such as Jeune syndrome (asphyxiating thoracic dysplasia), chondroectodermal dysplasia (Ellis-van Creveld syndrome), the short-rib polydactyly syndromes of Majewski and Saldino-Noonan, Elejalde syndrome, trisomy 9, Zellweger syndrome, Ivemark renal-hepatic-pancreatic dysplasia, vaginal atresia, tuberous sclerosis, and glutaric aciduria type II.2,10,16 Esmer et al.17 described two unrelated children with fibrocystic disease of the liver associated with postaxial polydactyly of all four limbs and normal funduscopic exams. Stoll and Gasser18 reported male and female siblings with DPM, polysyndactyly, and congenital heart defects born to second-cousin parents. CHF has also been seen in association with nephronophthisis.19–21 Several of these reported patients have significant clinical overlap with

the Senior-Loken syndrome (retinal dysplasia, nephronophthisis, coned epiphyses) and the Mainzer-Saldino syndrome (retinal dysplasia, nephronophthisis, coned epiphyses, cerebellar ataxia). Polycystic liver disease, in which the cysts are not in direct continuity with the biliary ducts, is not associated with symptoms of cholestasis. It is pathologically distinct from the biliary ectasias, with or without hepatic fibrosis, described above, because there are no cysts in the bile ducts. The cysts contain mucus instead of bile, and there is no pain or cholangitis.5 Patients may remain asymptomatic in spite of cysts being numerous and large. This is the type of hepatic cystic disease that is typically associated with the autosomal dominant ‘‘adult’’ type of polycystic kidney disease, but patients who have both this picture and biliary dysgenesis have been reported.22 Cerebral aneurysms are also associated when polycystic kidney disease is present. Presymptomatic diagnosis of both the hepatic and renal cysts is possible with ultrasonography. If one separates patients with polycystic kidney disease by the severity of their renal involvement, a continuous spectrum emerges.12 In this spectrum, the severity and clinical importance of the hepatic manifestations are inversely proportional to the degree and severity of the renal disease. Thus, babies who die in the newborn period with ‘‘infantile polycystic kidney disease’’ usually have some type of cystic hepatic dysplasia. Death in these patients is from pulmonary insufficiency caused by prenatal oliguria and oligohydramnios. At the other end of the spectrum are those patients with the mildest degree of renal involvement who present in childhood with symptoms of portal hypertension due to hepatic fibrosis. Between these two extremes are patients who come to medical attention in infancy with renal failure and systemic hypertension, with or without significant portal hypertension. Some of these patients also have pancreatic cystic dysplasia, leading to further nosologic confusion. While some authors include patients with renal, hepatic, and pancreatic dysplasia in the same category with autosomal recessive childhood polycystic kidney disease (ARPKD, OMIM No. 263200), others point out that the pancreas is usually not involved in typical ARPKD (see Chapter 26).12 Etiology and Distribution

It has been suggested that all cystic malformations involving the hepatobiliary tree may be etiologically and/or pathogenetically related.6 A difference in timing or location of a limited number of developmental errors may result in the entire spectrum of cystic disease that is observed. Caroli3 pointed out that ‘‘there are practically no primary diseases of the intrahepatic bile duct system without dilatation of the extrahepatic ducts.’’ The histologic pattern seen in patients with hepatic fibrosis and biliary dysgenesis is frequently interpreted as representing ‘‘arrested’’ development of the intrahepatic bile ducts.11 The observation that choledochal cyst, Caroli disease, congenital hepatic fibrosis, and polycystic disease of the kidney and liver have each occurred in association with the others supports the hypothesis that these represent a causally or pathogenetically related spectrum of developmental anomalies. The histologic finding of DPM (Fig. 27-9) in these disorders provides an insight into a common pathogenesis of the entities discussed in this chapter, although few genes have been implicated. The variability of the liver phenotype in these disorders can be explained by disruption of the normal processes involved in the maturation and differentiation of the ductal plate to form functioning intrahepatic bile ducts at discrete points of the biliary tree (Figure 27-7).1 The spectrum of hepatic and renal dysplasia described appears to be frequently caused by recessively expressed autosomal

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1133

Hepatic cysts are present in close to 50% of patients with adult polycystic kidney disease, and the same proportion of patients with polycystic liver disease have polycystic kidney disease. Occasional families reported suggest that polycystic liver without polycystic kidneys may be a distinct entity inherited as an autosomal dominant condition (MIM No. 174050).25 Table 27-2 lists syndromes that have been reported to include hepatic dysplasia. A national survey carried out in Japan studied 273 cases of ‘‘primary’’ hepatolithiasis, in which stones formed primarily within the intrahepatic bile ducts.61 In 13 patients (4.8%) there was associated biliary malformation or dysplasia. There was one case of ‘‘Caroli disease,’’ one case with adult-type polycystic disease of the liver and kidneys, and 11 cases with extrahepatic biliary tract anomalies such as choledochal cysts and anomalous pancreaticobiliary ductal union. Prognosis, Prevention, and Treatment

Fig. 27-9. A. Histologically normal developing liver showing a portal space with double layer of biliary epithelial cells of the ductal plate with two immature bile ducts (arrow heads). At the time of maturity only one bile duct will remain in the portal space. B. Abnormal portal space with multiple ductal structures that are abnormal in position and shape. Arrowheads indicate dilated bile ducts and remnants of early ductal plate that failed to regress. (Courtesy of Dr. David Piccoli, Department of Gastroenterology, The Children’s Hospital of Philadelphia.)

mutations. The data of Blyth and Ockenden12 supported autosomal recessive inheritance in each group of patients with childhood polycystic kidney disease. Furthermore, the severity in each family tended to ‘‘breed true’’; that is, there was interfamilial variability but not intrafamilial variability. These observations are consistent with statements made elsewhere that Caroli disease seems to affect both sexes equally and to be inherited in an autosomal recessive fashion.7 Several reports of affected sibs suggest that some cases of the Ivemark renal-hepatic-pancreatic dysplasia may also be autosomal recessive, even though most cases are sporadic. Hepatic fibrosis has been observed in several children with prenatal alcohol exposure.23 The histologic picture resembles that seen in adult alcoholic liver disease with fat accumulation in addition to portal fibrosis and bile duct proliferation. Polycystic liver disease without biliary tract communication is thought to arise from von Meyenburg complexes, collections of dilated intrahepatic bile ducts embedded in a fibrous stroma that are present during early development and that persist into fetal and postnatal life (i.e., embryonic remnants).24 It has been postulated that these complexes may represent partially fibrosing remnants of DPM of the small peripheral branches of the intrahepatic biliary tree.1 The cysts thus formed enlarge gradually throughout life.

Congenital hepatic fibrosis and biliary dysgenesis with localized biliary obstruction is frequently complicated by cholangiolitis or suppurative cholangitis. Such biliary tract infection may be involved in the pathogenesis of the portal and perilobular fibrosis that leads to a pattern similar to micronodular cirrhosis. Severe infantile polycystic kidney disease is lethal in the newborn period because of pulmonary insufficiency due to prenatal oligohydramnios. Those with less severe forms develop symptoms of renal insufficiency, hypertension, and eventually renal failure. Prenatal diagnosis by level II ultrasonography is feasible for infantile polycystic kidney disease (cystic kidneys) and Meckel syndrome (polydactyly, encephalocele, cystic kidneys). Prenatal diagnostic studies for Meckel syndrome should also include maternal serum or amniotic fluid a-fetoprotein assay to screen for encephalocele. References (Liver Dysplasias/Ductal Plate Malformations) 1. Desmet VJ: The cholangiopathies. In: Liver Disease in Children, ed 2. FJ Suchy, RJ Sokol, WF Balistreri, eds. Lippincott Williams and Wilkins, Philadelphia, 2001. 2. Desmet VJ: Pathogenesis of ductal plate abnormalities. Mayo Clinic Proc 73:80, 1998. 3. Caroli J: Diseases of intrahepatic ducts. Isr J Med Sci 4:21, 1968. 4. Bemstein J: What is Caroli’s disease? Gastroenterology 68:417, 1975. 5. Caroli J: Diseases of the intrahepatic biliary tree. Clin Gastroenterol 2:147, 1973. 6. Thaler MM: Biliary disease in infancy and childhood. In: Gastrointestinal Disease, ed 4. MH Sleisenger, IS Fordtran, eds. WB Saunders Company, Philadelphia, 1989, p 1640. 7. Hermansen MC, Starshak RJ, Werline SL: Caroli disease: the diagnostic approach. J Pediatr 94:879, 1979. 8. Kerr DNS, Harrison CY, Sherlock S, et al.: Congenital hepatic fibrosis. Q J Med 30:91, 1961. 9. Alvarez F, Bernard O, Brunelle F, et al.: Congenital hepatic fibrosis in children. J Pediatr 99:370, 1981. 10. Bernstein J: Hepatic and renal involvement in malformation syndromes. Mt Sinai J Med 53:421, 1986. 11. Blankenberg TA, Ruebner BH, Ellis WG, et al.: Pathology of renal and hepatic anomalies in Meckel syndrome. Am J Med Genet Suppl 3:395, 1987. 12. Blyth H, Ockenden BG: Polycystic disease of kidneys and liver presenting in childhood. J Med Genet 8:257, 1971. 13. Lieberman E, Salinas-Madrigal L, Gwinn JL, et al.: Infantile polycystic disease of the kidneys and liver. Medicine 50:277, 1971. 14. Fraser FC, Lytwyn A: Spectrum of anomalies in the Meckel syndrome, or: ‘‘maybe there is a malformation syndrome with at least one constant anomaly.’’ Am J Med Genet 9:67, 1981. 15. Salonen R: The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet 18:671, 1984.

Table 27-2. Syndromes with dysplastic liver/ductal plate malformations Syndrome

Prominent Features

Causation Gene/Locus

Adult polycystic kidney disease22,27,28

Nephromegaly with variable development of renal cystic dysplasia, hypertension, renal failure, polycystic liver disease without cystic dilation of the intrahepatic bile ducts; cystic dilation of the intrahepatic bile ducts with or without hepatic fibrosis may also occur

AD (173900) Genetically heterogeneous Polycystin 1, 16p13 Polycystin 2, 4q21-23 Other loci

Asplenia with cystic liver, kidney, and pancreas38,39

Renal-hepatic-pancreatic dysplasia with other malformations and heterotaxy (situs inversus, situs ambiguus)

AR (208540)

Autosomal recessive polycystic kidney disease12,13,26

Nephromegaly, oliguria, renal insufficiency with tubular ductal ectasia, biliary dysgenesis

AR (263200) Fibrocystin 6p21.1-p12

Bardet-Biedl51,52

Mental retardation, short stature, obesity, hypogenitalism, postaxial polydactyly, pigmentary retinopathy, variable renal dysplasia including glomerulopathy and/or medullary cystic dysplasia (nephronophthisis), and hepatic fibrosis with dilation of intrahepatic bile ducts

AR (209900) Genetically heterogeneous Oligogenic inheritance reported BBS1, 11q13 BBS2, 16q21 BBS3, 3p13 BBS4, 15q22.3 BBS5, 2q31 BBS6, 20p12 BBS7, 4q27

Caroli disease3

Congenital polycystic dilation of intrahepatic bile ducts, polycystic kidney disease, recurrent fevers

AD (600643)

COACH36

Ataxia, hypoplastic vermis, hepatic fibrosis, mental retardation, medullary renal cysts, ocular coloboma

AR (216260)

Cumming campomelia40

Polysplenia; campomelia; cervical lymphocele; short bowel; polycystic dysplasia of kidneys, liver, and pancreas

AR (211890)

Elejalde56

Mental retardation, seizures, hypotonia, generalized hypopigmentation, abnormal melanolysosomes

AR (256710) May be same entity as Griscelli syndrome caused by mutations in the MYO5A gene

Ellis-van Creveld41–43 (chondroectodermal dysplasia)

Short stature with short limbs, postaxial polydactyly, hypoplastic teeth and nails, natal teeth, congenital heart defects

AR (225500) EVC, EVC2, 4p16

Glutaric aciduria type II60

Acidosis, hypoglycemia, nausea, vomiting, hepatomegaly, hypotonia, macrocephaly, cystic kidneys, glutaric aciduria

AR (231680, 231675) Genetically heterogeneous ETFA, Type IIA, 15q23-q25 ETFB, Type IIB, 19q13.3 ETFQO, Type IIC, 4q32

Goldston31,32 (renal-hepatic-pancreatic dysplasia with Dandy-Walker cyst)

Cystic renal dysplasia, Dandy-Walker malformation, hepatic dysplasia with fibrosis (similar to Meckel syndrome)

AR (267010)

Jeune37

Short ribs, narrow thorax, short stature, postaxial polydactyly in 50%, variable limb shortening, cystic kidney disease

AR (208500)

Juvenile nephronophthisis19,47,48

Hepatomegaly, histologic pattern of congenital hepatic fibrosis, severe cystic renal disease (nephronophthisis), death from renal failure, splenomegaly in some, blindness associated with retinal hypoplasia/tapetoretinal lesions, mental retardation, cerebellar hypoplasia, osseous abnormalities

AR (256100, 266900) NHP1, 2q13 Genetically heterogeneous Other loci

Meckel11,29,30

Occipital encephalocele, cleft lip and palate, postaxial polydactyly, polycystic dysplastic renal disease, hepatic fibrosis with biliary dysgenesis

AR (249000) Genetically heterogeneous 17q22-q23, 11q, 8q

Prenatal alcohol23

Short stature, microcephaly, mental retardation, congenital heart malformation, wide spectrum of variable anomalies including craniofacial dysmorphism, skeletal defects, renal malformation

Prenatal alcohol exposure

Renal-hepatic-pancreatic dysplasia16,53

Renal cystic dysplasia, hepatic fibrosis/biliary dysgenesis, pancreatic fibrosis and cysts, included by some in the autosomal recessive polycystic kidney disease spectrum (above)

AR (263200)

Senior-Loken49,50

Renal dysplasia, congenital hepatic fibrosis, retinitis pigmentosa, retinal aplasia/hypoplasia and dystrophy, cone epiphyses, variable age of onset

AR (266900) NPHP1, 2q13 (likely genetically heterogeneous) (continued)

1134

Liver, Gallbladder, and Pancreas

1135

Table 27-2. Syndromes with dysplastic liver/ductal plate malformations (continued) Causation Gene/Locus

Syndrome

Prominent Features

Short rib-polydactyly, type I (Saldino-Noonan)54

Lethal dwarfism with postaxial polydactyly, severe micromelia, short ribs, polycystic kidneys, hydrops, congenital heart defects

AR (263530)

Short rib-polydactyly, type II (Majewski)55

Lethal dwarfism, hydrops, postaxial/preaxial polydactyly, syndactyly, micromelia, median cleft lip, brain malformations, ambiguous genitalia, polcystic kidneys

AR (263520)

Syndrome with features of Joubert, Meckel, and Smith-Lemli-Opitz syndromes33–35

Cerebellar vermis hypoplasia/aplasia, encephalocele, postaxial polydactyly, renal cystic dysplasia, hepatic fibrosis with intrahepatic duct dilation

AR (213010)

Trisomy 957

Prenatal growth deficiency, severe mental retardation, dysmorphia, congenital heart defects, skeletal defects, brain malformations, renal cysts, bile duct proliferation

Chromosomal

Tuberous sclerosis58,59

Renal cysts, facial angiofibromas and other cutaneous manifestations, seizures, neoplasia, lymphangiomyomatosis

AD (191100) Hamartin, TSC1, 9q34 Tuberin, TSC2, 16p13.3

Zellweger cerebro-hepato-renal44–46

Hypotonia in infancy, craniofacial dysmorphism, stippled epiphyses, polycystic kidneys, intrahepatic biliary dysgenesis with progressive hepatic fibrosis and failure

AR (2141000) Peroxisomal disorder Genetically heterogeneous PEX1, 7q21-22 PEX2, 8q21.1 PEX3, 6q23-24 PEX5, 12p13.3 PEX6, 6p21.1 PEX12, 17 Other loci

16. Bernstein J, Chandra M, Creswell J, et al.: Renal-hepatic-pancreatic dysplasia: a syndrome reconsidered. Am J Med Genet 26:391, 1987. 17. Esmer C, Alvarez-Mendoza A, Lieberman E, et al.: Liver fibrocystic disease and polydactyly: proposal of a new syndrome. Am J Med Genet 101:12, 2001. 18. Stoll C, Gasser B: Polysyndactyly, complex heart malformations cardiopathy, and hepatic ductal plate anomalies: an autosomal recessive syndrome diagnosed antenatally. Am J Med Genet 119A:223, 2003. 19. Boichis H, Passwell J, David R, et al.: Congenital hepatic fibrosis and nephronophthisis. A family study. Q J Med 42:221, 1973. 20. Delaney V, Mullaney J, Bourke E: Juvenile nephronophthisis, congenital hepatic fibrosis and retinal hypoplasia in twins. Q J Med 47:281, 1978. 21. Robins DG, French TA, Chakera TM: Juvenile nephronophthisis associated with skeletal abnormalities and hepatic fibrosis. Arch Dis Child 51:799, 1976. 22. Terada T, Nakanuma Y: Congenital biliary dilatation in autosomal dominant adult polycystic disease of the liver and kidneys. Arch Pathol Lab Med 112:1113, 1988. 23. Lefkowitch JH, Rushton AR, Feng-Chen K: Hepatic fibrosis in fetal alcohol syndrome. Gastroenterology 85:951, 1983. 24. Elias J, Skandalakis JE: Embryology for Surgeons, ed 2. Lippincott Williams & Wilkins, Philadelphia, 1993. 25. Berrebi G, Erickson RP, Marks BW: Autosomal dominant polycystic liver disease: a second family. Clin Genet 21:342, 1982. 26. Ward CJ, Hogan MC, Rossetti S, et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259, 2002. 27. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 10:151, 1995. 28. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339, 1996. 29. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997.

30. Roume J, Genin E, Cormier-Daire V, et al.: A gene for Meckel syndrome maps to chromosome 11q13. Am J Hum Genet 63:1095, 1998. 31. Kudo M, Tamura K, Fuse Y: Cystic dysplastic kidneys associated with Dandy-Walker malformation and congenital hepatic fibrosis. Report of two cases. Am J Clin Pathol 84:459, 1985. 32. Gloeb DJ, Valdes-Dapena M, Salman F, et al.: The Goldston syndrome: report of a case. Pediatr Pathol 9:337, 1989. 33. Hunter AG, Rothman SJ, Hwang WS, et al.: Hepatic fibrosis, polycystic kidney, colobomata and encephalopathy in siblings. Clin Genet 6:82, 1974. 34. Thompson E, Baraitser M: An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts. Am J Med Genet 24: 151, 1986. 35. Casamassima AC, Mamunes P, Gladstone IM Jr, et al.: A new syndrome with features of the Smith-Lemli-Opitz and Meckel-Gruber syndromes in a sibship with cerebellar defects. Am J Med Genet 26:321, 1987. 36. Verloes A, Lambotte C: Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. Am J Med Genet 32:227, 1989. 37. Whitley CB, Schwarzenberg SJ, Burke BA, et al.: Direct hyperbilirubinemia and hepatic fibrosis: a new presentation of Jeune syndrome (asphyxiating thoracic dystrophy). Am J Med Genet Suppl 3:211, 1987. 38. Crawfurd MA: Renal dysplasia and asplenia in two sibs. Clin Genet 14:338, 1978. 39. Hiraoka K, Haratake J, Horie A, et al.: Bilateral renal dysplasia, pancreatic fibrosis, intrahepatic biliary dysgenesis, and situs inversus totalis in a boy. Hum Pathol 19:871, 1988. 40. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 41. Bohm N, Fukuda M, Staudt R, et al.: Chondroectodermal dysplasia (Ellis-van Creveld syndrome) with dysplasia of renal medulla and bile ducts. Histopathology 2:267, 1978. 42. Ruiz-Perez VL, Ide SE, Strom TM, et al.: Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24:283, 2000. Erratum: Nat Genet 25:125, 2000.

1136

Gastrointestinal and Related Structures

43. Ruiz-Perez VL, Tompson SWJ, Blair HJ, et al.: Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet 72:728, 2003. 44. Danks DM, Tippett P, Adams C, et al.: Cerebro-hepato-renal syndrome of Zellweger. J Pediatr 86:382, 1975. 45. Kelly RI: Review: the cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet 23:869, 1986. 46. Brosius U, Gartner J: Cellular and molecular aspects of Zellweger syndrome and other peroxisome biogenesis disorders. Cell Mol Life Sci 59:1058, 2002. 47. Witzleben CL, Sharp AR: Nephronophthisis-congenital hepatic fibrosis: an additional hepatorenal disorder. Hum Pathol 13:728, 1982. 48. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 17: 149, 1997. 49. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p. Nat Genet 3:342, 1993. 50. Schuermann MJ, Otto E, Becker A, et al.: Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 70:1240, 2002. 51. Pagon RA, Haas JE, Bunt AH, et al.: Hepatic involvement in the BardetBiedl syndrome. Am J Med Genet 13:373, 1982. 52. Beales PL, Badano JL, Ross AJ, et al.: Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet 72:1187, 2003. 53. Caries D, Serville F, Dubecq JP, et al.: Renal, pancreatic and hepatic dysplasia sequence. Eur J Pediatr 147:431, 1988. 54. Martinez-Frias ML, Bermejo E, Urioste M, et al.: Lethal short rib polydactyly syndromes: further evidence for their overlapping in a continuous spectrum. J Med Genet 30:937, 1993. 55. Walley VM, Coates CF, Gilbert JJ, et al.: Short rib-polydactyly syndrome, Majewski type. Am J Med Genet 14:445, 1983. 56. Sanal O, Yel L, Kucukali T, et al.: An allelic variant of Griscelli disease: presentation with severe hypotonia, mental-motor retardation, and hypopigmentation consistent with Elejalde syndrome (neuroectodermal melanolysosomal disorder). J Neurol 247:570, 2000. 57. Blair JD: Trisomy C and cystic dysplasia of kidneys, liver and pancreas. Birth Defects Orig Artic Ser XII(5):139, 1976. 58. Van Slegtenhorst M, de Hoogt R, Hermans C, et al.: Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805, 1997. 59. European Chromosome 16 Tuberous Sclerosis Consortium: Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305, 1993. 60. Freneaux E, Sheffield VC, Molin L, et al.: Glutaric acidemia type II: heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha-subunit of electron transfer flavoprotein in eight patients. J Clin Invest 90:1679, 1992. 61. Nakanuma Y, Terada T, Nagakawa T, et al.: Pathology of hepatolithiasis associated with biliary malformation in Japan. Liver 8:287, 1988.

27.3 Intrahepatic Biliary Duct Atresia and Hypoplasia Definition

Intrahepatic biliary duct atresia and hypoplasia is the underdevelopment or absence of the lumens of the intrahepatic biliary ducts. A number of terms have been applied to these anomalies, including intrahepatic biliary atresia, hypoplasia of the interlobular ducts, syndromic and nonsyndromic paucity of the intrahepatic bile ducts (PIHBD), paucity of the interlobular bile ducts (PILBD), Alagille syndrome, Watson-Alagille syndrome, and arteriohepatic dysplasia.

Diagnosis

Paucity of the intrahepatic bile ducts may be syndromic and nonsyndromic. The most common syndromic paucity is Alagille syndrome (Fig. 27-10), and it may be seen as a component of Ivemark syndrome.1 Nonsyndromic causes of bile duct paucity may be idiopathic or associated with underlying primary diseases such as metabolic conditions (a-l-antitrypsin deficiency, Zellweger syndrome, hypopituitarism, cystic fibrosis, trihydroxycoprostanic acid excess), chromosomal disorders (Down syndrome and others), infectious causes (congenital cytomegalovirus, congenital rubella, congenital syphilis, hepatitis B), and immunologic disorders (graftversus-host disease, chronic hepatic allograft rejection, primary sclerosing cholangitis). Patients usually present in early infancy with jaundice and other symptoms of cholestasis. Because of the long list of disease entities that present with neonatal jaundice, a systematic approach to diagnosis is necessary.2 Neonates may have paucity of the bile ducts in livers that appear otherwise normal. Many patients, however, present with clinical and histologic features of neonatal hepatitis that progress with subsequent disappearance of both the inflammatory picture and the number of interlobular ducts. Occasionally, the predominant picture may be periportal inflammation with abundant fibrous tissue and atresia of the interlobular ducts (Fig. 27-11). Alagille syndrome, also known as Watson-Alagille syndrome, arteriohepatic dysplasia, or syndromic paucity of the intrahepatic bile ducts (SPIHBD), is characterized by chronic cholestasis due to paucity of interlobular bile ducts, cardiovascular anomalies (primarily involving the pulmonary arteries), vertebral anomalies (butterfly vertebrae), prominent Schwalbe lines in the eyes (posterior embryotoxon), and characteristic craniofacial features that include broad or prominent forehead with relatively deep-set eyes, prominent nasal tip, and a pointed chin (Fig. 27-10). The specificity of the facial features and whether they should be included in the diagnostic criteria for Alagille syndrome has been questioned.3 Alagille et al.4 have expressed the opinion, however, that patients with nonsyndromic PILBD and a-l-antitrypsin deficiency do not have the ‘‘typical’’ facies found in syndromic patients, and recent studies argue in favor of specificity of the craniofacies.5 Individuals with Alagille syndrome may also have a variety of other problems, including structural and functional renal abnormalities, pancreatic

Fig. 27-10. Facial features in Alagille syndrome in a 15-year-old girl. Note the broad forehead, deep-set and widely spaced eyes, and pointed chin. The constellation of features gives the face an ‘‘inverted triangle’’ appearance.

Liver, Gallbladder, and Pancreas

1137

insufficiency, intracranial bleeds, vascular anomalies, short stature, developmental delay, lack of widening of the interpedicular distance in the lumbar spine, retinal pigmentary changes, high-pitched voice, and delayed puberty. Those individuals with Alagille syndrome caused by larger deletions of chromosome 20p12 may have an expanded phenotype that includes cleft palate, intestinal atresias, hearing loss, and cognitive involvement. There is great variability in phenotypic expression among individuals described with this diagnosis both between and within families. Severity is variable, with some dying in the first several years of life (generally those children with more severe cardiac manifestations) and many surviving well into adulthood with normal life expectancy. Alagille et al.6 suggested distinguishing between a ‘‘complete’’ syndrome and incomplete forms in which affected individuals have only two or three extrahepatic anomalies. It has been well-documented that mutations in Jagged-1, the Alagille syndrome disease gene, can cause severe disease with all of the features of Alagille syndrome, as well as very mild subclinical differences, often even within the same family. Individuals with apparent isolated heart defects and mutations in JAG1 have also been identified.7 There have been reports of clinically unaffected parents who were diagnosed with bile duct paucity at the time of surgery while serving as living related donors for liver transplantation to their severely affected children.8 Another syndrome associated with PILBD has been reported by Lambert et al.9 in four sibs. Variable features included cholestatic jaundice, malar hypoplasia, macrostomia, preauricular tags and fistulas, auditory canal atresia, large fontanels, hypospadias, clubfeet, bilateral inguinal hernias, moderate mental retardation,

hypotonia, agenesis of the vermis (by ultrasonography), congenital heart disease (ventricular septal defect), normal karyotype, normal skeletal radiographs, and early death in two of the four sibs at ages 8 and 26 months. Bile duct paucity can only be defined histologically. Normal, unaffected livers have, on average, one or two bile ducts per portal tract, whereas in SPIHBD there is only one duct found in every two to four portal areas scanned (Fig. 27-11). Bile duct paucity is defined by a ratio of ducts to portal tracts less than 0.9 in patients beyond 37 weeks gestational age. The standard number of portal tracts to be evaluated is 20, which requires that a wedge biopsy be performed, although fewer may be sufficient if other features suggesting Alagille syndrome are present.1,10 Cholangiographic evidence of extrahepatic bile duct hypoplasia may be seen in SPIHBD.11,12 Hepatobiliary scintigraphy may result in findings similar to those seen in extrahepatic biliary atresia.13 A liver biopsy is therefore essential for the correct diagnosis of SPIHBD to avoid a misdiagnosis of extrahepatic biliary atresia. It has been suggested that bile duct hypoplasia may be acquired and secondary to inflammatory or autoimmune processes.12,14,15 This is based on observations that some young infants may have cholestasis with portal inflammation or giant cell transformation and some paucity but no absence of interlobular ducts, whereas paucity and absence of ducts appear later along with persistent cholestasis and portal fibrosis (Fig. 27-11b). PIHBD is usually apparent after 3 months, but since the rate of duct disappearance is not uniform, it may not be possible to predict accurately

Fig. 27-11. a. Histologically normal liver showing bile duct (arrow) next to portal vein. b. Liver biopsy material from an 18-month-old patient with paucity of intrahepatic bile ducts in the periportal regions, ophthalmologic finding of posterior embryotoxon, and a similarly affected sister. There is no bile duct associated with

the vein in this portal area. This region also has some fibrosis, while others have inflammatory changes. (Both sections at  200 magnification. (Courtesy of Dr. Dale Ellison, Department of Pathology, University of North Carolina Hospitals, Chapel Hill.)

1138

Gastrointestinal and Related Structures

the age at which the ducts will disappear.12,14 It is important to note that some infants with Alagille syndrome may not exhibit bile duct paucity in the newborn period, and some may actually have bile duct proliferation, making the timing of the biopsy important for proper interpretation.16 Others have failed to confirm a progressive obliteration of bile ducts with increasing age.4 In early infancy, inflammation and nonspecific proliferation of intrahepatic ductules may obscure a developing paucity of the interlobular ducts. Inflammation has not been a uniform finding, but most cases have not been studied in early infancy. This has led to diagnoses of extrahepatic biliary atresia in some patients and neonatal hepatitis in others who also have giant cells present. Etiology and Distribution

The pathogenetic mechanisms involved in producing paucity or hypoplasia of the intrahepatic ducts are unknown. Some cases may appear to involve a sclerosing process similar to (or causally related to) the process implicated in extrahepatic biliary atresia.17 It has been suggested that fetal and neonatal hepatitis may progress to produce a variety of clinical and histologic phenotypes, including intrahepatic and/or extrahepatic biliary atresia and/or hypoplasia.15 A hypothesis has been proposed that neonatal hepatitis, EHBA, choledochal cysts in infants, and possibly some cases of intrahepatic biliary atresia without EHBA are all ‘‘ordinary manifestations or permissible outcomes of a single basic disease process called infantile obstructive cholangiopathy.’’18 Other patients show a morphologic pattern incompatible with the hypothesis of sclerosing cholangitis, but consistent with an autoimmune process.12 In most ‘‘nonsyndromic’’ cases, a specific cause is not determined. In one series, seven of 31 (23%) patients with nonsyndromic PILBD had either a-l-antitrypsin deficiency or congenital rubella.6 Other viral infections may also be of causal importance.4,15 The Alagille syndrome, or syndromic paucity of the intrahepatic bile ducts, is more common than nonsyndromic paucity of the intrahepatic bile ducts.6 The incidence has been estimated at one per 100,000 live births when selecting for neonatal liver disease.19 The true incidence is unknown, however, and likely higher because of clinical variability, with some individuals presenting with cardiac disease and not with liver disease. There does not appear to be any obvious geographic or ethnic predominance.4 Alagille syndrome is caused by mutations in the JAG1 gene, a ligand in the Notch signaling pathway.20 The Notch signaling pathway is an evolutionarily conserved pathway involved in cell fate determination in many different tissues. The exact role of JAG1 in bile duct development has not been defined. Approximately 60% of newly diagnosed individuals have a de novo mutation in JAG1, with the remaining 40% representing familial cases. Mutations are identified in greater than 70% of individuals meeting the clinical criteria of Alagille syndrome.21 Haploinsufficiency of JAG1 is an established mechanism of pathogenesis, as evidenced by the 6–7% of individuals with Alagille syndrome caused by a large deletion of chromosome 20p12 encompassing the entire JAG1 gene.22 Most mutations identified to date are protein truncating deletions, insertions, or splice site, although many missense mutations have also been described. Several of the missense mutations have been shown to be improperly processed and do not get appropriately targeted to the cell surface where they are biologically active, effectively resulting in haploinsufficiency as well.23 No genotype/phenotype correlation has been established, but one family with a unique missense mutation has been described without any overt liver involvement.24

The observation of parental consanguinity and four affected sibs in the family described by Lambert et al.9 suggests that this entity with paucity of interlobular bile ducts is probably autosomal recessive. Other types of ‘‘syndromic’’ PILBD have been observed in a few patients with a variety of other diagnostic entities, including familial deficiency of cholic acid with accumulation of trihydroxycoprostanic acid and fetal progesterone exposure. Cholestasis associated with PIHBD needs to be distinguished from other intrahepatic causes of cholestasis such as Zellweger syndrome and Byler disease.25 PIHBD has been found in children with Down syndrome, Turner syndrome, and trisomy 18 who do not have other characteristic features of the Alagille syndrome.11 Both intrahepatic and extrahepatic biliary atresia are reported as infrequent findings in the cat eye syndrome.26 Prognosis, Prevention, and Treatment

Patients usually develop jaundice and other clinical manifestations of cholestasis, including steatorrhea (with fat-soluble vitamin deficiencies), pruritis, xanthomas, and elevated levels of blood cholesterol, triglycerides, and liver enzymes. Patients with Alagille syndrome present significant management challenges. In addition to management of concomitant heart defects, aggressive nutritional support and management of cholestasis and associated pruritus must be undertaken. Infants with intrahepatic cholestasis have significant fat malabsorption, which may require supplementation with medium-chain triglycerides (absorbed in the absence of bile salt micelle formation) with optimization of carbohydrate and protein intake to ensure adequate caloric intake.1 Some degree of fat-soluble vitamin deficiency is present in most patients. Multivitamin preparations may not provide the correct ratio of fat-soluble vitamins, and thus vitamins are best administered as individual supplements. Administration of vitamin A is not generally recommended because toxicity is largely hepatic. Stimulants of bile flow such as the ursodeoxycholic acid has improved the cholestasis, but in many patients the pruritus continues unabated. Therapy with antihistamines may provide some relief, but many patients require additional therapy with agents such as rifampin or naltrexone. Biliary diversion has been successful in a limited number of patients.27 Liver transplantation is indicated in those patients with synthetic liver dysfunction, intractable portal hypertension, bone fractures, severe pruritus, xanthomata, and growth failure.28 Transplantation becomes necessary in 21–50% of patients with hepatic manifestations in infancy29,30 with post transplant survival ranging from 79–100%.29–31 These results indicate that individuals with Alagille syndrome are good candidates for transplantation, although morbidity and mortality post-transplant is influenced by the degree of cardiopulmonary involvement. Although sometimes lethal in early childhood, SPIHBD frequently runs a long and relatively benign course. Cholestasis may be present during infancy but improve with increasing age. Most adults have normal serum bilirubin levels. Although a Kasai type of surgical portoenterostomy is not indicated, such a procedure does not seem to have worsened the long-term prognosis of SPIHBD in those who have had these operations. There are no distinctive early histologic features that will help to predict the development of severe hepatic fibrosis or long-term prognosis. References (Intrahepatic Biliary Duct Atresia and Hypoplasia) 1. Piccoli DA, Witzleben CL: Disorders of the biliary tract: intrahepatic bile ducts. In: Pediatric Gastrointestinal Disease. WA Walker, PR Durie, JR Hamilton, et al., eds. BC Decker, Ontario, Canada, 2000.

Liver, Gallbladder, and Pancreas 2. Balistreri WF: Neonatal cholestasis: lessons from the past, issues for the future. Semin Liver Dis 7(2):61, 1987. 3. Sokol RJ, Heubi JE, Balistreri WF: Intrahepatic ‘‘cholestasis facies’’: is it specific for Alagille syndrome? J Pediatr 103:205, 1983. 4. Alagille D, Odievre M, Hadchouel M: Paucity of interlobular bile ducts: recent concepts. In: Biliary Atresia and Its Related Disorders. M Kasai, ed. Exerpta Medica, Amsterdam, 1983, p 59. 5. Kamath BM, Loomes KM, Oakey RJ, et al.: Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet 112:163, 2002. 6. Alagille D, Estrada A, Hadchouel M, et al.: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110:195, 1987. 7. Krantz ID, Smith R, Colliton RP, et al.: Jagged1 mutations in patients ascertained with isolated congenital heart defects. Am J Med Genet 84: 56, 1999. 8. Gurkan A, Emre S, Fishbein TM, et al.: Unsuspected bile duct paucity in donors for living-related liver transplantation: two case reports. Transplantation 67:416, 1999. 9. Lambert JC, Saint-Paul MC, Bastiani F, et al.: Branchial dysplasia, mental deficiency, club feet, and inguinal herniae: a report of two further cases associated with paucity of interlobular bile ducts. J Med Genet 27:330, 1990. 10. Kahn E, Markowitz J, Aiges H, et al.: Human ontogeny of the bile duct to portal space ratio. Hepatology 10:21, 1989. 11. Hashida Y, Yunis EJ: Syndromatic paucity of interlobular bile ducts: hepatic histopathology of the early and endstage liver. Pediatr Pathol 8:1, 1988. 12. Kahn E, Daum F: Arteriohepatic dysplasia: evaluation of the extrahepatic biliary tract, porta hepatis, and hepatic parenchyma. In: Extrahepatic Biliary Atresia. F Daum, ed. Marcel Dekker, New York, 1983, p 193. 13. Summerville DA, Marks M, Treves ST: Hepatobiliary scintigraphy in arteriohepatic dysplasia (Alagille’s syndrome). A report of two cases. Pediatr Radiol 18:32, 1988. 14. Dahms BB, Petrelli M, Wyllie R, et al.: Arteriohepatic dysplasia in infancy and childhood: a longitudinal study of six patients. Hepatology 2:350, 1982. 15. Heathcote J, Deodhar KP, Scheuer PJ, et al.: Intrahepatic cholestasis in childhood. N Engl J Med 295:801, 1976. 16. Novotny NM, Zetterman RK, Antonson DL, et al.: Variation in liver histology in Alagille’s syndrome. Am J Gastroenterol 75:449, 1981. 17. Thaler MM: Biliary disease in infancy and childhood. In: Gastrointestinal Disease, ed 4. MH Sleisenger, JS Fordtran, eds. WB Saunders Company, Philadelphia, 1989, p 1640. 18. Landing BH: Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 6:113, 1974. 19. Berman MD, Ishak KG, Schaefer EJ, et al: Syndromatic hepatic ductular hypoplasia (arteriohepatic dysplasia): a clinical and hepatic histologic study of three patients. Dig Dis Sci 26:485, 1981. 20. Li L, Krantz ID, Deng Y, et al.: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243, 1997. 21. Krantz ID, Colliton RP, Genin A, et al.: Spectrum and frequency of Jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet 62:1361, 1998. 22. Krantz ID, Rand EB, Genin A, et al.: Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet 70:80, 1997. 23. Morrissette JD, Colliton RP, Spinner NB: Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet 10:405, 2001. 24. Eldadah ZA, Hamosh A, Biery NJ, et al.: Familial tetralogy of Fallot caused by mutation in the Jagged1 gene. Hum Mol Genet 10:163, 2001. 25. Riely CA, Cotlier E, Jensen PS, et al.: Arteriohepatic dysplasia: a benign syndrome of intrahepatic cholestasis with multiple organ involvement. Ann Intern Med 91:520, 1979. 26. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘‘cat eye’’ syndrome: dicentric small marker chromosome probably derived from a No. 22

27.

28. 29.

30.

31.

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(tetrasomy 22pter to qll) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet 57:148, 1981. Emerick KM, Whitington PF: Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome. Hepatology 35:1501, 2002. Piccoli DA, Spinner NB: Alagille syndrome and the Jagged1 gene. Semin Liver Dis 21:525, 2001. Emerick KM, Rand EB, Goldmuntz E, et al.: Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29:822, 1999. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al.: Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 127:220, 1995. Cardona J, Houssin D, Gauthier F, et al.: Liver transplantation in children with Alagille syndrome—a study of twelve cases. Transplantation 60:339, 1995.

27.4 Agenesis of the Gallbladder Definition

Agenesis of the gallbladder is the congenital absence of the gallbladder. Diagnosis

Agenesis of the gallbladder may be discovered incidentally at autopsy or at surgery for unrelated indications. Sometimes gallbladder agenesis is found in patients who undergo laparoscopy or surgery for symptoms of cholecystitis. Absence of the gallbladder may also be found as part of a broader pattern of malformation in infants and children with multiple congenital anomalies. Frey et al.1 state that preoperative diagnosis of this entity is ‘‘impossible’’ and point out that a number of reported cases may in fact have had common duct stones rather than gallbladder agenesis. Asymptomatic Group

In their extensive review, Bennion et al.2 found that one-third of reported cases were asymptomatic, agenesis of the gallbladder being found incidentally at autopsy or at laparotomy for an unrelated condition. The average age at diagnosis was 33.3 years, with a range of 1 day to 84 years. Symptomatic Group

In the same review cited above, 55% of affected individuals were symptomatic.2 The mean age was 46.4 years, with a range of 12 to 79 years. Over 90% had right upper quadrant abdominal pain, and many presented with other symptoms suggestive of acute or chronic cholecystitis, including nausea, vomiting, fatty food intolerance, bloating, chills, fever, and jaundice. Over one-half of the patients had preoperative oral cholecystograms or intravenous cholangiograms, and absence of gallbladder opacification was consistently interpreted as acute cholecystitis. Ultrasonography also has yielded consistent false-positive diagnoses of apparently diseased, contracted, and scarred gallbladders, suggesting chronic cholecystitis.3 One-third of patients undergoing surgery are found to have common duct dilation, and 27% have stones in the common duct.2 Syndromic Group

The term syndromic is used to mean that gallbladder agenesis occurs in a patient who also has other malformations. The associated malformations may be etiologically, or even pathogenetically,

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related but do not necessarily constitute a well-delineated or diagnosable ‘‘syndrome.’’ A wide variety of associated anomalies have been reported in patients with gallbladder agenesis. Most common are malformations of the heart, gastrointestinal system, genitourinary tract, anterior abdominal wall, and biliary tract, such as biliary atresia and common duct atresia or absence. Absence of the gallbladder may be found in as many as 15–20% of patients with extrahepatic biliary atresia (EHBA).4 Gallbladder agenesis may occur in babies with sirenomelia and in patients with anomalies in the VATER or VACTERL association spectrum, but the frequencies at which gallbladder agenesis occurs with these malformations are unknown.5 Anomalies reported associated with gallbladder agenesis are listed in Table 27-3.

Table 27-3. Anomalies associated with gallbladder agenesis2,4,6

Etiology and Distribution

Genitourinary: polycystic kidneys, horseshoe kidney, urinary obstruction and hydronephrosis, hypoplastic kidneys, unilateral and bilateral renal agenesis, renal dysgenesis, lobulated kidneys, persistent cloaca, vesicovaginal fistula with double vagina, unicornuate and bicornuate uterus, double uterus and vagina, absent gonads, absent bladder and uterus, hypospadias, shawl scrotum, microphallus, unfused labioscrotal folds, unilateral testicular absence, absent penis, urethral and ureteral atresia, exstrophy of the bladder

Most cases of nonsyndromic gallbladder agenesis are sporadic. Familial cases have been reported, including at least one threegeneration family.6–9 Only two families have had two proven cases. These families also included other relatives with suspected involvement based on oral studies. Two other families had one proven case and one suspected case. The largest family reported includes 12 presumed affected individuals in two generations.8 The pattern is compatible with autosomal dominant inheritance, with one instance of nonpenetrance. Only one of the affected individuals in this family presented with symptoms of abdominal pain, and none of them had any associated anomalies. In cases of syndromic gallbladder agenesis, a diagnosis of a specific malformation syndrome is usually not made. Absence of the gallbladder has been noted in association with a few syndromes of known and unknown causes (Table 27-4) but, for reasons already discussed, is probably underdiagnosed. In a review of 54 published cases of the amniotic band sequence, absence of the gallbladder was noted in six cases (11%).19 Three chromosomal syndromes are listed, trisomy 18 and del 4p because of their relative frequency and recognizable phenotypes and del 5q because of its relationship to Gardner syndrome. Schinzel10 lists a number of other patients with rarer chromosome abnormalities in whom absence or hypoplasia of the gallbladder has been noted. Those in whom the anomaly has been found frequently have been diagnosed with dup(1)(q25qter), dup(8)(q21qter), del(13)(q14qter), dup(19)(q13.1qter), and triploidy. Others in whom an occasional association is seen have had dup(2)(pterp23), dup(3)(pterp21), dup(3)(q21qter), del(4) (q13qter), dup(6)(q21qter), dup(8)(pterp12), trisomy 8 mosaicism, dup(11)(q21qter), del(13q14), r(13), trisomy 13, and dup(16p). Gallbladder agenesis is not a specific, characteristic, or major feature of any well-defined malformation syndrome (situs ambiguus is treated here as a spectrum of phenotypes or associations rather than as a single malformation syndrome). Pathogenesis is unknown but presumably involves an abnormality in the early development of the pars cystica. Cases in which there is no hypoplastic remnant found may be the result of a primary failure of the pars cystica to develop. Other cases that have a strand of tissue present as an apparent remnant may be developmental errors that occurred during the hypothesized recanalization phase of biliary tract development.20 In his survey of the records of more than 2300 pathologists, Monroe21 found 181 cases of gallbladder agenesis in 1,352,000 autopsies, giving an approximate incidence of one per 7500 (0.0133%). The review of Bennion et al.2 brought the total number of reported cases to 393. Their finding of 287 reported cases in 1,501,061

Heart and vessels: tetralogy of Fallot, common atrium with agenesis of left lung, anomalous pulmonary venous return, atrial septal defect, hypoplastic left heart, preductal coarctation of aorta, dextroposition of aorta, ventricular septal defect, patent foramen ovale, pulmonic stenosis, aortic stenosis, mitral stenosis, truncus arteriosus, tricuspid atresia, persistent left vena cava, double superior vena cava Gastrointestinal: imperforate anus with rectovaginal fistula, esophageal atresia with tracheoesophageal fistula, annular pancreas, intestinal malrotation, pyloric stenosis, pyloric atresia, agenesis of the ventral pancreas, biliary atresia, absence or atresia of the common duct, anomalous liver lobation including supernumerary lobe, absent right lobe Spleen: polysplenia, multilobed spleen, asplenia

Craniofacial: cleft lip and palate, cleft palate, prominent occiput, absent ear Skeletal: sirenomelia, phocomelia, hemivertebrae, Klippel-Fiel anomaly, abnormal fifth digit, absent fibula, preaxial polydactyly, clubfoot, other upper limb defects Nervous system: agenesis of the corpus callosum, cystic dilation of the fourth ventricle, berry aneurysm, cerebellar hypoplasia, meningomyelocele, other unspecified central nervous system defects Anterior abdominal wall: omphalocele, gastroschisis, inguinal hernias, severe but unspecified body wall defects Pulmonary: unilobed or bilobed lungs, laryngeal stenosis Other: single umbilical artery, situs inversus, situs ambiguus, sirenomelia

autopsies represented a prevalence of approximately one per 6300 live births. In the asymptomatic group, the male to female ratio was 1.4:1, while in the symptomatic group, the ratio was 1:2 (69 men and 139 women), a statistically significant difference from the expected ratio. Prognosis, Prevention, and Treatment

After surgical exploration for a presumptive diagnosis of cholelithiasis, over 90% of symptomatic patients are greatly improved or symptom free. This is true both for patients who are found to have stones and for those without stones. The reason for improvement in patients without stones is not known. One speculation is that improvement may be the result of lysis of periportal and right upper quadrant adhesions during the exploration. Patients whose symptoms do recur postoperatively may be treated with oral smooth muscle relaxants and analgesics, a conservative regimen that has proven successful in most patients with biliary dyskinesia. More extensive evaluation and treatment is only necessary for the few patients who fail to respond. Patients with syndromic gallbladder agenesis frequently have severe malformations that result in early death. In the Bennion et al.2 review of 52 affected children, the average survival was less than 6 months with a range of 1 day to 6 years. Prenatal detection of the fetal gallbladder appears to be feasible, but it seems unlikely to be of current practical importance because of the lack of serious consequences associated with

Liver, Gallbladder, and Pancreas

1141

Table 27-4. Syndromes with gallbladder agenesis Syndrome

Prominent Features

Causation

4p- (Wolf-Hirschhorn)

Prenatal and postnatal growth retardation, severe mental retardation with seizures, ocular hypertelorism, prominent glabella, cleft lip and palate, wide variety of other anomalies

Chromosomal trisomy

Craniomicromelic17

Intrauterine growth retardation; craniosynostosis; cleft palate; shortness of all limbs; bilateral absence of the middle phalanx of the index finger; micrognathia; hypoplastic ileum, lungs, uterus, and fallopian tubes; hydronephrosis

AR (602558)

Interstitial deletion of chromosome 5 long arm12

Single patient with absent left lobe of liver, mental retardation, features of Gardner syndrome including colon cancer

Chromosomal deletion

Opitz oculo-genitolaryngeal (G; BBB; Opitz; Opitz-Frias)13

Ocular hypertelorism or telecanthus, laryngotracheal cleft, esophageal dysmotility, tracheoesophageal fistula, cryptorchidism, bifid scrotum, inguinal hernia, hypospadias, renal or ureteral anomalies, developmental retardation, orofacial clefts, congenital heart malformation

AD (145410)

Smith-Lemli-Opitz type II (Rutledge; lethal acrodysgenital dwarfism)14

Mesomelic dwarfism, cleft palate, micrognathia, hypoplastic tongue with cysts, cerebellar hypoplasia, webbed neck, congenital heart defects, abnormal lung lobation, postaxial polydactyly, renal hypoplasia, ambiguous genitalia, XY female ‘‘sex reversal,’’ Hirschsprung disease, early death

AR (268670) DHCR7, 11q12-q13

Steinfeld15,16

Holoprosencephaly, dysplastic radius and ulna, thumb aplasia/ hypoplasia, renal dysplasia, bilobed lungs, dislocated shoulders

AD (184705)

Thalidomide, prenatal18

Various limb reduction anomalies, especially amelia and phocomelia; hypoplasia of ears and eyes; congenital heart defects; renal anomalies; GI anomalies; genital anomalies

Prenatal drug exposure

Trisomy 184,10

Prenatal and postnatal growth retardation, prominent occiput, micrognathia, congenital heart disease, cryptorchidism, wide variety of other anomalies, early death

Chromosomal trisomy

11

isolated gallbladder agenesis.22 Such studies might possibly be of use in diagnosing fetuses with multiple anomalies, however. References (Agenesis of the Gallbladder) 1. Frey C, Bizer L, Ernst C: Agenesis of the gallbladder. Am J Surg 114: 917, 1967. 2. Bennion RS, Thompson JE Jr, Tompkins RK: Agenesis of the gallbladder without extrahepatic biliary atresia. Arch Surg 123:1257, 1988. 3. Jackson RJ, McClellan D: Agenesis of the gallbladder: a cause of falsepositive ultrasonography. Am Surg 55:36, 1989. 4. Turkel SB, Swanson V, Chandrasoma P: Malformations associated with congenital absence of the gall bladder. J Med Genet 20:445, 1983. 5. Duncan PA, Shapiro LR: Sirenomelia and VATER association: possible interrelated disorders with common embryologic pathogenesis. Dysmorphol Clin Genet 2:96, 1988. 6. Wilson JE, Deitrick JE: Agenesis of the gallbladder: case report and familial investigation. Surgery 99:106, 1986. 7. Kobacker JL: Congenital absence of the gallbladder—a possible hereditary defect. Ann Intern Med 33:1008, 1950. 8. Nadeau LA, Cloutier WA, Konecki JT, et al.: Hereditary gallbladder agenesis: twelve cases in the same family. J Maine Med Assoc 63:1, 1972. 9. Sterchi JM, Baine RW, Myers RT: Agenesis of the gallbladder—an inherited defect. South Med J 70:498, 1977. 10. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, Berlin, 2001. 11. Fernandes BJ, Gardner HA, Bedard YC: The 4p- syndrome—an autopsy study. Hum Pathol 11:683, 1980.

12. Herrera L, Kakati S, Gibas L, et al.: Gardner syndrome in a man with an interstitial deletion of 5q. Am J Med Genet 25:473, 1986. 13. Kasner J, Gilbert EF, Viseskul C, et al.: Studies of malformation syndromes VID: the G syndrome. Further observations. Z Kinderheilkd 118:81, 1974. 14. Rutledge JC, Friedman JM, Harrod MJE, et al.: A ‘‘new’’ lethal multiple congenital anomaly syndrome: joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortness of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations. Am J Med Genet 19:255, 1984. 15. Steinfeld HJ: Holoprosencephaly and visceral defects with familial limb abnormalities. Synd Ident VIII(1):1, 1982. 16. No¨then MM, Kno¨pfle G, Fo¨disch HJ, et al.: Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet 46:467, 1993. 17. Barr M Jr, Heidelberger KP, Comstock CH: Craniomicromelic syndrome: a newly recognized lethal condition with craniosynostosis, distinct facial anomalies, short limbs, and intrauterine growth retardation. Am J Med Genet 58:348, 1995. 18. Newman CGH: The thalidomide syndrome: risks of exposure and spectrum of malformations. Clin Perinatol 13:555, 1986. 19. Bamforth JS: Amniotic band sequence: Streeter’s hypothesis reexamined. Am J Med Genet 44:280, 1992. 20. Hamlin JA: Anomalies of the biliary tract. In: Bockus Gastroenterology, ed 4. JE Berk, ed. WB Saunders Company, Philadelphia, 1985, p 3486. 21. Monroe SE: Congenital absence of the gallbladder. J Int Coil Surg 32: 369, 1959. 22. Hata K, Aoki S, Hata T, et al.: Ultrasonographic identification of the human fetal gallbladder in utero. Gynecol Obstet Invest 23:79, 1987.

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27.5 Extrahepatic Biliary Atresia Definition

Extrahepatic biliary atresia (EHBA) is a term used to describe the obliteration or discontinuity of the lumen of the extrahepatic biliary tree within the first 3 months of life resulting from various etiologies including defects in initial development and/or destruction of normally developed ducts by progressive inflammation and fibrosis. Diagnosis

Patients present with the characteristic features of conjugated hyperbilirubinemia, pale stools, dark urine, and hepatomegaly within the first 3 months of life.1 Splenomegaly will be found in most patients. Approximately 15–20% of infants with biliary atresia will have associated anomalies including defects of laterality (situs inversus, bilateral bilobed lungs, abdominal situs inversus, intestinal malrotation, anomalies of the portal vein and hepatic artery, polysplenia, and asplenia) and cardiac and renal defects.2 Rapid diagnosis of EHBA is necessary to optimize the response to surgery.3 No single biochemical test is specifically diagnostic of EHBA. Abdominal ultrasound will identify choledochal cysts, or other causes of extrahepatic obstruction, and would be strongly suggestive of biliary atresia if there is an inability to visualize the extrahepatic biliary tree, or if segments of normal caliber are seen separated by atretic segments. Ultrasound examination may also be useful diagnostically if the associated finding of polysplenia is present. 99mTc-labeled diisopropyl iminodiacetic acid (DISIDA) scintigraphy evaluation of hepatic uptake and biliary secretion into the duodenum can be extremely helpful in delineating the anatomy and will rule out the diagnosis of EHBA if normal secretion is detected. Other modalities such as the identification of bile acids and bilirubin in homogenized stool specimens by near infrared reflectance spectroscopy (NIRS) has been successfully used for establishing a diagnosis. A percutaneous liver biopsy may be needed, showing characteristic bile duct proliferation in association with cholestasis and polymorphonuclear exudate, in cases where other modalities are not diagnostic. Cholangiography (endoscopic retrograde cholangiopancreatography [ERCP] or percutaneous gallbladder puncture) may be necessary as well as direct surgical exploration to confirm a diagnosis of EHBA.4 Because of the many disease entities that present with neonatal jaundice, a systematic approach to diagnosis is necessary.5

As many as 15–20% of patients have what has been called correctable biliary atresia with patent proximal ducts (Fig. 27-12a). The remainder of patients have noncorrectable EHBA with nonpatent proximal ducts, with or without patency of some distal ducts (Fig. 27-12b,c).

Etiology and Distribution

EHBA is not a single disease, but rather a phenotypic outcome of various processes. EHBA occurs with a frequency of one per 8000 to 12,000 live births. In infants and children, it is the most common cause of cholestasis and the most frequent reason for liver transplantation.5–8 In nonfamilial cases, there is no clear racial predominance. Overall there is a slight predominance of females. There is, however, an unexplained excess of males in the group of patients who have only patency of the distal ducts with nonpatency of the proximal ducts (Fig. 27-12c).9 In rarely reported familial cases, there is a predominance of males.10 Conflicting views exist concerning the cause and pathogenesis of EHBA. Some feel that many cases represent a primary developmental anomaly or inborn error of morphogenesis. A defect in recanalization after the 5th week could account for some cases.11 On the other hand, some patients have histologic features that suggest atresia is a secondary phenomenon occurring in response to inflammation induced by either infectious or toxic environmental agents.12 Fetal and neonatal hepatitis may progress to produce a variety of clinical and histologic phenotypes, including intrahepatic and/or extrahepatic biliary atresia and/or hypoplasia.13 A hypothesis has been proposed that neonatal hepatitis, EHBA, choledochal cysts in infants, and possibly some cases of intrahepatic biliary atresia without EHBA are all ‘‘ordinary manifestations or permissible outcomes of a single basic disease process called infantile obstructive cholangiopathy.’’14 Animal experiments have shown that EHBA can be produced by interruption of the vascular supply to the region. EHBA, therefore, probably includes a group of disorders that are causally and pathogenetically heterogeneous. Observation of geographic and temporal clustering of cases has led to the conjecture of significant environmental factors.15 Other investigators have failed to demonstrate any significant clustering, supporting the concept that EHBA is pathogenetically heterogeneous.16 In some patients, there are strong similarities to the pattern of findings seen in neonatal hepatitis. Several viruses, including rubella, Cytomegalovirus, Reovirus type 3, group C rotavirus, and

Fig. 27-12. Extrahepatic biliary atresia. a. So-called correctable type with patent proximal ducts. b. Noncorrectable type with complete extrahepatic duct atresia. c. Noncorrectable type with proximal duct atresia and some patency of distal ducts.

Liver, Gallbladder, and Pancreas

human papilloma virus (HPV), have been implicated as primary causative factors, but in most cases a cause-and-effect relationship cannot be established.8 Experimentally, Reovirus causes a disorder in mice similar to that seen in patients who have EHBA associated with inflammatory changes in the intrahepatic and extrahepatic ducts. Antibodies to Reovirus type 3 have been found in the sera of over 50% of patients with EHBA and neonatal hepatitis, and in a single rhesus monkey with EHBA (an extremely uncommon anomaly in that species).17,18 RT-PCR of the Reovirus L1 gene segments from extracts of liver and/or biliary tissues from 23 patients with EHBA, nine patients with choledochal cysts, and 33 controls with other forms of hepatobiliary disease demonstrated Reovirus DNA in 55% of patients with EHBA, in 78% of patients with choledochal cysts, and in 21% of controls.19 Discordance for EHBA has been observed in 20 pairs of twins (including monozygous, dizygous, and unknown zygosity twins).20 This is cited as evidence against both genetic and environmental (including infectious) causes but consistent with the hypothesis of vascular insufficiency as a primary causative factor. Limited studies in experimental animals have not produced a satisfactory perinatal ischemia model of the human disorder.21,22 An additional observation against a vascular etiology is the rarity with which EHBA and small bowel atresia are associated. Rare familial recurrence and twin concordances have been reported,23–26 supporting an argument for a genetic contribution. Additional support for a genetic contribution include (1) the finding of biliary atresia in the Inv mouse (mutant for the inversin gene, also causing situs inversus),27 although mutations in this gene have not been identified in humans with biliary atresia; and (2) the identification of missense mutations in the Alagille syndrome disease gene, JAG1, in nine of 102 cases of EHBA (no features of Alagille syndrome were identified in these individuals).28 EHBA may occur in association with a number of other anomalies, especially anomalies of the gastrointestinal tract, but it is not a prominent or frequent feature of many well-defined multiple malformation syndromes. Associated malformations are found in approximately 14% of patients with EHBA, with frequencies in individual series ranging from 12–27%.29,30 Cardiovascular malformations were most frequently associated in a large Japanese series in which over 50% of patients had some form of congenital heart anomaly. Common cardiac anomalies are found most commonly (patent foramen ovale, patent ductus arteriosus, ventricular septal defect). Splenic and gastrointestinal anomalies are the next most commonly seen types. A strong association is seen with anomalies that are part of the situs ambiguus phenotypes, including polysplenia, visceral ‘‘situs inversus,’’ intestinal malrotation, and abnormal lung lobation.31 When patients are ascertained by having features of situs ambiguus (also known as the polysplenia, asplenia, and polyasplenia syndromes), biliary atresia is frequently found to be associated with this phenotype. Carmi et al.,30 in a review of 251 cases of EHBA, found other associated anomalies in 51 (20%) and suggested a classification into three subgroups: group I with various combinations of anomalies falling within the laterality spectrum of defects (29% of the 51 cases); group II with one or two anomalies primarily involving the cardiac, gastrointestinal, and urinary systems (59% of the 51 cases); and group III with intestinal malrotation (possibly milder variants of the situs [group I] patients) (12% of the 51 cases). The gallbladder is absent in 15–20% of patients with EHBA.32 Renal cystic disease, hypoplasia, and hydronephrosis are also reported. An infant with a lethal syndrome of ichthyosis and EHBA was described by Gould33 in 1854 (OMIM 242400). The child’s sister had also died in infancy with ichthyosis. She was

1143

described as being hydrocephalic, but there was no mention of jaundice or a postmortem examination. No subsequent similar cases have been recorded. Three unrelated children with Kabuki syndrome with choledochal cysts and EHBA have been reported.34–36 Annere´n et al.37 described two siblings born to distantly consanguineous parents: a boy with patent ductus arteriosus, esophageal atresia and fistula, duodenal atresia, malrotation, hypoplastic pancreas, and EHBA, and his sister with an atrial septal defect, duodenal atresia, malrotation, and EHBA. Gentile and Fiorente38 reported a single child born to nonconsanguineous parents with esophageal, duodenal, rectoanal, and biliary atresia with an annular pancreas and hypospadias. An additional family with male and female siblings born to consanguineous parents has been described with a similar constellation of findings, with EHBA being reported in the female child.39 These entities have been catalogued in OMIM as ‘‘multiple gastrointestinal anomalies’’ (OMIM 601346). Other syndromic diagnoses in which biliary atresia has been reported include cat eye syndrome (OMIM 115470), Mutchinick syndrome (OMIM 249630), and cholestatic jaundice and renal tubular insufficiency syndrome (OMIM 210550). The finding of associated anomalies not likely caused by infection or inflammation also supports the hypothesis of a primary developmental anomaly in some patients. The bile duct system begins developing during early embryogenesis when the first signs of asymmetry and laterality appear. It is therefore not surprising that a general disturbance of laterality determination would also disrupt the coincident development of extrahepatic ducts that are growing at the same time they are rotating and migrating to a rightsided position. The finding of EHBA in patients with chromosome abnormalities suggests that the anomaly may be a primary developmental malformation in these cases. Stenosis or atresia of the extrahepatic bile ducts has been observed in cases of trisomy 13, trisomy 18, trisomy 21, dup(10p), dup(1)(q32qter), and dup(22) (pterq13).40–42 Some cases of trisomy 18, however, also have had a picture consistent with neonatal hepatitis.43,44 Prognosis, Prevention, and Treatment

In the group of patients with ‘‘correctable’’ biliary atresia with patent proximal ducts (Fig. 27-12a), the mortality is 15% despite the fact that uniform success has been achieved in establishing bile drainage.9 Lilly7 points out that many patients formerly included in this category may actually not have had well-formed, patent proximal ducts and that the true incidence of ‘‘correctable’’ lesions may be less than 5%. In patients who have so-called noncorrectable forms of EHBA with nonpatent proximal ducts, surgical correction is usually attempted, using the Kasai hepatic portoenterostomy procedure, in those who do not have other associated malformations.45–49 The success rate is less than 50%, and the reported 10-year survival rate of those undergoing this procedure is only 25–35%.50 Kasai and colleagues49 observe that most of their postoperative patients who do survive long term have normal growth and development. Surgical success appears to be related to the size and patency of the ducts at the point of anastomosis. Most will develop some degree of cirrhosis, with portal hypertension, ascites, and gastrointestinal hemorrhage (Fig. 27-13). Supportive treatment includes diuretics and a lowsodium diet with medium-chain triglycerides and fat-soluble vitamins added. In those who are not treated or in whom surgery is not successful, these symptoms develop earlier, and survival is less than 2 years. Reoperation may be beneficial for some patients who had good bile drainage after the initial procedure but does not appear to be helpful for those who had a poor initial result.51

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Gastrointestinal and Related Structures

Fig. 27-13. Cut surface of cirrhotic liver from 18-month-old child with extrahepatic biliary atresia (EHBA) after ‘‘failed’’ Kasai procedure. (Courtesy of Dr. F. Dalldorf, Department of Pathology, University of North Carolina Hospitals, Chapel Hill, NC.)

Biliary atresia is the most common indication for liver transplantation in childhood, and, although the presence of situs ambiguus may require technical adjustments, associated anomalies do not preclude transplantation.52 Survival rates after transplantation may be as high as 80% at 1 to 2 years and 60% at 5 years.53 Aggressive attention to and treatment of cholangitis, growth and nutritional problems, osteomalacia, portal hypertension, and psychosocial problems are recommended.46 References (Extrahepatic Biliary Atresia) 1. Thaler MM: Biliary disease in infancy and childhood. In: Gastrointestinal Disease, ed 4. MH Sleisenger, JS Fordtran, eds. WB Saunders Company, Philadelphia, 1989, p 1640. 2. Perlmutter DH, Shepherd RW: Extrahepatic biliary atresia: a disease or a phenotype? Hepatology 35:1297, 2002. 3. Ryckman FC, Noseworthy J: Neonatal cholestatic conditions requiring surgical reconstruction. Semin Liver Dis 7:134, 1987. 4. Witzleben CL, Piccoli DA: Disorders of the biliary tract: extrahepatic bile ducts. In: Pediatric Gastrointestinal Disease. WA Walker, PR Durie, JR Hamilton, et al., eds. BC Decker, Ontario, Canada, 2000. 5. Balistreri WF, Grand R, Hoofnagle JH, et al.: Biliary atresia: current concepts and research directions. Summary of a symposium. Hepatology 23:1682, 1996. 6. Moore TC: Congenital atresia of the extrahepatic bile ducts. Report of 31 proved cases. Surg Gynecol Obstet 96:215, 1953. 7. Lilly JR: Biliary atresia: the jaundiced infant. In: Pediatric Surgery, ed 4. KJ Welch, JG Randolph, MM Ravitch, et al., eds. Year Book Medical Publishers, Chicago, 1986, p 1047. 8. Sokol RJ, Mack C: Etiopathogenesis of biliary atresia. Semin Liver Dis. 21:517, 2001.

9. Lilly JR, Stellin A, Pau CML, et al.: Historical background of the biliary atresia registry. In: Extrahepatic Biliary Atresia. F Daum, ed. Marcel Dekker, New York, 1983, p 73. 10. Krauss AN: Familial extrahepatic biliary atresia. J Pediatr 65:933, 1964. 11. Elias J, Skandalakis JE: Embryology for Surgeons, ed 2. Lippincott Williams & Wilkins, Philadelphia, 1993. 12. Howard ER, Tan KC: Biliary atresia. Br J Hosp Med 41:123, 1989. 13. Heathcote J, Deodhar KP, Scheuer PJ, et al.: Intrahepatic cholestasis in childhood. N Eng J Med 295:801, 1976. 14. Landing BH: Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 6:113, 1974. 15. Strickland AD, Shannon K: Studies in the etiology of extrahepatic biliary atresia: time-space clustering. J Pediatr 100:749, 1982. 16. Houwen RHJ, Kerremans IIA, van Steensel-Moll HA, et al.: Timespace distribution of extrahepatic biliary atresia in the Netherlands and West Germany. Z Kinderchir 43:68, 1988. 17. Morecki R, Glaser J: Pathogenesis of extrahepatic biliary atresia and reovirus type 3 infection. In: Biliary Atresia and Its Related Disorders. M Kasai, ed. Exerpta Medica, Amsterdam, 1983, p 20. 18. Glaser JH, Morecki R: Reovirus type 3 and neonatal cholestasis. Semin Liver Dis 7:100, 1987. 19. Tyler KL, Sokol RJ, Oberhaus SM, et al.: Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 27:1475, 1998. 20. Silveira TR, Salzano FM, Howard ER, et al.: Extrahepatic biliary atresia and twinning. Braz J Med Biol Res 24(1):67, 1991. 21. Hashimoto T, Yura J, Mahour OH, et al.: Recent topics of experimental production of biliary atresia, and an experimental model using devascularization of the extrahepatic bile duct in fetal sheep. In: Biliary Atresia and Its Related Disorders. M Kasai, ed. Exerpta Medica, Amsterdam, 1983, p 38. 22. Pickett LK, Briggs HC: Biliary obstruction secondary to hepatic vascular ligation in fetal sheep. J Pediatr Surg 4:95, 1969. 23. Strickland AD, Shannon K: Studies in the etiology of extrahepatic biliary atresia: time-space clustering. J Pediatr 100:749, 1982. 24. Smith BM, Laberge JM, Schreiber R, et al.: Familial biliary atresia in three siblings including twins. J Pediatr Surg 26:1331, 1991. 25. Cunningham ML, Sybert VP: Idiopathic extrahepatic biliary atresia: recurrence in sibs in two families. Am J Med Genet 31:421, 1988. 26. Gunasekaran TS, Hassall EG, Steinbrecher UP, et al.: Recurrence of extrahepatic biliary atresia in two half sibs. Am J Med Genet 43:592, 1992. 27. Mazziotti MV, Willis LK, Heuckeroth RO, et al.: Anomalous development of the hepatobiliary system in the Inv mouse. Hepatology 30:372, 1999. 28. Kohsaka T, Yuan ZR, Guo SX, et al.: The significance of human jagged 1 mutations detected in severe cases of extrahepatic biliary atresia. Hepatology 36:904, 2002. 29. Miyamoto M, Kajimoto T: Associated anomalies in biliary atresia patients. In: Biliary Atresia and Its Related Disorders. M Kasai, ed. Excerpta Medica, Amsterdam, 1983, p 13. 30. Carmi R, Magee CA, Neill CA, et al.: Extrahepatic biliary atresia and associated anomalies: etiologic heterogeneity suggested by distinctive patterns of associations. Am J Med Genet 45:683, 1993. 31. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001. 32. Turkel SB, Swanson V, Chandrasoma P: Malformations associated with congenital absence of the gall bladder. J Med Genet 20:445, 1983. 33. Gould AA: Ichthyosis in an infant; hemorrhage from umbilicus; death. Am J Med Sci 27:356, 1854. 34. Ewart-Toland A, Enns GM, Cox VA, et al.: Severe congenital anomalies requiring transplantation in children with Kabuki syndrome. Am J Med Genet 80:362, 1998. 35. McGaughran JM, Donnai D, Clayton-Smith J: Biliary atresia in Kabuki syndrome. Am J Med Genet 91:157, 2000. 36. Van Haelst MM, Brooks AS, Hoogeboom J, et al.: Unexpected lifethreatening complications in Kabuki syndrome. Am J Med Genet 94: 170, 2000.

Liver, Gallbladder, and Pancreas 37. Annere´n G, Meurling S, Lilja H, et al.: Lethal autosomal recessive syndrome with intrauterine growth retardation, intra- and extrahepatic biliary atresia, and esophageal and duodenal atresia. Am J Med Genet 78:306, 1998. 38. Gentile M, Fiorente P: Esophageal, duodenal, rectoanal and biliary atresia, intestinal malrotation, malformed/hypoplastic pancreas, and hypospadias: further evidence of a new distinct syndrome. Am J Med Genet 87:82, 1999. 39. Martı´nez-Frı´as ML, Frı´as JL, Gala´n E, et al.: Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency. Am J Med Genet 44:352, 1992. 40. Ikeda S, Sera Y, Yoshida M, et al.: Extrahepatic biliary atresia associated with trisomy 18. Pediatr Surg Int 15(2):137, 1999. 41. Windmiller J, Marks JF, Reimold EW, et al.: Trisomy 18 with biliary atresia. J Pediatr 67:327, 1965. 42. Schinzel A: Catalogue of Unbalanced Chromosome Aberrations in Man, ed 2. Walter de Gruyter, Berlin, 2001. 43. Warkany J, Passarge E, Smith LB: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502, 1966. 44. Alpert LI, Strauss L, Hirschhorn K: Neonatal hepatitis and biliary atresia associated with trisomy 17-18 syndrome. N Engl J Med 280:16, 1969. 45. Odievre M, Valayer J, Razemon-Pinta M, et al.: Hepatic portoenterostomy or cholecystostomy in the treatment of extrahepatic biliary atresia. A study of 49 cases. J Pediatr 88:774, 1976. 46. Barkin RM, Lilly JR: Biliary atresia and the Kasai operation: continuing care. J Pediatr 96:1015, 1980. 47. Hays DM, Altman P, Hitch DC, et al.: Biliary atresia in the United States: the survey of the surgical section, American Academy of Pediatrics. In: Biliary Atresia and Its Related Disorders. M Kasai, ed. Excerpta Medica, Amsterdam, 1983, p 161. 48. Ohi R: A history of the Kasai operation: hepatic portoenterostomy for biliary atresia. World J Surg 12:871, 1988. 49. Kasai M, Mochizuki I, Ohkohchi N, et al.: Surgical limitation for biliary atresia: indication for liver transplantation. J Pediatr Surg 24:851, 1989. 50. Bates MD, Bucuvalas JC, Alonso MH, et al.: Biliary atresia: pathogenesis and treatment. Semin Liver Dis 18(3):281, 1998. 51. Ohi R, Hanamatsu M, Mochizuki I, et al.: Reoperation in patients with biliary atresia. J Pediatr Surg 20:256, 1985. 52. Hoffman MA, Celli S, Ninkov P, et al.: Orthotopic transplantation of the liver in children with biliary atresia and polysplenia syndrome: report of two cases. J Pediatr Surg 24:1020, 1989. 53. Otte JB, Eucher Ph, Latour JP, et al.: Liver transplantation for biliary atresia: indications and results. Z Kinderchir 43:99, 1988.

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27.6 Cysts of the Biliary System Definition

Cysts of the biliary system are cystic dilations of the extrahepatic biliary tract, including choledochal cysts and megacystis. Diagnosis

Choledochal cysts, Caroli disease (intrahepatic dilation of major branches of the lobar ducts), congenital hepatic fibrosis, and polycystic liver (and kidney) disease have each been observed in association with the others, suggesting that all cystic malformations of the biliary system may be etiologically and/or pathogenetically related.1 These entities are discussed separately because they may present with somewhat different findings and may have different therapeutic implications. Choledochal Cysts

A classification system is illustrated in Figure 27-14. Cystic dilation of the common duct may become very large. Most commonly there is dilation of the common duct itself (type I) or, rarely, dilation in a diverticulum of the common duct wall (type II).2–4 Of cases presenting in childhood, over 90% have been reported as type I and 75% of the remainder as type II.5 The dilated region is usually sharply demarcated, and the common duct below the cystic area may appear narrowed.6 The intrahepatic tree is usually normal, but closer examination may reveal that some type I cysts actually have associated intrahepatic or extrahepatic cysts. These may then be classified as type IV-A with associated intrahepatic cysts and IV-B with associated extrahepatic cysts. When a cyst involves only the part of the duct in the wall of the duodenum where the common bile duct and pancreatic duct empty, it is called a choledochocele or a type III cyst. Rarely the cystic duct or the intrahepatic ducts are significantly involved or drain directly into the cystic area.7 Single or multiple intrahepatic cysts are classified as type V cysts and appear to be rare. This category overlaps and blends into Caroli disease, a condition characterized by intrahepatic dilation of major ducts. (Section 27.2) Choledochal cysts may remain asymptomatic throughout childhood, but they may be found in young infants or in adults with

Fig. 27-14. Common types (I, II, and III) of choledochal cysts. Type I is a cystic dilation of the common duct. Type II is a diverticulum in the wall of the common duct. Type III is a choledochocele, a cystic dilation of the distal portion of the common duct in the duodenal wall.

1146

Gastrointestinal and Related Structures

histories of symptoms since childhood. Presenting symptoms include biliary colic, jaundice, and a palpable abdominal mass in the right upper quadrant. This classic clinical triad is only seen in approximately 25% of patients.8–11 A correct diagnosis is frequently not made until after the 1st year of life, because early symptoms can be mild or intermittent. In one large review, 18% of cases were diagnosed in infants under age 1 year, and 83% were diagnosed by age 30 years.6 Occasional patients present with symptoms of acute pancreatitis. Preoperative diagnosis may be difficult, but ultrasound is especially helpful in diagnosing a choledochal cyst in an infant. Hepatobiliary scintigraphy and endoscopic retrograde cholangiography may also be very useful. Choledochal cysts usually are nonsyndromic (i.e., usually not associated with primary malformations of other organ systems), but they may occur in association with other anomalies of the hepatopancreatobiliary duct system, including gallbladder agenesis, double gallbladder, accessory or aberrant hepatic ducts, anomalous pancreatic duct draining into the cyst, pancreas divisum, parallel or unfused right and left hepatic ducts, and common duct hypoplasia or atresia.3,7 Megacystis

At least one case of what appeared to be a syndromic cystic gallbladder has been observed.12 A patient with imperforate anus had, at the end of the cystic duct, a large multiloculated cystic mass that extended into the right lobe of the liver. No other gallbladder structure was identified. Etiology and Distribution

It is commonly assumed that most choledochal cysts are congenital, but it is not clear in most cases whether the pathogenetic process is primarily obstruction below the cystic area, weakness in the wall of the dilated segment, or reflux cholangitis.8,13 Cystic dilation in a diverticulum may be the result of a localized area of weakness in the wall of the duct.2 One theory implicates unequal proliferation of bile duct epithelium at the time of duct recanalization.3,4 As choledochal cysts are frequently associated with an anomalous pancreaticobiliary junction and/or abnormal function of the sphincter of Oddi, which may allow pancreatic secretions to reflux into the biliary system, it has been postulated that this would result in increased pressure within the common bile duct and lead to cyst formation.14 RT-PCR of Reovirus RNA has demonstrated significantly higher prevalence of this virus in biliary tissue from individuals with choledochal cysts than in controls (78% versus 21%, respectively), suggesting an infectious or autoimmune contribution.15 Familial recurrences have been rarely reported,16,17 indicating a possible genetic or environmental predisposition; however, Uchida et al.18 reported monozygotic twins that were discordant for an anomalous pancreaticobiliary junction and choledochal cyst. A hypothesis has been proposed that neonatal hepatitis, extrahepatic biliary atresia (EHBA), choledochal cysts in infants, and possibly some cases of intrahepatic biliary atresia without EHBA are all ‘‘ordinary manifestations or permissible outcomes of a single basic disease process called infantile obstructive cholangiopathy.’’19 Choledochal cysts occur so rarely that the true incidence has not been accurately determined, but it is probably less than one per million population.7 They seem to occur more commonly in Asian populations, for whom the male to female ratio is close to 1:1, than in Western cultures, for whom the male to female ratio is 1:4–1:5.3,6,10,20

Prognosis, Prevention, and Treatment

Once significant symptoms occur, surgery is usually necessary for the choledochal cyst.3 If untreated, cirrhosis occurs. Even delayed surgery may be very effective.10 Other complications include malignancy, rupture, calculi, and rarely portal hypertension and/or hemorrhage. Cholangiocarcinoma develops in 4–8% of patients, often after 20 years of age.21,22 Rupture may be caused by minor trauma.7 In spite of few abnormalities in liver function, affected patients may have mild to severe degrees of hepatic fibrosis. Because of the occasional association with other anomalies of the biliary tract, as precise an anatomic evaluation as possible must be performed prior to surgery. Response to surgery is usually very good if done early. If excision of the cyst is not possible, a choledochocystojejunostomy may be performed.23 References (Cysts of the Biliary System) 1. Thaler MM: Biliary disease in infancy and childhood. In: Gastrointestinal Disease, ed 4. MH Sleisenger, JS Fordtran, eds. WB Saunders Company, Philadelphia, 1989, p 1640. 2. Elias J, Skandalakis JE: Embryology for Surgeons, ed 2. Lippincott Williams & Wilkins, Philadelphia, 1993. 3. Ryckman FC, Noseworthy J: Neonatal cholestatic conditions requiring surgical reconstruction. Semin Liver Dis 7:134, 1987. 4. Crittenden SL, McKinley MJ: Choledochal cyst—clinical features and classification. Am J Gastroenterol 80:643, 1985. 5. Kim SH: Choledochal cyst: survey by the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg 16:402, 1981. 6. Alonso-Lej F, Rever WB Jr, Pessagno DJ: Congenital choledochal cyst, with a report of 2, and an analysis of 94 cases. Int Abstr Surg Gynecol Obstet 108:1, 1959. 7. PM Hatfield, RE Wise: Radiology of the Gallbladder and Bile Ducts. Williams & Wilkins, Baltimore, 1976. 8. Tsardakas EN, Robnett AH: Congenital cystic dilatation of the common bile duct: report of 3 cases, analysis of 57 cases, and review of literature. Arch Surg 72:311, 1956. 9. Klotz D, Cohn BD, Kottmeier PO: Choledochal cysts: diagnostic and therapeutic problems. J Pediatr Surg 8:271, 1973. 10. Valayer J, Alagille D: Experience with choledochal cyst. J Pediatr Surg 10:65, 1975. 11. Desmet VJ: The cholangiopathies. In: Liver Disease in Children, ed 2. FJ Suchy, RJ Sokol, WF Balistreri, eds. Lippincott Williams & Wilkins, Philadelphia, 2001. 12. Lobe TE, Hayden CK, Merkel M: Giant congenital cystic malformation of the gallbladder. J Pediatr Surg 21:447, 1986. 13. Babbitt DP, Starshak RJ , Clemett AR: Choledochal cyst: a concept of etiology. Am J Roentgenol Rad Ther Nucl Med 119:57, 1973. 14. Metcalfe MS, Wemyss-Holden SA, Maddern GJ: Management dilemmas with choledochal cysts. Arch Surg. 138:333–9, 2003. 15. Tyler KL, Sokol RJ, Oberhaus SM, et al.: Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 27:1475, 1998. 16. Iwata F, Uchida A, Miyaki T, et al.: Familial occurrence of congenital bile duct cysts. J Gastroenterol Hepatol 13:316, 1998. 17. Lane GJ, Yamataka A, Kobayashi H, et al.: Different types of congenital biliary dilatation in dizygotic twins. Pediatr Surg Int 15:403, 1999. 18. Uchida M, Tsukahara M, Fuji T, et al.: Discordance for anomalous pancreaticobiliary ductal junction and congenital biliary dilatation in a set of monozygotic twins. J Pediatr Surg 27:1563, 1992. 19. Landing BH: Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 6:113, 1974. 20. Han SY, Collins LC, Wright RM: Choledochal cyst: report of five cases. Clin Radiol 20:332, 1969. 21. Yamaguchi M: Congenital choledochal cyst. Analysis of 1,433 patients in the Japanese literature. Am J Surg 140:653, 1980.

Liver, Gallbladder, and Pancreas

1147

Variant structure of the gallbladder and extrahepatic biliary ducts occurs commonly.4–7 It has been stated that the extrahepatic biliary tree has more anomalies than any other area of the body. The prevalence of anatomic variation in this region is close to 50%.6 The significance of this observation becomes apparent when one realizes that this is also one of the most common areas explored by surgeons. Over half a million cholecystectomies are performed each year in the United States and the presence of anomalies and variant structure may be a major causative factor in surgical complica-

tions.8 Hepatobiliary scanning may be helpful in diagnosing some variants prior to surgical exploration.9 Many anatomic variations are asymptomatic and found incidentally at surgery, radiography, or autopsy. Figure 27-15 shows the ‘‘normal’’ or usual configuration. Minor anomalies and variants include aberrant (sometimes called accessory) hepatic ducts (Fig. 27-16); duplication of the common duct;10 numerous variations in the configuration of the hepatic ducts and common duct (Fig. 27-17); ectopic orifice of the common duct (in the stomach or proximal duodenum); asymptomatic absence of the gallbladder (Section 27.4); multiple gallbladders1–3,11; septation of the gallbladder; congenital variation in gallbladder shape; ectopic position of the gallbladder (left-sided, free floating, retrodisplaced, retroperitoneal, transverse, suprahepatic, supradiaphragmatic, in the falciform ligament, in the mesocolon, in the abdominal wall); and anomalous junction between the cystic and common ducts. Gallbladder hypoplasia or ‘‘microgallbladder’’ is usually seen in association with and presumably secondary to cystic fibrosis. References at the end of this entry include detailed descriptions from surveys and reviews of the numerous anatomic variations observed in humans.6–8,12–15 Anomalies of potential pathologic significance include cystic duct draining into the left side of the main duct (Fig. 27-18) or rarely directly into the duodenum, aberrant hepatic duct with dorsocaudal branch draining into the common duct, unusually mobile gallbladder, double common duct,16 ‘‘interposed gallbladder’’ (anomalous insertion of both hepatic ducts into the gallbladder with the cystic duct draining into the duodenum),17 intrahepatic gallbladder, intrahepatic junction of the hepatic ducts,18 situs inversus (Section 5.1), gallbladder agenesis (Section 27.4) when symptomatic or associated with other anomalies, choledochal cyst (Section 27.6), and extrahepatic biliary atresia (Section 27.5).

Fig. 27-15. a. Percutaneous cholangiogram demonstrating normal collecting system anatomy. (Radiograph courtesy of Dr. M. Mauro, Department of Radiology, University of North Carolina Hospitals, Chapel Hill, NC.) b. Drawing of normal duct system from radiograph.

(A, anterior branch of right hepatic duct; P, posterior or dorsocaudal branch of right hepatic duct; R, right hepatic duct; L, left hepatic duct; H, common hepatic duct; G, gallbladder; Cy, cystic duct; C, common duct.)

22. Todani T, Watanabe Y, Narusue M, et al.: Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg 134:263, 1977. 23. Lapointe R, Gamache A, Pare P: Bile-duct cyst with cystlithiasis: a case report. Can J Surg 27:271, 1984.

27.7 Structural Variation and Miscellaneous Anomalies of the Gallbladder and Extrahepatic Ducts Definition

Structural variation and miscellaneous anomalies of the gallbladder and extrahepatic ducts include accessory ducts, positional alterations, duplications, and anomalies of the gallbladder and extrahepatic ducts. These anomalies are frequently asymptomatic but may have pathologic significance. Gallbladder duplication includes double gallbladder, triple gallbladder, septate gallbladder, bifid gallbladder, and bilobed gallbladder.1–3 Diagnosis

1148

Gastrointestinal and Related Structures

Fig. 27-16. Aberrant duct draining right lobe.

Only rarely are true ‘‘accessory’’ ducts present connecting the major ducts. Normally there is no intrahepatic interductal communication. Anomalous ducts, when present, are usually necessary for drainage of the portion of liver to which they are connected and therefore should be considered ‘‘aberrant’’ rather than ‘‘accessory.’’15 They vary in size from tiny and threadlike to very large with corresponding variation in the area of liver being drained. Most commonly, anomalous hepatic ducts emerge from the right side of the liver and empty into the gallbladder, the cystic duct, or the common duct (Fig. 27-16).5,19 Rarely, aberrant ducts drain portions of the left side of the liver. Occasionally, there is anomalous insertion of the posterior or dorsocaudal branch into the junction between the right and left hepatic branches (called trifurcation) (Fig. 27-19a) or into the left hepatic branch (Fig. 27-19b). The clinical significance of the latter is that complete surgical removal of the left lobe is not possible because ligation of the posterior branch would produce cirrhosis in portions of the remaining right lobe. Positional Alterations

Rarely the gallbladder may be intrahepatic or left-sided, lying underneath the left lobe. Even rarer are reports of other positions such as suprahepatic in the absence of right lobe aplasia, retroperitoneal, and in the anterior abdominal wall. Suprahepatic positioning of the gallbladder has been observed in association with eventration of the diaphragm and ‘‘inversion’’ of the liver.20 A patient with BeckwithWiedemann syndrome has been described with the gallbladder embedded in an accessory lobe of the liver.21 Septation

The gallbladder may have a septum dividing the cavity into two parts (septate gallbladder). These parts may be partially or completely separated, leading to a bilobed gallbladder with a single cystic duct (‘‘vesica divisa’’). Some authors think of these malformations as duplications, while others make a distinction between these and

Fig. 27-17. Short common duct with low point of joining of left and right ducts.

Fig. 27-18. Cystic duct drains into the left side of the common duct.

Fig. 27-19. a. Posterior (dorsocaudal) branch of the right hepatic duct inserts into the junction between the right and left hepatic ducts, the so-called trifurcation configuration. b. Posterior (dorsocaudal) branch of the right hepatic duct inserts into the left hepatic duct.

Liver, Gallbladder, and Pancreas

‘‘true’’ duplications. Cases of multiseptate gallbladder are rare (26 reported cases as of 2000) and are not considered part of the spectrum of gallbladder duplication but are more clearly due to defects in recanalization.3,22,23 Duplication

Occasionally, two separate gallbladders, each with its own cystic duct, may develop (‘‘vesica duplex’’). These gallbladder duplications may be found incidentally at autopsy, surgery, or radiography. Ryrberg24 noted that a double gallbladder with gallstone formation in a sacrificial animal was interpreted as an omen of victory by the ancient Babylonians and that Pliny the Elder commented on finding a double gallbladder in a sacrificial animal in 31 BC. There are no clinical symptoms that are specific. Controversy exists over whether these anomalies predispose to stone formation. The cystic ducts may join to form a single, Y-shaped cystic duct; the two cystic ducts may remain separate and both empty into the common duct, or one of the cystic ducts may connect elsewhere, such as into an hepatic duct. Occasionally the second or ‘‘accessory’’ gallbladder may be found in another site such as under the left lobe of the liver, imbedded within the liver, or within the gastrohepatic ligament. Multiple gallbladders may be missed by routine radiographic diagnostic studies, especially if one is nonvisualized because of disease. At least three surgically proven cases have been diagnosed by ultrasonography, but lack of resolution makes demonstration of two cystic ducts difficult with this technique.25 False-positive diagnoses have been caused by a folded gallbladder, choledochal cyst, phrygian cap, pericholecystic fluid, gallbladder diverticulum, a vascular band across the gallbladder, and focal adenomyomatosis.26 Etiology and Distribution

Variation in biliary tree structure has been found in 47% of patients undergoing primary biliary tract operations and 42% of patients having operative cholangiography.6,7 In the latter study, this was considered to be normal anatomic variation in 24% and variant structure with pathologic significance in 18% of the 3845 patients reviewed. Reported prevalence figures for anomalous bile ducts vary from 1.7–28%. Gallbladder duplication (either divisa or duplex) is a common anomaly in some animals, occurring in one of eight cats, one of 28 calves, one of 85 lambs and sheep, and one of 198 pigs, but it is a relatively rare anomaly in humans, occurring at a rate of less than one per 3000 autopsies.1 By 1977, double gallbladder had been reported in 207 patients and triple gallbladder in eight patients. The male to female ratio of reported cases up to 1977 was 1:1.68; the ratio was 1:1 in those found incidentally but 1:3 in those requiring surgery. This suggests that the actual incidence of this group of anomalies may be equal in the sexes, with a predominance of symptomatic gallbladder disease in females, as is true for disease in single gallbladders.3 There are probably several different pathogenetic mechanisms involved in the various forms of gallbladder duplication. These include the development of more than one pars cystica primordium at two different sites in the developing common duct, splitting of the pars cystica during the 5th and 6th weeks of development, growth of diverticula from the cystic duct or from intrahepatic ducts, or aberrant canalization after the solid stage of development. As in duct development, the formation of a ‘‘double-barreled,’’ septate, or duplicate configuration is thought sometimes to arise

1149

as the result of vacuolization occurring in two separate, nonconnecting rows during the canalization phase. On the other hand, it is also possible that some cases of septate or bilobed gallbladder (vesica divisa) arise through a splitting or division of the cystic primordium. Division of the primordium could also result in double gallbladders (vesica duplex) with separate cystic ducts (or Ytype configuration), but widely separated duplicate (accessory) gallbladders probably arise from double cystic primordia. Although some examples of accessory gallbladders in cats appear to have developed from the ventral pancreatic bud rather than from the pars cystica and a similar anomaly has been seen in at least one human specimen, the occasional finding of pancreatic tissue in the gallbladder wall should not be interpreted as indicating pancreatic origin in these cases.3 Prognosis, Prevention, and Treatment

These minor anomalies and variations become significant at surgery. Accidental severing of an anomalous duct may result in postoperative drainage leading to peritonitis. Ligation of an unrecognized duct may be symptomatic if the area of liver that is drained is large enough. In performing cholecystectomy on patients with an anomalous right hepatic duct that empties into the cystic duct, care must be taken to ligate the cystic duct between the gallbladder and the junction with the anomalous duct to maintain adequate drainage of the anomalous duct.19 Unrecognized anomalous ducts may also cause recurrence of symptoms after cholecystectomy. There is some suggestion that biliary anomalies may predispose to lithiasis.27 This seems to be a relatively uncommon complication considering the frequency of biliary tract structural variation. Lithiasis may be related to dysplastic hepatic anomalies such as Caroli disease (intrahepatic dilation of major branches of the lobar ducts), hepatic fibrosis, and polycystic disease; duct damage from regurgitation of pancreatic secretions (as in anomalous pancreaticobiliary duct union); or mechanical obstruction to gallbladder emptying caused by torsion of the cystic duct in cases of malpositioning (as has been suggested to account for the high incidence of stones in intrahepatic gallbladders). Malposition of the gallbladder may also lead to torsion and gangrene.28 It has been suggested that gallbladder duplication anomalies may predispose to disease, but the large number of healthy double gallbladders identified incidentally suggests that this effect, if any, may be very small. In one series, the age at diagnosis of gallbladder disease was several years younger in those with duplications than in those with single organs (43.5 compared with 51.3 years). Other authors suggest that ‘‘true’’ gallbladder duplication (vesica duplex) is frequently related to cholelithiasis and cholecystitis.29 Evaluation and treatment as usual are recommended for symptoms of cholecystitis. Patients with symptomatic multiple gallbladders generally benefit from removal of all of these cystic structures. When duplicate gallbladders are widely separated, only one may be diseased, while in closely positioned or connected organs, concordance for disease is more likely. When the condition is missed at surgery, subsequent reoperation may be required because of the persistence or reoccurrence of symptoms.8 Symptomatic duplication is usually reported in adults and only rarely in childhood. In one notable case, removal of double gallbladders from a 4-year-old girl resulted in cessation of her recurrent attacks of abdominal pain, jaundice, and vomiting and reversal of histologic features of progressive cirrhosis.29

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Gastrointestinal and Related Structures

References (Structural Variation and Miscellaneous Anomalies of the Gallbladder and Extrahepatic Ducts) 1. Boyden EA: The accessory gallbladder—an embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat 38:177, 1926. 2. Gross RE: Congenital anomalies of the gallbladder. Arch Surg 32:131, 1936. 3. Harlaftis N, Gray SW, Skandalakis JE: Multiple gallbladders. Surg Gynecol Obstet 145:928, 1977. 4. Michel NA: Blood Supply and Anatomy of the Upper Abdominal Organs. JB Lippincott, Philadelphia, 1955. 5. Elias J, Skandalakis JE: Embyrology for Surgeons, ed 2. Lippincott Williams & Wilkins, Philadelphia, 1993. 6. Hayes MA, Goldenberg IS, Bishop CC: The developmental basis for bile duct anomalies. Surg Gynecol Obstet 107:447, 1958. 7. Puente SO, Bannura GC: Radiological anatomy of the biliary tract: variations and congenital abnormalities. World J Surg 7:271, 1983. 8. Hamlin JA: Anomalies of the biliary tract. In: Bockus Gastroenterology, ed 4. JE Berk, ed. WB Saunders Company, Philadelphia, 1985, p 3486. 9. Reitz MD, Vasinrapee P: Anomalous insertion of the right hepatic duct into the cystic duct demonstrated by hepatobiliary imaging. Clin Nucl Med 13:61, 1988. 10. Hoyden EA: The problem of the double ductus choledochus (an interpretation of an accessory bile duct found attached to the pars superior of the duodenum). Anat Rec 55:71, 1932. 11. Harlaftis N, Gray SW, Olafson RP, et al.: Three cases of unsuspected double gallbladder. Am Surg 42:178, 1976. 12. Flannery MG, Caster MP: Congenital abnormalities of the gallbladder; 101 cases. Int Abstr Surg (Surg Gynecol Obstet) 103:439, 1956. 13. Hatfield PM, Wise RE: Anatomic variation in the gallbladder and bile ducts. Semin Roentgenol 11:157, 1976. 14. Hatfield PM, Wise RE: Radiology of the Gallbladder and Bile Ducts. Williams & Wilkins, Baltimore, 1976. 15. Hamlin JA: Biliary ductal anomalies. In: Operative Biliary Radiology. G Berci, JA Hamlin, eds. Williams & Wilkins, Baltimore, 1981, p 109. 16. Voitk AJ: Double barreled common bile duct: a threat to biliary surgery. Am J Surg 131:611, 1976. 17. Walia HS, Abraham TK, Baraka A: Gallbladder interposition: a rare anomaly of the extrahepatic ducts. Int Surg 71:117, 1986. 18. Stokes TL, Old L Jr: Cholecystohepatic duct. Am J Surg 135:703, 1978. 19. Reid SH, Cho SR, Shaw CI, et al.: Anomalous hepatic duct inserting into the cystic duct. AJR Am J Roentgenol 147:1181, 1986. 20. Hopper KD: Hepatic inversion with an epigastric gallbladder. Gastrointest Radiol 13:355, 1988. 21. Azmy A, Boddy SA, Eckstein HB: Torsion of gall bladder, embedded in an accessory lobe of liver in a neonate with Beckwith syndrome. Z Kinderchir Grenzgeb 30:277, 1980. 22. Shaw RB, Donato CA, Douglas DD, et al.: Multiseptate gallbladder diagnosed during pregnancy. Am Surg 41:818, 1975. 23. Miwa W, Toyama K, Kitamura Y, et al.: Multiseptate gallbladder with cholelithiasis diagnosed incidentially in an elderly patient. Intern Med 39(12):1054, 2000. 24. Ryrberg CH: Gallbladder duplication. Case report and review of the literature. Acta Chir Scand 119:36, 1960. 25. Garfield HD, Lyons EA, Levi CS: Sonographic findings in double gallbladder with cholelithiasis of both lobes. J Ultrasound Med 7:589, 1988. 26. Goiney RC, Schoenecker SA, Cyr DR, et al.: Sonography of gallbladder duplication and differential considerations. AJR Am J Roentgenol 145:241, 1985. 27. Nakanuma Y, Terada T, Nagakawa T, et al.: Pathology of hepatolithiasis associated with biliary malformation in Japan. Liver 8:287, 1988. 28. Dever RC: Suprahepatic gallbladder with torsion and gangrene. J Fla Med Assoc 55:531, 1968. 29. Granot E, Deckelbaum RJ, Gordon R, et al.: Duplication of the gallbladder associated with childhood obstructive biliary disease and biliary cirrhosis. Gastroenterology 85:946, 1983.

27.8 Pancreatic Agenesis Definition

Pancreatic agenesis is the congenital absence of the pancreas. Diagnosis

Patients with congenital absence of the pancreas present with intrauterine growth retardation and neonatal diabetes. Symptoms of exocrine pancreatic deficiency soon follow. Etiology and Distribution

Targeted disruption of the mouse insulin promotor factor 1 gene (Ipf1) results in pancreatic agenesis.1,2 The gene is expressed in both exocrine and endocrine progenitor cells in very early pancreas development. The human IPF1 gene maps to chromosome 13q12.1. Stoffers et al.3 identified homozygosity for an IPF1 frame shift mutation in a patient with pancreatic agenesis. The parents were heterozygous, and both of them had strong family histories of diabetes. Studies in this family showed that heterozygotes for the frame shift mutation are susceptible to a mild type of maturity-onset diabetes of the young, designated as MODY 4. At the time of the report, the authors could find only eight previously reported cases. Prognosis, Prevention, and Treatment

This condition is lethal if not diagnosed and treated early in the neonatal period. It is very rare, and success of long-term treatment is unknown. References (Pancreatic Agenesis) 1. Jonsson J, Ahlgren U, Edlund T, et al.: IPF1, a homeodomain protein with a dual function in pancreas development. Int J Dev Biol 39:789, 1995. 2. Jonsson J, Carlsson L, Edlund T, et al.: Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606, 1994. 3. Stoffers DA, Zinkin NT, Stanojevic V, et al.: Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106, 1997.

27.9 Structural Variation and Anomalies of the Pancreas Definition

Annular pancreas refers to a ring- or horseshoe-shaped mass of pancreatic tissue that encircles the duodenum. Pancreas divisum refers to a situation that occurs when the two embryonic pancreatic buds fail to fuse completely, resulting in two separate dorsal and ventral ducts with lack of communication between them. Diagnosis

While variation in pancreatic structure is not uncommon, symptomatic developmental anomalies seem to occur relatively rarely. Endoscopic retrograde cholangiopancreatography (ERCP) has proved to be a valuable tool for diagnosing the developmental variants that occur in this area, especially those with anomalous development of the duct system.1–3 Computed tomography and angiography may also be useful.4–6 Annular pancreas and pancreas divisum can both be present in the same patient.7–9

Liver, Gallbladder, and Pancreas

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Fig. 27-20. Lecco’s theory of annular pancreas development. The ventral pancreatic anlage (VP) becomes fixed at its free end. During its subsequent migration toward the dorsal pancreatic anlage (DP) with rotation of the duodenum (D), the ventral anlage is drawn out. With fusion of the two anlagen, the pancreas comes to surround the duodenum. (From Howard,28 used by permission of Surgery, Gynecology, and Obstetrics.)

Annular Pancreas

Annular pancreas usually occurs at the level of the normal pancreas but may occur anywhere along the duodenum (Fig. 27-20).10–12 It may be completely asymptomatic, presenting as a coincidental finding at autopsy, or it may cause problems in infancy or later adult life. When symptomatic in young infants, annular pancreas presents with vomiting, usually due to obstruction of the descending duodenum. Epigastric distension is frequently present. Pressure on the common duct may produce obstructive jaundice. Polyhydramnios is a prenatal indicator of significant obstruction.13,14 Annular pancreas may also be symptomatic later in adult life, typically presenting between ages 30 and 50 years.7 Epigastric pain and vomiting can be of relatively recent onset or chronic and recurrent over a period of years. Jaundice is also seen in adults. The diagnosis may be missed on routine laparotomy. Some patients have had previous unsuccessful operations for gallbladder disease, with their annular pancreas being diagnosed later. Patients who have jaundice as one presenting symptom seem to be at increased risk for this kind of misdiagnosis. The diagnosis of annular pancreas should be suspected in a neonate with epigastric fullness, vomiting, and a plain abdominal radiograph that shows a ‘‘doublebubble’’ sign. This radiographic sign is due to gas in the stomach and dilated duodenal bulb, with none extending further beyond the area of duodenal constriction. Diagnosis may be aided further by upper gastrointestinal tract radiographic studies showing a smooth, concentric duodenal obstruction that does not vary from film to film, small mucosal folds in the constricted region, and a dilated duodenal bulb. ERCP may provide more definitive evidence by outlining the configuration and course of the pancreatic duct of Wirsung throughout the ring of pancreatic tissue.2,8 When symptomatic in children, annular pancreas is frequently associated with other anomalies (Table 27-5). Duodenal stenosis or atresia occurs most commonly.10,13 In one series, the incidence of associated anomalies in children was 70%.15 These other anomalies are frequently lethal.10 Associated anomalies are less commonly found in adults with annular pancreas, but the frequency is as high as 14–25% in some series.7,10,12 Symptomatic annular pancreas is not usually associated with mental retardation, but it has been observed in a man with seizures

and an IQ of 75.16 Although this association is probably coincidental, the authors noted with interest that the patient’s seizures disappeared completely after surgery and suggested that the seizure activity may have been triggered by the episodes of abdominal pain. Another isolated report describes annular pancreas with duodenal obstruction in a patient with features of Brackmann–de Lange syndrome.17 Pancreas Divisum

Characteristically, in pancreas divisum, the two ducts fail to fuse normally, and the dorsal body and tail are drained by the duct of Santorini while the ventral segment that makes up the head of the

Table 27-5. Anomalies associated with annular pancreas7,10,12,15,18 System

Anomalies

Cardiovascular

Occasional patients reported with ‘‘multiple defects’’ or ‘‘congenital heart disease’’ otherwise unspecified, also tricuspid atresia, tetralogy of Fallot, patent ductus arteriosus, patent foramen ovale

CNS

‘‘Cerebral agenesis,’’ microcephaly

Craniofacial

Cleft palate

Gastrointestinal, other abdominal

Duodenal atresia or stenosis, duodenal bands, colon malrotation, gastric ulcer, duodenal ulcer, esophageal atresia with tracheoesophageal fistula, imperforate anus, portal vein over duodenum, intramesenteric hernia

Genitourinary

Cryptorchidism, agenesis of kidney and ureter, horseshoe kidney, cross-fused ectopic kidney, urethral stenosis, polycystic kidney disease

Liver, gallbladder, biliary tract

Liver hemangioma, common duct atresia or stenosis associated with doudenal atresia or stenosis, gallbladder agenesis

Respiratory

Diaphragmatic hernia, agenesis of right lung

Skeletal

Clubfoot, Sprengel anomaly, spine deformity, polydactyly

Other

Pelvic dermoid cyst

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pancreas is drained by a small duct of Wirsung (Fig. 27-21).19–25 This is sometimes referred to as isolated ventral pancreas. Two other variations include an ‘‘incomplete’’ form in which there is a very small, hypoplastic communication between the two ducts and another where the ventral duct of Wirsung has disappeared entirely.26 Dominant dorsal duct syndrome refers to all of these structural variants. These variations are usually asymptomatic. As discussed below, controversy exists over whether pancreas divisum and its variants predispose one to develop pancreatitis. Some feel strongly that these are normal structural variants without clinical significance, while others believe with equal conviction that some predisposition to pancreatic disease is associated.25,26 Some of the contradictions produced by different reports may be due to differences in definitions, ascertainment biases, and the difficulty with which a demonstration of papillary stenosis is made. Etiology and Distribution

The main body and tail of the pancreas are formed from the original dorsal pancreatic bud, which arises from the dorsal wall of the duodenum. The ventral bud has right and left parts.10,27 The right-sided portion of this ventral bud rotates from its initial position to the right of the midline, dorsally around the right side of the gut, eventually fusing with the dorsal bud and forming the head of the pancreas. This apparent rotation comes about as the result of differential growth of the duodenum. The left side of the ventral bud atrophies or is hypoplastic and never develops. The most commonly accepted theory of annular pancreas formation was suggested by Lecco in 1910 and restated by numerous authors since.28 The proposed sequence of events begins with the ventral pancreatic bud becoming adherent to tissue at the anterior aspect of the duodenum and therefore becoming fixed before rotating dorsally to fuse with the dorsal bud.7,12 The ventral bud is drawn out during the process of ‘‘rotation’’ or migration and forms a ring around most or all of the duodenum.

Fig. 27-21. Common pancreatic ductal variants. (From Warshaw et al.,26 used by permission of the American Journal of Surgery.)

Other theories of annular pancreas formation have been proposed, including overgrowth of both dorsal and ventral buds around both sides of the duodenum, a consolidation of heterotopic pancreatic tissue, and persistent growth (instead of atrophy) of the left side of the ventral bud.29,30 Analysis of the duct system present in annular pancreas specimens suggests that the mechanism proposed by Lecco is probably responsible for most cases.28,31 Immunohistochemical studies have been used to show that the tissue comprising a ring was derived from the ventral pancreatic bud.8 Although rare, annular pancreas is the most common malformation of the pancreas, being found in 12% of 300 patients who entered Boston Children’s Hospital with a pancreatic disorder over a period of 46 years.32 Well over 300 cases have been reported.11,12 The reported incidence in surgical and autopsy series varies over a wide range, from less than one per 28,000 to one per 6667.7,12 A slight male predominance appears to occur at all ages.10,12 Two fetuses with annular pancreas were found among 3307 induced abortuses, suggesting that the true incidence of this developmental anomaly may be much higher than that estimated from postnatal autopsy or surgical series.33 The most common multiple anomaly syndrome associated with annular pancreas is Down syndrome.15,34,35 Two recent studies demonstrate a greater than 300-fold risk for this anomaly in children with Down syndrome over non-Down syndrome births.36,37 Duodenal atresia is associated with Down syndrome, and some of these are due to annular pancreas. As many as 15–20% of infants who present with obstructive symptoms due to annular pancreas have this condition.15,30,38 Conversely, in a series of 2421 children with Down syndrome, 63 presented with symptoms of duodenal obstruction, and 15 of those had annular pancreas.39 It should be noted that this is an underestimation of the true frequency of annular pancreas in Down syndrome, because individuals with asymptomatic annular pancreas were not identified in this study. Evidence that annular pancreas can be caused by a dominantly expressed mutation in a single autosomal gene has been presented by means of four families with affected individuals in two generations.40–43 All families involved affected children of affected mothers. Two reports of affected sib pairs have been reported: a male and female pair in one,44 and two female siblings in the other.45 The parents were asymptomatic in both families; however, no further imaging studies were reported. Since annular pancreas may be asymptomatic, these families may represent variable expression of a dominant trait rather than recessive inheritance. A syndrome of multiple gastrointestinal anomalies (OMIM 601346) reported in two families among sibs and in one isolated case has annular or hypoplastic pancreas associated with duodenal atresia as well as multiple other anomalies including esophageal atresia and fistula, rectoanal atresia, biliary atresia, malrotation, congenital heart defects, and hypospadias.46–48 Annular pancreas has been observed in three unrelated neonates with abdominal heterotaxia characterized by left-sided liver, right-sided stomach and spleen, and apparent thoracic situs solitus.49 None of the patients had polysplenia or asplenia. One of two brothers reported by Toriello et al.50 who had polysplenia and variable manifestations of situs abnormalities also had an annular pancreas. These observations gave rise to the suggestion that a ‘‘multiple organ malrotation syndrome’’ (MOMS) exists that results from event(s) that interfere with the normal rotation experienced by these organs between 5 and 6 weeks gestation. Pancreas divisum, or failure of total fusion of the dorsal and ventral pancreatic buds, is not rare but probably occurs in at least 2–3% of the general population, with a range of incidences from less

Liver, Gallbladder, and Pancreas

than 1% to over 5% reported in different series.19–22,25,51 Close to 10% of individuals in Western populations have one of the three structural variations characterized by the presence of a functionally dominant dorsal duct.26 These therefore are considered normal variants. A subgroup appears to have, in addition, stenosis of the accessory papilla, which may be related to the development of symptoms and clinical presentation with pancreatitis. The male to female ratio for pancreas divisum was 0.92:1 in one series of 357 cases.25 Other structural abnormalities of the pancreas have been reported in association with polysplenia and situs abnormalities, including short pancreas52 and absence of the body and tail.53 Prognosis, Prevention, and Treatment

Annular pancreas may cause duodenal atresia that presents immediately in the newborn period. This appears to be due to a mechanically compromised vascular supply to this region of the bowel caused by the annular pancreas. If annular pancreas causes these symptoms, it is usually early in infancy. Those not symptomatic at this early stage rarely cause significant problems later in life. Pancreatitis may occur in an annular pancreas because abnormal and inadequate development of the duct system in the extra segment does not provide adequate drainage of the pancreatic tissue present.7 Adult patients with annular pancreas who present with abdominal pain occasionally have associated duodenal ulcers. Treatment of the symptomatic annular pancreas in infants and adults usually involves bypassing the constricted region with a duodenojejunostomy. The annular pancreas itself cannot be divided or removed easily because of the high incidence of complications such as interference with pancreatic duct function, pancreatitis, or pancreatic duct fistula that results from surgical manipulation of that area.7,12 In one patient with severe, chronic pancreatitis associated with both pancreas divisum and an annular pancreas, complete relief of symptoms was achieved by pancreatoduodenectomy.8 The clinical significance of pancreas divisum and its variants is somewhat controversial. Many authors have presented data suggesting that this anomaly predisposes one to develop acute or chronic pancreatitis.19,24,54,55 Others, however, find no significant difference in the prevalence of pancreas divisum between groups of patients with and without pancreatitis.20,25,56 Some evidence suggests that the factor of critical importance in producing pancreatitis is a stenosis of the accessory opening of the duct of Santorini, which interferes with drainage.26 When pancreas divisum or one of its variants is found in a patient with recurrent pancreatitis, sphincteroplasty of one or both pancreatic ducts is frequently recommended.24,26 Pancreatitis is usually, but not invariably, cured after such a procedure. Patients with stenosis seem to respond best to surgery. After accessory papilla sphincteroplasty, 85% of patients with stenosis improved compared with a 27% improvement rate observed in those patients in whom no stenosis could be demonstrated.26 References (Structural Variation and Anomalies of the Pancreas) 1. Glazer GM, Margulis AR: Annular pancreas: etiology and diagnosis using endoscopic retrograde cholangiopancreatography. Radiology 133:303, 1979. 2. Dharmsathaphorn K, Burrell M, Dobbins J: Diagnosis of annular pancreas with endoscopic retrograde cholangiopancreatography. Gastroenterology 77:1109, 1979. 3. Bluestone PK, Gaskin K, Filler R, et al.: Endoscopic retrograde cholangiopancreatography in pancreatitis in children and adolescents. Pediatrics 68:387, 1981.

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4. Nguyen KT, Pace R, Groll A: CT appearance of annular pancreas: a case report. Can Assoc Radiol 140:322, 1989. 5. Novetsky GJ, Berlin L, Smith C, et al.: CT diagnosis of annular pancreas. J Comput Assist Tomogr 8:1031, 1984. 6. Degryse HR, Duyck PC, Van Hedent EF, et al.: Vascular ring in annular pancreas associated with rare variant of celiac trunk. Case report. Eur J Radiol 7:63, 1987. 7. Lloyd-Jones W, Mountain JC, Warren KW: Annular pancreas in the adult. Ann Surg 176:163, 1972. 8. Dowsett JF, Rode J, Russell RC: Annular pancreas: a clinical, endoscopic, and immunohistochemical study. Gut 30:130, 1989. 9. Lehman GA, O’Connor KW: Coexistence of annular pancreas and pancreas divisum ERCP diagnosis. Gastrointest Endosc 31:25, 1985. 10. Kiesewetter WB, Koop CE: Annular pancreas in infancy. Surgery 36:146, 1954. 11. Ravitch MM: The pancreas in infants and children. Surg Clin North Am 55:377, 1975. 12. Kiernan PD, ReMine SG, Kiernan PC, et al.: Annular pancreas: Mayo Clinic experience from 1957 to 1976 with review of the literature. Arch Surg 115:46, 1980. 13. Merrill JR, Raffensperger JG: Pediatric annular pancreas: twenty years’ experience. J Pediatr Surg 11:921, 1976. 14. Boomsma JH, Weemhoff RA, Polman HA: Sonographic appearance of annular pancreas in utero. A case report. Diagn Imaging 51:288, 1982. 15. Jackson JM: Annular pancreas and duodenal obstruction in the neonate. Arch Surg 87:379, 1963. 16. Singer D, Weintraub S, Assael M: Annular pancreas in an adult associated with epilepsy and borderline retardation: a case report. J Clin Dysmorphol 2(3):20, 1984. 17. Wick MR, Simmons PS, Ludwig J, et al.: Duodenal obstruction, annular pancreas, and horseshoe kidney in an infant with Cornelia de Lange syndrome. Minn Med 65:539, 1982. 18. Manning RJ: Annular pancreas associated with cross-fused ectopic kidney. J Arkansas Med Soc 84:329, 1988. 19. Gregg JA: Pancreas divisum: its association with pancreatitis. Am J Surg 134:539, 1977. 20. Mitchell CJ, Lintott DJ, Ruddell WSJ, et al.: Clinical relevance of an unfused pancreatic duct system. Gut 20:1066, 1979. 21. Cotton PB: Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis. Gut 21:105, 1980. 22. Thompson MH, Williamson RC, Salmon PR: The clinical relevance of isolated ventral pancreas. Br J Surg 68:101, 1981. 23. Cooperman M, Ferrar JJ, Fromkes JJ, et al.: Surgical management of pancreas divisum. Am J Surg 143:107, 1982. 24. Bernstein D, Ferrera J, Caren L: The medical and surgical management of pancreas divisum. Surg Rounds 7:64, 1983. 25. Delhaye M, Engelholm L, Cremer M: Pancreas divisum: controversial clinical significance. Dig Dis 6:30, 1988. 26. Warshaw AL, Simeone JF, Schapiro RH, et al.: Evaluation and treatment of the dominant dorsal duct syndrome (pancreas divisum redefined). Am J Surg 159:59, 1990. 27. Patten BM: Human Embryology, ed 3. McGraw-Hill, New York, 1968. 28. Howard NJ: Annular pancreas. Surg Gynecol Obstet 50:533, 1930. 29. Baldwin WM: A specimen of annular pancreas in association with other developmental abnormalities. Anat Rec 4:299, 1910. 30. Elias J, Skandalakis JE: Embryology for Surgeons, ed 2. Lippincott Williams & Wilkins, Philadelphia, 1993. 31. Ikeda Y, Irving IM: Annular pancreas in a fetus and its three dimensional reconstruction. J Pediatr Surg 19:160, 1984. 32. Welch KJ: The pancreas. In: Pediatric Surgery, ed 4. KJ Welch, JG Randolph, MM Ravitch, et al., eds. Year Book Medical Publishers, Chicago, 1986, p 1086. 33. Kirillova IA, Kulazhenko VP, Kulazhenko LG, et al.: Pancreas annulare in human embryos. Acta Anat 118:214, 1984. 34. Warkany J, Passarge E, Smith LB: Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 112:502, 1966. 35. Milunsky A, Fisher JH: Annular pancreas in Down’s syndrome. Lancet 2:575, 1968.

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36. Ka¨lle´n B, Mastroiacovo P, Robert E: Major congenital malformations in Down syndrome. Am J Med Genet 65:160, 1996. 37. Torfs CP, Christianson RE: Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet 77:431, 1998. 38. Knox GB, ten Bensel RW: Gastrointestinal malformations in Down’s syndrome. Minn Med 55:542, 1972. 39. Fabia J, Drolette M: Malformations and leukemia in children with Down’s syndrome. Pediatrics 45:60, 1970. 40. Jackson LG, Apostolides P: Autosomal dominant inheritance of annular pancreas. Am J Med Genet 1:319, 1978. 41. MacFadyen OM, Young ID: Annular pancreas in mother and son. Am J Med Genet 27:987, 1987. 42. Rogers JC, Harris DJ, Holder T: Annular pancreas in a mother and daughter. Am J Med Genet 45:116, 1993. 43. Hendricks SK, Sybert VP: Association of annular pancreas and duodenal obstruction—evidence for Mendelian inheritance Clin Genet 39:383, 1991. 44. Montgomery RC, Poindexter MH, Hall GH, et al.: Report of a case of annular pancreas of the newborn in two consecutive siblings. Pediatrics 48:148, 1971. 45. Claviez A, Heger S, Bohring A: Annular pancreas in two sisters. Am J Med Genet 58:384, 1995. 46. Martı´nez-Frı´as ML, Frı´as JL, Gala´n E, et al.: Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency. Am J Med Genet 44:352, 1992. 47. Annere´n G, Meurling S, Lilja H, et al.: Lethal autosomal recessive syndrome with intrauterine growth retardation, intra- and extrahepatic biliary atresia, and esophageal and duodenal atresia. Am J Med Genet 78:306, 1998. 48. Gentile M, Fiorente P: Esophageal, duodenal, rectoanal and biliary atresia, intestinal malrotation, malformed/hypoplastic pancreas, and hypospadias: further evidence of a new distinct syndrome. Am J Med Genet 87:82, 1999. 49. Adeyemi SD: Combination of annular pancreas and partial situs inversus: a multiple organ malrotation syndrome associated with duodenal obstruction. J Pediatr Surg 23:188, 1988. 50. Toriello HV, Kokx N, Higgins JV, et al.: Sibs with the polyasplenia developmental field defect. Am J Med Genet Suppl 2:31, 1986. 51. Griboski J: The pancreas. Gastrointestinal problems in the infant. Major Probl Clin Pediatr 13:450, 1975. 52. Wainwright H, Nelson M: Polysplenia syndrome and congenital short pancreas. Am J Med Genet 47:318, 1993. 53. Ming JE, McDonald-McGinn DM, Markowitz RI, et al.: Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia, and multicystic dysplastic kidneys: expanding the phenotype of Cumming syndrome. Am J Med Genet 73:419, 1997. 54. Richter JM, Schapiro RH, Mulley AG, et al.: Association of pancreas divisum and pancreatitis, and its treatment by sphincteroplasty of the accessory ampulla. Gastroenterology 81:1104, 1981. 55. Britt LG, Samuels AD, Johnson JW Jr: Pancreas divisum: is it a surgical disease? Ann Surg 197:654, 1983. 56. Hayakawa T, Kondo T, Shibata T, et al.: Pancreas divisum. A predisposing factor to pancreatitis. Int J Pancreat 5:317, 1989.

27.10 Pancreatic Cysts and Dysplasias Definition

Pancreatic cysts and dysplasias are congenital cystic and dysplastic changes in the pancreas, with or without functional pancreatic deficiency. Diagnosis

True congenital or developmental cysts of the pancreas are rare.1,2 When present, they are lined with epithelium and found most

commonly in that part of the pancreas derived from the dorsal bud. They may be single, multiloculated, or multiple and scattered along the length of the body of the pancreas.3 Most congenital pancreatic cysts are multiple and often associated with disorders that primarily affect other organ systems (i.e., autosomal recessive polycystic kidney disease, autosomal dominant polycystic kidney disease, Von Hippel-Lindau disease, cystic fibrosis), while solitary pancreatic cysts results from anomalous development of the pancreatic ducts.4 Cysts usually grow to a large size (sometimes up to 6–8 inches in diameter) before causing symptoms, which are usually due to pressure of the enlarging mass on other structures such as the stomach, large bowel, and common bile duct. Ultrasonography is an excellent tool to use in screening for cysts of the pancreas.5 Computed tomography and magnetic resonance imaging have largely replaced angiography and radionuclide scanning as a second-level technique to provide more anatomic detail. Upper and lower gastrointestinal tract radiography with radiopaque contrast material may show displacement of the stomach and/or the transverse colon by the enlarging cystic mass. The differential diagnosis of pancreatic cysts includes secondary cystic structures that may be either true cysts or pseudocysts. Such cystic structures occur as the result of trauma, pancreatic duct obstruction, neoplasia, pancreatitis, parasitic infection, cystic fibrosis, and intrapancreatic duplications of the stomach and duodenum.3,6,7 In a review of 212 adult patients with cystic lesions of the pancreas (mean age of 59 ± 14.7 years), 37% were asymptomatic, of which 59% had an invasive or premalignant lesion (compared to almost 70% in the symptomatic group).8 Polycystic disease of the pancreas occurs in some patients who have polycystic disease of the liver and kidneys (Section 27.2).9,10 An early report of this condition was by Ivemark et al.11 in 1959, and this association sometimes is called Ivemark syndrome or renal-hepaticpancreatic dysplasia. It should not be confused with the so-called Ivemark asplenia syndrome, although patients with apparent features of both ‘‘Ivemark’’ syndromes have had renal-hepatic-pancreatic dysplasia as well as abnormalities in the determination of laterality (Section 5.1).12,13 Balci et al.14,15 reported a family with three sibs (two females and one male) with cystic dysplasia of the pancreas and kidneys, situs inversus, bowing of the lower limbs, hydrocephalus, and intrauterine growth retardation (IUGR). The authors concluded that the findings in this family differed from the renal-hepatic-pancreatic dysplasia (RHPD) described by Ivemark because of the absence of liver involvement and the presence of situs inversus (OMIM 603643). White et al.16 presented a similar isolated case and suggested that their case and that of Balci et al.14,15 should be included in the RHPD spectrum, which includes a variety of laterality fibrocystic conditions of the liver, kidney, and pancreas. Other associations with the RHPD spectrum include Dandy-Walker cyst17 (OMIM 267010) and campomelia.18 Some authors include patients with renal, hepatic, and pancreatic dysplasia in the same category with autosomal recessive infantile polycystic kidney disease (ARPKD, OMIM 263200), but it should be pointed out that the pancreas is usually not involved in typical cases of ARPKD.19 ARPKD is caused by mutations in the fibrocystin gene. Mutations have been found in individuals with ARPKD associated with hepatic fibrosis and Caroli disease, but none has been reported yet in individuals with associated pancreatic cysts.20,21 Pancreatic cystic disease may also occur in patients with an apparent generalized form of lymphangiectasis. One reported infant with pulmonary cystic lymphangiectasis also had a pancreatic cystic dysplasia characterized by cystically dilated, endotheliallined channels within the interstitial tissue similar in appearance to

Table 27-6. Syndromes with cysts or dysplasia of the pancreas Syndrome

Prominent Features

Causation

Asplenia with cystic liver, kidney, and pancreas12,13

Renal-hepatic-pancreatic dysplasia with other malformations and heterotaxy (situs inversus, situs ambiguus)

AR (208540)

Beemer-Langer34 (short rib-polydactyly, Type IV)

Short ribs, narrow chest, short bowed limbs, median cleft lip/palate, pulmonary hypoplasia, renal cystic dysplasia, intrahepatic bile duct cysts, hepatic fibrosis, pancreatic cysts

AR (269860)

Cumming campomelia18

Polysplenia; campomelia; cervical lymphocele; short bowel; polycystic dysplasia of kidneys, liver, and pancreas

AR (211890)

Cystic fibrosis

Recurrent and chronic bronchopulmonary disease, elevated sweat chloride, malabsorption due to exocrine pancreatic insufficiency, growth failure

AR (219700) CFTR, 7q31.2

Fryns36

Facial dysmorphia; various congenital heart defects; small thorax; pulmonary lobation defects; diaphragmatic hernia; malrotation; Meckel diverticulum; multiple accessory spleens; esophageal and duodenal atresia; ectopic pancreatic tissue and other gastrointestinal defects; genitourinary anomalies; CNS anomalies, and mental retardation in those that survive

AR (229850)

Goldston17 (renalhepatic-pancreatic dysplasia with DandyWalker cyst)

Cystic renal dysplasia, Dandy-Walker malformation, hepatic dysplasia with fibrosis (similar to Meckel syndrome)

AR (267010)

Jeune37

Short ribs, narrow thorax, short stature, postaxial polydactyly in 50%, variable limb shortening, cystic kidney disease, sometimes a variable degree of pancreatic fibrosis

AR (208500)

Johanson-Blizzard27,28

Hypoplasia of the alae nasi, deafness, hypothyroidism, midline scalp defects, postnatal linear growth retardation, developmental delay in some, absence of the permanent dentition, malabsorption, exocrine pancreatic deficiency associated with fibrous and fatty tissue replacement

AR (243800)

Meckel31–33

Occipital encephalocele, cleft lip and palate, postaxial polydactyly, polycystic dysplastic renal disease, hepatic fibrosis with biliary dysgenesis

AR (249000) Genetically heterogeneous 17q22-q23, 11q, 8q

Polycystic liver29

Multiple cysts in the liver, occasional isolated cysts in kidneys without impairment of renal function, occasional multiple cysts in the pancreas

AD (174050)

Renal-hepatic-pancreas dysplasia9,10,11

Renal cystic dysplasia, hepatic fibrosis/biliary dysgenesis, pancreatic fibrosis and cysts, included by some in the autosomal recessive polycystic kidney disease spectrum

AR (263200)

Shwachman26,38

Pancreatic exocrine deficiency due to fatty replacement of exocrine pancreas, neutropenia, short stature, metaphyseal chondrodysplasia

AR (260400) SBDS, 7q11

Thrombocytopeniaabsent radius (TAR)35

Short stature, brachycephaly, micrognathia, various congenital heart defects, absent radii and other upper and lower limb anomalies, thrombocytopenia, Meckel diverticulum, pancreatic cysts

AR (274000)

Trisomy 1339

Retarded linear growth and brain growth of prenatal onset, profound mental retardation, holoprosencephaly, congenital heart defect, omphalocele, polydactyly, numerous other malformations, lethal in infancy in majority of cases, intrapancreatic accessory splenic tissue, multiple pancreatic microcysts, increased numbers of intralobular pancreatic ducts lined with goblet cells and tall columnar epithelial cells

Chromosomal trisomy

Von Hippel-Lindau23,24,30

Angiomatous growths in the retina, cerebellum, spinal cord, and other organs; pheochromocytoma; cysts and tumors in many organs including the pancreas, kidney, liver, omentum, mesentery, spleen, epididymis, and adrenal; pancreatic involvement is usually but not always asymptomatic

AD (193300) VHL, 3p25

1155

1156

Gastrointestinal and Related Structures

the changes found in the lungs (OMIM 265300).22 That hydropic stillborn male also had similar cystic dysplastic changes involving the heart, kidneys, and mesenteric tissue. Multiple cysts of the pancreas have been seen in some patients with von Hippel-Lindau syndrome (OMIM 193300), in which condition renal cysts may also be present.23 The pancreatic involvement in this syndrome is usually cystic and asymptomatic, although it may be severe. Rarely, exocrine or endocrine pancreatic insufficiency occurs.24 In addition to single or multiple cysts, patients may also have angiomas, adenomas, and even hemangioblastomas of the pancreas. Another patient reported with pancreatic cystic dysplasia had a unique syndrome characterized by radiographic features of chondroectodermal dysplasia (Ellis-van Creveld syndrome), postaxial hexadactyly of hands and feet, and a number of other findings not usually included in that syndrome such as situs inversus totalis, cleft epiglottis and larynx, skin tags on the neck, renal dysplasia, ambiguous genitalia with micropenis, and imperforate anus.25 Most cases of pancreatic exocrine insufficiency are due to cystic fibrosis.6 Progressive fibrosis and fatty replacement of the exocrine pancreatic elements occurs early in most patients with this disorder. Shwachman syndrome (OMIM 260400), the next most common cause of pancreatic insufficiency, is characterized by fatty change throughout the organ that causes exocrine deficiency but usually leaves the islets functionally intact. The syndrome’s other characteristic features are metaphyseal chondrodysplasia with short stature and neutropenia with increased susceptibility to infection.6,26 Because patients present with diarrhea and growth failure associated with pancreatic insufficiency, cystic fibrosis may be suspected. The neutrophil count, sweat chloride, and skeletal radiographs should help to differentiate between these two entities most commonly associated with exocrine pancreatic deficiency. The Johanson-Blizzard syndrome (OMIM 243800) is characterized by hypoplasia of the alae nasi, deafness, hypothyroidism, midline scalp defects, postnatal linear growth retardation, developmental delay in some, absence of the permanent dentition, and malabsorption that appears to be due to exocrine pancreatic deficiency. The exocrine pancreas in one affected newborn was replaced by connective tissue, while in an older child, fatty tissue predominated.27,28 Etiology and Distribution

Congenital, developmental cysts of the pancreas occur rarely and are much less common than acquired cysts or pseudocysts.1–3 Of 300 patients presenting to Children’s Hospital in Boston between 1938 and 1984 with disorders of the pancreas, only six (2%) had cysts that appeared to be developmental in nature.3 Exocrine pancreatic insufficiency is most commonly due to cystic fibrosis, a common autosomal recessive disease characterized by chronic bronchopulmonary disease and increased concentrations of sweat electrolytes. Pancreatic insufficiency appears to be due to blockage by inspissated secretions, one manifestation of defects in exocrine secretion that exist throughout the body and that are caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene at chromosome 7q31.3-q32. Long-term sequelae include shrinkage and fibrosis of the pancreas. Other autosomal recessive causes of exocrine pancreatic deficiency include the second most common one, Shwachman syndrome (caused by mutations in the SBDS gene on chromosome 7q11), and the rarer Johanson-Blizzard syndrome.6,27,28 Other etiologies of exocrine pancreatic deficiency include congenital

rubella and severe familial or nonfamilial pancreatitis. Isolated deficiencies of single enzymes such as amylase, lipase, enterokinase, and trypsinogen also occur and present with symptoms of malabsorption and growth failure. As mentioned above, pancreatic cysts have been found in a number of patients with dysplasias involving other organs, primarily the liver and kidney. This phenotype is causally heterogeneous.9 Evidence that some of these appear to be caused by mutations in single genes is based on analyses of affected individuals and their families (Sections 6.1 and 27.2). While a minority of patients with ARPKD have pancreatic cysts, the recent identification20 of the ARPKD disease gene fibrocystin on chromosome 6p21.1-p12 may shed some light on the etiology of phenotypically similar disorders with pancreatic cysts. Mutations in fibrocystin have been seen in individuals with ARPKD associated with hepatic fibrosis and Caroli disease, but none has been found to date in individuals with associated pancreatic cysts, possibly indicating a different molecular etiology for those individuals.21 Syndromes in which pancreatic cysts and dysplasia have been reported are listed in Table 27-6. Prognosis, Prevention, and Treatment

When unilocular and multilocular cysts become large enough to cause symptoms, surgical treatment is indicated.3 The cystic tissue should be excised when it occurs in the body or tail of the pancreas. Internal drainage has been accomplished for those rarer cases with involvement of the pancreatic head. The prognosis should be good, as these cysts are only rarely associated with complications such as infection or adhesions. In polycystic disease associated with similar dysplastic changes in the liver and kidney, the patient’s prognosis is usually related to the severity of the hepatic and renal disease (Section 18.2). Severe infantile polycystic kidney disease is usually lethal in the newborn period because of pulmonary insufficiency due to oligohydramnios. The original pair of sibs of Ivemark et al.11 with renalhepatic-pancreatic dysplasia both developed renal failure in the first 3 to 6 weeks of life. Other reported cases suggest that death is usually in the neonatal period, with occasional survival for up to 9 months.9–13 Prenatal diagnosis by mid-trimester ultrasonography is feasible for infantile polycystic kidney disease, some cases of Jeune syndrome, and dysplasias characterized by campomelia. Prenatal diagnosis of cystic fibrosis is now available to many couples at risk by either direct or indirect DNA analysis. References (Pancreatic Cysts and Dysplasias) 1. Miles RM: Pancreatic cyst in the newborn: a case report. Ann Surg 149:576, 1959. 2. Mares AJ, Hirsch M: Congenital cysts of the head of the pancreas. J Pediatr Surg 12:547, 1977. 3. Welch KJ: The pancreas. In: Pediatric Surgery, ed 4. KJ Welch, JG Randolph, MM Ravitch, et al., eds. Year Book Medical Publishers, Chicago, 1986, p 1086. 4. Demos TC, Posniak HV, Harmath C, et al.: Cystic lesions of the pancreas. AJR Am J Roentgenol 179:1375, 2002. 5. Spiro HM: Clinical Gastroenterology, ed 4. McGraw-Hill Professional, New York, 1995. 6. Lebenthal E, Shwachman H: The pancreas—development, adaptation and malfunction in infancy and childhood. Clin Gastroenterol 6:397, 1977. 7. Fried AM, Selke AC: Pseudocyst formation in hereditary pancreatitis. J Pediatr 93:950, 1978.

Liver, Gallbladder, and Pancreas 8. Ferna´ndez-del Castillo C, Targarona J, Thayer SP, et al.: Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 138:427–3; discussion 433, 2003. 9. Bernstein J, Chandra M, Creswell J, et al.: Renal-hepatic-pancreatic dysplasia: a syndrome reconsidered. Am J Med Genet 26:391, 1987. 10. Carles D, Serville F, Dubecq JP, et al.: Renal, pancreatic and hepatic dysplasia sequence. Eur J Pediatr 147:431, 1988. 11. Ivemark BI, Oldfelt V, Zetterstrom R: Familial dysplasia of kidneys, liver and pancreas. Acta Paediatr 48:1, 1959. 12. Crawfurd MA: Renal dysplasia and asplenia in two sibs. Clin Genet 14: 338, 1978. 13. Hiraoka K, Haratake J, Horie A, et al.: Bilateral renal dysplasia, pancreatic fibrosis, intrahepatic biliary dysgenesis, and situs inversus totalis in a boy. Hum Pathol 19:871, 1988. 14. Balci S, Bostanoglu S, Altinok G, et al.: Sibs diagnosed prenatally with situs inversus totalis, renal and pancreatic dysplasia, and cysts: a new syndrome? Am J Med Genet 82:166, 1999. 15. Balci S, Bostanoglu S, Altinok G, et al.: New syndrome? Three sibs diagnosed prenatally with situs inversus totalis, renal and pancreatic dysplasia, and cysts. Am J Med Genet 90:185, 2000. 16. White SM, Hurst JA, Hamoda H, et al.: Renal-hepatic pancreatic dysplasia: a broad entity. Am J Med Genet 95:399, 2000. 17. Hunter AG, Jimenez C, Tawagi FG: Familial renal-hepatic-pancreatic dysplasia and Dandy-Walker cyst: a distinct syndrome? Am J Med Genet 41:201, 1991. 18. Cumming WA, Ohlsson A, Ali A: Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am J Med Genet 25:783, 1986. 19. Blythe H, Ockenden BG: Polycystic disease of kidneys and liver presenting in childhood. J Med Genet 8:257, 1971. 20. Ward CJ, Hogan MC, Rossetti S, et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259, 2002. 21. Bergmann C, Senderek J, Sedlacek B, et al.: Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/ PKHD1). J Am Soc Nephrol 14:76, 2003. 22. Frank J, Piper PO: Congenital pulmonary cystic lymphangiectasis. JAMA 171:1094, 1959. 23. Melmon KL, Rosen SW: Lindau’s disease: review of the literature and study of a large kindred. Am J Med 36:595, 1964. 24. Fishman RS, Bartholomew LA: Severe pancreatic involvement in three generations in von Hippel-Lindau disease. Mayo Clin Proc 54:329, 1979. 25. Fraser FC, Jequier S, Chen MF: Chondrodysplasia, situs inversus totalis, cleft epiglottis and larynx, hexadactyly of hands and feet, pancreatic cystic dysplasia, renal dysplasia/absence, micropenis and ambiguous genitalia, imperforate anus. Am J Med Genet 34:401, 1989. 26. Shwachman H, Diamond LK, Oski FA, et al.: The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr 65: 645, 1964. 27. Daentl DL, Frias JL, Gilbert EF, et al.: The Johanson-Blizzard syndrome: case report and autopsy findings. Am J Med Genet 3:129, 1979. 28. Gould NS, Paton JB, Bennett AR: Johanson-Blizzard syndrome: clinical and pathological findings in 2 sibs. Am J Med Genet 33:194, 1989. 29. Berrebi G, Erickson RP, Marks BW: Autosomal dominant polycystic liver disease: a second family. Clin Genet 21:342, 1982. 30. Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317, 1993. 31. Rapola J, Salonen R: Visceral anomalies in the Meckel syndrome. Teratology 31:193, 1985. 32. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 33. Roume J, Genin E, Cormier-Daire V, et al.: A gene for Meckel syndrome maps to chromosome 11q13. Am J Hum Genet 63:1095, 1998. 34. Cideciyan D, Rodriguez MM, Haun RL, et al.: New findings in short rib syndrome. Am J Med Genet 46:255, 1993. 35. Hall JG, Levin J, Kuhn JP, et al.: Thrombocytopenia with absent radius (TAR). Medicine 48:411, 1969.

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36. Ayme S, Julian C, Gambarelli D, et al.: Fryns syndrome: report on 8 new cases. Clin Genet 35:191, 1989. 37. Turkel SB, Diehl EJ, Richmond JA: Necropsy findings in neonatal asphyxiating thoracic dystrophy. J Med Genet 22:112, 1985. 38. Boocock GRB, Morrison JA, Popovic M, et al.: Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 33:97, 2003. 39. Hashida Y, Jaffe R, Yunis EJ: Pancreatic pathology in trisomy 13. Pediatr Pathol 1:169, 1983.

27.11 Pancreatic Ectopia and Heterotopia Definition

Pancreatic ectopia and heterotopia are accessory tissues occurring at sites detached from the main body of the pancreas. Diagnosis

When accessory heterotopic pancreatic tissue is present, it is usually asymptomatic or only mildly symptomatic. Patients may complain of vague, nonspecific, abdominal discomfort over a period of months or years, but a definite causal relationship between ectopic pancreatic tissue and such symptoms is generally difficult to establish.1,2 Occasionally, accessory pancreatic nodules in the gastrointestinal tract ulcerate and present with symptoms of bleeding. Most patients reported to be symptomatic are between ages 30 and 50 years, but children have also been occasionally affected. Accessory nodules are usually single and rarely multiple. They are firm, yellow, and irregular, varying in size between several millimeters and 4 cm in diameter. The most common site is the stomach, near the pylorus, where they are usually submucosal, sessile nodules. In one series of symptomatic patients, 80% of the gastric lesions were found in the prepyloric region on the greater curvature of the stomach.2 The duodenum and jejunum are also relatively common sites to find accessory pancreatic nodules with central pits into which one or more ducts empty.2 Other reported sites for heterotopic pancreatic tissue include Meckel diverticulum, the umbilicus, the spleen, the gallbladder, the liver, the mesentery, and the esophagus. Accessory pancreatic tissue is usually diagnosed by upper gastrointestinal radiography or endoscopy when a patient presents with symptoms of abdominal discomfort. Ectopic pancreatic tissue in the stomach or small bowel is frequently identified as a nodule with a pit that fills with contrast medium. Ectopic pancreatic nodules may develop the same pathologic conditions as the main organ, such as pancreatitis, cysts, and tumors, causing patients to present with symptoms typical of these conditions.3–5 Nesidioblastosis (beta-cell hyperplasia with abnormal clusters in and near the ducts with decreased sensitivity to glucose regulation) in accessory, heterotopic pancreatic tissue has been implicated as the cause of hyperinsulinemic hypoglycemia in one patient and hypertension in another.6,7 This experience suggests that pathologists should look for nesidioblastosis in an ectopic, accessory pancreas in cases of unexplained, sudden infant death. Accessory pancreatic tissue was found in the gastroesophageal junction of a resected, stenotic region of distal esophagus from a 6-month-old infant who presented with symptoms and findings suggestive of achalasia.8 The resected segment of distal esophagus was hard and rubbery and also contained glandular and cartilaginous tissue characteristic of the trachea. Other than the occasional accessory pancreatic nodule found in a Meckel diverticulum, there is no strong association between

1158

Gastrointestinal and Related Structures

these heterotopias and other congenital malformations or dysplasias. An infant with Beemer-Langer syndrome and manifestations of orofaciodigital syndrome born to nonconsanguineous parents was reported who had two small foci of ectopic pancreas in the duodenal submucosa.9 Etiology and Distribution

Pancreatic tissue is found throughout the vertebrates.10 In nonhuman vertebrates, nodules of pancreatic tissue are found normally between the muscularis and serosal layers of the stomach of duodenum, buried in the mesentery, or along the blood vessels that supply the liver and spleen. In many mammals, multiple pancreatic nodules are normally distributed over a large region in the small bowel mesentery. Ectopic or accessory pancreatic tissue in humans, therefore, frequently follows a pattern that mimics that seen in lower vertebrates and appears to be determined early in the embryonic development of the pancreas. A number of theories exist to explain the origin of accessory, pancreatic heterotopias.1,2,10 These include speculation that the situation is caused by an extra initial pancreatic bud, by secondary budding of the developing ducts, or by engraftment from branching buds of the developing pancreas to the stomach, intestine, or mesentery as they come in contact during early growth, migration, and rotation of these tissues. Ectopic pancreas has been reported to occur in one per 200 to one per seven autopsies.2 Close to 600 cases had been reported by 1956.1,3 Over a 20-year period at the Mayo Clinic, 212 patients were diagnosed with heterotopic pancreas.2 The male to female ratio in this group of symptomatic cases was approximately 2:1. Prognosis, Prevention, and Treatment

Although ectopic pancreas is usually asymptomatic and found incidentally, patients occasionally present with symptoms that appear to be directly related to the accessory tissue. Heterotopic pancreatic tissue can secrete enough enzyme to produce symptoms of abdominal distress through inflammation and spasm, but it is not clear why such symptoms are usually of short duration and not

lifelong.2 Because of the question about whether a cause-and-effect relationship exists between heterotopic pancreatic tissue and abdominal symptoms, it has been suggested that, for these patients, conservative therapy with observation may be as therapeutically effective as surgical intervention.2 Hemorrhage and duodenal obstruction have also been reported as rare complications of heterotopic, accessory pancreatic tissue. Gastrointestinal tract hemorrhage can occur when there is ulceration of the mucosa overlying heterotopic pancreatic nodules. Hemorrhage has also been observed in the absence of mucosal ulceration or gastritis, in which cases it is much more difficult to explain the pathogenetic processes involved.2,3,11 References (Pancreatic Ectopia and Heterotopia) 1. Barbosa JJ deC, Dockerty MB, Waugh JM: Pancreatic heterotopia: review of the literature and report of 41 authenticated surgical cases, of which 25 were clinically significant, Surg Gynecol Obstet 82:527, 1946. 2. Dolan RV, ReMine WH, Dockerty MB: The fate of heterotopic pancreatic tissue. A study of 212 cases. Arch Surg 109:762, 1974. 3. Hudock JJ, Wanner H, Reilly CJ: Acute massive gastrointestinal hemorrhage associated with pancreatic heterotopic tissue of the stomach. Ann Surg 143:121, 1956. 4. Green PHR, Barratt PJ, Percy JP, et al.: Acute pancreatitis occurring in gastric aberrant pancreatic tissue. Am J Dig Dis 22:734, 1977. 5. Fam S, O’Briain DS, Borger JA: Ectopic pancreas with acute inflammation. J Pediatr Surg 17:86, 1982. 6. Risaliti A, Pizzolitto S: Nesidioblastosis arising from heterotopic pancreas and presenting with hypertension. A clinical, immunohistochemical and ultrastructural study. Ann Chir 43:459, 1989. 7. Seki S, Ikenoue T, Murakami N, et al.: Ectopic nesidioblastosis. Acta Paediatr Jpn 32:308, 1990. 8. Bricen˜o LI, Grases PJ, Gallego S: Tracheobronchial and pancreatic remnants causing esophageal stenosis. J Pediatr Surg 16:731, 1981. 9. Lin AE, Doshi N, Flom L, et al.: Beemer-Langer syndrome with manifestations of an orofaciodigital syndrome. Am J Med Genet 39:247, 1991. 10. Horgan EJ: Accessory pancreatic tissue. Arch Surg 2:521, 1921. 11. Razi MD: Ectopic pancreatic tissue of esophagus with massive upper gastrointestinal bleeding. Arch Surg 92:101, 1966.

Part VII Urogenital System Organs

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28 Urinary Tract Jane A. Evans

Embryogenesis

T

he urinary system consists of kidneys, which excrete urine, and the ureters, urinary bladder, and urethra, which collect it. Development of the urinary tract is closely related to that of the reproductive system. Both derive from intermediate mesoderm that extends along the entire length of the dorsal body wall of the embryo. During folding of the embryo in the horizontal plane, the intermediate mesoderm is carried ventrally away from the somites to form a longitudinal ridge on either side of the primitive paired aorta. This urogenital ridge has both a urinary component, the nephrogenic cord, and a genital component, the gonadal ridge.1,2 There are three successive sets of kidneys formed during human development. The first set, the pronephros, appears at the end of the 3rd week (Table 28-1) as clusters of cells in the cervical region. They are rudimentary and nonfunctioning. Although the pronephroi soon degenerate, their ducts become continuous with those of the next set of kidneys, the mesonephri, which develops in the 4th week from the dorsolumbar portions of the nephrogenic cord caudal to the pronephros. These are large organs that consist of simple glomeruli and tubules, similar to, but simpler than, those of the definitive kidneys. They produce urine and function as excretory organs until the final set of kidneys, the metanephros, start working. The tubules join the mesonephric duct that gradually extends caudally to connect with the cloaca at day 28. After the mesonephric glomeruli involute, some of the most caudal mesonephric tubules persist in males as the efferent ducts of the epididymis, while the mesonephric or Wolffian duct remains to form the genital duct. In females, only vestigial remnants such as Gartner duct persist. The definitive kidney or metanephros begins to develop in week 5 but does not begin functioning until 11 weeks. It develops from two distinct components: the ureteric bud and the metanephrogenic blastema. The ureteric bud begins as a dorsal outgrowth of the mesonephric duct near its opening into the cloaca and is the primordium of the ureter, renal pelvis, calyces, and collecting tubules. It penetrates the metanephrogenic blastema, where inductive interactions result in formation of a metanephric cap of

The author of the chapter on the Urinary Tract in the first edition was Dr. Margo van Allen, University of British Columbia. The use of material from that chapter is gratefully acknowledged.

mesenchyme over its end. The stalk of the ureteric bud becomes the ureter and the cranial end, the renal pelvis, calyces, and collecting tubules. Each collecting tubule undergoes repeated branching. The first three to six generations of branches enlarge, join, and form the major calyces. The next few coalesce to form the minor calyces, while the remaining branches form the permanent collecting tubules. The ampullary tip of each branch induces a cluster of cells in the blastema that form a metanephric vesicle. These vesicles develop into tubules that, as they develop, have their proximal ends invaginated by glomeruli, capillary clusters from branches of the renal arteries. This unit, consisting of glomerulus, Bowman’s capsule, proximal convoluted tubule, Henle’s loop, and distal convoluted tubule, forms a nephron. The distal convoluted tubule of each nephron unites with the ampulla of the arched collecting tubule. Thus, the collecting system is derived from the ureteric bud, while the metanephric blastema forms the excretory units. The process of development involves dual induction, with the branching of the bud induced by the metanephric mesoderm and the differentiation of the nephron induced by the collecting tubule. By 11 to 13 weeks, 20% of nephrons are functional. Their numbers increase rapidly and double between 20 and 36 weeks gestation. From then until term, no new nephrons are formed, but the loops of Henle continue to lengthen and the proximal and distal tubules become more tortuous. Positionally, the metanephric kidneys develop close together in the pelvis, ventral to the sacrum. They move into the abdomen as a consequence of increasing growth of the caudal end of the embryo and come to lie farther apart in the retroperitoneal space at the level of the 12th thoracic segment. During the repositioning process, they are supplied by successively higher arteries from the aorta. Most kidneys have only one artery, but there may be two or more. Initially, the hilum faces ventrally, but, as the kidney becomes higher in position, it rotates medially by 908 so that the hilum faces anteromedially. The fetal kidneys are subdivided into lobes that usually disappear during infancy as the nephrons grow. Occasionally, the lobes can still be detected in adulthood. The bladder and the urethra are largely derived from the urogenital sinus and the adjacent splanchnic mesenchyme. The urogenital sinus develops in weeks 6 to 7 when the terminal part of the hindgut or cloaca is divided by down growth of the urorectal septum into dorsal and ventral sections. The dorsal part forms the 1161

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Urogenital System Organs Table 28-1. Timing of normal development of the human urinary tract Age Postfertilization

Embryonic Stage

Developmental Process

Day: 18

8

20

9

22

10

Tail folding incorporates hindgut and forms cloaca; pronephros present as a few cell clusters and tubules

24

11

Pronephros tubules degenerate, leaving the ducts; nephrogenic cords appear in early mesonephros; blind ends of mesonephric ducts grow toward cloaca

26

12

Allantois incorporated into the embryo in the region of the umbilical cord primordium

28

13

Ureteric buds appear; septation of cloaca begins; metanephric (Wolffian) ducts have fused with the cloaca

32

14

Metanephric blastema induced and caps the bud

33

15

Ureteric bud tip expands to form primitive renal pelvis; mesonephric ducts distal to the ureteric bud dilate and become absorbed into urogenital sinus

37

16

Ureteric bud has caudal and cranial branches; metanephros assumes reniform shape; ureteric orifices exstrophy and evaginate into developing bladder; ureters transiently occluded

41

17

Further ureteric budding has produced major calyces; ureters recanalize beginning in midureter and proceeding bidirectionally

44

18

Urogenital sinus and rectum are separated; further branching of collecting tubules; metanephric ducts descend to drain separately into the urogenital sinus

48

19

Septation of cloaca complete; urogenital membrane ruptures; nephrogenesis begins

51

20

Kidneys are in the lumbar region; formation of minor calyces; common metanephric ducts fuse in the midline and contribute to trigone formation

52

21

Glomeruli appear

54

22

Week: 8 9

Cloacal membrane at caudal end of primitive streak Paraxial, intermediate, and lateral mesoderm apparent

Kidneys ‘‘rise’’ above the gonads Urethral groove forming; bladder muscularization has been initiated Kidneys reach final anatomic position and start to function

10

The bladder is a cylindrical tube and starts to expand

11

Urethral groove fuses in males to form spongy urethra

12

Glandular urethra in males starts to form; external genitalia distinctly male or female; ureteral muscularization begins; urachus involutes to form median umbilical ligament; bladder muscularization complete

16

Mesonephroi are involuted; kidneys are lobulated

18 20–40

Ureteropelvic junction apparent Later generations of collecting tubules elongate and converge on minor calyces to give renal pyramids; further growth and fine modeling of the system

For further details and references, see Moore and Persaud1 and Walsh et al.28

anorectal canal; the ventral portion (the urogenital sinus) has three parts: a cranial vesicourethral canal, which is continuous with the allantoic duct and which receives the mesonephric ducts; a narrow middle section, termed the pelvic portion; and a caudal phallic section closed externally by the urogenital membrane. As the ureteric bud is an outgrowth of the mesonephric duct, initially the ureters and mesonephric ducts are connected. However, differential growth rates cause the caudal end of the mesonephric ducts to be incorporated into the developing bladder and the ureters open laterally to the ducts. Later, the duct openings become farther apart. The caudal end of each ureter becomes incorporated into the developing bladder to form the trigonum, while the mesonephric duct, in males, opens into that part of the urogenital sinus that forms the prostatic urethra. Thus, the bladder endothelium is formed primarily from the endodermal cloaca and allantois, with small contributions to the trigone from the intermediate mesoderm. The apex

of the vesicourethral canal courses within the umbilicus as a narrow canal, the urachus. After birth, the blind upper end of the urachus becomes the median umbilical ligament, while the patent lower end is drawn down as the bladder descends and may retain its connection with the bladder’s apex.3 The urethra in females is formed completely from the vesicourethral region of the cloaca. In males, this area, in conjunction with the caudal ends of the mesonephric ducts, gives rise to that portion of the prostatic urethra proximal to the opening of the prostatic utricle. Distally, the remaining sections are derived from the urogenital sinus, from fusion of the genital folds, and from closure of an ectodermal groove that forms at the tip of the glans.4 Figure 28-1 illustrates development of the urinary system. The developmental periods that correspond with specific malformations of the urinary tract are given in Table 28-2.

Urinary Tract

Fig. 28-1. Development of the genitourinary system. A. Stage 16, 37 days. Cloaca is incompletely divided by urogenital septum, mesonephros is located in the thoracic region with the gonadal ridge along its medial margin, metanephric duct and metanephros are in early stage of formation, and pronephros, which existed in the cervical region, has disappeared. B. Stage 23, 57 days. Cloaca has divided into urogenital sinus and rectum, mesonephros is beginning to regress, and metanephros is further developed and metanephric duct elongated.

Molecular Aspects of Urinary Tract Embryogenesis

Modern techniques of molecular biology have added significantly to the knowledge of urinary tract development gained by earlier embryologists. In particular, the roles of several genes in the inductive processes involved in normal development have been elucidated, especially through the use of mouse models and analyses of the impact of specific mutations on renal dysmorphogenesis. A number of genes have been identified that are involved in one or more of the following stages of renal development: induction of ureteric bud outgrowth by mesenchymal signals, initial branching of the bud, branching and growth of the collecting ducts, corticomedullary patterning to produce the renal pelvis and calyces, mesenchymal differentiation, and mesenchymal-epithelial transformation.2,5–7 Ureteric bud outgrowth occurs in response to inductive signals from the metanephric blastema mediated by transcription

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C. By 8 weeks in the female, the ovaries are taking form from the gonadal ridge and the paramesonephric duct forms the fallopian tube and uterus, and the mesonephros and mesonephric duct further regress. D. By 8 weeks in the male, the testes are forming in the gonadal ridge and are linked to the urethra by components of the mesonephros and mesonephric duct. (After Gilbert SG: Pictorial Human Embryology. University Washington Press, Seattle, 1989.)

factors including WT1 and signaling molecules such as GDNF and its receptor, RET. Other transcription factors, including PAX2, LIM 1, and FORMIN, control the bud’s response. The initiation and maintenance of branching of the bud is again influenced by interaction with the mesenchyme and regulated by EMX2. GDNF and RET expressed at the tips of the branching bud, along with other ligand–receptor-mediated interactions such as FGF7 and BMP7, are involved in iterative branching and growth of the collecting ducts. Other transcription factors and receptors produced by stromal cells near the developing ducts, including RARa/RARb2 and BF2, may control these interactions. The process of corticomedullary patterning to produce the renal pelvis and calyces is under the control of BMP5, BMP7, FGF7, and AGT and their receptors and may be mediated by cell surface proteins such as GPC3. Mesenchymal differentiation requires inductive signaling from the ureteric bud and involves WT1 and PAX2. HOXA-11 and HOXD-11 are expressed in uninduced blastema,

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Urogenital System Organs Table 28-2. Timing of embryologic development and related urinary tract anomalies Developmental Process

Development of cloaca

Timing (weeks)

3

Anomaly

Bladder agenesis, duplication, hypoplasia, septation

Formation of ureteric bud

4–5

Renal agenesis, supernumerary kidney

Induction of metanephric blastema

4–5

Renal agenesis, supernumerary kidney

Failure of blastemata to remain separate

4–6

Horseshoe kidney, fused pelvic kidney, crossed renal ectopia

Initiation of ureteric bud branching

5

Renal agenesis, hypoplasia, dysplasia, supernumerary kidney, duplication of renal pelvis

Septation of cloaca

5–7

Urorectal anomalies, persistent cloaca, urethral duplication (females)

Exstrophy of ureters into urogenital sinus

5–6

Ureteric orifice ectopia, reflux, hydroureter, hydronephrosis

Rupture of urogenital membrane Recanalization of ureters

6

Urethral atresia, posterior urethral valves

6

Ureteral stenosis, hydronephrosis

Cephalad migration and rotation of kidneys

6–9

Crossed renal ectopia, fused pelvic kidney, renal malrotation

Development of renal pelvis and major calyces

6–11

Duplication of renal pelvis, duplication of ureters

Trigone formation

7

Ureterocele, megaloureter, posterior urethral valves

Bladder innervation and muscularization

7–12

Aganglionic, flaccid bladder, bladder diverticula

Nephronogenesis

8–32

Renal dysplasia, polycystic kidneys, renal hypoplasia, glomerulopathies

Involution of urachus

10–12

Patent urachus, umbilical sinus, vesical sinus, urachal cyst

Outgrowth of genital tubercle and fusion of urethral groove

10–12

Duplication, atresia, stenosis of urethra, epispadias (males), prune belly syndrome, renal dysplasia secondary to obstruction

Development of glandular urethra (males)

12–14

Urethral stenosis or atresia, hypospadias (males)

Formation of minor calyces, collecting tubules, papillary ducts

14–15

Medullary cystic disease, nephronophthisis, medullary sponge kidney

Cortico-medullary patterning, nephron growth, collecting tubule attachment

20–22

Renal hypoplasia, polycystic kidney, hydronephrosis, hydroureter, nephromegaly

For details and references, see Gray and Skandalakis29 and Moore and Persaud.1

though their roles in renal patterning are not yet clear. PAX2 is expressed in the induced mesenchyme and may be important in maintaining expression of WT1. The mesenchymal-epithelial transformation that results in production of metanephric vesicles goes through a series of steps, including the condensation of pretubular aggregates, comma-shaped bodies, and S-shaped bodies. WT1 and another transcription factor, EYA1, as well as the signaling molecule WNT4 and BF2 are important genes in this process, while PAX2 is seen to be downregulated.5 Table 28-3 summarizes the nature and role of these key genes, including the phenotypes observed when they are mutated in mouse models and/or humans. Other genes, including the a3 and a8 integrins, COX2, FGF10, FGFR2, JAGGED1, p57, POD1, and SALL1, have also been implicated as functioning in renal development.6 Less is known about the genes involved in the formation of the lower urinary tract. HOXA-13, HOXD-13, SHH, SALL1, and Gli proteins are involved in partitioning of the cloaca and formation of the resulting structures.8 Other genes involved in

bladder development include GATA-69 and BMP5, which is mutated in the se (short ear) mouse mutant.10 In addition to skeletal anomalies, homozygous se mice have reduced contractility or diameter of the ureter or vesicoureteral junction leading to hydronephrosis.11 Urinary Tract Anomalies Overall Frequency

Developmental defects of the urinary tract represent one of the most common forms of human congenital malformations and range from lethal anomalies such as bilateral renal agenesis to mild and asymptomatic variations in the structure of the ureter or renal pelvis. Genitourinary abnormalities comprise 35–45% of all congenital abnormalities,12 with urinary tract defects potentially representing half of these. They are frequently associated with other structural defects. Considering the total spectrum from lethal to

Urinary Tract

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Table 28-3. Key genes in urinary tract development Gene

Function

Stage of Development Involved

Urinary Tract Mutant Phenotype

WT1

Zinc finger transcription factor

Ureteric bud induction, mesenchymal differentiation, mesenchymalepithelial transformation

Mouse nulls have bilateral renal agenesis, human heterozygotes have glomerulopathies, increased risk for Wilms tumor

GDNF

Secreted signaling molecule

Ureteric bud induction, initiation and maintenance of bud branching, iterative branching

Mouse nulls have bilateral renal agenesis or dysgenesis, mouse heterozygotes have unilateral agenesis or bilateral dysplasia

RET

Receptor tyrosine kinase

Ureteric bud induction, iterative branching

Mouse nulls have bilateral renal agenesis or dysplasia, heterozygotes are normal, human heterozygotes have increased risk for Hirschprung’s, no renal phenotype

PAX2

Paired box transcription factor

Initiation and maintenance of bud branching, mesenchymal differentiation, downregulated in mesenchymal-epithelial transformation

Mouse nulls have bilateral renal agenesis, human heterozygotes have renal-colobomata syndrome with renal hypoplasia, unilateral renal agenesis and reflux

LIM1

Transcription factor

Initiation and maintenance of bud branching

Mouse nulls occasionally have bilateral renal agenesis

FORMIN

Cell polarity regulator

Initiation and maintenance of bud branching, mesenchymal-epithelial transformation

Ld mouse has renal agenesis or hypoplasia, hydronephrosis or megaloureter depending on the allele

EMX2

Homeobox transcription factor

Initiation and maintenance of bud branching

Mouse nulls have bilateral renal agenesis

FGF7

Secreted signaling molecule

Iterative branching

Mouse nulls have reduced branching, smaller collecting system, fewer nephrons, renal hypoplasia

FGFR2b

Growth factor receptor

Iterative branching

Dominant negative mouse model has renal agenesis, human heterozygotes with Apert syndrome have hydronephrosis

BMP7

Secreted signaling molecule

Iterative branching

Mouse nulls have marked decrease in branching and dysplasia

RARa, RARb2

Retinoic acid receptors

Iterative branching

Double mouse nulls have renal hypoplasia

BF2

Winged helix transcription factor

Iterative branching, mesenchymalepithelial transformation

Mouse nulls have renal hypoplasia with decreased branching, reduced numbers of nephrons and arrested maturation of mesenchymal aggregates

BMP5

Secreted signaling molecule

Corticomedullary patterning

Gene is disrupted in the short ear (se) mouse; homozygotes have hydroureters and hydronephrosis

AGT

Secreted peptide

Corticomedullary patterning

Mouse nulls have progressive widening of the calyx and papillae atrophy

AGTR1

AGT receptor

Corticomedullary patterning

Mouse nulls have progressive widening of the calyx and papillae atrophy

AGTR2

AGT receptor

Corticomedullary patterning

Nulls have variable CAKUT (congenital anomalies of the kidney and urinary tract) and a decreased rate of apoptosis around the ureters; human patients with CAKUT had an increased frequency of a specific polymorphism

GPC3

Cell surface heparin sulphate proteoglycan

Corticomedullary patterning

Mouse nulls have dysplasia, nephromegaly, hydroureter due to overgrowth of the collecting system; human males with haploinsufficiency have Simpson-Golabi-Behmel syndrome

EYA1

Transcription factor

Mesenchymal-epithelial transformation

Human heterozygotes have BOR syndrome

WNT4

Secreted signaling molecule

Mesenchymal-epithelial transformation

Mouse nulls have severe dysplasia due to arrest of mesenchymal aggregates

For details and references, see Piscione and Rosenblum,5,6 Risdon and Woolf,2 and Woolf and Winyard.7

minor structural variants, urinary tract anomalies may occur in as many as 5–10% of the population. However, serious defects are much rarer. Postmortem surveys of infants and children indicate that approximately 9–13%13,14 have urinary tract anomalies, many (35–70%) associated with other defects.13,15

Unless a serious defect such as bladder or cloacal exstrophy or urethral atresia is present, clinical examination of newborn infants will not detect the majority of urinary tract anomalies. Using deep abdominal palpation may help identify such anomalies in approximately one in 200.16,17 Routine ultrasound screening of

1166

Urogenital System Organs

apparently healthy infants identifies a higher proportion of significantly affected infants (1–2%),18–20 and an additional 4% have mild pelvic dilation.20 Such screening is indicated in infants with multiple congenital anomaly disorders and certain isolated structural anomalies or when there are signs or symptoms of urinary dysfunction (Table 28-4), even when clinical examination of the abdomen is normal. Prenatal ultrasonographic assessment also reveals a rate of ~1.5% for serious anomalies.21 Although neonatal mortality is high in many cases,22 early detection of potentially treatable infants may allow optimal renal function to be maintained. However, the use of fetal assessment as a routine screening tool for urinary tract anomalies remains controversial.23 As well as the high frequency of untreatable anomalies, there is a high (72%) incidence of transient hydronephrosis21 and there may be both false-negative and false-positive findings.24 Associations with Other Anomalies

Structural anomalies in most, but not all, systems confer an increased risk for associated anomalies of the urinary tract (Table 28-5). When associated major anomalies, increased minor anomalies, and/or recurrence within a family are observed, the presence of a monogenic or syndromic disorder should be considered. Many isolated structural anomalies are due to multifactorial inheritance (i.e., genetic and environmental factors interact to determine liability), and thus have an empiric recurrence risk that is higher than the general population risk, approximating the square root of the incidence. Urinary tract anomalies have been found in more than 650 patterns of malformations.25 Table 28-4. Structural and functional anomalies that should prompt investigation for a urinary tract malformation Structural defects

Abdominal mass Abdominal distension and/or lax musculature Ambiguous or abnormal external genitalia Anal anomalies Aniridia Athelia Exstrophy of the bladder or cloaca Hemihypertrophy Lumbosacral vertebral anomalies including hairy tufts and sinuses Meningocele or myelomeningocele

Although urinary tract defects are seen in many multiple congenital anomaly syndromes, they are preferentially associated with specific types of defects forming communities of syndromes. Others are potentially due to pathogenetic processes that involve similar molecular or mechanical mechanisms. These syndrome communities include the acrorenal field disorders, in which limb deficiency defects are present (Table 28-6); the conditions with more generalized skeletal dysplasias forming the osteorenal defect community (Table 28-7); the cerebro-renal-digital field defects, which have significant brain involvement and digital defects (Table 28-8); and those where renal dysplasia is associated with hepatic and pancreatic dysplasia (Table 28-9).26 It should be noted that there is considerable overlap between these groupings, and the classification used here is not intended to be rigid. Information on many of the other complex disorders involving the urinary tract is provided in other tables in this chapter. The classification system used in this chapter is based primarily on the appearance and structure of the urinary tract and generally follows the order used in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10).27 Urinary tract anomalies associated with chromosomal defects are listed in Table 28-10. The high frequency of this association suggests that cytogenetic analysis, including molecular technique where appropriate, is indicated in all infants with urinary tract defects who have multiple anomalies, dysmorphic features, growth retardation, or developmental delay. Teratogenic exposures that can give rise to urinary tract anomalies are presented in Table 28-11. A review of possible teratogenic exposures should be an intrinsic component of all prenatal assessment and is essential in the evaluation of infants with congenital malformations. Up-to-date information on specific agents can be obtained from several sources, including teratogen hotlines and databases such as Motherisk (www.motherisk.org). Before an environmental agent is implicated as a cause of anomalies, confirmation of the timing and magnitude of the exposure is necessary as is the exclusion of other causes. As development of the urinary tract spans most of embryonic and fetal life, these organs are very susceptible to teratogenic exposures. Appropriate anticipatory preconceptual counseling with thorough patient education is perhaps the best method of prevention. Identification of potential teratogenic agents through birth defect monitoring programs, case reports, epidemiologic studies, and teratology research is essential for prevention. Ongoing physician and patient education is necessary for appropriate selection of prescription and nonprescription drugs for medical treatment during the child-bearing years.

Preauricular pits and tags

References Potential urinary dysfunction

Anuria-oliguria (especially in neonates) Edema Hypertension Oligohydramnios Persistent wetness, dribbling Polydypsia, polyuria Poor urinary stream Recurrent urinary tract infection Infants with only supernumerary nipples or single umbilical artery do not require intensive follow-up for urinary tract anomalies.30–32

1. Moore KL, Persaud TVN: The Developing Human Clinically Oriented Embryology, ed 7. Saunders, Philadelphia, 2003. 2. Risdon RA, Woolf AS. Development of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 67. 3. Begg RC. The urachus: its anatomy, histology and development. J Anat 64:170, 1930. 4. Warwick R, Williams PL, eds. Gray’s Anatomy, ed 35. Longman Group Ltd, Edinburgh, 1973, pp 1858–1973. 5. Piscione TD, Rosenblum ND: The malformed kidney: disruption of glomerular and tubular development. Clin Genet 56:341, 1999. 6. Piscione TD, Rosenblum ND: The molecular control of renal branching morphogenesis: current knowledge and emerging insights. Differentiation 70:227, 2002.

Urinary Tract

1167

Table 28-5. Frequency of urinary tract anomalies in cases with other structural defects Structural Anomaly/Pattern

Absent gallbladder33

Percentage with Urinary Tract Anomalies

32 45–55

Agenesis of the corpus callosum34,35 Anencephaly36,37

5–16

Anorectal malformations38–40 Biliary atresia41

26–58* 3

Caudal dysplasia42

40

CHARGE43

42

Most Common Urinary Tract Defects (in Relative Order of Frequency)

Cystic dysplasia, renal agenesis, horseshoe kidneys Reflux, ureterocele, unilateral renal agenesis, crossed fused renal ectopia, bladder diverticulae Hydronephrosis, horseshoe kidneys, polycystic kidneys, renal agenesis, renal hypoplasia, urethral atresia Hydronephrosis, unilateral renal agenesis, cystic dysplasia, reflux, cystic dysplasia, renal ectopia, cloacal exstrophy Double ureter, hydronephrosis, renal cysts Renal agenesis, hypoplasia, cystic dysplasia; horseshoe kidneys, crossed renal ectopia, urachal anomalies NB *100% have neurogenic bladder

44–46

Diaphragmatic hernia

Esophageal atresia and tracheoesophageal fistula47 Gastroschisis48

15–18 33 15

Heart defect49,50

5–39*

Lateral body wall defect51,52

50–65

Unilateral renal agenesis, hydronephrosis, renal hypoplasia Renal agenesis, cystic dysplasia, hydronephrosis, ureteropelvic obstruction Unilateral renal agenesis, horseshoe kidneys, reflux Unilateral renal agenesis, horseshoe kidneys Duplex collecting system, unilateral renal agenesis, renal ectopia Renal agenesis, urethral atresia, hydronephrosis NB More have cloacal and bladder defects

Limb reduction defects53

9

MURCS association54,55

28–80

Myelomeningocele56

9

Omphalocele48,58–60

11–47

Oral clefts57

4 61

Penoscrotal transposition

90

Persistent cloaca62

83

Pulmonary hypoplasia63–65 Single umbilical artery (isolated)32 Sirenomelia66

Renal agenesis, hydronephrosis, cystic dysplasia, horseshoe kidney Renal agenesis, renal ectopia Renal agenesis, horseshoe kidney Cloacal exstrophy, horseshoe kidneys, patent urachus Renal agenesis, horseshoe kidney Renal agenesis, cystic dysplasia, ectopia, horseshoe kidneys Cloacal and bladder anomalies

18–21

Cystic dysplasia, renal agenesis, horseshoe kidney, polycystic kidney, urethral atresia

26

Dilated renal pelvis, duplicated renal pelvis, reflux, hydronephrosis, horseshoe kidneys, unilateral renal agenesis

100

Renal agenesis, cystic dysplasia, urethral atresia Kidneys very occasionally are normal67

30

Supernumerary nipples Tracheal agenesis68

4 38

66,69

No specific pattern Renal agenesis, cystic dysplasia, horseshoe kidney

VACTERL association

82–87

Reflux, unilateral renal agenesis, ureteropelvic junction obstruction, crossed fused ectopia

Vertebral defects70–72

27–46

Unilateral renal agenesis, duplicated ureter, renal ectopia, horseshoe kidney

*Higher numbers seen in autopsy series and/or those with
3 congenital anomalies.

7. Woolf AS, Winyard PJ: Molecular mechanisms of human embryogenesis: developmental pathogenesis of renal tract malformations. Pediatr Dev Pathol 5:108, 2002. 8. Jo MT, Albertine KH: Urorectal septum malformation sequence: insights into pathogenesis. Anat Rec 268:405, 2002. 9. Morrisey EE, Ip HS, Lu MM, et al.: GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev Biol 177:309, 1996. 10. King JA, Marker PC, Seung KJ, et al.: BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol 166:112, 1994.

11. Green MC: Mechanisms of the pleiotropic effects of the short ear mutant gene in the mouse. J Exp Zool 167:129, 1968. 12. Campbell M: Embryology and anomalies of the urinary tract. In: Urology, vol 1. M Campbell, ed. WB Saunders Company, Philadelphia, 1954, p 227. 13. Rubinstein M, Meyer R, Bernstein J: Congenital abnormalities of the urinary system. J Pediatr 58:356, 1961. 14. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 15. Evans PR, Polani N: Congenital malformations in a post-mortem series. Teratology 22:207, 1980.

Table 28-6. Acrorenal disorders Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Acrofacial dysostosis (Arens)73

Facial dysmorphism, oligodactyly, central polydactyly, atresia auditory canals

Hydronephosis

AR

Acrofacial dysostosis (Nager)74

Micrognathia, malar hypoplasia, radial ray aplasia, short stature, laryngeal and heart defects

Unilateral renal agenesis, duplicated calyx

AD (154400), most cases sporadic ?ZFP37, 9q32

Acrofacial dysostosis (Rodriquez)75

Renal hypoplasia

AR (201170)

Acrorenal (Buttiens)76,77

Facial dysmorphism, limb deficiency defects; Central nervous system (CNS), heart, and lung lobation defects Monodactyly (fifth digits present), small jaw, dental and palatal defects, mental retardation (overlap with Acrorenal [Miltenyi])

Renal dysplasia, hypoplasia, oligomeganephronia, proteinuria

AR (246560)

Acrorenal (Dieker)78

Oligodactyly, split hand/foot

Unilateral renal agenesis, hydronephrosis, double ureters, renal hypoplasia

Usually sporadic, AD (102520)

Acrorenal (Miltenyi)79

Split hand/foot

Oligomeganephronic renal hypoplasia

AR (201310)

Acrorenal (Siegler)80

Radial ray defects, short stature

Uncertain

Acrorenal (Sofer)81

Radial ray defects, short stature, ear anomalies, increased chromosomal breakage

Crossed fused renal ectopia, hydronephrosis Unilateral renal agenesis, crossed renal ectopia

Acro-renal-mandibular82

Split hand/foot, mandibular hypoplasia, uterine defects

Renal agenesis, cystic dysplasia

AR (200980)

Acro-renal-ocular/ Okihiro84,85

Thumb anomalies, microphthalmia, colobomata, anal stenosis, vertebral defects

Renal ectopia, unilateral renal agenesis, renal hypoplasia, horseshoe kidney, reflux, bladder diverticulae

AD (102490, 126800) Some families have mutations in SALL4 at 20q13

Acro-renal-uterinemandibular (severe)83

Tetra-phocomelia, oligodactyly, micrognathia, uterine defects, esophageal and anal atresia, olfactory nerve agenesis

Renal agenesis

AR (200980)

Amelia with anal atresia86,87

Absence of one or more limbs, radial ray deficiencies, imperforate anus, lung lobation and vertebral defects, pelvic bone agenesis, single umbilical artery

Renal agenesis, absent ureters and bladder

Uncertain, usually sporadic

Axial mesodermal dysplasia spectrum88,89

Hemifacial microsomia, vertebral anomalies, caudal dysplasia, anal anomalies

Renal agenesis, hydronephrosis

Unknown, probably heterogeneous, maternal diabetes in some cases

Baller-Gerold90,91

Craniosynostosis and radial ray defects; anal, CNS and heart anomalies (overlap with Roberts, VACTERL-Hydrocephalus, Saethre-Chotzen)

Renal agenesis, hypoplasia, dysgenesis, ectopia

Heterogeneous AR (218600) Some patients without visceral anomalies have mutations in TWIST 7p21

Caudal dysplasia92

Sacral defects, lower limb hypoplasia, anal and genital defects

Renal agenesis or dysplasia, bladder or cloacal exstrophy, hydronephrosis, urethral atresia

Heterogeneous Maternal diabetes seen in approximately one-third

AD (179280)

Chromosomal disorders —See Table 28-10 Czeizel split hand-urinary defects93

Split hand/foot, spina bifida, diaphragmatic hernia, ventricular septal defect

Hydronephrosis, ureteral atresia

AD (183802)

De Lange94,95

Facial dysmorphism, microcephaly, short stature, ulnar ray defects, mental retardation

Cortical cysts, nephrogenic rests, horseshoe kidney

AD (122470), NIPBL, 5p13.1 (continued)

1168

Table 28-6. Acrorenal disorders (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Disorganization96,97

Limb duplications and deficiencies, hamartomata, skin tags, facial clefts, pharyngeal and CNS defects

Renal agenesis, horseshoe kidney

AD (223200), potentially requires a second ‘‘hit’’ to be penetrant Possibly the human homolog of the semidominant mouse mutant Ds

DK-Phocomelia98,99

Phocomelia, CNS and genital anomalies, thrombocytopenia

Renal agenesis or ectopia, horseshoe kidneys, ureteral defects

Unknown (223340)

Early amnion rupture100

Digital and limb amputations, ring constrictions, facial clefts, body wall defects, brain anomalies

Renal dysplasia, agenesis and ectopia, ureteral anomalies, urethral stenosis

Sporadic

Ectrodactyly-ectodermal dysplasia-clefting101,102

Split hand/foot, ectodermal dysplasia, facial clefts

Renal agenesis and dysplasia, ureteral and bladder defects, reflux

AD (129900) EEC1, 7q11.2-21.3 AD (604292) EEC3, 3q27 Most cases are EEC3 and have mutations in TP63, 3q27

Facio-auriculo-vertebral (hemifacial microsomia, Goldenhar)103

Hemifacial microsomia, heart, radial ray and vertebral defects

Renal agenesis, dysplasia and ectopia, reflux, ureteropelvic junction obstruction, posterior urethral valves

Heterogeneous, usually sporadic, AD (164210) 1 family mapped to 14q32

Fanconi pancytopenia104

Pancytopenia, anemia; radial ray defects; microcephaly, dilated ventricles, microphthalmia; short stature; increased chromosome breakage

Renal agenesis (usually unilateral), dysplasia, hypoplasia, or ectopia; horseshoe kidney, hydronephrosis, double ureters, urethral atresia

Heterogeneous AR (227650) FANCA, 16q24.3 FANCB, 13q12.3, BRCA2 FANCC, 9q22.3 FANCD1/D2, 3p25.3 FANCE, 6p22-p21 FANCF, 11p15 FANCG, 9p13 Several complementation groups identified

Femoral-facial105,106

Femoral hypoplasia, unusual facies, micrognathia, cleft palate

Renal agenesis

Likely heterogeneous, AD (134780), most cases sporadic, some have diabetic mothers

Johnson-Munson107,108

Aphalangy, hypoplastic radius and ulna, hemivertebra, anal and genital anomalies, mental retardation

Renal agenesis, urethral atresia, urethral fistula

AR (207620)

Kaplan-Bellah109

Ulnar ray deficiency, postaxial polydactyly

Renal cystic dysplasia

Uncertain

Lacrimo-auriculo-dentodigital (Levy-Hollister, LADD)110

A/hypoplasia of lacrimal ducts and salivary glands, cup-shaped ears, dental anomalies, radial ray defects

Renal agenesis, nephrosclerosis, stones

AD (149730)

Limb/pelvis-hypoplasia/ aplasia111,112

Severe deficiencies of all limbs, barrel-shaped chest, pelvic hypoplasia, CNS and genital defects, facial dysmophism, nail hypoplasia (overlap with Schinzel phocomelia)

Renal agenesis or dysplasia, bladder exstrophy

AR (276820)

(continued)

1169

Table 28-6. Acrorenal disorders (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Limb-body wall complex51

Lateral body wall defects, limb deficiency defects, neural tube defects

Renal agenesis or dysplasia, ureteral anomalies, renal ectopia, bladder exstrophy

Sporadic, amnion disruption

Microgastria-upper limb anomalies113

Radial ray defects, asplenia, other laterality defects, heart anomalies

Renal agenesis, ectopia, horseshoe kidney

Unknown, discordant MZT (156810)

Mirror polydactyly, limb deficiencies, vertebral defects114

Phocomelia, oligodactyly, mirror polydactyly, duodenal atresia, vertebral defects

Renal agenesis, absent bladder and ureters

AR

Poland115

Hypoplastic radius and ulna, oligodactyly, pectoral major and mammary gland anomalies

Renal agenesis or hypoplasia, ureteral anomalies, ureteropelvic junction obstruction, reflux

Heterogeneous, AD with reduced penetrance (173800), vascular disruption to embryonic subclavian and vertebral arteries

Roberts (pseudothalidomide)116

Tetra-phocomelia, short stature, facial dysmorphism, cleft lip and palate, genital and CNS defects, mental retardation, centromeric puffing of chromosomes

Renal agenesis or dysplasia, horseshoe kidneys, hydronephrosis

AR (268300), likely allelic to SC phocomelia (269000)

Saito117

Fibula and ulna deficiency defects, heart anomalies

Renal hypoplasia or dysplasia

AR (228940)

Schinzel phocomelia118

Phocomelia, especially of the lower limbs, skull defects, uterine defects (overlap with Limb/pelvis aplasia/hypoplasia)

Hydronephrosis, reflux

AR (276820)

Sirenomelia119,120

Fusion of the lower limbs, anal atresia, genital anomalies, single umbilical artery

Renal agenesis or dsyplasia, bladder or cloacal extrophy, bladder agenesis, hydronephrosis, ureteral anomalies, urethral atresia

Probably heterogeneous, AD with reduced penetrance, vascular steal from persistent vitelline vessels, excess of MZT and maternal diabetes

Steinfeld121

Very short radius and ulna, absent thumbs, holoprosencephaly, absent gallbladder, facial clefts, costovertebral defects

Renal dysplasia, ectopia

AD (184705), reduced penetrance

Teratogenic exposures —See Table 28-11 Thromobocytopeniaabsent radius (TAR)122

Radial deficiency, phocomelia with preserved thumb, thrombocytopenia, cardiac defects

Renal ectopia, horseshoe kidney, ureteral anomalies

Uncertain (27400)

Townes-Brocks123,124

Radial ray and hallucal defects, anal anomalies, ear anomalies, deafness

Renal agenesis, dysplasia or hypoplasia, reflux, urethral atresia, urethral valves, horseshoe

AD (107480) SALL1, 16q12.1

Ulbright125

Phocomelia, absent ulna and fibula, postaxial polydactyly of toes, facial dysmorphism, rib anomalies

Renal hypoplasia or dysplasia

AR (266910)

Ulnar-mammary126,127

Ulnar ray aplasia; oligodactyly; breast, nipple, and apocrine gland anomalies; genital defects

Unilateral renal agenesis

AD (181450) TBX, 12q24.1

VACTERL association128

Vertebral, anal, cardiac, tracheoesophageal, and limb defects

Renal agenesis, dysplasia or ectopia, horseshoe kidneys

Sporadic

VACTERL with hydrocephalus129–131

VACTERL anomalies with hydrocephalus or other severe CNS defects, clefting, microtia, lung lobation defects, some have increased chromosome breakage

Renal agenesis, dysplasia, hypoplasia or ectopia, horseshoe kidneys, ureteral atresia

(276950) Genetically heterogeneous, XLR, AR, some cases are Fanconi (AR 227650) An atypical case had a mutation in PTEN (continued)

1170

Urinary Tract

1171

Table 28-6. Acrorenal disorders (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Weyers oligodactyly132,133

Ulnar and fibular ray deficiencies, split hand/foot, facial clefts, micrognathia, spleen defects

Renal dysplasia, hydronephrosis, ureteral anomalies

AR (602418) Similar to the mouse mutant oligodactyly

Zimmer134

Tetra-amelia; facial clefts; CNS, heart, lung, genital, and anal anomalies; athelia

Renal dysplasia, horseshoe kidneys

XLR (301090)

16. Museles M, Gaudry CL Jr, Bason WM: Renal anomalies in the newborn found by deep palpation. Pediatrics 47:97, 1971. 17. Perlman M, Williams J: Detection of renal anomalies by abdominal palpation in newborn infants. Br Med J 2:347, 1976. 18. Steinhart JM, Kuhn JP, Eisenberg B, et al.: Ultrasound screening of healthy infants for urinary tract abnormalities. Pediatrics 82:609, 1988. 19. Jelen Z: The value of ultrasonography as a screening procedure of the neonatal urinary tract: a survey of 1021 infants. Int Urol Nephrol 25:3, 1993. 20. Riccipetitoni G, Chierici R, Tamisari L, et al.: Postnatal ultrasound screening of urinary malformations. J Urol 148:604, 1992. 21. Gunn TR, Mora JD, Pease P: Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks’ gestation: incidence and outcome. Am J Obstet Gynecol 172:479, 1995. 22. Oliveira EA, Cabral AC, Pereira AK, et al.: Outcome of fetal urinary tract anomalies associated with multiple malformations and chromosomal abnormalities. Prenat Diagn 21:129, 2001. 23. Malone PS: Antenatal diagnosis of renal tract anomalies: has it increased the sum of human happiness? J R Soc Med 89:155P, 1996. 24. Greig JD, Raine PA, Young DG, et al.: Value of antenatal diagnosis of abnormalities of the urinary tract. BMJ 298:1417, 1989. 25. London Dysmorphology Database. Oxford University Press, Oxford, 2001. 26. Martinez-Frias ML, Frias JL, Opitz JM: Errors of morphogenesis and developmental field theory. Am J Med Genet 76:291, 1998. 27. Canadian Institute for Health Information: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Canadian Institute for Health Information, Ottawa, 2001. 28. Walsh PC, Retik AB, Vaughen ED, et al.: Campbell’s Urology, ed 8. WB Saunders Company, Philadelphia, 2003. 29. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 30. Jojart G, Seres E: Supernumerary nipples and renal anomalies. Int Urol Nephrol 26:141, 1994. 31. Grotto I, Browner-Elhanan K, Mimouni D, et al.: Occurrence of supernumerary nipples in children with kidney and urinary tract malformations. Pediatr Dermatol 18:291, 2001. 32. Thummala MR, Raju TN, Langenberg P: Isolated single umbilical artery anomaly and the risk for congenital malformations: a meta-analysis. J Pediatr Surg 33:580, 1998. 33. Turkel SB, Swanson V, Chandrasoma P: Malformations associated with congenital absence of the gall bladder. J Med Genet 20:445, 1983. 34. Franco I, Kogan S, Fisher J, et al.: Genitourinary malformations associated with agenesis of the corpus callosum. J Urol 149:1119, 1993. 35. Parrish ML: Agenesis of the corpus callosum: a study of the frequency of associated malformations. Ann Neurol 6:349, 1976. 36. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 37. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983.

38. Sangkhathat S, Patrapinyokul S, Tadtayathikom K: Associated genitourinary tract anomalies in anorectal malformations: a thirteen year review. J Med Assoc Thai 85:289, 2002. 39. Cho S, Moore SP, Fangman T: One hundred three consecutive patients with anorectal malformations and their associated anomalies. Arch Pediatr Adolesc Med 155:587, 2001. 40. Metts JC III, Kotkin L, Kasper S, et al.: Genital malformations and coexistent urinary tract or spinal anomalies in patients with imperforate anus. J Urol 158:1298, 1997. 41. Silveira TR, Salzano FM, Howard ER, et al.: Congenital structural abnormalities in biliary atresia: evidence for etiopathogenic heterogeneity and therapeutic implications. Acta Paediatr Scand 80:1192, 1991. 42. Rubenstein MA, Bucy JG: Caudal regression syndrome: the urologic implications. J Urol 114:934, 1975. 43. Ragan DC, Casale AJ, Rink RC, et al.: Genitourinary anomalies in the CHARGE association. J Urol 161:622, 1999. 44. Benjamin DR, Juul S, Siebert JR: Congenital posterolateral diaphragmatic hernia: associated malformations. J Pediatr Surg 23:899, 1988. 45. Philip N, Gambarelli D, Guys JM, et al.: Epidemiological study of congenital diaphragmatic defects with special reference to aetiology. Eur J Pediatr 150:726, 1991. 46. Torfs CP, Curry CJ, Bateson TF, et al.: A population-based study of congenital diaphragmatic hernia. Teratology 46:555, 1992. 47. Berkhoff WB, Scholtmeyer RJ, Tibboel D, et al.: Urogenital tract abnormalities associated with esophageal atresia and tracheoesophageal fistula. J Urol 141:362, 1989. 48. Mabogunje OA, Mahour GH: Omphalocele and gastroschisis. Trends in survival across two decades. Am J Surg 148:679, 1984. 49. Rao S, Engle MA, Levin AR: Silent anomalies of the urinary tract and congenital heart disease. Chest 67:685, 1975. 50. Murugasu B, Yip WC, Tay JS, et al.: Sonographic screening for renal tract anomalies associated with congenital heart disease. J Clin Ultrasound 18:79, 1990. 51. Van Allen MI, Curry C, Gallagher L: Limb body wall complex: I. Pathogenesis. Am J Med Genet 28:529, 1987. 52. Russo R, D’Armiento M, Angrisani P, et al.: Limb body wall complex: a critical review and a nosological proposal. Am J Med Genet 47:893, 1993. 53. Evans JA, Vitez M, Czeizel A: Patterns of acrorenal malformation associations. Am J Med Genet 44:413, 1992. 54. Duncan PA, Shapiro LR, Stangel JJ, et al.: The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 95:399, 1979. 55. Mahajan P, Kher A, Khungar A, et al.: MURCS association—a review of 7 cases. J Postgrad Med 38:109, 1992. 56. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 57. Stoll C, Alembik Y, Dott B, et al.: Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37:41, 2000. 58. Sermer M, Benzie RJ, Pitson L, et al.: Prenatal diagnosis and management of congenital defects of the anterior abdominal wall. Am J Obstet Gynecol 156:308, 1987.

Table 28-7. Osteo-renal disorders Urinary Tract Anomalies

Causation Gene/Locus

Craniosynostosis, brachycephaly, frontal bossing, depressed nasal root, downslanting pallebral fissures, bowed femurs, slender bones, multiple fractures, heart and genital defects

Renal agenesis, horseshoe kidneys

AR (207410) heterogeneous POR, 7q11.2 FGFR2, 10q26 Prenatal fluconazole exposure

Acrocephaly, craniosynostosis, frontal bossing, syndactyly, ‘‘mitten’’ hands and feet

Hydronephrosis

AD (101200), increased paternal age effect for new mutations FGFR2, 10q26

Polydactyly, osteopenia, dental anomalies

Renal hypoplasia

?AR

Beemer-Robinow

Dense bones, hydrocephalus, cardiac and genital defects

Renal hypoplasia, ureteral defects

AR (209970) peroxisomal defect

Campomelia-short gutrenal dysplasia (Cumming)140

Short bowed limbs, cleft palate, short bowel, cystic dysplasia of liver and pancreas, polysplenia, cervical lymphocele

Renal dysplasia

AR (211890)

Campomelic dysplasia141

Bowing of the femur and tibia, hypoplastic scapula, facial dysmorphism, cardiac defects, ambiguous genitalia, sex reversal

Renal hypoplasia, hydronephrosis, calyceal dilation

AD (114290), most cases are new mutations SOX9, 7q24.3-q25.1

Carpenter-Hunter142

Severe short limbed dwarfism, CNS and facial defects, postaxial polydactyly, multiple fractures

Renal dysplasia

Unknown

Cerebro-osteonephrodysplasia143,144

Short stature, mild spondylorhizomelic dysplasia, microcephaly, mental retardation, postnatal growth failure

Unknown, terminal renal failure and nephrosis

AR (236450) Seen predominantly in Hutterites

Chondrodysplasia-situs inversus143,145

Delayed bone age, wide metaphyses, short stature, liver and pancreatic cystic dysplasia, situs inversus, postaxial polydactyly, anal and genital defects (overlap with Renal-hepatic-pancreatic dysplasia Ivemark)

Renal agenesis, hypoplasia or dysplasia

Uncertain

Disorder

Prominent Features

Antley-Bixler135,136

Apert137

Barakat (1996)138 139

Chromosomal disorders—See Table 28-10 Cross146

Short stature, osteoporosis, hypopigmentation, microphthalmia, seizures, mental retardation

Ureteral anomalies

AR (257800)

Ear-patella-short stature (Meier-Gorlin)147

Epiphyseal flattening, slender bones, patella and rib anomalies, short stature, microtia, craniosynostosis and mental retardation in some cases Osteoporosis, delayed bone age, short stature, hypoplastic pituitary, developmental delay

Hydronephrosis, urethral hypoplasia

AR (224690)

Renal dysplasia or hypoplasia

Uncertain

Fibromatosis, generalized149

Skeletal cysts, lytic bone lesions, scalp and facial tumors, vertebral defects

Renal hypoplasia, renal tumors (including Wilms)

AR (228550)

Fronto-metaphyseal dysplasia (Gorlin)150,151

Bony overgrowth of superorbital ridges, cortical hyperostosis, metaphyseal dysplasia, tibial bowing, vertebral defects, cardial defects (overlap with Melnick-Needles)

Supernumerary kidneys, hydronephrosis, ureteral defects, urethral valves

XLD (305620) FLNA, Xq28

Glycogen storage disease type 1152

Osteoporosis, lordosis, abdominal protuberance, hepatomegaly, hypogylcemia, growth failure

Large kidneys, renal stones/calcification

AR (232200) G6PT, 17q21

Goldblatt genito-patellar

Osteoporosis, absent or hypoplastic patella, joint contractures, facial dysmorphism, scrotal hypoplasia, agenesis or corpus callosum, mental retardation

Renal dysplasia and ectopia, hydronephrosis, large kidneys

Unknown, usually sporadic, more common in males

Hajdu-Cheney (acro-osteolysis)154

Osteoporosis, osteolysis, multiple fractures, facial dysmorphism (overlap with serpentine fibula)

Polycystic kidney disease

AD (102500)

Jeune (asphyxiating thoracic dysplasia)155

Metaphyseal and epiphyseal dysplasia, small bell-shaped thorax, pulmonary hypoplasia, polydactyly, short limbs, hepatic and pancreatic dysplasia, retinal dystrophy

Renal dysplasia, glomerular nephritis, juvenile nephronophthisis, hydronephrosis

AD (208500)

Elmer148

153

(continued)

1172

Table 28-7. Osteo-renal disorders (continued) Urinary Tract Anomalies

Causation Gene/Locus

Epiphyseal dysplasia, delayed bone age, joint contractures, short stature, XY sex reversal, absent gonads, vertebral and heart defects, omphalocele, mental retardation

Renal agenesis or dysplasia

AR (202660, 600908)

Kozlowski (humerospinal dyspostosis)157

Short humeri with distal bifurcation, coronal clefts and other vertebral anomalies, slender bones, joint anomalies, heart defects

Ureteral anomalies

(143095)

Kozlowski-Tsurata (dysplastic cortical hyperostosis)158

Osteosclerosis, vertebral defects, hydrops, lung lobation defects, lissencephaly

Supernumerary kidneys

AR based on parental consanguinity

Kurtoglu159

Osteosclerosis, multiple joint dislocations, vertebral defects, biliary dysgenesis

Polycystic kidney disease

AR based on parental consanguinity

Kyphomelic dysplasia160

Metaphyseal dysplasia, bowing of long bones, short ribs, immunodeficiency

Hydronephrosis

AR (211350), potentially heterogeneous

Leprechaunism161

Slender bones, delayed bone age, facial dysmorphism, hirsutism, growth retardation, hyperplasia, pancreatic islet cells, gonadal cysts

Cortical cysts, glomerulopathy, large kidneys, glucosuria

AR (246200) INSR, 19p13.2

Lethal metaphyseal dysplasia (SprangerMaroteaux)162

Metaphyseal dysplasia, thin bones, poorly ossified skull and facial bones, osteopathia striata

Renal agenesis

AR on the basis of parental consanguinity

Mainzer-Saldino163

Metaphyseal dysplasia, delayed bone age, thin bones, osteoporosis, cerebellar anomalies, cone-shaped epiphyses in hands, retinal dysplasia, cerebellar hypoplasia, ataxia, hepatic fibrosis

Renal dysplasia or hypoplasia, glomerulopathy

AR (266920)

Marshall-Smith164

Osteosclerosis, osteoporosis, advanced bone age, facial dysmorphism, laryngeal defects, failure to thrive, mental retardation

Hydronephrosis

Unknown (602535)

Melnick-Needles osteodysplasty150,151

Short stature, wide metaphyses, facial dysmorphism, omphalocele in males (overlap with fronto-metaphyseal dysplasia)

Renal ectopia, ureteral anomalies, urethral atresia

XLD (309350) FLNA, Xq28

Mievis165

Severe short stature, metaphyseal dysplasia, delayed bone age, facial dysmorphism

Horseshoe kidneys

Uncertain (601350)

Moerman166

Very short limbs, spondylocostal dysostosis, cleft palate, Dandy-Walker cyst, cardiac defects

Renal hypoplasia and dysgenesis, ureteral anomalies

Occipital Horn167,168

Osteoporosis, exostoses, bone bowing, carpal bone fusions, cutis laxa

Multiple urinary infections, bladder diverticulae, hydronephrosis, urethral stenosis

XLR (304150) ATP7A, Xq12-13

Pearson169

Osteoporosis, delayed bone age, short stature, metaphyseal dysplasia, sideroblastic anemia, pancreatic dysfunction

Multiple cortical cysts, organicaciduria

Mitochondrial deletions (557000)

Pfeiffer-HirschfelderRott170,171

Acromesomelia, wide metaphyses, wrist and hand bone defects, synostoses, ptosis

Hydronephrosis, ureteral anomalies

Probably AD (600383)

Pseudo-Zellweger172

Osteoporosis, delayed bone age, postaxial polydactyly, CNS defects, facial dysmorphism, hypotonia, seizures, mental retardation

Multiple cortical cysts, large kidneys

AR (261515) HSD17B4, 5q2

Schinzel-Giedion173

Cortical hyperostosis, acrosteolysis, mesomelic lower limbs, bowed long bones, facial dysmorphism, CNS and cardiac defects, mental retardation, teratomata

Renal ectopia hydronephrosis, ureteral anomalies, megacalysis

AR (269150)

Serpentine fibula174

Osteoporosis, S-shaped fibula, bowed long bones, cortical hyperostosis, hirsutism, vertebral anomalies, deafness (overlap with Melnick-Needles)

Polycystic kidney disease

Uncertain (600330)

Disorder

Prominent Features

Kennerknecht156

(continued)

1173

1174

Urogenital System Organs

Table 28-7. Osteo-renal disorders (continued) Urinary Tract Anomalies

Causation Gene/Locus

Lethal short rib dwarfism; metaphyseal dysplasia; postaxial polydactyly; hydrops; genital, anal, and cardiac defects

Renal dysplasia, polycystic kidney disease, urethral fistula, ureteral anomalies, persistent cloaca

(263530)

Short rib-polydactyly II (Majewski)176

Lethal short rib dwarfism; pre- and postaxial polydactyly; median cleft lip; disproportionate shortening of the tibia; genital, laryngeal, epiglottal, and CNS anomalies; hydrops

Renal dysplasia and hypoplasia, polycystic kidney disease, glomerular and tubular cysts

(263520)

Short rib-polydactyly III (Verma-Naumoff )177

Lethal short rib dwarfism, postaxial polydactyly, cloacal defects, heart and laterality anomalies

Renal dysplasia, pyelectasia, urethral fistulae

AR (263510)

Short rib-polydactyly IV (Beemer-Langer)178

Lethal short rib dwarfism, pre- and postaxial polydactyly, hydrops, CNS defects, natal teeth, oral clefts

Renal dysplasia or hypoplasia, hydronephrosis, ureteral anomalies

AR (269860)

Silverman dyssegmental dwarfism179

Lethal, metaphyseal dysplasia, short stature, vertebral defects, cleft palate, flat face

Hydronephrosis, ureteral anomalies

AR (224410) HSPG2, 1p36.1

Spondyloepimetaphyseal dysplasia joint laxity180

Metaphyseal and epiphyseal dysplasia, short stature, kyphoscoliosis, joint mobility, cleft palate, heart defects

Ureteral anomalies

(271640)

Spondyloepimetaphyseal dysplasia (Strudwick)181

Metaphyseal and epiphyseal dysplasia, short stature, scoliosis, delayed bone age, accessory metacarpals, metaphyseal dappling developing in childhood, cleft palate, retinal detachment

Hydronephrosis

AD (184250), possibly an AR form also COL2A1, 12q13.11-q13.2

Renal dysplasia

(312150)

Disorder

Prominent Features

Short rib-polydactyly I (Saldino-Noonan)175

Teratogenic exposures—See Table 28-11 Tolmie182

Lethal, multiple pterygia, undermodeled long bones, hypoplastic radius and ulna, preaxial polydactyly, cystic hygroma, cleft palate

59. Gilbert WM, Nicolaides KH: Fetal omphalocele: associated malformations and chromosomal defects. Obstet Gynecol 70:633, 1987. 60. Chen CP, Liu FF, Jan SW, et al.: Prenatal diagnosis and perinatal aspects of abdominal wall defects. Am J Perinatol 13:355, 1996. 61. Parida SK, Hall BD, Barton L, et al.: Penoscrotal transposition and associated anomalies: report of five new cases and review of the literature. Am J Med Genet 59:68, 1995. 62. Warne SA, Wilcox DT, Ransley PG: Long-term urological outcome of patients presenting with persistent cloaca. J Urol 168:1859, 2002. 63. Nakamura Y, Harada K, Yamamoto I, et al.: Human pulmonary hypoplasia. Statistical, morphological, morphometric, and biochemical study. Arch Pathol Lab Med 116:635, 1992. 64. Page DV, Stocker JT: Anomalies associated with pulmonary hypoplasia. Am Rev Respir Dis 125:216, 1982. 65. Knox WF, Barson AJ: Pulmonary hypoplasia in a regional perinatal unit. Early Hum Dev 14:33, 1986. 66. Duncan PA, Shapiro LR, Klein RM: Sacrococcygeal dysgenesis association. Am J Med Genet 41:153, 1991. 67. McCoy MC, Chescheir NC, Kuller JA, et al.: A fetus with sirenomelia, omphalocele, and meningomyelocele, but normal kidneys. Teratology 50:168, 1994. 68. Evans JA, Greenberg CR, Erdile L: Tracheal agenesis revisited: analysis of associated anomalies. Am J Med Genet 82:415, 1999. 69. Uehling DT, Gilbert E, Chesney R: Urologic implications of the VATER association. J Urol 129:352, 1983. 70. Rai AS, Taylor TK, Smith GH, et al.: Congenital abnormalities of the urogenital tract in association with congenital vertebral malformations. J Bone Joint Surg Br 84:891, 2002.

71. Beals RK, Robbins JR, Rolfe B: Anomalies associated with vertebral malformations. Spine 18:1329, 1993. 72. Tori JA, Dickson JH: Association of congenital anomalies of the spine and kidneys. Clin Orthop Relat Res May (148):259, 1980. 73. Arens R, Reichman B, Katznelson MB, et al.: New form of postaxial acrofacial dysostosis? Am J Med Genet 41:438, 1991. 74. McDonald MT, Gorski JL: Nager acrofacial dysostosis. J Med Genet 30:779, 1993. 75. Wessels MW, den Hollander NS, Cohen-Overbeek TE, et al.: Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez. Am J Med Genet 113:97, 2002. 76. Buttiens M, Fryns JP: Apparently new autosomal recessive syndrome of mental retardation, distal limb deficiencies, oral involvement, and possible renal defect. Am J Med Genet 27:651, 1987. 77. Keymolen K, Damme-Lombaerts R, Verloes A, et al.: Distal limb deficiencies, oral involvement, and renal defect: report of a third patient and confirmation of a distinct entity. Am J Med Genet 93:19, 2000. 78. Dieker H, Opitz JM: Associated acral and renal malformations. Birth Defects Orig Artic Ser V(3):68, 1969. 79. Miltenyi M, Czeizel AE, Balogh L, et al.: Autosomal recessive acrorenal syndrome. Am J Med Genet 43:789, 1992. 80. Siegler RL, Larsen P, Buehler BA: Upper limb anomalies and renal disease. Clin Genet 17:117, 1980. 81. Sofer S, Bar-Ziv J, Abeliovich D: Radial ray aplasia and renal anomalies in father and son: a new syndrome. Am J Med Genet 14:151, 1983. 82. Tobias ES, Patrick WJA, MacKenzie JR, et al.: A case of acro-renalmandibular syndrome in an 18 week male fetus. Clin Dysmorphol 10: 61, 2001.

Table 28-8. Cerebro-renal-digital disorders Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Acrocephalopolydactylous dysplasia (Elejalde)183,184

Swollen body, short limbs, postaxial polydactyly, agenesis of the corpus callosum, craniosynostoses, omphalocele, polysplenia, organomegaly, lethal

Cystic renal dysplasia, ureteral anomalies

AR (200995)

Agnathiaholoprosencephaly185

Holoprosencephaly, missing or small jaw, midline defects, situs inversus

Horseshoe kidneys, hydronephrosis

Probably heterogeneous, may be AR in some families (202650)

Bendon186

Hydranencephaly, cerebellar defects, second to third toe syndactyly (overlap with Severe Smith-Lemli-Opitz syndrome)

Small dysplastic kidneys, ureteral defects, bladder hypoplasia

Uncertain (236500)

Bowen-Conradi187,188

Proud nose, micrognathia, microcephaly, hypospadias, rocker-bottom feet, death in infancy

Horseshoe kidneys, double ureters

AR (211180) Predominantly seen in Hutterites

BRESHECK189

Microcephaly, dilated ventricles, agenesis of the corpus callosum, mental retardation, microphthalmia, polydactyly, ectodermal dysplasia

Small dysplastic kidneys

XLR (300404)

Carbohydrate-deficient glycoprotein type I190

Agenesis of the corpus callosum, cerebral atrophy, Dandy-Walker cyst, long fingers and toes, inverted nipples, fat pads

Multiple microcysts, large solitary cysts, proteinuria

AR, heterogeneous AR (212065) CGPIa, 16p13, PMM2 AR (602579) CGPIb, 15q22-qter, MPI AR (603147) CGDIc, 1p22.3, ALG6

Chromosomal disorders—See Table 28-10 Coffin-Siris191

Agenesis of the corpus callosum, Dandy-Walker cyst, microcephaly, mental retardation, hypoplastic phalanges and nails on fifth fingers, sparse scalp hair, coarse facies

Hydronephrosis, renal ectopia and hypoplasia

Uncertain (135900)

Craniomicromelic syndrome192

Macrocephaly, craniosynostosis, encephalocele, facial dysmorphism, tapering digits, syndactyly, talonlike nails, gastrointestinal defects

Hydronephrosis

AR

Deafnessonychodystrophyonycholysis-retardation (DOOR)193

Deafness, seizures, hydrocephalus, Dandy-Walker cyst, nail abnormalies, triphalangeal thumb, cardiac defects

Hydronephrosis, ureteral defects

Heterogeneous, AD, AR (220500)

Fryns-acral defects194

Structural brain anomalies, digital hypoplasia, diaphragmatic defects, facial dysmorphism, cloudy corneae, heart defects, usually lethal in infancy

Renal agenesis or dysplasia, cortical cysts, hydronephrosis

AR (229850)

Greig195,196

Macrocephaly, frontal bossing, agenesis of corpus callosum, ventricular dilation, polysyndactyly

Double Ureters

AD (175700) microdeletion, GLI3, 7p13

Holzgreve197,198

Abnormal septum pellucidum, polydactyly, cleft lip, cleft palate, cardiac and genital defects, lethal

Renal agenesis, dysplasia or hypoplasia

AR, probably heterogeneous (236110)

Hydrolethalus199

Structural brain anomalies, occipitoschisis, micrognathia, cleft lip and palate, tongue anomalies, postaxial polydactyly, cardiac, pulmonary and genital defects

Hydronephrosis, urethral stenosis

AR (236680), more common in Finns, 11q23-25

Janssen200

Cystic hygroma, fourth to fifth toe syndactyly, microcephaly, facial dysmorphism (overlap with Fraser cryptophthalmos syndrome)

Renal dysplasia

AR

Kivlin/Peters plus201

Hydrocephalus, agenesis of the corpus callosum, dysmorphic face, Peters’ anomaly, sclerocornea, dysmorphic face, cleft lip, short stature, broad hands and feet, clinodactyly, brachdactyly, mental retardation

Renal ectopia, double ureters

AR (261540)

(continued)

1175

Table 28-8. Cerebro-renal-digital disorders (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Lachiewicz-agenesis of the corpus callosum, renal defects202

Macrocephaly, agenesis of corpus callosum, mental retardation, long thumbs and halluces (overlap with FG syndrome)

Hydronephrosis, hydroureters, ureteroceles, urethral valves

Uncertain

Lin-Gettig203

Agenesis of corpus callosum, mental retardation, dysmorphic face, camptodactyly, hypogonadism

Hydronephrosis, double ureters, urinary reflux

Uncertain (218649)

MacDermot-Winter204

Microcephaly, dilated ventricles, dysmorphic face, camptodactyly, hypoplastic genitalia, growth deficiency, mental retardation

Hydronephrosis

AR (247990)

Marden-Walker205,206

Structural brain anomalies, cerebral atrophy, blepharophimosis, joint contractures, arachnodactyly, camptodactyly, cleft palate, kyphoscoliosis, mental retardation

Cystic dysplasia, renal hypoplasia

AR (248700), probably heterogeneous

Meckel-Gruber207

Occipital encephalocele, other structural brain anomalies, ear anomalies, postaxial polydactyly, cleft lip and palate, ambiguous genitalia, biliary and pancreatic dysgenesis, lethal

Polycystic or dysplastic kidneys, renal agenesis, duplicated ureters, hypoplastic bladder, urethral atresia

AR with genetic heterogeneity (249000, 603194) MKS1, 17q22-q23 MKS2, 11q MKS3, 8q

Neish-Roberts208

Absent septum pellucidum, dysmorphic face, camptodactyly, heart defects

Large kidneys, hydronephrosis

Uncertain

Neuro-facio-digitalrenal209

Megaloencephaly, mental retardation, short stature, hypotonia, triphalangeal thumb, grooved nasal tip

Unilateral renal agenesis, renal hypoplasia

AR (256690)

Nezelof (ARC)210

Agenesis of corpus callosum, spinal muscular atrophy, joint contractures, proximal thumbs, liver dysfunction, diabetes insipidus, mental retardation

Renal dysplasia, renal tubular dysfunction, nephritis, renal stones

AR (208085)

Oculo-encephalo-hepatorenal211,212

Cerebellar anomalies, hydrocephalus, encephalocele, colobomata, hepatic fibrosis, mental retardation (overlap with Smith-Lemli-Opitz and Meckel syndromes)

Single cysts, medullary cysts, renal aplasia or hypoplasia

AR (213010), possibly heterogeneous

Oral-facial-digital (type I)213

Structural brain anomalies, hallucal polydactyly, skin syndactyly, midline cleft lip, oral frenulae, cleft palate, lobulated tongue, mental retardation

Polycystic kidneys hydronephrosis

XLD (311200), usually lethal in males prenatally CXORF5, Xp22.2-22.3

Oral-facial-digital (type IV) Mohr-Majewski214

Structural brain defects, postaxial polydactyly, oral frenulae, tongue nodules, midline cleft upper lip, visceral defects, tibial hypoplasia

Renal agenesis, dysplasia, or hypoplasia, hydronephrosis

AR (258860)

Oral-facial-digital (type VI) Varadi-Papp215

Structural brain defects, duplicated halluces, central polydactyly in hands, oral frenulae, lobed tongue, midline cleft upper lip

Renal hypoplasia, dysplasia or agenesis

AR (277170)

Pallister-Hall216

Hypothalamic hamartoblastoma, complex polydactyly, imperforate anus, buccal frenulae, cleft larynx, visceral anomalies Cerebral atrophy, hydrocephalus, craniosynostosis, syndactyly, heart defects, cleft palate, rib anomalies, mental retardation

Renal agenesis, dysplasia or ectopia, hydronephrosis, inverted horseshoe kidneys Renal hypoplasia, urinary reflux

AD (146510) GLI3, 7p13

Proud218

Agenesis of corpus callosum, porencephaly, microencephaly, coarse facies, tapering fingers, overlapping toes, genital anomalies, mental retardation

Renal dysplasia or hypoplasia, ureteral anomalies

XLD (300004) ARX, Xp22.1

Reuss219

Hydrocephalus, postaxial polydactyly

Corticomedullary cysts, partial renal duplication with double ureters

AR (219730)

Ritscher-Schinzel220

Dandy-Walker malformation, heart defects, downslanting fissures, colobomata, brachydactyly, syndactyly, anal anomalies, mental retardation

Hydronephrosis

AR (220210)

Rubinstein-Taybi221,222

Characteristic facies, broad thumbs and halluces, short stature, mental retardation, Dandy-Walker malformation, agenesis of corpus callosum, heart and vertebral defects

Renal agenesis, hypoplasia and ectopia, caliectasis, hydronephrosis, ureterocele, reflux, nephrosis

AD (180849), most cases are sporadic, microdeletions seen in *10% and cause a more severe phenotype CREBBP, 16p13.3

Pfeiffer type cardiocranial217

AR (218450)

(continued)

1176

Urinary Tract

1177

Table 28-8. Cerebro-renal-digital disorders (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Russell-Silver

Short stature, small triangular face, blue sclerae, asymmetric limbs, clinodactyly fifth fingers, genital defects, variable mental retardation, feeding problems, excessive sweating

Hydronephrosis, renal tubular acidosis, horseshoe kidney, urethral valves

AD (180860), most cases sporadic, maternal uniparental disomy for chromosome 7 in *10% 7p11.2

Smith-Lemli-Opitz (severe)223

Postaxial polydactyly, second to third toe syndactyly, oligodactyly, CNS and heart defects, ambiguous genitalia, facial clefts, facial dysmorphism, mental retardation

Renal agenesis, dysplasia and hypoplasia

AR (270400), potential inverse correlation between plasma and amniotic fluid sterol levels and clinical severity DHCR7, 11q12-q13

Teratogenic exposures —See Table 28-11 Young-Madders (pseudotrisomy 13)224

Holoprosencephaly, other structural brain defects, premaxillary agenesis, preaxial polydactyly, heart defects

Renal agenesis, horseshoe kidneys

AR (264480)

Zlotogora-Dagan225

Microcephaly, holoprosencephaly, thumb anomalies, short stature, low birth weight, mental retardation

Renal ectopia

AR

83. Evans JA, Phillips S, Reed M, et al.: Severe acro-renal-uterinemandibular syndrome. Am J Med Genet 93:67, 2000. 84. Al Baradie R, Yamada K, St Hilaire C, et al.: Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 71:1195, 2002. 85. Aalfs CM, van Schooneveld MJ, van Keulen EM, et al.: Further delineation of the acro-renal-ocular syndrome. Am J Med Genet 62:276, 1996. 86. Lazjuk GI, Lurie IW, Cherstvoy ED, et al.: A syndrome of multiple congenital malformations including amelia and oligodactyly occurring in half-cousins. Teratology 13:161, 1976. 87. Price SM, Berry AC, Raymond FL, et al.: Four cases of amelia of the upper limb associated with anal atresia—is this VACTERL with extreme limb involvement? Clin Dysmorphol 7:35, 1998. 88. Dennis NR, Atwell JD: Axial mesodermal dysplasia spectrum: affected sisters with oculoauriculovertebral ‘‘dysplasia’’ and caudal ‘‘regression’’ sequence. Am J Med Genet 52:237, 1994. 89. Martinez-Frias ML, Gomar JL: New case of axial mesodermal dysplasia sequence: epidemiologic evidence of a single entity. Am J Med Genet 49: 74, 1994. 90. Gripp KW, Stolle CA, Celle L, et al.: TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome. Am J Med Genet 82:170, 1999. 91. Galea P, Tolmie JL: Normal growth and development in a child with Baller-Gerold syndrome (craniosynostosis and radial aplasia). J Med Genet 27:784, 1990. 92. Makhoul IR, Aviram-Goldring A, Paperna T, et al.: Caudal dysplasia sequence with penile enlargement: case report and a potential pathogenic hypothesis. Am J Med Genet 99:54, 2001. 93. Czeizel A, Losonci A: Split hand, obstructive urinary anomalies and spina bifida or diaphragmatic defect syndrome with autosomal dominant inheritance. Hum Genet 77:203, 1987. 94. Charles AK, Porter HJ, Sams V, et al.: Nephrogenic rests and renal abnormalities in Brachmann-de Lange syndrome. Pediatr Pathol Lab Med 17:209, 1997. 95. Wick MR, Simmons PS, Ludwig J, et al.: Duodenal obstruction, annular pancreas, and horseshoe kidney in an infant with Cornelia de Lange syndrome. Minn Med 65:539, 1982. 96. Robin NH, Adewale OO, McDonald-McGinn D, et al.: Human malformations similar to those in the mouse mutation disorganization (Ds). Hum Genet 92:461, 1993.

97. Alashari M, Torakawa J: True tail in a newborn. Pediatr Dermatol 12:263, 1995. 98. Lubinsky MS, Kahler SG, Speer IE, et al.: Von Voss-Cherstvoy syndrome: a variable perinatally lethal syndrome of multiple congenital anomalies. Am J Med Genet 52:272, 1994. 99. Bamforth JS, Lin CC: DK phocomelia phenotype (von Voss-Cherstvoy syndrome) caused by somatic mosaicism for del(13q). Am J Med Genet 73:408, 1997. 100. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 101. Celli J, Duijf P, Hamel BC, et al.: Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99:143, 1999. 102. Maas SM, de Jong TP, Buss P, et al.: EEC syndrome and genitourinary anomalies: an update. Am J Med Genet 63:472, 1996. 103. Horgan JE, Padwa BL, LaBrie RA, et al.: OMENS-Plus: analysis of craniofacial and extracraniofacial anomalies in hemifacial microsomia. Cleft Palate Craniofac J 32:405, 1995. 104. De Kerviler E, Guermazi A, Zagdanski AM, et al.: The clinical and radiological features of Fanconi’s anaemia. Clin Radiol 55:340, 2000. 105. Johnson JP, Carey JC, Gooch WM III, et al.: Femoral hypoplasiaunusual facies syndrome in infants of diabetic mothers. J Pediatr 102: 866, 1983. 106. Urban JE, Ramus RM, Stannard MW, et al.: Autopsy, radiographic, and prenatal ultrasonographic examination of a stillborn fetus with femoral facial syndrome. Am J Med Genet 71:76, 1997. 107. Johnson VP, Munson DP: A new syndrome of aphalangy, hemivertebrae, and urogenital-intestinal dysgenesis. Clin Genet 38:346, 1990. 108. Johnson VP, Munson DP: Addendum: a new syndrome of aphalangy, hemivertebrae and urogenital-intestinal dysgenesis. Clin Genet 39:311, 1991. 109. Kaplan BS, Bellah RD: Postaxial polydactyly, ulnar ray dysgenesis, and renal cystic dysplasia in sibs. Am J Med Genet 87:426, 1999. 110. Bamforth JS, Kaurah P: Lacrimo-auriculo-dento-digital syndrome: evidence for lower limb involvement and severe congenital renal anomalies. Am J Med Genet 43:932, 1992. 111. Al Awadi SA, Teebi AS, Farag TI, et al.: Profound limb deficiency, thoracic dystrophy, unusual facies, and normal intelligence: a new syndrome. J Med Genet 22:36, 1985. 112. Raas-Rothschild A, Goodman RM, Meyer S, et al.: Pathological features and prenatal diagnosis in the newly recognised limb/pelvishypoplasia/aplasia syndrome. J Med Genet 25:687, 1988.

Table 28-9. Renal-hepatic-pancreatic disorders Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Alagille226

Facial dysmorphism, retinal defects, cholestasis, pancreatic defects, retinitis pigmentosa, heart defects, hemivertebrae

Medullary cystic disease, renal dysplasia, unilateral renal agenesis, ureteral fistulae

AD (118450) JAG1, 20p12

Bardet-Biedl227,228

Mental retardation, retinitis pigmentosa, hypogonadism, polydactyly, obesity, biliary atresia, hepatic fibrosis

Renal agenesis, hypoplasia and dysplasia; calyceal cysts, diverticula, clubbing; hydronephrosis; fetal lobulations; nephritis; urethral defects

AR (209900); alleles at different BSS loci act as modifiers BSS1, 11q13 BSS2, 16q21 BSS3, 3p13 BSS4, 15q22.3 BSS5, 2q31 BSS6, 20p12 BSS7, 4q27 BSS8, 14q32.11

Chromosomal disorders —See Table 28-10 Gillessen-Kaesbach229,230

Microbrachycephaly, short limbs, facial dysmophism, heart defects, biliary and pancreatic dysplasia, hepatic fibrosis, lethal

Infantile polycystic kidneys, renal hypoplasia

AR (263210) Linkage to 6p21.1p12 (ARPKD excluded)

Glutaric aciduria type II231

Multiple acyl-CoA dehygrogenase deficiencies, facial dysmorphism, cerebral gliosis, fatty liver, biliary atresia, pancreatic dysplasia, genital defects

Renal dysplasia, cortical cysts, large kidneys

AR (231680) GAIIA-EFTA, 15q23-q25 AR (130410) GAIIB-EFTB, 19q13.3 AR (231675) GAIIC-EFTDH, 4q32-qter

Polycystic kidneys AD—See Section 28.5 Polycystic kidneys AR—See Section 28.4 Renal-hepatic-pancreatic dysplasia (Caroli)232

Biliary dysgenesis, hepatic and pancreatic cysts, Potter facies, lung hypoplasia

Infantile polycystic kidneys, large kidneys

AR (263200) PKHD1, 6p21.1-p12 fibrocystin

Renal-hepatic-pancreatic dysplasia (Ivemark)233

Biliary dysgenesis, liver fibrosis, pancreatic defects, spleen defects, heart defects

Infantile polycystic kidneys, large kidneys

AR (208540)

Renal-hepatic dysplasia with Dandy-Walker cyst234

Hepatic fibrosis, gallbladder and pancreatic defects, Dandy-Walker malformation, microphthalmia, heart defects

Cystic dysplasia

AR (267010)

Teratogenic exposures —See Table 28-11 Von Hippel-Lindau235,236

Pancreatic and liver cysts; adrenal tumors; retinal, cerebellar, and spinal angiomata

Cystic dysplasia, hypernephromas, renal cell carcinoma

AD (193300) 3p26-p25 VHL tumour suppressor gene

Zellweger (cerebrohepato-renal)237

Cerebral anomalies, mental retardation, hypotonia, biliary and pancreatic dysgenesis, peroxisomal deficiency, facial dysmorphism

Renal cortical dysplasia, glomerular tufts, hydroureter, proteinuria

AR (214100), genetically heterogeneous with multiple complementation groups Multiple genes involved in peroxisome assembly and function PEX1–PEX6, PEX12

1178

Table 28-10. Urinary tract anomalies in chromosomal disorders Chromosome Aberration

Urinary Tract Anomalies

Estimated Frequency

3q partial duplication

Hydronephrosis, ureteral duplication, cortical cysts

50%

4p deletion

Renal agenesis or hypoplasia, vesicoureteral reflux, hydronephrosis

25–35%

4q partial deletion

Renal hypoplasia and dysplasia, caliceal dilation, pelvic duplication

Frequent

4q partial duplication

Horseshoe kidney, renal agenesis or hypoplasia, hydronephrosis, vesicoureteral reflux

Frequent

5p deletion

Horseshoe kidney, renal agenesis or hypoplasia, precaliceal ectasia

Occasional

6p partial duplication

Renal hypoplasia, renal infections, proteinuria

Uncertain

7 trisomy

Renal agenesis and dysplasia

Frequent

8 trisomy including mosaics

Renal agenesis or cystic dysplasia, hydronephrosis

Occasional

9 trisomy including mosaics

Hydronephrosis, cystic dysplasia, renal agenesis, ureteral and pelvic duplication kidneys and ureters, horseshoe kidney

Frequent

10p partial deletion

Renal dysplasia and hypoplasia

40%

10p partial duplication

Unilateral agenesis, cystic dysplasia

Uncertain

10q partial duplication

Renal hypoplasia or dysplasia, hydronephrosis

Frequent

11p13 deletion

Wilms tumor

Frequent

11q partial duplication

Renal agenesis, renal artery anomalies

13q deletion

Hydronephrosis, vesicoureteral junction obstruction

Uncommon

13 ring

Renal agenesis, hypoplasia or ectopia, hydonephrosis, ureteral and pelvic duplication, hydronephrosis

50–100%

13 trisomy

Hydronephrosis, micropolycystic dysplasia, hydroureter, horseshoe kidneys, ureteral and pelvic duplication, renal agenesis, urethral atresia

50%

17 partial deletion

Renal agenesis or dysplasia, polycystic kidneys

Uncertain

18q deletion

Horseshoe kidneys, renal agenesis, hydronephrosis

10%

18 ring

Unilateral agenesis, reflux

20%

18 trisomy

Horseshoe kidney, crossed renal ectopia, ureteral duplication, cortical cysts, cloacal exstrophy, hydronephrosis, renal agenesis, nephroblastomatosis, urethral atresia

55–65%

19q partial duplication

Cystic dysplasia, hydronephrosis, hydroureter, renal ectopia

Frequent

21q deletion

Unilateral renal agenesis, abnormal kidney shape, horseshoe kidneys

Uncertain

21 trisomy

Renal agenesis, hypoplasia, horseshoe kidney, posterior urethral valves, hydronephrosis, ureteropelvic junction obstruction, cystic malformation of collecting tubules, urtheral atresia, prune belly syndrome

3–7%

22 partial trisomy (pter-q11)

Renal agenesis or hypoplasia, horseshoe kidneys, hydronephrosis, ureteral or pelvic duplication, renal ectopia

Frequent

22q11 deletion

Renal agenesis or cystic dysplasia, hydronephrosis, vesicourethral reflux, dysfunctional voiding

30%

45,X (plus other Turner karyotype abnormalities)

Horseshoe kidneys, ureteral or pelvic duplication, renal agenesis or dysplasia, hydronephrosis, renal ectopia, ureteropelvic obstruction

30–60%

XXX

Cystic dysplasia, renal agenesis, cloacal exstrophy

Uncertain

XXY (Klinefelter)

Unilateral agenesis, hydronephrosis

Uncertain

XYY

Renal agenesis or cystic dysplasia

Uncertain

Triploidy

Hydronephrosis, cystic dysplasia

Frequent

Diploid/tetraploid mosaicism

Renal agenesis, ureteral defects, urethral atresia, prune belly syndrome

25%

Data from references 238 to 251.

1179

1180

Urogenital System Organs Table 28-11. Teratogenic exposure in utero and urinary tract anomalies Teratogen

Predominant Features

Urinary Tract Anomalies

Alcohol

Heavy use is associated with prenatal onset of growth retardation, microcephaly, short palpebral fissures, smooth philtrum, heart and skeletal defects, behavioral difficulties, mental retardation; effects of light to moderate exposure are variable

Renal agenesis, hypoplasia, ectopia, dysplasia; horseshoe kidneys, hydronephrosis Overall risk for renal anomalies may be relatively low254

Angiotensin-converting enzyme (ACE) inhibitors255–257 (captopril, enalapril)

Growth retardation, oligohydramnios, patent ductus arteriosus, calvarial and limb anomalies, increased fetal and neonatal mortality

Glomerulonephritis, glomerulopathy, interstitial nephritis, nephrotic syndrome, progressive renal failure, renal artery stenosis, neonatal anuria

Carbamazepine258

Microcephaly, epicanthus, upslanting fissures, short nose, long philtrum, distal digital hypoplasia, cleft palate, heart and neural tube defects

Renal dysplasia, hydronephrosis, ureteric duplication

Cocaine259–261

Defects from vascular disruption, e.g., limb defects, intestinal atresia

Renal and ureteral agenesis, hydronephrosis, urethral stenosis/atresia, prune belly syndrome, cloacal anomalies, hypospadias, ambiguous genitalia

Diabetes mellitus259,262,263

Caudal regression, neural tube defects, congenital heart defects, other anomalies

Renal agenesis, ureteral anomalies, urethral anomalies, cystic dysplasia, urorectal septum malformations

Misoprostol264

Vascular disruptions, cranial nerve defects, limb deficiencies, microcephaly, hydrocephalus, amyloplasia, microcephaly, anterior horn cell deficiencies

Renal agenesis, urethral stenosis/atresia, neurogenic bladder, bladder exstrophy

Rubella265,266

Prenatal and postnatal growth retardation, cataracts, microphthalmia, pigmentary retinopathy, heart defects, especially patent ductus arteriosus, skeletal anomalies, sensorineural deafness, neurologic impairment, microcephaly

Renal artery stenosis, polycystic kidney, ureteral duplication, unilateral renal agenesis, malrotation, nephritis

Thalidomide, prenatal267

Limb reduction anomalies, micrognathia, vertebral defects, neural tube defects, heart and other visceral anomalies

Renal agenesis, obstructive uropathy, renal ectopia, horseshoe kidneys, hydronephrosis, double ureter

Trimethadione, prenatal268

Prenatal and postnatal growth retardation; distinctive facial features; developmental delay; omphalocele; heart, skeletal, and limb anomalies

Renal and ureteric agenesis, fetal lobulations

Valproate269

Brachycephaly, prominent eyes, thin eyebrows, fold of skin below lower eyelid, small mouth, polydactyly, radial ray anomalies, heart and neural tube defects

Renal hypoplasia, hydronephrosis, cysts, calyceal duplication

Vitamin A congeners270–272 (etretinate, isotretinoin, retinoic acid)

Micrognathia, cleft palate, microphthalmia, midfacial hypoplasia, heart defects, anotia, microtia, neural tube defects, hydrocephalus and other brain anomalies, thymic hypoplasia, hypoparathyroidism

Hypoplastic kidneys, hydronephrosis, ureteral defects

Warfarin273

Hypoplastic midface, hypertelorism, anteverted nares, depressed bridge, stippled epiphyses

Renal agenesis, hypoplasia

252,253

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116. Van Den Berg DJ, Francke U: Roberts syndrome: a review of 100 cases and a new rating system for severity. Am J Med Genet 47:1104, 1993. 117. Saito N, Kuba A, Tsuruta T: Lethal form of fibuloulnar a/hypoplasia with renal abnormalities. Am J Med Genet 32:452, 1989. 118. Evliyaoglu N, Temocin AK, Altintas DU, et al.: Phocomelia, ectrodactyly, skull defect and urinary system anomaly: Schinzel-phocomelia syndrome? Clin Genet 49:70, 1996. 119. Rudd NL, Klimek ML: Familial caudal dysgenesis: evidence for a major dominant gene. Clin Genet 38:170, 1990.

Urinary Tract 120. Selig AM, Benacerraf B, Greene MF, et al.: Renal dysplasia, megalocystis, and sirenomelia in four siblings. Teratology 47:65, 1993. 121. Nothen MM, Knopfle G, Fodisch HJ, et al.: Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet 46:467, 1993. 122. Bradshaw A, Donnelly LF, et al.: Thrombocytopenia and absent radii (TAR) syndrome associated with horseshoe kidney. Pediatr Nephrol 14:29, 2000. 123. Newman WG, Brunet MD, Donnai D: Townes-Brocks syndrome presenting as end stage renal failure. Clin Dysmorphol 6:57, 1997. 124. Salerno A, Kohlhase J, Kaplan BS: Townes-Brocks syndrome and renal dysplasia: a novel mutation in the SALL1 gene. Pediatr Nephrol 14:25, 2000. 125. Schrander-Stumpel C, Die-Smulders C, Fryns JP, et al.: Limb reduction defects and renal dysplasia: confirmation of a new, apparently lethal, autosomal recessive MCA syndrome. Am J Med Genet 37:133, 1990. 126. Schinzel A: Ulnar-mammary syndrome. J Med Genet 24:778, 1987. 127. Gonzalez CH, Herrmann J, Opitz JM: Studies of malformation syndromes of man XXXXIIB: mother and son affected with the ulnarmammary syndrome type Pallister. Eur J Pediatr 123:225, 1976. 128. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8, 1997. 129. Evans JA, Stranc LC, Kaplan P, et al.: VACTERL with hydrocephalus: further delineation of the syndrome(s). Am J Med Genet 34:177, 1989. 130. Cox PM, Gibson RA, Morgan N, et al.: VACTERL with hydrocephalus in twins due to Fanconi anemia (FA): mutation in the FAC gene. Am J Med Genet 68:86, 1997. 131. Reardon W, Zhou XP, Eng C: A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. J Med Genet 38:820, 2001. 132. Elejalde BR, de Elejalde MM, Booth C, et al.: Prenatal diagnosis of Weyers syndrome (deficient ulnar and fibular rays with bilateral hydronephrosis). Am J Med Genet 21:439, 1985. 133. Kaplan BS, Bellah RD: Postaxial polydactyly, ulnar ray dysgenesis, and renal cystic dysplasia in sibs. Am J Med Genet 87:426, 1999. 134. Zimmer EZ, Taub E, Sova Y, et al.: Tetra-amelia with multiple malformations in six male fetuses of one kindred. Eur J Pediatr 144:412, 1985. 135. Hassell S, Butler MG: Antley-Bixler syndrome: report of a patient and review of literature. Clin Genet 46:372, 1994. 136. Reardon W, Smith A, Honour JW, et al.: Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J Med Genet 37:26, 2000. 137. Cohen MM Jr, Kreiborg S: Visceral anomalies in the Apert syndrome. Am J Med Genet 45:758, 1993. 138. Barakat AJ, Saba C, Rennert OM: Kidney abnormalities in HajduCheney syndrome. Pediatr Nephrol 10:712, 1996. 139. Beemer FA, von Ertbruggen I: Peculiar facial appearance, hydrocephalus, double-outlet right ventricle, genital anomalies and dense bones with lethal outcome. Am J Med Genet 19:391, 1984. 140. Brueton LA, Dillon MJ, Winter RM: Ellis-van creveld syndrome, Jeune syndrome, and renal-hepatic-pancreatic dysplasia: separate entities or disease spectrum? J Med Genet 27:252, 1990. 141. Houston CS, Opitz JM, Spranger JW, et al.: The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al. in 1971. Am J Med Genet 15:3, 1983. 142. Carpenter BF, Hunter AG: Micromelia, polysyndactyly, multiple malformations, and fragile bones in a stillborn child. J Med Genet 19:311, 1982. 143. Opitz JM, Lowry RB, Holmes TM, et al.: Hutterite cerebro-osteonephrodysplasia: autosomal recessive trait in a Lehrerleut Hutterite family from Montana. Am J Med Genet 22:521, 1985. 144. Lowry RB: A further case of Hutterite cerebro-osteo-nephrodysplasia. Am J Med Genet 72:386, 1997. 145. Ming JE, McDonald-McGinn DM, Markowitz RI, et al.: Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia, and multicystic dysplastic kidneys: expanding the phenotype of Cumming syndrome. Am J Med Genet 73:419, 1997.

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172. Goldfischer S, Collins J, Rapin I, et al.: Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities. J Pediatr 108:25, 1986. 173. Labrune P, Lyonnet S, Zupan V, et al.: Three new cases of the SchinzelGiedion syndrome and review of the literature. Am J Med Genet 50:90, 1994. 174. Majewski F, Enders H, Ranke MB, et al.: Serpentine fibula—polycystic kidney syndrome and Melnick-Needles syndrome are different disorders. Eur J Pediatr 152:916, 1993. 175. Grote W, Weisner D, Janig U, et al.: Prenatal diagnosis of a short-ribpolydactylia syndrome type Saldino-Noonan at 17 weeks’ gestation. Eur J Pediatr 140:63, 1983. 176. Montemarano H, Bulas DI, Chandra R, et al.: Prenatal diagnosis of glomerulocystic kidney disease in short-rib polydactyly syndrome type II, Majewski type. Pediatr Radiol 25:469, 1995. 177. Chen CP, Tzen CY: Short-rib polydactyly syndrome type III (VermaNaumoff) in a third-trimester fetus with unusual associations of epiglottic hypoplasia, renal cystic dysplasia, pyelectasia and oligohydramnios. Prenat Diagn 21:1101, 2001. 178. Lurie IW: Further delineation of the Beemer-Langer syndrome using concordance rates in affected sibs. Am J Med Genet 50:313, 1994. 179. Gruhn JG, Gorlin RJ, Langer LO: Dyssegmental dwarfism. A lethal anisospondylic camptomicromelic dwarfism. Am J Dis Child 132:382, 1978. 180. Beighton P: Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL). J Med Genet 31:136, 1994. 181. Anderson CE, Sillence DO, Lachman RS, et al.: Spondylometepiphyseal dysplasia, Strudwick type. Am J Med Genet 13:243, 1982. 182. Tolmie JL, Patrick A, Yates JR: A lethal multiple pterygium syndrome with apparent X-linked recessive inheritance. Am J Med Genet 27:913, 1987. 183. Lurie IW, Lazjuk GI, Korotkova IA, et al.: The cerebro-reno-digital syndromes: a new community. Clin Genet 39:104, 1991. 184. Thornton CM, Stewart F: Elejalde syndrome: a case report. Am J Med Genet 69:406, 1997. 185. Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inversus: a third report. Am J Med Genet 37:286, 1990. 186. Bendon RW, Siddiqi T, de Court, et al.: Recurrent developmental anomalies: 1. Syndrome of hydranencephaly with renal aplastic dysplasia; 2. Polyvalvular developmental heart defect. Am J Med Genet Suppl 3:357, 1987. 187. Bowen P, Conradi GJ: Syndrome of skeletal and genitourinary anomalies with unusual facies and failure to thrive in Hutterite sibs. Birth Defects Orig Artic Ser XII(6):101, 1976. 188. Hunter AG, Woerner SJ, Montalvo-Hicks LD, et al.: The BowenConradi syndrome—a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities. Am J Med Genet 3:269, 1979. 189. Reish O, Gorlin RJ, Hordinsky M, et al.: Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome? Am J Med Genet 68:386, 1997. 190. Strom EH, Stromme P, Westvik J, et al.: Renal cysts in the carbohydrate-deficient glycoprotein syndrome. Pediatr Nephrol 7:253, 1993. 191. Fleck BJ, Pandya A, Vanner L, et al.: Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study. Am J Med Genet 99:1, 2001. 192. Baralle D, Firth H: Craniomicromelic syndrome: report of a third case. Am J Med Genet 87:360, 1999. 193. Thornton CM, Magee AC, Thomas PS, et al.: Congenital heart disease and urinary tract abnormalities in two siblings with DOOR syndrome. Pediatr Pathol 14:797, 1994. 194. Ayme S, Julian C, Gambarelli D, et al.: Fryns syndrome: report on 8 new cases. Clin Genet 35:191, 1989. 195. Conde F, Gomez S, Massa C: Polysyndactily with double pyeloureteral system. An Esp Pediatr 11:237, 1978.

196. Ausems MG, Ippel PF, Renardel de Lavalette PA: Greig cephalopolysyndactyly syndrome in a large family: a comparison of the clinical signs with those described in the literature. Clin Dysmorphol 3:21, 1994. 197. Meinecke P, Ziegenrucker W, Peters A: Potter sequence due to renal aplasia and postaxial hexadactyly. A distinct entity? Genet Couns 4:127, 1993. 198. Zlotogora J, Ariel I, Ornoy A, et al.: Thomas syndrome: Potter sequence with cleft lip/palate and cardiac anomalies. Am J Med Genet 62:224, 1996. 199. Aughton DJ, Cassidy SB: Hydrolethalus syndrome: report of an apparent mild case, literature review, and differential diagnosis. Am J Med Genet 27:935, 1987. 200. Maizels M, Stephens FD: The induction of urologic malformations. Understanding the relationship of renal ectopia and congenital scoliosis. Invest Urol 17:209, 1979. 201. Maillette de Buy Wenniger-Prick LJ, Hennekam RC: The Peters’ plus syndrome: a review. Ann Genet 45:97, 2002. 202. Lachiewicz AM, Kogan SJ, Levitt SB, et al.: Concurrent agenesis of the corpus callosum and ureteroceles in siblings. Pediatrics 75:904, 1985. 203. Lin AE, Gettig E: Craniosynostosis, agenesis of the corpus callosum, serve mental retardation, distinctive facies, camptodactyly, and hypogonadism. Am J Med Genet 35:582, 1990. 204. MacDermot KD, Winter RM: Two brothers with facial anomalies, microcephaly, hypoplastic genitalia, and a failure of psychomotor development. Am J Med Genet 32:60, 1989. 205. Giacoia GP, Pineda R: Expanded spectrum of findings in MardenWalker syndrome. Am J Med Genet 36:495, 1990. 206. Ben Neriah Z, Yagel S, Ariel I: Renal anomalies in Marden-Walker syndrome: a clue for prenatal diagnosis. Am J Med Genet 57:417, 1995. 207. Salonen R, Paavola P: Meckel syndrome. J Med Genet 35:497, 1998. 208. Neish AS, Roberts DJ: Hypoplastic left heart, nephromegaly, and distinctive facies in two siblings. Am J Hum Genet 50:153, 1992. 209. Rump P, Gruijters MY, Van der Burgt CJ: A female patient with neurological, facial, digital and renal abnormalities: another case of the neurofaciodigitorenal (NFDR) syndrome? Clin Dysmorphol 6:337, 1997. 210. Coleman RA, Van Hove JL, Morris CR, et al.: Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: additional findings or a new syndrome (ARCC-NDI)? Am J Med Genet 72:335, 1997. 211. Hunter AG, Rothman SJ, Hwang WS, et al.: Hepatic fibrosis, polycystic kidney, colobomata and encephalopathy in siblings. Clin Genet 6:82, 1974. 212. Lewis SM, Roberts EA, Marcon MA, et al.: Joubert syndrome with congenital hepatic fibrosis: an entity in the spectrum of oculoencephalo-hepato-renal disorders. Am J Med Genet 52:419, 1994. 213. Connacher AA, Forsyth CC, Stewart WK: Orofaciodigital syndrome type I associated with polycystic kidneys and agenesis of the corpus callosum. J Med Genet 24:116, 1987. 214. Moerman P, Fryns JP: Oral-facial-digital syndrome type IV (MohrMajewski syndrome): a fetopathological study. Genet Couns 9:39, 1998. 215. Mattei JF, Ayme S: Syndrome of polydactyly, cleft lip, lingual hamartomas, renal hypoplasia, hearing loss, and psychomotor retardation: variant of the Mohr syndrome or a new syndrome? J Med Genet 20:433, 1983. 216. Kang S, Allen J, Graham JM Jr, et al.: Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 34:441, 1997. 217. Digilio MC, Marino B, Borzaga U, et al.: Intrafamilial variability of Pfeiffer-type cardiocranial syndrome. Am J Med Genet 73:480, 1997. 218. Proud VK, Levine C, Carpenter NJ: New X-linked syndrome with seizures, acquired micrencephaly, and agenesis of the corpus callosum. Am J Med Genet 43:458, 1992. 219. Reuss A, den Hollander JC, Niermeijer MF, et al.: Prenatal diagnosis of cystic kidney disease with ventriculomegaly: a report of six cases in two related sibships. Am J Med Genet 33:385, 1989. 220. Leonardi ML, Pai GS, Wilkes B, et al.: Ritscher-Schinzel craniocerebello-cardiac (3C) syndrome: report of four new cases and review. Am J Med Genet 102:237, 2001.

Urinary Tract 221. Bartsch O, Wagner A, Hinkel GK, et al.: FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. Eur J Hum Genet 7:748, 1999. 222. Kanjilal D, Basir MA, Verma RS, et al.: New dysmorphic features in Rubinstein-Taybi syndrome. J Med Genet 29:669, 1992. 223. Joseph DB, Uehling DT, Gilbert E, et al.: Genitourinary abnormalities associated with the Smith-Lemli-Opitz syndrome. J Urol 137:719, 1987. 224. Hennekam RC, van Noort G, de la Fuente AA: Familial holoprosencephaly, heart defects, and polydactyly. Am J Med Genet 41:258, 1991. 225. Zlotogora J, Dagan J, Ganen A, et al.: A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism. J Med Genet 34:813, 1997. 226. Martin SR, Garel L, Alvarez F: Alagille’s syndrome associated with cystic renal disease. Arch Dis Child 74:232, 1996. 227. Gershoni-Baruch R, Nachlieli T, Leibo R, et al.: Cystic kidney dysplasia and polydactyly in 3 sibs with Bardet-Biedl syndrome. Am J Med Genet 44:269, 1992. 228. Beales PL, Reid HA, Griffiths MH, et al.: Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant 15:1977, 2000. 229. Gillessen-Kaesbach G, Meinecke P, Garrett C, et al.: New autosomal recessive lethal disorder with polycystic kidneys type Potter I, characteristic face, microcephaly, brachymelia, and congenital heart defects. Am J Med Genet 45:511, 1993. 230. Hallermann C, Mucher G, Kohlschmidt N, et al.: Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p. Am J Med Genet 90:115, 2000. 231. Wilson GN, de Chadarevian JP, Kaplan P, et al.: Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am J Med Genet 32:395, 1989. 232. Ward CJ, Hogan MC, Rossetti S, et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259, 2002. 233. Crawfurd MD: Renal dysplasia and asplenia in two sibs. Clin Genet 14:338, 1978. 234. Hunter AG, Jimenez C, Tawagi FG: Familial renal-hepatic-pancreatic dysplasia and Dandy-Walker cyst: a distinct syndrome? Am J Med Genet 41:201, 1991. 235. Maddock IR, Moran A, Maher ER, et al.: A genetic register for von Hippel-Lindau disease. J Med Genet 33:120, 1996. 236. Olschwang S, Richard S, Boisson C, et al.: Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. Hum Mutat 12:424, 1998. 237. Fitzpatrick DR: Zellweger syndrome and associated phenotypes. J Med Genet 33:863, 1996. 238. Crawfurd MD: The Genetics of Renal Tract Disorders. Oxford University Press, Oxford, 1988. 239. Borgaonkar DS: Chromosomal Variation in Man: Online Database. John Wiley & Sons, New York, 2002. 240. Kravtzova GI, Lazjuk GI, Lurie IW: The malformations of the urinary system in autosomal disorders. Virchows Arch A Pathol Anat Histol 368:167, 1975. 241. Amacker EA, Grass FS, Hickey DE, et al.: An association of prune belly anomaly with trisomy 21. Am J Med Genet 23:919, 1986. 242. Lippe B, Geffner ME, Dietrich RB, et al.: Renal malformations in patients with Turner syndrome: imaging in 141 patients. Pediatrics 82:852, 1988. 243. Rudnik-Schoneborn S, Schuler HM, Schwanitz G, et al.: Further arguments for non-fortuitous association of Potter sequence with XYY males. Ann Genet 39:43, 1996. 244. Hoang MP, Wilson KS, Schneider NR, et al.: Case report of a 22-week fetus with 47,XXX karyotype and multiple lower mesodermal defects. Pediatr Dev Pathol 2:58, 1999. 245. Ozata M, Yesilova Z, Saglam M, et al.: A case of Klinefelter’s syndrome associated with unilateral renal aplasia. Med Sci Monit 6:1000, 2000. 246. Bilge I, Kayserili H, Emre S, et al.: Frequency of renal malformations in Turner syndrome: analysis of 82 Turkish children. Pediatr Nephrol 14:1111, 2000.

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247. Stankiewicz P, Brozek I, Helias-Rodzewicz Z, et al.: Clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18. Am J Med Genet 101:226, 2001. 248. Wu HY, Rusnack SL, Bellah RD, et al.: Genitourinary malformations in chromosome 22q11.2 deletion. J Urol 168:2564, 2002. 249. Linden MG, Bender BG, Robinson A: Sex chromosome tetrasomy and pentasomy. Pediatrics 96:672, 1995. 250. Barakat AY, Butler MG: Renal and urinary tract abnormalities associated with chromosome aberrations. Int J Pediatr Nephrol 8:215, 1987. 251. Edwards MJ, Park JP, Wurster-Hill DH, et al.: Mixoploidy in humans: two surviving cases of diploid-tetraploid mixoploidy and comparison with diploid-triploid mixoploidy. Am J Med Genet 52:324, 1994. 252. Moore CA, Khoury MJ, Liu Y: Does light-to-moderate alcohol consumption during pregnancy increase the risk for renal anomalies among offspring? Pediatrics 99:E11, 1997. 253. Havers W, Majewski F, Olbing H, et al.: Anomalies of the kidneys and genitourinary tract in alcoholic embryopathy. J Urol 124:108, 1980. 254. Taylor CL, Jones KL, Jones MC, et al.: Incidence of renal anomalies in children prenatally exposed to ethanol. Pediatrics 94:209, 1994. 255. Barr M Jr: Teratogen update: angiotensin-converting enzyme inhibitors. Teratology 50:399, 1994. 256. Hanssens M, Keirse MJ, Vankelecom F, et al.: Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol 78:128, 1991. 257. Shotan A, Widerhorn J, Hurst A, et al.: Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 96:451, 1994. 258. Matalon S, Schechtman S, Goldzweig G, et al.: The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol 16:9, 2002. 259. Greenfield SP, Rutigliano E, Steinhardt G, et al.: Genitourinary tract malformations and maternal cocaine abuse. Urology 37:455, 1991. 260. Lezcano L, Antia DE, Sahdev S, et al.: Crossed renal ectopia associated with maternal alkaloid cocaine abuse: a case report. J Perinatol 14:230, 1994. 261. Battin M, Albersheim S, Newman D: Congenital genitourinary tract abnormalities following cocaine exposure in utero. Am J Perinatol 12: 425, 1995. 262. Gripp KW, Barr M Jr, Anadiotis G, et al.: Aphallia as part of urorectal septum malformation sequence in an infant of a diabetic mother. Am J Med Genet 82:363, 1999. 263. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. Am J Med Genet 78:140, 1998. 264. Orioli IM, Castilla EE: Epidemiological assessment of misoprostol teratogenicity. BJOG 107:519, 2000. 265. Singer DB, Rudolph AJ, Rosenberg HS, et al.: Pathology of the congenital rubella syndrome. J Pediatr 71:665, 1967. 266. Webster WS: Teratogen update: congenital rubella. Teratology 58:13, 1998. 267. Smithells RW, Newman CG: Recognition of thalidomide defects. J Med Genet 29:716, 1992. 268. Feldman GL, Weaver DD, Lovrien EW: The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child 131:1389, 1977. 269. Kozma C: Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 98:168, 2001. 270. Lynberg MC, Khoury MJ, Lammer EJ, et al.: Sensitivity, specificity, and positive predictive value of multiple malformations in isotretinoin embryopathy surveillance. Teratology 42:513, 1990. 271. Lammer EJ, Chen DT, Hoar RM, et al.: Retinoic acid embryopathy. N Engl J Med 313:837, 1985. 272. Rosa FW, Wilk AL, Kelsey FO: Teratogen update: vitamin A congeners. Teratology 33:355, 1986. 273. Hall BD: Warfarin embryopathy and urinary tract anomalies: possible new association. Am J Med Genet 34:292, 1989.

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28.1 Renal Agenesis Definition

Renal agenesis is the complete absence of one or both kidneys (unilateral or bilateral renal agenesis). This definition excludes any anomaly of the kidney where there is residual renal tissue regardless of whether a ureteric remnant remains. Diagnosis

Bilateral renal agenesis can present as early as 14 weeks gestation with severe oligohydramnios. Stillbirth is common (~40%) and premature birth and low birth weight are frequent findings.1 Liveborn infants present with respiratory distress due to pulmonary hypoplasia, anuria, nonpalpable kidneys, and the physical features of apparent hypertelorism, infraorbital creases, flattened nasal tip, hypoplastic mandible, enlarged and posteriorly rotated ears, redundant dry skin, genu varum, talipes, and metatarsus adductus that are characteristic of Potter sequence (Fig. 28-2).2–4 Unilateral renal agenesis may be discovered by abdominal examination with enlargement or ectopic location of the remaining kidney, by ultrasound screening, or by investigation due to genitourinary tract symptoms. Many individuals remain asymptomatic and are identified serendipitously by ultrasound examination or at the time of abdominal surgery or autopsy. Over 50%5 of the remaining kidneys are found to have anomalies; however, this figure may be biased by easier ascertainment of patients with complications.6 Reflux and ureteropelvic and ureterojunctional obstruction are seen in a high proportion of cases.7 It is important to realize that failure to palpate a kidney of one side may be due not to unilateral agenesis, but to crossed renal ectopia or pelvic kidney. Crossed ectopia of a single kidney may also occur.8 Fig. 28-2. Oligohydramnios dysmorphism (Potter syndrome) in bilateral renal agenesis. (Reprinted with permission from Dimmick JE, Kalousek DK, eds: Developmental Pathology of the Embryo and Fetus. JB Lippincott, Philadelphia, 1992.)

The diagnosis of renal agenesis is made with abdominal ultrasound. If the ultrasound is equivocal, other imaging techniques such as computed tomography, magnetic resonance imaging, and radionuclide scanning can be used for confirmation. Cystoscopy for identification of the ureteral orifice in unilateral renal agenesis is reliable as ipsilateral absence of the ureter, ureteral orifice, and hemitrigone are common.9 Associated congenital defects are common. Defects of the contiguous structures in bilateral renal agenesis include complete absence of the ureters and hypoplasia, atresia, or absence of the bladder.1 In females, the vagina and uterus (Mu¨llerian duct derivatives) are absent or abnormal in 85%. Males are usually cryptorchid and the vas deferens and seminal vesicles (Wolffian duct derivatives) are abnormal or absent.3 More serious genital anomalies including penile agenesis10 or penoscrotal transposition11 may also be seen. In unilateral renal agenesis, the ipsilateral ureter and fallopian tube may be absent and other uterine and vaginal defects may be present, including uterus didelphys.12,13 Bladder exstrophy has also been reported.14 Anal atresia, malrotation, Meckel diverticulum, and lumbosacral vertebral defects may also be found. The ipsilateral adrenal gland is usually present in its usual position when a kidney is absent, but often takes on a more rounded shape (Fig. 28-3). Adrenal agenesis is more common with unilateral renal agenesis than when both kidneys are absent.15 Noncontiguous anomalies are also common16 and include limb deficiencies (see acrorenal field defects, Table 28-6), tracheal agenesis,17 esophageal or duodenal atresia, cleft lip or palate,3 hydrocephalus18 and other structural brain malformations (see cerebral-renal-digital field defects, Table 28-8). Pulmonary hypoplasia with arrest of alveolar development at the 12- to 16-week developmental stage occurs with severe oligohydramnios. Single umbilical artery was present in 12% of fetuses and stillbirths with bilateral renal agenesis in an autopsy series.3 Amnion nodosum commonly accompanies oligohydramnios. Fig. 28-3. Bilateral renal agenesis at autopsy in a day-old male infant. Note the aberrant shape of the adrenals.

Urinary Tract

Etiology and Distribution

Renal agenesis must result from a defect in embryogenesis occurring before day 35 (see Tables 28-1 and 28-2). Data from mouse models (Table 28-3) would indicate that total absence of the kidney can be the result of several abnormal processes, including absence of the metanephric duct from which the ureteric bud forms, failure of the bud to be induced, failure of the bud to contact and interact with the metanephric blastema, and absence of the metanephrogenic mesenchyme or key inductive signals produced within it. Renal agenesis is usually associated with absence of the ipsilateral ureter, which is compatible with absence of the lower portion of the mesonephric duct or other mechanisms that cause failure of normal ureteric bud development. If a ureter is present, it indicates at least an initially normal process of bud formation and rudimentary or residual renal tissue is usually apparent. Total absence or disruption of the urogenital ridge on one side results in the absence of both the internal genital and upper urinary tract structures, including the trigone on that side. Apparent renal agenesis may occur later in embryogenesis, in the fetal period, or postnatally, possibly due to the occlusion of a renal artery.19 Clearly, some single kidneys are due to involution of a dysplastic or hydronephrotic kidney as such structures may be observed on prenatal ultrasound, only to disappear after birth.20,21 In isolated renal agenesis, associated anomalies involve development of the Wolffian or Mu¨llerian ducts (see Fig. 28-1).22 A more widespread insult involving the hindgut and cloacal membrane could lead to anal anomalies, cloacal or bladder exstrophy, persistent cloaca, or urorectal septum malformation sequence. An even larger field of abnormality would involve the entire caudal end of the embryo and result in caudal dysplasia or sirenomelia. They include acrorenal (Table 28-6) and cerebrorenal-digital defects (Table 28-8), as well as the VACTERL,23 MURCS,24 and CHARGE25 associations. Syndromes of multiple congenital anomalies commonly associated with renal agenesis are listed in Table 28-12. Both bilateral and unilateral renal agenesis are etiologically heterogeneous. ‘‘Isolated’’ renal agenesis has often been considered a multifactorially inherited anomaly with a relatively low (~1–5%) chance of recurrence in first-degree relatives. However, familial cases suggesting autosomal dominant,26 autosomal recessive,27 and X-linked28 patterns of inheritance have been reported. Buchta et al.29 first coined the term ‘‘hereditary renal adysplasia’’ to document a family condition with renal agenesis and/or cystic dysplasia that was more common in males and where the females had Mu¨llerian duct anomalies. This condition is now referred to as hereditary urogenital adysplasia (OMIM 191830). Inheritance of this condition is usually considered to be autosomal dominant with variable expressivity and reduced penetrance. Renal ultrasound examinations of first-degree relatives and, when indicated, second-degree relatives may be appropriate in all cases of renal agenesis to exclude variable expression of an autosomal dominant disorder, unless another cause such as a de novo chromosomal abnormality is readily apparent. Information on parental renal status can be very useful in refining risk figures for counseling. Carter et al.30 used data from families to derive an empiric recurrence risk figure for bilateral renal agenesis of 3.5%. However, renal ultrasounds were not done on first-degree and second-degree relatives in this study. Roodhooft et al.31 carried out renal ultrasounds on 71 parents and 40 sibs of 41 probands with bilateral renal agenesis and/or cystic dysplasia as

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well as on six controls. They found a 9% risk for a related urogenital anomaly and a 4.4% risk for renal malformations in first-degree relatives. Another family study by McPherson et al.26 estimated that people who are affected with, or are obligate carriers of, a potential gene for hereditary renal adysplasia have a 15–20% risk of having a child with unilateral or bilateral renal agenesis. In many familial disorders, the spectrum of renal anomalies including renal agenesis and renal dysplasia can be broad, as is obvious from Tables 28-6 to 28-13 and 28-18 to 28-20. As expression may be variable, it is important to examine relatives carefully for subtle signs of these disorders such as preauricular tags or deafness in branchio-oto-renal syndrome.32 Another specific association of note is that between unilateral renal agenesis and congenital absence of the vas deferens as such men have an increased frequency of CFTR mutations33,34 In addition to single gene disorders, bilateral renal agenesis can also result from chromosomal abnormalities (Table 2810); from teratogenic exposures, especially maternal diabetes (Table 28-11); and in sporadic defects of morphogenesis. The incidence of unilateral renal agenesis based on autopsy series ranges from approximately one in 5003,35 to one in 1000.15 Ultrasound examination of 241 adults revealed an incidence of one in 241.31 In approximately 60% of cases, it is the left kidney that is absent.37 The incidence of bilateral renal agenesis is variable, depending on the proportion of fetuses and infants in the series under study. In 12,000 autopsies of fetuses and infants less than age 1 year, one in 240 were found to have had bilateral renal agenesis.22 This compares to one in 408 and one in 984 in a series of consecutive autopsies of children under age 18 years and all ages, respectively.35 Population studies have estimated the incidence to be 0.12 to 0.17 per 1000.36–39 Both unilateral and bilateral renal agenesis show a significant excess of males (65–75%).2,3,40 Prognosis, Prevention, and Treatment

Bilateral renal agenesis is a uniformly fatal disorder. Prenatal loss rates approximate 40%.1 In infants who survive to live birth, death usually occurs within 24 hours due to pulmonary insufficiency. In occasional cases where the presence of an unaffected monozygous co-twin41 or esophageal atresia42 allows the maintenance of relatively normal amniotic fluid levels, pulmonary hypoplasia may not be present. In such circumstances, death may occur sometime later due to uremia. No effective treatment for bilateral renal agenesis is currently available. One attempt to use amnio-infusion to avoid pulmonary hypoplasia and compression defects in a fetus diagnosed prenatally with bilateral renal agenesis ended in the delivery at 33 weeks gestation of an infant who had neither of these complications. Peritoneal dialysis was unsuccessful and the infant died at 23 days of age.43 The remaining kidney is anomalous in 30–50% of individuals with unilateral renal agenesis that come to medical attention,40 but this is probably an overestimate. Such problems can include ectopia, pyelonephritis, ureteral pelvic junction obstruction, stone formation, and especially renal dysplasia. Remaining kidneys, even when structurally normal, usually undergo compensatory hypertrophy and ureteral dilation, and vesicoureteral reflux is common.1 These enlarged kidneys may be more prone to traumatic injury, and it is recommended that individuals with a single kidney not take part in contact sports or other activities that place the organ at risk of damage. Given the high frequency of this malformation, it is imperative that the presence of two kidneys is confirmed before nephrectomy or renal biopsy is considered.1 Prenatal diagnosis with fetal ultrasound examination can detect oligohydramnios as early as 14 to 16 weeks. However, this

Table 28-12. Disorders with renal agenesis Disorder

Prominent Features

Uninary Tract Anomalies

Causation Gene/Locus

Medullary cystic disease, renal dysplasia, unilateral renal agenesis, ureteral fistulae

AD (118450) JAG1, 20p12

Acrorenal disorders—See Table 28-8 for conditions with limb deficiency anomalies Alagille47

Facial dysmorphism, retinal defects, cholestasis, pancreatic defects, retinitis pigmentosa, heart defects, hemivertebrae

Al Gazali48

Bifid nose, anorectal malformations

Renal agenesis

AR

Bardet-Biedl49,50

Mental retardation, retinitis pigmentosa, hypogonadism, polydactyly, obesity, biliary atresia, hepatic fibrosis

Renal agenesis, hypoplasia and dysplasia; calyceal cysts, diverticula, clubbing; hydronephrosis; fetal lobulations; nephritis; urethral defects

AR (209900); alleles at different BSS loci act as modifiers BSS1, 11q13 BSS2, 16q21 BSS3, 3p13 BSS4, 15q22.3 BSS5, 2q31 BSS6, 20p12 BSS7, 4q27 BSS8, 14q32.11

Branchio-oto-renal (BOR)51

Mixed hearing loss, temporal bone anomalies, abnormal pinnae, branchial cleft sinuses or fistulae, preauricular pits and tags

Renal agenesis, dysplasia or ectopia, duplication of pelvis and ureter, megaureter, reflux

AD (113650) EYA1, 8q13.3

Caudal duplication52

Double and/or malformed colon, genitalia, sacrum, and lower spinal cord; meningomyleocele, omphalocele; possible overlap with heteropagus twinning.

Duplicated bladder, bladder or cloacal exstrophy, renal agenesis and malrotation, single pelvic kidney

Sporadic

Cerebro-reno-digital disorders —See Table 28-10 for conditions with structural brain anomalies and digital defects with renal agenesis CHARGE25

Coloboma, heart defect, choanal atresia, mental retardation, genital hypoplasia, ear anomalies, growth impairment, deafness

Renal agenesis or hypoplasia, hydronephrosis, duplication of pelvis or ureter, reflux, neurogenic bladder

AD (214800) CHD7, 8q12.1

Chromosomal disorders—See Table 28-10 Colobomas-brachydactyly (type Sorsby)53

Macular colobomata, type B brachydactyly of hands and feet

Unilateral renal agenesis

AD (120400)

DiGeorge54,55

Parathyroid and thymic hypoplasia, conotruncal heart defects, facial dysmorphism in some cases

Renal agenesis and cystic dysplasia, ureteral defects, hydronephrosis, hydroplastic bladder, urethral atresia, stones

Heterogenous, often sporadic, AD (188400) Many cases have deletions of 22q11.2

Duplication of lower limb-agenesis of the kidney56,57

Partial duplication lower limb, hallucal polydactyly, femoral duplication, tibial agenesis (overlap with disorganization and Wolfgang-Gollop)

Unilateral renal agenesis, hydronephrosis, duplication of pelvis and ureter, dilated bladder, reflux, bladder or cloacal exstrophy

Sporadic

Early amnion rupture58

Digital and limb amputations, ring constrictions, facial clefts, body wall defects, brain anomalies

Renal dysplasia, agenesis, and ectopia; ureteral anomalies; urethral stenosis

Sporadic

Ellis microcephaly, heart and renal defects59

Microcephaly, cardiac and brain anomalies, lung lobation defects

Unilateral renal agenesis

AR (601355)

Finlay-Marks60

Scalp tumors, dysplastic ears, absent or hypoplastic nipples, reduced body hair and sweat glands, skin syndactyly

Unilateral renal agenesis, renal hypoplasia, duplication of pelvis and ureter, reflux

AD (181270)

Fraser (cryptophthalmos)61,62

Crypophthalmos, abnormal anterior hairline; laryngeal, umbilical, and genital defects; skin syndactyly; mental retardation

Renal agenesis, urethral atresia

AR (607830), human equivalent of mouse, ‘‘blebbed’’ FRAS1 4q21

Frontonasal dysplasia63

Marked hypertelorism, broad or notched nasal tip, ophthalmologic and heart defects, usually normal intelligence

Unilateral renal agenesis, renal ectopia

Mostly sporadic, rarely AD, AR (136760) (continued)

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Table 28-12. Disorders with renal agenesis (continued) Causation Gene/Locus

Disorder

Prominent Features

Uninary Tract Anomalies

Goltz64

Focal dermal hypoplasia, papillomata, digital anomalies, oral and ocular defects, striated bones

Unilateral renal agenesis or hypoplasia, horseshoe kidneys, duplication of pelvis or ureter

XLD (305600), lethal in males

Green65

Anal stenosis, toe syndactyly

Unilateral renal agenesis

AD

Hypoparathyroidismdeafness-renal dysgenesis66–69

Hypoparathyroidism, sensorineural deafness

Unilateral renal agenesis, hypoplasia and dysplasia, simple cysts, progressive renal failure

AD (146255), contiguous gene syndrome GATA3, 10p15

Iniencephaly70

Spinal retroflexion, encephalocele, holoprosencephaly, cardiac and gastrointestinal anomalies

Renal agenesis, hypoplasia and cystic dysplasia, horseshoe kidneys

Sporadic

Jejunal atreasia-renal dysplasia71

Jujenal atresia

Unilateral renal agenesis or cystic dysplasia, cortical cysts

AD

Kallmann72–74

Hypogonadotropic hypogonadism, anosmia, cryptorchidism, cleft lip and palate, obesity

Renal agenesis, hypoplasia and dysplasia

Heterogeneous XLR (308700) AD (147950) AR (244200) KAL1, Xp22.3

Klippel-Feil deafnessabsent vagina75

Klippel-Feil anomaly, short stature, conductive deafness, absent vagina

Unilateral renal agenesis, renal ectopia

Unknown (148860)

Lenz microphthalmia76

Microphthalmia; coloboma; mental retardation; dental, cardiovascular, ear genital, and digital anomalies; cleft palate

Renal agenesis or dysplasia, ureteral defects, duplication of pelvis and ureter, hydronephrosis, neurogenic bladder

XLR (309800) Xq27-Xq28

Lower mesodermal defects77,78

Prune belly, absent or malformed genitalia, sacral defects, imperforate anus, prolapsed perineum

Renal agenesis, dysgenesis, hypoplasia or ectopia, hydronephrosis, malrotation, hypoplastic or absent bladder, absent or blind-ending urethra, urachal cyst

Sporadic

Malpuech79

Mental retardation, growth retardation, hypertelorism, cleft lip and palate, genital and cardiac defects, caudal appendage

Renal agenesis, dysplasia or ectopia, reflux

AR (248340)

MURCS association80

Mu¨llerian duct aplasia, renal agenesis, cervicothoracic somitic (vertebral) defects, hypoplastic uterus; absent vagina; short stature

Renal agenesis, dysplasia, or ectopia; ureteral anomalies, reflux

Sporadic (601076)

Neu-Laxova, type II (cerebro-arthro-digital)81

Microcephaly, severe growth retardation, exophthalmos, absent eyelids, micrognathia, hypoplastic nose, brain anomalies, joint pterygium, edema, collodion skin

Renal agenesis

AR (256520)

Neural tube defects82–84

Meningomyelocele, anencephaly, encephalocele, vertebral anomalies, midline anomalies

Renal agenesis, hypoplasia, dysplasia, or ectopia; ureteral anomalies, urethral atresia hydronephrosis, horseshoe kidney

Heterogeneous, multifactorial in most cases

Oculo-renal (Sommer type)85

Partial aniridia, glaucoma, prominent foreheads, telecanthus, mild mental retardation

Unilateral renal agenesis

AR (206750)

Osteo-renal disorders —See Table 28-7 for conditions with generalized skeletal dysplasia and renal agenesis Raas-Rothschild–KlippelFeil anomaly86

Klippel-Feil anomaly, short stature, scoliosis

Renal agenesis, hydronephrosis

Sporadic (148900)

Rokitansky (von MayerRokitansky-Ku¨ster, MRK anomaly)87,88

Absent uterus, cervix, and upper vagina; vertebral defects; hemifacial microsomia (overlap with MURCS and urogenital dysplasia)

Renal agenesis or hypoplasia, duplication of pelvis and ureter

Heterogeneous, most cases sporadic (277000)

Smith-Magenis89

Short stature, obesity, mental retardation, self-destructive behavior, brachydactyly, midface hypoplasia

Renal agenesis, duplication of pelvis and ureter

Microdeletion (182290) 17p11.2 RAI1 potentially important

Spondylocostal dysostosis with urogenital defects90,91

Multiple costovertebral segmentation defects, sacral agenesis, imperforate anus, preaxial polydactyly, single umbilical artery

Renal agenesis and cystic dysplasia; cloacal dysgenesis, cyst

Usually sporadic, AR (271520) (continued)

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1188

Urogenital System Organs

Table 28-12. Disorders with renal agenesis (continued) Disorder

Prominent Features

Uninary Tract Anomalies

Causation Gene/Locus

Teratogenic exposures —See Table 28-11 Thymic-renal-anal-lung dysplasia92

Intruterine growth retardation, absent or hypoplasia of thymus and parathyroids, imperforate anus

Renal agenesis and dysplasia

AR (274265)

Twin reversed arterial perfusion93

Co-twin with incomplete development of all organ systems, limbs, and body form; upper body more severely affected than lower body

Renal agenesis, hypoplasia and cystic dysplasia; ureteral and urethral anomalies

Sporadic Restricted to MZ twins

Urogenital adysplasia, congenital26,31

Mu¨llerian duct anomalies

Renal agenesis and dysplasia, urethral atresia

AD (191830), with reduced penetrance and variable expressivity

Urorectal septum malformation94

Pseudohermaphroditism, cloacal and Mu¨llerian duct anomalies, ambiguous genitalia, imperforate anus (overlap with lower mesodermal defects)

Renal agenesis, hypoplasia and dysplasia; ureteral and urethral anomalies

Sporadic

Van Nesselrooij95

Craniosynostosis, cardiac defects, aganglionosis of colon

Renal agenesis, dysplasia

Uncertain Concordant male MZT

Winter renalgenital-ear87,96

Abnormal internal genitalia, vaginal atresia, abnormal ossicles in middle ear, small ears, deafness (overlap with MURCS and urogenital dysplasia)

Renal agenesis and hypoplasia, pelvic kidney

AR (267400)

finding does not necessarily imply renal dysfunction. In one study of 60 pregnancies terminated because of oligohydramnios, the kidneys were normal in 50%.44 Fisk et al.45 used amnio-infusion to evaluate 61 pregnancies with oligohydramnios and apparently intact membranes. This technique allowed confirmation of renal anomalies in 27 of 30 cases and demonstrated kidneys in three others suspected of having renal agenesis. Maternal serum afetoprotein evaluations may also be useful in such cases as approximately 80% of pregnancies with structurally normal fetuses with oligohydramnios have elevated MSAFP levels, compared to approximately 20% of those where the fetus had a urinary tract defect.46 Renal structure by ultrasonography is best evaluated at 18 to 19 weeks of pregnancy. Ultrasound can also be used to detect unilateral renal agenesis with or without contralateral cystic dysplasia. Careful examination of the affected fetus for other structural defects, including single umbilical artery, may help in the identification of specific syndromes or other patterns of multiple congenital anomalies. References (Renal Agenesis) 1. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 2. Potter EL: Bilateral renal agenesis. J Pediatr 29:68, 1946. 3. Potter EL: Bilateral absence of ureters and kidneys: a report of 50 cases. Obstet Gynecol 25:3, 1965. 4. Bain AD, Scott JS: Renal agenesis and severe urinary tract dysplasia. Br Med J 1:841, 1960. 5. Dees JE: Prognosis of the solitary kidney. J Urol 83:550, 1960. 6. Atiyeh B, Husmann D, Baum M: Contralateral renal abnormalities in patients with renal agenesis and noncystic renal dysplasia. Pediatrics 91: 812, 1993. 7. Cascio S, Paran S, Puri P: Associated urological anomalies in children with unilateral renal agenesis. J Urol 162:1081, 1999.

8. Alexander JC, King KB, Fromm CS: Congenital solitary kidney with crossed ureter. J Urol 164:230, 1950. 9. Cope JR, Trickey SE: Congenital absence of the kidney: problems in diagnosis and management. J Urol 127:10, 1982. 10. Evans JA, Erdile LB, Greenberg CR, et al.: Agenesis of the penis: patterns of associated malformations. Am J Med Genet 84:47, 1999. 11. Parida SK, Hall BD, Barton L, et al.: Penoscrotal transposition and associated anomalies: report of five new cases and review of the literature. Am J Med Genet 59:68, 1995. 12. Broseta E, Boronat F, Ruiz JL, et al.: Urological complications associated to uterus didelphys with unilateral hematocolpos. A case report and review of the literature. Eur Urol 20:85, 1991. 13. Li S, Qayyum A, Coakley FV, et al.: Association of renal agenesis and Mullerian duct anomalies. J Comput Assist Tomogr 24:829, 2000. 14. Dorairajan LN, Roby G, Kumar S, et al.: Exstrophy of bladder associated with unilateral renal agenesis and bicornuate uterus: a case report. Int Urogynecol J Pelvic Floor Dysfunct 12:410, 2001. 15. Ashley DJB, Mostofi FK: Renal agenesis and dysgenesis. J Urol 83:211, 1960. 16. Davidson WM, Ross GIM: Bilateral absence of the kidneys and related congenital anomalies. J Path Bact 68:459, 1954. 17. Evans JA, Greenberg CR, Erdile L: Tracheal agenesis revisited: analysis of associated anomalies. Am J Med Genet 82:415, 1999. 18. Evans JA, Stranc LC, Kaplan P, et al.: VACTERL with hydrocephalus: further delineation of the syndrome(s). Am J Med Genet 34:177, 1989. 19. Van Allen MI: Fetal vascular disruptions: mechanisms and some resulting birth defects. Pediatr Ann 10:219, 1981. 20. Mesrobian HG, Rushton HG, Bulas D: Unilateral renal agenesis may result from in utero regression of multicystic renal dysplasia. J Urol 150: 793, 1993. 21. Hitchcock R, Burge DM: Renal agenesis: an acquired condition? J Pediatr Surg 29:454, 1994. 22. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. 23. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8, 1997.

Urinary Tract 24. Mahajan P, Kher A, Khungar A, et al.: MURCS association—a review of 7 cases. J Postgrad Med 38:109, 1992. 25. Ragan DC, Casale AJ, Rink RC, et al.: Genitourinary anomalies in the CHARGE association. J Urol 161:622, 1999. 26. McPherson E, Carey J, Kramer A, et al.: Dominantly inherited renal adysplasia. Am J Med Genet 26:863, 1987. 27. Morse RP, Rawnsley E, Crowe HC, et al.: Bilateral renal agenesis in three consecutive siblings. Prenat Diagn 7:573, 1987. 28. Pashayan HM, Dowd T, Nigro AV: Bilateral absence of the kidneys and ureters. Three cases reported in one family. J Med Genet 14:205, 1977. 29. Buchta RM, Viseskul C, Gilbert EF, et al.: Familial bilateral renal agenesis and hereditary renal adysplasia. Z Kinderheilkd 115:111, 1973. 30. Carter CO, Evans K, Pescia G: A family study of renal agenesis. J Med Genet 16:176, 1979. 31. Roodhooft AM, Birnholz JC, Holmes LB: Familial nature of congenital absence and severe dysgenesis of both kidneys. N Engl J Med 310:1341, 1984. 32. Greenberg CR, Trevenen CL, Evans JA: The BOR syndrome and renal agenesis—prenatal diagnosis and further clinical delineation. Prenat Diagn 8:103, 1988. 33. Daudin M, Bieth E, Bujan L, et al.: Congenital bilateral absence of the vas deferens: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications for genetic counseling. Fertil Steril 74:1164, 2000. 34. Casals T, Bassas L, Egozcue S, et al.: Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod 15:1476, 2000. 35. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 36. International Clearinghouse for Birth Defects Monitoring Systems. Annual Report 2001. International Centre for Birth Defects, Rome, 2001. 37. Carter CO, Evans K: Birth frequency of bilateral renal agenesis. J Med Genet 18:158, 1981. 38. Wilson RD, Baird PA: Renal agenesis in British Columbia. Am J Med Genet 21:153, 1985. 39. Cunniff C, Kirby RS, Senner JW, et al.: Deaths associated with renal agenesis: a population-based study of birth prevalence, case ascertainment, and etiologic heterogeneity. Teratology 50:200, 1994. 40. Collins DC: Congenital renal agenesia. Ann Surg 95:715, 1932. 41. Klinger G, Merlob P, Aloni D, et al.: Normal pulmonary function in a monoamniotic twin discordant for bilateral renal agenesis: report and review. Am J Med Genet 73:76, 1997. 42. McLeod DR, Akierman A, Trevenen C: Combination of renal agenesis with respiratory and alimentary tract atresia results in normal lung development. Am J Med Genet 102:327, 2001. 43. Cameron D, Lupton BA, Farquharson D, et al.: Amnioinfusions in renal agenesis. Obstet Gynecol 83:872, 1994. 44. Scott RJ, Goodburn SF: Potter’s syndrome in the second trimester— prenatal screening and pathological findings in 60 cases of oligohydramnios sequence. Prenat Diagn 15:519, 1995. 45. Fisk NM, Ronderos-Dumit D, Soliani A, et al.: Diagnostic and therapeutic transabdominal amnioinfusion in oligohydramnios. Obstet Gynecol 78: 270, 1991. 46. Los FJ, Hagenaars AM, Cohen-Overbeek TE, et al.: Maternal serum markers in second-trimester oligohydramnios. Prenat Diagn 14:565, 1994. 47. Martin SR, Garel L, Alvarez F: Alagille’s syndrome associated with cystic renal disease. Arch Dis Child 74:232, 1996. 48. Al Gazali LI, Bakir M, Hamud OA, et al.: An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations. Clin Dysmorphol 11:33, 2002. 49. Gershoni-Baruch R, Nachlieli T, Leibo R, et al.: Cystic kidney dysplasia and polydactyly in 3 sibs with Bardet-Biedl syndrome. Am J Med Genet 44:269, 1992. 50. Beales PL, Reid HA, Griffiths MH, et al.: Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant 15:1977, 2000. 51. Chen A, Francis M, Ni L, et al.: Phenotypic manifestations of branchiooto-renal syndrome. Am J Med Genet 58:365, 1995.

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52. Dominguez R, Rott J, Castillo M, et al.: Caudal duplication syndrome. Am J Dis Child 147:1048, 1993. 53. Thompson EM, Baraitser M: Sorsby syndrome: a report on further generations of the original family. J Med Genet 25:313, 1988. 54. Ryan AK, Goodship JA, Wilson DI, et al.: Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 34:798, 1997. 55. Goodship J, Robson SC, Sturgiss S, et al.: Renal abnormalities on obstetric ultrasound as a presentation of DiGeorge syndrome. Prenat Diagn 17:867, 1997. 56. Weisselberg B, Ben Ami T, Goodman RM: Partial duplication of the lower limb with agenesis of ipsilateral kidney—a new syndrome: report of a case and review of the literature. Clin Genet 33:234, 1988. 57. Evans JA, Chudley AE: Tibial agenesis, femoral duplication, and caudal midline anomalies. Am J Med Genet 85:13, 1999. 58. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 59. Ellis IH, Yale C, Thomas R, et al.: Three sibs with microcephaly, congenital heart disease, lung segmentation defects and unilateral absent kidney: a new recessive multiple congenital anomaly (MCA) syndrome? Clin Dysmorphol 5:129, 1996. 60. Picard C, Couderc S, Skojaei T, et al.: Scalp-ear-nipple (Finlay-Marks) syndrome: a familial case with renal involvement. Clin Genet 56:170, 1999. 61. Boyd PA, Keeling JW, Lindenbaum RH: Fraser syndrome (cryptophthalmos-syndactyly syndrome): a review of eleven cases with postmortem findings. Am J Med Genet 31:159, 1988. 62. Slavotinek AM, Tifft CJ: Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 39:623, 2002. 63. Roizenblatt J, Wajntal A, Diament AJ: Median cleft face syndrome or frontonasal dysplasia: a case report with associated kidney malformation. J Pediatr Ophthalmol Strabismus 16:16, 1979. 64. Goltz RW: Focal dermal hypoplasia syndrome. An update. Arch Dermatol 128:1108, 1992. 65. Green AJ, Sandford RN, Davison BC: An autosomal dominant syndrome of renal and anogenital malformations with syndactyly. J Med Genet 33:594, 1996. 66. Barakat AY, D’Albora JB, Martin MM, et al.: Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61, 1977. 67. Muroya K, Hasegawa T, Ito Y, et al.: GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 38:374, 2001. 68. Ishida S, Isotani H, Kameoka K, et al.: Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia. Intern Med 40: 110, 2001. 69. Lichtner P, Konig R, Hasegawa T, et al.: An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J Med Genet 37:33, 2000. 70. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 71. Kilani RA, Hmiel P, Garver MK, et al.: Familial jejunal atresia with renal dysplasia. J Pediatr Surg 31:1427, 1996. 72. Kirk JM, Grant DB, Besser GM, et al.: Unilateral renal aplasia in Xlinked Kallmann’s syndrome. Clin Genet 46:260, 1994. 73. Zenteno JC, Mendez JP, Maya-Nunez G, et al.: Renal abnormalities in patients with Kallmann syndrome. BJU Int 83:383, 1999. 74. Rudnik-Schoneborn S, John U, Deget F, et al.: Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 157:666, 1998. 75. Baird PA, Lowry RB: Absent vagina and the Klippel-Feil anomaly. Am J Obstet Gynecol 118:290, 1974. 76. Forrester S, Kovach MJ, Reynolds NM, et al.: Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome. Am J Med Genet 98:92, 2001. 77. Lubinsky MS: Female pseudohermaphroditism and associated anomalies. Am J Med Genet 6:123, 1980.

1190

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78. Pauli RM: Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet 50:154, 1994. 79. Crisponi G, Marras AR, Corrias A: Two sibs with Malpuech syndrome. Am J Med Genet 86:294, 1999. 80. Duncan PA, Shapiro LR, Stangel JJ, et al.: The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 95:399, 1979. 81. Turkel SB, Ebbin AJ, Towner JW: Additional manifestations of the Neu-Laxova syndrome. J Med Genet 20:227, 1983. 82. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 83. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983. 84. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 85. Sommer A, Rathbun MA, Battles ML: Letter: A syndrome of partial aniridia, unilateral renal agenesis, and mild psychomotor retardation in siblings. J Pediatr 85:870, 1974. 86. Raas-Rothschild A, Goodman RM, Grunbaum M, et al.: Klippel-Feil anomaly with sacral agenesis: an additional subtype, type IV. J Craniofac Genet Dev Biol 8:297, 1988. 87. Willemsen WN: Renal-skeletal-ear- and facial-anomalies in combination with the Mayer-Rokitansky-Kuster (MRK) syndrome. Eur J Obstet Gynecol Reprod Biol 14:121, 1982. 88. Wulfsberg EA, Grigbsy TM: Rokitansky sequence in association with the facio-auriculo-vertebral sequence: part of a mesodermal malformation spectrum? Am J Med Genet 37:100, 1990. 89. Greenberg F, Lewis RA, Potocki L, et al.: Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 62:247, 1996. 90. Casamassima AC, Morton CC, Nance WE, et al.: Spondylocostal dysostosis associated with anal and urogenital anomalies in a Mennonite sibship. Am J Med Genet 8:117, 1981. 91. Murr MM, Waziri MH, Schelper RL, et al.: Case of multivertebral anomalies, cloacal dysgenesis, and other anomalies presenting prenatally as cystic kidneys. Am J Med Genet 42:761, 1992. 92. Rudd NL, Curry C, Chen KT, et al.: Thymic-renal-anal-lung dysplasia in sibs: a new autosomal recessive error of early morphogenesis. Am J Med Genet 37:401, 1990. 93. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 7:285, 1983. 94. Wenstrup RJ, Pagon RA: Female pseudohermaphroditism with anorectal, Mullerian duct, and urinary tract malformations: report of four cases. J Pediatr 107:751, 1985. 95. Van Nesselrooij BP, Spliet W, Beemer FA: Unusual association of congenital malformations: craniosynostosis, heart defect, abnormal intestinal innervation and urogenital abnormalities. Clin Dysmorphol 7:51, 1998. 96. Winter JS, Kohn G, Mellman WJ, et al.: A familial syndrome of renal, genital, and middle ear anomalies. J Pediatr 72:88, 1968.

28.2 Renal Hypoplasia Definition

Renal hypoplasia refers to a congenitally small kidney that is less than 50% of the expected weight for age, but lacking abnormal parenchymal differentiation (renal dysplasia) or evidence of acquired disease. It is also termed small kidney. Diagnosis

Bilateral renal hypoplasia may be diagnosed in children suffering from chronic renal failure. In adults with unilateral renal hypo-

plasia, lumbar pain, hematuria, urinary frequency, and/or hypertension are seen in about half the cases.1 It is difficult to distinguish congenitally hypoplastic kidneys from some of those with cystic dysplasia or that have become atrophic through other disease processes. Plain abdominal radiographs may demonstrate a small renal shadow. Renal hypoplasia is usually associated with a marked reduction in the number of renal lobes from eight to 10 to five or less. This can be shown by radiologic examination after using contrast medium to fill the pelvicaliceal cavity. The renal artery may also be narrow and hypoplastic.2 Histologic examination of the hypoplastic kidney is often required to exclude signs of dysplasia or infection. It will also help distinguish the two main forms of renal hypoplasia: simple hypoplasia and oligomeganephronia or oligonephronic hypoplasia. In simple hypoplasia, the number of renal lobes is reduced to as few as one. The renal parenchymal tissue is normally differentiated, but reduced in volume. Simple hypoplasia may be an isolated finding or can be seen in association with multiple congenital anomalies or chromosomal defects such as Down syndrome. In these cases, the number of lobes may be normal, suggesting that the hypoplasia is due more to generalized postnatal growth retardation than a primary defect in renal mass.2 Unlike hypoplastic cystic dysplasia, renal hypoplasia is not normally associated with ureteral or other urinary tract anomalies, again indicating a more localized defect in renal development. However, renal hypoplasia may be associated with hydronephrosis due to vesicoureteral reflux. In such cases, neonatal ultrasonography may indicate decreased renal length.3 Normal ranges for fetal renal length4 and renal parenchymal volume5 have been established, but reports of prenatal diagnosis of renal hypoplasia are rare.6,7 In oligomeganephronia, there is a significant reduction in both the number of lobes and renal mass. Occasionally only one or two renal pyramids are present. Histologically, the most pronounced feature is a reduced number of nephrons that show individual hypertrophy such that the glomeruli are enlarged and tubular dilation is present (Fig. 28-4). Microdissection of the kidney of one patient showed that the glomerular cross-section was five times normal while the mean volume was increased 12-fold. Mean proximal tubular length was fourfold greater than normal and the volume increased 17 times.8 Oligomeganephronia is usually bilateral but occasionally is seen in association with unilateral renal agenesis.9 The symptoms of oligomeganephronia include polyuria, polydipsia, urine concentration, salt wasting, and proteinuria. Vomiting, dehydration, fever, and growth retardation may also occur and often bring the child to medical attention in the first 2 years of life.2 During childhood or adolescence, there is a gradual onset of focal glomerular sclerosis, tubular atrophy, and interstitial fibrosis, which heralds the onset of chronic renal failure.10 Etiology and Distribution

The fact that renal hypoplasia is associated with a significant reduction in the number of renal pyramids suggests a potential anomaly in ureteric bud branching and a concomitant failure to induce an adequate response of mesenchymal differentiation. Alternatively, there may be a primary deficiency in the metanephric blastema.6 Hypoplasia may also be seen in ectopic or malrotated kidneys, potentially due to an anomalous blood supply.2 Most cases of renal hypoplasia are unilateral. In a series of 13,775 autopsies, 26 unilateral and eight bilateral cases were

Urinary Tract

1191

However, it is imperative that adequate function in the contralateral kidney is established. Hypoplastic kidneys do not have the ability to undergo compensatory hypertrophy.24 In the absence of a recognized genetic disorder, the recurrence risk is low, but families could be offered fetal monitoring prenatally to look for reduced size and associated anomalies. References (Renal Hypoplasia)

Fig. 28-4. Bottom: A markedly enlarged glomerulus from a child with oligomeganephronic renal hypoplasia. Top: A glomerulus of normal size from an age-matched control (H&E; x300). (Reprinted with permission from Jennette JC, Olson JL, Schwartz MM, et al., eds.: Heptinstall’s Pathology of the Kidney, ed 5. Lippincott Williams & Wilkins, Philadelphia, 1998.)

observed, giving an overall incidence of one in 405.11 The incidence was higher (2.5%) in a series of pediatric autopsies.12 Renal hypoplasia is usually a sporadic disorder, which helps differentiate it from familial juvenile nephronophthisis, an autosomal recessive disorder with a usually later age of onset (see Section 28.7). However, it can occur in a number of complex disorders (Table 28-13). Heterozygous PAX2 gene mutations may occasionally cause apparently isolated renal hypoplasia13 or oligomeganephronia14 representing variable expressions of the renal-coloboma syndrome. An autosomal dominant form of small smooth kidneys with progressive renal failure has been reported.15 Oligomeganephronia is usually nonfamilial and occurs more often in males (3:1).16 It has been seen in a form of acrorenal defects with limb deficiencies.17,18 Park and Chi19 documented 4p deletions in two such patients, indicating that this might represent a microdeletion syndrome. Sibs with mental retardation and facial dysmorphism in addition to the acrorenal defects have been identified.20 There is also one report of isolated oligomeganephronia in sibs21 and another that documented two brothers with multiple anomalies resembling 4p monosomy in whom G-banded karyotypes were normal.22 A case of ring 4 mosaicism also had oligomeganephronia, indicating that the locus for this condition may be on 4p distal to the Wolf-Hirschhorn critical region.23 Prognosis, Prevention, and Treatment

Bilateral renal hypoplasia is a severe disorder leading to renal failure in childhood or adolescence. No specific treatment other than dialysis and renal transplantation is available. Nephrectomy can be considered for symptomatic unilateral hypoplasia.

1. Powers JH, Murray MF: Juvenile hypertension associated with unilateral lesions of the upper urinary tract. JAMA 118:600, 1942. 2. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 3. Farhat W, McLorie G, Bagli D, et al.: Greater reliability of neonatal ultrasonography in defining renal hypoplasia with antenatal hydronephrosis and vesicoureteral reflux. Can J Urol 9:1459, 2002. 4. Zalel Y, Lotan D, Achiron R, et al.: The early development of the fetal kidney—an in utero sonographic evaluation between 13 and 22 weeks’ gestation. Prenat Diagn 22:962, 2002. 5. Kennedy WA, Chitkara U, Abidari JM, et al.: Fetal renal growth as assessed through renal parenchymal area derived from prenatal and perinatal ultrasonography. J Urol 169:298, 2003. 6. Foster SV, Hawkins EP: Deficient metanephric blastema—a cause of oligomeganephronia? Pediatr Pathol 14:935, 1994. 7. Latini JM, Curtis MR, Cendron M, et al.: Prenatal failure to visualize kidneys: a spectrum of disease. Urology 52:306, 1998. 8. Fetterman GH, Habib R. Congenital bilateral oligonephronic renal hypoplasia with hypertrophy of nephrons (oligome´gane´phronie): studies by microdissection. Am J Clin Pathol 52:199, 1969. 9. Nomura S, Osawa G: Focal glomerular sclerotic lesions in a patient with unilateral oligomeganephronia and agenesis of the contralateral kidney: a case report. Clin Nephrol 33:7, 1990. 10. McGraw M, Poucell S, Sweet J, et al.: The significance of focal segmental glomerulosclerosis in oligomeganephronia. Int J Pediatr Nephrol 5:67, 1984. 11. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 12. Rubinstein M, Meyer R, Bernstein J: Congential abnormalities of the urinary system. J Pediatr 58:356, 1961. 13. Nishimoto K, Iijima K, Shirakawa T, et al.: PAX2 gene mutation in a family with isolated renal hypoplasia. J Am Soc Nephrol 12:1769, 2001. 14. Salomon R, Tellier AL, Attie-Bitach T, et al.: PAX2 mutations in oligomeganephronia. Kidney Int 59:457, 2001. 15. Kaplan BS, Milner LS, Jequier S, et al.: Autosomal dominant inheritance of small kidneys. Am J Med Genet 32:120, 1989. 16. Campbell MF, Walsh PC, Retik AG: Campbell’s Urology, ed 8. WB Saunders Company, Philadelphia, 2002. 17. Elfenbein IB, Baluarte HJ, Gruskin AB: Renal hypoplasia with oligomeganephronia: light, electron, fluorescent microscopic and quantitative studies. Arch Pathol 97:143, 1974. 18. Miltenyi M, Balogh L, Schmidt K, et al.: A new variant of the acrorenal syndrome associated with bilateral oligomeganephronic hypoplasia. Eur J Pediatr 142:40, 1984. 19. Park SH, Chi JG: Oligomeganephronia associated with 4p deletion type chromosomal anomaly. Pediatr Pathol 13:731, 1993. 20. Buttiens M, Fryns JP: Apparently new autosomal recessive syndrome of mental retardation, distal limb deficiencies, oral involvement, and possible renal defect. Am J Med Genet 27:651, 1987. 21. Moerman P, Van Damme B, Proesmans W, et al.: Oligomeganephronic renal hypoplasia in two siblings. J Pediatr 105:75, 1984. 22. Kusuyama Y, Tsukino R, Oomori H, et al.: Familial occurrence of oligomeganephronia. Acta Pathol Jpn 35:449, 1985. 23. Anderson CE, Wallerstein R, Zamerowski ST, et al.: Ring chromosome 4 mosaicism coincidence of oligomeganephronia and signs of Seckel syndrome. Am J Med Genet 72:281, 1997.

Table 28-13. Disorders with renal hypoplasia Syndrome

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Acro-renal disorders —See Table 28-6 for conditions with limb deficiencies and renal hypoplasia Alsing25

Atypical colobomata, radio-humeral synostosis, fibular hypoplasia

Small kidneys, juvenile nepronophthisis, proteinuria

Uncertain

Bardet-Biedl26,27

Mental retardation, retinitis pigmentosa, hypogonadism, polydactyly, obesity, biliary atresia, hepatic fibrosis

Renal agenesis, hypoplasia and dysplasia; calyceal cysts, diverticula, clubbing; hydronephrosis; fetal lobulations; nephritis; urethral defects

AR (209900); alleles at different BSS loci act as modifiers BSS1, 11q13 BSS2, 16q21 BSS3, 3p13 BSS4, 15q22.3 BSS5, 2q31 BSS6 (MKKS), 20p12 BSS7, 4q27

Branchio-oto-renal (BOR)28

Mixed hearing loss, temporal bone anomalies, abnormal pinnae, branchial cleft sinuses or fistulae, preauricular pits and tags

Renal agenesis, dysplasia or ectopia, duplication of pelvis and ureter, megaureter, reflux

AD (113650) EYA1, 8q13.3

Cerebro-renal-digital disorders—See Table 28-8 for conditions with structure brain anomalies and digital defects with renal hypoplasia CHARGE29

Coloboma, heart defect, choanal atresia, mental retardation, genital hypoplasia, ear anomalies, growth impairment, deafness

Renal agenesis or hypoplasia, hydronephrosis, duplication of pelvis or ureter, reflux, neurogenic bladder

AD (214800) CHD7, 8q12.1

Chromosomal disorders —See Table 28-10 Finlay-Marks30

Scalp tumors, dysplastic ears, absent or hypoplastic nipples, reduced body hair and sweat glands, skin syndactyly

Unilateral renal agenesis, renal hypoplasia, duplication of pelvis and ureter, reflux

AD (181270)

Fitzsimmons31

Speech delay, progressive spastic paraparesis, sensorineural deafness, mild mental retardation

Small kidneys, hydronephrosis, hematuria, proteinuria, progressive nephropathy

AD (182690)

Fraiser32

XY gonadal dysgenesis, streak gonads, gonadoblastoma

Small kidneys, hematuria, proteinuria, progressive glomerular sclerosis

AD (136680) De novo splice site mutations WT1, 11p13

Gillessen-Kaesbach33,34

Microbrachycephaly, short limbs, facial dysmorphism, heart defects, biliary and pancreatic dysplasia, hepatic fibrosis, lethal

Infantile polycystic kidneys, renal hypoplasia

AR (263210) Linkage to 6p21.1-p12 (ARPKD excluded)

Glomerulocystic disease, familial35,36

No extrarenal anomalies

Small kidneys, absence of renal papillae, glomerulocystic disease cysts, stable chronic renal failure

AD (137920) TCF2, 17cen-q21.3

Goltz37

Focal dermal hypoplasia, papillomata, digital anomalies, oral and ocular defects, striated bones

Unilateral renal agenesis or hypoplasia, horseshoe kidneys, duplication of pelvis or ureter

XLD (305600), lethal in males

Hypoparathyroidismdeafness-renal dysgenesis38–41

Hypoparathyroidism, sensorineural deafness

Unilateral renal agenesis, hypoplasia and dysplasia, simple cysts, progressive renal failure

AD (146255), contiguous gene syndrome GATA3, 10p15

Iniencephaly42

Spinal retroflexion, encephalocele, holoprosencephaly, cardiac and gastrointestinal anomalies

Renal agenesis, hypoplasia and cystic dysplasia, horseshoe kidneys

Sporadic

Juberg/Hayward43

Microcephaly, cleft lip and palate, thumb anomalies, nasal defects

Horseshoe kidneys, small kidneys

AR (216100) (continued)

1192

Table 28-13. Disorders with renal hypoplasia (continued) Causation Gene/Locus

Syndrome

Prominent Features

Urinary Tract Anomalies

Kallmann44–46

Hypogonadotropic hypogonadism, anosmia, cryptorchidism, cleft lip and palate, obesity

Renal agenesis, hypoplasia and dysplasia

Heterogeneous XLR (308700) AD (147950) AR (244200) KAL1, Xp22.3

Lachiewicz-renal disease, preauricular pits47

Preauricular pits

Small kidneys, progressive glomerular sclerosis, proteinuria

AD

Lower mesodermal defects48,49

Prune belly, absent or malformed genitalia, sacral defects, imperforate anus, prolapsed perineum

Renal agenesis, dysgenesis, hypoplasia or ectopia, hydronephrosis, malrotation, hypoplastic or absent bladder, absent or blind-ending urethra, urachal cyst

Sporadic

Neural tube defects50–52

Meningomyelocele, anencephaly, encephalocele, vertebral anomalies, midline anomalies

Renal agenesis, hypoplasia, dysplasia, or ectopia; ureteral anomalies, urethral atresia hydronephrosis, horseshoe kidney,

Heterogeneous, multifactorial in most cases

Osteo-renal disorders—See Table 28-7 for generalized skeletal dysplasias with renal hypoplasia Persistent Mu¨llerian ductlymphangiectasis (Urioste)53

Persistent mu¨llerian ducts in males, intestinal lymphangiectasis, polydactyly, facial dysmorphism

Renal dysplasia, hydronephrosis, small kidneys, ureteral anomalies

Uncertain AR (235255)

Renal and Mu¨llerian duct hypoplasia-craniofacial anomalies54

Severe developmental delay, growth retardation, genital anomalies, facial dysmorphism, dimples at elbows and wrists

Small kidneys, horseshoe kidneys, reflux

AR (266810)

Renal-coloboma (oculo-renal Karcher type)55,56

Optic nerve coloboma, myopia, strabismus, nystagmus

Renal hypoplasia, nephritis

AD (120330) Heterogenous Some families have PAX2 mutations 10q24.1-q25.1

Renal-hepatic-pancreatic disorders —See Table 28-9 for other conditions with liver and pancreatic anomalies with renal hypoplasia Rokitansky (von MayerRokitansky-Ku¨ster, MRK anomaly)57,58

Absent uterus, cervix, and upper vagina; vertebral defects; hemifacial microsomia (overlap with MURCS and urogenital dysplasia)

Renal agenesis or hypoplasia, duplication of pelvis and ureter

Heterogeneous, most cases sporadic (277000)

Co-twin with incomplete development of all organ systems, limbs, and body form; upper body more severely affected than lower body

Renal agenesis, hypoplasia and cystic dysplasia; ureteral and urethral anomalies

Sporadic Restricted to MZ twins

Pseudohermaphroditism, cloacal and Mu¨llerian duct anomalies, ambiguous genitalia, imperforate anus (overlap with Lower mesodermal defects)

Renal agenesis, hypoplasia and dysplasia; ureteral and urethral anomalies

Sporadic

Williams61–63

Characteristic facies, stellate irides, mental retardation, heart defects, radioulnar synostosis, infantile hypercalcemia

Small kidneys, renal ectopic or aplasia, duplicated pelvis or ureter, other ureteral defects, renal artery stenosis, urethral stenosis, bladder diverticula

AD (194050) ELN, 7q11.2

Winter renal-genital-ear57,64

Abnormal internal genitalia, vaginal atresia, abnormal ossicles in middle ear, small ears, deafness (overlap with MURCS and urogenital dysplasia)

Renal agenesis and hypoplasia, pelvic kidney

AR (267400)

Teratogenic exposures—See Table 28-11 Twin reversed arterial perfusion59

Urorectal septum malformation

60

1193

1194

Urogenital System Organs

24. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 25. Alsing A, Christensen C: Atypical macular coloboma (dysplasia) associated with familial juvenile nephronophthisis and skeletal abnormality. Ophthalmic Paediatr Genet 9:149, 1988. 26. Gershoni-Baruch R, Nachlieli T, Leibo R, et al.: Cystic kidney dysplasia and polydactyly in 3 sibs with Bardet-Biedl syndrome. Am J Med Genet 44:269, 1992. 27. Beales PL, Reid HA, Griffiths MH, et al.: Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant 15:1977, 2000. 28. Chen A, Francis M, Ni L, et al.: Phenotypic manifestations of branchiooto-renal syndrome. Am J Med Genet 58:365, 1995. 29. Ragan DC, Casale AJ, Rink RC, et al.: Genitourinary anomalies in the CHARGE association. J Urol 161:622, 1999. 30. Picard C, Couderc S, Skojaei T, et al.: Scalp-ear-nipple (Finlay-Marks) syndrome: a familial case with renal involvement. Clin Genet 56:170, 1999. 31. Fitzsimmons JS, Watson AR, Mellor D, et al.: Familial spastic paraplegia, bilateral sensorineural deafness, and intellectual retardation associated with a progressive nephropathy. J Med Genet 25:168, 1988. 32. Barbaux S, Niaudet P, Gubler MC, et al.: Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467, 1997. 33. Gillessen-Kaesbach G, Meinecke P, Garrett C, et al.: New autosomal recessive lethal disorder with polycystic kidneys type Potter I, characteristic face, microcephaly, brachymelia, and congenital heart defects. Am J Med Genet 45:511, 1993. 34. Hallermann C, Mucher G, Kohlschmidt N, et al.: Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p. Am J Med Genet 90:115, 2000. 35. Kaplan BS, Gordon I, Pincott J, et al.: Familial hypoplastic glomerulocystic kidney disease: a definite entity with dominant inheritance. Am J Med Genet 34:569, 1989. 36. Bingham C, Bulman MP, Ellard S, et al.: Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 68:219, 2001. 37. Goltz RW. Focal dermal hypoplasia syndrome. An update. Arch Dermatol 128:1108, 1992. 38. Barakat AY, D’Albora JB, Martin MM, et al.: Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61, 1977. 39. Muroya K, Hasegawa T, Ito Y, et al.: GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 38:374, 2001. 40. Ishida S, Isotani H, Kameoka K, et al.: Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia. Intern Med 40:110, 2001. 41. Lichtner P, Konig R, Hasegawa T, et al.: An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J Med Genet 37:33, 2000. 42. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 43. Verloes A, Le Merrer M, Davin JC, et al.: The orocraniodigital syndrome of Juberg and Hayward. J Med Genet 29:262, 1992. 44. Kirk JM, Grant DB, Besser GM, et al.: Unilateral renal aplasia in X-linked Kallmann’s syndrome. Clin Genet 46:260, 1994. 45. Zenteno JC, Mendez JP, Maya-Nunez G, et al.: Renal abnormalities in patients with Kallmann syndrome. BJU Int 83:383, 1999. 46. Rudnik-Schoneborn S, John U, Deget F, et al.: Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 157:666, 1998. 47. Lachiewicz AM, Sibley R, Michael AF: Hereditary renal disease and preauricular pits: report of a kindred. J Pediatr 106:948, 1985. 48. Lubinsky MS: Female pseudohermaphroditism and associated anomalies. Am J Med Genet 6:123, 1980. 49. Pauli RM: Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet 50:154, 1994.

50. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 51. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983. 52. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 53. Urioste M, Rodriguez JI, Barcia JM, et al.: Persistence of Mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet 47:494, 1993. 54. Davee MA, Moore CA, Bull MJ, et al.: Familial occurrence of renal and Mullerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay. Am J Med Genet 44:293, 1992. 55. Schimmenti LA, Shim HH, Wirtschafter JD, et al.: Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome. Hum Mutat 14:369, 1999. 56. Parsa CF, Silva ED, Sundin OH, et al.: Redefining papillorenal syndrome: an underdiagnosed cause of ocular and renal morbidity. Ophthalmology 108:738, 2001. 57. Willemsen WN: Renal-skeletal-ear- and facial-anomalies in combination with the Mayer-Rokitansky-Kuster (MRK) syndrome. Eur J Obstet Gynecol Reprod Biol 14:121, 1982. 58. Wulfsberg EA, Grigbsy TM: Rokitansky sequence in association with the facio-auriculo-vertebral sequence: part of a mesodermal malformation spectrum? Am J Med Genet 37:100, 1990. 59. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 7:285, 1983. 60. Wenstrup RJ, Pagon RA: Female pseudohermaphroditism with anorectal, Mullerian duct, and urinary tract malformations: report of four cases. J Pediatr 107:751, 1985. 61. Pober BR, Lacro RV, Rice C, et al.: Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 46:271, 1993. 62. Pankau R, Partsch CJ, Winter M, et al.: Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 63:301, 1996. 63. Morris CA, Leonard CO, Dilts C, et al.: Adults with Williams syndrome. Am J Med Genet Suppl 6:102, 1990. 64. Winter JS, Kohn G, Mellman WJ, et al.: A familial syndrome of renal, genital, and middle ear anomalies. J Pediatr 72:88, 1968.

28.3 Cystic Diseases Many renal diseases present with fluid-filled cysts either within or immediately adjacent to the renal parenchyma. Those disorders where cysts are a predominant feature form the heterogeneous group of conditions referred to as cystic renal disease. Such cysts may involve the cortex, the medulla, or both. They can involve all or only part of the kidney, and may be unilateral or bilateral. Also, renal cysts may be the sole abnormality or part of a broader pattern of urinary tract and/or systematic anomalies.1 The classification and terminology for cystic kidney disease has engendered much debate and controversy among medical specialists. In particular, the indiscriminate use of such terms as polycystic and multicystic disease has led to much confusion and inconsistency in the diagnosis and description of renal abnormalities in patients with both isolated and complex disorders. Although Potter’s classification of renal cystic disease of the newborn is no longer widely used, it is shown in Table 28-14 because of its historical importance and because of its relevance to prenatally detected cases and infants with severe anomalies. The classification is based on microdissections of the kidney2–6 and

Urinary Tract

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Table 28-14. Potter’s classification of cystic diseases of the kidneys in newborn infants Type

Description

Pathogenesis

Type I—autosomal recessive polycystic kidney disease (ARPKD)

Normal renal architecture, diffuse enlargement of collecting tubules, liver involvement usual

Structural abnormality of collecting tubules

Type II—multicystic kidney, multilocular cysts, renal aplasia, renal dysplasia

Reduced number of nephrons, abnormal remaining nephrons, increased diameter collecting tubules, terminations cystic, tissue dysplasia

Inhibition of action of ureteral bud of one or more of first-generation branches; failure of ampullae to initiate tubular division and induce formation of nephrons, collecting tubules and nephrons

Type IIA—multicystic

Kidneys mildly to greatly enlarged due to cysts, liver usually normal, associated malformations common

Same as above

Type IIB—renal aplasia, renal dysplasia

Variable cyst size and number, liver usually normal, associated malformations common

Ampullae affected early and severely so all tubular divisions greatly inhibited, nephrons not induced

Type III—polycystic kidneys, infantile presentation of autosomal dominant polycystic kidney disease (ADPKD)

Architecturally normal kidney; cysts develop in Bowman’s capsules, nephrons, or part of the collecting tubules; increased number of cysts with age; no urinary obstruction; liver involvement usual; bile ducts cystic

Results from variable interference with ampullary function at a later stage than type II; segmental abnormal ampullae with abnormal division and nephron induction

Type IV—obstructive kidney disease

In severe cases, kidneys markedly distorted; cysts present throughout; tissue dysplasia. In mild cases, cysts only visible on close inspection. Collecting tubules and all nephrons except the last generations normally formed.

Partial or intermittent urethral or ureteral obstruction

From references 8 to 13.

appears to reflect underlying pathogenesis and/or errors in embryogenesis.7–13 The limitation of Potter’s classification is its restriction to disorders presenting in the newborn or infant. Modifications of Potter’s classification by Zerres et al.14 and Bernstein and Gardner15 still employed a primarily histologically based focus but allowed inclusion of later-onset disorders and highlighted some of those conditions that involve multiple congenital anomalies. The Committee on Classification, Nomenclature, and Terminology of the Section on Urology of the American Academy of Pediatrics, striving for consensus with respect to terminology and nomenclature, proposed a third classification system for renal dysgenesis and cystic diseases of the kidney that divided these conditions into those with ‘‘genetic’’ versus ‘‘nongenetic’’ etiologies16 (Table 28-15). The Bernstein and Gardner classification (Table 28-15) is most universally accepted. Despite the conceptual framework of the consensus classification, it is of less value in the clinical setting where the diagnostic workup is driven more by the presenting renal anomaly than the pattern of inheritance, especially as further evaluation of the patient, his or her associated anomalies, the family history, and the literature may be required before an etiologic category can be determined. This drawback also applies to a lesser extent to the Bernstein and Gardner classification; nevertheless, it is the one most often used today. From the dysmorphologist’s perspective, many conditions that present with renal dysplasia or other forms of cystic disease cannot be easily classified using the etiologically based classifications, since many of the patterns that give rise to them (e.g., polytopic field defects, associations, and sequences) are either not ‘‘hereditary’’ or ‘‘genetic’’ or are casually heterogeneous. Thus, many of the disorders with renal cysts documented in the tables in this chapter would not be categorized in the current classification systems or alternatively would appear in more than one category. In view of the large number of disorders associated with renal cystic disease, a classification system is needed that integrates the

clinical, pathologic, and diagnostic features with respect to etiology and pathogenesis. In lieu of such a system, the disorders in the section on cystic renal disease have been divided according to the presenting renal anomaly in the order in which they appear in International Classification of Disease Codes Version 10 (ICDC-10), that is, using a modified Bernstein and Gardner classification (Table 28-15). The sonographic appearances of renal cysts are given in Table 28-16. In the absence of a specific diagnostic test, a diagnosis may not be immediately apparent. In that case, identification of a particular syndrome or other pattern of anomalies will initially be based on the presence of a constellation of clinical features associated with that disorder. The most important confirmatory ‘‘test’’ may be the passage of time to see if the patient’s clinical course follows the natural history expected for the provisional diagnosis. Disorders in which cystic renal disease may occur, including those associated with teratogenic exposures and chromosome abnormalities, are listed in many tables in this chapter. References (Cystic Diseases) 1. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 2. Osathanondh V, Potter EL: Development of human kidney as shown by microdissection. I. Preparation of tissue with reasons for possible misinterpretation of observations. Arch Pathol 76:271, 1963. 3. Osathanondh V, Potter EL: Development of human kidney as shown by microdissection. II. Renal pelvis, calyces and pelvis. Arch Pathol 76:277, 1963. 4. Osathanondh V, Potter EL: Development of human kidney as shown by microdissection. III. Formation and inter-relationship of collecting tubules and nephrons. Arch Pathol 76:290, 1963. 5. Osathanondh V, Potter EL: Development of human kidney as shown by microdissection. IV. Development of tubular portions of nephrons. Arch Pathol 82:391, 1966.

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Table 28-15. Comparison of three classifications of renal parenchyma cysts Zerres et al.14

Bernstein and Gardner15

Type I Autosomal recessive polycystic kidney disease (ARPKD)

Polycystic disease A. Autosomal recessive polycystic disease (IPCD)

Type II Renal dysplasia A. Normal or enlarged kidneys (type IIA; including segmental involvement, multicystic kidney) B. Reduced size with few or only small cysts (type IIB; dysgenetic, aplastic, rudimentary kidneys) C. Multilocular cyst Type III Cystic kidney type III: autosomal dominant polycystic kidney disease (ADPKD) A. Type III cystic kidney with a positive family history B. Cystic kidneys type III without family history

Glassberg et al.16

1. Polycystic disease of newborns and young infants

B. Autosomal dominant (adult) polycystic kidneys

2. Polycystic disease of older children and adults  Medullary tubular ectasia  Congenital hepatic fibrosis  Caroli syndrome

C. Juvenile nephronophthisis-medullary cystic disease complex

B. Autosomal dominant polycystic disease (APCD) 2. Classic polycystic disease of older children and adults

E. Cysts associated with multiple malformation syndromes

Renal cysts in hereditary syndromes A. Tuberous sclerosis

D. Cystic kidneys type II as part of nonhereditary malformation complexes

D. Zellweger cerebrohepatorenal syndrome and Jeune asphyxiating thoracic dysplasia

Cystic diseases of the renal medulla A. Medullary sponge kidneys B. Juvenile nephronophthisis/ medullary cystic disease Cystic kidneys as part of syndromes

2. Medullary cystic disease (autosomal dominant) D. Congenital nephrosis (autosomal recessive)

B. Oral-facial-digital syndrome 1

Glomerulocystic kidneys (dilation of Bowman’s space)

1. Juvenile nephronophthisis (autosomal recessive)

1. Glomerulocystic disease of newborn

C. Cystic kidneys type II with manifestations within the spectrum of a syndrome

Type IV Cystic kidneys due to urethral obstruction

Genetic A. Autosomal recessive (infantile) polycystic kidneys

C. Von Hippel-Lindau disease

E. Cortical cysts and syndromes of multiple malformations F. Glomerulocystic disease of newborn Simple cysts, solitary and multiple Segmental and unilateral cystic disease Acquired cystic disease Renal medullary cysts A. Hereditary tubulointerstitial nephritis 1. Familial juvenile nephronophthisis 2. Medullary cystic disease 3. Renal-retinal dysplasia and congeners B. Medullary sponge kidney Renal dysplasia A. Multicystic and aplastic dysplasia B. Diffuse cystic dysplasia, isolated and syndromic

1. Mendelian (single gene) disorders a. Autosomal dominant  Tuberous sclerosis  von Hippel-Lindau disease b. Autosomal recessive  Meckel syndrome  Jeune asphyxiating thoracic dystrophy  Zellweger cerebrohepatorenal syndrome  Goldston syndrome  Lissencephaly c. X-linked dominant  Oral-facial-digital syndrome, type I 2. Chromosome disorders  Trisomy 21 (Down syndrome)  Trisomy 13 (trisomy D, Patau syndrome)  Trisomy 18 (trisomy E, Edwards syndrome)  Trisomy C Nongenetic A. Multicystic kidney (multicystic dysplasia) B. Multilocular cyst (multilocular cystic nephroma) C. Simple cysts D. Medullary sponge kidneys (<5% inherited) E. Acquired renal cystic disease in chronic hemodialysis patients F. Caliceal diverticulum (pyelogenic cysts)

C. Cystic dysplasia associated with lower urinary tract obstruction

6. Osathanondh V, Potter EL: Development of human kidney as shown by microdissection. V. Development of vascular pattern of glomerulus. Arch Pathol 82:403, 1966. 7. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. 8. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: historical survey. Arch Pathol 77:459, 1964. 9. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type I due to hyperplasia of interstitial portions of collecting tubules. Arch Pathol 77:466, 1964. 10. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type II due to inhibition of ampullary activity. Arch Pathol 77:474, 1964.

11. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type III due to multiple abnormalities of development. Arch Pathol 77:485, 1964. 12. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type IV due to urethral occlusion. Arch Pathol 77:502, 1964. 13. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: survey of results of microdissection. Arch Pathol 77:510, 1964. 14. Zerres K, Volpel MC, Weiss H: Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 68:104, 1984. 15. Bernstein J, Gardner KD Jr: Cystic diseases of the kidney and renal dysplasia. In: Campbell’s Urology, ed 5. PC Walsh, RF Gittes, AD Perlmutter, et al., eds. WB Saunders Company, Philadelphia, 1986.

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Table 28-16. Characteristic sonographic appearance of renal cystic disease Type of Cysts

Distribution and Sonographic Pattern

Polycystic kidney disease, autosomal recessive

Uniform enlargement of both kidneys; ectatic collecting tubules; numerous tiny cysts (1–2 mm); increased echogenicity in cortex and medulla, with medulla often brighter than cortex; prenatally there may be an increased kidney circumference to abdominal circumference ratio, a peripheral rim of hypoechoic parenchyma, poor delineation of more central renal structures, poor visualization of fetal bladder and oligohydramnios; in childhood, cysts may enlarge, with some reaching 2 cm; may resemble ADPKD with time.

Polycystic kidneys, autosomal dominant

Thin-walled, anechoic (fluid-filled) cysts in both kidneys interspersed with normal renal tissue, nodular renal outline; may be unequal distribution of cysts between kidneys; prenatally, kidneys appear normal until the third trimester, then may have nonspecific renal enlargement, hyperechogenic kidneys, multiple cysts.

Renal dysplasia

This may present in one of two ways. One or both kidneys may be small and dysplastic with small (<1 cm) but variably sized anechoic masses randomly distributed throughout the kidney; separated by highly echoic septa, and there is loss of normal corticomedullary patterning. In multicystic dysplasia, there is gross enlargement of one or both kidneys with multiple well-encapsulated anechoic cysts up to 5–6 cm in diameter, and loss of lobular organization. Again there is loss of normal corticomedullary patterning, an increase in connective tissue, and very little residual parenchyma. The vascular pedicle and proximal ureter may be atretic. Prenatally, in bilateral cases, there will be oligohydramnios and poor visualization of the fetal bladder.

Juvenile nephronophthisis/medullary cystic disease

Both kidneys are small or rarely normal in size with thinned cortex and medulla. In 75% of cases, there are variable numbers of small (microscopic to 2 cm) anechoic cysts in the medulla or at the medullary-cortical junction.

Medullary sponge kidney

Ectasia of papillary collecting ducts; about 30% of cases show renal enlargement; medullary cysts up to 8 mm in diameter, occasional calculi; smooth renal outline and normal cortex

Renal cystic disease secondary to obstruction

Bilateral hydroureter and hydronephrosis with dilated renal pelvices, thinning of cortex, and increased echogenicity of renal parenchyma, with or without parenchymal cysts; the kidneys may be normal in size or enlarged. Cysts are more common in the cortex with more normal renal architecture in the inner layer. Prenatally, oligohydramnios is present and the bladder is usually grossly dilated.

Simple cysts

Single or rarely multiple, thin-walled, anechoic cysts, usually confined to one kidney.

Data from references 1 and 17 to 19.

16. Glassberg KI, Stephens FD, Lebowitz RL, et al.: Renal dysgenesis and cystic disease of the kidney: a report of the Committee on Terminology, Nomenclature and Classification, Section on Urology, American Academy of Pediatrics. J Urol 138:1085, 1987. 17. Grossman H, Rosenberg ER, Bowie JD, et al.: Sonographic diagnosis of renal cystic diseases. AJR Am J Roentgenol 140:81, 1983. 18. Fong KW, Rahmani MR, Rose TH, et al.: Fetal renal cystic disease: sonographic-pathologic correlation. AJR Am J Roentgenol 146:767, 1986. 19. De Bruyn R, Gordon I: Imaging in cystic renal disease. Arch Dis Child 83:401, 2000.

28.4 Autosomal Recessive (Infantile) Polycystic Kidney Disease Definition

Autosomal recessive (infantile) polycystic kidney disease (ARPKD) consists of large kidneys with medullary ductal ectasia and conical cysts, associated with hepatic fibrosis and inherited in an autosomal recessive manner. Congenital hepatic fibrosis has been used to refer to the subgroup of patients that present with less severe

renal involvement associated with liver involvement and portal hypertension; however, it should be recognized that congenital hepatic fibrosis may also occur as an isolated anomaly (OMIM 600643). ARPKD has also been called infantile polycystic kidney disease (IPKD); Potter type I; infantile polycystic disease of the liver and kidneys; congenital hepatic fibrosis with renal tubular ectasia; and perinatal, neonatal, infantile, and juvenile polycystic kidney disease. Multicystic kidney, a kidney with multiple cysts, medullary sponge kidney, nephronophthisis, multiple cortical cysts associated with disorders of multiple congenital anomalies, and infantile presentation of autosomal dominant polycystic kidney disease are not included in this definition. Diagnosis

The presentation of ARPKD is highly variable.1 Frequently, based on the age at clinical presentation, this disorder has been divided into perinatal, neonatal, infantile, and juvenile types (Table 28-17).2–4 In one series of 42 patients, the proportion of cases falling into each of these subgroups was 29%, 21%, 31%, and 19%, respectively.5 In general, the younger the patient presents, the more severe is the renal impairment. Renal involvement is also inversely

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Urogenital System Organs Table 28-17. Clinical presentation of autosomal recessive polycystic kidney disease Polycystic Kidneys

3

" Hepatic Fibrosis

Time of presentation

Perinatal

Neonatal

Infantile

Juvenile

Proportion of dilated renal tubules

>90%

*60%

*20%

<10%

Extent of periportal fibrosis

Minimal

Mild

Moderate

Severe

Survival time

Hours

Months

Years

50 or more years

Clinical presentation

Potter sequence, severe oligohydramnios

Mild Potter sequence, decreased renal function

Renal function decreased more than liver function

Decreased liver function, mild renal impairment

Modified from Blyth and Ockenden2 and Zerres at al.3

proportional to the degree of hepatic fibrosis, with older patients presenting with hepatic fibrosis and biliary cirrhosis rather than renal insufficiency. However, some patients with severe liver disease present in early childhood and overlap in diagnosis with congenital hepatic fibrosis. Blyth and Ockenden2 initially reported that the relative severity of kidney and liver disease was consistent within families; later studies have indicated that the separation of the subtypes based on age is less clear and that there is more intrafamilial variability.6 Prenatally, the presenting clinical features are large echogenic kidneys and oligohydramnios and related findings such as clubfeet, small thorax, and micrognathia. However, these findings are not universal and were not present in Potter’s original cases.7 The stillbirth rate is increased. Dystocia due to increased abdominal distension can complicate the delivery. The neonate with ARPKD usually presents with respiratory distress due to pulmonary hypoplasia and pneumothorax. Abdominal distension due to nephromegaly with or without hepatomegaly or hepatosplenomegaly is common. Infants who survive the neonatal period may present with enlarging kidneys and progressive renal insufficiency with variable hepatic involvement. If they can be maintained on dialysis until 9 to 12 months of age, kidney transplantation will ameliorate the renal symptoms, but the hepatic fibrosis may continue to worsen, with variable onset of portal hypertension. It should be noted that not all infants who present in the 1st month of life develop severe disease. In one series of 19 such patients, six were still alive without transplantation at 5 years of age and several had lived into their teens.8 In the adolescent or adult with ARPKD, the renal cysts tend to be fewer in number, but larger and more spherical. Papillary and medullar ectasia are constant findings, giving a radiologic appearance with intravenous urography that is indistinguishable from medullary sponge kidney. Hepatic cirrhosis and portal hypertension with variceal bleeding are more frequent initial findings than renal insufficiency in this age group, but are not constant. Renal size does not increase with age and may diminish, which is a useful feature separating this condition from autosomal dominant polycystic kidney disease in the older patient.9 Structural anomalies of organs other than the kidney and liver are unusual in ARPKD.10 Ultrasound examination of the kidney demonstrates generalized enlargement of both kidneys, increased cortical echogeneity with absent corticomedullary differentiation, and tiny cortical cysts. Occasionally, especially in older patients, the most variable size of the cysts may resemble the findings seen in autosomal dominant polycystic kidney. The kidney may sometimes be difficult to outline because of its increased echogeneity, but in one-third of patients, the renal outline is well-defined and the

cortical echogeneity is normal. Dilated collecting systems are seen in another third, and occasionally reflux, renal calcification or stones, and liver cysts may be observed. Renal examination of the fetus and infant with ARPKD with ultrasound is more problematic as it usually lacks the resolution to visualize the lumens of the ectatic tubules. Instead, the interface produced by the walls of these tubules causes increased echogenicity throughout the parenchyma of the kidney.11 This may make ARPKD difficult to diagnosis prenatally in the absence of oligohydramnios or a positive family history. The fetal sonographic diagnosis is made by the presence of oligohydramnios, an absent urinary bladder, bilateral renal enlargement as measured by the kidney circumference-toabdominal circumference ratio, and a hyperechogenic appearance of the kidneys with no apparent distinction between cortical and medullary tissue (Table 28-16). In severe cases, oligohydramnios may be apparent as early as 16 weeks gestation.12 On pathologic examination, the kidneys show symmetrical and bilateral enlargement, but there is usually retention of normal renal shape and lobulation (Fig. 28-5). The capsular surface is

Fig. 28-5. Autosomal recessive polycystic kidney disease. Gross appearance of the kidneys at autopsy in a newborn female.

Urinary Tract

smooth but has multiple small opalescent spots up to 2 mm in diameter. The cut surface displays diverticular, saccular, and cystic ectasia of the collecting system with radially elongated cortical cysts (Fig. 28-6). Histologically, there is medullary ductal ectasia and the cortical cysts are seen to be fusiform dilations running through the cortex. There is tubular atrophy with interstitial fibrosis. The cortex and medulla can be differentiated, but the boundary is obscured. Between the cysts are groups of normal but crowded glomeruli and tubules. The pelvis and papillae are enlarged, but normal in shape and configuration. The ureter is in its normal position and is not enlarged.13 The nephrons are usually normal. Microdissection of the kidney has shown that the cysts derive from the collecting ducts with dilation of the collecting ducts and less obvious ectasia of the more proximal collecting ducts, convoluted tubules, and ascending limbs of the loops of Henle.14 The liver histology consists of a variable increase in fibrous connective tissue and proliferation of the bile ducts. The ducts form a ring of interconnecting sacs in the portal zone. As this pattern resembles a stage of normal embryologic development prior to the differentiation of tubular ducts, it suggests that the underlying pathogenetic mechanism is an arrest of normal development.13 Portal hypertension usually occurs in older patients and may cause splenomegaly, ascites, and esophageal varices. Intrahepatic ductal ectasia, known as Caroli disease, can be seen in ARPKD and may give rise to cholangitis.15 However, it is a nonspecific finding. Cysts in other organs are rare, but have been observed in the pancreas and much less rarely in the lung. Berry aneurysms have also been reported, but are much rarer than in autosomal dominant polycystic kidney.16 Etiology and Distribution

The frequency of ARPKD varies considerably between populations. In her classic study, Potter7 reported two brothers with ARPKD among 110,000 births. The incidence in pediatric (<18 years) necropsies in a Tennessee study was one in 238.17 Using Hungarian data, Zerres et al.3 reached an estimate of one in 40,000 births including patients with milder manifestations, while MartinezFrias et al.18 found an incidence of one in 70,000 in Spain. A rate of one in 8000 for all types of polycystic kidney disease has been

Fig. 28-6. Autosomal recessive polycystic kidney disease. Cut sections of kidney are from the same patient as Fig. 28-5.

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published for Finland4 with 20% of the families having ARPKD. Higher figures have also been reported. Bosniak and Ambos19 reported a figure of one in 6000 to 14,000 live births, while in Manitoba, Canada, the incidence is approximately one in 20,00020 as a whole, but higher in aboriginal populations. The Afrikaansspeaking populations of South Africa also have a high incidence.21 Males and females are equally affected. Mapping of the gene for ARPKD to 6p21-cen was first made in 199422 with further refinement to 6p21.1-p12.23 Genetic analysis of a rat model for ARPKD (pkd) identified an orthologous relationship between the rat locus and the human ARPKD region. Subsequently, a candidate gene approach was used to identify the PKHD1 gene, which was predicted to encode a large protein. Ward et al.1 demonstrated that the protein, termed fibrocystin, was expressed in adult kidney, liver, and pancreas and in fetal kidney. They identified six truncating and 12 missense mutations in 14 probands, eight of which were compound heterozygotes. This protein has multiple copies of domains seen in transcription factors and plexins, and it is suggested that it represents a receptor protein that is important in collecting duct and bile duct differentiation. Despite the phenotypic differences in presentation and wide geographic distribution, no genetic heterogeneity has been demonstrated. Presumably, the high incidences in specific populations are due to founder effect with respect to specific alleles. Phenotypic variation may result from allelic diversity.1 Prognosis, Prevention, and Treatment

ARPKD is frequently lethal in the neonatal period. Infants who survive may have little evidence of renal insufficiency at first, but often develop progressive renal failure unless the renal involvement is mild. In older children and adults, hypertension is common due to hepatic fibrosis. Inherited as an autosomal recessive condition, there is a 25% chance of recurrence risk in sibs. As previously noted, the phenotype may be variably expressed within family members. All sibs of an affected infant or child should be investigated with ultrasound to assess renal and hepatic function and appearance. Parents should also be evaluated to exclude autosomal dominant polycystic kidney disease. In families known to be at risk, prenatal diagnosis of echogenic enlarged kidneys and oligohydramnios with level II ultrasound by an experienced fetal ultrasonographer may detect recurrence of ARPKD. However, such a diagnosis may be problematic, especially in less severe cases, due to less renal involvement and later onset of oligohydramnios.12,24–26 Prenatal molecular testing is now available, but, to be accurate, requires confirmation of the diagnosis in a previous sib. This can be done, if necessary, using DNA extracted from stored paraffin-embedded tissue samples.1,27 Treatment consists of dialysis and transplantation for severe renal disease and appropriate therapy for hypertension when present. References (Autosomal Recessive Polycystic Kidney Disease) 1. Ward CJ, Hogan MC, Rossetti S, et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259, 2002. 2. Blyth H, Ockenden BG: Polycystic disease of kidney and liver presenting in childhood. J Med Genet 8:257, 1971. 3. Zerres K, Volpel MC, Weiss H: Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 68:104, 1984.

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4. Kaariainen H: Polycystic kidney disease in children: a genetic and epidemiological study of 82 Finnish patients. J Med Genet 24:474, 1987. 5. Deget F, Rudnik-Schoneborn S, Zerres K: Course of autosomal recessive polycystic kidney disease (ARPKD) in siblings: a clinical comparison of 20 sibships. Clin Genet 47:248, 1995. 6. Kaplan BS, Kaplan P, de Chadarevian JP, et al.: Variable expression of autosomal recessive polycystic kidney disease and congenital hepatic fibrosis within a family. Am J Med Genet 29:639, 1988. 7. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. 8. Landing BH, Wells TR, Claireaux AE: Morphometric analysis of liver lesions in cystic diseases of childhood. Hum Pathol 11:549, 1980. 9. Blickman JG, Bramson RT, Herrin JT: Autosomal recessive polycystic kidney disease: long-term sonographic findings in patients surviving the neonatal period. AJR Am J Roentgenol 164:1247, 1995. 10. Patel PJ: Imaging of infantile polycystic kidney disease with some rare association. Urol Int 48:87, 1992. 11. Grossman H, Rosenberg ER, Bowie JD, et al.: Sonographic diagnosis of renal cystic diseases. AJR Am J Roentgenol 140:81, 1983. 12. Luthy DA, Hirsch JH: Infantile polycystic kidney disease: observations from attempts at prenatal diagnosis. Am J Med Genet 20:505, 1985. 13. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 14. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type I due to hyperplasia of interstitial portions of collecting tubules. Arch Pathol 77:466, 1964. 15. Alvarez F, Hadchouel M, Bernard O: Latent chronic cholangitis in congenital hepatic fibrosis. Eur J Pediatr 139:203, 1982. 16. Lieberman E, Salinas-Madrigal L, Gwinn JL, et al.: Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine 50:277, 1971. 17. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 18. Martinez-Frias ML, Bermejo E, Cereijo A, et al.: Epidemiological aspects of Mendelian syndromes in a Spanish population sample: II. Autosomal recessive malformation syndromes. Am J Med Genet 38: 626, 1991. 19. Bosniak MA, Ambos MA: Polycystic kidney disease. Semin Roentgenol 10:133, 1975. 20. Evans JA, Stranc LC: Cystic renal disease and cardiovascular anomalies. Am J Med Genet 33:398, 1989. 21. Ramsay M, Reeders ST, Thomson PD, et al.: Mutations for the autosomal recessive and autosomal dominant forms of polycystic kidney disease are not allelic. Hum Genet 79:73, 1988. 22. Zerres K, Mucher G, Bachner L, et al.: Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet 7:429, 1994. 23. Mucher G, Wirth B, Zerres K: Refining the map and defining flanking markers of the gene for autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12. Am J Hum Genet 55:1281, 1994. 24. Romero R, Cullen M, Jeanty P, et al.: The diagnosis of congenital renal anomalies with ultrasound. II. Infantile polycystic kidney disease. Am J Obstet Gynecol 150:259, 1984. 25. Zerres K, Hansmann M, Mallmann R, et al.: Autosomal recessive polycystic kidney disease. Problems of prenatal diagnosis. Prenat Diagn 8:215, 1988. 26. Fong KW, Rahmani MR, Rose TH, et al.: Fetal renal cystic disease: sonographic-pathologic correlation. AJR Am J Roentgenol 146:767, 1986. 27. Zerres K, Mucher G, Becker J, et al.: Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 76:137, 1998.

28.5 Autosomal Dominant Polycystic Kidney Disease Definition

Autosomal dominant polycystic kidney disease (ADPKD) is cystic disease of the renal medulla and cortex caused by at least three different autosomal dominant genes with variable expressivity. ADPKD is characterized by bilateral enlarged kidneys with cortical and medullary involvement of thin-walled, spherical cysts in the nephrons and collecting tubules. The cysts range in size from several millimeters to several centimeters. The disorder is also known as Potter type III (Table 28-14). It has been referred to as adult polycystic kidney disease. However, since it can present in childhood or be diagnosed in utero or infancy, the term ADPKD is preferable. Diagnosis

Gene carriers usually become symptomatic between 30 and 50 years of age. However, affected individuals can present at any age, including the fetal period.1–3 Prior to the use of presymptomatic testing in family members, autopsy studies suggested that only 25% of patients were diagnosed before death.4 One-third of the cases diagnosed postmortem had clinical manifestations, including hypertension or renal insufficiency. Ultrasound examination can identify asymptomatic at-risk patients who have obvious cystic disease. Carrier testing by molecular techniques will detect individuals with even milder or no cystic changes. Since previous studies of the natural history followed subjects who were clinically symptomatic, this disorder may have a better prognosis than previously anticipated. Common clinical symptoms in affected individuals include headache, nausea, hematuria, flank or low back pain, nocturia, dysuria, hypertension, and an enlarging abdomen.1,5 Rupture of a berry aneurysm may occasionally be a presenting finding in a patient without obvious renal disease. Hematuria may be the presenting symptom in childhood6 or cysts may be detected serendipitously during investigations for other anomalies. Physical findings on examination include hypertension, peripheral edema, abdominal tenderness, hepatomegaly, and palpable or enlarged kidneys. Routine laboratory studies and urinalysis may not distinguish affected from unaffected family members, except when uremia is present. Abdominal ultrasound studies are able to identify enlargement of the kidneys and cysts in the kidneys, liver, and other organs and are probably more reliable and cost-effective than excretory pyelography with tomograms or radionuclide studies in confirming the diagnosis.3,7 When deformation of the pelvicaliceal system is found on a simple IV urography and ADPKD suspected, computed tomography scan is effective in diagnosis, especially in adolescents and young adults.8,9 The number of cysts deemed sufficient for diagnosis is debatable. Identification of five or more has been considered diagnostic of ADPKD in adults,3 but Bear et al.7 suggested that ultrasound demonstration of a single cyst bilaterally or more than one cyst unilaterally in an at-risk patient was sufficient. In children from ADPKD kindreds, one cyst is suggestive of the diagnosis because of the low incidence of acquired cysts in this age group.10 Conversely, more stringent criteria are needed in older individuals as simple cysts become more common with age. Ravine et al.11 used the screening criterion of bilateral cysts with at least two in one kidney and found it to have a sensitivity of

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89% in those 15 to 29 years and 100% in those over 30 years. However, they suggested that four cysts in each kidney was an appropriate criterion for patients over 60 years old. In general, the availability of better imaging techniques has lead to earlier diagnosis (mean age ~20 years) and greater penetrance at younger ages.12 ADPKD occasionally presents in fetal or infant life with large cystic kidneys and oligohydramnios, and thus may mimic autosomal recessive polycystic kidney disease or multicystic dysplasia. Infantile presentation of ADPKD is distinguished from these conditions by a combination of the lack of hepatic fibrosis; histology of the kidney with rounded cysts located in the nephrons, tubules, and glomeruli; and evidence of autosomal dominant inheritance from family history or diagnostic investigation of the parents.13–15 Despite the earlier presentation and more severe progression observed in families with symptomatic children, most map to the same gene loci responsible for adult-onset cases.16 Although prenatal diagnosis of renal cysts has been reported in at-risk fetuses, this usually occurs at later stages of gestation.17 Presentation in the fetal period with enlarged, cystic kidneys and oligohydramnios sequence is associated with a grim prognosis.10,17–19 Sedman et al.10 used history, physical examination, and ultrasonography to evaluate 154 children less than 18 years of age from 83 ADPKD families. Including children with a single renal cyst as affected, ADPKD was identifiable in childhood in as many as two-thirds of affected individuals. Although children diagnosed under 1 year of age were more likely to have deterioration of renal function early in life, asymptomatic individuals diagnosed by childhood screening did not appear to have a different clinical course from other family members. Parental investigations, especially with abdominal ultrasound, would be indicated prior to genetic counseling following the birth of a child with renal cysts. In contrast to adults, children with ADPKD present with unilateral cysts in 17% of cases. Also, the enlargement of the kidneys can be asymmetric in this age group, sometimes leading to diagnostic difficulties.20 Complications of ADPKD are common, with hypertension occurring in approximately 70% of symptomatic patients.1 Pain, described as a pulling or tugging discomfort, is the most common presenting symptom and appears to correlate with the size of the cysts and renal weight.5 Severe and persistent pain may indicate bleeding, infection, or malignancy. Gross hematuria can result from trauma to the kidneys or spontaneous rupture of the cysts. Renal stones are found in 5–15% of patients21 and can predispose to infection. Infection is of particular concern because it may hasten the progression of cystic deterioration of the kidney. Abscess formation within a cyst can be difficult to diagnose and treat. Renal tumors including benign adenomas, hypernephroma, and renal cell carcinoma have been reported,5,22–24 but the precise odds ratio for neoplasia, especially in asymptomatic individuals, is unclear. As carcinoma presents at a younger age than usual in ADPKD, it is likely that the renal pathology does increase risk. Ascites can develop in association with very large kidneys. Azotemia and renal failure occur as cystic involvement increases. In the past, the lifespan for symptomatic individuals was significantly reduced. However, since the availability of hemodialysis and renal transplantation, outcome for patients has improved considerably. Although cystic changes are seen in the liver in approximately 50% of patients with ADPKD and increase with age and severity of renal disease,25 they are not as severe as in the recessive form. Portal hypertension and hepatic fibrosis are unusual in ADPKD but have

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been seen in some families.26 Portal hypertension may result due to vascular compression by large cysts. Infection of hepatic cysts is uncommon unless there is end-stage renal failure.25,27,28 Cardiovascular abnormalities other than hypertension are also increased in this disorder. In one study, mitral valve prolapse was seen in 26% of patients, compared to 14% of unaffected family members and 2% of controls.29 Patients also have a higher prevalence of mitral, tricuspid, and aortic valve regurgitation and tricuspid valve prolapse. Berry aneurysms of the cerebral arteries are reported in 10–35% of affected individuals.1–3,30 Rupture of these aneurysms is a major contributor to mortality, causing death in approximately 10% of cases, and are the primary cause of death in some families. Abdominal aortic aneurysms are also more common, especially in patients requiring hemodialysis.31 Cystic involvement of the pancreas, spleen, lungs, ovaries, uterus, and esophagus may occur.2,32 Other problems that may occur more frequently in ADPKD, especially in patients receiving hemodialysis, are inguinal hernia, hiatal hernia, gastroesophageal reflux, and diverticulosis and diverticulitis of the colon.3,5,33 The differential diagnosis includes autosomal recessive polycystic kidney disease, especially when the disorder presents early. Similarly, late presentation of ARPKD may mimic the dominant form. The two conditions can be distinguished clinically on the basis of the course of the disease, the type of liver and other organ involvement, biopsy, family history, and the results of diagnostic renal ultrasonography testing of close relatives. Molecular analysis is also feasible in some circumstances. Patients on renal dialysis can develop renal cysts that are difficult to distinguish diagnostically from ADPKD.34–36 Medullary sponge kidney (Section 28.8) can occur in ADPKD and affected patients should be considered as ADPKD cases with predominantly medullary involvement, as is seen in the earlier stages of disease.2,37–39 Thus, investigation of medullary sponge kidney should include diagnostic evaluation of other family members for ADPKD. Several disorders have been described in association with ADPKD. In some cases, such as Caroli disease,40 congenital hepatic fibrosis,41 and aneurysms of the basal cerebral arteries,42 these reflect the pleiotropic effects of the gene mutations. In others, such as a-thalassemia,6,43 tuberous sclerosis,44–46 and a specific connective tissue disorder,47 the association is due to close linkage of these conditions with one of the known ADPKD loci. ADPKD has also been seen with myotonic dystrophy,48 hyperparathyroidism with jaw tumors,49 Peutz-Jeghers disease,50 spherocytosis,47 lattice corneal dystrophy,51 Hadju-Cheney syndrome,52,53 oro-facial-digital syndrome type I,54–56 and limb deficiencies.57 While some of these concordances may be due to related pathogenetic mechanisms, others may be chance findings due to the relatively high frequency of ADPKD. The kidneys of ADPKD patients can be of normal size to markedly increased in size, depending on the degree of cystic change. Cysts, which are usually round and unilocular, are grossly visible in both the cortex and the medulla intermixed with normal renal structures. With time, the normal reniform shape is obscured by the cysts and the corticomedullary demarcation is lost (Fig. 28-7). The renal papillae may not be identifiable and the pelvicaliceal region is distorted.9 The cysts can range in size from a few millimeters to several centimeters. As the cysts get larger and more extensive, symptoms ensue. One kidney may have more cysts than the other, but usually there is bilateral involvement. As the cysts increase in size, they compress normal parenchyma, interfering with nephron function and causing localized obstructions.

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Fig. 28-7. Autosomal dominant polycystic kidney disease. A. Gross appearance of the kidney at autopsy in a 50-year-old man. B. Liver from the same patient. (Reprinted with permission from Jennette JC, Olson JL, Schwartz MM, et al., eds.: Heptinstall’s Pathology of the Kidney, ed 5. Lippincott Williams & Wilkins, Philadelphia, 1998.)

This compression is likely the cause of renal failure when it occurs. The cysts are lined by cuboid epithelium and usually contain strawcolored fluid that can become hemorrhagic following trauma or infection. The intervening renal parenchyma is normal or shows changes of nephrosclerosis or interstitial nephritis. On microdissection, collecting tubules are abnormally branched, which Potter58 hypothesized could only occur during early development. The cysts can arise in any portion of the nephrons or collecting tubules and usually retain continuity with the tubule of origin.9 However, these connections may be lost in larger cysts, and they are not necessarily apparent in scanning electron micrographs.59 Etiology and Distribution

The incidence of ADPKD has been estimated to be between one in 1000 and one in 4000, depending on the population studied and the inclusion of family members as well as index cases.1,2,60–63 In autopsy series, ADPKD occurs in approximately one in 500 cases.64 Approximately 6% of patients entering dialysis and transplantation programs are ADPKD patients.9 ADPKD is a genetically heterogeneous autosomal dominant disorder, with at least three loci potentially involved.65 Prior to gene mapping, the mutation rate for ADPKD was calculated to be 6.9x105 alleles/generation, given an estimated incidence of one in 1000.12 This may well be an overestimate given genetic heterogeneity and the probability that low penetrance alleles and phenocopies exist. The most frequent locus involved in ADPKD, designated PKD1 (OMIM 173900), is situated at 16p13.3 and accounts for 85% of families. PKD1 is closely linked to the ahemoglobin gene complex and phosphoglycerate kinase. The complete structure of the PKD1 gene and its associated protein was reported in 1995.66 The 14.5 kb transcript codes for a 4304 amino

acid protein, called polycsytin 1, with a novel arrangement of domains. There is evidence for an alternatively spliced form that contains an additional exon in intron 16. If this exon is excluded, the reading frame is changed and a smaller protein is produced. Large deletions of the gene disrupt both forms of the protein and may lead to more severe manifestation of disease.67 In one patient with a large deletion of 16p, both severe infantile onset PKD1 and TSC2 (tuberous sclerosis 2) were present.68 However, not all deletions cause early onset of PKD1.69 The second locus for ADPKD is on chromosome 4q21-q23 (OMIM 173910). PKD2 accounts for a further 10% of patients. This gene codes for a protein called polycystin 2. Polycystin 1 and 2 are integral membrane proteins that localize to fetal and adult renal tubules and are also expressed in abundance in the brain.70 They associate and function through a common signaling pathway that is apparently necessary for normal tubulogenesis. They are involved in regulation of tubular epithelial proliferation.71 In ADPKD, an underlying pathogenetic mechanism may be epithelial hyperplasia. The cells proliferate and become blocked in an immature, undifferentiated stage. The tubule may then expand to accommodate the abundance of lining cells.72 The products of each gene modify those of the other, with PKD1 requiring PKD2 for stable expression. TSC2 and PAX2 have been recognized to be additional modifiers. The development of individual cysts is believed to be due to somatic mutations that remove the normal function of the remaining wild type allele. The potential for a ‘‘second hit’’ mechanism was first postulated in 1992.73 Later it was shown that individual cysts in PKD1 are monoclonal with loss of the normal haplotype.74,75 These studies suggested that there was an unusual 2.5 kb polypyrimadine tract in intron 24 that could lead to errors in transcription and defective repair, predisposing to somatic mutation. Somatic mutations in cysts were also documented in patients with PKD2.76 One Newfoundland family was found to be segregating both PKD1 and PKD2 independently; two individuals who carried both mutations had more severe renal disease than those with either single mutation.77 There are a few families that do not appear to map to either chromosome 16 or chromosome 4.78,79 Thus, other PKD loci potentially exist. However, some instances of lack of linkage may be due to genotyping errors, sample mix-ups, nonpaternity, misdiagnosis, or independent mutations for PKD1 or 2 segregating in the same family. Prognosis, Prevention, and Treatment

ADPKD-affected individuals from an extended family tend to have a similar age of onset and clinical course,1 but there are exceptions. Most notable are those families with severely affected fetuses and infants with the majority of affected family members presenting in adulthood. Presumably, modifying factors other than the mutation itself are responsible for the variation in age of onset. Peral et al.80 describe one three-generation family in which a stable nonsense mutation was segregating, but affected individuals had very different phenotypes, including infantile onset. Although penetrance is essentially complete by 80 years,1 many asymptomatic patients have normal lifespans.62 With the availability of molecular testing, it has become apparent that PKD1 is a somewhat more severe disorder than PKD2. Parfrey et al.81 found the prevalence of renal impairment among individuals with renal cysts in PKD1 to be 4% in those less than 20 years old, 11% in those 20 to 39 years, and 69% in individuals aged 40 to 59 years. Of affected individuals over 60 years of age, 86% had renal

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impairment. Although renal disease is usually considered more severe in PKD1, Ryynanen et al.82 reported a large four-generation Finnish family with all the affected members being asymptomatic and none developing renal failure. The mutation was closely linked to the a-globin cluster, so it was concluded to be allelic to PKD1. It is important to note that cumulative survival rates show no difference between males and females with respect to the development of end-stage renal disease.83 However, the disease may proceed more rapidly in males, with the onset of renal failure on average 5 to 6 years earlier than in females whose families did not map to the PKD1 locus. Bear et al.7 found that individuals have a longer mean age of survival to end-stage renal disease or death (68.7 years versus 56.3 years for PKD1). Ravine et al.84 also found that non-PKD1 patients lived longer (median survival 71.5 years versus 56.0 years for those with PKD1). Onset of kidney cysts, evident by ultrasonography, is later in non-PKD1 patients, with only 2–3% of cases aged 30 to 39 years having cysts versus 55–60% of those at risk for PKD1.7 Affected PKD2 individuals, thus, tend to be diagnosed later and have fewer cysts at diagnosis.84 They also have a lower probability of reaching end-stage renal failure.85 Unlike PKD1, females with PKD2 have greater mean length of survival than affected males. Despite the milder phenotype, however, PKD2 cannot be considered a benign disease.86 The most frequent causes of death due to complications to ADPKD are renal failure (uremia), cerebral aneurysm, and heart failure associated with chronic hypertension.1,2 The renal prognosis is worse in individuals whose unaffected parent has essential hypertension, indicating a multifactorial component.87 PKD2 patients are less likely to develop hypertension.84 Early detection, careful medical management, and genetic counseling may improve outcome in affected family members. Linkage studies can be done on families with PDK1 for prenatal diagnosis and/or presymptomatic carrier testing with a reliability exceeding 95% in informative families,88 and mutational analysis is potentially feasible for both PKD1 and PKD2 in select cases. Ethical issues surrounding presymptomatic carrier detection in healthy children and family members not wishing to know their carrier status should be considered before investigating a family. Sujansky et al.89 studied attitudes in affected and at-risk individuals from 107 families with ADPKD using a questionnaire design. It was found that 95% of individuals would use gene testing for themselves, 88% would use testing for offspring, and 65% of individuals of reproductive age would use prenatal diagnosis. However, only a minority of family members would terminate a pregnancy if the fetus was affected with ADPKD. In another study involving 100 families,90 the utilization of presymptomatic ultrasound screening was high among at-risk individuals, and many stated that the diagnosis had influenced their reproductive plans. However, the demand for prenatal diagnosis was very low. Despite the fact that some cases present early, prenatal diagnosis by ultrasound is not reliable.17 Most patients with ADPKD can be medically managed with careful attention to their risk for hypertension, urinary tract infections, nephrolithiasis, renal failure, and intracranial aneurysms.91 Clinical problems that may require surgical intervention include severe bleeding, uncontrollable infection, symptomatic stone disease not amenable to lithotripsy, malignancy, and uncontrollable hypertension. When renal failure develops, it can be managed with hemodialysis and with kidney transplantation. Transplantation will not prevent other complications of ADPKD, most notably berry aneurysm of the cerebral arteries. It is also very

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important to note that molecular testing should be used if transplantation from family members less than 30 years of age is considered, as cysts may occasionally not be found on ultrasound in this age group.92 References (Autosomal Dominant Polycystic Kidney Disease) 1. Dalgaard OZ: Bilateral polycystic disease of the kidneys: a follow-up of two-hundred and eighty-four patients and their families. Acta Med Scand 158 (Suppl. 328):1, 1957. 2. Zerres K, Volpel MC, Weiss H: Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 68:104, 1984. 3. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 329:332, 1993. 4. Hatfield PM, Pfister RC: Adult polycystic disease of the kidneys (Potter type 3). JAMA 222:1527, 1972. 5. Suki WN: Polycystic kidney disease. Kidney Int 22:571, 1982. 6. Kaplan BS, Rabin I, Nogrady MB, et al.: Autosomal dominant polycystic renal disease in children. J Pediatr 90:782, 1977. 7. Bear JC, McManamon P, Morgan J, et al.: Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling. Am J Med Genet 18:45, 1984. 8. Levine E, Grantham JJ: The role of computed tomography in the evaluation of adult polycystic kidney disease. Am J Kidney Dis 1:99, 1981. 9. Risdon RA, Woolf AS: Developmental Defects and Cystic Diseases of the Kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 10. Sedman A, Bell P, Manco-Johnson M, et al.: Autosomal dominant polycystic kidney disease in childhood: a longitudinal study. Kidney Int 31:1000, 1987. 11. Ravine D, Gibson RN, Walker RG, et al.: Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 343:824, 1994. 12. Dobin A, Kimberling WJ, Pettinger W, et al.: Segregation analysis of autosomal dominant polycystic kidney disease. Genet Epidemiol 10: 189, 1993. 13. Lieberman E, Salinas-Madrigal L, Gwinn JL, et al.: Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine (Baltimore) 50:277, 1971. 14. Zerres K, Rudnik-Schoneborn S, Deget F: Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft fur Padiatrische Nephrologie). J Med Genet 30:583, 1993. 15. Kaplan BS, Kaplan P, Rosenberg HK, et al.: Polycystic kidney diseases in childhood. J Pediatr 115:867, 1989. 16. Gal A, Wirth B, Kaariainen H, et al.: Childhood manifestation of autosomal dominant polycystic kidney disease: no evidence for genetic heterogeneity. Clin Genet 35:13, 1989. 17. Journel H, Guyot C, Barc RM, et al.: Unexpected ultrasonographic prenatal diagnosis of autosomal dominant polycystic kidney disease. Prenat Diagn 9:663, 1989. 18. Fryns JP, Vandenberghe K, Moerman F: Mid-trimester ultrasonographic diagnosis of early manifesting ‘‘adult’’ form of polycystic kidney disease. Hum Genet 74:461, 1986. 19. Pretorius DH, Lee ME, Manco-Johnson ML, et al.: Diagnosis of autosomal dominant polycystic kidney disease in utero and in the young infant. J Ultrasound Med 6:249, 1987. 20. Fick-Brosnahan G, Johnson AM, Strain JD, et al.: Renal asymmetry in children with autosomal dominant polycystic kidney disease. Am J Kidney Dis 34:639, 1999. 21. Amar AD, Das S, Egan RM: Management of urinary calculous disease in patients with renal cysts: review of 12 years of experience in 18 patients. J Urol 125:153, 1981.

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22. Ng RC, Suki WN: Renal cell carcinoma occurring in a polycystic kidney of a transplant recipient. J Urol 124:710, 1980. 23. Gardner KD Jr, Evan AP: Cystic kidneys: an enigma evolves. Am J Kidney Dis 3:403, 1984. 24. Gregoire JR, Torres VE, Holley KE, et al.: Renal epithelial hyperplastic and neoplastic proliferation in autosomal dominant polycystic kidney disease. Am J Kidney Dis 9:27, 1987. 25. Harris RA, Gray DW, Britton BJ, et al.: Hepatic cystic disease in an adult polycystic kidney disease transplant population. Aust N Z J Surg 66:166, 1996. 26. Ellis DS, Putschar WGJ: Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 16-1968. N Engl J Med 278:899, 1968. 27. Grunfeld JP, Albouze G, Jungers P, et al.: Liver changes and complications in adult polycystic kidney disease. Adv Nephrol Necker Hosp 14:1, 1985. 28. Levine E, Cook LT, Grantham JJ: Liver cysts in autosomal-dominant polycystic kidney disease: clinical and computed tomographic study. AJR Am J Roentgenol 145:229, 1985. 29. Hossack KF, Leddy CL, Johnson AM, et al.: Echocardiographic findings in autosomal dominant polycystic kidney disease. N Engl J Med 319: 907, 1988. 30. Levey AS, Pauker SG, Kassirer JP: Occult intracranial aneurysms in polycystic kidney disease. When is cerebral arteriography indicated? N Engl J Med 308:986, 1983. 31. Chapman JR, Hilson AJ: Polycystic kidneys and abdominal aortic aneurysms. Lancet 1:646, 1980. 32. Heinonen PK, Vuento M, Maunola M, et al.: Ovarian manifestations in women with autosomal dominant polycystic kidney disease. Am J Kidney Dis 40:504, 2002. 33. Scheff RT, Zuckerman G, Harter H, et al.: Diverticular disease in patients with chronic renal failure due to polycystic kidney disease. Ann Intern Med 92:202, 1980. 34. Ishikawa I, Saito Y, Onouchi Z, et al.: Development of acquired cystic disease and adenocarcinoma of the kidney in glomerulonephritic chronic hemodialysis patients. Clin Nephrol 14:1, 1980. 35. Bommer J, Waldherr R, van Kaick G, et al.: Acquired renal cysts in uremic patients—in vivo demonstration by computed tomography. Clin Nephrol 14:299, 1980. 36. Feiner HD, Katz LA, Gallo GR: Acquired cystic disease of kidney in chronic dialysis patients. Urology 17:260, 1981. 37. Nemoy NJ, Forsberg L: Polycystic renal disease presenting as medullary sponge kidney. J Urol 100:407, 1968. 38. Hockley BJ, Robinson MF, Tucker WG, et al.: Case report. Combined polycystic and medullary sponge renal disease. Australas Radiol 22:315, 1978. 39. Abreo K, Steele TH: Simultaneous medullary sponge and adult polycystic kidney disease: the need for accurate diagnosis. Arch Intern Med 142:163, 1982. 40. Jordon D, Harpaz N, Thung SN: Caroli’s disease and adult polycystic kidney disease: a rarely recognized association. Liver 9:30, 1989. 41. Tazelaar HD, Payne JA, Patel NS: Congenital hepatic fibrosis and asymptomatic familial adult-type polycystic kidney disease in a 19year-old woman. Gastroenterology 86:757, 1984. 42. Poutasse EF, Gardner WJ, McCormack LJ: Polycystic kidney disease and intracranial aneurysm. JAMA 154:741, 1954. 43. Vinet MC, Dode C, Pascal O, et al.: Autosomal dominant polycystic kidney disease and alpha-4.2 thalassemia in a Caucasian family. Hum Genet 83:55, 1989. 44. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium. Cell 77:881, 1994. 45. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet 61:843, 1997. 46. Kleymenova E, Ibraghimov-Beskrovnaya O, Kugoh H, et al.: Tuberindependent membrane localization of polycystin-1: a functional link

47.

48. 49.

50.

51.

52. 53.

54.

55.

56.

57.

58. 59.

60.

61. 62.

63.

64. 65. 66.

67.

68.

between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell 7:823, 2001. Chanmugam D, Rasaretnam R, Karunaratne KE: Genetic intelligence: hereditary spherocytosis and polycystic disease of the kidneys in four members of a family. Am J Hum Genet 23:66, 1971. Emery AE, Oleesky S, Williams RT: Myotonic dystrophy and polycystic disease of the kidneys. J Med Genet 4:26, 1967. Teh BT, Farnebo F, Kristoffersson U, et al.: Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J Clin Endocrinol Metab 81:4204, 1996. Kieselstein M, Herman G, Wahrman J, et al.: Mucocutaneous pigmentation and intestinal polyposis (Peutz-Jeghers syndrome) in a family of Iraqi Jews with polycystic kidney disease. With a chromosome study. Isr J Med Sci 5:81, 1969. Whitt JW, Wood BC, Sharma JN, et al.: Adult polycystic kidney disease and lattice corneal dystrophy: occurrence in a single family. Arch Intern Med 138:1167, 1978. Kaplan P, Ramos F, Zackai EH, et al.: Cystic kidney disease in HajduCheney syndrome. Am J Med Genet 56:25, 1995. Fryns JP, Stinckens C, Feenstra L: Vocal cord paralysis and cystic kidney disease in Hajdu-Cheney syndrome. Clin Genet 51:271, 1997. Harrod MJ, Stokes J, Peede LF, et al.: Polycystic kidney disease in a patient with the oral-facial-digital syndrome—type I. Clin Genet 9:183, 1976. Donnai D, Kerzin-Storrar L, Harris R: Familial orofaciodigital syndrome type I presenting as adult polycystic kidney disease. J Med Genet 24:84, 1987. Feather SA, Woolf AS, Donnai D, et al.: The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3. Hum Mol Genet 6:1163, 1997. Turco AE, Padovani EM, Chiaffoni GP, et al.: Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations. J Med Genet 30:419, 1993. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. Grantham JJ, Geiser JL, Evan AP: Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31:1145, 1987. Iglesias CG, Torres VE, Offord KP, et al.: Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis 2:630, 1983. Davies F, Coles GA, Harper PS, et al.: Polycystic kidney disease reevaluated: a population-based study. Q J Med 79:477, 1991. Simon P, Le Goff JY, Ang KS, et al.: [Epidemiologic data, clinical and prognostic features of autosomal dominant polycystic kidney disease in a French region]. Nephrologie 17:123, 1996. Higashihara E, Nutahara K, Kojima M, et al.: Prevalence and renal prognosis of diagnosed autosomal dominant polycystic kidney disease in Japan. Nephron 80:421, 1998. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. Wu G, Somlo S: Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab 69:1, 2000. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. The International Polycystic Kidney Disease Consortium. Cell 81:289, 1995. Peral B, San Millan JL, Ong AC, et al.: Screening the 3' region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations. Am J Hum Genet 58:86, 1996. Brook-Carter PT, Peral B, Ward CJ, et al.: Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease— a contiguous gene syndrome. Nat Genet 8:328, 1994.

Urinary Tract 69. Smulders YM, Eussen BH, Verhoef S, et al.: Large deletion causing the TSC2-PKD1 contiguous gene syndrome without infantile polycystic disease. J Med Genet 40:E17, 2003. 70. Ward CJ, Turley H, Ong AC, et al.: Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney. Proc Natl Acad Sci U S A 93:1524, 1996. 71. Grantham JJ, Calvet JP: Polycystic kidney disease: in danger of being X-rated? Proc Natl Acad Sci U S A 98:790, 2001. 72. Wilson PD, Burrow CR: Autosomal dominant polycystic kidney disease: cellular and molecular mechanisms of cyst formation. Adv Nephrol Necker Hosp 21:125, 1992. 73. Reeders ST: Multilocus polycystic disease. Nat Genet 1:235, 1992. 74. Qian F, Watnick TJ, Onuchic LF, et al.: The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87:979, 1996. 75. Brasier JL, Henske EP: Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-offunction model for cyst pathogenesis. J Clin Invest 99:194, 1997. 76. Torra R, Badenas C, San Millan JL, et al.: A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2. Am J Hum Genet 65:345, 1999. 77. Pei Y, Paterson AD, Wang KR, et al.: Bilineal disease and transheterozygotes in autosomal dominant polycystic kidney disease. Am J Hum Genet 68:355, 2001. 78. Daoust MC, Reynolds DM, Bichet DG, et al.: Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25:733, 1995. 79. De Almeida S, de Almeida E, Peters D, et al.: Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family. Hum Genet 96:83, 1995. 80. Peral B, Ong AC, San Millan JL, et al.: A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1). Hum Mol Genet 5:539, 1996. 81. Parfrey PS, Bear JC, Morgan J, et al.: The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N Engl J Med 323:1085, 1990. 82. Ryynanen M, Dolata MM, Lampainen E, et al.: Localisation of a mutation producing autosomal dominant polycystic kidney disease without renal failure. J Med Genet 24:462, 1987. 83. Simon P: Prognosis of autosomal dominant polycystic kidney disease. Nephron 71:247, 1995. 84. Ravine D, Walker RG, Gibson RN, et al.: Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease. Lancet 340:1330, 1992. 85. Deltas CC: Mutations of the human polycystic kidney disease 2 (PKD2) gene. Hum Mutat 18:13, 2001. 86. Hateboer N, Dijk MA, Bogdanova N, et al: Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 353:103, 1999. 87. Geberth S, Stier E, Zeier M, et al.: More adverse renal prognosis of autosomal dominant polycystic kidney disease in families with primary hypertension. J Am Soc Nephrol 6:1643, 1995. 88. Kimberling WJ, Fain PR, Kenyon JB, et al.: Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J Med 319:913, 1988. 89. Sujansky E, Kreutzer SB, Johnson AM, et al.: Attitudes of at-risk and affected individuals regarding presymptomatic testing for autosomal dominant polycystic kidney disease. Am J Med Genet 35:510, 1990. 90. Hodgkinson KA, Kerzin-Storrar L, Watters EA, et al.: Adult polycystic kidney disease: knowledge, experience, and attitudes to prenatal diagnosis. J Med Genet 27:552, 1990. 91. Pirson Y: Recent advances in the clinical management of autosomaldominant polycystic kidney disease. QJM 89:803, 1996. 92. Coto E, Aguado S, Alvarez J, et al.: Genetic and clinical studies in autosomal dominant polycystic kidney disease type 1 (ADPKD1). J Med Genet 29:243, 1992.

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28.6 Renal Dysplasia Definition

Renal dysplasia is the aberrant development of renal parenchyma due to abnormal metanephric differentiation characterized histologically by the presence of primitive ducts and nests of metaplastic cartilage.1,2 It may be diffuse, segmental, or focal. Anomalies in both lobar architecture and differentiation of ducts and tubules may occur. Cysts may or may not be present and may vary in size. Different terms have been used to describe specific forms of dysplastic kidneys, including Potter type IIA kidney, multicystic dysplasia, multicystic kidney, and multicystic dysplastic kidney for kidneys with multiple cysts that are normal or enlarged in size; Potter type IIB kidney, dysgenetic kidney, aplastic kidney, solid cystic dysplasia, or rudimentary kidney for small kidneys with few or small cysts; renal aplasia for severe dysplasia with rudimentary nubbins of disorganized tissue with dysplastic metanephric elements; and segmental dysplasia for dysplasia of a part of the kidney, usually the upper pole, associated with renal or ureteral duplication. All these forms are grouped together as renal dysplasia because they are believed to reflect different manifestations of the same pathogenic process. Renal anomalies that are not included in this definition are renal hypoplasia, oligonephronia, oligomeganephronia, polycystic kidneys, micromulticystic kidneys, medullary sponge kidneys, medullary cystic disease, nephronophthisis, obstructive nephropathy, and reflux nephropathy. Diagnosis

Renal dysplasia is the most common urinary tract abnormality in children and the most common cause of an abdominal mass at birth.3 It is the most common form of cystic renal disease.4 The clinical signs and symptoms and age of presentation of patients are usually determined by the severity of renal dysplasia or of associated major congenital anomalies. Severe bilateral renal dysplasia presents prenatally in a similar fashion to renal agenesis (Section 28.1). Newborns typically have Potter facies and other signs of oligohydramnios sequence and die in the neonatal period from respiratory insufficiency. Less severe renal dysplasia, including single cysts and unilateral anomalies that may have remained asymptomatic, are now being detected with prenatal ultrasound. Clinical symptoms in infants and children include anuria, oliguria, polyuria with polydipsia, hematuria, hypertension, uremia, back pain, growth delay, chronic or progressive renal failure, and other symptoms of renal dysfunction.5 Unilateral cases are often asymptomatic, but may cause pain, abdominal distension, or gastrointestinal tract obstruction.6 Segmental dysplasia may be clinically silent. As renal dysplasia is often one component of a pattern of anomalies, it may be ascertained during investigation of defects in other organ systems. Defects in other parts of the urinary tract, and ureteral defects in particular, are present in over 90% of patients with renal dysplasia4,7 and indicate that this is a disorder of the entire tract rather than the kidney alone. Ureteral atresia is usually seen when the whole kidney is dysplastic; ureteral duplication may give rise to segmental forms.8 Renal dysplasia may be found in ectopic kidneys9,10 or one limb of a horseshoe kidney.11 When only one kidney is dysplastic, the other

1206

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kidney and ureter may be absent12 or show milder changes such as ureteral stenosis. Other anomalies of the contralateral side include renal hypoplasia, hydronephrosis, ureterocele, or ectopic ureters. Genital anomalies are also common, including absence of the vas deferens,13 testicular cysts,11,14 penile agenesis,15 imperforate hymen,16 Gartner duct cyst,17,18 and penoscrotal transposition. Anomalies of noncontiguous structures have been reported in approximately 35–75% of patients with renal dysplasia.19–22 Many of these anomalies are one component of over 80 syndromes and multiple congenital anomaly disorders (see Tables 28-6 to 28-11 and 28-18). Associated defects frequently associated with renal dysplasia include cardiovascular anomalies,23 central nervous system abnormalities (anencephaly, hydrocephalus, iniencephaly, spina bifida, and encephalocele),24 diaphragmatic hernia, cleft palate, microphthalmia, duodenal stenosis, imperforate anus, tracheoesophageal fistula,25 and radial ray defects. In one autopsy study of 36 cases, musculoskeletal anomalies were seen in 50%, gastrointestinal defects in 36%, cardiovascular anomalies in 28%, and central nervous system abnormalities in 17%.21 Cystic changes of the liver, pancreas, or other parenchymatous organs are not usually seen with renal dysplasia, though congenital hepatic fibrosis occasionally occurs.26 Chromosome abnormalities are found in approximately 10–30% of fetuses diagnosed with multicystic renal dysplasia prenatally.19,20 Renal ultrasound is useful for evaluating patients with suspected structural renal anomalies including renal dysplasia and is especially useful for serial investigations (Table 28-16). Serial ultrasounds often show regression of a multicystic dysplastic kidney to the point of its apparent disappearance, where it resembles unilateral renal agenesis.27–30 Doppler ultrasound may be used to investigate renal artery function, which is often grossly abnormal with renal dysplasia.31 While intravenous pyelography (IVP) is commonly used to study the anatomy of the upper urinary tract, it is unreliable when the kidney is severely dysplastic. Determination of renal function based on serum creatinine, urea, electrolytes, and creatinine clearance is recommended in patients with renal dysplasia as they often have impairment of urinary concentration and acidification.32 Dysplastic kidneys may be increased or decreased in size, and reniform or misshapen. There is poor delineation of the renal pyramids. The cystic component is variable but frequently a prominent feature (Fig. 28-8). Cysts vary in size and are usually large in the central cortex and smaller in the tubes, ducts, and glomeruli. Renal dysplasia can be distinguished from other forms of renal dysgenesis by histology. The key elements are disorganization of normal renal architecture with abnormal ductal and mesenchymal elements, a variable increase in connective tissue, cartilaginous metaplasia, persistent embryonic nephrons and ducts, and variable cystic degeneration of cortical and medullary components.1,2 The primitive ducts in the medulla appear to represent persistent incompletely differentiated ureteric bud branches. As these sometimes form nodes, it is suggested that they may derive from a single branching stem. The bars of cartilage indicate abnormal differentiation of the metanephric blastema. There may be sites of extramedullary hematopoiesis and/or nodular blastoma (nephroblastomatosis).8 Microdissection of Potter type II kidneys containing multiple cysts has shown similar abnormalities.33 There is a marked reduction in the number of tubules derived from the ureteral bud; tubules can be of normal to increased size (1–2 mm). Almost all tubules terminate in cysts, with the wider tubules usually having larger cysts. Tubules may be kinked or looped. Tubules in the

kidney usually communicate with the cysts. Nephrons are reduced in number and are always abnormal. The intrarenal blood supply is abnormal due to abnormal branching with failure to form a normal capillary network. Etiology and Distribution

The incidence of renal dysplasia is difficult to determine as some cases may be asymptomatic or the defect may be grouped with renal agenesis. This is not surprising because, as noted earlier in Section 28.1, renal a/dysplasia represents a spectrum of diseases. One study found the incidence of Potter sequence due to agenesis or dysplasia of one or both kidneys to be one in 6369.34 This is compatible with a population-based study from Manitoba that reported a birth prevalence of renal cysts of one of 1824 total births,23 with one in 3226 births due to cystic dysplasia. Autopsy data indicate that this is the most common urologic manifestation seen, representing 6% of infant autopsies.21 Mir et al.25 found 65 cases (1%) in a consecutive series of autopsies that included infants and children. Barakat and Drougas found a rate of one in 626 in their autopsy series.35 In series of total populations, approximately 75% of cases are unilateral,36 but this drops to 50% in autopsy series.35 As with renal agenesis, the left side is preferentially involved.37 Approximately twice as many males as females are affected,38,39 but affected females are more likely to have bilateral involvement and syndromic disorders, including chromosomal defects.39 Clearly, there is etiologic heterogeneity for renal dysplasia. It may be due to a single error of embryogenesis or be a component of a wide range of monogenic, chromosomal, and teratogenic syndromes. Although isolated dysplasia is usually sporadic, familial recurrence with autosomal dominant40–42 and autosomal recessive43–45 patterns predominating has been reported. Renal ultrasound examinations of first-degree and, when indicated, second-degree relatives are necessary to exclude variable expression of an autosomal dominant disorder46 such as hereditary a/dsyplasia34 or Mu¨llerian duct anomalies with hydronephrosis or other renal anomalies.47,48 There are two main theories for the underlying pathogenesis in renal dysplasia.49 The first involves impairment of ampullae and subsequently interference of nephron induction by the metanephric blastema. Impaired ampullary division and induction of the metanephros could be caused by kinking or narrowing of the developing ureteric bud, resulting in embryonic obstruction at a much earlier stage than seen in reflux nephropathy, which occurs after the kidney is formed. The second theory suggests an earlier embryonic disturbance impeding communication between the urethral bud and the metanephric blastema. Complete failure to have an inductive interaction results in renal agenesis. Disturbances occurring immediately after union of the ureteric bud and metanephric blastema would result in renal dysplasia. The first hypothesis provides understanding for the severe renal dysplasia seen in the urethral obstruction sequence, the urorectal septum sequence, and other disorders with obstruction of the lower urinary tract and reflux nephropathy during early nephrogenesis. It also explains the high incidence of ipsilateral ureteral atresia in unilateral dysplasia and the finding of bilateral ureteral defects or lower tract obstruction in bilateral cases. The degree of abnormality would be dependent on the timing in renal embryogenesis and potentially could give rise to more diffuse cortical cystic changes, with reduction in the number of nephrons and rudimentary medullary development without obstruction.

Table 28-18. Disorders with renal dysplasia Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Acrorenal disorders —See Table 28-6 for conditions with limb deficiency anomalies and renal dysplasia Al-Gazali optic nerve colobomata-renal anomalies-arthrogryposis70

Optic nerve colobomata, loose joints, arthrogryposis (overlap with renal-colobomata syndrome)

Cystic dysplasia, dilated renal pelvis, hydronephrosis, calculi

Uncertain AD or AR with manifesting heterozygotes

Bardet-Biedl71,72

Mental retardation, retinitis pigmentosa, hypogonadism, polydactyly, obesity, biliary atresia, hepatic fibrosis

Renal agenesis, hypoplasia and dysplasia; caliceal cysts, diverticula, clubbing; hydronephrosis; fetal lobulations; nephritis; urethral defects

AR (209900); alleles at different BSS loci act as modifiers BSS1, 11q13 BSS2, 16q21 BSS3, 3p13 BSS4, 15q22.3 BSS5, 2q31 BSS6, 20p12 (MKKS) BSS7, 4q27

Becker nevus73

Pigmented hairy patch usually developing at puberty, breast and nipple hypoplasia, supernumerary nipples

Renal cysts

Usually, sporadic, may require second hit, most cases are male

Beckwith-Wiedemann74,75

High birth weight, omphalocele, macroglossia, hypoglycemia, visceromagaly, abdominal tumors

Renal dysplasia; large kidneys; medullary sponge kidney; Wilms tumor; urethral stenosis, obstruction

Complex AD, paternal imprinting, continguous gene duplication (130650) CDKN1C, 11p15.5

Branchio-oto-renal (BOR)76

Mixed hearing loss, temporal bone anomalies, abnormal pinnae, branchial cleft sinuses or fistulae, preauricular pits and tags

Renal agenesis, dysplasia or ectopia, duplication of pelvis and ureter, megaureter, reflux

AD (113650) EYA1, 8q13.3

Carnitine palmitoyl-transferase II deficiency (lethal neonatal form)77–79

Hypothermia, hypotonia, hepatomegaly, seizures, cardia arrythmia

Cystic dysplasia

AR (600649) CPT2, 1p32

Cerebro-reno-digital disorders —See Table 28-10 for conditions with structural brain anomalies and digital defects with renal dysplasia CHARGE80

Coloboma, heart defect, choanal atresia, mental retardation, genital hypoplasia, ear anomalies, growth impairment, deafness

Renal agenesis or hypoplasia, hydronephrosis, duplication of pelvis or ureter, reflux, neurogenic bladder

AD (214800) CHD7, 8q12.1

Clefting-coloboma of choroid-mental retardation81

Cleft lip and palate, coronal craniosynostosis, choroidal coloboma, mild mesomelic limb shortening, developmental delay, seizures

Segmental renal dysplasia, cystic dysplasia

AR (218650)

Cloacal exstrophy82

Persistent cloaca, exstrophy of cloaca, failure of fusion of genital tubercles, omphalocele, vertebral defects, spina bifida cystica, abnormal genitalia

Renal dysplasia and ectopia, exstrophy of cloaca, urethral and ureteral anomalies

Heterogeneous, associated with monozygous twinning (258040)

Craniofacial-digital-genital (Harrod) syndrome83

Arachnodactyly, hypospadias, cryptorchidism, facial dysmorphism, protruding ears, anomalous vasculature, gut malrotation, mental retardation

Cortical cysts of the kidney, ureteral anomalies, vesicoureteral reflux

Uncertain

Cystic hamartoma of lung and kidney84,85

Hamartomatous pulmonary cysts

Medullary dysplasia, cellular mesoblastic nephroma, nephromegaly

Unknown

Diabetes mellitus-renal dysfunction-genital anomalies86

Diabetes melitus, vaginal atresia, rudimentary uterus, hypertension

Renal cysts, proteinuria

AD (189907) TCF2, 17q11-17q21

Chromosomal disorders —See Table 28-10

(continued)

1207

Table 28-18. Disorders with renal dysplasia (continued) Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

DiGeorge87,88

Parathyroid and thymic hypoplasia, conotruncal heart defects, facial dysmorphism in some cases

Renal agenesis and cystic dysplasia, ureteral defects, hydronephrosis, hydroplastic bladder, urethral atresia, stones

Heterogenous, AD (188400), often sporadic Many cases have deletions of 22q11.2

Early amnion rupture89

Digital and limb amputations, ring constrictions, facial clefts, body wall defects, brain anomalies

Renal dysplasia, agenesis, and ectopia; ureteral anomalies; urethral stenosis

Sporadic

Faivre90

Exomphalos, short limbs, macrogonadism, facial dysmorphism, metaphyseal irregularities

Renal dysplasia, microcysts

Uncertain

Goeminne91

Torticollis, multiple keloids, cryptorchidism

Renal dysplasia and atrophy

X-linked with incomplete dominance (314300) Xq28

Hisama92

Absent nipples, ear and nose anomalies, visceral defects, early lethal

Renal dysplasia, tubular dysgenesis

Uncertain, ?SLR, AR

Hypoparathyroidismdeafness-renal dysgenesis93–96

Hypoparathyroidism, sensorineural deafness

Unilateral renal agenesis, hypoplasia and dysplasia, simple cysts, progressive renal failure

AD (146255) Contiguous gene syndrome GATA3, 10p15

Iniencephaly97

Spinal retroflexion, encephalocele, holoprosencephaly, cardiac and gastrointestinal anomalies

Renal agenesis, hypoplasia and cystic dysplasia, horseshoe kidneys

Sporadic

Ischio-spinal dyspostosis98,99

Multiple vertebral segmentation defects, ischial ossification anomalies

Multicystic dysplasia, nephroblastomatosis

AR

Ivemark asplenia-polysplenia100,101

Bilateral right- or left-sidedness, asplenia, polysplenia, complex congenital heart defects, situs inversus

Renal dysplasia, hydronephrosis, ureteral anomalies

Heterogeneous, most sporadic, AR (208530)

Jejunal atresia-renal dysplasia102

Jujenal atresia

Unilateral renal agenesis or cystic dysplasia, cortical cysts

AD

Joubert cerebellar vermis aplasia103,104

Cerebellar vermis aplasia, ataxia, episodic tachypnea, jerky eye movements, retinal dysplasia, mental retardation

Renal dysplasia

AR (213300) Genetic heterogeneity likely

Kabuki105,106

Facial dysmorphism, dental and cardiac anomalies, mental retardation common

Renal dysplasia, horseshoe kidney, hydronephrosis, ureteral defects, reflux

Likely AD with variable expressivity, most cases new mutations (147920)

Kallmann107–109

Hypogonadotropic hypogonadism, anosmia, cryptorchidism, cleft lip and palate, obesity

Renal agenesis, hypoplasia and dysplasia, hydroureter; ectopic urethra; urogenital sinus

Heterogeneous XLR (308700) AD (147950) AR (244200)

Kaufman-McKusick110

Hydrometrocolpos, transverse vaginal membrane, vaginal septum, postaxial polydactyly, cardiac anomalies, hypospadias

Renal dysplasia, hydroureter; ureteral duplication; ectopic urethra; persistent urogenital sinus

AR (236700)

Lenz microphthalmia111

Microphthalmia; coloboma; mental retardation; dental, cardiovascular, ear, genital, and digital anomalies; cleft palate

Renal agenesis or dysplasia, ureteral defects, duplication of pelvis and ureter, hydronephrosis, neurogenic bladder

XLR (309800)

Lower mesodermal defects112,113

Prune belly, absent or malformed genitalia, sacral defects, imperforate anus, prolapsed perineum

Renal agenesis, dysgenesis, hypoplasia or ectopia, hydronephrosis, malrotation, hypoplastic or absent bladder, absent or blind-ending urethra, urachal cyst

Sporadic

(continued)

1208

Table 28-18. Disorders with renal dysplasia (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Malpuech114

Mental retardation, growth retardation, hypertelorism, cleft lip and palate, genital and cardiac defects, caudal appendage

Renal agenesis, dysplasia or ectopia, reflux

AR (248340)

Microcephaly-hiatus hernianephrosis115,116

Microcephaly, neuronal migration defects, structural brain anomalies, eye anomalies, mental retardation

Renal dysplasia, glomerulosclerosis, nephrosis

AR (251300)

Mitochondrial cytopathy-diabetes mellitus-ataxia-renal anomalies117,118

Short stature, retinitis pigmentosa, deafness, diabetes mellitus, ataxia, cerebral atrophy

Renal dysplasia, tubular acidosis, nephritis

Mitochondrial (560000)

MURCS association119

Mu¨llerian duct aplasia, renal agenesis, cervicothoracic somitic (vertebral) defects; hypoplastic uterus, absent vagina; short stature

Renal agenesis, dysplasia, or ectopia; ureteral anomalies, reflux

Sporadic (601076)

Neural tube defects120–122

Meningomyelocele, anencephaly, encephalocele, vertebral anomalies, midline anomalies

Renal agenesis, hypoplasia, dysplasia, or ectopia; ureteral anomalies, urethral atresia hydronephrosis, horseshoe kidney,

Heterogeneous, multifactorial in most cases

Oculorenal (Pierson)123,124

Anterior chamber and other ocular defects

Renal dysplasia, microcysts, medullary cysts, polycystic disease

AR (263100)

Nephronophthisis —See Section 28.7

Osteo-renal field defects—See Table 28-7 for conditions with generalized skeletal dysplasia and renal dysplasia Pallister-Killian125

Facial dysmorphism, abnormal pigmentation, supernumerary nipples, visceral anomalies, ambiguous genitalia, mental retardation

Renal dysplasia, hydronephrosis

(601803) Mosaicism for tetrasomy 12p

Penoscrotal transposition/ diphallus126–128

Penoscrotal transposition, diphallus, other genital anomalies, cardiomyopathy, vertebral and anal anomalies, patellar defects (overlap with VACTERL)

Cystic dysplasia, renal ectopia, hydronephrosis, bladder diverticula, ureteral defects

AD, Heterogeneous del 13q32-q34

Perlman129

Fetal macrosomia, hypotonia, macroglossia, cardiovascular and diaphragmatic defects, hypospadias, mental retardation

Renal dysplasia, nephromegaly, cortical hamartomas, nephroblastomatosis, hydronephrosis, ureteral anomalies

AR (267000)

Renal and Mu¨llerian duct hypoplasia-craniofacial anomalies130

Severe developmental delay, growth retardation, genital anomalies, facial dysmorphism, dimples at elbows and wrists

Small kidneys, horseshoe kidneys, reflux

AR (266810)

Ramsing131

Cystic hygroma, multiple pterygia, cleft ip and palate, brachydactyly, multiple visceral anomalies (overlap with Fryns)

Renal dysplasia, small kidneys, ureteral anomalies

Uncertain

Renal-coloboma (oculorenal Karcher type)132,133

Optic nerve coloboma, myopia, strabismus, nystagmus

Renal hypoplasia, nephritis

AD (120330), heterogenous Some families have PAX2 mutations 10q24.1-q25.1

Renal-hepatic-pancreatic defects —See Table 28-9 for conditions with renal, hepatic and pancreatic dysplasia Renal-retinal (Loken-Senior)134

Pigmentary retinal dysplasia, structural brain anomalies, seizures, hearing loss, mental retardation

Renal dysplasia, juvenile nephronophthisis, medullary cystic disease

AR (166900), genetically heterogeneous NPHP4, 2q13 NPHP3, 3q22 (continued)

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Table 28-18. Disorders with renal dysplasia (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Rokitansky (von MayerRokitansky-Ku¨ster, MRK anomaly)135,136

Absent uterus, cervix, and upper vagina; vertebral defects; hemifacial microsomia (overlap with MURCS and urogenital dysplasia)

Renal agenesis or hypoplasia, duplication of pelvis and ureter

Heterogeneous, most cases sporadic (277000)

Say137

Short stature, microcephaly, cleft palate, large ears, micrognathia

Cystic dysplasia, tubular acidosis

AD (181180)

Simpson-Golabi-Behmel138,139

Prenatal and postnatal overgrowth, coarse facies, facial dysmorphism, postaxial polydactyly, multiple visceral anomalies, mental retardation

Renal dysplasia, duplication of renal pelvis, hydronephrosis

XLR (312870) SGBS1, GPC3, Xq26

Simpson-Golabi-Behmel, severe infantile form140

Hydrops, hypotonia, facial dysmorphism, visceral anomalies, early lethal

Renal dysplasia, large kidneys, hydronephrosis

XLR (312870) SGBS2, Xp22

Spondylocostal dysostosis with urogenital defects141,142

Multiple costovertebral segmentation defects, sacral agenesis, imperforate anus, preaxial polydactyly, single umbilical artery

Renal agenesis and cystic dysplasia; cloacal dysgenesis, cyst

Usually sporadic AR (271520)

Thymic-renal-anal-lung dysplasia143

Intrauterine growth retardation, absent or hypoplasia of thymus and parathyroids, imperforate anus

Renal agenesis and dysplasia

AR (274265)

Thyroid-renal-digital anomalies (Daneman)144

Multinodular goiter, triphalangeal thumbs, pre- and postaxial polydactyly

Renal dysplasia, polycystic kidney, dilated collecting system

AD (128790), with variable expressivity and incomplete penetrance

Tuberous sclerosis145,146

Hypopigmented macules, adenoma sebaceum, retinal and brain tumors or phakomas, mental retardation, seizures

Renal angiomyolipomas (40–80%), renal dysplasia, cortical cysts, renal vascular anomalies, renal cell carcinomas

AD (191100) Genetically heterogenous TSC1, 9q34 TSC2, 16p13 Probably other loci

Twin reversed arterial perfusion147

Co-twin with incomplete development of all organ systems, limbs, and body form; upper body more severely affected than lower body

Renal agenesis, hypoplasia and cystic dysplasia; ureteral and urethral anomalies

Sporadic Restricted to MZ twins

Mu¨llerian duct anomalies

Renal agenesis and dysplasia

AD (191830), with reduced penetrance and variable expressivity

Pseudohermaphroditism, cloacal and Mu¨llerian duct anomalies, ambiguous genitalia, imperforate anus (overlap with Lower mesodermal defects)

Renal agenesis, hypoplasia and dysplasia; ureteral and urethral anomalies

Sporadic

VACTERL association150

Vertebral, anal, cardiac, tracheoesophageal, and limb defects

Renal agenesis, dysplasia or ectopia, horseshoe kidneys

Sporadic

Van Nesselrooij149

Craniosynostosis, cardiac defects, aganglionosis of colon

Renal agenesis, dysplasia

Uncertain Concordant male MZT

Velo-cardio-facial syndrome151

Facial dysmorphism, cardiac defects, thymic hypoplasia, cleft palate, short stature, long fingers (overlap with Di George syndrome)

Renal dysplasia, single cysts, hydronephrosis, reflux

Heterogeneous AD (192430) del 22q11

Teratogen exposures—See Table 28-11

Urethral obstruction (prune belly triad)—See Section 28.15 Urogenital adysplasia, congenital34,41

Urorectal septum malformation

148

(continued)

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Urinary Tract

1211

Table 28-18. Disorders with renal dysplasia (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Von Hippel-Lindau152,153

Pancreatic and liver cysts; adrenal tumors; retinal, cerebellar, and spinal angiomata

Cystic dysplasia, hypernephromas, renal cell carcinoma

AD (193300) 3p26-p25 VHL tumour suppressor gene

Waters-West anemiagenital anomalies154

Lethal congenital hemolytic anemia, genital anomalies

Cystic dysplasia, dilated bladder, hydroureter, reflux

Uncertain (600461)

Williams155–157

Characteristic facies, stellate irides, mental retardation, heart defects, radioulnar synostosis, infantile hypercalcemia

Small kidneys, renal ectopic or aplasia, duplicated pelvis or ureter, other ureteral defects, renal artery stenosis, urethral stenosis, bladder diverticula

AD (194050) ELN, 7q11.2

Wilms tumor-aniridia (WAGR)158,159

Aniridia, hemihypertrophy, genital anomalies, short stature, mental retardation

Renal dysplasia, horseshoe kidney

Contiguous gene deletion syndrome 11p13

The second hypothesis is most consistent with the spectrum of clinical features seen in the majority of multiple congenital anomaly disorders in which dysplasia occurs as well as the clear correlation between dysplasia and agenesis. Mackie and Stephens50 noted the association between dysplasia in small kidneys and ectopic ureteral orifices. They suggested that an ectopically positioned ureteric bud might not reach the mesenchyme that was capable of being induced to form metanephric tissue. In this regard, it is important to consider that the atretic ureters seen in dysplasia may be a consequence of diminished flow from a severely defective kidney, rather than a causal mechanism. Certainly, the fact that the pelvicaliceal system, medulla, and cortex are all involved indicates a prolonged dysgenetic effect beginning at the earliest stages of organogenesis.8 Fig. 28-8. Bilateral multicystic renal dysplasia. Note the ureteral atresia.

A third possible cause for some cases of dysplasia is vascular compromise. One study found an excess of young mothers among infants with renal dysplasia, as has been noted in other conditions related to intrauterine vascular disruption.51,52 Little is yet known of molecular factors involved in renal dysplasia. However, it has been noted that dysplastic tubules express increased amounts of PAX2 and maintain this high expression pattern postnatally.53 It has also been found that apoptosis is increased in the mesenchyme of dysplastic kidneys, which may well account for the frequent regression seen in these organs after birth.54 Prognosis, Prevention, and Treatment

Long-term outcome is dependent on the severity of renal dysplasia and/or the associated anomalies. Progressive deterioration in renal function is the usual clinical course when dysplastic changes are bilateral or when there is contralateral renal agenesis or hypodysplasia.32 Vesicoureteric reflux becomes a problem in some patients and requires voiding cystourethography for proper evaluation as it may not be apparent on ultrasound.55 Unilateral renal dysplasia may remain asymptomatic. Dysplasia is not a cause of urinary tract infection nor does it result from infection because the atretic ureter usually protects the kidney from invasion by organisms in the lower urinary tract. Empiric recurrence risk figures can be used for families when monogenic, syndromic, and chromosomal disorders have been excluded. In families who have had ultrasound studies, the following recurrence risks have been determined. For perinatal lethal renal disease, there was a 3.6% recurrence risk for sibs and a 0.2% risk for first cousins.56 As noted earlier in the section on renal agenesis, Roodhooft et al.,34 studying parents and sibs of probands with bilateral renal agenesis and/or cystic dysplasia, determined a 9% risk for related urogenital anomalies and a 4–5% risk for renal anomalies. Prenatal diagnosis of renal dysplasia has been successful using ultrasound imaging,12,19,20 including vaginal ultrasound before 16 weeks of gestation.57 In some cases, maternal serum a-fetoprotein levels may be elevated.58 A diagnosis of renal dysplasia on ultrasound is suspected when there is oligohydramnios and a hypoplastic or an enlarged kidney with multiple cysts of variable size separated by thin layers of hyperechoic tissue (Table 28-16). The

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Urogenital System Organs

hypoplastic or atretic collecting system is usually not apparent. While decreased amniotic fluid volume is not obvious with unilateral disease, it is present in all bilateral cases by 21 to 31 weeks of gestation.59 Careful evaluation of an affected fetus for other structural malformations and karyotype determination is recommended. Forty percent of fetuses found by ultrasound to have one kidney with multicystic dysplasia have contralateral renal anomalies. Twenty percent have bilateral multicystic dysplasia, 10% have contralateral renal agenesis, and 10% have contralateral hydronephrosis, usually from ureteropelvic junction obstruction.12 There is little that can be done to treat the perinatal patients who have severe oligohydramnios, minimal renal function, and pulmonary hypoplasia. Prognosis is dependent on the extent of renal involvement, the amount of amniotic fluid, the associated structural malformations, and the underlying diagnosis. Surviving children with bilateral dysplasia fall into two groups based on their glomerular filtration rates. In one study, those with rates below 15 mL/minute per 1.73 m2 at 6 months of age had severe growth retardation; renal function did not improve; and four of five went on to end-stage renal failure by 8 months to 6 years and required dialysis and renal transplantation. The children with better filtration rates were less growth retarded and had a significant improvement of renal function with time, and none required transplantation.60 Operative removal of a unilateral dysplastic kidney may not be necessary in the absence of clinical symptomatology. Appropriate management is an initially conservative approach using cystography to rule out reflux, serial ultrasounds to assess renal size, and serum creatinine. In 19 patents followed in this fashion, complete involution of the dysplastic kidney was seen in 14, and only two required nephrectomies for increasing renal size.61 Another study followed 55 patients aged 2 to 69 months; in 40 of the cases, the dysplastic kidney regressed in size, and in 22 of these, ultimately it was not detectable by ultrasound.62 Another study of 204 cases compared 40 patients who had had nephrectomies with 164 treated conservatively and found no difference in long-term complications. A decrease in renal size was noted in 65% of the retained dysplastic kidneys. The patients displayed a mild decrease in renal function with serum creatine levels 0.63 standard deviations above the median. Levels were highest in patients with contralateral hypoplasia or obstructive disease other than reflux.160 Tumors may arise in the dysplastic kidney. These include Wilms tumor, nephroblastoma, mesothelioma, and renal cell carcinoma.63–68 The most important of these for surveillance purposes is Wilms tumor, where there is a three- to ten-fold increase in risk. Abdominal palpitation is the most cost-effective way of screening for these tumors in this patient population.69 References (Renal Dysplasia) 1. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. 2. Grossman H, Rosenberg ER, Bowie JD, et al.: Sonographic diagnosis of renal cystic diseases. AJR Am J Roentgenol 140:81, 1983. 3. Raffensperger J, Abousleiman A: Abdominal masses in children under one year of age. Surgery 63:514, 1968. 4. Bernstein J, Gardner KD Jr: Cystic diseases of the kidney and renal dysplasia. In: Campbell’s Urology, ed 5. PC Walsh, RF Gittes, AD Perlmutter, et al., eds. WB Saunders Company, Philadelphia, 1986. 5. Parkkulainen KV, Hjelt L, Sirola K: Congenital multicystic dysplasia of the kidney. Acta Chir Scand Supp 244:1, 1959.

6. Triest JA, Bukowski TP: Multicystic dysplastic kidney as cause of gastric outlet obstruction and respiratory compromise. J Urol 161:1918, 1999. 7. Rubinstein M, Meyer R, Bernstein J: Congential abnormalities of the urinary system. J Pediatr 58:356, 1961. 8. Risdon RA, Woolf AS: Developmental Defects and Cystic Diseases of the Kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 9. Maayan A, Mashiach R, Kessler OJ, et al.: Prenatal diagnosis of crossed ectopic multicystic kidney. Am J Perinatol 15:499, 1998. 10. Siegel RL, Rosenfeld DL, Leiman S: Complete regression of a multicystic dysplastic kidney in the setting of renal crossed fused ectopia. J Clin Ultrasound 20:466, 1992. 11. Borer JG, Glassberg KI, Kassner EG, et al.: Unilateral multicystic dysplasia in 1 component of a horseshoe kidney: case reports and review of the literature. J Urol 152:1568, 1994. 12. Kleiner B, Filly RA, Mack L, et al.: Multicystic dysplastic kidney: observations of contralateral disease in the fetal population. Radiology 161:27, 1986. 13. Drake MJ, Quinn FM: Absent vas deferens and ipsilateral multicystic dysplastic kidney in a child. Br J Urol 77:756, 1996. 14. Koumanidou C, Theofanopoulou M, Nikas J, et al.: Cystic dysplasia of the testis: a rare cause of painless hemiscrotal enlargement in childhood. Eur Radiol 10:1653, 2000. 15. Evans JA, Erdile LB, Greenberg CR, et al.: Agenesis of the penis: patterns of associated malformations. Am J Med Genet 84:47, 1999. 16. Winderl LM, Silverman RK: Prenatal diagnosis of congenital imperforate hymen. Obstet Gynecol 85:857, 1995. 17. Holmes M, Upadhyay V, Pease P: Gartner’s duct cyst with unilateral renal dysplasia presenting as an introital mass in a new born. Pediatr Surg Int 15:277, 1999. 18. Rosenfeld DL, Lis E: Gartner’s duct cyst with a single vaginal ectopic ureter and associated renal dysplasia or agenesis. J Ultrasound Med 12:775, 1993. 19. Rizzo N, Gabrielli S, Pilu G, et al.: Prenatal diagnosis and obstetrical management of multicystic dysplastic kidney disease. Prenat Diagn 7:109, 1987. 20. Wilson RD, Morrison MG, Wittmann BK, et al.: Clinical follow-up of fetal urinary tract anomalies diagnosed prenatally by ultrasound. Fetal Ther 3:141, 1988. 21. Singh ZN, Dinda AK: Renal dysplasia: an autopsy study of associated congenital malformations. Indian J Pediatr 65:311, 1998. 22. Blane CE, Barr M, DiPietro MA, et al.: Renal obstructive dysplasia: ultrasound diagnosis and therapeutic implications. Pediatr Radiol 21: 274, 1991. 23. Evans JA, Stranc LC: Cystic renal disease and cardiovascular anomalies. Am J Med Genet 33:398, 1989. 24. Forbes M: Renal dysplasia in infants with neurospinal dysraphism. J Pathol 107:13, 1972. 25. Mir S, Rapola J, Koskimies O: Renal cysts in pediatric autopsy material. Nephron 33:189, 1983. 26. Huang HY, Huang HY, Chen WJ: Non-syndromic association of congenital hepatic fibrosis and bilateral cystic renal dysplasia. J Formos Med Assoc 99:863, 2000. 27. Pedicelli G, Jequier S, Bowen AD, et al.: Multicystic dysplastic kidneys: spontaneous regression demonstrated with US. Radiology 161:23, 1986. 28. Hiraoka M, Tsukahara H, Ohshima Y, et al.: Renal aplasia is the predominant cause of congenital solitary kidneys. Kidney Int 61:1840, 2002. 29. Mesrobian HG, Rushton HG, Bulas D: Unilateral renal agenesis may result from in utero regression of multicystic renal dysplasia. J Urol 150:793, 1993. 30. Hitchcock R, Burge DM: Renal agenesis: an acquired condition? J Pediatr Surg 29:454, 1994. 31. Hendry PJ, Hendry GM: Observations on the use of Doppler ultrasound in multicystic dysplastic kidney. Pediatr Radiol 21:203, 1991.

Urinary Tract 32. Gur A, Siegel NJ, Davis DA, et al.: Clinical aspects of bilateral renal dysplasia in children. Nephron 15:50, 1975. 33. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type II due to inhibition of ampullary activity. Arch Pathol 77:474, 1964. 34. Roodhooft AM, Birnholz JC, Holmes LB: Familial nature of congenital absence and severe dysgenesis of both kidneys. N Engl J Med 310:1341, 1984. 35. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 36. Wu G: Current advances in molecular genetics of autosomal-dominant polycystic kidney disease. Curr Opin Nephrol Hypertens 10:23, 2001. 37. Vellios F, Garrett RA: Congenital unilateral multicystic disease of the kidney; a clinical and anatomical study of seven cases. Am J Clin Pathol 35:244, 1961. 38. Van Eijk L, Cohen-Overbeek TE, den Hollander NS, et al.: Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessment. Ultrasound Obstet Gynecol 19:180, 2002. 39. Lazebnik N, Bellinger MF, Ferguson JE, et al.: Insights into the pathogenesis and natural history of fetuses with multicystic dysplastic kidney disease. Prenat Diagn 19:418, 1999. 40. Srivastava T, Garola RE, Hellerstein S: Autosomal dominant inheritance of multicystic dysplastic kidney. Pediatr Nephrol 13:481, 1999. 41. McPherson E, Carey J, Kramer A, et al.: Dominantly inherited renal adysplasia. Am J Med Genet 26:863, 1987. 42. Schimke RN, King CR: Hereditary urogenital adysplasia. Clin Genet 18:417, 1980. 43. Cole BR, Kaufman RL, McAlister WH, et al.: Bilateral renal dysplasia in three siblings: report of a survivor. Clin Nephrol 5:83, 1976. 44. Schinzel A, Homberger C, Sigrist T: Bilateral renal agenesis in 2 male sibs born to consanguineous parents. J Med Genet 15:314, 1978. 45. Sase M, Tsukahara M, Oga A, et al.: Diffuse cystic renal dysplasia: nonsyndromal familial case. Am J Med Genet 63:332, 1996. 46. Buchta RM, Viseskul C, Gilbert EF, et al.: Familial bilateral renal agenesis and hereditary renal adysplasia. Z Kinderheilkd 115:111, 1973. 47. Devriendt K, Fryns JP: Genetic locus on chromosome 6p for multicystic renal dysplasia, pelvi-ureteral junction stenosis, and vesicoureteral reflux. Am J Med Genet 20;59:396, 1995. 48. Groenen PM, Vanderlinden G, Devriendt K, et al.: Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia. Genomics 49:218, 1998. 49. Zerres K, Volpel MC, Weiss H: Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 68:104, 1984. 50. Mackie GG, Stephens F: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol 114:274, 1975. 51. Fortier A, Bisson D, Evans JA: Is there a decreased maternal age effect for renal dysplasia? Proc Greenwood Genet Cen 21:108, 2002. 52. Lubinsky MS: Association of prenatal vascular disruptions with decreased maternal age. Am J Med Genet 69:237, 1997. 53. Winyard PJ, Risdon RA, Sams VR, et al.: The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations. J Clin Invest 98:451, 1996. 54. Winyard PJ, Nauta J, Lirenman DS, et al.: Deregulation of cell survival in cystic and dysplastic renal development. Kidney Int 49:135, 1996. 55. Flack CE, Bellinger MF: The multicystic dysplastic kidney and contralateral vesicoureteral reflux: protection of the solitary kidney. J Urol 150:1873, 1993. 56. Bankier A, de Campo M, Newell R, et al.: A pedigree study of perinatally lethal renal disease. J Med Genet 22:104, 1985. 57. Bronshtein M, Yoffe N, Brandes JM, et al.: First and early secondtrimester diagnosis of fetal urinary tract anomalies using transvaginal sonography. Prenat Diagn 10:653, 1990. 58. Freling EN, Kawada CY, Blake G: Elevated maternal serum alphafetoprotein associated with Potter’s syndrome. Am J Obstet Gynecol 146:218, 1983. 59. Takeuchi H, Koyanagi T, Yoshizato T, et al.: Fetal urine production at different gestational ages: correlation to various compromised fetuses in utero. Early Hum Dev 40:1, 1994.

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60. Ismaili K, Schurmans T, Wissing KM, et al.: Early prognostic factors of infants with chronic renal failure caused by renal dysplasia. Pediatr Nephrol 16:260, 2001. 61. Kessler OJ, Ziv N, Livne PM, et al.: Involution rate of multicystic renal dysplasia. Pediatrics 102:E73, 1998. 62. Rottenberg GT, Gordon I, de Bruyn R: The natural history of the multicystic dysplastic kidney in children. Br J Radiol 70:347, 1997. 63. Barrett DM, Wineland RE: Renal cell carcinoma in multicystic dysplastic kidney. Urology 15:152, 1980. 64. Birken G, King D, Vane D, et al.: Renal cell carcinoma arising in a multicystic dysplastic kidney. J Pediatr Surg 20:619, 1985. 65. Hartman GE, Smolik LM, Shochat SJ: The dilemma of the multicystic dysplastic kidney. Am J Dis Child 140:925, 1986. 66. Rackley RR, Angermeier KW, Levin H, et al.: Renal cell carcinoma arising in a regressed multicystic dysplastic kidney. J Urol 152:1543, 1994. 67. Homsy YL, Anderson JH, Oudjhane K, et al.: Wilms tumor and multicystic dysplastic kidney disease. J Urol 158:2256, 1997. 68. Oddone M, Marino C, Sergi C, et al.: Wilms’ tumor arising in a multicystic kidney. Pediatr Radiol 24:236, 1994. 69. Perez LM, Naidu SI, Joseph DB: Outcome and cost analysis of operative versus nonoperative management of neonatal multicystic dysplastic kidneys. J Urol 160:1207, 1998. 70. Al Gazali LI, Bakir M, Hamid ZM, et al.: A new syndrome of optic nerve colobomas and renal abnormalities associated with arthrogryposis multiplex. Clin Dysmorphol 9:183, 2000. 71. Gershoni-Baruch R, Nachlieli T, Leibo R, et al.: Cystic kidney dysplasia and polydactyly in 3 sibs with Bardet-Biedl syndrome. Am J Med Genet 44:269, 1992. 72. Beales PL, Reid HA, Griffiths MH, et al.: Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant 15:1977, 2000. 73. Urbani CE, Betti R: Supernumerary nipples occurring together with Becker’s naevus: an association involving one common paradominant trait? Hum Genet 100:388, 1997. 74. Elliott M, Maher ER: Beckwith-Wiedemann syndrome. J Med Genet 31:560, 1994. 75. Lam WW, Hatada I, Ohishi S, et al.: Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J Med Genet 36:518, 1999. 76. Chen A, Francis M, Ni L, et al.: Phenotypic manifestations of branchiooto-renal syndrome. Am J Med Genet 58:365, 1995. 77. North KN, Hoppel CL, De Girolami U, et al.: Lethal neonatal deficiency of carnitine palmitoyltransferase II associated with dysgenesis of the brain and kidneys. J Pediatr 127:414, 1995. 78. Taggart RT, Smail D, Apolito C, et al.: Novel mutations associated with carnitine palmitoyltransferase II deficiency. Hum Mutat 13:210, 1999. 79. Hug G, Bove KE, Soukup S: Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. N Engl J Med 325:1862, 1991. 80. Ragan DC, Casale AJ, Rink RC, et al.: Genitourinary anomalies in the CHARGE association. J Urol 161:622, 1999. 81. Baraitser M, Rodeck C, Garner A: A new craniosynostosis/mental retardation syndrome diagnosed by fetoscopy. Clin Genet 22:12, 1982. 82. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261, 2001. 83. Jurenka SB, Van Allen MI: Additional case of craniofacial and digital anomalies as reported by Harrod et al. Am J Med Genet 61:168, 1996. 84. Graham JM Jr, Boyle W, Troxell J, et al.: Cystic hamartomata of lung and kidney: a spectrum of developmental abnormalities. Am J Med Genet 27:45, 1987. 85. Weinberg AG, Zumwalt RE: Bilateral nephromegaly and multiple pulmonary cysts. Am J Clin Pathol 67:284, 1977. 86. Lindner TH, Njolstad PR, Horikawa Y, et al.: A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet 8:2001, 1999.

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87. Ryan AK, Goodship JA, Wilson DI, et al.: Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 34:798, 1997. 88. Goodship J, Robson SC, Sturgiss S, et al.: Renal abnormalities on obstetric ultrasound as a presentation of DiGeorge syndrome. Prenat Diagn 17:867, 1997. 89. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 90. Faivre L, Delezoide AL, Narcy F, et al.: A new lethal syndrome of exomphalos, short limbs, and macrogonadism. J Med Genet 36:131, 1999. 91. Goeminne L: A new probably X-linked inherited syndrome: congenital muscular torticollis, multiple keloids cryptorchidism and renal dysplasia. Acta Genet Med Gemellol (Roma ) 17:439, 1968. 92. Hisama FM, Reyes-Mugica M, Wargowski DS, et al.: Renal tubular dysgenesis, absent nipples, and multiple malformations in three brothers: a new, lethal syndrome. Am J Med Genet 80:335, 1998. 93. Barakat AY, D’Albora JB, Martin MM, et al.: Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61, 1977. 94. Muroya K, Hasegawa T, Ito Y, et al.: GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 38:374, 2001. 95. Ishida S, Isotani H, Kameoka K, et al.: Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia. Intern Med 40: 110, 2001. 96. Lichtner P, Konig R, Hasegawa T, et al.: An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J Med Genet 37:33, 2000. 97. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 98. Nisbet DL, Chitty LS, Rodeck CH, et al.: A new syndrome comprising vertebral anomalies and multicystic kidneys. Clin Dysmorphol 8:173, 1999. 99. Spranger J, Self S, Clarkson KB, et al.: Ischiospinal dysostosis with rib gaps and nephroblastomatosis. Clin Dysmorphol 10:19, 2001. 100. Krzelj V, Kragic I, Glavina-Durdov M, et al.: Ivemark syndrome: asplenia with kidney collecting duct cysts and polysplenia with cerebellar cyst. Turk J Pediatr 42:234, 2000. 101. Rose V, Izukawa T, Moes CA: Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 37:840, 1975. 102. Kilani RA, Hmiel P, Garver MK, et al.: Familial jejunal atresia with renal dysplasia. J Pediatr Surg 31:1427, 1996. 103. Silverstein DM, Zacharowicz L, Edelman M, et al.: Joubert syndrome associated with multicystic kidney disease and hepatic fibrosis. Pediatr Nephrol 11:746, 1997. 104. Saraiva JM, Baraitser M: Joubert syndrome: a review. Am J Med Genet 43:726, 1992. 105. Matsumoto N, Niikawa N: Kabuki make-up syndrome: a review. Am J Med Genet 117C:57, 2003. 106. Ewart-Toland A, Enns GM, Cox VA, et al.: Severe congenital anomalies requiring transplantation in children with Kabuki syndrome. Am J Med Genet 80:362, 1998. 107. Kirk JM, Grant DB, Besser GM, et al.: Unilateral renal aplasia in X-linked Kallmann’s syndrome. Clin Genet 46:260, 1994. 108. Zenteno JC, Mendez JP, Maya-Nunez G, et al.: Renal abnormalities in patients with Kallmann syndrome. BJU Int 83:383, 1999. 109. Rudnik-Schoneborn S, John U, Deget F, et al.: Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 157:666, 1998. 110. Chitayat D, Hahm SY, Marion RW, et al.: Further delineation of the McKusick-Kaufman hydrometrocolpos-polydactyly syndrome. Am J Dis Child 141:1133, 1987. 111. Forrester S, Kovach MJ, Reynolds NM, et al.: Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome. Am J Med Genet 98:92, 2001. 112. Lubinsky MS: Female pseudohermaphroditism and associated anomalies. Am J Med Genet 6:123, 1980. 113. Pauli RM: Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet 50:154, 1994.

114. Crisponi G, Marras AR, Corrias A: Two sibs with Malpuech syndrome. Am J Med Genet 86:294, 1999. 115. Cooperstone BG, Friedman A, Kaplan BS: Galloway-Mowat syndrome of abnormal gyral patterns and glomerulopathy. Am J Med Genet 47:250, 1993. 116. Palm L, Hagerstrand I, Kristoffersson U, et al.: Nephrosis and disturbances of neuronal migration in male siblings—a new hereditary disorder? Arch Dis Child 61:545, 1986. 117. Rotig A, Bessis JL, Romero N, et al.: Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus, and cerebellar ataxia. Am J Hum Genet 50:364, 1992. 118. Niaudet P: Mitochondrial disorders and the kidney. Arch Dis Child 78:387, 1998. 119. Duncan PA, Shapiro LR, Stangel JJ, et al.: The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 95:399, 1979. 120. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 121. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983. 122. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 123. Fairley KF, Leighton P, Kincaid-Smith: Familial visual defects associated with polycystic kidney and medullary sponge kidney. Br Med J 1: 1060, 1963. 124. Pierson M, Cordier J, Hervouet F: Une curieuse association malformative congenitale et familiale atteignant l’oeil et le rein. J Genet Hum 12:184, 1963. 125. Schinzel A: Tetrasomy 12p (Pallister-Killian syndrome). J Med Genet 28:122, 1991. 126. Parida SK, Hall BD, Barton L, et al.: Penoscrotal transposition and associated anomalies: report of five new cases and review of the literature. Am J Med Genet 59:68, 1995. 127. Dodat H, Rosenberg D, James-Pangaud I: Familial association of penoscrotal transposition and diphallia (double penis) with patella aplasia. Arch Pediatr 2:241, 1995. 128. Bartsch O, Kuhnle U, Wu LL, et al.: Evidence for a critical region for penoscrotal inversion, hypospadias, and imperforate anus within chromosomal region 13q32.2q34. Am J Med Genet 65:218, 1996. 129. Henneveld HT, van Lingen RA, Hamel BC, et al.: Perlman syndrome: four additional cases and review. Am J Med Genet 86:439, 1999. 130. Davee MA, Moore CA, Bull MJ, et al.: Familial occurrence of renal and Mu¨llerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay. Am J Med Genet 44:293, 1992. 131. Ramsing M, Gillessen-Kaesbach G, Holzgreve W, et al.: Variability in the phenotypic expression of Fryns syndrome: a report of two sibships. Am J Med Genet 95:415, 2000. 132. Schimmenti LA, Shim HH, Wirtschafter JD, et al.: Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome. Hum Mutat 14:369, 1999. 133. Parsa CF, Silva ED, Sundin OH, et al.: Redefining papillorenal syndrome: an underdiagnosed cause of ocular and renal morbidity. Ophthalmology 108:738, 2001. 134. Caridi G, Murer L, Bellantuono R, et al.: Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis 32:1059, 1998. 135. Willemsen WN: Renal-skeletal-ear- and facial-anomalies in combination with the Mayer-Rokitansky-Kuster (MRK) syndrome. Eur J Obstet Gynecol Reprod Biol 14:121, 1982. 136. Wulfsberg EA, Grigbsy TM: Rokitansky sequence in association with the facio-auriculo-vertebral sequence: part of a mesodermal malformation spectrum? Am J Med Genet 37:100, 1990.

Urinary Tract 137. Ashton-Prolla P, Felix TM: Say syndrome: a new case with cystic renal dysplasia in discordant monozygotic twins. Am J Med Genet 70:353, 1997. 138. Neri G, Marini R, Cappa M, et al.: Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. Am J Med Genet 30: 287, 1988. 139. Pilia G, Hughes-Benzie RM, MacKenzie A, et al.: Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12:241, 1996. 140. Terespolsky D, Farrell SA, Siegel-Bartelt J, et al.: Infantile lethal variant of Simpson-Golabi-Behmel syndrome associated with hydrops fetalis. Am J Med Genet 59:329, 1995. 141. Casamassima AC, Morton CC, Nance WE, et al.: Spondylocostal dysostosis associated with anal and urogenital anomalies in a Mennonite sibship. Am J Med Genet 8:117, 1981. 142. Murr MM, Waziri MH, Schelper RL, et al.: Case of multivertebral anomalies, cloacal dysgenesis, and other anomalies presenting prenatally as cystic kidneys. Am J Med Genet 42:761, 1992. 143. Rudd NL, Curry C, Chen KT, et al.: Thymic-renal-anal-lung dysplasia in sibs: a new autosomal recessive error of early morphogenesis. Am J Med Genet 37:401, 1990. 144. Daneman D, Davy T, Mancer K, et al.: Association of multinodular goiter, cystic renal disease, and digital anomalies. J Pediatr 107:270, 1985. 145. Brook-Carter PT, Peral B, Ward CJ, et al.: Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease— a contiguous gene syndrome. Nat Genet 8:328, 1994. 146. Torres VE, Zincke H, King BK, et al.: Renal manifestations of tuberous sclerosis complex. Contrib Nephrol 122:64, 1997. 147. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 7:285, 1983. 148. Wenstrup RJ, Pagon RA: Female pseudohermaphroditism with anorectal, Mullerian duct, and urinary tract malformations: report of four cases. J Pediatr 107:751, 1985. 149. Van Nesselrooij BP, Spliet W, Beemer FA: Unusual association of congenital malformations: craniosynostosis, heart defect, abnormal intestinal innervation and urogenital abnormalities. Clin Dysmorphol 7:51, 1998. 150. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8, 1997. 151. Czarnecki PM, Van Dyke DL, Vats S, et al.: A mother with VCFS and unilateral dysplastic kidney and her fetus with multicystic dysplastic kidneys: additional evidence to support the association of renal malformations and VCFS. J Med Genet 35:348, 1998. 152. Maddock IR, Moran A, Maher ER, et al.: A genetic register for von Hippel-Lindau disease. J Med Genet 33:120, 1996. 153. Olschwang S, Richard S, Boisson C, et al.: Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. Hum Mutat 12:424, 1998. 154. Waters BL, West BR: Lethal congenital non-spherocytic, non-immune hemolytic anemia with genital and other anomalies in two brothers. Am J Med Genet 55:319, 1995. 155. Pober BR, Lacro RV, Rice C, et al.: Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 46:271, 1993. 156. Pankau R, Partsch CJ, Winter M, et al.: Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 63:301, 1996. 157. Morris CA, Leonard CO, Dilts C, et al.: Adults with Williams syndrome. Am J Med Genet Suppl 6:102, 1990. 158. Fantes JA, Bickmore WA, Fletcher JM, et al.: Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization. Am J Hum Genet 51:1286, 1992. 159. Jotterand V, Boisjoly HM, Harnois C, et al.: 11p13 deletion, Wilms’ tumour, and aniridia: unusual genetic, non-ocular and ocular features of three cases. Br J Ophthalmol 74:568, 1990. 160. Rudnick-Scho¨neborn S, John U, Deget F, et al.: Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 157:666, 1998.

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28.7 Familial Nephronophthisis/Medullary Cystic Disease Definition

Familial nephronophthisis/medullary cystic disease is chronic renal failure associated with shrunken kidneys and usually cysts at the corticomedullary boundary. This definition excludes medullary sponge kidney and other forms of cystic kidney disease. Diagnosis

Once considered separate conditions, the clinical features and pathologic findings in juvenile nephronophthisis and medullary cystic disease, as well as the fact that individual families may have cases with and without medullary cysts, has led to the concept of a single phenotypic spectrum of disease.1 The kidneys are pale, firm, and shrunken, often to half the expected weight for age. There is thinning of both the medulla and cortex and, in almost all cases, there are fluid-filled cysts around the corticomedullary boundary that range in size from microscopic to 1 cm in diameter (Fig. 28-9). The lack of cysts at the papillary tips and absence of calcification distinguishes this group of disorders from medullary sponge kidney.2 There is an increase in tubular diverticula, especially in the collecting ducts, distal convoluted tubules, and loops of Henle.3 Microscopically, there are numerous changes including sclerosis of glomeruli, thickening of the basement membrane of Bowman’s capsule, diffuse interstitial fibrosis, and tubular atrophy. The changes are nonspecific, but significant, and increase in severity as the disease progresses. These conditions may present in childhood or adulthood. Affected children usually have poor growth, short stature, and anemia. Polydipsia and polyuria are common findings due to impaired urine concentration capacity. Salt wasting is frequent and may protect against hypertension as the renal function worsens. Urinalysis reveals no red or white cells, and proteinuria is usually mild or absent. Renal biopsies taken early in the disease show nonspecific findings, making diagnosis difficult in the absence of a typical

Fig. 28-9. Familial nephonopthisis-medullary cystic disease complex. Gross specimen of a kidney shows collections of cysts at the corticomedullary junction. (Reprinted with permission from Jennette JC, Olson JL, Schwartz MM, et al., eds.: Heptinstall’s Pathology of the Kidney, ed 5. Lippincott Williams & Wilkins, Philadelphia, 1998.)

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clinical history or familial cases.2 Unlike polycystic kidney disease, flank pain, hematuria, and hypertension are absent. Radiographs reveal small kidneys. Ultrasonography shows renal hyperechogenicity and poor cortical-medullary differentiation. Small kidneys and corticomedullary cysts become apparent as the disease progresses.4 These patients do not have a high frequency of other urinary tract anomalies, but nonrenal anomalies may occur, particularly in cases with onset in childhood. These include ocular defects such as retinitis pigmentosa and tapetoretinal degeneration (Senior-Løken syndrome5,6), skeletal anomalies including coneshaped epiphyses,7 congenital hepatic fibrosis,8 and ataxia.9,10 There appears to be an association with red or fair hair.11 In all cases, renal osteodystrophy and hypoparathyroidism may become apparent as the condition worsens, especially in children.2 Similar renal pathology may occur in Bardet-Biedl syndrome (Table 28-9) and Alstro¨m syndrome (OMIM 203800),12 which presents with blindness, diabetes mellitus, deafness, and obesity. Patients with Jeune’s asphyxiating thoracic dystrophy, who survive the neonatal period, often develop a similar nephropathy in childhood13,14 and it has also been reported in a patient with Ellis-van Creveld syndrome.15 Etiology and Distribution

This is a rare group of disorders with only one case of medullary cystic disease noted in 13,775 autopsies.16 Despite the phenotypic similarity, there is clearly etiologic heterogeneity with autosomal recessive, autosomal dominant, and sporadic forms, in addition to the syndromic disorders. The autosomal recessive disorder usually has an age of onset of 2 to 14 years, while the autosomal dominant form normally presents in the 3rd to 5th decade.17 In the genetic conditions, males and females are equally affected and, although the condition is usually fully penetrant, an affected parent of severely affected children may have occult disease.18 In a study of 59 Finnish cases, 17 came from four autosomal dominant families and 37 from recessive kindred. There were two apparently de novo dominant mutations and three sporadic cases. The overall incidence was approximately one in 60,000 livebirths.19 The first locus for the autosomal recessive form, termed nephronophthisis 1, has been mapped to 2q13. About two-thirds of the recessive patients are homozygous for a deletion of this region that includes a gene, NPHP1, that codes for a novel protein, nephrocystin, that may be related to signaling processes at sites of cell adhesion.20,21 Patients with deletions have an earlier age of onset than those without.19 Other families link to chromosome 9q (NPHP2—a form with infantile age of onset),22 chromosome 3q (NPHP3—later than average age of onset),23 and chromosome 1p (NPHP4).24 The gene mutated in NPHP4 encodes a novel protein that interacts with nephrocystin. Families with ocular manifestations have been linked to NPHP1,25 NPHP3,26 and NPHP4,27,28 indicating that Senior-Løken syndrome is also genetically heterogeneous. The autosomal dominant form has been less well-elucidated at the molecular level. However, two large Cypriot families with a relatively late age of onset have been mapped to 1q2129 and linkage to this region was also observed in a Jewish family.30 Italian and Welsh families map to a second locus, MCKD2, at 16p12.31,32 As some families map to neither locus, there are probably other genes that can cause this phenotype.33 Prognosis, Prevention, and Treatment

Despite its relative rarity, juvenile nephronophthisis is one of the most common causes of childhood renal failure.34 Children with

the autosomal recessive disorder develop terminal renal failure during the 2nd decade of life. They may suffer other complications if they have one of the syndromic forms of the disease. Adults obviously have a later age of onset than the juvenile type, but the progression of the renal disease is similarly rapid once it is diagnosed. Death usually occurs 2 to 4 years after diagnosis unless renal dialysis is instituted or a renal transplant obtained.17 Fortunately, transplanted kidneys do not undergo cystic degeneration.35 Mapping of some of the genes involved would now allow prenatal diagnosis, presymptomatic screening, and/or heterozygote detection in families where linkage has been confirmed. Family members at risk can be screened by ultrasound. Obligate carriers of Senior-Løken syndrome have been shown to have electroretinal abnormalities.36 References (Familial Nephronophthisis/Medullary Cystic Disease) 1. Chamberlin BC, Hagge WW, Stickler GB: Juvenile nephronophthisis and medullary cystic disease. Mayo Clin Proc 52:485, 1977. 2. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988: p 1149. 3. Sherman FE, Studnicki FM, Fetterman G: Renal lesions of familial juvenile nephronophthisis examined by microdissection. Am J Clin Pathol 55:391, 1971. 4. Chuang YF, Tsai TC: Sonographic findings in familial juvenile nephronophthisis-medullary cystic disease complex. J Clin Ultrasound 26:203, 1998. 5. Senior B: Familial renal-retinal dystrophy. Am J Dis Child 125:442, 1973. 6. Løken AC, Hanssen O, Halvorsen S, et al.: Hereditary renal dysplasia and blindness. Acta Paediatr 50:177, 1961. 7. Robins DG, French TA, Chakera TM: Juvenile nephronophthisis associated with skeletal abnormalities and hepatic fibrosis. Arch Dis Child 51:799, 1976. 8. Proesmans W, Van Damme B, Macken J: Nephronophthisis and tapetoretinal degeneration associated with liver fibrosis. Clin Nephrol 3: 160, 1975. 9. Popovic-Rolovic M, Calic-Perisic N, Bunjevacki G, et al.: Juvenile nephronophthisis associated with retinal pigmentary dystrophy, cerebellar ataxia, and skeletal abnormalities. Arch Dis Child 51:801, 1976. 10. Takano K, Nakamoto T, Okajima M, et al.: Cerebellar and brainstem involvement in familial juvenile nephronophthisis type I. Pediatr Neurol 28:142, 2003. 11. Rayfield EJ, McDonald FD: Red and blonde hair in renal medullary cystic disease. Arch Intern Med 130:72, 1972. 12. Collin GB, Marshall JD, Ikeda A, et al.: Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31:74, 2002. 13. Oberklaid F, Danks DM, Mayne V, et al.: Asphyxiating thoracic dysplasia. Clinical, radiological, and pathological information on 10 patients. Arch Dis Child 52:758, 1977. 14. Donaldson MD, Warner AA, Trompeter RS, et al.: Familial juvenile nephronophthisis, Jeune’s syndrome, and associated disorders. Arch Dis Child 60:426, 1985. 15. Moudgil A, Bagga A, Kamil ES, et al.: Nephronophthisis associated with Ellis-van Creveld syndrome. Pediatr Nephrol 12:20, 1998. 16. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 17. Crawfurd MD: The Genetics of Renal Tract Disorders. Oxford, Oxford University Press, 1988. 18. Whelton A, Ozer FL, Bias WB, et al.: Renal medullary cystic disease: a family study. Birth Defects Orig Artic Ser X 4:154, 1973. 19. Ala-Mello S, Koskimies O, Rapola J, et al.: Nephronophthisis in Finland: epidemiology and comparison of genetically classified subgroups. Eur J Hum Genet 7:205, 1999.

Urinary Tract 20. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 17:149, 1997. 21. Saunier S, Calado J, Benessy F, et al.: Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am J Hum Genet 66:778, 2000. 22. Haider NB, Carmi R, Shalev H, et al.: A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. Am J Hum Genet 63:1404, 1998. 23. Omran H, Fernandez C, Jung M, et al.: Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am J Hum Genet 66:118, 2000. 24. Mollet G, Salomon R, Gribouval O, et al.: The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet 32:300, 2002. 25. Caridi G, Murer L, Bellantuono R, et al.: Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis 32:1059, 1998. 26. Omran H, Sasmaz G, Haffner K, et al.: Identification of a gene locus for Senior-Loken syndrome in the region of the nephronophthisis type 3 gene. J Am Soc Nephrol 13:75, 2002. 27. Schuermann MJ, Otto E, Becker A, et al.: Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 70:1240, 2002. 28. Otto E, Hoefele J, Ruf R, et al.: A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 71:1161, 2002. 29. Christodoulou K, Tsingis M, Stavrou C, et al.: Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet 7:905, 1998. 30. Parvari R, Shnaider A, Basok A, et al.: Clinical and genetic characterization of an autosomal dominant nephropathy. Am J Med Genet 99:204, 2001. 31. Scolari F, Puzzer D, Amoroso A, et al.: Identification of a new locus for medullary cystic disease, on chromosome 16p12. Am J Hum Genet 64:1655, 1999. 32. Hateboer N, Gumbs C, Teare MD, et al.: Confirmation of a gene locus for medullary cystic kidney disease (MCKD2) on chromosome 16p12. Kidney Int 60:1233, 2001. 33. Kroiss S, Huck K, Berthold S, et al.: Evidence of further genetic heterogeneity in autosomal dominant medullary cystic kidney disease. Nephrol Dial Transplant 15:818, 2000. 34. Hildebrandt F, Waldherr R, Kutt R, et al.: The nephronophthisis complex: clinical and genetic aspects. Clin Investig 70:802, 1992. 35. Gardner KD Jr: Evolution of clinical signs in adult-onset cystic disease of the renal medulla. Ann Intern Med 74:47, 1971. 36. Hogewind BL, Veltkamp JJ, Polak BC, et al.: Electro-rentinal abnormalities in heterozygotes of renal-retinal dysplasia. Acta Med Scand 202:323, 1977.

28.8 Medullary Sponge Kidney Definition

Medullary sponge kidney is a normal-sized or slightly enlarged kidney characterized by ectasia of papillary collecting ducts, leading to the formation of small cysts limited to the renal pyramids and papillae. All pyramids of both kidneys are usually affected, but the pathologic changes may be restricted to only one or two pyramids or to a single kidney.1,2 There is no atrophy or interstitial fibrosis and no cortical cysts, which distinguishes medullary sponge kidney from infantile polycystic kidney disease. The medullary sponge kidney is also called Cacchi-Ricci disease, precaliceal canalicular ectasia, and cystic dilation of the renal

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tubules. The definition does not include nephronophthisis, medullary cystic disease, autosomal recessive polycystic kidney disease, or other cystic diseases of the kidneys. Diagnosis

Most patients with medullary sponge kidney (60%) are diagnosed between the ages of 30 and 50 years, but the diagnosis has been made in newborn infants and in elderly individuals.3–5 Diagnosis in infancy and childhood is usually as a result of investigations initiated because of an underlying genetic or syndromic disorder associated with medullary sponge kidney.5 Rarely will children present with primarily renal symptoms6; however, medullary cystic kidney is one of the main causes of nephrocalcinosis in childhood.7 A relatively common radiologic diagnosis, medullary sponge kidney is usually asymptomatic and is not detected until secondary complications occur or when an intravenous pyelography (IVP) is done for other reasons. It is rarely diagnosed by pathologists because nephrectomy is seldom required and the changes may easily be overlooked on routine autopsy.2 The most common clinical symptoms are a urinary concentrating defect and acidification, which usually goes unnoticed.8–10 Its course is usually benign and nonprogressive, but patients may present with stones and renal colic, hematuria, and urinary tract infections. In 10% of patients, the clinical course is complicated by repeated infections, stone formation, and ultimately renal failure.10,11 There appears to be an association between medullary sponge kidney and disorders of calcium metabolism (36%) or isolated hypercalcemia (36%). In 10 of 28 patients studied by Maschio et al.,12 there was evidence of parathyroid hyperplasia. Hypercalcemia in the absence of hyperparathyroidism was postulated to be the result of a calcium leak in the kidney. Certainly patients with medullary sponge kidney are predisposed to nephrolithiasis13 and they have lower levels of urinary inhibitors to stones than patients with idiopathic stone formation.14 The majority of affected individuals do not have other genitourinary anomalies and, when these or other effects are found, the diagnosis of an underlying syndromic, chromosomal, or genetic disorder should be considered. The defect has been reported to occur in association with ectopic and horseshoe kidneys11,15 and with unicornuate uterus.16 It may also be seen with congenital hepatic fibrosis,17 most often as an unusual presentation of autosomal dominant polycystic kidney disease.2,18 IVP is the best method of diagnosing medullary sponge kidney. There is characteristic renal linear streaking or round cystic collecting ducts affecting at least two or more papillae in a given kidney (Fig. 28-10). These lesions are described as fan-shaped striation, a bunch of grapes, or a bunch of flowers. Calcium deposits often occur in the swollen ducts and need to be distinguished from the contrast medium.2 Retrograde pyelography can be helpful if papillary necrosis is suspected. Renal ultrasound and arteriography are not reliable in the diagnosis of medullary sponge kidney. Grossly the kidneys are normal size or, if there are extensive cysts, slightly enlarged. The renal surface is smooth and the cortices are normal. The cysts vary in size, but are usually less than 8 to 10 mm.11 They are most obvious near the papillary tips and enlarge the associated calyces.2 The dilation of the collecting ducts does not progress beyond the corticomedullary junction. The majority of the time all renal pyramids are involved, but the cysts can be localized to one or two renal pyramids. Microdissection

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dominant polycystic kidney disease with IVP as well as renal ultrasound. In addition, medullary sponge kidney may occur with reflux and ureteropelvic junction obstruction in patients with a dominant form of familial ureteral abnormalities.33 Families with medullary sponge kidney as a part of genetic syndromes may also require further investigation as appropriate. Prognosis, Prevention, and Treatment

Fig. 28-10. Medullary sponge kidney. An excretory urogram with tomography shows radial linear streaking in the renal papillae resulting from contrast medium in the ectatic papillary ducts. (Courtesy of Dr. R. de Bruyn. Reprinted with permission from Jennette JC, Olson JL, Schwartz MM, et al., eds.: Heptinstall’s Pathology of the Kidney, ed 5. Lippincott Williams & Wilkins, Philadelphia, 1998.)

demonstrates severe, diffuse, uniform enlargement of collecting tubules in part of the papillae. The first few generations of collecting tubules are especially involved.19 Microscopic examination usually demonstrates evidence of inflammatory cell infiltration. Calcium deposits are present in cysts in 40–60% of cases20 and may erode through the cyst walls.21 Etiology and Distribution

The estimated incidence of medullary sponge kidney is one in 5000 to 20,000.2,22 This may be a significant underestimate given the high proportion of asymptomatic cases. Among urologic patients, the estimated incidence is one in 1000.11 A male predominance of 3:1 has been found in some studies, though this may be an ascertainment bias. The pathogenesis of medullary sponge kidney is not known and may be heterogenous. An association has been found with hypercalcemia with or without hyperparathyroidism. It may be found in patients with Ehlers-Danlos syndrome, raising the possibility of a structural abnormality within the collecting tubules.23 A defect in a structural protein is also supported by the association of medullary sponge kidney with autosomal dominant polycystic kidney disease, Marfan syndrome,24 and retinal-renal dysplasias,25 though the more usual diagnosis in these last cases is medullary cystic disease (see Section 28.7). An error in embryogenesis of the collecting tubules is also a possibility in view of the association with Beckwith-Wiedemann syndrome26,27 and congenital hemihypertrophy,28,29 though there is some suggestion that these conditions display medullary ductal dilation rather than medullary sponge kidney.2 Medullary sponge kidney has been seen in patients with hemoglobin SC.30 Proesmans et al. reported a 16year-old boy with medullary sponge kidneys, osteoporosis, and premature loss of all teeth.31 Most cases of medullary sponge kidney are sporadic. Autosomal dominant inheritance has been suggested in several families.11,32 The presence of congenital hepatic fibrosis in a case should alert the physician to investigate the family member for autosomal

Fortunately, for most patients, medullary sponge kidney is a benign disorder with a good prognosis. Long-term follow-up demonstrates no major changes in the radiologic findings and no deterioration in renal function.2 Symptoms arise from complications of the disease, including urolithiasis, hematuria, and urinary tract infection. Management should include treatment of hypercalcemia and hypercalciuria and control of infection. Stone formation is reported to occur more often in female patients.10 Stones usually contain calcium phosphates, so treatment has been empiric in hopes of preventing progressive stone formation. Such patients can be treated with extracorporeal shock wave lithotripsy, but appear to have more residual stones compared to those with other forms of renal malformations.34 Instrumentation or catheterization should be avoided in order to prevent ascending urinary tract infection. In 10% of diagnosed patients, recurrent complications lead to renal failure and the requirement for dialysis and transplantation. Prenatal diagnosis is currently not available, since the renal lesions in medullary sponge kidney are usually not evident until adulthood. References (Medullary Sponge Kidney) 1. Higashihara E, Nutahara K, Tago K, et al.: Unilateral and segmental medullary sponge kidney: renal function and calcium excretion. J Urol 132:743, 1984. 2. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 3. Abeshouse BS, Abeshouse GA: Sponge kidney: a review of the literature and report of five cases. J Urol 84:252, 1960. 4. Ekstro¨m T, Engfeldt B, Lagergren C, et al.: Medullary sponge kidneys. Clinical Appraisal. JAMA 188:233, 1964. 5. Zerres K, Volpel MC, Weiss H: Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 68:104, 1984. 6. Van den OD, Blom JH, Bangma C, et al.: Diagnosis and management of seminal vesicle cysts associated with ipsilateral renal agenesis: a pooled analysis of 52 cases. Eur Urol 33:433, 1998. 7. Kessel D, Hall CM, Shaw DG: Two unusual cases of nephrocalcinosis in infancy. Pediatr Radiol 22:470, 1992. 8. Granberg PO, Lagergren C, Theve NO: Renal function studies in medullary sponge kidney. Scand J Urol Nephrol 5:177, 1971. 9. Higashihara E, Nutahara K, Tago K, et al.: Medullary sponge kidney and renal acidification defect. Kidney Int 25:453, 1984. 10. Yendt ER: Medullary sponge kidney and nephrolithiasis. N Engl J Med 306:1106, 1982. 11. Kuiper JJ: Medullary sponge kidney in three generations. N Y State J Med 71:2665, 1971. 12. Maschio G, Tessitore N, D’Angelo A, et al.: Medullary sponge kidney and hyperparathyroidism—a puzzling association. Am J Nephrol 2:77, 1982. 13. Ginalski JM, Portmann L, Jaeger P: Does medullary sponge kidney cause nephrolithiasis? AJR Am J Roentgenol 155:299, 1990. 14. Yagisawa T, Kobayashi C, Hayashi T, et al.: Contributory metabolic factors in the development of nephrolithiasis in patients with medullary sponge kidney. Am J Kidney Dis 37:1140, 2001. 15. Lambrianides AL, John DR: Medullary sponge disease in horseshoe kidney. Urology 29:426, 1987.

Urinary Tract 16. Fedele L, Bianchi S, Agnoli B, et al.: Urinary tract anomalies associated with unicornuate uterus. J Urol 155:847, 1996. 17. Spence HM, Singleton R: What is sponge kidney disease and where does it fit in the spectrum of cystic disorders? J Urol 107:176, 1972. 18. Weiss L, Reynolds WA, Saeed SM, et al.: Congenital hepatic fibrosis and polycystic disease of kidneys with the roentgen appearance of medullary sponge kidney. Birth Defects Orig Artic Ser X(4):22, 1974. 19. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. 20. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 21. Bernstein J, Gardner KD Jr: Cystic diseases of the kidney and renal dysplasia. In: Campbell’s Urology, ed 5. PC Walsh, RF Gittes, AD Perlmutter, et al., eds. WB Saunders Company, Philadelphia, 1986. 22. Mayall GF. The incidence of medullary sponge kidney. Clin Radiol 21:171, 1970. 23. Levine AS, Michael AF Jr: Ehlers-Danlos syndrome with renal tubular acidosis and medullary sponge kidneys. A report of a case and studies of renal acidification in other patients with the Ehlers-Danlos syndrome. J Pediatr 71:107, 1967. 24. Shaul DB, Harrison EA: Classification of anorectal malformations— initial approach, diagnostic tests, and colostomy. Semin Pediatr Surg 6:187, 1997. 25. Senior B: Familial renal-retinal dystrophy. Am J Dis Child 125:442, 1973. 26. Silverstein AD, Weizer AZ, Anderson EE: Ruptured abdominal aortic aneurysm complicated by horseshoe kidney and renal cell carcinoma. Urology 60:1108, 2002. 27. Beetz R, Schofer O, Riedmiller H, et al.: Medullary sponge kidneys and unilateral Wilms tumour in a child with Beckwith-Wiedemann syndrome. Eur J Pediatr 150:489, 1991. 28. Thompson IM, Rodriguez FR, Spence CR: Medullary sponge kidney and congenital hemihypertrophy. South Med J 80:1455, 1987. 29. Indridason OS, Thomas L, Berkoben M: Medullary sponge kidney associated with congenital hemihypertrophy. J Am Soc Nephrol 7: 1123, 1996. 30. Ataiipour Y, Laville M, Combarnous F, et al.: Papillary necrosis and medullary sponge kidney in a patient with hemoglobin SC. Am J Nephrol 14:213, 1994. 31. Proesmans W, Van Molhem S, Lateur L: A 16-year-old boy with medullary sponge kidneys, osteoporosis, and premature loss of all teeth. Pediatr Nephrol 14:259, 2000. 32. Kliger AS, Scheer RL: Familial disease of the renal medulla. A study of progeny in a family with medullary cystic disease. Ann Intern Med 85:190, 1976. 33. Klemme L, Fish AJ, Rich S, et al.: Familial ureteral abnormalities syndrome: genomic mapping, clinical findings. Pediatr Nephrol 12: 349, 1998. 34. Gallucci M, Vincenzoni A, Schettini M, et al.: Extracorporeal shock wave lithotripsy in ureteral and kidney malformations. Urol Int 66:61, 2001.

28.9 Renal Cystic Disease Secondary to Obstruction Definition

Renal cystic disease secondary to obstruction consists of renal cystic changes caused by obstruction of urinary outflow during the fetal and early postnatal periods. These changes are also known as Potter type IV and peripheral cortical cystic dysplasia. Closely related noncystic changes occur later in life due to other forms of obstruction, including ureteropelvic junction obstruction and vesicoureteral obstruction with reflux. These can give rise to hydronephrosis and renal scarring. Reflux nephropathy causes caly-

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ceal clubbing or deformation with overlying corticomedullary scarring.1 Diagnosis

Renal cysts can be produced by obstruction of urinary outflow. While severe obstruction of the urethra in early prenatal life may give rise to cystic changes resembling multicystic dysplasia with enlarged kidneys and distended bladder and abdomen (see Section 28.16), milder forms of obstruction can be seen postnatally at any age and are more difficult to diagnose because they present with nonspecific findings of pain, abdominal mass, nocturia, incontinence, hematuria, hypertension, and febrile urinary tract infections. Such obstruction during the late fetal period, infancy, and childhood results in the more characteristic appearance of the ‘‘obstructive kidney’’ with caliectasis and parenchymal scarring.2 The most common anomalies resulting in obstructive kidney are ureteral duplication; hydronephrosis due to ureteropelvic junction obstruction or ureteral valves; strictures at the vesicoureteric junction caused by persistence of Chwalle’s membrane, which closes the lumen temporarily at the 6th week of development, or by absorbance of the distal portion of the Wolffian duct into the bladder; bladder outlet obstruction from posterior urethral valves or urethral stenosis, and ureterocele or ballooning of the lower end of the ureter into the bladder, usually (75%) associated with ureteral duplication.3–5 Other renal malformations associated with ureteral anomalies, such as horseshoe kidney, can result in a mixed pathologic picture of both renal dysplasia from a primary embryologic defect and secondary changes from obstruction. In segmental hypoplasia or Ask-Upmark kidney, there is a smaller kidney with one or more transverse grooves on the capsular surface demarking underlying atrophic lobes. Initially considered a developmental defect causing a form of renal hypoplasia, this is now considered an acquired disorder due to reflux nephropathy.6 One or both kidneys may be involved, depending on the site and nature of the obstruction. The involved segments show parenchymal thinning and an enlarged, elongated calyx. Microscopic examination reveals few or no glomeruli, tubular atrophy, and tortuous arterioles.7 Diagnostic investigations to determine the nature and extent of obstructive defects include a voiding cystourethrogram to demonstrate reflux, intravenous pyelography (IVP) or nuclear scan for detection of renal scarring, and IVP or renal ultrasound for detection of structural anomalies. The severity of vesicoureteral reflux is graded using an international classification system.8 The high frequency and lack of specificity of ureteral anomalies and secondary obstruction make them poor markers for specific syndromes. Disorders where they occur commonly are found in many of the tables in this chapter. Similarly, hydronephrosis and reflux occur in a large number of syndromes including, in particular, Johanson-Blizzard,9,10 Russell-Silver,11 lipodystrophic diabetes with acanthosis nigricans (Seip-Lawrence syndrome),12 ectromelia with ichythosis,13 Ochoa,14 spondylocostal dysostosis,15 renal-coloboma,16 and tibial agenesis with polysyndactyly.17 The pathologic appearance of the kidney varies depending on the degree and duration of obstruction.18,19 With mildly affected kidneys, cystic changes may be absent or restricted to small cysts that appear as minute punctate areas on the surface of the kidney. More severely affected kidneys have multiple cysts of varying size, resembling multicystic renal dysplasia (Fig. 28-11). Microscopically, there are microscopic glomerular and tubular cysts involving the subcapsular nephrogenic zone. The inner and deeper cortical

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Fig. 28-11. Renal cystic disease secondary to lower urinary tract obstruction in a newborn male with urethral obstruction. Note the dilated bladder and hydroureters. Cryptorchidism, esophageal atresia, annular pancreas, preauricular skin tags, and single umbilical artery were also present.

regions are usually normal. In medullary tissue, collecting tubules typically are dilated, and the interstitial tissues are edematous and fibrotic.20 The presence of cartilaginous bars due to aberrant mesenchymal differentiation are more commonly seen in renal dysplasia, but occasionally occur with severe obstructive renal disease of early onset. Etiology and Distribution

This form of renal disease requires a blockage at one or more sites in the urinary tract collecting system. Congenital hydronephrosis may be unilateral or bilateral. Bilateral hydronephrosis is usually due to lower urinary tract obstruction and is associated with hydroureter. Hydronephrosis without hydroureter is often caused by ureteropelvic obstruction. This may be due to aberrant renal vessels crossing the junction such as an artery to a lower pole. It may also be a primary defect related to pelvicaliceal duplication and vesicoureteral reflux, given the familial distribution of combinations of these findings.21,22 Many such cases show abnormal musculature at the ureteropelvic junction.23 Autosomal dominant inheritance with variable expression or multifactorial inheritance have long been postulated as potential mechanisms for vesicoureteral reflux and reflux nephropathy.24–26 Chapman et al.26 concluded that a single major autosomal dominant allele with an estimated frequency of 0.16% was responsible, potentially acting on a polygenic background to produce the short intravesical ureter that predisposes to disease. As adults, 45% of gene carriers would have vesicoureteric reflux (VUR) and/or reflux nephropathy and 15% would develop renal failure. One form of this condition, now referred to as OMIM 139300, has now been mapped to 1p1327 and is recognized to cause a whole range of renal defects. Obstructive anomalies including reflux and ureteropelvic and ureterovesical junction defects are most common, but

multicystic and hypoplastic renal dysplasia can also occur.28,29 Genetic heterogeneity is evident with at least 12 potential regions showing linkage.27 Regardless of the specific loci involved, firstdegree relatives are clearly at risk, especially if the proband presents with renal failure. Van den Abbeele et al.30 used radionuclide voiding cystography as a screening tool and found that 45% of 60 asymptomatic sibs of patients with vesicoureteral reflux were similarly affected. The condition was unilateral in 15 and bilateral in 12. It has also been suggested that polymorphisms in the angiotensin converting enzyme gene ACE 1/D may be a risk factor for renal parenchymal damage due to reflux. One study found that individuals with the D/D genotype had a relative risk of 4.2.31 However, a second study did not show any such association in familial cases.32 Autosomal dominant inheritance of unilateral hydronephrosis has been reported in a limited number of families.33,34 Familial occurrence has also been reported for bilateral megaloureters with hydronephrosis35 and for hydronephrosis due to ureteropelvic junction stenosis,36 aberrant vessels,37 duplication of the ureter,38 and ureteroceles.39 One predisposing gene has been mapped to chromosome 6 and potentially reflects the association of specific HLA markers with reflux nephropathy. HLA haplotypes A2–B8 and A9– B12 are more frequent in patients with reflux nephropathy than in patients with other end-stage renal disease.40 Izquierdo et al.41 showed a link to HLA in five families with ureteropelvic junction obstruction (OMIM 143400), and further documentation of a potential 6p locus was provided by a fetus with multicystic dysplasia due to bilateral UPJ obstruction and hydronephrosis and a reciprocal translocation: t(6;19)(p23.1;q13.4). Further evaluation of this translocation determined that the chromosome 6 breakpoint occurred in intron 9 of the CDC5L gene.42 Again, not all families with hydronephrosis as the predominant feature show linkage to 6p.43,44 Based on a family with three brothers and their maternal grandfather, all affected with vesicoureteral reflux, an X-linked form (OMIM 314550) may also exist.45 The precise frequency of these disorders is difficult to assess. In a postmortem series of unselected patients, the incidence of hydronephrosis was one in 417; one in 860 had ureteropelvic junction obstruction, while one in 984 had ureterovesical junction obstruction.46 Mulcahy et al.24 noted a significant ethnic difference for vesicoureteral reflux; he estimated the condition affected 1–2% of Caucasians, but was rare in blacks. Among a Japanese population, vesicoureteral reflux in infants was found to be considerably more common in males (83%); slightly more than half the cases (57%) were bilateral.47 In unilateral cases, the left side is preferentially involved.48 Prognosis, Prevention, and Treatment

The clinical course in patients with obstructive nephropathies depends on the amount of renal parenchymal loss and the underlying cause of the obstruction. Patient management is directed toward reducing ongoing damage to the kidneys from reflux nephropathy, and preventing recurrent infection and intrarenal reflux.1 A particular concern is when reflux occurs in a solitary kidney or where the contralateral kidney is multicystic. These cases must be treated aggressively to preserve renal function.49 One study involving routine voiding cystourethrography on all children attending a urologic clinic identified 1023 with vesicoureteral reflux, of which 16% were asymptomatic. Although the obstruction resolved spontaneously in most of these cases, 20% went on to develop high-grade reflux and renal parenchymal

Urinary Tract

scarring.50 Connelly et al.51 recommend expectant observation with annual imaging as the most appropriate management for asymptomatic cases. There has been considerable attention paid to cases of obstruction detected prenatally. Dilation of the renal pelvis is seen in approximately one in 140 fetuses on ultrasound examination.52 Most of these resolved spontaneously, but 15% were found to have vesicoureteral reflux on postnatal examination. Prenatal detection of severe obstruction and in utero treatment for eligible fetuses is an area of active investigation.5 Fetuses with evidence of significant hydronephrosis, an enlarged bladder, and some degree of oligohydramnios without irreversible pulmonary and renal damage would be eligible for possible in utero surgery. However, investigation to determine whether karyotypic anomalies or other structural anomalies are present should be carried out before considering intrauterine treatment. References (Renal Cystic Disease Secondary to Obstruction) 1. Lerner GR, Fleischmann LE, Perlmutter AD: Reflux nephropathy. Pediatr Clin North Am 34:747, 1987. 2. Woodard JR, Rushton HG: Reflux uropathy. Pediatr Clin North Am 34:1349, 1987. 3. Caldamone AA: Duplication anomalies of the upper tract in infants and children. Urol Clin North Am 12:75, 1985. 4. Churchill BM, Abara EO, McLorie GA: Ureteral duplication, ectopy and ureteroceles. Pediatr Clin North Am 34:1273, 1987. 5. Mandell J, Peters CA, Retik AB: Current concepts in the perinatal diagnosis and management of hydronephrosis. Urol Clin North Am 17:247, 1990. 6. Arant BS Jr, Sotelo-Avila C, Bernstein J: Segmental ‘‘hypoplasia’’ of the kidney (Ask-Upmark). J Pediatr 95:931, 1979. 7. Risdon RA, Woolf AS: Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 8. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics 67:392, 1981. 9. Johanson A, Blizzard R: A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 79:982, 1971. 10. Park IJ, Johanson A, Jones HW Jr, et al.: Special female hermaphroditism associated with multiple disorders. Obstet Gynecol 39:100, 1972. 11. Haslam RH, Berman W, Heller RM: Renal abnormalities in the Russell-Silver syndrome. Pediatrics 51:216, 1973. 12. Reed WB, Dexter R, Corley C, et al.: Congenital lipodystrophic diabetes with acanthosis nigricans. The Seip-Lawrence syndrome. Arch Dermatol 91:326, 1965. 13. Cullen SI, Harris DE, Carter CH, et al.: Congenital unilateral ichthyosiform erythroderma. Arch Dermatol 99:724, 1969. 14. Elejalde BR: Genetic and diagnostic considerations in three families with abnormalities of facial expression and congenital urinary obstruction: ‘‘The Ochoa syndrome.’’ Am J Med Genet 3:97, 1979. 15. Schinzel A, Giedion A: A syndrome of severe midface retraction, multiple skull anomalies, clubfeet, and cardiac and renal malformations in sibs. Am J Med Genet 1:361, 1978. 16. Dressler GR, Woolf AS: Pax2 in development and renal disease. Int J Dev Biol 43:463, 1999. 17. Tuysuz B, Beker BD, Centel T, et al.: Unilateral tibial agenesia with preaxial polysyndactyly and renal disorder in two patients: a new syndrome? Clin Dysmorphol 10:37, 2001. 18. Potter EL: Normal and Abnormal Development of the Kidney. Year Book Medical Publishers, Chicago, 1972. 19. Bernstein J, Gardner KD Jr: Cystic diseases of the kidney and renal dysplasia. In: PC Walsh, RF Gittes, AD Perlmutter, et al.: eds. WB Saunders Company, Philadelphia, 1986.

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20. Osathanondh V, Potter EL: Pathogenesis of polycystic kidneys: type IV due to urethral occlusion. Arch Pathol 77:502, 1964. 21. Atwell JD, Allen NH: The interrelationship between paraureteric diverticula, vesicoureteric reflux and duplication of the pelvicaliceal collecting system: a family study. Br J Urol 52:269, 1980. 22. Atwell JD: Familial pelviureteric junction hydronephrosis and its association with a duplex pelvicaliceal system and vesicoureteric reflux. A family study. Br J Urol 57:365, 1985. 23. Antonakopoulos GN, Fuggle WJ, Newman J, et al.: Idiopathic hydronephrosis. Light microscopic features and pathogenesis. Arch Pathol Lab Med 109:1097, 1985. 24. Mulcahy JJ, Kelalis PP, Stickler GB, et al.: Familial vesicoureteral reflux. J Urol 104:762, 1970. 25. Burger RH: A theory on the nature of transmission of congenital vesicoureteral reflux. J Urol 108:249, 1972. 26. Chapman CJ, Bailey RR, Janus ED, et al.: Vesicoureteric reflux: segregation analysis. Am J Med Genet 20:577, 1985. 27. Feather SA, Malcolm S, Woolf AS, et al.: Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1. Am J Hum Genet 66:1420, 2000. 28. Peeden JN Jr, Noe HN: Is it practical to screen for familial vesicoureteral reflux within a private pediatric practice? Pediatrics 89:758, 1992. 29. Devriendt K, Groenen P, Van Esch H, et al.: Vesico-ureteral reflux: a genetic condition? Eur J Pediatr 157:265, 1998. 30. Van den Abbeele AD, Treves ST, Lebowitz RL, et al.: Vesicoureteral reflux in asymptomatic siblings of patients with known reflux: radionuclide cystography. Pediatrics 79:147, 1987. 31. Hohenfellner K, Hunley TE, Brezinska R, et al.: ACE I/D gene polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol 13:514, 1999. 32. Yoneda A, Oue T, Puri P: Angiotensin-converting enzyme genotype distribution in familial vesicoureteral reflux. Pediatr Surg Int 17:308, 2001. 33. Cannon JF: Hereditary unilateral hydronephrosis. Ann Intern Med 41:1054, 1954. 34. Jewell JH: Unilateral hereditary hydronephrosis: a report of four cases in three consecutive generations. J Urol 88:129, 1962. 35. MacKay H: Congenital bilateral megalo-ureters with hydronephrosis. A remarkable family history. Proc Roy Soc Med 38:567, 1945. 36. Grosse FR, Kaveggia L, Opitz JM: Familial hydronephrosis. Z Kinderheilkd 114:313, 1973. 37. Atwell JD, Cook PL, Howell CJ, et al.: Familial incidence of bifid and double ureters. Arch Dis Child 49:390, 1974. 38. Aaron G, Robbins MA: Hydronephrosis due to aberrant vessels: remarkable familial incidence with report of cases. J Urol 60:702, 1948. 39. Abrams HJ, Sutton AP, Buchbinder MI: Ureteroceles in siblings. J Urol 124:135, 1980. 40. Bailey M, Wallace M: HLA-B12 as a genetic marker for vesicoureteric reflux? Br Med J 1:48, 1978. 41. Izquierdo L, Porteous M, Paramo PG, et al.: Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction, with one locus assigned to chromosome 6p. Hum Genet 89:557, 1992. 42. Groenen PM, Vanderlinden G, Devriendt K, et al.: Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia. Genomics 49:218, 1998. 43. McHale D, Porteous ME, Wentzel J, et al.: Further evidence of genetic heterogeneity in hereditary hydronephrosis. Clin Genet 50:491, 1996. 44. Santava A, Utikalova A, Bartova A, et al.: Familial hydronephrosis unlinked to the HLA complex. Am J Med Genet 70:118, 1997. 45. Middleton GW, Howards SS, Gillenwater JY: Sex-linked familial reflux. J Urol 114:36, 1975. 46. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 47. Nakai H, Kakizaki H, Konda R, et al.: Clinical characteristics of primary vesicoureteral reflux in infants: multicenter retrospective study in Japan. J Urol 169:309, 2003. 48. Kelalis PP: Proper perspective on vesicoureteral reflux. Mayo Clin Proc 46:807, 1971.

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49. Flack CE, Bellinger MF: The multicystic dysplastic kidney and contralateral vesicoureteral reflux: protection of the solitary kidney. J Urol 150:1873, 1993. 50. Shrestha GK, Ikoma F, Schumacher S, et al.: Asymptomatic vesicoureteral reflux in children. Int Urol Nephrol 26:283, 1994. 51. Connolly LP, Treves ST, Zurakowski D, et al.: Natural history of vesicoureteral reflux in siblings. J Urol 156:1805, 1996. 52. Gloor JM, Ramsey PS, Ogburn PL Jr, et al.: The association of isolated mild fetal hydronephrosis with postnatal vesicoureteral reflux. J Matern Fetal Neonatal Med 12:196, 2002.

28.10 Supernumerary Kidney Definition

A supernumerary kidney is one, or rarely more than one, additional kidney with its own blood supply and pelvicaliceal system. It is also termed accessory kidney or renal duplication. It does not include duplication of the renal pelvis or ureter. Diagnosis

The extra kidney is usually ectopic, situated cephalad (55%) or caudal (25%) to a normal kidney.1 However, it can be found close to the midline, either dorsal or ventral to the bladder. The ureter may join one of those draining the normal kidneys (more common when the extra kidney is caudal to the ipsilateral normal kidney) or can enter the bladder separately (more common when the extra kidney is cranially sited). Occasionally the additional ureter will enter the vagina or urethra. Most supernumerary kidneys are a distinct encapsulated mass, but occasionally there is a parenchymal bridge to another kidney, representing cases that are transitional between the supernumerary and fused kidney. Most cases are unilateral, but bilateral cases have been observed.2 The rarity of this condition and lack of specific symptoms make diagnosis a challenge. Many patients remain asymptomatic, but they may present in adulthood with back or abdominal pain or fever. The average age at diagnosis is about 36 years, with patients with double ureters tending to present earlier.1 Even in the presence of symptoms, the precise diagnosis is rarely made prior to exploratory surgery.3 Occasionally, the defect is detected fortuitously as a pelvic mass on computed tomography scan. Intravenous pyelography, angiography, and scintigraphy have been used to diagnosis this anomaly and assess renal function in the individual kidneys (Fig. 28-12).3,4 Most cases represent isolated findings. However, other genitourinary anomalies have been observed in a small proportion of cases and include ureteral atresia; horseshoe kidney; posterior urethral valves; penile, urethral, or bladder duplication; vaginal atresia; and cloacal exstrophy.1,3,5–7 Anomalies in other systems are rare, but cases with coarctation of the aorta and with meningomyelocele have been reported.1,8 One case was diagnosed in childhood with hypertensive encephalopathy.9 Etiology and Distribution

Supernumerary kidneys are believed to be due either to the formation of a second ureteric bud, which then induces a separate mesenchymal mass, or to splitting of the metanephric blastema into two parts, each penetrated by a branch of the ureteric bud. To date, approximately 100 cases have been reported. Males and females are equally affected. The accessory kidney is left-sided in about 65% of

Fig. 28-12. A total-body flow study of a 19-year-old male shows a left kidney of normal size, a smaller right kidney in a normal location, and an ovoid structure below and to the right of the aortic bifurcation suggesting a supernumerary pelvic kidney, later confirmed by CT and MRI. (Reprinted with permission from Sy et al.4)

cases.1,10 No recurrences have been reported, so risks for children and siblings would not appear to be increased. Prognosis, Prevention, and Treatment

Supernumerary kidneys discovered serendipitously usually have good renal function and require no treatment beyond observation. However, some have complications such as hypoplasia, hydronephrosis, renal cysts, infection, and renal calculi. The frequency and nature of these problems varies according to whether the ureter is bifid (~50% have complications) or separate (~70% have problems).1 Similar complications occur in 15% or more of the ipsilateral and contralateral normally situated kidneys. Treatment is based on the severity and nature of the symptoms. Extra kidneys with evidence of pathology can be removed after renal function in the remaining kidneys is shown to be adequate. Abdominal trauma may lead to rupture of a kidney, including an accessory one, and is an unusual cause of hematuria.11 Wilms tumor in supernumerary kidneys has been reported.12 This defect cannot be prevented. However, unnecessary interventions and complications may be avoided by a greater awareness of supernumerary kidney in the differential diagnosis of abdominal or back pain and urinary tract infection. References (Supernumerary Kidney) 1. N’Guessan G, Stephens FD: Supernumerary kidney. J Urol 130:649, 1983. 2. Oto A, Kerimoglu U, Eskicorapci S, et al.: Bilateral supernumerary kidney: imaging findings. JBR-BTR 85:300, 2002. 3. Bernik TR, Ravnic DJ, Bernik SF, et al.: Ectopic supernumerary kidney, a cause of para-aortic mass: case report and review. Am Surg 67:657, 2001. 4. Sy WM, Seo IS, Sze PC, et al.: A patient with three kidneys: a correlative imaging case report. Clin Nucl Med 24:264, 1999. 5. Lowry RB: A further case of Hutterite cerebro-osteo-nephrodysplasia. Am J Med Genet 72:386, 1997. 6. Antony J: Complete duplication of female urethra with vaginal atresia and supernumerary kidney. J Urol 118:877, 1977. 7. Gupta CL, Chrungoo RK, Gupta S, et al.: Supernumerary kidney with duplication of the urinary tract: a rare congenital anomaly. BJU Int 87:903, 2001. 8. Unal M, Erem C, Serce K, et al.: The presence of both horseshoe and a supernumerary kidney associated with coarctation of aorta. Acta Cardiol 50:155, 1995. 9. Komolafe F: Unilateral supernumerary kidney associated with hypertensive encephalopathy in a child. Pediatr Radiol 13:349, 1983.

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10. Carlson HE: Supernumerary kidney: a summary of fifty-one reported cases. J Urol 64:221, 1950. 11. Hicks CC, Boehm GA, Sybers RG, et al.: Traumatic rupture of horseshoe kidney with partial ureteral duplication associated with supernumerary kidney. Urology 8:149, 1976. 12. Pawel BR, de Chadarevian JP, Smergel EM, et al.: Teratoid Wilms tumor arising as a botryoid growth within a supernumerary ectopic ureteropelvic structure. Arch Pathol Lab Med 122:925, 1998.

28.11 Renal Ectopia Definition

Renal ectopia is the permanent sitting of one or more kidneys outside the normal lumbar position. This definition excludes horseshoe kidneys, which are discussed in the next section (Section 28.12), as well as kidneys that are abnormally mobile due to loose attachment to the posterior abdominal wall and which may alter position with respiratory movement. Diagnosis

Renal ectopia may affect one or both kidneys or may involve a single kidney when there is contralateral renal agenesis. In simple ectopia, the malpositioned kidney and ureter are on the correct side, but pelvic or thoracic in location. In crossed ectopia, one or both kidneys lie on the opposite side from the normal location, with the ureter(s) crossing the midline. The fused pelvic kidney, also called lump, pancake, or discoid kidney, based on the gross anatomic appearance,1 is another form of ectopia where there is an irregular mass of renal tissue with one or more anteriorly facing renal pelvises and a variable number of ureters in the pelvic midline. The weight is usually equivalent to two kidneys and no line of fusion is apparent. Approximately 60% of ectopic kidneys are pelvic due to failure to move from the embryonic position at the level of the second and third sacral vertebrae to the normal adult position at L1–4.1 Usually, the lower the ectopic kidney is sited, the closer it is to the midline. About 10% of such unascended kidneys are solitary.2 Thoracic renal ectopia occurs when a kidney ascends beyond its normal lumbar site. Occasionally it may be found above the diaphragm. In such cases, the diaphragm may be herniated or perforated only by a foramen through which the ureter passes. Crossed renal ectopia occurs when the kidney from one side is found on the opposite side (Fig. 28-13). The ureter crosses the midline to insert into the ‘‘correct’’ side of the bladder. Very occasionally both kidneys are crossed (double crossed ectopia). In 90% of cases of crossed ectopia, the kidneys are fused. This fusion is usually at the poles such that the kidneys lie end to end with the lower kidney usually being the ectopic one. Fusion may also occur to give an L-shaped kidney or two kidneys at the same level, fused along their lengths.3 Fusion of the renal pelvises may give rise to a single ureter being present.4 Occasionally, giant hypercalycosis may displace the rest of the kidney and mimic crossed ectopia.5 Renal ectopia is often asymptomatic, but may cause infection or renal stones. The location of the resulting pain in a pelvic kidney may lead to difficulties in diagnosis as it can mimic appendicitis or lower genitourinary tract infection. Hydronephrosis due to obstruction or reflux occurs in about 55% of cases.6 Pelvic kidneys can also present as pelvic masses. They may cause dyspareunia and, especially those on the left side, may predispose to

Fig. 28-13. Crossed fused renal ectopia. The left kidney is situated on the right side below the small dysmorphic right kidney. The left ureter crosses the midline. (Reprinted with permission from Jennette JC, Olson JL, Schwartz MM, et al., eds.: Heptinstall’s Pathology of the Kidney, ed 5. Lippincott Williams & Wilkins, Philadelphia, 1998.)

dystocia for women in labor requiring cesarean section.7 The abnormal position of thoracic kidneys can, again, lead to misleading symptoms.8 Approximately 75% of patients with crossed renal ectopia present with complications including pain, dysuria, increased frequency of urination, infection, calculi, or abdominal mass.9 Kinking of the renal pelvis of the ectopic kidney or obstruction of the ureteropelvic junction by aberrant vessels can give rise to hydronephrosis. Fused pelvic kidney may be asymptomatic, but can cause ureteral obstruction. Renal calculi and recurrent infection may occur. Like other forms of ectopia, because of its unusual shape and pelvic position, it may present as a tumor. Anomalies of the ureters with hydronephrosis, obstruction, and vesicoureteral reflux are common.10 Other anomalies of the genitourinary tract that have been observed with renal ectopia include multicystic dysplasia,11–13 bladder agenesis,14 patent urachus,15 duplication of the urethra,15 unicornuate uterus,16,17 Gartner duct cyst,18 and cystic testis.19 Anomalies of associated structures have been observed including imperforate anus17 and cloacal exstrophy.20 There is also a strong association with skeletal anomalies, which are seen in 50% of cases.21 Ectopic dysplastic renal tissue may be observed in intraspinal cystic lesions and diastomatomelia.22,23 A chick model suggests that scoliosis may impede renal ascent and explain the high frequency of vertebral anomalies in cases of simple ectopia.24,25 Cardiovascular defects may also be more common. Fused pelvic kidney has been reported with cloacal, genital tract, sacral, and neural tube defects.26 Renal ectopia has been described in a number of multiple congenital anomaly syndromes including trisomy 18, trisomy 21, Turner syndrome,27 VACTERL association,28 Klippel-Feil,29 caudal regression,30 and others (Table 28-19), as well as in association with maternal cocaine use.31 Given the frequency

Table 28-19. Disorders with renal ectopia Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Acrorenal disorders —See Table 28-6 for conditions with limb deficiency defects and renal ectopia Beckwith-Wiedemann45,46

High birth weight, omphalocele, macroglossia, hypoglycemia, visceromagaly, abdominal tumors

Renal dysplasia, large kidneys, Wilms tumor

AD (130650), paternal imprinting, contiguous gene duplication CDKN1C, 11p15.5

Branchio-oto-renal (BOR)47

Mixed hearing loss, temporal bone anomalies, abnormal pinnae, branchial cleft sinuses or fistulae, preauricular pits and tags

Renal agenesis, dysplasia or ectopia, duplication of pelvis and ureter, megaureter, reflux

AD (113650) EYA1, 8q13.3

Caudal duplication48

Double and/or malformed colon, genitalia, sacrum and lower spinal cord; meningomyleocele, omphalocele; possible overlap with heteropagus twinning

Duplicated bladder, bladder or cloacal exstrophy, renal agenesis and malrotation, single pelvic kidney

Sporadic

Cerebro-reno digital defects —See Table 28-8 for conditions with structural brain anomalies and digital defects with renal ectopia CHARGE49

Coloboma, heart defect, choanal atresia, mental retardation, genital hypoplasia, ear anomalies, growth impairment, deafness

Renal agenesis or hypoplasia, hydronephrosis, duplication of pelvis or ureter, reflux, neurogenic bladder

AD (214800) CHD7, 8q12.1

Cloacal exstrophy50

Persistent cloaca, exstrophy of cloaca, failure of fusion of genital tubercles, omphalocele, vertebral defects, spina bifida cystica, abnormal genitalia

Renal dysplasia and ectopia, exstrophy of cloaca, urethral and ureteral anomalies

Heterogeneous, associated with monozygous twinning (258040)

Coffin-Siris51

Agenesis of the corpus callosum, Dandy-Walker cyst, microcephaly, mental retardation, hypoplastic phalanges and nails on fifth fingers, sparse scalp hair, coarse facies

Hydronephrosis, renal ectopia and hypoplasia

Uncertain, (135900)

Conradi-Hunnerman CDPX252

Short stature, short limbs, pigmentary anomalies, stippled epiphyses, craniofacial defects

Crossed renal ectopia

XLD, usually lethal in males EBP, Xp11.23-p11.22

Early amnion rupture53

Digital and limb amputations, ring constrictions, facial clefts, body wall defects, brain anomalies

Renal dysplasia, agenesis, and ectopia; ureteral anomalies; urethral stenosis

Sporadic

Facio-cardio-renal54

Facial dysmorphism, cardiac defects, mental retardation

Renal ectopia, horseshoe kidney, ureteral anomalies

AR (227280)

Fronto-metaphyseal dysplasia (Gorlin)55,56

Bony overgrowth of superorbital ridges, cortical hyperostosis, metaphyseal dysplasia, tibial bowing, vertebral defects, cardial defects (overlap with Melnick-Needles)

Supernumerary kidneys, hydronephrosis, ureteral defects, urethral valves

XLD (305620) FLNA, Xq28

Frontonasal dysplasia57

Marked hypertelorism, broad or notched nasal tip, ophthalmologic and heart defects, usually normal intelligence

Unilateral renal agenesis, renal ectopia

Mostly sporadic, rarely AD, AR (136760)

Goldblatt genito-patellar58

Osteoporosis, absent or hypoplastic patella, joint contractures, facial dysmorphism, scrotal hypoplasia, agenesis of corpus callosum, mental retardation

Renal dysplasia and ectopia, hydronephrosis, large kidneys

Unknown, usually sporadic, more common in males

Green59

Anal stenosis, toe syndactyly

Unilateral renal agenesis

AD

Chromosomal disorders —See Table 28-10

(continued)

1224

Table 28-19. Disorders with renal ectopia (continued) Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Hypertelorismmicrotia-clefting60,61

Hypertelorism, microtia, deafness, cleft lip and palate, cardiac deafness, mental retardation in some cases

Renal ectopia, double ureters

AR (239800)

Kivlin/Peters plus62

Hydrocephalus, agenesis of the corpus callosum, dysmorphic face, Peters’ anomaly, sclerocornea, dysmorphic face, cleft lip, short stature, broad hands and feet, clinodactyly, brachdactyly, mental retardation

Renal ectopia, double ureters

AR (261540)

Klippel-Feil deafnessabsent vagina63

Klippel-Feil anomaly, short stature, conductive deafness, absent vagina

Unilateral renal agenesis, renal ectopia

Unknown (148860)

Lower mesodermal defects64,65

Prune belly, absent or malformed genitalia, sacral defects, imperforate anus, prolapsed perineum

Renal agenesis, dysgenesis, hypoplasia or ectopia, hydronephrosis, malrotation, hypoplastic or absent bladder, absent or blind ending urethra, urachal cyst

Sporadic

Malpuech66

Mental retardation, growth retardation, hypertelorism, cleft lip and palate, genital and cardiac defects, caudal appendage

Renal agenesis, dysplasia or ectopia, reflux

AR (248340)

Melnick-Needles osteodysplasty55,56

Short stature, wide metaphyses, facial dysmorphism, omphalocele in males (overlap with Frontometaphyseal dysplasia)

Renal ectopia, ureteral anomalies, urethral atresia

XLD (309350) FLNA, Xq28

MURCS association67

Mu¨llerian duct aplasia, renal agenesis, cervicothoracic somitic (vertebral) defects; hypoplastic uterus; absent vagina; short stature

Renal agenesis, dysplasia, or ectopia; ureteral anomalies, reflux

Sporadic (601076)

Neural tube defects68–70

Meningomyelocele, anencephaly, encephalocele, vertebral anomalies, midline anomalies

Renal agenesis, hypoplasia, dysplasia, or ectopia; ureteral anomalies, urethral atresia hydronephrosis, horseshoe kidney

Heterogeneous, multifactorial in most cases

Osteorenal defects —See Table 28-11 for conditions with generalized skeletal dysplasia and renal ectopia Pallister-Hall71

Hypothalamic hamartoblastoma, complex polydactyly, imperforate anus, buccal frenulae, cleft larynx, visceral anomalies

Renal agenesis, dysplasia or ectopia, hydronephrosis, inverted horseshoe kidneys

AD (146510), variable expressivity GLI3, 7p13

Passwell72

Ichthyosis, short stature, mental retardation

Pelvic kidney, double ureters, nephropathy

AR (242530)

Penoscrotal transposition/diphallus73–75

Penoscrotal transposition, diphallus, other genital anomalies, cardiomyopathy, vertebral and anal anomalies, patellar defects (overlap with VACTERL)

Cystic dysplasia, renal ectopia, hydronephrosis, bladder diverticula, ureteral defects

AD, heterogeneous, del 13q32-q34

Schinzel-Giedion76

Cortical hyperostosis, acrosteolysis, mesomelic lower limbs, bowed long bones, facial dysmorphism, CNS and cardiac defects, mental retardation, teratomata

Renal ectopia, hydronephrosis, ureteral anomalies, megacalysis

AR (269150)

Syndactyly type V77

Fusion of fourth and fifth metacarpals, other digital defects

Pelvic kidney, bladder exstrophy

AD (186300), variable expressivity

Thomas

Microphthalmia, microtia, cardiac and genital defects, camptodactyly

Renal ectopia, hydronephrosis, ureteric defects, dilated bladder

AR

VACTERL association78

Vertebral, anal, cardiac, tracheoesophageal, and limb defects

Renal agenesis, dysplasia or ectopia, horseshoe kidneys

Sporadic (continued)

1225

1226

Urogenital System Organs

Table 28-19. Disorders with renal ectopia (continued) Causation Gene/Locus

Disorder

Prominent Features

Urinary Tract Anomalies

Williams79–81

Characteristic facies, stellate irides, mental retardation, heart defects, radioulnar synostosis, infantile hypercalcemia

Small kidneys, renal ectopic or aplasia, duplicated pelvis or ureter, other ureteral defects, renal artery stenosis, urethral stenosis, bladder diverticula

AD (194050) ELN, 7q11.2

Winter renal-genital-ear82,83

Abnormal internal genitalia, vaginal atresia, abnormal ossicles in middle ear, small ears, deafness (overlap with MURCS and urogenital dysplasia)

Renal agenesis and hypoplasia, pelvic kidney

AR (267400)

Zlotogora-Dagan84

Microcephaly, holoprosencephaly, thumb anomalies, short stature, low birth weight, mental retardation

Renal ectopia

AR

of renal ectopia, its occurrence in some individuals with multiple anomaly syndromes is probably coincidental.32 A variety of imaging modalities including ultrasound, intravenous pyelography (IVP), voiding cystography, radionuclide scanning, computed tomography scan, and arteriography may be helpful in diagnosing renal ectopia and avoiding unnecessary surgery or vascular compromise. In crossed renal ectopia, IVP can help distinguish this condition from horseshoe kidney and from duplicated renal pelvis in a solitary kidney by allowing the course of the ureters to be traced. Etiology and Distribution

Simple renal ectopia of one kidney is a relatively common malformation occurring in approximately one in 800 individuals.1,33 It is observed more often in males.1 The left kidney is slightly (~55%) more susceptible. Bilateral ectopia is much rarer and is not seen with thoracic kidneys. Crossed ectopia occurs in one in 1000 to 7600 individuals.3,9 Males are more commonly affected (60%) and the left side crosses to the right in about 60% of cases.3 Fused pelvic kidney is even rarer, occurring in about one in 17,000 individuals.34 The cause of failure of the kidney to ascend in the absence of mechanical impediment is unclear. Potentially the kidney could start to rise and stop or not move at all. The renal vasculature remains established at the developmental stage appropriate to the height achieved, suggesting an arrest in movement. The mechanisms suggested for crossed renal ectopia are that the ureteric bud crosses the midline and induces a second kidney from the metanephric blastema on that side or that the ectopic kidney develops on the correct side, but, during ascent, its upper pole becomes fused to the lower pole of the leading kidney, and thus it gets dragged across the midline. The latter hypothesis would not explain crossed ectopia without fusion or those cases where the upper kidney is the ectopic one. Fused pelvic kidney most likely results from total fusion of the metanephric ducts, which would account for the occurrence of a single ureter in some cases. Alternatively, there may be fusion of the metanephric blastemata in early kidney embryogenesis. Most cases of isolated renal ectopia are sporadic. However, autosomal dominant inheritance has been postulated in some families35 and may represent cases of familial urogenital dysplasia. Concordance in monozygous twins has been reported.36,37

Prognosis, Prevention, and Treatment

The prognosis for patients with renal ectopia is dependent on associated urologic disease rather than the abnormal positioning per se; thus, treatment must be planned accordingly.6 Complications from obstructed and hydronephrotic ureters appears to be more common in fused pelvic kidneys than in horseshoe kidneys. Surgical correction may be difficult because of the aberrant blood supply and the abnormal structure of the pelvises and ureters. The association of renal ectopia with aortic aneurysm requires the need for careful evaluation of the renal vasculature before surgery to reduce the risk of renal ischemia.38–41 Iliac artery aneurysms are associated with fused pelvic kidneys.42 A variety of neoplasias, including Wilms tumor, adenocarcinoma and renal cell carcinoma, have been reported in ectopic kidneys, but the magnitude of the increased risk, if any, is unclear. Unless other family members are known to be affected, the recurrence risk for isolated renal ectopia is low. Risks for syndromic cases will depend on the underlying etiology. Prenatal diagnosis by ultrasound is feasible, but generally made after 24 weeks.43 If the finding of an isolated pelvic kidney is made coincidentally, parents can usually be reassured that renal function is unlikely to be impaired and that neonatal intervention is rarely required.43 In the absence of renal pathology, ectopic kidneys can be used for transplantation.44 References (Renal Ectopia) 1. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 2. Thompson GR, Pace JM: Ectopic kidney: a review of 97 cases. Surg Gynecol Obstet 64:935, 1937. 3. Toguri AG, Alton DJ, Miskin M, et al.: Crossed fused renal ectopia. Urology 13:61, 1979. 4. Bissada NK, Fried FA, Redman JF: Crossed-fused renal ectopia with a solitary ureter. J Urol 114:304, 1975. 5. Deliveliotis C, Sofras F, Picramenos D, et al.: A rare case of gigantic calyx dilatation manifested as renal ectopia. Int Urol Nephrol 27:365, 1995. 6. Gleason PE, Kelalis PP, Husmann DA, et al.: Hydronephrosis in renal ectopia: incidence, etiology and significance. J Urol 151:1660, 1994. 7. Anderson GW, Rice GG, Harris BA Jr: Pregnancy and labor complicated by pelvic ectopic kidney. J Urol 65:760, 1951.

Urinary Tract 8. William RR, Jeans WD: Thoracic ectopic kidney in an adult. Scand J Urol Nephrol 30:133, 1996. 9. McDoanld JH, McClellan DS: Crossed renal ectopia. Am J Surg 93:995, 1957. 10. Srivastava RN, Singh M, Ghai OP, et al.: Complete renal fusion (‘‘cake’’/’’lump’’ kidney). Br J Urol 43:391, 1971. 11. Maayan A, Mashiach R, Kessler OJ, et al.: Prenatal diagnosis of crossed ectopic multicystic kidney. Am J Perinatol 15:499, 1998. 12. Evans WP, Sumner TE, Lorentz WB Jr, et al.: Association of crossed fused renal ectopia and multicystic kidney. J Urol 122:821, 1979. 13. Nussbaum AR, Hartman DS, Whitley N, et al.: Multicystic dysplasia and crossed renal ectopia. AJR Am J Roentgenol 149:407, 1987. 14. Sarica K, Kupeli S: Agenesis of bladder associated with multiple organ anomalies. Int Urol Nephrol 27:697, 1995. 15. Lane V: Congenital patent urachus associated with complete (hypospadiac) duplication of the urethra and solitary crossed renal ectopia. J Urol 127:990, 1982. 16. Fedele L, Bianchi S, Agnoli B, et al.: Urinary tract anomalies associated with unicornuate uterus. J Urol 155:847, 1996. 17. Eckford SD, Westgate J: Solitary crossed renal ectopia associated with unicornuate uterus, imperforate anus and congenital scoliosis. J Urol 156:221, 1996. 18. Lee MJ, Yoder IC, Papanicolaou N, et al.: Large Gartner duct cyst associated with a solitary crossed ectopic kidney: imaging features. J Comput Assist Tomogr 15:149, 1991. 19. Burns JA, Cooper CS, Austin JC: Cystic dysplasia of the testis associated with ipsilateral renal agenesis and contralateral crossed ectopia. Urology 60:344, 2002. 20. Meglin AJ, Balotin RJ, Jelinek JS, et al.: Cloacal exstrophy: radiologic findings in 13 patients. AJR Am J Roentgenol 155:1267, 1990. 21. Hertz M, Rubinstein ZJ, Shahin N, et al.: Crossed renal ectopia: clinical and radiological findings in 22 cases. Clin Radiol 28:339, 1977. 22. Sharma MC, Arora R, Sharma P, et al.: Diastematomyelia associated with ectopic dysplastic renal tissue—report of a rare case. Childs Nerv Syst 17:689, 2001. 23. Ersahin Y, Demirtas E, Mutluer S, et al.: Split cord malformations: report of three unusual cases. Pediatr Neurosurg 24:155, 1996. 24. Maizels M, Stephens FD: The induction of urologic malformations. Understanding the relationship of renal ectopia and congenital scoliosis. Invest Urol 17:209, 1979. 25. Gotoh T, Shinno Y, Koyanagi T: Crossed renal ectopia and asymmetric fused kidney, with special reference to associated vertebral anomalies. Int Urol Nephrol 19:33, 1987. 26. Escobar LF, Weaver DD, Bixler D, et al.: Urorectal septum malformation sequence. Report of six cases and embryological analysis. Am J Dis Child 141:1021, 1987. 27. Lippe B, Geffner ME, Dietrich RB, et al.: Renal malformations in patients with Turner syndrome: imaging in 141 patients. Pediatrics 82:852, 1988. 28. Uehling DT, Gilbert E, Chesney R: Urologic implications of the VATER association. J Urol 129:352, 1983. 29. Da Silva EO: Preaxial polydactyly and other defects associated with Klippel-Feil anomaly. Hum Hered 43:371, 1993. 30. Brock JW III, Braren V, Phillips K, et al.: Caudal regression with cake kidney and a single ureter: a case report. J Urol 130:535, 1983. 31. Lezcano L, Antia DE, Sahdev S, et al.: Crossed renal ectopia associated with maternal alkaloid cocaine abuse: a case report. J Perinatol 14:230, 1994. 32. Caksen H, Cesur Y, Kirimi E, et al.: A case of Allgrove (Triple A) syndrome associated with renal ectopia. Genet Couns 13:179, 2002. 33. Risdon RA, Woolf AS. Developmental defects and cystic diseases of the kidney. In: Heptinstall’s Pathology of the Kidney. JC Jennette, JL Olson, MM Schwartz, et al., eds. Lippincott-Raven Publishers, Philadelphia, 1988, p 1149. 34. Campbell MF, Harrison JH: Urology, ed 3. WB Saunders Company, Philadelphia, 1970. 35. Rinat C, Farkas A, Frishberg Y: Familial inheritance of crossed fused renal ectopia. Pediatr Nephrol 16:269, 2001.

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36. De Dominicis C, Iori F, Mattioli D, et al.: Specular crossed renal ectopia and balanic hypospadias in monozygotic twins. Minerva Urol Nefrol 41:23, 1989. 37. Fanizza-Orphanos A, Bendon RW: Simple ectopia of the kidney in monozygotic twins. J Urol 137:706, 1987. 38. Crawford ES, Coselli JS, Safi HJ, et al.: The impact of renal fusion and ectopia on aortic surgery. J Vasc Surg 8:375, 1988. 39. De Virgilio C, Gloviczki P: Aortic reconstruction in patients with horseshoe or ectopic kidneys. Semin Vasc Surg 9:245, 1996. 40. Faggioli G, Freyrie A, Pilato A, et al.: Renal anomalies in aortic surgery: contemporary results. Surgery 133:641, 2003. 41. Yano H, Konagai N, Maeda M, et al.: Abdominal aortic aneurysm associated with crossed renal ectopia without fusion: case report and literature review. J Vasc Surg 37:1098, 2003. 42. Eckes D, Lawrence P: Bilateral iliac artery aneurysms and pancake kidney: a case report. J Vasc Surg 25:927, 1997. 43. Meizner I, Yitzhak M, Levi A, et al.: Fetal pelvic kidney: a challenge in prenatal diagnosis? Ultrasound Obstet Gynecol 5:391, 1995. 44. Bailey SH, Mone MC, Nelson EW: Transplantation of crossed fused ectopic kidneys into a single recipient. J Am Coll Surg 194:147, 2002. 45. Elliott M, Maher ER: Beckwith-Wiedemann syndrome. J Med Genet 31:560, 1994. 46. Lam WW, Hatada I, Ohishi S, et al.: Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J Med Genet 36:518, 1999. 47. Chen A, Francis M, Ni L, et al.: Phenotypic manifestations of branchiooto-renal syndrome. Am J Med Genet 58:365, 1995. 48. Dominguez R, Rott J, Castillo M, et al.: Caudal duplication syndrome. Am J Dis Child 147:1048, 1993. 49. Ragan DC, Casale AJ, Rink RC, et al.: Genitourinary anomalies in the CHARGE association. J Urol 161:622, 1999. 50. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261, 2001. 51. Fleck BJ, Pandya A, Vanner L, et al.: Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study. Am J Med Genet 99:1, 2001. 52. Milunsky JM, Maher TA, Metzenberg AB: Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP. Am J Med Genet 116A:249, 2003. 53. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 54. Eastman JR, Bixler D: Facio-cardio-renal syndrome: a newly delineated recessive disorder. Clin Genet 11:424, 1977. 55. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 56. Franceschini P, Guala A, Licata D, et al.: Esophageal atresia with distal tracheoesophageal fistula in a patient with fronto-metaphyseal dysplasia. Am J Med Genet 73:10, 1997. 57. Roizenblatt J, Wajntal A, Diament AJ: Median cleft face syndrome or frontonasal dysplasia: a case report with associated kidney malformation. J Pediatr Ophthalmol Strabismus 16:16, 1979. 58. Cormier-Daire V, Chauvet ML, Lyonnet S, et al.: Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. J Med Genet 37:520, 2000. 59. Green AJ, Sandford RN, Davison BC: An autosomal dominant syndrome of renal and anogenital malformations with syndactyly. J Med Genet 33:594, 1996. 60. Nevin NC, Hill AE, Carson DJ: Facio-cardio-renal (Eastman-Bixler) syndrome. Am J Med Genet 40:31, 1991. 61. Amiel J, Faivre L, Marianowskl R, et al.: Hypertelorism-microtiaclefting syndrome (Bixler syndrome): report of two unrelated cases. Clin Dysmorphol 10:15, 2001.

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Urogenital System Organs

62. Maillette de Buy Wenniger-Prick LJ, Hennekam RC: The Peters’ plus syndrome: a review. Ann Genet 45:97, 2002. 63. Baird PA, Lowry RB: Absent vagina and the Klippel-Feil anomaly. Am J Obstet Gynecol 118:290, 1974. 64. Lubinsky MS: Female pseudohermaphroditism and associated anomalies. Am J Med Genet 6:123, 1980. 65. Pauli RM: Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet 50:154, 1994. 66. Crisponi G, Marras AR, Corrias A: Two sibs with Malpuech syndrome. Am J Med Genet 86:294, 1999. 67. Duncan PA, Shapiro LR, Stangel JJ, et al.: The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 95:399, 1979. 68. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 69. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983. 70. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 71. Kang S, Allen J, Graham JM Jr, et al.: Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 34:441, 1997. 72. Passwell JH, Goodman RM, Ziprkowski M, et al.: Congenital ichthyosis, mental retardation, dwarfism and renal impairment: a new syndrome. Clin Genet 8:59, 1975. 73. Parida SK, Hall BD, Barton L, et al.: Penoscrotal transposition and associated anomalies: report of five new cases and review of the literature. Am J Med Genet 59:68, 1995. 74. Dodat H, Rosenberg D, James-Pangaud I: Familial association of penoscrotal transposition and diphallia (double penis) with patella aplasia. Arch Pediatr 2:241, 1995. 75. Bartsch O, Kuhnle U, Wu LL, et al.: Evidence for a critical region for penoscrotal inversion, hypospadias, and imperforate anus within chromosomal region 13q32.2q34. Am J Med Genet 65:218, 1996. 76. Labrune P, Lyonnet S, Zupan V, et al.: Three new cases of the SchinzelGiedion syndrome and review of the literature. Am J Med Genet 50:90, 1994. 77. Robinow M, Johnson GF, Broock GJ: Syndactyly type V. Am J Med Genet 11:475, 1982. 78. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8, 1997. 79. Pober BR, Lacro RV, Rice C, et al.: Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 46:271, 1993. 80. Pankau R, Partsch CJ, Winter M, et al.: Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 63:301, 1996. 81. Morris CA, Leonard CO, Dilts C, et al.: Adults with Williams syndrome. Am J Med Genet Suppl 6:102, 1990. 82. Winter JS, Kohn G, Mellman WJ, et al.: A familial syndrome of renal, genital, and middle ear anomalies. J Pediatr 72:88, 1968. 83. Willemsen WN. Renal-skeletal-ear- and facial-anomalies in combination with the Mayer-Rokitansky-Kuster (MRK) syndrome. Eur J Obstet Gynecol Reprod Biol 14:121, 1982. 84. Zlotogora J, Dagan J, Ganen A, et al.: A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism. J Med Genet 34:813, 1997.

28.12 Horseshoe Kidney Definition

Horseshoe kidneys are fused kidneys with an equal amount of renal tissue on each side of the midline. Fusion usually (90–95%) occurs at the lower poles, but may occur at the upper poles or

even at both (doughnut kidney).1 The ureters do not cross the midline before entering the renal sinuses. Crossed fused renal ectopia, lump kidney, discoid kidney, and pancake kidney are not included in this definition and are covered in Section 28.12 (renal ectopia). Diagnosis

Horseshoe kidneys are the most common type of fused kidneys. They remain in the pelvis because their ascent is blocked by the inferior mesenteric artery at its junction with the aorta. Rotation is also prevented, and thus the pelvises face anteriorly (Fig. 28-14). One-third of individuals with horseshoe kidneys remain asymptomatic.2 Horseshoe kidneys may be found in such individuals during the investigation of associated structural anomalies or unrelated medical problems, or in those undergoing abdominal surgery. Obstruction of the ureters may lead to clinical symptoms including pain, hematuria, and infection.3 Abdominal discomfort is found in approximately 55%, and 65% show a positive Rovsing’s sign.4 Infants and children may present with a lower abdominal mass.5 In such cases, fine needle biopsy revealing normal renal tissue can be helpul.6 In one study,7 40% of individuals with horseshoe kidneys presented with ureteropelvic junction obstruction, 18% with renal stones, and 22% with urinary tract infection. Hydronephrosis is the most frequent associated genitourinary anomaly and is often associated with reflux, ureteral obstruction, and/or megaureter. In one study of 52 cases,8 52% showed some degree of urinary tract obstruction. Duplicated and ectopic ureters are common. Horseshoe kidneys can be affected by the same forms of renal malformation documented elsewhere in this chapter, including polycystic kidney disease,9–11 medullary cystic disease,12 and medullary sponge kidney.13 Occasionally, a supernumerary kidney may be present between two pelvic kidneys, mimicking fused kidneys (pseudohorseshoe).14 Other associated genitourinary anomalies are hypospadias and cryptorchidism. Anomalies outside the genitourinary tract are found in onethird of individuals with horseshoe kidneys.15 Their frequency varies with age, reflecting ascertainment bias; 79% of infants, 28% of children, and 4% of adults with horseshoe kidneys have additional

Fig. 28-14. Ventral (A) and dorsal (B) views of horseshoe kidney. Note the duplicated renal pelvis and fused ureters on the right side. (Reprinted with permission from Moore KL, ed.: The Developing Human: Clinically Oriented Embryology, ed 5. WB Saunders Company, Philadelphia, 1988.)

Urinary Tract

defects, especially in the musculoskeletal, cardiac,16 and central nervous systems.17 Midline defects including neural tube defects, vertebral anomalies, and anal atresia are common, and situs inversus has also been reported.18,19 Horseshoe kidney is especially common in Turner syndrome20 and trisomy 18. Patterns of anomalies often associated with horseshoe kidneys are further documented in Table 2820. Due to its high frequency, this malformation may also be seen coincidentally in other syndromes. Ultrasound examination can identify the basic renal anatomy, evidence of obstruction, and dilation of the calyces.21 The most useful finding for diagnosis is demonstration of a band or isthmus of renal tissue crossing the midline.22 Ultrasound also reveals tapering and elongation of the lower renal poles and malrotation of each kidney with an anteriorly pointing pelvis.23 The malrotation is commonly more pronounced on the left side, and hydronephrosis is observable in approximately 50% of cases.24 Even when the band of fused tissue is not apparent, the diagnosis is strongly suggested by the inverted triangle conformation.22 Caution is needed in evaluating children with neural tube defects, as their pronounced gibbus may produce a similar renal pattern.25,26 Intravenous pyelograph can be used to define the anatomy of the ureters and kidneys and can be especially useful in evaluating horseshoe kidneys that present as retroperitoneal masses on computed tomography scan.27 Retrograde pyelography may be necessary to determine the entire course of the ureters. Angiography to define the blood supply is also important if surgery is planned. Radioisotope tests can be useful in the initial evaluation and in follow-up to evaluate renal function.28 Etiology and Distribution

Horseshoe kidneys are among the most common of renal malformations, occurring in one in 300 to 400 individuals, both in series of surviving patients and of autopsies.4,29,30 They are two to three times more common in males.4,31 The embryologic basis for horseshoe kidneys likely differs depending on whether the isthmus contains renal parenchyma. Primary fusion in the 4th to 6th week of development could occur because of close proximity of the lower poles of the kidneys, leading to adhesion of parenchymal elements from the two metanephric blastemas, or due to a single blastema interacting with separate ureteric buds arising from two mesonephric ducts. A third mechanism would involve abnormal migration of nephrogenic cells across the primitive streak.32 Secondary fusion may occur as late as weeks 7 to 9 because of disruption of vascular blood supply or premature ablation of the polar arteries during upward migration, resulting in partial necrosis and subsequent fusion of the kidneys. In this case, the isthmus contains fibrous tissue only.33 Most cases of isolated horseshoe kidney are sporadic. However, familial cases have been noted, including a brother and two sisters.34 Monozygous twin pairs have usually been discordant,35,36 but Bridge37 reported a pair where one had horseshoe kidney and the other crossed renal ectopia, suggesting a common etiology for the two defects. As noted, horseshoe kidney with associated malformations can be due to a variety of chromosomal, single gene, or teratogenic syndromes. Prognosis, Prevention, and Treatment

Rarely will isolated horseshoe kidneys lead to death. In only 5% of patients from one postmortem series was death attributable to the renal malformation.3 When the defect is found serendipitously in an asymptomatic patient, no specific management is required.

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Treatment is indicated for hydronephrosis and vesicoureteral reflux to ameliorate symptoms and prevent renal damage.8,38–40 Horseshoe kidneys are at increased risk for traumatic rupture41 and, because of their position and the frequent association of renal artery abnormalities, may complicate surgery for aortic aneurysms.42,43 The long-term outcome for most patients, however, is determined largely by the severity of associated anomalies. Horseshoe kidneys are at increased risk for neoplastic transformation.11 Wilms tumor44 is the most common tumor reported, but a variety of others including adenocarcinoma, teratoma, transitional cell tumors, primary carcinoid tumors, renal cell carcinoma, somatostatinoma, and oncocytoma11,45–50 have also been seen. Recurrence risks are not increased for isolated horseshoe kidney. Genetic counseling for complex situations must be based on the underlying etiologic disorder. Prenatal diagnosis is feasible because horseshoe kidneys have been identified via transvaginal ultrasound before 16 weeks gestation.51 Unless the potential donor suffered from other health problems, horseshoe kidneys are suitable for renal transplantation, either divided or on block.52,53 References (Horseshoe Kidney) 1. Gordon-Taylor G: On horseshoes and horseshoe kidneys concave downwards. Br J Urol 8:112, 1936. 2. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 3. Cook WA, Stephens FD: Fused kidneys: morphologic study and theory of embryogenesis. Birth Defects Orig Artic Ser XII(5):327, 1977. 4. Basar H, Basar R, Basar MM, et al.: The comparison of the incidence of horseshoe kidney in autopsy cases versus urologic patient population. Okajimas Folia Anat Jpn 76:137, 1999. 5. Karmi SA: Rare urologic pathology presenting as abdominal masses in children. J Urol 118:431, 1977. 6. Benito A, Vargas J, de Agustin P: Horseshoe kidney presenting as a retroperitoneal mass. Report of a case diagnosed by fine needle aspiration cytology. Acta Cytol 43:877, 1999. 7. Grainger R, Murphy DM, Lane V: Horseshoe kidney—a review of the presentation, associated congenital anomalies and complications in 73 patients. Ir Med J 76:315, 1983. 8. Cascio S, Sweeney B, Granata C, et al.: Vesicoureteral reflux and ureteropelvic junction obstruction in children with horseshoe kidney: treatment and outcome. J Urol 167:2566, 2002. 9. Caglar K, Kibar Y, Tahmaz L, et al.: Polycystic horseshoe kidney. Clin Nephrol 55:487, 2001. 10. Gittes GK, Snyder CL, Murphy JP, et al.: Inferior vena caval obstruction from a horseshoe kidney: report of a case with operative decompression. J Pediatr Surg 33:764, 1998. 11. Dische MR, Johnston R: Teratoma in horseshoe kidneys. Urology 13:435, 1979. 12. Van Every MJ: In utero detection of horseshoe kidney with unilateral multicystic dysplasia. Urology 40:435, 1992. 13. Lambrianides AL, John DR: Medullary sponge disease in horseshoe kidney. Urology 29:426, 1987. 14. Macpherson RI: Supernumerary kidney: typical and atypical features. Can Assoc Radiol J 38:116, 1987. 15. Boatman DL, Kolln CP, Flocks RH: Congenital anomalies associated with horseshoe kidney. J Urol 107:205, 1972. 16. Greenwood RD, Rosenthal A, Nadas AS: Cardiovascular malformations associated with congenital anomalies of the urinary system. Observations in a series of 453 infants and children with urinary system malformations. Clin Pediatr (Phila) 15:1101, 1976. 17. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976.

Table 28-20. Disorders with horseshoe kidney Syndrome

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Acrorenal disorders —See Table 28-6 for conditions with limb deficiency defects and horseshoe kidney Agnathia-holoprosencephaly54

Antley-Bixler

55,56

Bowen-Conradi57,58

Holoprosencephaly, missing or small jaw, midline defects, situs inversus

Horseshoe kidneys, hydronephrosis

Probably heterogeneous, may be AR in some families (202650)

Craniosynostosis, brachycephaly, frontal bossing, depressed nasal root, downslanting palpebral fissures, bowed femurs, slender bones, multiple fractures, heart and genital defects

Renal agenesis, horseshoe kidney

AR (207410) heterogeneous POR, 7q11.2 FGFR2, 10q26 Prenatal fluconazole exposure

Proud nose, micrognathia, microcephaly, hypospadias, rocker-bottom feet, death in infancy

Horseshoe kidney, double ureters

AR (211180), Predominantly seen in Hutterites

Chromosome defects —See Table 28-10 Facio-cardio-renal59

Facial dysmorphism, cardiac defects, mental retardation

Renal ectopia, horseshoe kidney, ureteral anomalies

AR (227280)

G (Opitz-Frias)

Hypertelorism; hypospadias; laryngeal, esophageal, and cardiac defects; cleft palate; mental retardation

Horseshoe kidney, ureteral defects

AD (145410) variable expressivity 22q11.2

Goltz60

Focal dermal hypoplasia, papillomata, digital anomalies, oral and ocular defects, striated bones

Unilateral renal agenesis or hypoplasia, horseshoe kidney, duplication of pelvis or ureter

XLD, lethal in males (305600)

Iniencephaly61

Spinal retroflexion, encephalocele, holoprosencephaly, cardiac and gastrointestinal anomalies

Renal agenesis, hypoplasia and cystic dysplasia, horseshoe kidney

Sporadic

Juberg/Hayward62

Microcephaly, cleft lip and palate, thumb anomalies, nasal defects

Horseshoe kidney, small kidneys

AR (216100)

Kabuki63,64

Facial dysmorphism, dental and cardiac anomalies, mental retardation common

Renal dysplasia, horseshoe kidney, hydronephrosis, ureteral defects, reflux

Likely AD with variable expressivity, most cases new mutations (147920)

Mievis65

Severe short stature, metaphyseal dysplasia, delayed bone age, facial dysmorphism

Horseshoe kidney

Uncertain, (601350)

Neural tube defects17,66,67

Meningomyelocele, anencephaly, encephalocele, vertebral anomalies, midline anomalies

Renal agenesis, hypoplasia, dysplasia, or ectopia; ureteral anomalies, urethral atresia hydronephrosis, horseshoe kidney

Heterogeneous, multifactorial in most cases

Pallister-Hall68

Hypothalamic hamartoblastoma, complex polydactyly, imperforate anus, buccal frenulae, cleft larynx, visceral anomalies

Renal agenesis, dysplasia or ectopia, hydronephrosis, inverted horseshoe kidney

AD (146510), variable expressivity GLI3, 7p13

Renal and Mu¨llerian duct hypoplasia-craniofacial anomalies69

Severe developmental delay, growth retardation, genital anomalies, facial dysmorphism, dimples at elbows and wrists

Small kidneys, horseshoe kidney, reflux

AR (266810)

Russell-Silver70–73

Short stature, small triangular face, blue sclerae, asymmetric limbs, clinodactyly of fifth fingers, genital defects, variable mental retardation, feeding problems, excessive sweating

Hydronephrosis, renal tubular acidosis, horseshoe kidney, urethral valves

AD (180860), most cases sporadic, maternal uniparental disomy for chromosome 7 in ~10% 7p11.2

Teebi-Shaltout74

Abnormal teeth and hair, camptodactyly, eye anomalies, caudal appendage

Horseshoe kidney, hydronephrosis, ureteral defects

AR (272950)

Renal agenesis, dysplasia or ectopia, horseshoe kidney

Sporadic

Teratogenic exposures —See Table 28-11 VACTERL association75

Vertebral, anal, cardiac, tracheoesophageal and limb defects

(continued)

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Urinary Tract

1231

Table 28-20. Disorders with horseshoe kidney (continued) Causation Gene/Locus

Syndrome

Prominent Features

Urinary Tract Anomalies

Wilms tumoraniridia (WAGR)76,77

Aniridia, hemihypertrophy, genital anomalies, short stature, mental retardation

Renal dysplasia, horseshoe kidney

Contiguous gene deletion, 11p13

X-linked laterality defects78–80

Laterality defects; caudal dysplasia; brain, spine, uterine, and anal defects

Horseshoe kidney, hydronephrosis, reflux

XLR (304750) ZIC3, Xq26.2

Young-Madders (pseudo-trisomy 13)81

Holoprosencephaly, other structural brain defects, premaxillary agenesis, preaxial polydactyly, heart defects

Renal agenesis, horseshoe kidney

AR (264480)

18. Treiger BF, Khazan R, Goldman SM, et al.: Renal cell carcinoma with situs inversus totalis. Urology 41:455, 1993. 19. Matsushita K, Ueda S, Ikegami K: Horseshoe kidney in a patient with situs inversus totalis. J Urol 128:604, 1982. 20. Lippe B, Geffner ME, Dietrich RB, et al.: Renal malformations in patients with Turner syndrome: imaging in 141 patients. Pediatrics 82:852, 1988. 21. Reinberg Y, Gonzalez R: Upper urinary tract obstruction in children: current controversies in diagnosis. Pediatr Clin North Am 34:1291, 1987. 22. Banerjee B, Brett I: Ultrasound diagnosis of horseshoe kidney. Br J Radiol 64:898, 1991. 23. Strauss S, Dushnitsky T, Peer A, et al.: Sonographic features of horseshoe kidney: review of 34 patients. J Ultrasound Med 19:27, 2000. 24. Whitehouse GH: Some urographic aspects of the horseshoe kidney anomaly—a review of 59 cases. Clin Radiol 26:107, 1975. 25. Mandell GA, Maloney K, Sherman NH, et al.: The renal axes in spina bifida: issues of confusion and fusion. Abdom Imaging 21:541, 1996. 26. Fernbach SK, Davis TM: The abnormal renal axis in children with spina bifida and gibbus deformity—the pseudohorseshoe kidney. J Urol 136:1258, 1986. 27. Siegfried MS, Rochester D: Computed tomography appearance of fused (horseshoe) kidney. J Comput Tomogr 7:301, 1983. 28. Grandone CH, Haller JO, Berdon WE, et al.: Asymmetric horseshoe kidney in the infant: value of renal nuclear scanning. Radiology 154:366, 1985. 29. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 30. Tan PH, Chiang GS, Tay AH: Pathology of urinary tract malformations in a paediatric autopsy series. Ann Acad Med Singapore 23:838, 1994. 31. Csontai A, Liptak J, Gaizler G, et al.: Horseshoe kidney and its therapeutic problems. (A review of seventy-one clinical cases.) Int Urol Nephrol 10:93, 1978. 32. Domenech-Mateu JM, Gonzalez-Compta X: Horseshoe kidney: a new theory on its embryogenesis based on the study of a 16-mm human embryo. Anat Rec 222:408, 1988. 33. Hohenfellner M, Schultz-Lampel D, Lampel A, et al.: Tumor in the horseshoe kidney: clinical implications and review of embryogenesis. J Urol 147:1098, 1992. 34. David RS: Horseshoe kidney: a report of one family. Br Med J 4:571, 1974. 35. Kalra D, Broomhall J, Williams J: Horseshoe kidney in one of identical twin girls. J Urol 134:113, 1985. 36. Leiter E: Horseshoe kidney: discordance in monozygotic twins. J Urol 108:683, 1972. 37. Bridge RAC: Horseshoe kidneys in identical twins. Br J Urol 32:32, 1960. 38. McLorie GA, McKenna PH, Jumper BM, et al.: High grade vesicoureteral reflux: analysis of observational therapy. J Urol 144:537, 1990. 39. Bellinger MF: The management of vesicoureteric reflux. Urol Clin North Am 12:23, 1985.

40. Lerner GR, Fleischmann LE, Perlmutter AD: Reflux nephropathy. Pediatr Clin North Am 34:747, 1987. 41. Hicks CC, Boehm GA, Sybers RG, et al.: Traumatic rupture of horseshoe kidney with partial ureteral duplication associated with supernumerary kidney. Urology 8:149, 1976. 42. Aljabri B, MacDonald PS, Satin R, et al.: Incidence of major venous and renal anomalies relevant to aortoiliac surgery as demonstrated by computed tomography. Ann Vasc Surg 15:615, 2001. 43. Illig KA, Green RM: Diagnosis and management of the ‘‘difficult’’ abdominal aortic aneurysm: pararenal aneurysms, inflammatory aneurysms, and horseshoe kidney. Semin Vasc Surg 14:312, 2001. 44. Neville H, Ritchey ML, Shamberger RC, et al.: The occurrence of Wilms tumor in horseshoe kidneys: a report from the National Wilms Tumor Study Group (NWTSG). J Pediatr Surg 37:1134, 2002. 45. Murphy DM, Zincke H: Transitional cell carcinoma in the horseshoe kidney: report of 3 cases and review of the literature. Br J Urol 54:484, 1982. 46. Crawford ED, Henning DC, Wendel RG: Renal cell carcinoma in a horseshoe kidney associated with von Hippel-Lindau disease. J Urol 121:677, 1979. 47. McVey RJ, Banerjee SS, Eyden BP, et al.: Carcinoid tumor originating in a horseshoe kidney. In Vivo 16:197, 2002. 48. Isobe H, Takashima H, Higashi N, et al.: Primary carcinoid tumor in a horseshoe kidney. Int J Urol 7:184, 2000. 49. Walsh IK, Kernohan RM, Johnston CF, et al.: Somatostatinoma in a horseshoe kidney. Br J Urol 78:958, 1996. 50. Klimberg I, Epstein H, Wajsman Z: Oncocytoma in a horseshoe kidney. J Urol 135:1002, 1986. 51. Bronshtein M, Yoffe N, Brandes JM, et al.: First and early secondtrimester diagnosis of fetal urinary tract anomalies using transvaginal sonography. Prenat Diagn 10:653, 1990. 52. Stroosma OB, Smits JM, Schurink GW, et al.: Horseshoe kidney transplantation within the eurotransplant region: a case control study. Transplantation 72:1930, 2001. 53. Stroosma OB, Schurink GW, Smits JM, et al.: Transplanting horseshoe kidneys: a worldwide survey. J Urol 166:2039, 2001. 54. Meinecke P, Padberg B, Laas R: Agnathia, holoprosencephaly, and situs inversus: a third report. Am J Med Genet 37:286, 1990. 55. Hassell S, Butler MG: Antley-Bixler syndrome: report of a patient and review of literature. Clin Genet 46:372, 1994. 56. Reardon W, Smith A, Honour JW, et al.: Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J Med Genet 37:26, 2000. 57. Bowen P, Conradi GJ: Syndrome of skeletal and genitourinary anomalies with unusual facies and failure to thrive in Hutterite sibs. Birth Defects Orig Artic Ser XII(6):101, 1976. 58. Hunter AG, Woerner SJ, Montalvo-Hicks LD, et al.: The BowenConradi syndrome—a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities. Am J Med Genet 3:269, 1979.

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59. Eastman JR, Bixler D: Facio-cardio-renal syndrome: a newly delineated recessive disorder. Clin Genet 11:424, 1977. 60. Goltz RW: Focal dermal hypoplasia syndrome. An update. Arch Dermatol 128:1108, 1992. 61. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 62. Verloes A, Le Merrer M, Davin JC, et al.: The orocraniodigital syndrome of Juberg and Hayward. J Med Genet 29:262, 1992. 63. Matsumoto N, Niikawa N. Kabuki make-up syndrome: A review. Am J Med Genet 117C:57, 2003. 64. Ewart-Toland A, Enns GM, Cox VA, et al.: Severe congenital anomalies requiring transplantation in children with Kabuki syndrome. Am J Med Genet 80:362, 1998. 65. Mievis C, Claus D, Clapuyt P, et al.: A new familial short stature syndrome: Brussels type. Clin Dysmorphol 5:9, 1996. 66. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983. 67. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 68. Kang S, Allen J, Graham JM Jr, et al.: Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 34:441, 1997. 69. Davee MA, Moore CA, Bull MJ, et al.: Familial occurrence of renal and Mullerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay. Am J Med Genet 44:293, 1992. 70. Spirer Z, Soferman R, Bogair N: Letter: renal abnormalities in the Russell-Silver syndrome. Pediatrics 54:120, 1974. 71. Alvarenga R, Gonzalez del AA, del Castillo V, et al.: Renal tubular acidosis in the Silver-Russell syndrome. Am J Med Genet 56:173, 1995. 72. Price SM, Stanhope R, Garrett C, et al.: The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet 36:837, 1999. 73. Arai Y, Wakabayashi Y, Pak K, et al.: Horseshoe kidney in RussellSilver syndrome. Urology 31:321, 1988. 74. Froster UG, Rehder H, Hohn W, et al.: Craniofacial anomalies, abnormal hair, camptodactyly, and caudal appendage (Teebi-Shaltout syndrome): clinical and autopsy findings. Am J Med Genet 47:717, 1993. 75. Botto LD, Khoury MJ, Mastroiacovo P, et al.: The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet 71:8, 1997. 76. Fantes JA, Bickmore WA, Fletcher JM, et al.: Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization. Am J Hum Genet 51:1286, 1992. 77. Jotterand V, Boisjoly HM, Harnois C, et al.: 11p13 deletion, Wilms’ tumour, and aniridia: unusual genetic, non-ocular and ocular features of three cases. Br J Ophthalmol 74:568, 1990. 78. Fullana A, Garcia-Frias E, Martinez-Frias ML, et al.: Caudal deficiency and asplenia anomalies in sibs. Am J Med Genet Suppl 2:23, 1986. 79. Mathias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:111, 1987. 80. Gebbia M, Ferrero GB, Pilia G, et al.: X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305, 1997. 81. Hennekam RC, van Noort G, de la Fuente AA: Familial holoprosencephaly, heart defects, and polydactyly. Am J Med Genet 41:258, 1991.

28.13 Anomalies of the Bladder and Ureters Anomalies involving the urachus, the ureteropelvic junction, and vesicoureteral reflux are discussed in several other sections in this chapter as are bladder anomalies associated with urethral abnormalities. Exstrophy of the bladder or cloaca is documented in more detail in the chapter on abdominal wall defects.

Agenesis of the bladder is usually found in sirenomelia, but is otherwise a very rare anomaly, especially in viable infants. Other anomalies of the urinary and genital systems are usually present and females are predominantly affected. Glenn1 described a child with absence of the bladder, a short blind urethra, duplex left kidney, and bicornuate uterus that appears to represent a typical presentation of this rare anomaly, where the ureters often drain ectopically into the vagina or cutaneously.2 Patients have incontinence and chronic infection. Presumably the anomaly is caused by maldevelopment of the cranial portion of the cloaca. True absence of the bladder may be difficult to distinguish from severe hypoplasia, especially in cases where infection and obstruction have caused secondary distortion of the lower urinary tract. A small bladder (Fig. 28-15) is usually associated with bilateral renal agenesis or other anomalies that prevent urine production and delivery to the bladder.3 Other bladder anomalies include diverticula, patent urachus, forms of bladder duplication, hourglass strictures, ureteroceles, and ectopic ureteral orifices. Most bladder diverticula are acquired due to mild urethral obstruction and are asymptomatic. However, they may not empty completely with voiding and cause recurrent urinary tract infection. Over 95% occur in men over 50 years of age and are associated with benign prostatic hypertrophy.4 Congenital diverticula in infants and children are evaginations of the bladder wall that may arise due to herniations because of urethral stenosis or atresia or as intrinsic defects of bladder musculature (Fig. 28-16). They have been seen in association with diverticula of the intestine and with several heritable syndromes, including Williams syndrome,5 Ochoa crying facies,6 and marfanoid habitus with diverticulosis of the bowel,7,8 as well as with cutis laxa,9 Ehlers-Danlos type 9 (occipital horn syndrome),10 and Menkes

Fig. 28-15. Cross sections through a hypoplastic bladder (UB) in a newborn infant with bilateral renal agenesis. Only a potential lumen (arrows) was noted. (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

Urinary Tract

Fig. 28-16. Bladder diverticula (arrows) in an infant with Menkes syndrome. A remnant of the left umbilical artery (LA) was present; the right umbilical artery was absent. UB, urinary bladder; U, remnant of the allantois. (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

syndrome.11 Abnormalities of copper metabolism or transport have been implicated in the last three disorders. Isolated bladder diverticula are usually sporadic, but one family is reported in which diverticula due to bladder outlet obstruction occurred in at least three generations. It was considered be an autosomal dominant condition with sex-limitation to males.12 A diverticulum of the dome of the bladder may represent persistence of the urachus; lateral diverticula may represent incomplete partition of the bladder. In such cases, a single bladder neck empties into a single urethra. The completely partitioned bladder will have two urethras, and the genitalia, rectum, and lumbosacral spine may be duplicated. One or more additional lower limbs may also be present.13 This anomaly is probably the result of incomplete caudal duplication,14 a caudal teratoma, or a gene defect similar to the mouse mutant disorganization (ds).15,16 Congenital dilation of the bladder results from distal obstruction as is seen with posterior urethral valves (Section 28.17) or urethral atresia (Section 28.16). Deficiency of the abdominal musculature (prune belly anomaly), ascites, hydroureter, and hydronephrosis may also occur. Neurologic impairment such as is seen with meningomyelocele can cause bladder dilation. Isolated bladder atony is rare and usually sporadic, though a threegeneration pedigree with eight affected males and one affected female has been reported.17 Megacystis or enlargement of the bladder in the absence of obstruction is also seen in two complex patterns of malformations. In the autosomal dominant megaduodenummegacystis syndrome (OMIM 155310), there is variable chronic obstruction of the gastrointestinal and/or urinary tract due to thinning and collagen replacement of the longitudinal muscle layer.18

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Constipation and urinary tract infection are important complications and death due to intestinal occlusion has been reported, but most affected individuals have a normal lifespan. The megacystis-microcolon-intestinal hypoperistalsis syndrome (OMIM 249210) is a more severe autosomal recessive condition. The apparent excess of females with this disorder is believed to be due to more severe disease and early lethality in males or misdiagnosis of affected males as having Prune-Belly.19,20 A candidate gene for this disorder is the alpha-3/beta-4 neuronal nicotinic acetylcholine receptor genes, which map to 15q24.21,22 Exstrophy of the bladder is one point on the spectrum that ranges from epispadias to cloacal exstrophy; however, these disorders appear to be distinct clinical entities. Cloacal exstrophy may be may be seen with omphalocele, imperforate anus, and spinal defects23 and is associated with monozygous twinning. These conditions are usually sporadic, but familial cases of both bladder exstrophy24 and cloacal exstrophy23 have been observed. Prenatal diagnosis by ultrasound and maternal serum a-fetoprotein screening is feasible. One autopsy series25 found bladder anomalies in one in 184 patients under 18 years of age. In contrast, ureteral anomalies were seen in one in 40. Agenesis of the ureters does not occur in the absence of other upper urinary tract anomalies, but is very common in cases of renal agenesis. Duplication of the ureters is the most common urinary tract anomaly, occurring in approximately 1% of the population. One study of excretory urograms identified one in 50 individuals as having duplications, but this would be a biased sample group.26 The renal parenchyma is not separate in these cases, as it is with supernumerary kidney (Section 28.10), but there are two pelvises, each with one ureter. Duplication may be complete with two ureters to the bladder, or the ureters may unite before entering the bladder (Fig. 28-17). Considerable variation in ureteral duplication exists with blind-ending ureters, abortive duplication, or even more than two ureters per kidney being present. Most blindending ureters and ectopic ureteral orifices are associated with

Fig. 28-17. Longitudinal section (A) and anterior surface (B) of a kidney with duplicated renal pelvis and ureter. Both ureters opened into the urinary bladder. (Reprinted with permission from Moore KL, ed.: The Developing Human: Clinically Oriented Embryology, ed 5. WB Saunders Company, Philadelphia, 1988.)

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ureters draining the upper pole of a partially duplicated kidney.27 Both sides are equally likely to be involved in unilateral defects, which are approximately five times more common than bilateral duplication.26 Females are affected twice as often as males, but this may also be due to biased ascertainment as ectopic orifices may lead to incontinence.28,29 Duplication of the ureters is often inherited as an autosomal dominant trait with variable expressivity.30,31 Because of the high prevalence of duplication of the ureters as an isolated malformation, it is not a useful finding in syndrome delineation. Initially, Fraser et al.32 described an otorenal syndrome that they believed could be distinguished from the branchio-otorenal (BOR) syndrome by the presence of duplication of the ureter and absence of cervical fistulae. However, families with members expressing both phenotypes have been reported.33 Rich et al.34 reported apparently autosomal or X-linked dominant transmission of ureteral triplication with bilateral amastia and unusual facies in a mother and son. The mother’s parents were unaffected, but her father was 60 years of age when she was born. Duplication of the ureter has been found as a nonobligatory feature in over 40 other syndromes and may well be a coincidental finding in many of these. Duplication of the ureters has been associated with maternal diabetes and thalidomide embryopathy. References (Anomalies of the Bladders and Ureters) 1. Glenn JF: Agenesis of the bladder. JAMA 169:2016, 1959. 2. Bhagwat AD, Samuel KV, Kulkarni MS, et al.: Agenesis of the urinary bladder with cutaneous ectopic ureteric orifice and multiple birth defects. Pediatr Surg Int 12:63, 1997. 3. Potter EL: Bilateral renal agenesis. J Pediatr 29:68, 1946. 4. MacKellar A, Stephens FD: Vesical diverticula in children. In: Congenital Malformations of the Rectum, Anus and Genito-Urinary Tracts. FD Stephens, ed. E.D.S. Livingstone Ltd., Edinburgh, 1963. 5. Babbitt DP, Dobbs J, Boedecker RA: Multiple bladder diverticula in Williams ‘‘Elfin-Facies’’ syndrome. Pediatr Radiol 8:29, 1979. 6. Ochoa B, Gorlin RJ: Urofacial (Ochoa) syndrome. Am J Med Genet 27:661, 1987. 7. Clunie GJA, Mason JM: Visceral diverticula and the Marfan syndrome. Br J Surg 50:51, 1962. 8. De Silva DG, Gunawardena TP, Law FM: Unusual complications in siblings with marfanoid phenotype. Arch Dis Child 75:247, 1996. 9. Van Maldergem L, Vamos E, Liebaers I, et al.: Severe congenital cutis laxa with pulmonary emphysema: a family with three affected sibs. Am J Med Genet 31:455, 1988. 10. Agha A, Sakati NO, Higginbottom MC, et al.: Two forms of cutis laxa presenting in the newborn period. Acta Paediatr Scand 67:775, 1978. 11. Peltonen L, Kuivaniemi H, Palotie A, et al.: Alterations in copper and collagen metabolism in the Menkes syndrome and a new subtype of the Ehlers-Danlos syndrome. Biochemistry 22:6156, 1983. 12. Hofmann R, Hegemann M, Mauermayer W, et al.: Hereditary autosomal dominant form of bladder diverticula in male patients. J Urol 131:338, 1984. 13. Weisselberg B, Ben Ami T, Goodman RM: Partial duplication of the lower limb with agenesis of ipsilateral kidney—a new syndrome: report of a case and review of the literature. Clin Genet 33:234, 1988. 14. Dominguez R, Rott J, Castillo M, et al.: Caudal duplication syndrome. Am J Dis Child 147:1048, 1993. 15. Robin NH, Adewale OO, McDonald-McGinn D, et al.: Human malformations similar to those in the mouse mutation disorganization (Ds). Hum Genet 92:461, 1993. 16. Alashari M, Torakawa J: True tail in a newborn. Pediatr Dermatol 12: 263, 1995. 17. Gundrum FF: Familial bladder atony. JAMA 78:411, 1922. 18. Faulk DL, Anuras S, Gardner GD, et al.: A familial visceral myopathy. Ann Intern Med 89:600, 1978.

19. Oliveira G, Boechat MI, Ferreira MA: Megacystis-microcolon-intestinal hypoperistalsis syndrome in a newborn girl whose brother had prune belly syndrome: common pathogenesis? Pediatr Radiol 13:294, 1983. 20. Young ID, McKeever PA, Brown LA, et al.: Prenatal diagnosis of the megacystis-microcolon-intestinal hypoperistalsis syndrome. J Med Genet 26:403, 1989. 21. Xu W, Orr-Urtreger A, Nigro F, et al.: Multiorgan autonomic dysfunction in mice lacking the beta2 and the beta4 subunits of neuronal nicotinic acetylcholine receptors. J Neurosci 19:9298, 1999. 22. Lev-Lehman E, Bercovich D, Xu W, et al.: Characterization of the human beta4 nAChR gene and polymorphisms in CHRNA3 and CHRNB4. J Hum Genet 46:362, 2001. 23. Carey JC, Greenbaum B, Hall BD: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Orig Artic Ser 14XIV(6B):253, 1978. 24. Messelink EJ, Aronson DC, Knuist M, et al.: Four cases of bladder exstrophy in two families. J Med Genet 31:490, 1994. 25. Barakat AJ, Drougas JG: Occurrence of congenital abnormalities of kidney and urinary tract in 13,775 autopsies. Urology 38:347, 1991. 26. Privett JT, Jeans WD, Roylance J: The incidence and importance of renal duplication. Clin Radiol 27:521, 1976. 27. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 28. Ellerker AG: The extra-vesical ectopic ureter. Br J Surg 45:344, 1958. 29. Nation EF: Duplication of the kidney and ureter: a statistical study of 230 new cases. J Urol 51:456, 1944. 30. Simpson JL, German J: Familial urinary tract anomalies. JAMA 212:2264, 1970. 31. Atwell JD, Cook PL, Howell CJ, et al.: Familial incidence of bifid and double ureters. Arch Dis Child 49:390, 1974. 32. Fraser FC, Ayme S, Halal F, et al.: Autosomal dominant duplication of the renal collecting system, hearing loss, and external ear anomalies: a new syndrome? Am J Med Genet 14:473, 1983. 33. Heimler A, Lieber E: Branchio-oto-renal syndrome: reduced penetrance and variable expressivity in four generations of a large kindred. Am J Med Genet 25:15, 1986. 34. Rich MA, Heimler A, Waber L, et al.: Autosomal dominant transmission of ureteral triplication and bilateral amastia. J Urol 137:102, 1987.

28.14 Urachal Anomalies Definition

Urachal anomalies are defects due to failure of normal obliteration of the lumen of the urachus. Omphalomesenteric duct abnormalities are excluded from this definition. Diagnosis

The most distal portion of the cloaca forms the urachus. In fetal life, the urachus connects the bladder with the allantois, which is primarily within the umbilical cord (Fig. 28-18). As the bladder descends into the pelvis, the urachus is drawn into a narrow tube. Progressive narrowing of the channel leads to formation of a fibrous cord with few, if any, areas of patency remaining. In adults, the urachal remnants form the median umbilical ligament. The urachal remnants will vary in length depending on how far the bladder has descended.1 Congenital urachal anomalies include urachal cysts, which are dilations of remaining areas of patency within the fibrous cord; superior urachal sinus, where the upper portion of the tube remains open; inferior urachal sinus, due to

Urinary Tract

1235

Fig. 28-18. Photograph of a dissection of the abdomen and pelvis of an 18-week female fetus, showing the relationship of the urachus to the urinary bladder and umbilical arteries. (Reprinted with permission from Moore KL, Persaud TVN, eds.: The Developing Human: Clinically Oriented Embryology, ed 7. Elsevier, Philadelphia, 2003.)

persistence and dilation of the portion emptying into the apex of the bladder, and patent urachus, where the urachus remains open along its length (Fig. 28-19). The symptoms associated with urachal anomalies will vary according to the type of defect. Patent urachus presents in the neonatal period with passage or dribbling of urine from the umbilicus and hydrops of the umbilical cord stump. A superior sinus may lead to discharge or infection. Cysts usually present as midline masses or are found at laparotomy for other reasons. Infected cysts may cause lower abdominal pain, fever, urinary tract infections, or even acute abdomen2 and can mimic appendicitis, peritonitis, or Meckel diverticulitis.3,4 Another presenting finding of urachal abnormalities include delayed separation of the umbilical cord,5 umbilical polyp,6 and retraction of the umbilicus or a tugging or paraumbilical pain7 with voiding. Occasionally, urachal remnants may present as a suprapubic fistula.8–10 Inferior sinuses or urachal diverticula are associated with calculi, but most drain well and thus are rarely symptomatic and probably underdiagnosed.11 Associated genitourinary anomalies are found in 25% of cases12 and include unilateral renal agenesis, renal dysplasia, hydronephrosis, ureteropelvic junction obstruction, hydroureter, ureteral stenosis, vesicoureteral reflux, prune belly, urethral atresia, urethral duplication, vaginal atresia, and penile agenesis. More children with urachal anomalies have such findings, but this potential bias in ascertainment as investigation of such urinary tract anomalies leads to earlier detection of the urachal defect.13 Anomalies outside the genitourinary system are relatively rare in these patients, but Meckel diverticulum, inguinal hernia, and omphalocele may occur.12,14 A urachal anomaly may form part of a wider midline defect such as an epigastric cleft.15 The most appropriate tools to use for diagnosis depend on the nature of the defect. Sinography or fistulography with radiopaque contrast medium is especially useful for patent urachus and superior sinus.16 Ultrasound and voiding cystourethrography are less helpful in defining the urachal anomaly in these cases, but can add in identifying associated genitourinary tract anomalies and differentiating the defect from a patent mesenteric duct. The fluid discharging from the umbilicus can be tested for creatinine and urea. The most appropriate imaging modalities for urachal cysts are ultrasound, computed tomography scanning, cystoscopy, and excretory urography.16,17 Voiding urethrocystography will delineate inferior urachal sinuses well.

Etiology and Distribution

As many cases of urachal anomalies go undiagnosed, the true frequency of such defects is unknown. In most newborns, at least some portion of the urachal lumen is still patent and, in 50% of these cases, this area is continuous with the bladder.1,18 Fully patent urachus is a rare anomaly.19 About 2% of adults have some degree of patency, usually inferiorly.20 The relative frequency of different types of anomalies depends on the age of presentation, with infants and children more often having a superior sinus or patent urachus, while adults usually present with cysts. Males are slightly (55%) more often affected than females.16,21–23 Urachal anomalies are caused by failure of complete obliteration of the urachal tube by desquamated epithelium in the 4th to 5th month of gestation. Failure of the bladder to descend, coupled with a superior urachal sinus, may also lead to formation of a vesicoumbilical fistula. Patent urachus or inferior sinus may be attributable in a small proportion of cases to urinary tract obstruction, as they may be seen with urethral atresia and prune belly. However, the majority of patients have no evidence of urinary tract obstruction24 and most individuals with obstruction do not have urachal anomalies. Urachal defects are usually sporadic, with little evidence for a genetic component. They have rarely been described in conjunction with multiple congenital anomalies. A female infant with megacystis-microcolon-intestinal hyperperistalsis syndrome (see Section 28.14) had a urachal anomaly and an affected brother who was considered to have prune belly,25 a not uncommon misdiagnosis in this condition. Prognosis, Prevention, and Treatment

In the absence of major anomalies of the genitourinary or other systems, the prognosis for patients with urachal anomalies is good. In the newborn with patent urachus, conservative management may be initially appropriate as the urachus may close spontaneously within the 1st few months of life. If it does not, the tract can be surgically removed. Small, asymptomatic cysts can also be treated by observation. Infected cysts or sinuses initially require excision drainage, percutaneous drainage, or marsupialization with complete removal of the tract once the inflammation has subsided. Simple drainage does not appear effective and can lead to recurrent

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Fig. 28-19. Diagram illustrating urachal anomalies. A. Urachal cysts. B. Superior and inferior urachal sinuses. C. Patent urachus. (Reprinted with permission from Moore KL, Persaud TVN, eds.: The Developing Human: Clinically Oriented Embryology, ed 7. Elsevier, Philadelphia, 2003.)

infections. Chronically infected cysts may drain into the umbilicus or bladder, leading to a condition known as alternating sinus.23 Infected cysts may also rupture into the peritoneum or form fistulous connections to the bowel.26–28 Tumors have been reported in urachal remnants. These include benign mesenchymal neoplasms,29 carcinoma,30 and adenocarcinoma.31 In the absence of a specific syndromal diagnosis, the recurrence risk for urachal anomalies is probably not increased over general population risks. Prenatal diagnosis of patent urachus has been made.32 References (Urachal Anomalies) 1. Cappele O, Sibert L, Descargues J, et al.: A study of the anatomic features of the duct of the urachus. Surg Radiol Anat 23:229, 2001.

2. Lewis JB, Morse JW, Eyolfson MF, et al.: Spontaneous rupture of a vesicourachal diverticulum manifesting as acute abdominal pain. Acad Emerg Med 3:1140, 1996. 3. Boyle G, Rosenberg HK, O’Neill J: An unusual presentation of an infected urachal cyst. Review of urachal anomalies. Clin Pediatr (Phila) 27:130, 1988. 4. Blichert-Toft M, Nielsen OV: Diseases of the urachus simulating intraabdominal disorders. Am J Surg 122:123, 1971. 5. Razvi S, Murphy R, Shlasko E, et al.: Delayed separation of the umbilical cord attributable to urachal anomalies. Pediatrics 108:493, 2001. 6. Oguzkurt P, Kotiloglu E, Tanyel FC, et al.: Umbilical polyp originating from urachal remnants. Turk J Pediatr 38:371, 1996. 7. Knoll LD, Pustka RA, Anderson JR, et al.: Periumbilical pain secondary to persistent urachal band. Urology 32:526, 1988. 8. Lawson A, Corkery JJ: Prepublic sinus: an unusual urachal remnant. Br J Surg 79:573, 1992. 9. Nirasawa Y, Ito Y, Tanaka H, et al.: Urachal cyst associated with a suprapubic sinus. Pediatr Surg Int 15:275, 1999. 10. Soares-Oliveira M, Julia V, Aparicio LG, et al.: Congenital prepubic sinus. J Pediatr Surg 37:1225, 2002. 11. Herman TE, Siegel MJ: Special imaging casebook. Prune-belly syndrome with urachal diverticular calcification, posterior urethral valves, and patent utricle. J Perinatol 19:610, 1999. 12. Rich RH, Hardy BE, Filler RM: Surgery for anomalies of the urachus. J Pediatr Surg 18:370, 1983. 13. Newman BM, Karp MP, Jewett TC, et al.: Advances in the management of infected urachal cysts. J Pediatr Surg 21:1051, 1986. 14. Mital VK, Mital DK: Umbilical cyst of vitello-intestinal duct origin associated with Meckel’s diverticulum in a child. Indian J Med Sci 24:571, 1970. 15. Andiran F, Dayi S, Mete E: A novel navel presenting as an umbilical polyp and urachal sinus associated with an epigastric cleft: a clue to anterior midline fusion defects. Surg Today 30:1053, 2000. 16. Cilento BG Jr, Bauer SB, Retik AB, et al.: Urachal anomalies: defining the best diagnostic modality. Urology 52:120, 1998. 17. Avni EF, Matos C, Diard F, et al.: Midline omphalovesical anomalies in children: contribution of ultrasound imaging. Urol Radiol 10:189, 1988. 18. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 19. Nix JT, Menville JG, Albert M, et al.: Congenital patent urachus. J Urol 79:264, 1958. 20. Hammond G, Yglesis L, David JE: The urachus, its anatomy and associated faschia. Anat Rec 80:271, 1941. 21. Mesrobian HG, Zacharias A, Balcom AH, et al.: Ten years of experience with isolated urachal anomalies in children. J Urol 158:1316, 1997. 22. Borer JG, Bauer SB, Peters CA, et al.: A single-system ectopic ureter draining an ectopic dysplastic kidney: delayed diagnosis in the young female with continuous urinary incontinence. Br J Urol 81:474, 1998. 23. Risher WH, Sardi A, Bolton J: Urachal abnormalities in adults: the Ochsner experience. South Med J 83:1036, 1990. 24. Schrenck WR, Campbell WA: The relationship of bladder outlet obstruction to urinary umbilical fistula. J Urol 108:641, 1972. 25. Oliveira G, Boechat MI, Ferreira MA: Megacystis-microcolon-intestinal hypoperistalsis syndrome in a newborn girl whose brother had prune belly syndrome: common pathogenesis? Pediatr Radiol 13:294, 1983. 26. Agatstein EH, Stabile BE: Peritonitis due to intraperitoneal perforation of infected urachal cysts. Arch Surg 119:1269, 1984. 27. Flanagan DA, Mellinger JD: Urachal-sigmoid fistula in an adult male. Am Surg 64:762, 1998. 28. Gomez BJ, Plata RJ, Espinosa GE, et al.: Urachal-sigmoid fistula in an adult male without urachal cyst. Rev Esp Enferm Dig 94:430, 2002. 29. Dawson JS, Crisp AJ, Boyd SM, et al.: Case report: benign urachal neoplasm. Br J Radiol 67:1132, 1994.

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30. Isotalo PA, Robertson SJ, Futter NG: Urinary bladder urachal remnants underlying papillary urothelial carcinoma. Arch Pathol Lab Med 126:1252, 2002. 31. Sekine H, Ohya K, Kojima S, et al.: Dermatomyositis associated with urachal adenocarcinoma. J Urol 168:1488, 2002. 32. Persutte WH, Lenke RR, Kropp K, et al.: Antenatal diagnosis of fetal patent urachus. J Ultrasound Med 7:399, 1988.

28.15 Urethral Agenesis or Atresia Definition

Urethral agenesis or atresia is the failure of development of all or part of the urethra, causing distal obstructive uropathy. This anomaly is frequently associated with prune belly (Eagle-Barrett syndrome, abdominal muscle deficiency-renal abnormality-cryptorchidism triad syndrome, early urethral obstruction sequence).1 Diagnosis

Urethra agenesis is rare and has been reported predominantly in males.2–4 Congenital segmental urethral atresia is more common. The level of obstruction is usually at the membranous urethra. Marked urethral dilation behind the obstruction can give the appearance of a dumbbell-shaped bladder.5 Urethral occlusion can present with abdominal distension and muscle laxity, bilateral cryptorchidism, oligohydramnios, respiratory insufficiency due to pulmonary hypoplasia, and anuria or evidence of a urinary fistula. Affected infants often have Potter facies (Figs. 28-20 and 28-21). Associated genitourinary anomalies include megacystis, hydroureter, hydronephrosis, and cystic kidneys (Fig. 28-22).

Fig. 28-20. Previable fetus with prune belly syndrome. (Reprinted from Dimmick JE, Kalousek DK, eds.: Developmental Pathology of the Embryo and Fetus. J.B. Lippincott, Philadelphia, 1992.)

Fig. 28-21. Late gestation infant with prune belly syndrome. (Reprinted from Dimmick JE, Kalousek DK, eds.: Developmental Pathology of the Embryo and Fetus. J.B. Lippincott, Philadelphia, 1992.)

Fig. 28-22. Gross appearance of the kidneys and bladder from a stillborn male infant with urethral atresia and prune belly. Note the renal dysplasia with a common ureter and grossly dilated bladder. Cryptorchidism, single umbilical artery, and anal ectopia were also present.

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Cryptorchidism in males is almost universal and differentiates this condition from urethral obstruction caused by posterior urethral valves (Section 28.16) or other forms of urethral stenosis. Urachal, cloacal, urethrorectal, urethropenile, urethroscrotal, or vesicovaginal fistulas are frequently found. Imperforate or ectopic anus and dysgenesis of the prostate, urinary tract musculature, and gubernaculum are common. Penile agenesis may occur.6 Bladder distension can lead to obstruction of the umbilical arteries with lower limb ischemia, hypoplasia, or deficiency.7–9 Other orthopedic problems include scoliosis, congenital hip dysplasia, clubfeet, and pectus excavatum.10,11 Hypoplastic abdominal musculature is present in prune belly syndrome, where, even after relief of the obstruction, the abdomen remains distended and wrinkled, with loops of bowel visible under the thin wall, giving the characteristic prunelike appearance (Fig. 28-21). Older children and adults may have a ‘‘pot belly.’’ Although prune belly syndrome is rare in females, affected females may also have bicornuate or duplicated uterus, vaginal atresia, clitoral hypertrophy, anal atresia or other cloacal defects, and upper urinary tract anomalies.12 Incomplete forms with unilateral abdominal wall hypoplasia13 and ‘‘pseudo prune belly’’ without abdominal wall defects14 are not uncommon. It should be noted that not all infants with ‘‘prune belly’’ have an occluded urethra.15,16 Similarly, those with urethral blockage may not develop the abdominal wall and renal findings usually associated with this condition if the urachus or a fistula to drain urine is patent. Almost one-third of cases with urethral occlusion have anomalies outside the genitourinary tract and adjacent tissues.17 This figure is higher for affected females.18 Disorders associated with urethral agenesis and atresia are listed in Table 28-21. Etiology and Distribution

The frequency of all forms of urethral atresia and agenesis is unknown. Prune belly occurs in approximately one in 30,000 live births.17,19 The condition is over five times more common in males,17 with the classic triad of abdominal wall muscle deficiency, obstructive uropathy, and cryptorchidism restricted to males. Black infants, those born to young mothers, and twins are also at increased risk.17 The male urethra is formed by prostatic, membranous, spongy, and glandular segments. Segmental urethral atresia or agenesis results from damage to or failure of formation of any part of the male urethra. The relative embryonic complexity of the male urethra is the best explanation for the predominance of urethral defects in males. Several theories about the etiology and pathogenesis of prune belly syndrome have been postulated. These include defective mesodermal development during early embryogenesis,20–22 urinary tract obstruction with massive abdominal distension,3,23 and intrauterine infection.13,24 Experiments with a fetal lamb model indicate that complete urethral obstruction in early gestation can result in massive abdominal distension and absence of the abdominal wall musculature.25 It is likely that more than one cause can give rise to the phenotype seen with urethral agenesis or atresia. Familial cases of urethral atresia have occurred, but the pattern of inheritance remains unclear.26–28 Gaboardi et al.29 described two brothers and a sister with prune belly, hydronephrosis, megacystis, and megaureter, but no urethral stenosis, suggesting that familial cases may have a different pathogenesis in some cases. Both concordance30 and discordance31 in monozygous twins have been recorded.

Prognosis, Prevention, and Treatment

Fetal or neonatal death is inevitable in this condition unless a urinary fistula is present, with one-third of liveborn patients dying as newborns or infants.25 In those who survive infancy, renal failure is common,32 but not universal. When prune belly is present, there is minimal recovery of the strength of the abdominal musculature. Familial cases occur, but the empiric recurrence risk is low.2 Prenatal diagnosis can be offered and has been made as early as 11 to 12 weeks.33,34 Elevated maternal serum a-fetoprotein has also been reported.35 Prenatal detection of urinary tract obstruction associated with megacystis, increased abdominal circumference, and oligohydramnios suggests the possibility of urethral agenesis or atresia. In utero urinary decompression with a vesicoamniotic shunt has been achieved as early as 14.5 weeks gestation. Normal renal function was preserved and only a mild prune belly was detectable at birth.36 However, not all such interventions have had positive outcomes37 and the long-term benefits of this approach on a large scale have not been evaluated.38 Before in utero surgery is contemplated, the fetus should be investigated for karyotypic abnormalities and associated malformations.18 In the newborn with oligohydramnios, pulmonary insufficiency is common and requires aggressive treatment. Cannulation of the bladder to relieve obstruction, correction of electrolyte balance, and determination of residual renal function is necessary. Determination of the etiology of the obstruction should include cystourethrogram for clarification of the anatomy and determination of the presence of a urinary fistula. Urethroscopy may not be possible because of narrowing of the urethra distal to the obstruction. The upper urinary tract must be evaluated with renal ultrasound, renography with radionuclides, and intravenous pyelography for associated anomalies. Urinary diversion or vesicostomy may be necessary prior to attempts to reconstruct the urethra. Kidney transplantation39,40 and the use of the bowel for reconstruction of the urinary bladder41 have improved the outcome in severe obstructive uropathy. In prune belly syndrome, surgical management of the genitourinary defects includes abdominoplasty, bilateral orchiopexy, reduction cystoplasty, and selective ureteral reconstruction and reimplantation.42 Peritoneal dialysis may be used to treat chronic renal failure,43 which develops in 25–30% of long-term survivors.44 A late complication in some children is hyperammonemic encephalopathy.45,46 Abdominoplasty47–49 can improve the appearance of the abdominal wall, and muscle transposition has been used to improve the ability to move the trunk and permit normal activity levels.50 If significant renal disease is avoided, a near normal lifespan can be expected. However, infertility is likely to occur without the use of sperm retrieval and intracytoplasmic sperm injection.51,52 Neoplasia appears to be rare, but testicular seminoma53 and retroperitoneal germ cell tumor54 have been reported. References (Urethral Agenesis and Atresia) 1. Eagle JR Jr, Barrett GS: Congenital deficiency of abdominal musculature with associated genitourinary abnormalities: a syndrome; report of 9 cases. Pediatrics 6:721, 1950. 2. Ives EJ: The abdominal muscle deficiency triad syndrome—experience with ten cases. Birth Defects Orig Artic Ser X(4):127, 1974. 3. Pagon RA, Smith DW, Shepard TH: Urethral obstruction malformation complex: a cause of abdominal muscle deficiency and the ‘‘prune belly.’’ J Pediatr 94:900, 1979.

Table 28-21. Disorders with agenesis or atresia of the urethra Causation Gene/Locus

Syndrome

Prominent Features

Urinary Tract Anomalies

Caudal dysplasia55

Sacral defects, lower limb hypoplasia, anal and genital defects

Renal agenesis or dysplasia, bladder or cloacal exstrophy, hydronephrosis, urethral atresia

Heterogeneous, maternal diabetes seen in approximately one-third

Chromosomal disorders —See Table 28-10 Cloacal exstrophy56

Persistent cloaca, exstrophy of cloaca, failure of fusion of genital tubercles, omphalocele, vertebral defects, spina bifida cystica, abnormal genitalia

Renal dysplasia and ectopia, exstrophy of cloaca, urethral and ureteral anomalies

Heterogeneous, associated with monozygous twinning (258040)

DiGeorge57,58

Parathyroid and thymic hypoplasia, conotruncal heart defects, facial dysmorphism in some cases

Renal agenesis and cystic dysplasia, ureteral defects, hydronephrosis, hydroplastic bladder, urethral atresia, stones

Heterogenous, AD (188400), often sporadic Many cases have deletions of 22q11.2

Fanconi pancytopenia59,60

Pancytopenia, anemia; radial ray defects; microcephaly, dilated ventricles, microphthalmia; short stature; increased chromosome breakage

Renal agenesis (usually unilateral), dysplasia, hypoplasia or ectopia; horseshoe kidney, hydronephrosis, double ureters, urethral atresia

Heterogeneous AR (227650) Several complementation groups identified FANCA, 16q24.3 FANCB, BRCA2, 13q12.3 FANCC, 9q22.3 FANCD1/D2, 3p25.3 FANCE, 6p22-p21 FANCF, 11p15 FANCG, 9p13

Fraser cryptophthalmos61,62

Cryptophthalmos, abnormal anterior hairline; laryngeal, umbilical, and genital defects; skin syndactyly; mental retardation

Renal agenesis, urethral atresia

AR (607830) Human equivalent of mouse ‘‘blebbed’’ FRAS1, 4q21

Johnson-Munson63,64

Aphalangy, hypoplastic radius and ulna, hemivertebra, anal and genital anomalies, mental retardation

Renal agenesis, urethral atresia, urethral fistula

AR (207620)

Lower mesodermal defects65,66

Prune belly, absent or malformed genitalia, sacral defects, imperforate anus, prolapsed perineum

Renal agenesis, dysgenesis, hypoplasia or ectopia, hydronephrosis, malrotation, hypoplastic or absent bladder, absent or blind-ending urethra, urachal cyst

Sporadic

Meckel-Gruber67

Occipital encephalocele, other structural brain anomalies, ear anomalies, postaxial polydactyly, cleft lip and palate, ambiguous genitalia, biliary and pancreatic dysgenesis, lethal

Polycystic or dysplastic kidneys, renal agenesis, duplicated ureters, hypoplastic bladder, urethral atresia

AR with genetic heterogeneity (249000, 603194) MKS1, 17q22-q23 MKS2, 11q MKS3, 8q

Melnick-Needles osteodysplasty68,69

Short stature, wide metaphyses, facial dysmorphism, omphalocele in males (overlap with Frontometaphyseal dysplasia)

Renal ectopia, ureteral anomalies, urethral atresia

XLD (309350) FLNA, Xq28

Prune bellypulmonic stenosis70

Pulmonic stenosis, deafness, mental retardation

Prune belly syndrome

Uncertain (264140)

Neural tube defects71–73

Meningomyelocele, anencephaly, encephalocele, vertebral anomalies, midline anomalies

Renal agenesis, hypoplasia, dysplasia, or ectopia; ureteral anomalies, urethral atresia, hydronephrosis, horseshoe kidney

Heterogeneous, multifactorial in most cases (continued)

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Table 28-21. Disorders with agenesis or atresia of the urethra (continued) Syndrome

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Sirenomelia74,75

Fusion of the lower limbs, anal atresia, genital anomalies, single umbilical artery

Renal agenesis or dsyplasia, bladder or cloacal extrophy, bladder agenesis, hydronephrosis, ureteral anomalies, urethral atresia

Probably heterogeneous, vascular steal from persistent vitelline vessels, excess of MZT and maternal diabetes

Teratogen exposures —See Table 28-11 Townes-Brocks76,77

Radial ray and hallucal defects, anal anomalies, ear anomalies, deafness

Renal agenesis, dysplasia or hypoplasia, reflux, urethral atresia, urethral valves, horseshoe kidney

AD (107480) SALL1, 16q12.1

Twin reversed arterial perfusion78

Co-twin with incomplete development of all organ systems, limbs, and body form; upper body more severely affected than lower body

Renal agenesis, hypoplasia and cystic dysplasia; ureteral and urethral anomalies

Sporadic Restricted to MZ twins

Urogenital adysplasia, congenital79,80

Mu¨llerian duct anomalies

Renal agenesis and dysplasia, urethral atresia

AD (191830), with reduced penetrance and variable expressivity

Urorectal septum malformation81

Pseudohermaphroditism, cloacal and Mu¨llerian duct anomalies, ambiguous genitalia, imperforate anus (overlap with Lower mesodermal defects)

Renal agenesis, hypoplasia and dysplasia; ureteral and urethral anomalies

Sporadic

4. Manivel JC, Pettinato G, Reinberg Y, et al.: Prune belly syndrome: clinicopathologic study of 29 cases. Pediatr Pathol 9:691, 1989. 5. Chen CP, Tzen CY, Wang W: Prenatal diagnosis of cystic bladder distension secondary to obstructive uropathy. Prenat Diagn 20:260, 2000. 6. Evans JA, Erdile LB, Greenberg CR, et al.: Agenesis of the penis: patterns of associated malformations. Am J Med Genet 84:47, 1999. 7. Perez-Aytes A, Graham JM, Hersh JH, et al.: Urethral obstruction sequence and lower limb deficiency: evidence for the vascular disruption hypothesis. J Pediatr 123:398, 1993. 8. Genest DR, Driscoll SG, Bieber FR: Complexities of limb anomalies: the lower extremity in the ‘‘prune belly’’ phenotype. Teratology 44:365, 1991. 9. Carey JC, Eggert L, Curry CJ: Lower limb deficiency and the urethral obstruction sequence. Birth Defects Orig Artic Ser XVIII(3B):19, 1982. 10. Brinker MR, Palutsis RS, Sarwark JF: The orthopaedic manifestations of prune-belly (Eagle-Barrett) syndrome. J Bone Joint Surg Am 77:251, 1995. 11. Loder RT, Guiboux JP, Bloom DA, et al.: Musculoskeletal aspects of prune-belly syndrome. Description and pathogenesis. Am J Dis Child 146:1224, 1992. 12. Reinberg Y, Shapiro E, Manivel JC, et al.: Prune belly syndrome in females: a triad of abdominal musculature deficiency and anomalies of the urinary and genital systems. J Pediatr 118:395, 1991. 13. Donnelly LF, Johnson JF III: Unilateral abdominal wall hypoplasia: radiographic findings in two infant girls. Pediatr Radiol 25:278, 1995. 14. Bellah RD, States LJ, Duckett JW: Pseudoprune-belly syndrome: imaging findings and clinical outcome. AJR Am J Roentgenol 167:1389, 1996. 15. Tank ES, McCoy G: Limited surgical intervention in the prune belly syndrome. J Pediatr Surg 18:688, 1983. 16. Reinberg Y, Chelimsky G, Gonzalez R: Urethral atresia and the prune belly syndrome. Report of 6 cases. Br J Urol 72:112, 1993. 17. Druschel CM: A descriptive study of prune belly in New York State, 1983 to 1989. Arch Pediatr Adolesc Med 149:70, 1995. 18. Brumfield CG, Davis RO, Joseph DB, et al.: Fetal obstructive uropathies. Importance of chromosomal abnormalities and associated anomalies to perinatal outcome. J Reprod Med 36:662, 1991.

19. Baird PA, MacDonald EC: An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million consecutive live births. Am J Hum Genet 33:470, 1981. 20. Straub E, Spranger J: Etiology and pathogenesis of the prune belly syndrome. Kidney Int 20:695, 1981. 21. Greskovich FJ III, Nyberg LM Jr: The prune belly syndrome: a review of its etiology, defects, treatment and prognosis. J Urol 140:707, 1988. 22. Stephens FD, Gupta D: Pathogenesis of the prune belly syndrome. J Urol 152:2328, 1994. 23. Burton BK, Dillard RG: Brief clinical report: prune belly syndrome: observations supporting the hypothesis of abdominal overdistention. Am J Med Genet 17:669, 1984. 24. Pramanik AK, Altshuler G, Light IJ, et al.: Prune-belly syndrome associated with Potter (renal nonfunction) syndrome. Am J Dis Child 131:672, 1977. 25. Gonzalez R, De Filippo R, Jednak R, et al.: Urethral atresia: long-term outcome in 6 children who survived the neonatal period. J Urol 165: 2241, 2001. 26. Riccardi VM, Grum CM: The prune belly anomaly: heterogeneity and superficial X-linkage mimicry. J Med Genet 14:266, 1977. 27. Garlinger P, Ott J: Prune belly syndrome. Possible genetic implications. Birth Defects Orig Artic Ser X(8):173, 1974. 28. Adeyokunnu AA, Familusi JB: Prune belly syndrome in two siblings and a first cousin. Possible genetic implications. Am J Dis Child 136: 23, 1982. 29. Gaboardi F, Sterpa A, Thiebat E, et al.: Prune-belly syndrome: report of three siblings. Helv Paediatr Acta 37:283, 1982. 30. Balaji KC, Patil A, Townes PL, et al.: Concordant prune belly syndrome in monozygotic twins. Urology 55:949, 2000. 31. Greene C, Wilson A, Shapira E: Prune belly syndrome and heart defect in one of monozygotic twins following exposure to Tigan and Bendectin. Acta Genet Med Gemellol (Roma) 34:101, 1985. 32. Reinberg Y, Manivel JC, Pettinato G, et al.: Development of renal failure in children with the prune belly syndrome. J Urol 145:1017, 1991. 33. Hoshino T, Ihara Y, Shirane H, et al.: Prenatal diagnosis of prune belly syndrome at 12 weeks of pregnancy: case report and review of the literature. Ultrasound Obstet Gynecol 12:362, 1998.

Urinary Tract 34. Yamamoto H, Nishikawa S, Hayashi T, et al.: Antenatal diagnosis of prune belly syndrome at 11 weeks of gestation. J Obstet Gynaecol Res 27:37, 2001. 35. Pescia G, Cruz JM, Weihs D: Prenatal diagnosis of prune belly syndrome by means of raised maternal AFP levels. J Genet Hum 30: 271, 1982. 36. Drugan A, Zador IE, Bhatia RK, et al.: First trimester diagnosis and early in utero treatment of obstructive uropathy. Acta Obstet Gynecol Scand 68:645, 1989. 37. Makino Y, Kobayashi H, Kyono K, et al.: Clinical results of fetal obstructive uropathy treated by vesicoamniotic shunting. Urology 55: 118, 2000. 38. Irwin BH, Vane DW: Complications of intrauterine intervention for treatment of fetal obstructive uropathy. Urology 55:774, 2000. 39. Dreikorn K, Palmtag H, Rohl L: Prune belly syndrome: treatment of terminal renal failure by hemodialysis and renal transplantation. Eur Urol 3:245, 1977. 40. Fontaine E, Salomon L, Gagnadoux MF, et al.: Long-term results of renal transplantation in children with the prune-belly syndrome. J Urol 158:892, 1997. 41. Hatch DA, Koyle MA, Baskin LS, et al.: Kidney transplantation in children with urinary diversion or bladder augmentation. J Urol 165: 2265, 2001. 42. Anderson GW, Rice GG, Harris BA Jr.: Pregnancy and labor complicated by pelvic ectopic kidney. J Urol 65:760, 1951. 43. Crompton CH, Balfe JW, Khoury A: Peritoneal dialysis in the prune belly syndrome. Perit Dial Int 14:17, 1994. 44. Noh PH, Cooper CS, Winkler AC, et al.: Prognostic factors for longterm renal function in boys with the prune-belly syndrome. J Urol 162:1399, 1999. 45. Diamond DA, Blight A, Ransley PG: Hyperammonemic encephalopathy: a complication associated with the prune belly syndrome. J Urol 142:361, 1989. 46. Das A, Henderson D: Hyperammonemic encephalopathy in a fouryear-old child with prune belly syndrome. Pediatr Infect Dis J 15:922, 1996. 47. Ehrlich RM, Lesavoy MA, Fine RN: Total abdominal wall reconstruction in the prune belly syndrome. J Urol 136:282, 1986. 48. Ehrlich RM, Lesavoy MA: Umbilicus preservation with total abdominal wall reconstruction in prune-belly syndrome. Urology 41:231, 1993. 49. Furness PD III, Cheng EY, Franco I, et al.: The prune-belly syndrome: a new and simplified technique of abdominal wall reconstruction. J Urol 160:1195, 1998. 50. Ger R, Coryllos EV: Management of the abdominal wall defect in the prune belly syndrome by muscle transposition: an 18-year follow-up. Clin Anat 13:341, 2000. 51. Kolettis PN, Ross JH, Kay R, et al.: Sperm retrieval and intracytoplasmic sperm injection in patients with prune-belly syndrome. Fertil Steril 72:948, 1999. 52. Woodhouse CR: Prospects for fertility in patients born with genitourinary anomalies. J Urol 165:2354, 2001. 53. Parra RO, Cummings JM, Palmer DC: Testicular seminoma in a longterm survivor of the prune belly syndrome. Eur Urol 19:79, 1991. 54. Sayre R, Stephens R, Chonko AM: Prune belly syndrome and retroperitoneal germ cell tumor. Am J Med 81:895, 1986. 55. Makhoul IR, Aviram-Goldring A, Paperna T, et al.: Caudal dysplasia sequence with penile enlargement: case report and a potential pathogenic hypothesis. Am J Med Genet 99:54, 2001. 56. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261, 2001. 57. Ryan AK, Goodship JA, Wilson DI, et al.: Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 34:798, 1997. 58. Goodship J, Robson SC, Sturgiss S, et al.: Renal abnormalities on obstetric ultrasound as a presentation of DiGeorge syndrome. Prenat Diagn 17:867, 1997. 59. De Kerviler E, Guermazi A, Zagdanski AM, et al.: The clinical and radiological features of Fanconi’s anaemia. Clin Radiol 55:340, 2000.

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60. Frydman M, Cohen HA, Ashkenazi A, et al.: Familial segregation of cervical ribs, Sprengel anomaly, preaxial polydactyly, anal atresia, and urethral obstruction: a new syndrome? Am J Med Genet 45:717, 1993. 61. Boyd PA, Keeling JW, Lindenbaum RH: Fraser syndrome (cryptophthalmos-syndactyly syndrome): a review of eleven cases with postmortem findings. Am J Med Genet 31:159, 1988. 62. Slavotinek AM, Tifft CJ: Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 39:623, 2002. 63. Johnson VP, Munson DP: A new syndrome of aphalangy, hemivertebrae, and urogenital-intestinal dysgenesis. Clin Genet 38:346, 1990. 64. Johnson VP, Munson DP: Addendum: a new syndrome of aphalangy, hemivertebrae and urogenital-intestinal dysgenesis. Clin Genet 39:311, 1991. 65. Lubinsky MS: Female pseudohermaphroditism and associated anomalies. Am J Med Genet 6:123, 1980. 66. Pauli RM: Lower mesodermal defects: a common cause of fetal and early neonatal death. Am J Med Genet 50:154, 1994. 67. Salonen R, Paavola P: Meckel syndrome. J Med Genet 35:497, 1998. 68. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 69. Franceschini P, Guala A, Licata D, et al.: Esophageal atresia with distal tracheoesophageal fistula in a patient with fronto-metaphyseal dysplasia. Am J Med Genet 73:10, 1997. 70. Halal F: Distal obstructive uropathy with polydactyly: a new syndrome? Am J Med Genet 24:753, 1986. 71. David TJ, Nixon A: Congenital malformations associated with anencephaly and iniencephaly. J Med Genet 13:263, 1976. 72. David TJ, McCrae FC, Bound JP: Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338, 1983. 73. Whitaker RH, Hunt GM: Incidence and distribution of renal anomalies in patients with neural tube defects. Eur Urol 13:322, 1987. 74. Rudd NL, Klimek ML: Familial caudal dysgenesis: evidence for a major dominant gene. Clin Genet 38:170, 1990. 75. Selig AM, Benacerraf B, Greene MF, et al.: Renal dysplasia, megalocystis, and sirenomelia in four siblings. Teratology 47:65, 1993. 76. Newman WG, Brunet MD, Donnai D: Townes-Brocks syndrome presenting as end stage renal failure. Clin Dysmorphol 6:57, 1997. 77. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 7:285, 1983. 78. McPherson E, Carey J, Kramer A, et al.: Dominantly inherited renal adysplasia. Am J Med Genet 26:863, 1987. 79. Roodhooft AM, Birnholz JC, Holmes LB: Familial nature of congenital absence and severe dysgenesis of both kidneys. N Engl J Med 310:1341, 1984. 80. Wenstrup RJ, Pagon RA: Female pseudohermaphroditism with anorectal, Mullerian duct, and urinary tract malformations: report of four cases. J Pediatr 107:751, 1985.

28.16 Posterior Urethral Valves and Urethral Stenosis Definition

Posterior urethral valves are tissue folds of the posterior urethra that function as valves obstructing urine outflow. Four types of posterior urethral valves have been described (Table 28-22). Stenosis of the urethra can also occur due to anterior valves, strictures, diaphragms, and abnormal thickening of the urethral wall. Although patients with posterior urethral valves and other forms of urethral stenosis may present with abdominal distension due to a dilated bladder, this condition is distinct from urethral agenesis or atresia, which is discussed in Section 28.15.

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Urogenital System Organs

Table 28-22. Classification of posterior urethral valves Type

Anatomy

I

Valves arise as a single membrane from the posterior and inferior rim of the verumonatum and attach anteriorly to the proximal margin of the membraneous urethra. There is an opening in the membrane posterior to the verumonatum. Most common type of posterior urethral valves (~95%). Obstruction varies from mild to severe.

II

Valves are folds radiating from the verumonatum cranially toward the bladder neck. Nonobstructive, associated with severe type I valves.

III

A diaphragm, usually with central perforation. Usually sited distal to the verumonatum at the level of the membraneous urethra. Occurs in ~5% of cases and causes severe obstruction.

Variations

Valves arising from the anterior wall of the posterior urethra (type IV of Stephens). A unilateral valve, usually type I. Windsock membrane, variation of type III.

Fig. 28-23. Hydronephrosis and hydroureter (U) in the right kidney of a fetus with posterior urethral valves. The right pelvis (P) is dilated, and the minor calyces (arrows) appear as cystic areas underlying the abnormally thin cortex. (Courtesy of Dr. Will Blackburn, Fairhope, AL.)

Modified from Young et al.,12 Stephens,2 and Gonzales.35

Diagnosis

Posterior urethral valves (PUV) are found in males, virilized females, and rarely in normal females. PUV are the most common form of obstructive uropathy leading to end-stage renal disease in children.1 The age of presentation, clinical symptoms, and ease of diagnosis are variable and depend on the severity of obstruction. It is estimated that one-third to one-half of individuals with PUV present within the first 3 to 6 months of life and the majority within the 1st year.2 Newborns can present at birth with abdominal masses, a distended bladder, and hydronephrosis, or with respiratory distress, oligohydramnios, and Potter’s facies. A thickwalled bladder is usually palpable. Severely affected children not presenting at birth are usually affected within a few weeks with urinary tract infection, dehydration, electrolyte imbalance, and failure to thrive. In some cases, a dibbling urinary stream is noted. Toddlers diagnosed with this condition have better kidney function and present with urinary tract infection or abnormal voiding. Voiding dysfunction and incontinence may be the predominant findings in affected school-aged children. Associated anomalies in the urinary tract system include a thickened trabeculated and functional bladder, ureterovesical junction obstruction, hydronephrosis, and renal dysplasia (Fig. 28-23). Inguinal hernia, anal stenosis, spina bifida, hemivertebrae, and multiple congenital anomalies may be associated findings in some cases.3 Like other forms of urinary tract obstruction, PUV may be detected in utero with ultrasound, but it is important to note that 90% of patients who present with acute symptoms neonatally had no pathology detected on early ultrasound; thus, the findings of obstructive uropathy and oligohydramnios may not present until after 24 weeks gestation.4 Initial evaluation of an infant with bladder obstruction includes determination of renal function and electrolyte balance. Diagnosis of PUV is made with a voiding cystourethrogram and by urethral endoscopy. The posterior urethra appears elongated and markedly dilated with a sharp cut-off distal to the verumontanum

and a narrowed distal urethral segment. Diagnostic evaluation of the upper urinary tract with ultrasound and renography with radioisotopes should be carried out to determine the degree of obstructive renal damage. Excretory urography is less useful in the newborn with decreased concentrating ability and uremia.5 PUV differs from prune belly syndrome in the thickened musculature of the bladder wall6 and the fact that cryptorchidism is much less common (10%) in PUV patients7,8 but almost universal in prune belly syndrome. Like PUV, other forms of isolated urethral stenosis are almost always found in males. There may be narrowing of the canal with dilation of the urethra proximal to the obstruction. Diaphragms can be found either above or below the verumontanum and usually have a central perforation. Bladder diverticula, hydroureter, hydronephrosis, and renal obstructive uropathy can occur if the stricture is not enlarged or the diaphragm ablated.9 Etiology and Distribution

The incidence of PUV varies from one in 2500 to 12,000, depending on the study population,3 with PUV causing 2–3% of neonatal deaths in male infants.10 Other forms of urethral stenosis are rarer. The normal tissue folds of the urethral crest occur proximal and distal to the verumontanum, but do not project into the posterior urethra. Maximal development of the urethral folds occurs in week 14 of development (100 mm CR fetus). Various hypotheses for the origin of PUV include overdevelopment of the embryonic posterior urethral folds, remnants of the urogenital membrane, anomalous junction of the ejaculatory duct with the prostatic utricles, and persistence of remnants of the Wolffian ducts. The etiology is unknown and probably variable, as PUV do occur in a number of disorders with multiple congenital anomalies (Table 28-23). Urethral stenosis can also arise due to extrinsic mechanical constriction from amniotic bands11 or due to thickening of the urethral wall caused by systemic disorders (Table 28-23). Obstruction due to PUV results in incomplete emptying of the bladder. Back pressure leads to dilation of the posterior ure-

Table 28-23. Disorders with posterior urethral valves or urethral stenosis Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Al-Gazali36

Hirschprung disease, imperforate anus, hypoplastic nails, facial dysmorphism

Posterior urethral valves, hydronephrosis

AR (235760)

Alveolar capillary dysplasiapulmonary vein misalignment37,38

Alveolar capillary dysplasia, pulmonary vein misalignment, persistent neonatal pulmonary hypertension, apnea, lung lobation defects

Urethral stenosis, posterior urethral valves, hydronephrosis, hydroureter, ureteropelvic junction obstruction, reflux

AR

Amyloidosis, familial cutaneous39,40

Amyloidosis, pigmentary anomalies, failure to thrive, seizures, developmental delay, blindness

Urethral stricture

XLR (301220) Xp22-p21

Caudal dysplasia41

Sacral defects, lower limb hypoplasia, anal and genital defects

Renal agenesis or dysplasia, bladder or cloacal exstrophy, hydronephrosis, urethral atresia

Heterogeneous, maternal diabetes seen in approximately one-third

Chromosomal abnormalities —See Table 28-10 Bardet-Biedl42,43

Mental retardation, retinitis pigmentosa, hypogonadism, polydactyly, obesity, biliary atresia, hepatic fibrosis

Renal agenesis, hypoplasia and dysplasia; calyceal cysts, diverticula, clubbing; hydronephrosis; fetal lobulations; nephritis; urethral defects

AR (209900); alleles at different BSS loci act as modifiers BSS1, 11q13 BSS2, 16q21 BSS3, 3p13 BSS4, 15q22.3 BSS5, 2q31 BSS6 (MKKS), 20p12 BSS7, 4q27

Beckwith-Wiedemann44,45

High birth weight, omphalocele, macroglossia, hypoglycemia, visceromegaly, abdominal tumors

Renal dysplasia; large kidneys; medullary sponge kidney; Wilms tumor; urethral stenosis, obstruction

Complex AD (130650), paternal imprinting, contiguous gene duplication CDKN1C, 11p15.5

Distal obstructive uropathy-polydactyly46

Postaxial polydactyly

Posterior urethral valve with hydronephrosis, hydroureter, dilated bladder

Unknown

Early amnion rupture47,48

Digital and limb amputations, ring constrictions, facial clefts, body wall defects, brain anomalies

Renal dysplasia, agenesis, and ectopia; ureteral anomalies; urethral stenosis

Sporadic

Epidermolysis bullosa-pyloric atresia-obstructive uropathy49

Epidermolysis bullosa, pyloric and esophageal atresia, corneal abrasions, aplasia cutis

Urtheral stenosis, hydroureter

AR (226730) ITGA6, 17q11-qter

Facio-auriculo-vertebral (hemifacial microsomia, Goldenhar)50,51

Hemifacial microsomia; heart, radial ray, and vertebral defects

Renal agenesis, dysplasia and ectopia, reflux, ureteropelvic junction obstruction, posterior urethral valves

AD (164210) Heterogeneous, usually sporadic, one family mapped to 14q32

Fronto-metaphyseal dysplasia (Gorlin)52,53

Bony overgrowth of superorbital ridges, cortical hyperostosis, metaphyseal dysplasia, tibial bowing, vertebral defects, cardial defects (overlap with Melnick-Needles)

Supernumerary kidneys, hydronephrosis, ureteral defects, urethral valves

XLD (305620) FLNA, Xq28

Hand-foot-genital54,55

Hypoplasia of thumbs and great toes; duplication of female internal genitalia; chordee; hypospadias and epididymal cyst in males

Ectopic ureteral orifices, intravaginal urethra, hydronephrosis, reflux, urethral stenosis

AD (140000) HOXA13, 7p15-p14.2

Hydrolethalus56

Hydrocephalus, postaxial polydactyly, micrognathia, tongue anomalies, cardiac and tracheoesophageal defects, early lethal

Hydronephrosis, urethral stenosis

AR (236680) 11q23-q25

Kindler57

Acrokeratotic poikiloderma with bullous atrophy, pigmentary abnormalities

Urethral stenosis

AD, AR (173650) Possibly heterogeneous KIND1, 20p12.3

Lachiewicz58

Agenesis of corpus callosum, macrocephaly, mental retardation

Urethral valves, hydronephrosis, reflux, ureteral anomalies

Uncertain (continued)

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Urogenital System Organs

Table 28-23. Disorders with posterior urethral valves or urethral stenosis (continued) Disorder

Prominent Features

Urinary Tract Anomalies

Causation Gene/Locus

Michels oculo-palato-skeletal59,60

Cleft lip/palate, deafness, blepharophimosis, anterior chamber eye anomalies, skeletal anomalies

Urethral and ureteral anomalies

AR (257920)

Neurofibromatosis61

Cafe´-au-lait spots, neurofibromas, Lisch nodules, axillary freckling, overgrowth

Neurofibromas of the urethra, bladder, or ureter; renal artery stenosis; hydronephrosis

AD (162200) NF1, 17q11.2

Occipital horn62,63

Osteoporosis, exostoses, bone bowing, carpal; bone fusions, cutis laxa

Multiple urinary infections, bladder diverticulae, hydronephrosis, urethral stenosis

XLR (304150) ATP7A, Xq12-13

Ochoa64–66

‘‘Inversion’’ of facial expression when laughing

Hydronephrosis, hydroureter, neuropathic bladder, posterior urethral valves, urethral stenosis

AD (236730)

Rubinstein-Taybi67,68

Characteristic facies, broad thumbs and halluces, short stature, mental retardation, Dandy-Walker malformation, agenesis of corpus callosum, heart and vertebral defects

Renal agenesis, hypoplasia and ectopia, caliectasis, hydronephrosis, ureterocele, reflux, urethral stenosis, nephrosis

AD (180849), variable expression, most cases are sporadic, microdeletions seen in ~10% and cause a more severe phenotype CREBBP, 16p13.3

Russell-Silver69–73

Short stature, small triangular face, blue sclerae, asymmetric limbs, clinodactyly of fifth fingers, genital defects, variable mental retardation, feeding problems, excessive sweating

Hydronephrosis, renal tubular acidosis, horseshoe kidney, urethral valves

AD (180860), most cases sporadic, maternal uniparental disomy for chromosome 7 in ~10% 7p11.2

Sirenomelia74,75

Fusion of the lower limbs, anal atresia, genital anomalies, single umbilical artery

Renal agenesis or dsyplasia, bladder or cloacal extrophy, bladder agenesis, hydronephrosis, ureteral anomalies, urethral atresia

Probably heterogeneous, vascular steal from persistent vitelline vessels, excess of MZT and maternal diabetes

Townes-Brocks76,77

Radial ray and hallucal defects, anal anomalies, ear anomalies, deafness

Renal agenesis, dysplasia or hypoplasia, reflux, urethral atresia, urethral valves, horseshoe kidney

AD (107480) SALL1, 16q12.1

Urogenital adysplasia, congenital78,79

Mu¨llerian duct anomalies

Renal agenesis and dysplasia, urethral atresia

AD (191830), reduced penetrance and variable expressivity

Urorectal septum malformation80

Pseudohermaphroditism, cloacal and Mu¨llerian duct anomalies, ambiguous genitalia, imperforate anus (overlap with Lower mesodermal defects)

Renal agenesis, hypoplasia and dysplasia; ureteral and urethral anomalies

Sporadic

Werner81

Premature aging, short stature, atrophic skin, endocrine anomalies, hypospadias

Urethral stenosis, megaureter

AR (277700) RECQL2, 8p12-p11.2

Williams82–84

Characteristic facies, stellate irides, mental retardation, heart defects, radioulnar synostosis, infantile hypercalcemia

Small kidneys, renal ectopia or aplasia, duplicated pelvis or ureter, other ureteral defects, renal artery stenosis, urethral stenosis, bladder diverticula

AD (194050) ELN, 7q11.2

Wolfram85

Diabetes insipidus, diabetes mellitus, optic atrophy, deafness

Posterior urethral valves, hydronephrosis, hydroureter, neurogenic bladder

AR (222300) WFS1, 4p16.1 WFS2, 4q22-q24

thra and hypertrophy and thickening of the bladder neck and detrusor musculature. The bladder itself often becomes trabeculated and sacculated with thickened walls. Urinary ascites can develop by transudation of urine through small bladder perforations, fistulae with surrounding organs, or a patent urachus. The ureters are dilated in 70% of cases.12 Functional obstruction of the

ureterovesical junction can occur secondary to thickened detrusors. Vesicoureteral reflux is present in 45% of cases with PUV and is unilateral in 17%. Reflux, especially when associated with urinary tract infections, contributes to more rapid loss of renal function. As noted in Section 28.9, cystic changes of the kidneys can occur due to obstructive nephropathy, but the finding in

Urinary Tract

removed kidneys of areas of both primary renal dysplasia and well-differentiated renal parenchyma, as well as changes due to reflux nephropathy, indicate that obstruction is not the sole cause of renal disease in these patients.13 PUV have been reported in brothers on several occasions14,15; in a father, son, and paternal uncle16; and in concordant monozygous twins.17–19 There has been variability in such families, with some cases going unrecognized until the ascertainment of a more severely affected relative. In general, familial cases have presented later in infancy or childhood and have had less severe renal disease. The pattern of inheritance is unclear, with both autosomal recessive and autosomal dominant modes suggested. Data from a population study in Oman3 showed a higher frequency of parental consanguinity in cases compared to the general Omani population, but the low recurrence risk (2–6%) mitigated against a simple recessive model. Thus, multifactorial inheritance appears a likely explanation for most cases. As PUV are commonly seen in patients with terminal deletions of 10q and ring 10 chromosomes, a major predisposing gene may be located in this region.20,21 Maternal inheritance was postulated as a possible mechanism based on a family where a mother with recurrent urinary tract infections had two affected sons.22 However, the finding of a branchial cleft cyst and anteriorly rotated ear in one son also suggests branchiooto-renal syndrome. Urethral strictures may also be familial; affected brothers23,24 and an affected father and son25 are among the familial cases reported. Prognosis, Prevention, and Treatment

The treatment of PUV is dependent on the nature of the defect and the degree of renal impairment, with patients that present early in life doing less well.26 With normal renal function, a period of transurethral drainage by catheter and the use of antibiotic therapy may lead to amelioration of symptoms. If this is unsuccessful, primary ablation of the valves with transurethral fulguration is usually successful. When the anterior urethral lumen is too narrow for endoscopy, a temporary vesicostomy may be necessary. When renal impairment is present, upper tract drainage with cutaneous pyelostomy or high ureterostomy may be indicated, with later reconstruction. Continued problems with decreased renal function may necessitate renal transplantation. Factors that may help predict patients at risk for ultimate renal failure include glomerular filtration rate at 1 year of age, persistently raised serum creatinine levels a year after decompression, bilateral high-grade reflux, persistent hydronephrosis or hydroureter, and voiding abnormalities.27,28 New treatment modalities include in utero drainage of the obstructed fetal bladder to prevent continued renal damage and complications of oligohydramnios. In fetuses with adequate residual renal function, methods of surgical treatment include transabdominal placement of a vesicoamniotic shunt or percutaneous cystoscopy.29–31 Follow-up of 17 patients detected at 24 weeks gestation or earlier indicated that 53% had died or had chronic renal failure. All of 19 patients diagnosed later in pregnancy had had normal second trimester scans and only one had a poor outcome.26 Survival is dependent on the severity of the obstruction and associated anomalies. Mortality is higher when associated nonrenal congenital anomalies are present. Occasionally, there may be spontaneous remission of the obstruction and associated ascites before birth.32

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Long-term complications include recurrent urinary tract infection, persistent vesicoureteral reflux and hydronephrosis, urinary incontinence after ablation of the PUV, bladder dysfunction, polyuria, and late onset of renal failure. However, fertility and sexual functioning are usually not impaired.33,34 The recurrence risk for isolated PUV would appear to be 2–6%.3 Prenatal diagnosis with fetal sonograms at 18, 24, and 32 weeks of pregnancy can be offered to families, because it may detect recurrence of bladder enlargement and incomplete emptying, hydroureter, hydronephrosis, and oligohydramnios. Male relatives of affected boys may also be at risk and should be investigated if they show any signs of urinary dysfunction. References (Posterior Urethral Valves and Urethral Stenosis) 1. Woolf AS, Thiruchelvam N: Congenital obstructive uropathy: its origin and contribution to end-stage renal disease in children. Adv Ren Replace Ther 8:157, 2001. 2. Stephens FD: Congenital Malformations of the Urinary Tract. Praeger Publishers, New York, 1983. 3. Rajab A, Freeman NV, Patton M: The frequency of posterior urethral valves in Oman. Br J Urol 77:900, 1996. 4. Dinneen MD, Dhillon HK, Ward HC, et al.: Antenatal diagnosis of posterior urethral valves. Br J Urol 72:364, 1993. 5. Farnsworth RH, Rossleigh MA, Leighton DM, et al.: The detection of reflux nephropathy in infants by 99mtechnetium dimercaptosuccinic acid studies. J Urol 145:542, 1991. 6. Workman SJ, Kogan BA: Fetal bladder histology in posterior urethral valves and the prune belly syndrome. J Urol 144:337, 1990. 7. Krueger RP, Ash JM, Silver MM, et al.: Primary hydronephrosis. Assessment of diuretic renography, pelvis perfusion pressure, operative findings, and renal and ureteral histology. Urol Clin North Am 7:231, 1980. 8. Orvis BR, Bottles K, Kogan BA: Testicular histology in fetuses with the prune belly syndrome and posterior urethral valves. J Urol 139:335, 1988. 9. Ehrlich A: Congenital stenosis of prostatic urethra. Am J Dis Child 91:625, 1956. 10. Churchill BM, McLorie GA, Khoury AE, et al.: Emergency treatment and long-term follow-up of posterior urethral valves. Urol Clin North Am 17:343, 1990. 11. Chen CP, Liu FF, Jan SW, et al.: First report of distal obstructive uropathy and prune-belly syndrome in an infant with amniotic band syndrome. Am J Perinatol 14:31, 1997. 12. Young HH, Frontz WA, Baldwin JC: Congenital obstruction of the posterior urethra. J Urol 3:289, 1919. 13. Haecker FM, Wehrmann M, Hacker HW, et al.: Renal dysplasia in children with posterior urethral valves: a primary or secondary malformation? Pediatr Surg Int 18:119, 2002. 14. Doraiswamy NV, Al Badr MS, Freeman NV: Posterior urethral valves in siblings. Br J Urol 55:448, 1983. 15. Farkas A, Skinner DG: Posterior urethral valves in siblings. Br J Urol 48:76, 1976. 16. Hanlon-Lundberg KM, Verp MS, Loy G: Posterior urethral valves in successive generations. Am J Perinatol 11:37, 1994. 17. Kroovand RL, Weinberg N, Emami A: Posterior urethral valves in identical twins. Pediatrics 60:748, 1977. 18. Morini F, Ilari M, Casati A, et al.: Posterior urethral valves and mirror image anomalies in monozygotic twins. Am J Med Genet 111:210, 2002. 19. Livne PM, Delaune J, Gonzales ET Jr.: Genetic etiology of posterior urethral valves. J Urol 130:781, 1983. 20. Shapiro SD, Hansen KL, Pasztor LM, et al.: Deletions of the long arm of chromosome 10. Am J Med Genet 20:181, 1985. 21. Michels VV, Driscoll DJ, Ledbetter DH, et al.: Phenotype associated with ring 10 chromosome: report of patient and review of literature. Am J Med Genet 9:231, 1981.

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22. Trembath DG, Rijhsinghani A: Possible maternal inheritance of a common obstructive urinary tract anomaly. Report of a case of a woman with multiple urinary tract infections and two sons with posterior urethral valves. J Reprod Med 47:962, 2002. 23. Jones DJ: Congenital bulbar urethral stricture occurring in two brothers. Urol Int 43:366, 1988. 24. Aragona F, Maio G, Oliva G, et al.: Familial occurrence of congenital stricture of bulbar urethra. Urol Int 46:112, 1991. 25. English PJ, Pryor JP: Congenital bulbar urethral stricture occurring in a father and son. Br J Urol 58:732, 1986. 26. Hutton KA, Thomas DF, Arthur RJ, et al.: Prenatally detected posterior urethral valves: is gestational age at detection a predictor of outcome? J Urol 152:698, 1994. 27. Lal R, Bhatnagar V, Mitra DK: Long-term prognosis of renal function in boys treated for posterior urethral valves. Eur J Pediatr Surg 9:307, 1999. 28. Lopez PP, Espinosa L, Martinez Urrutina MJ, et al.: Posterior urethral valves: prognostic factors. BJU Int 91:687, 2003. 29. Quintero RA, Johnson MP, Romero R, et al.: In-utero percutaneous cystoscopy in the management of fetal lower obstructive uropathy. Lancet 346:537, 1995. 30. Quintero RA, Hume R, Smith C, et al.: Percutaneous fetal cystoscopy and endoscopic fulguration of posterior urethral valves. Am J Obstet Gynecol 172:206, 1995. 31. Holmes N, Harrison MR, Baskin LS: Fetal surgery for posterior urethral valves: long-term postnatal outcomes. Pediatrics 108:E7, 2001. 32. Hecher K, Henning K, Spernol R, et al.: Spontaneous remission of urinary tract obstruction and ascites in a fetus with posterior urethral valves. Ultrasound Obstet Gynecol 1:426, 1991. 33. Parkhouse HF, Barratt TM, Dillon MJ, et al.: Long-term outcome of boys with posterior urethral valves. Br J Urol 62:59, 1988. 34. Parkhouse HF, Woodhouse CR: Long-term status of patients with posterior urethral valves. Urol Clin North Am 17:373, 1990. 35. Gonzales ET: Posterior urethral valves and other urethral anomalies. In: Campbell’s Urology, ed 8. MF Campbell, PC Walsh, AB Retik, eds. WB Saunders Company, Philadelphia, 2002, p 2209. 36. Al Gazali LI, Donnai D, Mueller RF: Hirschsprung’s disease, hypoplastic nails, and minor dysmorphic features: a distinct autosomal recessive syndrome? J Med Genet 25:758, 1988. 37. Kashani IA, Strom CM, Utley JE, et al.: Hypoplastic pulmonary arteries and aorta with obstructive uropathy in 2 siblings. Angiology 35:252, 1984. 38. Vassal HB, Malone M, Petros AJ, et al.: Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia). J Med Genet 35:58, 1998. 39. Partington MW, Marriott PJ, Prentice RS, et al.: Familial cutaneous amyloidosis with systemic manifestations in males. Am J Med Genet 10:65, 1981. 40. Gedeon AK, Mulley JC, Kozman H, et al.: Localisation of the gene for X-linked reticulate pigmentary disorder with systemic manifestations (PDR), previously known as X-linked cutaneous amyloidosis. Am J Med Genet 52:75, 1994. 41. Makhoul IR, Aviram-Goldring A, Paperna T, et al.: Caudal dysplasia sequence with penile enlargement: case report and a potential pathogenic hypothesis. Am J Med Genet 99:54, 2001. 42. Gershoni-Baruch R, Nachlieli T, Leibo R, et al.: Cystic kidney dysplasia and polydactyly in 3 sibs with Bardet-Biedl syndrome. Am J Med Genet 44:269, 1992. 43. Beales PL, Reid HA, Griffiths MH, et al.: Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant 15:1977, 2000. 44. Elliott M, Maher ER: Beckwith-Wiedemann syndrome. J Med Genet 31: 560, 1994. 45. Lam WW, Hatada I, Ohishi S, et al.: Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J Med Genet 36:518, 1999.

46. Halal F: Distal obstructive uropathy with polydactyly: a new syndrome? Am J Med Genet 24:753, 1986. 47. Higginbottom MC, Jones KL, Hall BD, et al.: The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544, 1979. 48. Chen CP, Liu FF, Jan SW, et al.: First report of distal obstructive uropathy and prune-belly syndrome in an infant with amniotic band syndrome. Am J Perinatol 14:31, 1997. 49. Wallerstein R, Klein ML, Genieser N, et al.: Epidermolysis bullosa, pyloric atresia, and obstructive uropathy: a report of two case reports with molecular correlation and clinical management. Pediatr Dermatol 17:286, 2000. 50. Horgan JE, Padwa BL, LaBrie RA, et al.: OMENS-Plus: analysis of craniofacial and extracraniofacial anomalies in hemifacial microsomia. Cleft Palate Craniofac J 32:405, 1995. 51. Johnson KA, Fairhurst J, Clarke NM: Oculoauriculovertebral spectrum: new manifestations. Pediatr Radiol 25:446, 1995. 52. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33:487, 2003. 53. Franceschini P, Guala A, Licata D, et al.: Esophageal atresia with distal tracheoesophageal fistula in a patient with fronto-metaphyseal dysplasia. Am J Med Genet 73:10, 1997. 54. Halal F: The hand-foot-genital (hand-foot-uterus) syndrome: family report and update. Am J Med Genet 30:793, 1988. 55. Mortlock DP, Innis JW: Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet 15:179, 1997. 56. Aughton DJ, Cassidy SB: Hydrolethalus syndrome: report of an apparent mild case, literature review, and differential diagnosis. Am J Med Genet 27:935, 1987. 57. Forman AB, Prendiville JS, Esterly NB, et al.: Kindler syndrome: report of two cases and review of the literature. Pediatr Dermatol 6:91, 1989. 58. Lachiewicz AM, Kogan SJ, Levitt SB, et al.: Concurrent agenesis of the corpus callosum and ureteroceles in siblings. Pediatrics 75:904, 1985. 59. Cunniff C, Jones KL: Craniosynostosis and lid anomalies: report of a girl with Michels syndrome. Am J Med Genet 37:28, 1990. 60. Guion-Almeida ML, Rodini ES: Michels syndrome in a Brazilian girl born to consanguineous parents. Am J Med Genet 57:377, 1995. 61. Gonzalez-Angulo A, Reyes HA: Neurofibromatosis involving the lower urinary tract. J Urol 89:804, 1963. 62. Tsukahara M, Imaizumi K, Kawai S, et al.: Occipital horn syndrome: report of a patient and review of the literature. Clin Genet 45:32, 1994. 63. Moller LB, Tumer Z, Lund C, et al.: Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. Am J Hum Genet 66:1211, 2000. 64. Elejalde BR: Genetic and diagnostic considerations in three families with abnormalities of facial expression and congenital urinary obstruction: ‘‘The Ochoa syndrome.’’ Am J Med Genet 3:97, 1979. 65. Ochoa B, Gorlin RJ: Urofacial (ochoa) syndrome. Am J Med Genet 27:661, 1987. 66. Wang CY, Hawkins-Lee B, Ochoa B, et al.: Homozygosity and linkagedisequilibrium mapping of the urofacial (Ochoa) syndrome gene to a 1-cM interval on chromosome 10q23-q24. Am J Hum Genet 60:1461, 1997. 67. Bartsch O, Wagner A, Hinkel GK, et al.: FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. Eur J Hum Genet 7: 748, 1999. 68. Kanjilal D, Basir MA, Verma RS, et al.: New dysmorphic features in Rubinstein-Taybi syndrome. J Med Genet 29:669, 1992. 69. Rudd NL, Klimek ML: Familial caudal dysgenesis: evidence for a major dominant gene. Clin Genet 38:170, 1990. 70. Selig AM, Benacerraf B, Greene MF, et al.: Renal dysplasia, megalocystis, and sirenomelia in four siblings. Teratology 47:65, 1993. 71. Newman WG, Brunet MD, Donnai D: Townes-Brocks syndrome presenting as end stage renal failure. Clin Dysmorphol 6:57, 1997.

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72. McPherson E, Carey J, Kramer A, et al.: Dominantly inherited renal adysplasia. Am J Med Genet 26:863, 1987. 73. Roodhooft AM, Birnholz JC, Holmes LB: Familial nature of congenital absence and severe dysgenesis of both kidneys. N Engl J Med 310:1341, 1984. 74. Wenstrup RJ, Pagon RA: Female pseudohermaphroditism with anorectal, Mullerian duct, and urinary tract malformations: report of four cases. J Pediatr 107:751, 1985. 75. Haddad F, Debs R, Tohme A, et al.: Werner’s syndrome. Ann Dermatol Venereol 125:24, 1998. 76. Pober BR, Lacro RV, Rice C, et al.: Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 46:271, 1993. 77. Pankau R, Partsch CJ, Winter M, et al.: Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 63:301, 1996. 78. Morris CA, Leonard CO, Dilts C, et al.: Adults with Williams syndrome. Am J Med Genet Suppl 6:102, 1990. 79. Caione P, Mazzeo D, Di Marco A, et al.: [Wolfram syndrome. Peculiar urologic aspects]. Minerva Pediatr 47:77, 1995.

28.17 Urethral Duplication Definition

Urethral duplication is the complete or partial duplication of the urethra. Diagnosis

Duplication of the urethra is a rare anomaly that is predominantly found in males. It may be asymptomatic or associated with postmicturition dribbling,1 incontinence, or ectopic urethral openings in the prepubic area,2,3 perineum, anus, or rectum. Patients may occasionally present with acute abdomen,4 recurrent urinary tract infections,5 or a perianal abcess.6 Approximately 40% of patients have reflux. In one series of patients,7 the mean age at diagnosis was 29 months, with 10 of 16 patients having a double meatus. Clinical presentation will vary depending on the type of duplication present. Voiding cystourethrograms may help in determining the precise relationships between the urethra and the bladder. Ultrasound, retrograde urethrography, and endoscopy may also be helpful for diagnosis. Effman et al.8 classified male cases into three main groups, examples of which are shown in Figure 28-24. In type I, there is incomplete duplication and the accessory urethra has no connection with the bladder or normal urethra. In type IA, the accessory urethra opens on the penile surface, while in type IB, it ends blindly in the periurethral tissue (duplication cyst). In type II, the duplication is complete and the accessory urethra is patent. In type IIA, there is a double meatus; the urethras either have independent channels from the bladder (type IIA1) or the accessory urethra arises from the main channel and exits on the glans (Fig. 28-25) or ectopically (type IIA2). In type IIB, there is a single meatus; the two urethras arise separately from the bladder, but join more distally. In type III, duplication of the urethra forms part of a more extended pattern of caudal duplication. Very occasionally, there may be three9 or even four10 urethras. In one series,7 the proportion of cases falling into types I, II, and III were 25%, 63%, and 12%, respectively. The duplication is usually ventral or dorsal; coronal duplication is more often associated with bladder duplication.

Fig. 28-24. Classification of urethral duplication modified from Effman.8 Note that duplication may be in any plane. (Reprinted from Salle JLP, Sibai H, Rosenstein D, et al.: J Urol 163:1936, 2000.)

Patients with urethral duplication may have a variety of other genitourinary tract anomalies. Renal agenesis has been reported,11 but is rare. Renal ectopia,12,13 posterior urethral valves,14 and penile chordee15 have also been described. Ventral duplication of the Fig. 28-25. Urethral duplication in the coronal plane with double urethral meatus. (Reprinted from Salle JLP, Sibai H, Rosenstein D, et al.: J Urol 163:1936, 2000.)

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urethra is seen with hypospadias and dorsal duplication with epispadias.16 Urethral duplication may also occur with abnormal development of the urogenital sinus, leading to bladder exstrophy17 or cloacal exstrophy,18 or in lateral body wall defects.19 Associated anomalies of contiguous and noncontiguous structures occur in almost all of these patients. Type III duplication is associated with partial or complete duplication of the hindgut anlage.16,18 Associated anomalies of contiguous structures include bifid penis or clitoris, diphallus, bifid scrotum, duplicated vulva and labia, duplicated or septate bladder and vagina, and duplication of the colon, rectum, and anus. Duplication of the urethra can be associated with two normalappearing phalli, but more commonly there is one phallus with hypospadias or a urethral-rectal fistula. The duplicated colon can terminate as two separate perineal ani; as one normal anus and a rectovaginal or rectovesicular fistula; or with one or both ani imperforate and blind ending. Less frequently there are abnormalities of the upper urinary tract, including duplication of the ureter, horseshoe kidney, and unilateral renal agenesis. Commonly associated anomalies outside the hindgut region include vertebral defects, meningomyelocele, and omphalocele. Etiology and Distribution

Urethral duplications with separate bladder openings presumably arise from abnormal relationships between the lateral anlagen of the genital tubercle and the ventral end of the cloacal membrane. If these join more posteriorly than usual or if the cloacal membrane extends more ventrally, a longer membrane will be produced. A range of anomalies from bladder exstrophy to an epispadiac urethra would result, with urethral duplication with separate openings representing a midpoint in this range.18 Duplication of the urethra associated with partial or complete duplication of the hindgut results from abnormal development of the caudal notochord and associated endoderm. Although much more frequent in males, urethral duplication does occur in females.20–24 Vaginal anomalies including duplication,25 atresia,26 and stenosis27 are frequent. Other than in the patterns of malformations already described, urethral duplication is rarely seen in conjunction with other anomalies. It has been reported in VACTERL association28 and was found in a boy with progressive vitiligo, dysmorphic facies, and mental retardation, whose parents were first cousins.29 There was no evidence of excess chromosome breakage and his immune system was normal. Another family of note is that reported by Dodat et al.,29 where two brothers had penoscrotal transposition, in one case associated with diphallus. Their mother had been born with a similar form of genital anomaly with a phallic structure between the partially fused labial folds. All three also had absent or hypoplastic patellae. Prognosis, Prevention, and Treatment

Treatment for urethral duplication must be individualized depending on the presenting symptoms and the precise anatomy. Complete duplication without hypospadias may require no therapy. When surgical correction is required, it is important to ascertain and preserve the most functional urethra rather than the one in the most anatomically normal position.7 Generally, the long-term prognosis for these patients is determined by severity of any associated anomalies.

Recurrence risk figures are not available for isolated duplication of the urethra and phallus. Risks for complex cases would depend on the underlying disorder. Prenatal diagnosis with a detailed fetal ultrasound would detect the majority of severe structural anomalies associated with duplication of the urethra. However, the urethral defect itself may not be seen. Maternal serum a-fetoprotein screening is likely to detect neural tube defects and body wall defects. References (Urethral Duplication) 1. Wells GR, Davies ML: A rare cause of post-micturition dribbling: incomplete urethral duplication. Br J Urol 65:212, 1990. 2. Al Wattar KM: Congenital prepubic sinus: an epispadiac variant of urethral duplication: case report and review of literature. J Pediatr Surg 38:E10, 2003. 3. Huang CC, Wu WH, Chai CY, et al.: Congenital prepubic sinus: a variant of dorsal urethral duplication suggested by immunohistochemical analysis. J Urol 166:1876, 2001. 4. Chaplin BJ, Mastboom WJ: Urethral duplication presenting as an acute abdomen: an unusual presentation of a rare anomaly. BJU Int 84:175, 1999. 5. Saussine C, Bertrand P, Jacqmin D, et al.: Recurrent urinary infection secondary to urethral duplication. Br J Urol 71:613, 1993. 6. Arda IS, Hicsonmez A: An unusual presentation of Y-type urethral duplication with perianal abscess: case report. J Pediatr Surg 37:1213, 2002. 7. Salle JL, Sibai H, Rosenstein D, et al.: Urethral duplication in the male: review of 16 cases. J Urol 163:1936, 2000. 8. Effman EL, Lebowitz RL, Colodny AH: Duplication of the urethra. Radiology 119:179, 1976. 9. Zimmermann H, Mildenberger H: Posterior urethral duplication and triplication in the male. J Pediatr Surg 15:212, 1980. 10. Woodhouse CR, Williams DI: Duplications of the lower urinary tract in children. Br J Urol 51:481, 1979. 11. Mehan DJ, Gonzales JH: Urethral duplication, with associated agenesis of left kidney and right ureteral ectopia. Urology 6:476, 1975. 12. Berrocal T, Novak S, Arjonilla A, et al.: Complete duplication of bladder and urethra in the coronal plane in a girl: case report and review of the literature. Pediatr Radiol 29:171, 1999. 13. Barker A, Ahmed S: Duplication of the male urethra associated with crossed renal ectopia. Aust N Z J Surg 60:62, 1990. 14. Ramanujam TM, Sergius A, Usha V, et al.: Incomplete hypospadiac urethral duplication with posterior urethral valves. Pediatr Surg Int 14:134, 1998. 15. Lawson GM, Scobie WG: Urethral duplication and chordee—a rare association. Br J Urol 65:545, 1990. 16. Stephens FD: Congenital Malformations of the Urinary Tract. Praeger Publishers, New York, 1983. 17. Pippi Salle JL, Sibai H, Jacobson AI, et al.: Bladder exstrophy associated with complete urethral duplication: a rare malformation with excellent prognosis. J Urol 165:2434, 2001. 18. Gray SW, Skandalakis JE: Embryology of Surgeons: The Embryological Basis for the Treatment of Congenital Defects. WB Saunders Company, Philadelphia, 1972. 19. Van Allen MI, Curry C, Gallagher L: Limb body wall complex: I. Pathogenesis. Am J Med Genet 28:529, 1987. 20. Susan LP, Roth RB, Kaminsky AF: Complete duplication of urethra. Urology 05:390, 1975. 21. Bellagha I, Chaouachi B, Hammou A, et al.: [An exceptional combined malformation: duplication of the lower urinary tract, the vulva and the posterior intestine]. Ann Urol (Paris) 27:101, 1993. 22. Park WH, Choi SO, Park KK, et al.: Prepubic dermoid sinus: possible variant of dorsal urethral duplication (Stephens type 3). J Pediatr Surg 28:1610, 1993. 23. Goh DW, Davey RB, Dewan PA: Bladder, urethral, and vaginal duplication. J Pediatr Surg 30:125, 1995.

Urinary Tract 24. Perez-Brayfield MR, Clarke HS, Pattaras JG: Complete bladder, urethral, and vaginal duplication in a 50-year-old woman. Urology 60:514, 2002. 25. Antony J: Complete duplication of female urethra with vaginal atresia and supernumerary kidney. J Urol 118:877, 1977. 26. Bonney WW, Young HH, Levin D, et al.: Complete duplication of the urethra with vaginal stenosis. J Urol 113:132, 1975. 27. Fernbach SK: Urethral abnormalities in male neonates with VATER association. AJR Am J Roentgenol 156:137, 1991.

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28. Labrune P, Assathiany R, Penso D, et al.: Progressive vitiligo, mental retardation, facial dysmorphism, and urethral duplication without chromosomal breakage or immunodeficiency. J Med Genet 29:592, 1992. 29. Dodat H, Rosenberg D, James-Pangaud I: Familial association of penoscrotal transposition and diphallia (double penis) with patella aplasia. Arch Pediatr 2:241, 1995.

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29 Male Genital System Rick A. Martin

W

‘‘

hat is it?’’ is a question posed countless times each day after the birth of a baby. Of course the intent of the question is to know the sex of the baby. But is the questioner’s interest directed at the genetic sex, or is there more curiosity about the gonadal sex? Truth be told, it is the phenotypic sex people want to know about, and a quick peek under the diaper generally confirms the genital dimorphism of our species, correctly predicts both the genetic and gonadal sex of the child, and sows the first seeds of the gender identity process. Genital anomalies often impede this process and cause great anxiety. Of equal importance is the fact that such defects can herald considerable morbidity or mortality. Human sexual dimorphism is the result of two cellular processes: genetic sex determination and sexual differentiation. Genetic sex is determined by a brief cytogenetic event at fertilization that establishes the presence or absence of a Y chromosome. Sexual differentiation, on the other hand, is a complex, temporal series of events that act on early bipotent primordial embryonic cells and end with development of complementary male or female internal genitalia, external genitalia, body habitus and brain development that define the human dimorphic state. Which sequence occurs is a function of genetic sex. In the absence of a Y chromosome, bipotent germ cells migrating from the yolk sac to the urogenital ridge follow a developmental course that leads to female internal and external genitalia (see Chapter 30). However, the effect of a Y chromosome on these same primordial cells is to set in motion an elaborate choreographed sequence of molecular and hormonal events that result in male genitalia (Fig. 29-1). Male genitalia are derived from three distinct embryonic regions: the urogenital (or gonadal) ridge that gives rise to the testis, the mesonephric duct that gives rise to the male genital ducts (epididymis, vas deferens, and seminal vesicles) and the genital tubercle, urogenital folds and scrotal folds that give rise to the penis and scrotal sac. Testes Development

Primordial germ cells (PGC) migrate from the intermediate mesoderm of the yolk sac and arrive at the urogenital ridge during Some materials in this chapter were drawn from Dr. Barbara C. McGillivray’s chapter on the Male Genital System in the first edition of this book.

the 6th week of gestation (Fig. 29-2).1 The determination of these bipotent PGC is under the control of at least two genes, WT1 and SF-1 (Fig. 29-1).1,2 Their subsequent differentiation into specific testicular cell types is largely determined by the sex-determining region Y (SRY) gene. The SRY gene coordinates a complex temporal interaction of a host of other genes (Table 29-1) now known to influence gonadal developmental processes such as cell proliferation, migration, differentiation, and vascularization. However, the specific mechanisms of SRY interaction with these genes are not yet well-established. It is clear that Sertoli cells play a critical role in the organization of the cellular architecture of the testes.3 Supporting cells surrounding the PGC develop into Sertoli cells under the influence of the SRY gene product known as high mobility group (HMG) box.1 Sertoli cells then orchestrate development of the seminiferous (or testicular) cords in which they reside along with the PGC by 7 weeks. The seminiferous cords condense and grow into the medulla of the developing testis where they form the rete testis. The cords are surrounded by the tunica albuginea and eventually canalize to form the seminiferous tubules. The PGC within the tubules will ultimately give rise to early spermatogonia, which will remain quiescent until puberty, when other genes yet to be defined (likely non-Y linked) initiate spermatogenesis. Within the mesenchyme surrounding the seminiferous cords are Leydig cells. Production of testosterone by the Leydig cells begins by the 8th week of gestation. It is testosterone production that is critical to continuation of male genital phenotype differentiation. The developing gonad is held in place intraabdominally near the inferior pole of the kidney by the cranial suspensory ligament (CSL) and the gubernaculum.1 In the male, the CSL involutes under the influence of testosterone while the gubernaculum enlarges and guides the transabdominal migration of the testes to the inguinal ring by week 15. Regression of the gubernaculum then initiates descent of the testes through the inguinal ring and into the scrotum by week 35. While inguinal descent of the testes appears to be an androgen-dependent process, recent evidence suggests that transabdominal testicular descent is not dependent upon androgens or anti-Mu¨llerian hormone as previously believed.1,4 Another hormone secreted by Leydig cells, insulinlike 3 (INSL3), is now believed to play a crucial role in this phase of testicular descent.4 1251

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Fig. 29-1. Cascade of molecular events leading to differentiation of male genitalia.

Fig. 29-2. Scanning electron micrograph of developing genital tract showing (A) gonad, (B) mesonephric ducts, paramesonephric ducts, and remaining mesonephros, (C) bladder, (D) definitive kidney (metanephros), and (E) gubernaculum. (Courtesy of Dr. Kathy Sulik, University of North Carolina, Chapel Hill.)

Penoscrotal Development

Traditional embryology of penoscrotal development focuses on the androgen-associated aspect of genital differentiation that commences after the 8th gestational week and initiates masculinization of the heretofore undifferentiated genitalia. However, recent work in the mouse has demonstrated significant insight

into androgen-independent mechanisms of external genitalia development prior to 8 weeks of human development. Most remarkable is the discovery that early growth of the genital tubercle has many similarities to early limb bud development.5–7 Like the limb bud, the genital tubercle also buds out from lateral plate mesoderm. Evidence suggests that its continued proximodistal outgrowth is controlled by the overlying epithelium, analogous to the apical ectodermal ridge of the limb bud. Similarly, there appears to be a ZPA (zone of polarizing activity) region of the urethral epithelium that controls patterning of the genital tubercle. Finally, sonic hedgehog (SHH) in the genital tubercle region seems to be critical in mediating the signaling activity of many of the same genes essential to limb growth (Fig. 29-1, Table 29-1). By the end of the first 8 weeks of development, the embryo has developed a genital tubercle, urethral (urogenital) folds, labioscrotal folds, and a urogenital sinus (Fig. 29-3). These structures are bipotent and their final external appearance is dependent upon exposure to testosterone and dihydrotestosterone (DHT). Genital differentiation begins with the onset of testosterone production by the Leydig cells. Initially under the influence of placentally derived human chorionic gonadotropin and then fetally produced luteinizing hormone (LH), the Leydig cells are stimulated to make testosterone via their LH receptors. The ability to generate DHT from testosterone via 5a-reductase in the peripheral end organ tissue is critical to male differentiation. The genital tubercle enlarges and forms the glans penis in the presence of DHT and normal androgen receptors. Simultaneously, the urethral folds lengthen and fuse to form the penile urethra while the labioscrotal folds move inferiorly, merge, and form the scrotal sac. These fusion and merging processes leave behind a continuous raphe, extending from the ventral surface of the glans penis inferiorly down the shaft of the penis to the scrotal raphe and ending with the perineal raphe (Fig. 29-4).

Table 29-1. Selected genes that play significant roles in male genital development Gene

Gene Product and Gene Location

Function

WT1

WT1 11p13

TF*, gonadogenesis

NR5A1

Steroidogenic factor (SF1) 9q33

TF, gonadogenesis, Leydig differentiation, regulates steroidogenesis genes and MIS**

NROB1

Nuclear receptor (DAX1) Xp21.3

TF(repressor), gonadogenesis

LHX1

LIM Homeobox protein (LIM1) 17q11.2

TF, gonadogenesis

LHX9

LIM Homeobox protein 1q31-32

TF, gonadogenesis

EMX2

Drosophila head gap 10q26

TF, gonadogenesis

GATA4

GATA 4-binding protein 8p23.1-22

TF, gonadogenesis

FOG2

Friend of GATA Zinc finger protein Chrom 8

TF, interacts with GATA4, gonadogenesis

SRY

HMG box Yp11.3

TF, activates and/or represses downstream genes, testicular differentiation

SOX9

SRY HMG-box-like protein 17q24-25

TF, upregulation, testicular differentiation

CBX2

Chromobox homolog 17q25

TF, testicular differentiation

DMRT1/DMRT2

DM domain protein 9p24.3

TF, testicular differentiation

XH2(ATRX)

DNA helicase Xq13

TF, chromatin modulation

FGF9

Fibroblast growth factor 9 13q11-13

SM****, mesonephric cell migration, Sertoli cell development

AMH

MIS 19p13.3

SM, regression of Mu¨llerian structures

AMH-R1

AMH receptor(kinase)

Required for signaling AMH type II receptor

AMH-R2

AMH receptor(kinase) 12q13

Regression of Mu¨llerian ducts

LHR

LH receptor(G-protein) 2p21

Leydig cell induction

StAR

Steroidogenic acute regulatory protein 8p11.2

First step in steroid biosynthesis from cholesterol

HSD3b2

Type 2 3b-hydroxysteroid dehydrogenase 1p13

Converts androstenediol to testosterone

CYP17

P450C17 10q24.3

17a-hydroxylation of pregnenolone and progesterone

HSD17b3

Type 3 17b-hydroxysteroid dehydrogenase 9q22

Converts androstenedione to testosterone

SRD5A2

5a-reductase 2p23

Testosterone conversion to dihydrotestosterone

AR

Androgen receptor (ligand TF) Xq11-12

Mediates testosterone end organ action

DHH

Desert hedgehog 12q13.1

Sertoli and Leydig cell differentiation

SHH

Sonic hedgehog 7q36

Regulates GT*** polarization and cell survival

FGF8

Fibroblast growth factor 8 10q24

GT growth and patterning

FGF10

Fibroblast growth factor 5p13-12

GT growth and patterning (continued)

1253

1254

Urogenital System Organs Table 29-1. Selected genes that play significant roles in male genital development (continued) Gene

Gene Product and Gene Location

Function

BMP4

Bone morphogenetic protein 14q22-23

GT cell apoptosis

WNT5A

Signaling glycoprotein 3p21-24

GT cell proliferation

HOXD13

Homeobox protein 2q31-32

GT patterning

HOXA13

Homeobox protein 7p15-14.1

GT patterning

*Transcription factor **Mu¨llerian inhibiting substance

***Genital tubercle ****Signaling molecule1–9

Fig. 29-3. Undifferentiated external genitalia, week 8. (Electron micrograph courtesy of Dr. Kathy Sulik, University of North Carolina, Chapel Hill; illustration courtesy of Dr. Stephen Gilbert, 1989, reprinted with permission by University Washington Press.)

Genital Duct Development

Two pairs of genital ducts are present in the undifferentiated embryo. The Wolffian, or mesonephric, ducts arise from the remnants of the primitive mesonephric kidney. The paramesonephric, or Mu¨llerian, ducts arise from the coelomic epithelium lateral to each mesonephros. In males, the Sertoli cells produce anti-mu¨llerian hormone (AMH, also known as Mu¨llerian inhibiting substance or MIS). AMH is a member of the transforming growth factor beta (TGF) family and binds to a TGF receptor in the Mu¨llerian ducts, which causes regression of the ducts by apoptosis.3 Simultaneously, the testosterone produced by the Leydig cells stabilizes

portions of the mesonephros that normally involute. The stabilized efferent ductules join the proximal portion of the Wolffian duct to the rete testis. Caudal to the entrance of the efferent ductules, the Wolffian duct becomes highly convoluted, forming the epididymis. The distal portion of the duct becomes the vas deferens and lateral outgrowths of each duct become the seminal vesicles. References 1. Ahmed SF, Hughes IA: The genetics of male masculinization. Clin Endo 56:1, 2002. 2. Parker KL, Schimmmer BP: Genes essential for early events in gonadal development. Ann Med 34:171, 2002.

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Fig. 29-4. Continuous raphe from glans to perineum. (Illustration courtesy of Dr. Stephen Gilbert, 1989, reprinted with permission by University Washington Press.)

3. Tilmann C, Capel B: Cellular and molecular pathways regulating mammalian sex determination. Recent Prog Horm Res 57:1, 2002. 4. Tomboc M, Lee PA, Mitwally MF, et al.: Insulin-like 3/Relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endo Metab 85:4013, 2000. 5. Haraguchi R, Mo R, Hui C, et al.: Unique functions of sonic hedgehog signaling during external genitalia development. Development 128: 4241, 2001. 6. Perriton CL, Powles N, Chiang C, et al.: Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Bio 247:26, 2002. 7. Ogino Y, Suzuki K, Haraguchi R, et al.: External genitalia formation— role of fibroblast growth factor, retinoic acid signaling, and distal urethral epithelium. Ann NY Acad Sciences 948:13, 2001. 8. Tevosian SG, Albrecht KH, Crispino JD, et al.: Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 129:4627, 2002. 9. Cotinot C, Pailhoux E, Jaubert F, et al.: Molecular genetics of sex determination. Sem Reprod Med 20:157, 2002.

29.1 Micropenis Definition

Micropenis is a small but normally formed penis, measuring less than 2.5 standard deviations (SD) of the mean in length.1 (Endocrinologists have established the unusual convention of using 2.5 SD as the lower limit of normal rather than 2 SD, which is used for most continuously variable traits.) Micropenis is to be distinguished from microphallus in that the latter is associated with hypospadias. Diagnosis

Although micropenis is often diagnosed subjectively, the diagnosis should be based on measurement and morphologic criteria. Micropenis has normal morphology with a glans penis, shaft, ventral median raphe, and urinary meatus on the glans penis (Fig. 29-5).

Fig. 29-5. Three males with micropenis: left, at birth; middle, at age 6 years; and right, in adulthood. (Patient at right has Prader-Willi syndrome.)

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Urogenital System Organs

Usually the meatus is placed at the tip of the glans penis, but a minor degree of hypospadias may be present. The foreskin may completely or only partially cover the glans penis. Micropenis may be accompanied by unilateral or bilateral cryptorchidism. The appearance of the scrotum is quite variable, depending in part on the location and size of the testes. Penis length is generally used to delineate penis size. Length is determined with the penis stretched to the point of resistance and measured along the dorsal surface from the pubis to the tip of the glans penis.1 The suprapubic fat pad is depressed as much as possible. Standards for penile length at various ages are available (Table 29-2).2–6 A penis of less than 2.5 cm at term birth is considered a micropenis. In the adult, 9.3 cm is considered the lower limit of normal. There is some variation in normal penile length based on ethnicity.7–9 The period of greatest penile growth occurs during the pubertal years. The stage of puberty must be taken into account when assessment is made during these years. Penile diameter and circumference may also be used in determining Table 29-2. Stretched penile length (cm) in normal malesa Mean  SD

Mean  2.5 SD

Preterm 23

1.50*

0.60**

24

1.60

0.75

25

1.75

0.90

26

1.90

1.15

27

2.10

1.25

28

2.25

1.40

29

2.40

1.55

30

2.55

1.75

31

2.70

1.90

32

2.85

2.10

33

3.10

2.25

34

3.25

2.40

35

3.40

2.55

36

3.55

2.70

37

3.70

2.85

b

0–5 months

3.9  0.8

1.90

6–12 months

4.3  0.8

2.30

1–2 years

4.7  0.8

2.60

2–3 years

5.1  0.9

2.90

3–4 years

5.5  0.9

3.30

4–5 years

5.7  0.9

3.50

5–6 years

6.0  0.9

3.80

6–7 years

6.1  0.9

3.90

7–8 years

6.2  1.0

3.70

8–9 years

6.3  1.0

3.80

9–10 years

6.3  1.0

3.80

6.4  1.1

3.70

17–19 yearsc

12.5  2.5

7.50

Adult

13.3  1.6

9.30

10–11 years

a

Data based on Schonfeld and Beebe,2 unless otherwise noted.

b

Preterm data based on Tuladhar et al.5 (*no standard deviations, **values are 5th percentile) c

Data 17–19 years based on Ponchietti et al.6

penis size, but these measurements are more difficult to obtain in a standardized manner. Micropenis must be distinguished from the buried or hidden penis (vide infra). In such a case, the normal size penis is embedded in the suprapubic fat pad or hidden by encircling folds of the scrotum. In both circumstances, the surrounding soft tissues may be pressed away from the shaft, allowing the penis to be seen and measured. Micropenis must also be distinguished from an enlarged clitoris that might be seen in congenital adrenal hyperplasia. Usually confusion arises only if the urinary meatus is displaced from the glans penis. The penis normally has a single median raphe; in contrast, the clitoris has two paramedian frenula that extend onto the labia minora. Etiology and Distribution

Micropenis is considerably heterogeneous in its occurrence with other conditions and in its underlying pathogenesis. Table 29-3 lists conditions frequently associated with micropenis. Several pathogenetic mechanisms may result in micropenis. Hypergonadotropic (primary) hypogonadism is a feature in numerous conditions. Early androgen production in these conditions is presumably sufficient for complete differentiation of the genitalia but insufficient to produce normal penile growth. The testes are small in these patients, plasma testosterone level is low, and the gonadotropin (LH) level is elevated. A less severe degree of hypogonadism may explain some cases of micropenis in otherwise normal males. Hypogonadism resulting in micropenis may also be caused by inadequate gonadotropin production (hypogonadotropic hypogonadism) either because of primary pituitary insufficiency or a primary hypothalamic dysfunction. Pituitary stimulation of the testes begins at about 14 to 15 weeks gestation, a point at which differentiation of the male genitalia is complete. Androgen action on penile growth is also abnormal in 5areductase deficiency and androgen insensitivity syndrome (Section 29.14). 5a-reductase deficiency results in low or absent dihydrotestosterone levels and is typically associated with genital ambiguity rather than isolated micropenis.10 Genital tissue may also be insensitive to normal amounts of androgens as a result of androgen receptor (AR) point mutations or CAG repeat length expansions in exon 1 of the AR gene (causing decreased expression). In complete androgen insensitivity syndrome (CAIS, Section 29.14), the AR receptor is rendered nonfunctional, resulting in complete lack of masculinization and consequent development of female external genitalia. AR mutations that fail to completely inactivate the receptor (partial androgen insensitivity syndrome or PAIS) result in ambiguous genitalia or micropenis with hypospadias (microphallus). Isolated micropenis as a result of an AR mutation is rare.11,12 Finally, isolated micropenis may be the result of Leydig cell hypoplasia caused by mutations in the leuteinizing hormone (LH) receptor gene,13 although such defects typically result in more severe degrees of undermasculinization (Section 29.14). Using 2.5 SD as the cutoff between normal and small, 0.6% of males will have micropenis as a part of normal variation. Normal variation thus constitutes the single largest cause of micropenis. Patients so affected have normal hypothalamic-pituitarygonadal function, have no associated anomalies, and masculinize appropriately at puberty. Other patients with micropenis may have associated hormonal imbalance or structural anomalies (Table 29-3).

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Table 29-3. Syndromes associated with micropenis Causation Gene/Locus

Syndrome

Prominent Features

Androgen insensitivity, partial19

Gynecomastia

XLR (312300) AR, Xq11-q12

5-a-reductase deficiency19

Genital ambiguity

AR (264600) SRD5A2

Bardet-Biedl20

Pigmentary retinopathy, obesity, polydactyly, mental retardation

AR (209900) multiple genes

Biemond, type II21

Iris coloboma, obesity, polydactyly, mental retardation

AR (210350)

CHARGE22

Coloboma of the eye; heart anomaly; atresia, choanal; retardation of development; genital defects; ear abnormalities and/or deafness

AD (214800) CHD7, 8q12.1

Chromosomal trisomies, duplications, deletions (multiple)

Depend on underlying chromosome aberration

Chromosomal

Cornelia de Lange23

Growth deficiency, micro/phocomelia, long philtrum, synophrys

AD (122470) NIPBL, 5p13.1

Kallmann24

Hyposmia/anosmia

XLR (308700) KAL1, Xp22.3 AD (147950) FGFR1, 8p11.2-p11.1 AR (244200)

Laurence-Moon25

Retinitis pigmentosa, spasticity, mental retardation

AR (245800)

Prader-Willi26

Neonatal hypotonia, obesity, mental retardation

(176270) imprinting defect deletion 15q, mat UPD 15

Robinow27

‘‘Fetal face,’’ prominent forehead, depressed nasal bridge, short stature, mesomelia

AD (180700) AR (268310) ROR2, 9q22

Schinzel-Giedeon28

Midfacial hypoplasia, choanal atresia, hirsutism, mental retardation

AR (269150)

Septo-optic dysplasia29

Hypopituitarism, absent septum pellucidum, hypoplastic optic discs

Sporadic (182230) HESX1, 3p21.2-p21.1

Short rib-polydactyly type I,II,III,IV30

Chondrodysplasia, polydactyly, narrow thorax, cleft lip, genitourinary anomalies

AR (263510, 263520, 263530, 269860)

Smith-Lemli-Opitz31

Microcephaly, anteverted nares, long philtrum, hypospadias, syndactyly

AR (270400) DHCR7, 11q12-q13

Ulnar-mammary32

Ulnar ray defects, post-axial polydactyly, anal atresia

AD (181450) TBX3, 12q24.1

In the Johns Hopkins series of 132 genetic males with underdevelopment of the genitalia, 45 had micropenis with otherwise normally formed genitalia (16 had female-appearing genitalia and 71 had ambiguous genitalia).14 Of the 45 males with micropenis, 14 (31%) had hypothalamic or pituitary dysfunction, 11 (23%) had primary hypogonadism, one (2%) had partial androgen insensitivity, and 19 had micropenis of undetermined cause. Prognosis, Treatment, and Prevention

The ultimate prognosis for micropenis is measured in terms of the ability to urinate from a standing position and to achieve adequate sexual function. In the neonatal period, however, understanding and acceptance of the defect by the parents and family and determination of the sex of rearing are the major issues. The difficulty for parents and for the diagnostic and counseling team increases when the sexual structures are ambiguous. The evaluation of micropenis is best initiated immediately upon recognition, usually at birth. Parents should be involved

from the outset and should be given full information as it becomes available. Genetic sex, internal anatomy, and the cause of the genital ambiguity must be quickly determined when the genital sex of the baby is called into question because of the size of the phallus. When the genitalia are clearly male with isolated micropenis, sex of rearing may be the only issue for resolution. Lee et al.14 suggest the sex of rearing to be female when the penis is unequivocally small at birth, that is, less than 2.5 SD below the mean. In contrast, Burstein et al.15 believe that the decision regarding sex of rearing can be based on the growth response to short-term androgens (one or two 3-month courses of intramuscular testosterone enanthate). If the penis responds to androgen stimulation and reaches normal size for age, male sex of rearing is advocated. However, a penile growth response to such a trial does not ensure that appropriate genital maturation, masculinization, and spermatogenesis will occur at puberty.16 The infant who is to be reared as female requires further reduction in penis size, removal of the testes, movement of the urinary meatus

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to the perineum, and construction of a vagina. Female hormones can be provided at the age of puberty. Long-term follow-up on individuals with micropenis raised as either male or female has been limited. Wisniewski et al.16,17 surveyed 18 genetic males with micropenis, 13 raised as males and five as females. Lifelong problems related to treatment and outcomes were common to both groups. However, almost all indicated satisfaction with their sex of rearing and their conclusion, also supported by that of Bin-Abbas et al.,18 was that male gender assignment is preferable for most infants with micropenis. Most men with the conditions having micropenis listed in Table 29-3 are subfertile. Sibling recurrences within the family may be seen in those conditions caused by single gene mutations. The question of micropenis or sexual ambiguity may arise during prenatal diagnosis when the ultrasound appearance of the genitalia does not agree with the amniocentesis results. References (Micropenis) 1. Migeon CJ, Berkovitz GD, Brown TR: Sexual differentiation and ambiguity. In: Wilkins: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescents. MS Kappy, RM Blizzard, Migeon CJ, eds. Charles C. Thomas, Springfield IL, 1994, p 661. 2. Schonfeld WA, Beebe GW: Normal growth and variation in the male genitalia from birth to maturity. J Urol 48:759, 1942. 3. Feldman KW, Smith DW: Fetal phallic growth and penile standards for newborn male infants. J Pediatr 86:395, 1975. 4. Aatau E, Josefsberg Z, Reisner SH, et al.: Penile size in the newborn infant. J Pediatr 87:663, 1975. 5. Tuladhar R, Davis PG, Batch J, et al.: Establishment of a normal range of penile length in preterm infants. J Paediatr Child Health 34:471, 1998. 6. Ponchietti R, Mondaini N, Bonafe M, et al.: Penile length and circumference: a study on 3,300 young Italian males. Eur Urol 39:183, 2001. 7. Al-Herbish AS: Standard penile size for normal full term newborns in the Saudi population. Saudi Med J 23:314, 2002. 8. Cheng PK, Chanoine JP: Should the definition of micropenis vary according to ethnicity? Horm Res 55:278, 2001. 9. Lian WB, Lee WR, Ho LY: Penile length of newborns in Singapore. J Pediatr Endrocrinol Metab 13:55, 2000. 10. Gad Yz, Nasr H, Mazen I, et al.: 5 Alpha-reductase deficiency in patients with micropenis. J Inherit Metab Dis 20:95, 1997. 11. Ishii T, Sato S, Kosaki K, et al.: Micropenis and the AR gene: mutation and CAG repeat-length analysis. J Clin Endo Metab 86:5372, 2001. 12. Sasagawa I, Suzuki Y, Muroya K, et al.: Androgen receptor gene and male genital anomaly. Arch Androl 48:461, 2002. 13. Richter-Unruh A, Martens J, Verhoef-Post M, et al.: Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene Clin Endo 56:103, 2002. 14. Lee PA, Mazur T, Danish R, et al.: Micropenis. I. Criteria, etiologies and classification. Johns Hopkins Med J 146: 156, 1980. 15. Burstein S, Grumbach MM, Kaplan SL: Early determination of androgenresponsiveness is important in the management of microphallus. Lancet 2:983, 1979. 16. Wisniewski AB, Migeon CJ, Gearhart JP, et al.: Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female. Horm Res 56:3, 2001. 17. Wisniewski AB, Migeon CJ: Long-term perspectives for 46,XY patients affected by complete androgen insensitivity syndrome or congenital micropenis. Semin Reprod Med 20:297, 2002. 18. Bin-Abbas B, Conte F, Grumbach MM, et al.: Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size: why sex reversal is not indicated. J Pediatr 134:579, 1999. 19. Sultan C, Lumbroso S, Paris F, et al.: Disorders of androgen action. Semin Reprod Med 20:217, 2002.

20. Katsanis N, Lupski JR, Beales PL, et al.: Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10:2293, 2001. 21. Verloes A, Temple IK, Bonnet S, et al.: Coloboma, mental retardation, hypogonadism, and obesity: critical review of the so-called Biemond syndrome type 2, updated nosology, and delineation of three ‘‘new’’ syndromes. Am J Med Genet 69:370, 1997. 22. Wheeler P, Quigley C, Sadeghi-Nejad A, et al.: Hypogonadism and CHARGE association. Am J Med Genet 94:228, 2000. 23. Ireland M, Donnai D, Burn J: Brachmann-de Lange syndrome. Delineation of the clinical phenotype. Am J Med Genet 47:959, 1993. 24. Hu Y, Tanriverdi F, MacColl GS, et al.: Kallmann’s syndrome: molecular pathogenesis. Int J Biochem Cell Biol 35:1157, 2003. 25. Laurence JC, Moon RC: Four cases of retinitis pigmentosa occurring in the same family and accompanied by general imperfection of development. Ophthalmol Rev 2:32, 1966. 26. Cassidy SB, Dykens E, Williams CA: Prader-Willi and Angelman syndromes: sister imprinted disorders. Am J Med Genet 97:136, 2000. 27. Patton MA, Afzal AR: Robinow syndrome. J Med Genet 39:305, 2002. 28. Minn D, Christmann D, De Saint-Martin A, et al.: Further clinical and sensorial delineation of Schinzel-Giedion syndrome: report of two cases. Am J Med Genet 109:211, 2002. 29. Dattani ML, Martinez-Barbera J, Thomas PQ, et al.: Molecular genetics of septo-optic dysplasia. Horm Res 53(suppl 1):26, 2000. 30. Elcioglu NH, Hall CM: Diagnostic dilemmas in the short ribpolydactyly syndrome group. Am J Med Genet 111:392, 2002. 31. Opitz JM, Gilbert-Barness E, Ackerman J: Cholesterol and development: the RSH (‘‘Smith-Lemli-Opitz’’) syndrome and related conditions. Pediatr Pathol Mol Med 21:153, 2002. 32. Bamshad M, Le T, Watkins WS, et al.: The spectrum of mutations in TBX3: genotype/phenotype relationship in ulnar-mammary syndrome. Am J Hum Genet 64:1550, 1999.

29.2 Hypospadias Definition

Hypospadias is the displacement of the urethral meatus ventrally and proximally from the tip of the glans penis.1 The condition is classified according to the position of the meatus on the penile shaft. First-degree (anterior) hypospadias has the urethral meatus in the distal third of the penis (includes glandular and coronal), second-degree (mid) has the opening between the distal third to the penoscrotal junction (penile), and third-degree (posterior) has scrotal or perineal openings (Figs. 29-6 and 29-7).2 Hypospadias may be associated with chordee of the penis.

Fig. 29-6. Schematic shows various locations of urethral meatus in hypospadias.

Male Genital System

1259

Fig. 29-7. A. Glandular hypospadias. B. Penile hypospadias. C. Scrotal hypospadias. (Courtesy of Drs. Paul Austin and Douglas Coplen.)

Diagnosis

The diagnosis is often made at birth, but glandular hypospadias may be missed. Such males may present later with deviation of the urinary stream. The presence of testes should be ascertained, as females with congenital adrenal hyperplasia may present similarly (Fig. 29-8), and other anomalies should be considered. Renal malformations are more likely with severe degrees of hypospadias.3 As hypospadias can be part of a number of chromosomal, single gene, and other multisystem syndromes, the infant should be carefully examined. Investigations may include abdominal ultrasound, retrograde urethrocystography, or a voiding cystourethrogram. A prostatic utricle, usually a rudimentary structure derived from the Mu¨llerian duct and the urogenital sinus, may be enlarged in association with hypospadias and create a source for recurrent urinary tract infections. Etiology and Distribution

The classic embryologic explanation of hypospadias is failure of the urethral folds to completely fuse during development of the

Fig. 29-8. Glandular hypospadias in female with congenital adrenal hyperplasia. (Courtesy of Drs. Paul Austin and Douglas Coplen, Washington University, St. Louis.)

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Urogenital System Organs

penile urethra (Fig. 29-3). Such fusion requires dihydrotestosterone (DHT), so any mechanism that reduces DHT availability may cause hypospadias. However, the majority of isolated cases of hypospadias do not appear to have any abnormalities of DHT production or receptor response, which raises the possibility of additional etiologic mechanisms. Recently, Baskin et al.4 demonstrated that significant urethral seam remodeling and cell migration occur after urethral fold fusion and suggested that disruption in these processes may also lead to hypospadias. The incidence of hypospadias appears to be increasing,5–7 not only in the United States but in Europe as well. The incidence in the United States doubled from two per 1000 births to four per 1000 births between 1973 and 1993. The use of maternal sex hormones has been questioned and the frequency of hypospadias appears to be increased with assisted reproduction.8–10 However, an extensive meta-analysis of first-trimester fetal maternal hormone exposure does not support this association.11 Another theory to explain the increase in hypospadias is a rise in environmental exposure to endocrine disrupters (Section 29.14), emphasized in a recent study

that demonstrated an association of intrauterine growth deficiency with hypospadias.7 Other birth defects occur in 8–12% of cases and most frequently involve the genital or inguinal regions.1,12–14 Table 29-4 lists syndromes in which hypospadias occurs frequently. Single gene inheritance has been proposed (autosomal dominant and autosomal recessive) for a small number of families with isolated hypospadias,15 but a 9–10% recurrence rate8 is more consistent with multifactorial causation, with both genetic and environmental factors. Androgen receptor defects do not appear to be a significant cause for isolated hypospadias,16 but 5a-reductase type 2 mutations have been described in 8.6% of males with isolated hypospadias.17 Prognosis, Treatment, and Prevention

Of immediate concern in hypospadias is the assessment and treatment of associated conditions, including possible renal tract problems. Numerous surgical approaches have been used for repair of first-degree or anterior hypospadias using various combinations of meatal advancement, urethroplasty, and glanuloplasty. Such

Table 29-4. Syndromes associated with hypospadias Syndrome

Prominent Features

Causation Gene/Locus

ATRX19

Telecanthus, carp-shaped mouth, a-thalassemia, mental retardation

XLR (300032) XNP, Xq13

Chromosomal XXY, XXXXY

Hypogonadism, tall stature

Chromosomal

Chromosomal trisomies 13,18,14p,9p

Poor growth, multiple malformations

Chromosomal

Fraser cryptophthalmos20

Cryptophthalmia, mental retardation, syndactyly, renal agenesis

AR (219000) FRAS1

Fryns21

Diaphragmatic hernia, absent corpus callosum, cleft palate, heart defect

AR (229850)

GBBB (Opitz)22,23

Hypertelorism, cryptorchidism, cleft lip, laryngotracheal clefts

AD (145410) 22q11.2 XLR (300000) MID1, Xp22

Hand-foot-genital24

First digit brachydactyly, carpal/tarsal fusion

AD HOXA13, 7p15-p14.2

Jarcho-Levin25

Multiple rib and vertebral anomalies, short stature

AD (122600) AR (277300) DLL3, 19q13

Lenz microphthalmia26

Microphthalmia, mental retardation, malformed ears, skeletal anomalies

XLR (309800) Xq27-28

Meckel27

Encephalocele, polycystic kidneys, polydactyly

AR (249000) Multiple loci

Rieger28

Anterior chamber defects, periumbilical redundancy, hypodontia

AD (180500) AD (601499) PITX2, 13q14

Roberts SC29

Cleft lip, limb deficiency, intrauterine growth retardation, centromeric separation

AR (268300)

Russell-Silver30

Growth retardation, body asymmetry, triangular face

Mat UPD 7(<10%) or AD (180860)

Short rib-polydactyly type I,II,III,IV31

Chondrodysplasia, polydactyly, narrow thorax, cleft lip, genitourinary anomalies

AR (263510, 263520, 263530, 269860)

Smith-Lemli-Opitz32

Ptosis, anteverted nostrils, syndactyly, microcephaly

AR (270400) DHCR7, 11q12-q13

Wilms-Aniridia (WAGR)33

Growth deficiency, cryptorchidism, Wilms tumor in 50%, aniridia, mental retardation

Microdeletion WT1, 11p13

Valproate, hydantoin and trimethadion embryopathy

Multiple

Teratogens

Male Genital System

surgery is mainly for cosmetic reasons and correction of urinary flow direction. Complications of these procedures can include fistula formation, meatal stenosis, and regression of the neomeatus.18 More severe degrees of hypospadias are often corrected with staged procedures and microscopic techniques. Repair is done at a much earlier age, with age 13 to 15 months thought to be desirable for psychological reasons. The initial decision of whether to repair a hypospadias must depend on the cause and on the amount of penile tissue available (especially the corpora), with the goal being adequate sexual functioning. Prenatal diagnosis of isolated hypospadias would be unlikely unless severe and associated with microphallus. If the hypospadias is part of a syndrome or chromosome anomaly, prenatal diagnosis could be directed to detectable components of the syndrome. References (Hypospadias) 1. Leung TJ, Baird PA, McGillivray BC: Hypospadias in British Columbia. Am J Med Genet 21:39, 1985. 2. Sorensen HR: Hypospadias With Special Reference to Aetiology. Andreassen & Co, Denmark, 1953. 3. Kelly D, Harte FB, Roe P: Urinary tract anomalies in patients with hypospadias. Br J Urol 56:316, 1984. 4. Baskin LS, Erol A, Jegatheesan P, et al.: Urethral seam formation and hypospadias. Cell Tissue Res 305:379, 2001. 5. Paulozzi LJ, Erickson D, Jackson RJ: Hypospadias trends in two US surveillance systems. Pediatrics 100:831, 1997. 6. Paulozzi LJ: International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect 107:297, 1999. 7. Hussain N, Chaghtai A, Herndon CA, et al.: Hypospadias and early gestation growth restriction in infants. Pediatrics 109:473, 2002. 8. Neto RM, Castilla EE, Paz JE: Hypospadias: an epidemiological study in Latin America. Am J Med Genet 10:5, 1981. 9. Silver RI, Rodriquez R, Chang TS, et al.: In vitro fertilization is associated with increased risk of hypospadias. J Urol 161:1954, 1999. 10. Macnab AF, Zouves C: Hypospadias after assisted reproduction incorporating in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 56:918, 1991. 11. Raman-Wilms L, Tseng AL, Wighardt S, et al.: Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 85:141, 1995. 12. Calzolari E, Contiero MR, Roncarati E, et al.: Aetiological factors in hypospadias. J Med Genet 23:333, 1986. 13. Wu WH, Chuang JH, Ting YC, et al.: Developmental anomalies and disabilities associated with hypospadias. J Urol 168:229, 2002. 14. Bjerkedal T, Bakketeig LS: Surveillance of congenital malformations and other conditions of the newborn. Int J Epidemiol 4:31, 1975. 15. Fredell L, Iselius L, Collins A, et al.: Complex segregation analysis of hypospadias. Hum Genet 111:231, 2002. 16. Sasagawa I, Suzuki Y, Muroya K, et al.: Androgen receptor gene and male genital anomaly. Arch Androl 48:461, 2002. 17. Silver RI, Russell DW: 5 Alpha-reductase type 2 mutations are present in some boys with isolated hypospadias. J Urol 162:1142, 1999. 18. Zaontz MR, Dean GE: Glandular hypospadias repair. Urol Clin North Am 29:291, 2002. 19. Villard L, Fontes M: Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032). Eur J Hum Genet 10:223, 2002. 20. Slavotinek AM, Tifft CJ: Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 39:623, 2002. 21. Cunniff C, Jones KL, Saal HM, et al.: Fryns syndrome: an autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia. Pediatrics 85:499, 1990. 22. De Falco F, Cainarca S, Andolfi G: X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet 120A:222, 2003.

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23. Robin NH, Opitz JM, Muenke M: Opitz G/BBB syndrome: clinical comparisons of families linked to Xp22 and 22q, and a review of the literature. Am J Med Genet 62:305, 1996. 24. Frisen L, Lagerstedt K, Tapper-Persson M, et al.: A novel duplication in the HOXA13 gene in a family with atypical hand-foot-genital syndrome. J Med Genet 40:e49, 2003. 25. Bannykh SI, Emery SC, Gerber JK, et al.: Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review. Am J Med Genet 120A:241, 2003. 26. Ng D, Hadley DW, Tifft CJ, et al.: Genetic heterogeneity of syndromic X-linked recessive microphthalmia-anophthalmia: is Lenz microphthalmia a single disorder? Am J Med Genet 110:308, 2002. 27. Salonen R, Paavola P: Meckel syndrome. J Med Genet 35:497, 1998. 28. Amendt BA, Semina EV, Alward WL: Rieger syndrome: a clinical, molecular, and biochemical analysis. Cell Mol Life Sci 57:1652, 2000. 29. Sinha AK, Verma RS, Mani VJ: Clinical heterogeneity of skeletal dysplasia in Roberts syndrome: a review. Hum Hered 44:121, 1994. 30. Bernard LE, Penaherrera MS, Van Allen MI, et al.: Clinical and molecular findings in two patients with Russell-Silver syndrome and UPD7: comparison with non-UPD7 cases. Am J Med Genet 87:230, 1999. 31. Elcioglu NH, Hall CM: Diagnostic dilemmas in the short rib-polydactyly syndrome group. Am J Med Genet 111:392, 2002. 32. Opitz JM, Gilbert-Barness E, Ackerman J: Cholesterol and development: the RSH (‘‘Smith-Lemli-Opitz’’) syndrome and related conditions. Pediatr Pathol Mol Med 21:153, 2002. 33. Pavilack MA, Walton DS: Genetics of aniridia: the Aniridia-Wilms’ Tumor Association. Int Ophthalmol Clin 33:77, 1993.

29.3 Epispadias Definition

Epispadias is the dorsal malposition of the penile urethra (Fig. 29-9). Diagnosis

The severity of penile urethral malposition in isolated epispadias is broad and represents a continuum, but three general classifications exist: balanic epispadias where the meatus opens on the dorsal aspect of the glans, penile epispadias where the urethral plate is open along the length of the dorsal penis, and penopubic

Fig. 29-9. Penopubic epispadias. (Courtesy of Drs. Paul Austin and Douglas Coplen, Washington University, St. Louis.)

1262

Urogenital System Organs

epispadias where the urethral plate and bladder neck are widely open with a deficient external sphincter, short penis, and variable separation of the symphysis pubis. Penopubic epispadias is the most common form of isolated epispadias.1 Etiology and Distribution

Epispadias occurs as an isolated defect in approximately one per 117,000 live births.2 However, it is more commonly found in association with exstrophy of the bladder, which occurs much more frequently, perhaps as often as one per 30000 live births. This association is referred to as the bladder exstrophy and epispadias complex (BEEC).3 Some believe that cloacal exstrophy and OEIS (omphalocele, exstrophy, imperforate anus, and spinal defects) are also part of the spectrum and represent its most severe end.4 BEEC is rarely seen as part of a broader pattern of malformation or other syndrome outside of OEIS. The occurrence of BEEC is generally sporadic, although a number of familial cases have been described.3 There has been one recent report suggesting an association of in vitro fertilization and BEEC.5

3. Reutter H, Shapiro E, Gruen JR: Seven new cases of familial isolated bladder exstrophy and epispadias complex (BEEC) and review of the literature. Am J Med Genet 120A:215, 2003. 4. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al.: Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet 99:261, 2001. 5. Wood HM, Trock BJ, Gearhart JP: In vitro fertilization and the cloacal-bladder exstrophy-epispadias complex: is there an association? J Urol 169:1512, 2003. 6. Thiersch K: Uber die enstehungsweise and operative bedanlung der epispadie. Archiv der Heilkunde 10:20, 1869. 7. Lottmann HB, Yaqouti M, Melin Y: Male epispadias repair: surgical and functional results with the Cantwell-Ransley procedure in 40 patients. J Urol 162:1176, 1999. 8. Grady RW, Mitchell ME: Complete primary repair of exstrophy. Surgical technique. Urol Clin North Am 27:569, 2000. 9. Diseth TH, Emblem R, Schultz A: Mental health, psychosocial functioning, and quality of life in patients with bladder exstrophy and epispadias—an overview. World J Urol 17:239, 1999. 10. Lee EH, Shim JY: New sonographic finding for the prenatal diagnosis of bladder exstrophy: a case report. Ultrasound Obstet Gynecol 21:498, 2003.

Prognosis, Treatment, and Prevention

Prognosis for normal penile function after surgical repair is primarily dependent upon the severity of the defect. The goal of repair is to allow voiding in the standing position, maintenance of urinary continence, and a straight penis for adequate sexual functioning. Numerous techniques and modifications for epispadias repair have been used since Thiersch’s first description in 1869.6 The most widely used modern approach has been the Cantwell-Ransley repair,7 although more recently the technique of complete disassembly of the corporal bodies and urethral plate described by Mitchell has been gaining acceptance.8 Repair of the bladder and abdominal wall, usually staged, is also necessary in those cases of bladder exstrophy. Little comparable data exist as to the extent of psychological impact BEEC has on the affected male, and there is conflict between the data of the existing studies.9 Clearly the effect on appearance and function of the penis put the affected male at risk for life-long difficulties. Bladder exstrophy has been diagnosed antenatally but not isolated epispadias.10 References (Epispadias) 1. Kramer SA, Kelalis PP: Assessment of urinary continence in epispadias: review of 94 patients. J Urol 140:577, 1988. 2. Dees JE: Congenital epispadias and incontinence. J Urol 62:513, 1949.

29.4 Hidden or Concealed Penis Definition

Hidden or concealed penis is a normal size penis that appears to be small because of surrounding tissue (Fig. 29-10). The penis may be concealed as a result of redundant prepubic tissue (buried penis), hidden in excess scrotal tissue (penis palmatus), or obscured by hernia or hydrocele. Phimosis, postcircumcision adhesions, and trauma can also conceal the penis. Etiology and Distribution

Numerous etiologies for buried penis have been suggested: (1) dartos band attachment only to the corona (and not the shaft) of the penis,1 (2) inferior displacement of the root of the penis,2 (3) large suprapubic fat pad,3 and (4) hypermobility of the angle of the dangle,2 among others. Several varieties of penis palmatus are described, all related to abnormalities of scrotal placement. Webbed penis is the result of the scrotal placement on the proximal shaft of the penis. Other variants are the doughnut scrotum (‘‘toad in the hole penis’’) and

Fig 29-10. Two examples of hidden penis. (Courtesy of Drs. Paul Austin and Douglas Coplen, Washington University, St. Louis.)

Male Genital System

1263

the shawl scrotum (Section 29.8, penoscrotal transposition). No familial forms of concealed penis have been reported, and it does not frequently appear as part of a broader pattern of malformation.

Table 29-5. Megalourethra: clinical findings in 32 cases (literature and personal)

Prognosis, Treatment, and Prevention

Large penis

28

In addition to the cosmetic embarrassment of a hidden penis, the condition also predisposes to difficulty directing the urinary stream, persistent wetness, balanoposthitis, and urinary infections. Surgical correction of buried penis is advocated if it has not resolved by the age of toilet training. There appear to be as many surgical approaches as there are proposed etiologies.1 Correction of penis palmatus involves variations on Z and V-Y plasties.

Scaphoid lesion

25

Fusiform lesion

7

Finding

Hypospadias

References (Hidden Penis) 1. Radhakrishnan J, Razzaqq A, Manickam K: Concealed penis. Pediatr Surg Int 18:668, 2002. 2. Joseph VT: A new approach to the surgical correction of buried penis. J Pediatr Surg 30:727, 1995. 3. Horton CE, Vorstman B, Teasley D, et al.: Hidden penis release: adjunctive suprapubic lipectomy. Ann Plast Surg 19:131, 1987.

29.5 Megalourethra Definition

A dilation of the penile urethra is called megalourethra. Two types of megalourethra are usually described: absence of both corpora cavernosa and corpus spongiosum (fusiform variety) or, more commonly, absence of corpus spongiosum alone (scaphoid type) (Fig. 29-11). Diagnosis

The male infant presents at birth with an enlarged, flaccid penis, often in association with abdominal distension or prune belly sequence. Urinary obstruction is associated with megacystis, hydroureters, and hydronephrosis.1,2 The fusiform variety of megalourethra is associated with absence of all erectile tissue and results in massive dilation of the penile structure. It is often accompanied

Fig. 29-11. Scaphoid type of megalourethra.

No.

2

Megacystis

20

Hydronephrosis

24

Renal malformation

11

Imperforate anus

7

Other extraurinary anomalies

7

by upper tract damage with renal dysplasia, and it is frequently associated with other malformations, including anal atresia and hemivertebrae (Table 29-5). The scaphoid type of megalourethra has intact corpora cavernosa and milder penile dilation. Infants may have urinary infection on the basis of stasis and ballooning of the penis during voiding; older children may present with dribbling or enuresis. Megalourethra has been described infrequently in association with posterior urethral valves.3 Etiology and Distribution

Nesbitt first used the term megalourethra in 1955.4 The cause of megalourethra is unknown. The most widely held theory is that it results from a mesenchymal defect of the urethra. Absence, poor migration, or underdevelopment of this tissue is thought to result in the deficient corpora. Another hypothesis is that megalourethra is a form fruste of the prune belly sequence, with distal urethral obstruction resulting from delayed canalization of the glans urethra as the primary insult.5–7 The defect is rare, with less than 100 cases being described in the literature.1 Recurrence within families has not been described. Prognosis, Treatment, and Prevention

The prognosis of megalourethra will depend on the degree of upper tract damage as well as the nature and severity of extraurinary tract malformations. The majority of cases present with significant genitourinary anomalies (Table 29-6). Those infants with prune belly sequence and Potter sequence do poorly, and most die

Table 29-6. Mortality and morbidity of megalourethra Scaphoid

N

60

Age of diagnosis (year)

1.9

Fusiform

18 0.2

Total

78 1.5

Anomalies All

80%

100%

86%

Genitourinary

60%

100%

69%

All

13%

66%

25%

Pre-1980

30%

63%

40%

7%

70%

20%

Mortality

1980–present Adapted from Jones et al.1

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Urogenital System Organs

of respiratory complications. Renal failure from the secondary dysplasia is a frequent finding in lethal cases. The fusiform lesion, with severe dilation and other malformations, generally has a poor prognosis. Infants with the scaphoid lesion may survive with varying degrees of renal function. The classic surgical approach consists of urethral reconstruction using the Nesbitt procedure, involving reduction of excess skin and urethra with urethroplasty over a catheter.4 Reimplantation of ureters may be necessary for reflux. Anal agenesis is initially treated with colostomy. Attention must be paid to avoidance of urinary infection, and antibiotic prophylaxis may be of help.8 In surviving infants, severe lesions of erectile tissue, primarily of the fusiform type, will be associated with impotence. For this reason, reassignment of sex rather than phallic reconstruction has been the traditional method, although questions about this approach have been raised (Section 29.14). A primary goal should be optimal renal function. Prenatal diagnosis of megalourethra has been reported.9 References (Megalourethra) 1. Jones EA, Freedman AL, Ehrlich RM: Megalourethra and urethral diverticula. Urol Clin North Am 29:341, 2002. 2. Sharma AK, Shekhawat NS, Agarwal R, et al.: Megalourethra: a report of 4 cases and review of the literature. Pediatr Surg Int 12:458, 1997. 3. Harjai MM, Sharma AK: Congenital scaphoid megalourethra associated with posterior urethral valves. Pediatr Surg Int 15:425, 1999. 4. Nesbitt TE: Congenital megalourethra. J Urol 73:839, 1955. 5. Appel RA, Kaplan GW, Brock WA, et al.: Megalourethra. J Urol 135:747, 1986. 6. Beasley SW, Bettenay F, Hutson JM: The anterior urethra provides clues to the aetiology of prune belly syndrome. Pediatr Surg Int 3:169, 1988. 7. Stephens FD, Fortune DW: Pathogenesis of megalourethra. J Urol 149:1512, 1993. 8. Shrom SH, Cromie WJ, Duckett JW: Mega1ourethra. Urology 17:152, 1981. 9. Ardiet E, Houfflin-Debarge R, Besson D, et al.: Prenatal diagnosis of congenital megalourethra associated with VACTERL sequence in twin pregnancy: favorable postnatal outcome. Ultrasound Obstet Gynecol 21:619, 2003.

Fig. 29-12. Diphallia. (Courtesy of Dr. Marilyn Jones, University of California, San Diego.)

Table 29-7. Concomitant findings in diphallia Anomaly

Total cases

Definition

Diphallia is the presence of two penile structures (Fig. 29-12). Diagnosis

Diphallia occurs in one of two circumstances. The most common presentation is termed bifid phallus, whereby the corpora are divided and each is associated with a distinct hemigland. In true diphallia, each penis has normal corporal structures. Within these two groups the phenotypic spectrum is wide, ranging from two normally developed penes to just an accessory rudimentary penile structure. Penile duplication is typically associated with other urinary tract malformations such as bladder exstrophy or duplication. There is some suggestion that the risk of genitourinary and other malformations is greater in cases of true diphallia (Table 29-7). Etiology and Distribution

Diphallia is rare. First described by Wecker in 1609, it is estimated to occur in only one per 5 million births.1 The pathogenesis of diphallia is not clear but likely involves duplication of the cloacal

Bifid Phallus (n)

50

27

Upper urinary tract Renal agenesis

1

1

Ectopic kidney

3

0

Horseshoe kidney

4

0

Bilateral duplication

1

0

Bifid ureter

1

1

Single ureter

1

0

5

4

15

3

2

0

17

1

1

1

Gastrointestinal tract Imperforate anus

16

3

Colon duplication

8

1

Pyloric stenosis

1

0

Urointestinal fistula

5

0

Bladder Exstrophy

29.6 Diphallia (Penile Duplication)

True Diphallia (n)

Duplication Third urethra Scrotum Bifid Undescended testes

Musculoskeletal Pubic diastasis

14

3

10

2

7

1

Limb hypoplasia

4

0

Hernias

8

0

Cardiac anomalies

1

0

Liver anomalies (abnormal lobation)

1

0

Lumbosacral anomalies Foot anomalies

From Gyftopoulos et al.1

Male Genital System

1265

membrane and genital tubercle. Diphallia is typically a sporadic and isolated malformation. However, one family has been reported in which diphallia is associated with penoscrotal transposition and patellar aplasia.2 Prognosis, Treatment, and Prevention

Several aspects of penile duplication need to be determined before attempting any correction. All associated genitourinary malformations need to be identified and their repair anticipated. Second, a detailed assessment of the corporal bodies and neurovascular bundles needs to be performed. One or both penes often have erectile and sometimes ejaculatory function, but the primary surgical goal is to separate the urogenital and gastrointestinal tracts and establish urinary continence. Penile ultrasound3 and magnetic resonance imaging4 have been useful imaging modalities in such cases. References (Diphallia) 1. Gyftopoulos K, Wolffenbuttel KP, Nijman RM: Clinical and embryologic aspects of penile duplication and associated anomalies. Urology 60:675, 2002. 2. Dodat H, Rosenberg D, James-Pangaud I: Familial association of penoscrotal transposition and diphallia (double penis) with patellar aplasia. Arch Pediatr 2:241, 1995. 3. Marti-Bonmati L, Menor F, Gomez J, et al.: Value of sonography in true complete diphallia. J Urol 142:356, 1989. 4. Lapointe SP, Wei DC, Hricak H, et al.: Magnetic resonance imaging in the evaluation of congenital anomalies of the external genitalia. Urology 58:452, 2001.

Fig. 29-14. Aphallia in sirenomelic infant.

be a part of severe malformation complexes that involve the perineal area such as sirenomelia (Fig. 29-14), cloacal exstrophy, and the urorectal septum malformation sequence.1–3 A skin tag or dimple may be found on the perineum in some cases of sirenomelia. In cloacal exstrophy, there may be vestiges of the penis on the margins of the exstrophy. Etiology and Distribution

29.7 Aphallia

Aphallia results from failure of the genital tubercle to develop.4 It is extremely rare, with an estimated incidence of one in 30 million births,1,5 and has been associated with infants of diabetic mothers.

Definition

Aphallia is the congenital absence of the penis, also termed penile agenesis (Fig. 29-13). Diagnosis

A high percentage of cases of aphallia are associated with renal aplasia/dysplasia and imperforate anus. Absence of the penis may Fig. 29-13. Aphallia in an infant of a diabetic mother. (Courtesy of Drs. Paul Austin and Douglas Coplen, University of Washington, St. Louis.)

Prognosis, Treatment, and Prevention

Historically, boys with aphallia have been reassigned a female gender at birth and undergone orchiectomy and vaginal reconstruction. However, recent controversy regarding issues surrounding gender reassignment (Section 29.14) suggests that significant counseling and parental education in this regard should be undertaken before proceeding with surgical reconstruction. References (Aphallia) 1. Evans JA, Erdile LB, Greenberg CR, et al.: Agenesis of the penis: patterns of associated malformations. Am J Med Genet 84:47, 1999. 2. Gripp KW, Barr M, Anadiotis G, et al.: Aphallia as part of urorectal septum malformation sequence in an infant of a diabetic mother. Am J Med Genet 82:363, 1999. 3. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986. 4. Kessler WO, McLaughlin AP: Agenesis of penis: embryology and management. Urology 1:226, 1973. 5. Skoog SJ, Belman AB: Aphallia: its classification and management. J Urol 141:589, 1989.

29.8 Penoscrotal Transposition Definition

Penoscrotal transposition (PST) is location of the scrotal sac cephalad to the penile shaft rather than in its normal position caudal to the penis (Fig. 29-15).

1266

Urogenital System Organs

Fig. 29-15. Penoscrotal transposition. A. Complete. B. Partial. (A, courtesy of Dr. Dorothy Grange, Washington University, St. Louis; B, courtesy of Dr. Lynne Bird, University of California, San Diego.)

Diagnosis

PST can be complete or partial. Partial forms of PST have been given various terms such as shawl, bifid, doughnut, or prepenile scrotum.1 Etiology and Distribution

The cause of PST is not known. One hypothesis put forth is failure of the urogenital sinus to develop associated with failure of the labioscrotal swellings to move dorsally.2 This supposition presupposes that the penis remains in its anatomically correct position and is supported by the occurrence of the PST equivalent (clitoral transposition) in females.3,4 However, there are cases of PST where the penis is clearly malpositioned posteriorly to the anatomically correct position of the scrotum5 (Fig. 29-16). Unilateral PST has been reported.6,7 PST is usually associated with other genitourinary defects, often hypospadias and renal defects. However, a host of other malformations have also been frequently

reported suggesting significant heterogeneity.8 Familial cases were reported in 13% of 53 patients reviewed and X-linked inheritance as a result of an androgen receptor defect is likely.1,9 Prognosis, Treatment, and Prevention

The major cause of morbidity and mortality in PST are the severe renal dysplasia and aplasia so often seen. Malformations of the gastrointestinal tract and heart also take their toll. However, survival is possible in uncomplicated cases, and fertility has been described.5 The traditional concept of PST is that it is the scrotum that is in malposition while the penis is in its normal location. It is on the basis of this tenet that all of the classical repair approaches are based. Repair in this manner involves scrotal rotation and advancement flaps. At least one group suggests that it is the penis that is in malposition, not the scrotum, and advocates a completely novel pull-through technique to reposition the penis.10 PST (bifid scrotum) has been diagnosed by ultrasound prenatally.11 References (Penoscrotal Transposition)

Fig. 29-16. Penoscrotal transposition (PST) with severe posterior location of penis.

1. Pinke LA, Rathbun SR, Husmann DA, et al.: Penoscrotal transposition: review of 53 patients. J Urol 166:1865, 2001. 2. Francis CC: A case of prepenile scrotum (Marsupial type of genitalia) associated with absence of the urinary system. Anat Rec 76:303, 1940. 3. Meyer R: Dislocation of the phallus, penis, clitoris following pelvic malformations in the human fetus. Anat Rec 79:231, 1941. 4. Lage JM, Driscoll SG, Bieber FR: Transposition of the external genitalia with caudal regression. J Urol 138:387, 1987. 5. MacKenzie J, Chitayat D, McLorie G, et al.: Penoscrotal transposition: a case report and review. Am J Med Genet 49:103, 1994. 6. Adair EL, Lewis EJ: Ectopic scrotum and diphallia: report of a case. J Urol 84:115, 1960. 7. Flanagan MJ, McDonald JH, Kiefer JH: Unilateral transposition of the scrotum. J Urol 86:273, 1961. 8. Parida SK, Hall BD, Barton L, et al.: Penoscrotal transposition and associated anomalies: report of 5 new cases and review of the literature. Am J Med Genet 59:68, 1995. 9. Bals-Pratsch M, Schweikert HU, Nieschlag E, et al.: Androgen receptor disorder in three brothers with bifid prepenile scrotum and hypospadias. Acta Endocrinol (Copenh) 123:271, 1990.

Male Genital System 10. Kolligan ME, Franco I, Reda EF: Correction of penoscrotal transposition: a novel approach. J Urol 164:994, 2000. 11. Vijayaraghavan SB, Muruganand SK, Ravikumar VR, et al.: Prenatal sonographic features of penoscrotal transposition. J Ultrasound Med 21:1427, 2002.

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3. Hoar RM, Calvano CJ, Reddy PR: Unilateral suprainguinal ectopic scrotum: the role of the gubernaculum in the formation of an ectopic scrotum. Teratology 57:64, 1998.

29.10 Cryptorchidism

29.9 Ectopic /Accessory Scrotum

Definition

Definition

Cryptorchidism is the lack of descent of one or both testes into the scrotum by the time of term birth (Fig. 29-18).

Ectopic/accessory scrotum is a scrotum outside of its normal anatomic location. An accessory scrotum is, by definition, also an ectopic scrotum (Fig. 29-17). Diagnosis

The perineum is the typical location of ectopic scrotum, but it can also be found in the inguinal region and the medial thigh.1 An ectopic scrotum on the penis has also been described.2 A normal testicle is usually in or near the scrotal sac. It is frequently associated with other urogenital anomalies. Etiology and Distribution

Ectopic and accessory scrotums are rare. An anomalous tail of the gubernaculum has been proposed as the etiology for this defect. While this explanation is reasonable for the inguinal placement of an ectopic scrotum, it does not explain those found in the perineum, thigh, or penis. The role of the gubernaculum and other mechanisms in this regard is explored in detail by Hoar et al.3 Prognosis, Treatment, and Prevention

A normal testicle is often associated with ectopic scrotum and, with relocation of the scrotal sac, the testis can usually be preserved. References (Ectopic/Accessory Scrotum) 1. Kumar V, Marulaiha M, Chattopadhyay A, et al.: Unilateral inguinal ectopic scrotum with covered exstrophy. Pediatr Surg Int 18:511, 2002. 2. Coplen DE, Mikkelson D, Manley CB: Accessory scrotum located on the distal penile shaft. J Urol 154:1908, 1995.

Fig. 29-17. Accessory scrotum of the penis. (Courtesy of Drs. Paul Austin and Douglas Coplen, University of Washington, St. Louis.)

Diagnosis

The diagnosis may be made by observation at birth or later. Bilateral undescended testes may be associated with a small, flat scrotum and may be more readily noted. A unilateral undescended testis can be missed unless the scrotum is palpated. Cryptorchidism is normal in the preterm male, so examination should be repeated at intervals. Care should be taken to exclude the retractile testis by examination with the child in a variety of positions or in a warm bath. Additional investigations can include ultrasound to delineate renal structures, intraabdominal testes or the presence of Mu¨llerian structures (suspect congenital adrenal hyperplasia with a masculinized female fetus), and measurement of serum testosterone before and after stimulation to document presence of intraabdominal

Fig. 29-18. Bilateral cryptorchidism.

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Urogenital System Organs

testes (rule out anorchia). Measurement of a basal anti-mu¨llerian hormone (AMH) level has been shown to have a higher predictive value than stimulated testosterone studies in determining the likelihood of testicular dysgenesis or anorchia in cryptorchid prepubertal males.1 Etiology and Distribution

About 3–4% of males with a birth weight greater than 2500 grams and 21–23% of male infants with a birth weight less than 2500 grams will have an undescended testicle.2 One-fourth of these cases will be bilateral. By age 3 months, the incidence falls to 0.8%,3 with the descent of the testes thought to be secondary to increased testosterone levels in infancy. Of those cases of truly undescended testes (versus retractile), about half are found intraabdominally at surgical exploration and the other half are absent or atrophic (Section 29.11, Anorchia).4 Renal anomalies are seen in 3–5% of affected males and are more likely in cases with bilateral cryptorchidism. The etiology of cryptorchidism is clearly heterogeneous since it occurs in numerous syndromes and disorders of undermasculinization. Part of this heterogeneity is due to the multistage process of testicular descent (chapter introduction) that involves a complex interaction of gonadotropins, androgens, and mechanical mechanisms. Cryptorchidism is an almost universal finding in various conditions of male pseudohermaphroditism (Section 29.14) and hypogonadism syndromes associated with micropenis (Table 29-3), for which the paucity of androgens or androgen receptors can at least be partially implicated. The mechanisms for the pathogenesis of syndromic and isolated cryptorchidism, on the other hand, are poorly understood. However, some headway in this area has been made recently with the discovery of mutations in two genes necessary for testicular descent, INSL3 and GREAT. INSL3 (insulinlike factor 3) and its receptor, GREAT (G proteincoupled receptor affecting descent, also known as Lgr8 or leucinerich repeat-containing G protein-coupled receptor 8), are believed to be involved in the growth and thickening of the gubernaculum, critical to the intraabdominal descent of the testis. A heterozygous mutation of either INSL3 or GREAT was discovered in 9.2% of males (eight of 87) with isolated cryptorchidism.5 Prognosis, Treatment, and Prevention

Treatment of cryptorchidism first involves hormonal stimulation with human chorionic gonadotropin, testosterone, or gonadotropinreleasing hormone at about 6 months of age as evidence favors testosterone being involved in testicular descent.6 Published success rates vary, with evidence suggesting that the best results are obtained with retractile testes or inguinally positioned testes. If hormone therapy fails, orchidopexy should follow for testes that are palpable because of the associated risk of testicular neoplasm in the undescended testis. The optimum age and the reasons to do orchidopexy with respect to neoplasm risk are controversial. Some suggest that orchidopexy does not reduce the risk of neoplasm but should be performed to allow testicular self-examination.7 However, several studies have shown an increased risk of neoplasm if surgery is not performed by age 10 years, and two interview-based studies suggest that surgery should be done even earlier.8 The risk of testicular cancer in men who have not had orchidopexy is broad, ranging from a relative risk of two to 32.8 About 20% of tumors in men with unilateral cryptorchidism occur in the contralateral normally descended testicle. The long-term outlook for fertility is improved for those treated early.9 In males undergoing orchidopexy after the age of

5 years, fertility was markedly decreased in bilateral cryptorchidism and unchanged with unilateral cryptorchidism.10 In contrast, fertility is thought to be normal in those males with retractile testes. Surgery by age 1 to 2 years may be technically easier, may increase initiation of tubular maturation, and may decrease undesirable changes that may be associated with infertility (mitochondrial degeneration, volume loss, increased deposition of collagen). For testes that are not palpable, open surgical or laparoscopic exploration are the only options. If a testis is discovered, it can be brought down to the scrotum or removed depending on how atrophic it appears.6 References (Cryptorchidism) 1. Misra M, MacLaughlin DT, Donaoe PK, et al.: Measurement of Mu¨llerian inhibiting substance facilitates management of boys with microphallus and cryptorchidism. J Clin Endocrinol Metab 87:3598, 2002. 2. Anonymous: John Radcliffe Hospital cryptorchidism study: cryptorchidism, a prospective study of 7500 consecutive male births, 1984– 1988. Arch Dis Child 67:892, 1992. 3. Berkowitz GS, Lapinski RH, Dolgin SE, et al.: Prevalence and natural history of cryptorchidism. Pediatrics 92:44, 1993. 4. Smolko MJ, Kaplan GW, Brock WA: Location and fate of the nonpalpable testis in children. J Urol 129:1204, 1983 5. Ferlin A, Simonato M, Bartolini L, et al.: The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. J Clin Endocrinol Metab 88:4273, 2003. 6. Docimo SG, Silver RI, Cromie W: The undescended testicle: diagnosis and management. Am Fam Physician 62:2037, 2000. 7. Swerdlow AJ, Higgins CD, Pike MC: Risk of testicular cancer in cohort of boys with cryptorchidism. BMJ 314:1507, 1997 (erratum in BMJ 315:1129, 1997). 8. Herrinton LJ, Zhao W, Husson G: Management of cryptorchidism and risk of testicular cancer. Am J Epidemiol 157:602, 2003. 9. McAleer IM, Packer MG, Kaplan GW, et al.: Fertility index analysis in cryptorchidism. J Urol 153:1255, 1995. 10. Fallom B, Kennedy TJ: Long-term follow-up of fertility in cryptorchid patients. Urology 25:502. 1985.

29.11 Microorchia/Anorchia/Agonadism Definitions

Microorchia is a testis that measures 2 standard deviations (SD) or more below the mean volume for age. Anorchia and agonadism refer to the absence of both testes in an individual with a Y chromosome. Diagnosis

Microorchia is determined by comparing the measurement of the testis with normal values for age (Table 29-8). Some clinicians prefer to determine testicular volume by direct comparison with Prader beads. Others prefer measurement of the length and width of the testis and calculating the volume (testicular volume ¼ 0.5lengthwidth).1 At birth the testicular volume is 2 mL or less. At maturity, the mean testicular volume is 16 mL, with the lower limit of normal (2 SD) being 9 mL.1,2 Microorchidism as a part of normal variation has normal androgen level, sperm production, and gonadotropin level. Persons with small testes in which the Leydig cells fail to produce adequate androgen will have elevated levels of gonadotropin at birth.3,4 Those with microorchidism secondary to central nervous

Male Genital System Table 29-8. Testicular size (cm3) 10

th

Centile

50

th

Centile

90

th

Centile

Birth to age 10 years

1.0

1.6

2.25

11 years

1.0

1.75

4.0

12 years

1.75

3.25

7.0

13 years

3.0

6.0

12.75

14 years

5.0

10.5

17.0

15 years

8.0

13.8

19.0

16 years

10.0

15.8

20.0

Adapted from Zachmann et al.1

system malformation or hypothalamic-pituitary problems will be hypogonadotropic. Klinefelter syndrome is always a major consideration when microorchidism is noted, so a karyotype is warranted.3 Robinson et al.4 have reported that males with a 47,XXY karyotype usually have normal testicular volume during childhood and that the consistency of the testes appears normal. Following puberty, the testes are typically small and firm. Anorchia is a condition in which males have normalappearing genitalia except for the absence of the testes. It is also sometimes referred to as the vanishing testes or testicular regression syndrome. Older reports suggest the condition is rare; however, approximately 40% of males with nonpalpable testes were found to be so affected.5 Thus, the incidence may be as high as one per 1250.6 The phallus appears normal, Wolffian ducts are present, and there are no Mu¨llerian derivatives. The testes are also absent in primary XY agonadism. However, in these cases, the genitalia are generally female and both Wolffian and Mu¨llerian ducts are missing.7 True nonpalpable testes always require surgical exploration of the region from the spleen to the scrotum to exclude malposition of the testis (Section 29.10, Cryptorchidism). Etiology and Distribution

Testes that measure 2 standard deviations (SD) or more below the mean are present in 2.5% of the population. Only a small portion of these cases are pathologic, with deficient production of androgens and sperm. Klinefelter syndrome, with an incidence of one per 1000 males, is the most common of the pathologic causes of small testes.8 Table 29-9 lists a number of other syndromes associated with microorchidism. Most of these conditions can be categorized into either those with deficient androgen production (primary hypogonadism) or those with abnormalities of the hypothalamic-pituitary axis (hypogonadotropic hypogonadism). The presence of normal male genitalia in cases of anorchia suggests that testicular regression must occur after the period of embryonic masculinization. Intrauterine testicular torsion is felt to be a primary cause and is supported as a mechanism by the presence of a blind-ending spermatic cord; it is typically sporadic in nature.6,9 However, given the rare occurrence of familial cases of anorchia, other mechanisms are possible.10 The etiology of primary XY agonadism is less clear. The lack of masculinization associated with agonadism indicates that the timing of pathogenesis is much earlier than in anorchia. Growth and differentiation of the embryonic gonad into a testis is dependent on a number of genes (see chapter introduction). However, mutations in those genes important in testicular development typically result in dysgenetic testes rather than absent testes (Table 29-10).

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Agonadism is also more frequently associated with other malformations and syndromes (Table 29-10).7 Prognosis, Treatment, and Prevention

Most testes that measure 2 SD or more below the mean volume represent normal variation and function adequately. The pathologically small testis, however, fails to produce the androgens necessary for masculinization and may also have failure of spermatogenesis. Very small testes fail to fill out the scrotum and may cause embarrassment, although prosthetic testes are now available. Hypogonadotropic patients may be treated with gonadotropin with or without testosterone supplementation.11 In some cases, spermatogenesis may increase to a sufficient level to permit success at impregnation. Patients with hypergonadotropic microorchidism will require testosterone therapy to achieve adequate masculinization. In most cases, these patients will not produce adequate sperm for impregnation. Patients with absent testes need to be surgically explored to document the absence (Section 29.10, Cryptorchidism). Prenatal diagnosis is possible in those conditions with a chromosomal basis. Gene identification will permit prenatal diagnosis with molecular techniques in the years ahead. References (Microorchia/Anorchia/Agonadism) 1. Zachmann M, Prader A, Kind HP, et al.: Testicular volume during adolescence, cross-sectional and longitudinal studies. Helv Paediatr Acta 29:61, 1974. 2. Schonfeld WA: Primary and secondary sexual characteristics. Am J Dis Child 65:535, 1943. 3. Leonard JM, Bremner WJ, Cape PT II, et al.: Male hypogonadism: Klinefelter and Reifenstein syndromes. Birth Defects Orig Artic Ser XI(4):17, 1975. 4. Robinson A, Puck M, Pennington B, et al.: Abnormalities of the sex chromosomes: a prospective study on randomly identified newborns. Birth Defects Orig Artic Ser XV(1):203, 1979. 5. Kirsch AJ, Escala J, Duckett JW, et al.: Surgical management of the non-palpable testis: the Children’s Hospital of Philadelphia’s experience. J Urol 159:1340, 1998. 6. Spires SE, Woolums CS, Pulito AR, et al.: Testicular regression syndrome: a clinical and pathologic study of 11 cases. Arch Path Lab Med 124:694, 2000. 7. Zenteno JC, Jimenez AL, Canto P, et al.: Clinical expression and SRY gene analysis in XY subjects lacking gonadal tissue. Am J Med Genet 99:244, 2001. 8. Hamerton JL, Canning N, Ray M, et al.: A cytogenetic survey of 14,069 newborn infants. Clin Genet 8:223, 1975. 9. Docimo SG, Silver RI, Cromie W: The undescended testicle: diagnosis and management. Am Fam Physician 62:2037, 2000. 10. Rai M, Agrawal JK, Sasikuma V, et al.: Bilateral congenital anorchia in three siblings. Clin Pediatr (Phila) 33:367, 1994. 11. Nielsen J, Pelsen B, Sorensen K: Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet 33:262, 1988. 12. Maffei P, Munno V, Marshall JD, et al.: The Alstrom syndrome: is it a rare or unknown disease? Ann Ital Med Int 17:221, 2002. 13. Seminara SB, Acierno JS Jr, Abdulwahid NA, et al.: Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J Clin Endocrinol Metab 87:1607, 2002. 14. Katsanis N, Lupski JR, Beales PL, et al.: Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10:2293, 2001. 15. Verloes A, Temple IK, Bonnet S, et al.: Coloboma, mental retardation, hypogonadism, and obesity: critical review of the so-called Biemond syndrome type 2, updated nosology, and delineation of three ‘‘new’’ syndromes. Am J Med Genet 69:370, 1997.

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Urogenital System Organs Table 29-9. Conditions with small testes Causation Gene/Locus

Syndrome

Prominent Features

Alstrom12

Pigmentary retinopathy, obesity, deafness

AR (203800) ALMS1

Bardet-Biedl14

Pigmentary retinopathy, obesity, polydactyly, mental retardation

AR (209900) Multiple genes

Biemond, type II15

Iris coloboma, obesity, polydactyly, mental retardation

AR (210350)

Bo¨rjeson-Forssman-Lehmann16

Microcephaly, small hands, obesity, hypotonia, mental retardation

XLR (301900) PHF6, Xq26.3

Carbohydrate-deficient glycoprotein syndrome, Type Ia17

Hypotonia, cerebellar hypoplasia, inverted nipples

AR (212065) PMM2

Chromosomal aberrations (18p, XXY, XXYY, XXXY)

Depend on underlying chromosome aberration

Chromosomal

De Sanctis-Cacchione18

Short stature, xeroderma pigmentosum, mental retardation

AR (278800) 10q11

Gordon-Holmes13

Ataxia

AR (212840)

Ichthyosis-hypogonadism19

Ichthyosis, mental retardation

XLR (308200) Xp22

Johnson-McMillin20

Alopecia, deafness, anosmia

AD (147770)

Kallmann21

Hyposmia/anosmia

XLR (308700) Anosmin, Xp22.3 AD (147950) FGFR1, 8p11.2-p11.1 AR (244200)

Kenny-Caffey22

Short stature, hypoparathyroidism, hyperostosis

AD (127000) AR (244460) TBCE, 1q42-q43

Klinefelter

Tall stature, gynecomastia

Chromosomal 47,XXY

Retinitis pigmentosa, spasticity, mental retardation

AR (245800)

Leptin deficiency

Morbid obesity

AR (164460) 7q31.3

Miles-Carpenter25

Microcephaly, ptosis, camptodactyly

XLD (309605) Xq21.31

Oliver-McFarlane26

Trichomegaly, chorioretinopathy, hypopituitarism

AR (275400)

Pallister-Hall27

Imperforate anus, polydactyly, hypopituitarism, hypothalamic hamartoma (hamartoblastoma)

AD (146510) GLI3, 7p13

Prader-Willi28

Neonatal hypotonia, obesity, mental retardation

(176270) Imprinting defect, deletion 15q, maternal UPD

Rothmund-Thompson29

Poikiloderma, alopecia, cataracts, photosensitivity

AR (268400) RECQL4, 8q24.3

Sutherland-Haan30

Microcephaly, spastic diplegia, mental retardation

XLR (309470) PQBP-1, Xp11.2

Werner Syndrome31

Cataracts, premature aging

AR (277700) RECQL2, 8q24.3

Laurence-Moon23 24

16. Baumstark A, Lower KM, Sinkus A, et al.: Novel PHF6 mutation p.D333del causes Borjeson-Forssman-Lehmann syndrome. J Med Genet 40:e50, 2003. 17. Miller BS, Freeze HH: New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system. Rev Endocr Metab Disord 4:103, 2003. 18. Colella S, Nardo T, Botta E, et al.: Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-Cacchione variant of xeroderma pigmentosum. Hum Molec Genet 9:1171, 2000.

19. Pike MG, Hammerton M, Edge J, et al.: A family with X-linked ichthyosis and hypogonadism. Eur J Pediatr 148:442, 1989. 20. Schweitzer DN, Yano S, Earl DL, et al.: Johnson-McMillin syndrome, a neuroectodermal syndrome with conductive hearing loss and microtia: report of a new case. Am J Med Genet 120A:400, 2003. 21. Oliveira LM, Seminara SB, Beranova M, et al.: The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab 86:1532, 2001.

Male Genital System

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Table 29-10. Conditions with absent testis Syndrome

Prominent Features

Causation

Cross

Microphthalmia, corneal opacity, hypopigmentation, mental retardation

AR (257800)

PAGOD (Kennerknecht)33

Pulmonary and pulmonic artery hypoplasia, agonadism, omphalocele, diaphragmatic hernia, dextrocardia

AR (202660)

Familial testicular regression34

Variable, from phenotypic males to phenotypic females

AR (237250)

OEIS35

Omphalocele, exstrophy(bladder), imperforate anus, spine anomalies

Sporadic (258040)

Axial mesodermal dysplasia36

Renal defects, vertebral defects, ambiguous or absent genitalia

Sporadic

Sirenomelia37

Single lower limb, absent genitalia and anus, renal agenesis

Sporadic

Temocin38

Upper limb amelia, sex reversal

Sporadic

9p deletion39

Arched eyebrows, long philtrum, short neck, heart defect, sex reversal

Chromosomal

32

22. Hoffman WH, Kovacs K, Li S, et al.: Kenny-Caffey syndrome and microorchidism. Am J Med Genet 80:107, 1998. 23. Laurence JC, Moon RC: Four cases of retinitis pigmentosa occurring in the same family and accompanied by general imperfection of development. Ophthalmol Rev 2:32, 1966. 24. Farooqi IS: Leptin and the onset of puberty: insights from rodent and human genetics. Semin Reprod Med 20:139, 2002. 25. Miles JH, Carpenter NJ: Unique X-linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31. Am J Med Genet 38:215, 1991. 26. Kondoh T, Amamoto N, Hirota T, et al: Very long eyelashes, long eyebrows, sparse hair, and mental retardation in two unrelated boys: An atypical form of Oliver-McFarlane syndrome without retinal degeneration, or a new clinical entity? Am J Med Genet 120A:437, 2003. 27. Kang S, Graham JM Jr, Olney AH, et al.: GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 15:266, 1997. 28. Gunay-Aygun M, Schwartz S, Heeger S, et al.: The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics 108:e92, 2001. 29. Wang LL, Levy ML, Lewis RA, et al.: Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet 102:11, 2001. 30. Fichera M, Borgione E, Avola E, et al.: A new MRXS locus maps to the X chromosome pericentromeric region: a new syndrome or narrow definition of Sutherland-Haan genetic locus? J Med Genet 39:276, 2002. 31. Bohr VA: Werner syndrome and its protein: clinical, cellular and molecular advances. Mech Ageing Dev 124:1073, 2003. 32. Tezcan I, Demir E, Asan E, et al.: A new case of oculocerebral hypopigmentation syndrome (Cross syndrome) with additional findings. Clin Genet 51:118, 1997 33. Silengo M, Del Monaco A, Linari A, et al.: Low birth-weight, microcephalic malformation syndrome in a 46,XX girl and her 46,XY sister with agonadism: third report of the Kennerknecht syndrome or autosomal recessive Seckel-like syndrome with previously undescribed genital anomalies. Am J Med Genet 101:275, 2001. 34. Josso N, Briard ML: Embryonic testicular regression syndrome: variable phenotypic expression in siblings. J Pediatr 97: 200, 1980. 35. Keppler-Noreuil KM: OEIS complex (omphalocele-exstrophyimperforate anus-spinal defects): a review of 14 cases. Am J Med Genet 99:271, 2001. 36. Bergmann C, Zerres K, Peschgens T, et al.: Overlap between VACTERL and hemifacial microsomia illustrating a spectrum of malformations seen in axial mesodermal dysplasia complex (AMDC). Am J Med Genet 121A:151, 2003. 37. Stevenson RE, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451, 1986.

38. Ohro Y, Suzuki Y, Tsutsumi Y, et al.: Female external genitalia, absent uterus, and probable agonadism in a 46,XY infant with bilateral upper amelia. Clin Genet 54:52, 1998. 39. Muroya K, Okuyama T, Goishi K, et al.: Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases. J Clin Endocrinol Metab 85:3094, 2000.

29.12 Polyorchidism (Supernumerary Testes) Definition

Polyorchidism is the presence of more than two testicles. Diagnosis

Supernumerary testes usually present as a double testicle on the left side discovered as a scrotal or inguinal mass on physical examination. Etiology and Distribution

The etiology of polyorchidism is unknown but has been postulated to occur as the result of an early division of the genital ridge. A majority of cases are left-sided and consist of a single extra testicle. Rare patients have been reported with bilateral testicular duplication or even triple testes within the same hemiscrotum. Infrequently, the epididymis and vas are also duplicated. The major presenting symptom is an inguinal or testicular mass, but up to 20% may present with infertility.1 Polyorchidism is not typically associated with any other abnormality, but there are occasional reports of its presence in multiple malformation syndromes and chromosomal defects.2 Prognosis, Treatment, and Prevention

Complications of polyorchidism are rare. Some reports have suggested a possible increased risk of malignancy, but there are no data to support such a risk at this time. In fact, removal appears to be unnecessary in most cases.3 References (Polyorchidism) 1. Nocks BN: Polyorchidism with normal spermatogenesis and equal sized testes: a theory of embryological development. J Urol 120:638, 1978. 2. Ozok G, Taneli C, Yazici M, et al.: Polyorchidism: a case report and review of the literature. J Pediatr Surg 2:306, 1992.

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Urogenital System Organs

3. Spranger R, Gunst M, Ku¨hn M: Polyorchidism: a strange anomaly with unsuspected properties. J Urol 168:198, 2002.

29.13 Ectopic Testis Definition

Ectopic testis is a testis in a location not anatomically related to the path of normal testicular descent. Diagnosis

The most common location for an ectopic testis is in the superficial inguinal pouch.1 Other less common locations are the contralateral scrotal sac, base of the penis, ipsilateral thigh, and perineum. Ectopic testes have also been found in the penis.2 It is usually associated with inguinal hernia and sometimes hypospadias. Etiology and Distribution

The embryologic basis of the ectopic testis is unknown. Numerous theories have been suggested and are well reviewed by Heyns and Hutson.3 Prognosis, Treatment, and Prevention

Since the spermatic cord is usually intact, the testicle is customarily brought down to the appropriate scrotal sac. The risk for malignancy is presumably similar to cryptorchidism, and postsurgical monitoring for tumor is appropriate. References (Ectopic Testis) 1. Celayir AC, Sander S, Elecivik M: Timing of surgery in perineal ectopic testis: analysis of 16 cases. Pediatr Surg Int 17:167, 2001. 2. Pugach JL, Steinhardt GF: Evaluation and management of ectopic penile testis. Urology 59:137, 2002. 3. Heyns CF, Hutson JM: Historical review of theories on testicular descent. J Urol 153:754, 1995.

29.14 Male Pseudohermaphroditism and 46,XY Sex Reversal Definition

Male pseudohermaphroditism is a word used to describe genetic males who have abnormalities of external genitalia that preclude establishment of genetic sex based on physical examination alone. Diagnosis

Undermasculinization has been suggested as a more appropriate term to describe this group of patients since it emphasizes the general pathology and avoids confusion with hermaphroditism, which is a distinct, unrelated entity.1 However, the range of effect on external and internal genitalia in conditions of undermasculinization is more expansive than seen in pseudohermaphroditism, from minor micropenis and/or hypospadias at the mild end of the spectrum to complete 46,XY sex reversal at the severe end. Genotypic males in the middle of this spectrum with ambiguous genitalia are to whom the term pseudohermaphroditism applies and for whom the most immediate consternation occurs in the delivery room. The term ambiguous genitalia reflects the difficulty in trying to determine gonadal or genotypic sex of an infant by examination of the external genitalia alone. Figure 29-19 is illustrative of this difficulty.

Etiology and Distribution

An erudite discussion of the numerous causes of male pseudohermaphroditism is beyond the scope of this summary. Two special journal editions on disorders of sexual differentiation offer excellent reviews.2,3 In brief, however, these conditions can be categorized into six groups as listed in Table 29-11. 46,XX males and true hermaphrodites are not considered in this chapter (see Section 30.3) Mutations in genes that function in the early critical pathway of bipotential gonad determination constitute a significant cause of male pseudohermaphroditism. The importance of these genes in this pathway has historically been determined by mouse transgenic and knock-out models. Until recently, only defects of the WT1 gene had been linked to human disorders, but mutations of SF-1 leading to 46,XY sex reversal have now been described.4 Mechanisms interfering with normal development of the testes constitute another major group that causes male pseudohermaphroditism. Dysgenetic testes have long been known to be associated with ambiguous genitalia or complete 46,XY sex reversal. The development of dysgenetic testes is heterogeneous in nature, but many cases are familial and some of these cases are now known to be the result of SRY mutations or DAX1 duplications.5,6 Dysgenetic testes can also be caused by XY/XO mosaicism, mutations in SOX9 (camptomelic dysplasia), and monosomy 9p. Defects of androgen biosynthesis that cause male pseudohermaphroditism are rarer than those that cause female pseudohermaphroditism. There are five enzyme defects in this group, listed in Table 29-11. Four of these enzymes are defects of testosterone synthesis or one of its precursors. The fifth enzyme defect, 5a-reductase deficiency, is a defect of testosterone conversion to the more potent dihydrotestosterone. Another cause of deficient testosterone production is Leydig cell hypoplasia, recently shown to be secondary to luteinizing hormone receptor (LHR) gene defects.7 All defects of testosterone synthesis are autosomal recessive. The most common cause of male pseudohermaphroditism is a defect in the androgen receptor (AR) gene on the X chromosome.1 Mutations that cause complete receptor insensitivity (complete androgen insensitivity syndrome or CAIS) result in normal external female genitalia with no Mu¨llerian structures (Fig. 29-19). Normal testes may reside intraabdominally or present as an inguinal hernia. Partial androgen insensitivity syndrome (PAIS) covers a range of external genitalia phenotypes as wide as the degree of functional receptor loss (Fig. 29-19). Genital ambiguity and absence of Mu¨llerian structures in the presence of elevated AMH and testosterone, particularly after HCG stimulation, is the hallmark of PAIS. Historically, the diagnosis of AI is confirmed by analysis of ligand receptor binding on genital skin fibroblasts. However, the technique is difficult and time consuming. Molecular diagnostics now offer another option, particularly for CAIS and familial PAIS where mutations are detected in up to 90% of cases.8 Unfortunately, the technique fails to detect mutations in more than 15% of sporadic PAIS, confirming the heterogeneity of this clinical presentation. Another group classification of male pseudohermaphroditism is that of environmental endocrine disrupters. Currently, this category is theoretical since there is little human evidence that targets any specific environmental agent to defects of male sexual differentiation. However, there are significant animal data that document disruption of normal sexual differentiation via numerous antiandrogenic agents.9 Given the recent rise in the number of

Male Genital System

1273

Fig. 29-19. A. 46,XX with 21-OH deficiency. B. 46,XY with penoscrotal hypospadias. C. 46,XX with 21-OH deficiency. D. 46,XY with complete androgen insensitivity syndrome (CAIS). (A, B, and D courtesy of Drs. Paul Austin and Douglas Coplen, University of Washington, St. Louis. C courtesy of Dr. Marilyn Jones, University of California, San Diego.)

births with hypospadias and cryptorchidism, environmental endocrine disrupters should be a causal consideration.10 The last classification of male pseudohermaphrodites is those conditions with multiple malformations and genital defects as part of the malformation syndrome where the genetic defect is not known. Prognosis, Treatment, and Prevention

As a result of the myriad causes for male pseudohermaphroditism outlined in this section, prognosis and treatment recommendations must be individualized. In fact, prognosis and treatment are inexplicably entwined because outcome is usually tied to a particular course of intervention. Historically, the biggest confounder in the early consideration of a treatment course, typically in the newborn period, is the agonizing parental choice of sex of rearing. One might predict that this choice has been made easier as a result of advanced cytogenetic techniques, imaging modalities, and molecular genetics. However, such a prediction presupposes that there are absolute biologic criteria that establish gender identity

and therein lies the difficulty. Do parents ‘‘choose’’ the ‘‘sex’’ of their child based on genetic sex, gonadal sex, or genital sex, and do these physical aspects of sex identification relate to future gender identity? Historically, the sex of rearing decision in these cases has been based on a balancing act, trying to obtain the best possible outcome with respect to appearance and sexual function while using the least surgical intervention possible and, if feasible, retaining reproductive function. This ‘‘optimal sex policy’’ was developed at Johns Hopkins School of Medicine in the mid-1950s and assumes that one’s gender identity is a blank slate at birth, amenable to postnatal social and environmental sex of rearing influences.11 However, this optimal sex policy has been challenged, both by proponents of the theory that fetal androgen exposure exerts a significant effect on future gender identity and by a large number of intersex individuals themselves, who are critical of the traditional medical model of optimal sex selection at birth.12,13 Some have gone to the extreme and proposed that no decision about gender should be made at birth and that such

Table 29-11. Syndromes with male pseudohermaphroditism Prominent Features

Causation Gene/Locus

Denys-Drash16

Genital ambiguity, renal disease, Wilms tumor, gonadal dysgenesis

AD (194080) WT1

Frasier16

Female genitalia, renal disease, gonadoblastoma (not Wilms tumor)

AD (136680) WT1

WAGR17

Wilms tumor, aniridia, genitourinary defects, mental retardation

(194072) Microdeletions of WT1 and contiguous genes, 11p13

SF-118

46,XY sex reversal, adrenal failure

AD(184757) NR5A1

XY gonadal dysgenesis (Swyer)19

Female genitalia, persistent Mu¨llerian structures, dysgenetic testes

(480000, 306100) Y linked (SRY), Xp duplication (DAX1), SRY mutation or deletion (20% of cases), DAX1 duplication

Mixed gonadal dysgenesis20

Variable genital ambiguity, unilateral testes, streak gonad, variable persistent Mu¨llerian structures

AR (233420) X/XY mosaicism monosomy 9p

Testicular regression (gonadal agenesis/anorchia)21

Absent gonads, variable internal and external ambiguity depending on timing

AR(273250)

Campomelic dysplasia22

Bowed lower extremities, Pierre-Robin, ambiguous genitalia(in two-third of XY cases)

AD(114290) SOX9

Leydig cell hypoplasia23

Variable genital ambiguity to complete female genitalia

AR(152790) LHR

17a-hydroxylase deficiency24

Variable genital ambiguity to complete female genitalia

AR(202110) CYP17

17b3-hydroxysteroid dehydrogenase deficiency25

Female genitalia

AR(605573) HSD17B3

3b-hydroxysteroid dehydrogenase deficiency26

Ambiguous genitalia, cortisol deficiency

AR(109715) HSD3B2

Congenital lipoid adrenal hyperplasia27 (steroid acute regulatory protein)

Female genitalia, salt wasting

AR(201710) StAR

Smith-Lemli-Opitz28

Ambiguous genitalia, polydactyly, renal defects

AR(270400) DHCR7

Complete androgen insensitivity syndrome(CAIS)29

Female genitalia

XLR(300068) AR, Xq11-q12

Partial androgen insensitivity syndrome (PAIS)29

Ambiguous genitalia

XLR(300068) AR, Xq11-q12

5a-reductase deficiency30

Variable genital ambiguity

AR(264600) SRD5A2

Diethylstilbestrol (DES)

Cryptorchidism, testicular hypoplasia

AR downregulation

Antiandrogens (Linuron, Vinclozolin, DDT, DDE, phthalate esters, PCB, PCDF, TCDD)

Antiandrogen effects in animal studies only to date

Syndrome

Defects of Early Bipotential Gonadal Development

Defects of Testicular Development

Defects of Testosterone Synthesis

Defects of Androgen Action

Environmental Endocrine Disrupters31

(continued)

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Male Genital System

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Table 29-11. Syndromes with male pseudohermaphroditism (continued) Syndrome

Causation Gene/Locus

Prominent Features

Multiple Malformation Syndromes

Cloacal exstrophy32

Epispadias, diphallia, bladder and colon exstrophy, imperforate anus, renal defects

Possible defect of early mesoderm

Limb-body wall sequence33

Thoracoabdominoschisis, exencephaly, limb defects, renal agenesis

Vascular disruption, amniotic membrane

Sirenomelia sequence34

Single central lower limb, renal aplasia, imperforate anus

Vascular steal

Urorectal septum malformation sequence35

Genitourinary defects, imperforate anus, absent urethral opening

Defect of mesodermal proliferation

Meckel36

Encephalocele, polydactyly, cystic dysplastic kidneys

AR (249000) Multiple loci

Short rib-polydactyly type I, II, III, IV37

Chondrodysplasia, polydactyly, narrow thorax, cleft lip, genitourinary anomalies

AR(263510, 263520, 263530, 269860)

children should grow up as an intersex individual until they are old enough to make their own choice.14 No data exist that suggest this view is that of any majority nor about what the effects would be, positive or negative, on a child raised as an intersex individual. However, in one study of 59 children with intersex disorders, 13% had a gender identity disorder, suggesting that there is room for improvement in the optimal sex selection process.15 References (Male Pseudohermaphroditism and 46,XY Sex Reversal) 1. Ahmed SF, Hughes IA: The genetics of male masculinization. Clin Endo 56:1, 2002. 2. Simpson JE: Sex determination and sexual differentiation in humans. Am J Med Genet 89:175, 1999. 3. Sultan C: Normal and abnormal sexual differentiation: from genes to patient. Sem Reprod Med 20:155, 2002. 4. Ozisik G, Achermann JC, Jameson JL: The role of SF1 in adrenal and reproductive function: insight from naturally occurring mutations in humans. Mol Genet Metab 76:85, 2002. 5. Sarafoglou K, Ostrer H: Familial sex reversal: a review. J Clin Endo Metab 85:483, 2000. 6. Dewing P, Bernard P, Vilian E: Disorders of gonadal development. Sem Reprod Med 20:189, 2002. 7. Richter-Unruh A, Martens JWM, Verhoef-Post M, et al.: Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in luteinizing hormone receptor gene. Clin Endo 56:103, 2002. 8. Sultan C, Lumbruso S, Paris F, et al.: Disorders of androgen action. Sem Reprod Med 20:217, 2002. 9. Toppari J: Environmental endocrine disrupters and disorders of sexual differentiation. Sem Reprod Med 20:305, 2002. 10. Toppari J: Trends in the incidence of cryptorchidism and hypospadias, and methodological limitations of registry-based data. Hum Reprod Update 7:282, 2001. 11. Gooren LG: Psychological consequences. Sem Reprod Med 20:285, 2002. 12. Meyer-Bahlburg HL: Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J Clin Endocrinol Metab 84:3455, 1999. 13. Intersex Society of North America. Recommendations for treatment: intersex infants and children. Pamphlet, available at www.isna.org, 2003.

14. Minto CL, Liao LM, Woodhouse CR, et al.: The effect of clitoral surgery on sexual outcome in individuals who have intersex conditions with ambiguous genitalia: a cross-sectional study. Lancet 361:1252, 2003. 15. Slijper FM, Drop SL, Molenaar JC: Long-term psychological evaluation of intersex children. Arch Sex Behav 27:125, 1998. 16. McTaggart SJ, Algar E, Chow CW, et al.: Clinical spectrum of DenysDrash and Frasier syndrome. Pediatr Nephrol 16:335, 2001. 17. Breslow NE, Norris R, Norkool PA, et al.: Characteristics and outcomes of children with the Wilms tumor-aniridia syndrome: a report from the National Wilms Tumor Study Group. J Clin Oncol 21:4579, 2003. 18. Ozisik G, Achermann JC, Meeks JJ, et al.: SF1 in the development of the adrenal gland and gonads. Horm Res 59(suppl 1):94, 2003. 19. Mitchell CL, Harley VR: Biochemical defects in eight SRY missense mutations causing XY gonadal dysgenesis. Mol Genet Metab 77:217, 2002. 20. Alvarez-Nava F, Soto M, Borjas L, et al.: Molecular analysis of SRY gene in patients with mixed gonadal dysgenesis. Ann Genet 44:155, 2001. 21. Spires SE, Woolums CS, Pulito AR, et al.: Testicular regression syndrome: a clinical and pathologic study of 11 cases. Arch Pathol Lab Med 124:694, 2000. 22. Schafer AJ, Foster JW, Kwok C, et al.: Campomelic dysplasia with XY sex reversal: diverse phenotypes resulting from mutations in a single gene. Ann NY Acad Sci 785:137, 1996. 23. Themmen AP, Verhoef-Post M: LH receptor defects. Semin Reprod Med 20:199, 2002. 24. Auchus RJ: The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 30:101, 2001. 25. Boehmer AL, Brinkmann AO, Sandkuijl LA, et al.: 17Betahydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab 84:4713, 1999. 26. Simard J, Moisan AM, Morel Y: Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase deficiency. Semin Reprod Med 20:255, 2002. 27. Stocco DM: Clinical disorders associated with abnormal cholesterol transport: mutations in the steroidogenic acute regulatory protein. Mol Cell Endocrinol 191:19, 2002. 28. Herman GE: Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum Mol Genet 12 Spec No 1:R75-88, 2003.

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Urogenital System Organs

29. Brinkmann AO: Molecular basis of androgen insensitivity. Mol Cell Endocrinol 179:105, 2001. 30. Sultan C, Lumbroso S, Paris F, et al: Disorders of androgen action. Semin Reprod Med 20:217, 2002. 31. McLachlan JA, Newbold RR, Burow ME, et al.: From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters. Acta Pathol Microbiol Immunol Scand 109:263, 2001. 32. Schober JM, Carmichael PA, Hines M, et al.: The ultimate challenge of cloacal exstrophy. J Urol 167:300, 2002. 33. Russo R, D’Armiento M, Angrisani P, et al.: Limb body wall complex: a critical review and a nosological proposal. Am J Med Genet 47:893, 1993. 34. Valenzano M, Paoletti R, Rossi A, et al.: Sirenomelia. Pathological features, antenatal ultrasonographic clues, and a review of current embryogenic theories. Hum Reprod Update 5:82, 1999. 35. Jo Mauch T, Albertine KH: Urorectal septum malformation sequence: insights into pathogenesis. Anat Rec 268:405, 2002. 36. Salonen R, Paavola P: Meckel syndrome. J Med Genet 35:497, 1998. 37. Elcioglu NH, Hall CM: Diagnostic dilemmas in the short ribpolydactyly syndrome group. Am J Med Genet 111:392, 2002.

29.15 Wolffian Duct Malformations Definition

The mesonephric (Wolffian) duct system persists in males as a result of androgen production and differentiates into the seminal vesicles, epididymis, and vas deferens. This duct system is critical to normal male fertility. Diagnosis

The most common clinical problem related to an anomaly of the Wolffian duct system is infertility as a result of absence of a portion of the duct. Congenital absence of the vas deferens (CAVD) is by far the most common of the ductal defects. Bilateral CAVD (BCAVD) accounts for 1–2% of men with infertility.1 In cases of BCAVD, the epididymis and the seminal vesicles may also be absent. Absence of the vas is detectable on palpation of the testis and usually confirmed by transrectal ultrasound. Renal agenesis and other urinary tract anomalies occur in 14–21% of cases. Unilateral CAVD (UCAVD) is not associated with infertility unless contralateral duct defects are present and is usually detected during a vasectomy procedure. Ipsilateral renal agenesis is frequently associated with UCAVD. Other anomalies of the vas deferens can occur and are listed in Table 29-12 but are very rare if not associated with CAVD. Etiology and Distribution

While BCAVD occurs in the majority of men with cystic fibrosis (CF), mutations in the CFTR gene are also frequent in asymptomatic males, with up to 64% of men having two detectable CF mutations.2 However, CF mutations are rare in males with renal agenesis, suggesting a different pathogenesis. A much smaller percentage of males with UCAVD have CF mutations than in BCAVD. Prognosis, Treatment, and Prevention

Bilateral Wolffian duct malformations that result in one or more ducts being absent are associated with obstructive azoospermia and male infertility. Until recently, little could be offered to allow

Table 29-12. Anomalies of the Wolffian duct system Vas Deferens

Epididymis

Bilateral absence

Agenesis

Unilateral absence

Ectopic

Segmental aplasia

Anomalous attachment

Ectopic

Cysts

Duplication

Duplication

Crossed Diverticulum

Seminal Vesicles

Agenesis Hypoplasia Fusion Cyst

such an affected male the opportunity of biologic offspring. However, with the introduction of the assisted reproduction technique known as ICSI (intracytoplasmic sperm injection), these men now have an excellent chance of reaching this goal. Undertaking this procedure should be done with appropriate CF screening and counseling given the risk to the offspring of inheriting cystic fibrosis. Concern has also been raised recently about an increased risk of uniparental disomy and assisted reproduction technology.3 Finally, a proportion of male infertility is likely due to mutations and deletions of Y-linked fertility genes. Thus, ICSI poses a potential risk for passing on the infertility trait to male offspring.4 References (Wolffian Duct Malformations) 1. Vohra S, Morgentaler A: Congenital anomalies of the vas deferens, epididymus and seminal vesicles. Urology 49:313, 1997. 2. Jezequel P, Dubourg C, Le Lannou D, et al.: Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. Mol Hum Reprod 6:1063, 2000. 3. Maher ER, Brueton LA, Bowdin SC, et al.: Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet 40:62, 2003. 4. Komori S, Kato H, Kobayashi S, et al.: Transmission of Y chromosomal microdeletions from father to son through intracytoplasmic sperm injection. J Hum Genet 47:465, 2002.

29.16 Persistent Mu¨llerian Ducts Definition

Absence or abnormal anti-mu¨llerian hormone (AMH) causes persistence of the Mu¨llerian duct system (PMDS) in a phenotypic male. Diagnosis

The usual presentation of PMDS is unilateral cryptorchidism and contralateral inguinal hernia with otherwise normal male genitalia. Bilateral cryptorchidism as a presentation is less common.1 At the time of surgery, the hernias are found to contain a uterus and fallopian tubes. The undescended testes are usually in the normal position for ovaries. Some patients have a testis as well as the

Male Genital System

uterus and tube in the hernia, and a small number have both testes in the same hernia. Etiology and Distribution

Persistence of the upper vagina, uterus, and fallopian tubes in a male may be secondary either to nonproduction of AMH as a result of mutations in the AMH gene (45%) or to resistance of the target tissue because of mutations in the AMH type II receptor gene, AMH-R2 (39%).1 The AMH type I receptor is required for signal transduction and is activated by the type II receptor via phosphorylation. The gene for the type I receptor has not been identified. PMDS is rare and is autosomal recessive. At least one multiple malformation syndrome has also been associated with PMDS. Urioste et al. reported four males with PMDS who had long smooth philtrum, anteverted nostrils, notched alae nasi, prominent alveolar ridges, short neck, lymphangiectasia, hypoplastic kidneys, and hepatic failure.2 Prognosis, Treatment, and Prevention

Surgical reduction of the unilateral or bilateral hernias is performed first, followed by removal of the Mu¨llerian structures. Because the vas deferens is often attached to Mu¨llerian structures, great care must be taken. The procedure is often not completely successful because of a short spermatic cord and integration of the vasa deferentia into Mu¨llerian structures as well. Even with good surgical results, normal fertility occurs in only 11% of patients secondary to epididymal and superior vas deferens aplasia. Orchidopexy is required for most males because there is no anchoring of the testes by the gubernaculum. Reports of malignancy in the testes also suggest a need for ongoing follow-up. Prenatal diagnosis in a subsequent pregnancy is possible now with the delineation of the molecular defect in most cases. References (Persistent Mu¨llerian Ducts) 1. Belville C, Josso N, Picard JY: Persistence of mullerian derivatives in males. Am J Med Genet (Semin Med Genet) 89:218, 1999. 2. Urioste M, Rodriguez JI, Barcia JM, et al.: New syndrome. Persistence of Mu¨llerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet 47:494, 1993.

29.17 Splenogonadal Fusion Definition

Splenogonadal fusion is a connection between the spleen or accessory splenic tissue and the gonad. Diagnosis

A direct connection with the spleen, often fibrous in nature, is referred to as continuous splenogonadal fusion (SGF). Discontinuous SGF is the term given to gonadal connection to accessory splenic tissue but not the spleen proper. Etiology and Distribution

The pathogenesis of SGF is unknown. Caudal movement of the gonad between the 5th and 10th weeks brings it close to the primordial spleen and it may be at this time that the fusion occurs. Many have proposed a vascular etiology,1 but a significant number of cases are associated with malformations that cannot be explained by a vascular mechanism.1 Almost half of cases with

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continuous SGF have associated anomalies; the frequency of malformations in discontinuous SGF is much lower.2 In particular, limb and orofacial malformations are especially prevalent in continuous SGF, and the overlap with the Hanhart syndrome and femoral-facial syndrome has not been lost.1,3 A developmental field defect has been proposed to explain the wide range of associated anomalies.3 Familial cases have not been reported. Prognosis, Treatment, and Prevention

The prognosis of SGF is primarily dependent on the associated malformations. Those with limb malformations have a particularly high mortality, with less than 50% surviving beyond a year of life.3 Cases of isolated SGF may only come to attention at autopsy. References (Splenogonadal Fusion) 1. McPherson F, Frias JL, Spicer D, et al.: Splenogonadal fusion-limb defect ‘‘syndrome’’ and associated malformations. Am J Med Genet 120A: 518, 2003. 2. Gouw AH, Elema JD, Bink-Boelkens ME, et al.: The spectrum of splenogonadal fusion. Case report and review of 84 cases. Eur J Pediatr 144:316, 1985. 3. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb defect syndrome. Report of five new cases and review. Am J Med Genet 86:347, 1999.

29.18 Inguinal Hernia Definition

An inguinal hernia is a protrusion of the abdominal contents into the inguinal canal at the internal abdominal ring (Fig. 29-20). Diagnosis

Inguinal hernias may be defined as direct or indirect according to their position in relation to the inferior epigastric artery, with indirect leaving the abdomen lateral to the artery and direct leaving medial to the artery. Indirect inguinal hernias are more frequent and are usually slow to develop. The protruding element first appears at the external inguinal ring as a widening. As the ring enlarges with pressure, an inguinal protrusion develops. Standing, sharp coughing, and crying increases the size of the inguinal bulge or may be felt as an impulse. The hernia may then escape the external ring and push into the scrotum as far as the scrotal sac. The child or adult is noted to have a fullness of the scrotum. The external inguinal ring may be assessed by invaginating the scrotal skin with an index finger and sliding the finger up over the route of the spermatic cord until the external ring is encountered lateral to the pubic tubercle. With straining or coughing, the ring size and the presence of an impulse can be palpated. Indirect hernias are an oval shape descending obliquely in the inguinal region. These hernias are easily reducible, but a widened inguinal ring is noted. Scrotal hernias push the cord posteriorly, but are intimately associated with the testicle. Direct hernias descend through a posterior defect in the inguinal canal with a short course within the canal. The ring is greatly widened and often distorted. The hernial sac is medial to the spermatic cord. Because the majority of patients with cryptorchidism have inguinal hernias, the scrotum should be carefully examined for undescended testes.

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Urogenital System Organs

incidence is 20 to 30 per 1000 male live births and three to four per 1000 female live births. When hernias occur in the infant or young child, both sides are more likely to be affected. Overall, 10% of inguinal hernias are bilateral. Preterm infants are more likely to develop inguinal hernias, perhaps because of the increase in intraabdominal pressure in association with an undescended testis at the time of birth. Five percent of infants at or less than 32 weeks gestational age or under 1250 g develop inguinal hernias.2 Intrauterine growth retardation may further increase the risk. As well, incarceration is more likely in infancy, perhaps occurring in 25% of patients.3 Ten percent of inguinal hernias are bilateral, and females are more likely to have bilateral involvement. A phenotypic female presenting with a hernia should be explored carefully surgically, as the absence of uterus and tubes may indicate a diagnosis of androgen insensitivity. Hernias have an increased prevalence in disorders of connective tissue, including Marfan, Ehlers-Danlos, and cutis-laxa syndromes. The inheritance of inguinal hernia is complex, and most recurrence risk figures are empiric. Sawaguchi et al.4 found a recurrence risk of 30% in brothers of males and 27% in sisters of females. In addition, recurrence risks were highest for siblings of females with bilateral involvement. Prognosis, Treatment, and Prevention

Fig. 29-20. Massive inguinal hernias in a male infant with chondrodysplasia punctata.

Etiology and Distribution

Independent of testicular descent, the peritoneum of the coelomic cavity evaginates bilaterally into the ventral abdominal wall following the course of the gubernaculum testis (the vaginal process) into the scrotum or labia. Along with the muscle and fascial layers, the evagination forms the inguinal canal. The process begins at the third month. Prior to or at the time of birth, the testis descends through the inguinal ring into the scrotum. The processus vaginalis begins obliteration after that time. The processes are patent in 85% of infants at birth, in 60% of infants at age 1 year, and in 15–35% of adults.1 Inguinal hernias in children occur most commonly in the first 6 months of life in a male to female sex ratio of 9:1. The

The greatest concern with inguinal hernia is incarceration of hernial contents, which may occur frequently in the young infant. Repair involves initial reduction of hernial contents and then high ligation of the hernial sac (processus vaginalis) at the internal inguinal ring with removal of the sac distally. The Lichtenstein tension-free mesh onlay repair is the most common technique used, although the laparoscopic approach is also being used more frequently.5 Most hernias are repaired electively, as an outpatient procedure. The exceptions would be premature infants, who are at increased risk for apnea during anesthesia, and the child with an incarcerated hernia. Care must be taken at the time of the surgery to avoid damage to the vas deferens or to the vascular supply to the testis. Whether the contralateral side should be explored electively is controversial. Generally, the premature infant and all females should have exploration, as bilateral involvement is common. References (Inguinal Hernia) 1. Campbell JR: Inguinal and scrotal problems in infants and children. Pediatr Ann 18:189, 1989. 2. Peevy KJ, Speed FA, Holf CJ: Epidemiology of inguinal hernia in preterm infants. Pediatrics 77:246, 1986. 3. Powell TG, Hallows JA, Cooke RWI, et al.: Why do so many small infants develop an inguinal hernia? Arch Dis Child 61:991, 1986. 4. Sawaguchi S, Matsunaga E, Honna T: A genetic study on indirect inguinal hernia. Jpn J Hum Genet 20:187, 1975. 5. Nathan JD, Pappas TN: Inguinal hernia: an old condition with new solutions. Ann Surg 238(suppl 6):S148, 2003.

30 Female Genital System Leah W. Burke

T

he genetic sex of an individual is determined at fertilization. However, the development of the reproductive tract and its identity as male or female continues throughout gestation, and indeed through prepubertal, life. The reproductive tract includes the gonads, the ductal structures, and the external genitalia. The primordial cells of the ducts and gonads have their origin in the tissues of the intermediate mesoderm that forms during gastrulation. Several homeobox-containing gene transcription factors (Lim1, Lhx9, and Emx2) are expressed during gastrulation in the visceral and lateral folds that form the intermediate mesoderm.1–3 Following the development of the urogenital ridge, gonaddetermining genes act to differentiate the bipotential cells into the gonads and ducts of the reproductive tract. PAX2 acts on the cells of the Wolffian ducts to cause them to develop into the epididymides, seminal vesicles, and vas deferens. WNT4, WNT7A, and HOXA9, 10, 11, and 13 act upon the cells of the Mu¨llerian ducts to develop into the uterus, Fallopian tubes, cervix, and the upper part of the vagina.4–6 The genes responsible for the development of the testes have been more clearly elucidated than the genes responsible for the development of the ovary, thus giving rise to the ‘‘default gonad’’ theory of ovarian development. This theory is not consistent with the development of other systems in the embryo and does not explain the development of ovaries in the absence of hormonal influence. Recent evidence indicates that the development of the ovary is indeed not a passive occurrence and involves the expression of both unique and shared genes (Fig. 30-1). Testis organization begins between the 6th and 7th week of development under the influence of the Y chromosomal genes as well as autosomal genes. Testes can be detected morphologically by the end of the 7th week.7,8 It has been the accepted dogma until recently that the expression of SRY initiates Sertoli cell development and it is after the development of Sertoli cells that the differences in female and male gonadal development begin. Prior to the discovery of SRY, the presence of TDF (testis-determining factor) was proposed to explain this phenomenon. It is now apparent that differences in development between males and females may precede the development of the Sertoli cells or any histologic evidence of testis development. The initial difference may be at least in part due to growth factors activated by SRY that are as yet unknown.9 Evidence in both rats and humans sug-

gests that the growth rate of male embryos exceeds that of female embryos prior to the time of gonadal differentiation.10,11 Using ultrasound data in humans, 8 to 12 menstrual week female fetuses were found to be 1 day behind male counterparts in crown-rump length and parietal diameter.11 In human embryos produced in vitro, male embryos had developed more cells on average than their female counterparts by day 2 after insemination.12 In mouse studies, an increase in cell proliferation was seen less than 24 hours after the onset of Sry expression in Sertoli primordial cells in XY mice, prior to histologic changes and any production of hormone.13 In addition to sex differences in the rate of cell proliferation, there is also left–right asymmetry in cell proliferation. In true hermaphrodites, ovaries occur twice as often on the left as the right and testes and ovotestes are more frequent on the right.14 In studies of human fetuses, right gonads on average exceed left gonads in net weight, DNA, and protein content and testes exceed ovaries in the same parameters.15,16 As the sex differences in growth begin soon after fertilization, the asymmetry of expression in true hermaphrodites may suggest that the development of testes rather than ovaries may be determined at least in part by the underlying growth patterns already established. It is not known whether the early growth patterns of the embryo are determined by sexdetermining genes.9 In addition to SRY, the expression of several other genes is necessary for normal differentiation of the fetal testes. Steroidogenic factor (SF1) expression is necessary for the development of both the Sertoli cells and the Leydig cells and acts as a critical positive regulator of other genes required for sexual differentiation.17 Expression of SOX9, GATA4, and WT1 (Wilms tumor related 1) are necessary for the development and normal functioning of the Sertoli cells.4,6 Desert hedgehog (DHH) functions after the action of SRY and regulates Sertoli-germ cell interactions.18 The genes responsible for the normal development of the ovaries in females are less well-known. Recent studies indicate that the expression of DAX-1, an orphan nuclear receptor gene responsible for X-linked congenital adrenal hypoplasia, acts as an inhibitor of the male developmental pathway through its inhibition of SF-1.19,20 However, in the female Dax1 knockout mouse, the development of ovaries and reproductive function is completely normal, suggesting the lack of a role for DAX-1 in the development of the female reproductive pathway.21 1279

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Urogenital System Organs

Fig. 30-1. Genes involved in the embryology of the reproductive tract. SF-1 ¼ steroidogenetic factor; WT1 ¼ Wilms tumor related 1; EMX2, LIM1, LHX9 ¼ homeobox-containing transcription factors; GATA4 ¼ zinc finger transcription factor; DHH ¼ Desert hedgehog; AMH ¼ anti-Mu¨llerian hormone; WNT7,

WNT4 ¼ members of the WG/WNT family; FOXL2 ¼ winged helix/ forkhead transcription factor; FIGa ¼ helix-loop-helix transcription factor; HOXA 9, 10, 11, 13 ¼ homeobox containing; DAX-1 ¼ deleted in adrenal hypoplasia congenita on the X chromosome.

The role of WT1 in the development of the adrenal glands as well as the reproductive tract has been well-established. Mutations in WT1 lead to urogenital abnormalities and Wt1 knockout mice have renal agenesis as well as gonadal agenesis with female genitalia.22 The specific target genes are unknown, but WT1 appears to be involved in the regulation expression of the genes involved in the early development of the urogenital ridge.21 At least two of the genes responsible for the development of ovarian follicles have been elucidated, although their role in initiating ovarian development is less well-known. FOXL2 is a putative winged helix/forkhead transcription factor gene. Dominant mutations in FOXL2 lead to blepharophimosis-ptosis-epicanthus inversus syndrome, a rare syndrome associated with premature ovarian failure.23 The expression of FOXL2 appears to occur only in the developing eyelids and in fetal and adult ovaries. The expression in ovaries begins early in fetal development before the development of follicles, persists into adulthood, and occurs primarily in the follicle or granulose cells with weak expression in the stromal cells. The germ cells, or developing oocytes, do not express FOXL2.24–26 The exact role that FOXL2 plays in the initiation of ovarian development is unknown. The other gene implicated in the development of ovarian follicles is FIGa, a basic helix-loop-helix transcription factor that is oocyte-specific. Female Figa knockout mice were sterile and showed no postnatal sexual maturation and no primordial follicle forma-

tion.27 Additional genes may be involved in the maturation of ovarian follicles. Growth differentiation factor 9 (GDF9) is a member of the transforming growth factor beta (TGFb) family of secreted glycoproteins that is produced only by oocytes. Evidence in knockout mice shows a role for GDF9 in the maturation of ovarian follicles from the primordial follicle stage to the primary follicle stage.28 Independent of gonadal differentiation is the process of ductal and external genital development, processes that depend on the presence or absence of certain hormones. During the 6th week of gestation, the urorectal septum descends to intersect with the cloacal membrane and induces the breakdown of the membrane, dividing the cloaca into an anterior segment, the urogenital sinus, and a posterior cavity, the eventual rectum and anus. The caudal ends of the paired mu¨llerian ducts fuse in the midline and eventually become the mu¨llerian contribution to the vagina. The interaction of these terminal fused Mu¨llerian ducts with the urogenital sinus is necessary for the normal canalization of the vagina. The urogenital sinus becomes obliterated in females. The genital tubercle that began its development in the 4th week of gestation enlarges to form the clitoris. The urethral folds remain largely open to form the labia majora, with the anterior end fusing to become the mons pubis and the posterior end fusing to become the posterior labial commissure.8 In the absence of testosterone and AMH (anti-Mu¨llerian hormone), the external genitalia are female. The Mu¨llerian ducts

Female Genital System

form the uterus and the fallopian tubes, and the Wolffian ducts regress. In mouse studies, Wnt4 is expressed in the coelomic epithelium that invaginates to form the mu¨llerian duct. In female knockout mice, the mu¨llerian duct-derived internal reproductive structures do not develop.29 Wnt4 is expressed in both males and females, and its expression is required for both the development of the kidneys and the development of the mu¨llerian structures. The expression of Wnt4 is then down-regulated in the male and persists in the female. Duplications of WNT-4 in humans have been associated with dosage-sensitive XY sex reversal.30 Male mice that lack the signaling molecule Wnt7a fail to undergo regression of the mu¨llerian duct structures, suggesting that WNT7A expression is necessary for the development of the receptor for AMH. Females with deficient expression of Wnt7a have incomplete development of their Mu¨llerian duct structures. Thus, Wnt7a appears to be important not only in the regression of the Mu¨llerian structures in males, but also in the differentiation of the Mu¨llerian duct structures in females.31 The expression of hox transcription factors HOX9, 10, 11, and 12 occurs along the length of the developing Mu¨llerian duct and is continued in the adult structures of the Fallopian tubes (HOXA 9), uterus (HOXA 10), cervix (HOXA 11), and upper vagina (HOXA 13).4 The interaction of Wnt7a and the expression of the hox transcription factors is demonstrated by the teratogenic effects of DES (diethylstilbestrol), which causes uterine abnormalities in fetal females. DES suppresses Wnt7a expression32 and alters the expression of HOX9 and 10.33 Although DES is a synthetic estrogen, the effects of disrupting Wnt7a cannot be explained by a disruption of hormonal regulation as the ovaries develop normally.6 The interaction of these genetic factors and their role in producing errors in Mu¨llerian fusion and the development of the female external genitalia is largely unknown. References 1. Tsang TE, Shawlot W, Kinder SJ, et al.: Lim1 activity is required for intermediate mesoderm differentiation in the mouse embryo. Dev Biol 223:77, 2000. 2. Birk OS, Casiano DE, Wassif CA, et al.: The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature 403:909, 2000. 3. Miyamoto N, Yoshida M, Kuratani S, et al.: Defects of urogenital development in mice lacking Emx2. Development 124:1653, 1997. 4. Taylor HS, Vanden Heuvel GB, Igarashi P: A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod 57:1338, 1997. 5. Parr BA, McMahon AP: Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7. Nature 395:707, 1998. 6. MacLaughlin DT, Teixeira J, Donahoe PK: Perspective: reproductive tract development—new discoveries and future directions. Endocrinology 142:2167, 2001. 7. Gustafson ML, Donahoe PK: Male sex determination: current concepts of male sexual differentiation. Ann Rev Med 45:505, 1994. 8. Pinsky L, Erickson RP, Schimke RN: The embryology of normal gonadal and genital development. In: Genetic Disorders of Human Sexual Development. Oxford University Press, New York, 1999. 9. Mittwoch U: Genetics of sex determination: exceptions that prove the rule. Mol Genet Metab 71:405, 2000. 10. Scott WJ, Holson JF: Weight differences in rat embryos prior to sexual differentiation. J Embryol Exp Morphol 40:259, 1977. 11. Pederson FJF: Ultrasound evidence of sexual difference in fetal size in first trimester. Br Med J 281:1253, 1980. 12. Ray PF, Conoghan J, Winston RML, et al.: Increased number of cells and metabolic activity in human preimplantation embryos following in vitro fertilization. J Reprod Fertil 104:165, 1995.

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13. Schmahl J, Eicher EM, Washburn LL, et al.: Sry induces cell proliferation in the mouse gonad. Development 127:65, 2000. 14. Van Niekirk WA, Retief A: The gonads of human true hermaphrodites. Hum Genet 58:117, 1981. 15. Mittwoch U, Kirk D: Superior growth of the right gonad in human fetuses. Nature 257:791, 1975. 16. Mittwoch U: Differential growth of human fetal glands with respect to sex and body side. Ann Hum Genet 42:133, 1976. 17. Bakke M, Zhao L, Hanley NA, et al.: SF-1: a critical mediator of steroidogenesis. Mol Cell Endocrin 171:5, 2001. 18. Bitgood MJ, Shen L, McMahon AP: Sertoli cell signaling by desert hedgehog regulates the male germline. Curr Biol 6:298, 1996. 19. Yu R, Ito T, Sauders S, et al.: Role of Ahch in gonadal development and gametogenesis. Nat Genet 20:353, 1998. 20. Goodfellow PN, Camerino G: DAX-1, an ‘‘antitestis’’ gene. Cell Mol Life Sci 857, 1999. 21. Parker KL, Schimmer BP: Genes essential for early events in gonadal development. Ann Med 34:171, 2002. 22. Scharnhost V, van der Erb AJ, Jochemsen AG: WT1 proteins: functions in growth and differentiation. Gene 273:141, 2001. 23. Crisponi L, Deiana M, Loi A, et al.: The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159, 2001. 24. Cocquet J, Pailhoux E, Jaubert F, et al.: Evolution and expression of FOXL2. J Med Genet 39:916, 2002. 25. Pannetier M, Servei N, Cocquet J, et al.: Expression studies of the PISregulated genes suggest different mechanisms of sex-determination within mammals. Cytogenet Genome Res 101:199, 2003. 26. Cocquet J, De Baere E, Gareil M, et al.: Structure, evolution and expression of the FOXL2 transcription unit. Cytogenet Genome Res 101:206, 2003. 27. Soyal SM, Amich A, Dean J: FIGa, a germ cell-specific transcription factor required for ovarian follicle formation. Development 127:4645, 2000. 28. Dong J, Albertinie DF, Nishimori K, et al.: Growth differentiation factor9 is required during early ovarian folliculogenesis. Nature 383:531, 1996. 29. Vanio S, Heikkila M, Kispert A, et al.: Female development in mammals is regulated by Wnt-4 signaling. Nature 397:405, 1999. 30. Jordan BK, Mohammed M, Ching ST, et al.: Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet 68:1102, 2001. 31. Parr BA, McMahon AP: Sexually dimorphic development of mammalian reproductive tract requires Wnt-7a. Nature 395:707, 1998. 32. Miller C, Degenhardt K, Sassoon DA: Fetal exposure to DES results in deregulation of Wnt-7a during uterine morphogenesis. Nat Genet 20:228, 1998. 33. Block K, Kardana A, Igarashi P, et al.: In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing Mu¨llerian system. FASEB J 14:1101, 2000.

30.1 Ovarian Dysgenesis Definition

Ovarian dysgenesis consists of streak gonads that are devoid of germ cells. Streak gonads occur in individuals with varying chromosomal complements, including 45,X; 46,XX; 46,XY; various mosaics; and structural aberrations of the X chromosome. The discussion here is limited to streak gonads that are ovarian in origin. Individuals with streak gonads that are entirely testicular in origin are not included in this discussion. Diagnosis

Streak ovaries are located in the position ordinarily occupied by the ovary. In adults with ovarian dysgenesis, the normal gonad

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is usually replaced by a white fibrous streak 2 to 3 cm long and about 0.5 cm wide (Fig. 30-2). This streak gonad is characterized histologically by interlacing waves of dense fibrous stroma, devoid of oocytes but otherwise indistinguishable from normal ovarian stroma. Individuals with ovarian dysgenesis are phenotypic females. Those with 46,XY do not produce testosterone or AMH (antiMu¨llerian hormone); therefore, they develop both female internal and external genitalia. Secondary sexual development usually does not occur in patients with ovarian dysgenesis. Pubic and axillary hair fail to develop in normal quantity. Although well-differentiated, the external genitalia, the vagina, and the Mu¨llerian derivatives (uterus) remain small. Estrogen and androgen levels are decreased and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are increased. During infancy, gonadotropins are also elevated, but during late childhood (prepubertal) they are not necessarily elevated. Turner syndrome is used to describe females with streak ovaries and a 45,X karyotype or a variant that includes 45,X. The most commonly associated defects are short stature, primary amenorrhea, and lack of development of secondary sexual characteristics. Facial features commonly include micrognathia, a low posterior hairline, webbed neck and low-set or posteriorly rotated ears (Fig. 30-3).1 Congenital heart defects are common, found in about 75% of fetuses and 25–50% of infants with Turner syndrome. Left-sided outflow tract anomalies are the most common. Bicuspid aortic valve is seen in up to 50%, coarctation of the aorta in 30%, and aortic stenosis in another 10%. Other cardiac malformations are also seen but are much less common.2 Structural anomalies of the kidneys are found in 60% (i.e., horseshoe kidney) and are often without clinical significance. The nipples are widely spaced, giving a shieldlike chest. Lymphedema is common, often presenting in utero as a cystic hygroma or in more severe cases as fetal hydrops (Fig. 30-4). In infancy there is often residual lymphedema of the dorsa of the hands and feet, causing nail abnormalities (Fig. 30-5). The aberrations in the lymphatic flow are proposed to be the cause of many of the skeletal, cardiac, and renal defects.3 About 65% of females with Turner syndrome are 45,X, Fig. 30-2. Histologic appearance of a streak gonad from a 45,X individual showing fibrous stroma without oocytes. (From Simpson J: Disorders of Sexual Differentiation. Etiology and Clinical Delineation. Academic Press, New York, 1976.)

Fig. 30-3. Child with Turner syndrome. Note the low-set ears and webbed neck.

20% have structural abnormalities of X (i.e., ring X), and at least 20% are mosaic, including 45,X/46,XX and 45,X/46,XY.1 Short stature affects 95–100% of individuals with Turner syndrome. Individuals with Turner syndrome have low birth weights and total body lengths. The growth rate is often normal in infancy and early childhood with a retarded bone age. After the age of 3 years, the growth rate slows. In untreated adults with Turner syndrome, the average height is 140 cm ± 13 cm.2 Recent studies have identified SHOX (short stature homeobox-containing gene) as the candidate gene for the short stature seen in Turner syndrome. SHOX is located within the pseudoautosomal region of the X chromosome between Xp22.3.3,4 Most individuals with monosomy X have normal intelligence. Performance IQ is lower than verbal IQ, 45,X individuals having primarily a visuospatial learning disability.5 The fact that most girls with Turner syndrome are short and sexually immature may aggravate any perception of diminished intelligence. In contrast, however, are individuals with Turner syndrome who have a structural abnormality of their X chromosome, particularly a ring X. These individuals have a high risk of mental retardation.6 Fig. 30-4. Eighteen-week-old fetus with Turner syndrome. Note the large cystic hygroma and generalized edema.

Female Genital System

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Fig. 30-5. Infant with Turner syndrome. Note the dorsal edema of the hands and feet.

Etiology and Distribution

Prognosis, Treatment, and Prevention

Turner syndrome is the only viable monosomy and has an incidence in liveborn infants of one in 2000 to 5000. It is estimated, however, that greater than 99% of fetuses affected with Turner syndrome do not survive to term, giving an incidence in fetal life of about 3%.2 There is no evidence of variation in ethnic distribution in 45,X abortuses or liveborns. In humans, 70% of liveborn 45,X individuals have lost a paternal sex chromosome. This helps explain why mean maternal age is not increased in 45,X abortuses or liveborns. Although Turner syndrome is referred to as exhibiting gonadal dysgenesis, the development of the ovary is normal until at least 14 to 18 weeks gestation. In normal female development, oocytes number about 7 million by 20 weeks gestation. After this there is programmed apoptosis until the number of oocytes at the onset of puberty is about 300,000. In individuals with Turner syndrome, this apoptosis is accelerated and results in ovarian failure either prenatally or in the first few months to years of postnatal life. The cause for this premature ovarian failure (POF) is unclear, although autosomal genes responsible for POF are well-established (i.e., FSHR on chromosome 2 and FOXL2 on chromosome 3 and possibly WNT4 on chromosome 1).7–9 X-linked premature ovarian failure is also genetically heterogeneous, but seems to involve genes located on the long arm of the X chromosome in the areas Xq26-28 and Xq22.10 Whether these genes are also involved in or responsible for the POF seen in Turner syndrome remains to be seen. POF has been noted among women with premutations of the fragile X gene, FMR1 but not among women with full mutations.11 Still other genes necessary for ovarian function may lie in areas of the X chromosome that escapes inactivation and therefore may cause POF through a loss of function. Occasionally the process of ovarian failure or oocyte loss is slowed or is incomplete and 2–16% of individuals with nonmosaic 45,X menstruate spontaneously.2 There have been reports of only a few spontaneous pregnancies in individuals with apparently nonmosaic 45,X karyotypes, although it has been described more often in individuals with a mosaic Turner karyotype.12 Pregnancy through assisted reproductive technologies, such as egg donation and in vitro implantation, have been accomplished in others.13

The evaluation and treatment of individuals with Turner syndrome including those with variant or mosaic karyotypes has been outlined in the Health Supervision Guidelines established by the Committee on Genetics of the American Academy of Pediatrics and published in the journal of the Academy.13 These guidelines are reviewed and updated periodically and provide the primary care practitioner with valuable expertise and advice. They will be reviewed briefly here. Chromosomal studies are indicated to exclude the presence of a Y chromosome. In the presence of Y chromosome mosaicism, there is an increased risk for developing gonadoblastoma or dysgerminoma in the dysgenetic gonads. This risk is estimated to be 7–10% and prophylactic gonadectomy is recommended. In addition to endocrinologic evaluation and treatment for development of secondary sexual characteristics, ongoing medical care involves the monitoring of the other somatic findings in Turner syndrome. Those somatic findings include short stature, cardiovascular abnormalities, hypertension, hearing loss, strabismus, craniofacial anomalies, obesity, glucose intolerance, urinary tract abnormalities, thyroid dysfunction and other autoimmune disorders, orthopedic problems, and the need for psychosocial support. The guidelines include recommendations for testing and interventions needed from the prenatal period through adulthood. Growth hormone therapy is widely used in Turner syndrome. The success of growth hormone treatment depends upon the age of onset of treatment, dosage, frequency of administration, patient weight, and familial growth parameters. Karyotype is not predictive of outcome.2 References (Ovarian Dysgenesis) 1. Pinsky L, Erickson RP, Schimke RN: X chromosome aberrations. In: Genetic Disorders of Human Sexual Development. Oxford University Press, New York, 1999. 2. Karnis MF, Reindollar RH: Turner syndrome in adolescence. Obstet Gynecol Clin North Am 30:303, 2003. 3. Ogata T, Matsuo N: Turner syndrome and female sex chromosome aberrations: deduction of the principle factors involved in the development of clinical features. Hum Genet 95:607, 1995.

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4. Ellison JW, Wardak Z, Young MF, et al.: SHOX, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 6:1341, 1997. 5. Bender BG, Linden MG, Robinson A: Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities. Am J Med Genet 48:169, 1993. 6. Van Dyke DL, Wiktor A, Palmer CG, et al.: Ullrich-Turner syndrome with a small ring X chromosome and presence of mental retardation. Am J Med Genet 43:996, 1992. 7. Aittomaki K, Lucena M, Pakarinen P, et al.: Mutation in the folliclestimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959, 1995. 8. Crisponi L, Deiana M, Loi A, et al.: The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159, 2001. 9. Vanio S, Heikkila M, Kispert A, et al.: Female development in mammals is regulated by Wnt-4 signaling. Nature 397:405, 1999. 10. Marozzi A, Manfredini E, Tibiletti MG, et al.: Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure. Hum Genet 107:304, 2000. 11. Sherman SL: Premature ovarian failure in the fragile X syndrome. Am J Med Genet 97:189, 2000. 12. Tarani L, Lampariello S, Raguso G, et al.: Pregnancy in patients with Turner’s syndrome: six new cases and review of the literature. Gynecol Endocrinol 12:83, 1998. 13. Hovatta O: Pregnancies in women with Turner’s syndrome. Ann Med 31:106, 1999.

30.2 Mixed Gonadal Dysgenesis Definition

Mixed gonadal dysgenesis consists of a streak gonad (ovarian) on one side and a testis or dysgenetic gonad on the other. Those affected typically show some degree of virilization and may have some ambiguity of the external genitalia (Fig. 30-6). Mu¨llerian structures are usually present. The most common karyotype is mosaic 45,X/46,XY.

Fig. 30-6. Infant with mixed gonadal dysgenesis and a mosaic karyotype 45,X/46,XY. a. Ambiguous genitalia. b. Phallus. c. Vaginal opening. d. Genitogram, e. Postoperative appearance.

Diagnosis

The external genitalia of individuals with 45,X/46,XY is quite variable. Of those diagnosed postnatally, the majority have some degree of ambiguous genitalia. Some have physical stigmata of Turner syndrome, specifically short stature, webbed neck, and widely spaced nipples. The presence of ambiguous genitalia in an individual with a Turner phenotype should always prompt an investigation looking for a 46,XY cell line. Reviews of the phenotype in prenatally diagnosed cases show that the majority of prenatally diagnosed cases have normal male external genitalia.1 In one review of 92 cases of prenatally diagnosed 45,X/46,XY, 95% had normal male external genitalia. Autopsy evaluations were performed on the gonadal tissue of a subset of these and 27% were found to have abnormal gonadal histology, including bilateral ovotestes. Therefore, even in cases in which the external genitalia are normal, there may be underlying risk for gonadoblastoma. The risk for development of other complications such as short stature, sexual dysfunction, and infertility is not known.2 The gonads include streak gonads of ovarian origin, dysgenetic testes, normal testes, and ovotestes. The external genitalia anomalies include frankly ambiguous genitalia, normal male or female genitalia, and genital abnormalities such as hypospadias and clitoromegaly. The risk for gonadoblastoma in 45,X/46,XY individuals diagnosed postnatally is estimated at 15–20%.3 These tumors are sometimes calcified and often hormone producing. Secondary sexual development would not be expected in an individual with one streak ovary and one testis. Therefore, breast development or increased virilization should lead one to suspect an estrogenproducing tumor such as a gonadoblastoma or dysgerminoma. Etiology and Distribution

Mixed gonadal dysgenesis is a rare condition, with an incidence of 0.7 to 2.8 per 10,000 and apparently having no predilection to any given ethnic group. The phenotype of asymmetric or mixed gonadal

Female Genital System

dysgenesis is almost always associated with 45,X/46,XY mosaicism, ostensibly nonmosaic cases reflecting merely an inability to analyze appropriate tissue. While it was thought previously that mixed gonadal dysgenesis was only found in individuals with 45,X/46,XY mosaicism who had ambiguous genitalia, prenatal studies have shown this to be a false assumption. The degree of mosaicism in the prenatal sample does not seem to be correlated to the degree of genital or gonadal abnormality.2 The etiology of the gonadoblastoma is thought to be the abnormal expression of genes at a locus on the Y chromosome known as the GBY locus or gonadoblastoma locus. The GBY locus has been mapped to a critical interval on the short arm and adjacent centromere region on the Y chromosome. There are five functional genes in the GBY critical region, one of which is the testis-specific protein Y-encoded gene or TSPY. The protein expression pattern of TSPY in gonadaoblastomas and in the spermatogonia, along with evidence of homology to a family of cyclin B-binding proteins, suggests that TSPY may be the most likely candidate gene.4 Additional syndromes associated with gonadal dysgenesis are listed in Table 30-1.5–16 Gonadal dysgenesis is often accompanied by ambiguous external genitalia (Section 30.4).

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References (Mixed Gonadal Dysgenesis)

Prognosis, Treatment, and Prevention

In cases of genital ambiguity, the same considerations should be made in mixed gonadal dysgenesis as in other cases of ambiguous genitalia. These considerations are outlined in the following section. Hormone replacement therapy is required at the expected age of puberty. The uterus should be left for possible donor in vitro fertilization or embryo transfer. Because neoplasia may arise as early as the first 2 decades of life, the gonads of 45,X /46,XY individuals with female external genitalia should be extirpated regardless of the patient’s age. Because of this risk of neoplasia, one should distinguish 45,X /46,XY gonadal dysgenesis from forms of gonadal dysgenesis lacking a Y chromosome. As mentioned above, in the cases of prenatally diagnosed 45,X/46,XY with normal male genitalia, the guidelines for observation and treatment are less clear. Some recommend a gonadal biopsy, while others recommend only a close watch on sexual development.2 If somatic features of Turner syndrome exist, they should be managed as described in the previous section. The potential for renal, ventricular, and auditory problems necessitates periodic clinical surveillance.

1. Pinsky L, Erickson RP, Schimke RN: X chromosome aberrations. In: Genetic Disorders of Human Sexual Development. Oxford University Press, New York, 1999. 2. Chang HJ, Clark RD, Bachman H: The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Hum Genet 46:156, 1990. 3. Simpson JL: Disorders of Sexual Differentiation. Etiology and Clinical Delineation. Academic Press, New York, 1976. 4. Lau WFC, Chou PM, Iezzoni JC, et al.: Expression of a candidate gene for the gonadoblastoma locus in gonadoblastoma and testicular seminoma. Cytogenet Cell Genet 91:160, 2000. 5. Nishi Y, Hamamoto K, Kajiyama M, et al.: The Perrault syndrome: clinical report and review. Am J Med Genet 31:623, 1988. 6. Moreira-Filho CA, Toledo SPA, Bagnolli VR, et al.: H-Y antigen in Swyer syndrome and the genetics of XY gonadal dysgenesis. Hum Genet 53:51, 1979. 7. Arn P, Chen H, Tuck-Muller CM, et al.: SRVX, a sex reversing locus in Xp21.2-p22.11. Hum Genet 93:389, 1994. 8. Umehara F, Yamaguchi N, Kodama D, et al.: Case report: polyneuropathy with minifascicle formation in a patient with 46XY mixed gonadal dysgenesis. Acta Neuropathol 98:309, 1999. 9. Sugie K, Futamura N, Suzumura A, et al.: Hereditary motor and sensory neuropathy with minifascicle formation in a patient with 46XY pure gonadal dysgenesis: a new clinical entity. Ann Neurol 51:385, 2002. 10. Umehara F, Tate G, Itoh K, et al.: A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am J Hum Genet 67:1302, 2000. 11. Klamt B, Koziell A, Poulat F, et al.: Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 þ/KTS splice isoforms. Hum Mol Genet 7:709, 1998. 12. Pelletier J, Bruening W, Kashtan CE, et al.: Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437, 1991. 13. Poulat F, Morin D, Konig A, et al.: Distinct molecular origins for Denys-Drash and Frasier syndromes. Hum Genet 91:285, 1993. 14. McDonald MT, Flejter W, Sheldon S, et al.: XY sex reversal and gonadal dysgenesis due to 9p24 monosomy. Am J Med Genet 73:321, 1997. 15. Muroya K, Okuyama T, Goishi K, et al.: Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases. J Clin Endocrinol Metab 85:3094, 2000. 16. Veitia RA, Nunes M, Quintana-Murci L, et al.: Swyer syndrome and 46,XY partial gonadal dysgenesis associated with 9p deletions in the absence of monosomy-9p syndrome (Letter). Am J Hum Genet 63:901, 1998.

Table 30-1. Syndromes with gonadal dysgenesis (sex chromosome aneuploidy excluded) Syndrome

Additional Prominent Features

OMIM Number Gene/Locus

Perrault5

Deafness

233400

Swyer

XY female type

306100 SRVX, Xp22.11-p21.2

Gonadal dysgenesis with minifascicular neuropathy8–10

Minifascicular neuropathy

607080 DHH, 12q13.1

Frasier, Denys-Drash11–13

Wilms tumor, male pseudohermaphroditism, gonadal dysgensis, chronic renal failure, nephrotic syndrome, gonadoblastoma, focal and segmental glomerulosclerosis, primary amenorrhea, diaphragmatic hernia

136680, 194080 WT1, 11p13

Autosomal sex reversal14–16

No additional somatic findings

154230 DMRT1, SRA2, TDFA, 9p24

6,7

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30.3 Hermaphroditism Definition

Hermaphroditism is a condition in which both ovarian and testicular tissues are present. In individuals with true hermaphroditism, 60% have a 46,XX chromosomal complement, 33% are mosaic with a second cell line containing a Y chromosome complement, and the remaining 7% are 46,XY.1 Diagnosis

Gonadal tissue may be located in the ovarian, inguinal, or labioscrotal region. A testis or an ovotestis is more likely to be present in the right side than on the left. The greater the proportion is of testicular tissue in an ovotestis, the greater is the likelihood of gonadal descent. In 80% of ovotestes, testicular and ovarian components exist immediately adjacent to each other in an end-to-end fashion.2,3 Thus, an ovotestis usually can be detected by inspection, or possibly by palpation, because testicular tissue is softer and darker than ovarian tissue. Spermatozoa are rarely present; however, apparently normal oocytes often are present, even in ovotestes. Usually a uterus is present, albeit often bicornuate or unicornuate. Absence of a uterine horn usually indicates an ipsilateral testis or ovotestis. The fimbriated end of the Fallopian tube may be occluded ipsilateral to an ovotestis, and squamous metaplasia of the endocervix may occur. Most true hermaphrodites with a uterus will menstruate. In fact, 46,XX true hermaphrodites have become pregnant, usually but not always after removal of testicular tissue.3 About two-thirds of true hermaphrodites are raised as males, although their external genitalia may be frankly ambiguous or predominantly female (Fig. 30-7). Paradoxically, breast development usually occurs at puberty despite male external genitalia; virilization usually does not. Etiology and Distribution

The etiology of true hermaphroditism is heterogeneous. 46,XX/ 46,XY chimerism presents in a variety of different phenotypes, including ambiguous genitalia, hypospadias, gynecomastia, inguinal hernia, and rarely a normal female or male phenotype.4 It is also responsible for about 13% of the cases of true hermaphroditism.5,6 46,XX true hermaphrodites show an unusual racial distribution, the frequency being relatively higher in South African Bantu and perhaps other African blacks.7 A few 46,XX true hermaphrodites may result from undetected chimerism; however, undetected chimerism cannot readily explain all 46,XX true hermaphrodites. Recent molecular studies have shed some light on the etiology of 46,XX true hermaphrodites. Immunohistochemistry for the SRY protein and PCR for the SRY gene fragments has demonstrated that SRY activity is present in the testicular tissue and ovotestes of the majority of individuals with 46,XX true hermaphroditism tested. These same tests failed to demonstrate the presence of SRY gene segments or SRY protein in the leukocytes. From the results of these studies, it appears that confined mosaicism for SRY segments may be a common etiology of 46,XX true hermaphroditism.8,9 In addition to sex chromosome abnormalities, partial duplication of chromosome 22 has been reported as a cause of true hermaphroditism. In this case, neither testicular tissue nor leukocytes had SRY expression or protein identified.10

Fig. 30-7. Photographs and diagrams illustrating a patient with true hermaphroditism. This 21-year-old Bantu had abnormal external genitalia. Four centimeters inferior to the tip of the phallus was an opening through which urine passed. Two rudimentary labia minora are fused below the phallus. At laparotomy, a left ovary (vertical hatching in the diagram) and a right ovotestis (testicular portion stippled) were detected. The dark portion of the ovotestis contained testicular tissue; the lighter portion contained ovarian tissue. The right Fallopian tube was abnormal. (From Van Niekerk WA: True Hermaphroditism. Harper & Row, New York, 1974.)

Prognosis, Prevention, and Treatment

The diagnosis of true hermaphroditism is usually only made after excluding the more common forms of male and female pseudohermaphroditism. Ambiguous genitalia are present in 90% of cases. In past studies, the majority of true hermaphrodites were reared as males (65–75%).2 This may have been due at least in part to cultural preferences. Some more recent studies have shown a reversal of this trend, indicating a female sex-of-rearing preference.11 Despite the ‘‘dysgenetic’’ nature of the gonads in true hermaphrodites and a Y chromosome sometimes being present, gonadoblastomas have been reported far less frequently than in XY gonadal dysgenesis.1 References (Hermaphroditism) 1. Pinsky L, Erickson RP, Schimke RN: X chromosome aberrations. In: Genetic Disorders of Human Sexual Development. Oxford University Press, New York, 1999. 2. Van Niekerk WA, Retief AE: The gonads of human true hermaphrodites. Hum Genet 58:117, 1981.

Female Genital System 3. Tegenkamp TR, Brazzell JW, Tegenkamp I, et al.: Pregnancy without benefit of reconstructive surgery in a bisexually active true hermaphrodite. Am J Obstet Gynecol 135:427, 1979. 4. Freiberg AS, Blumberg B, Lawee H, et al.: XX/XY chimerism encountered during prenatal diagnosis. Prenat Diagn 8:423, 1988. 5. Danon M, Friedman SC: Ambiguous genitalia, micropenis, hypospadias, and cryptorchidism. In: Pediatric Endocrinology: A Clinical Guide, ed 3. Lifshitz F, ed. New York: Marcel Dekker, 1996, p 281. 6. Amor D, Delatycki MB, Susman M, et al.: 46,XX/46,XY at amniocentesis in a fetus with true hermaphroditism. J Med Genet 36:866, 1999. 7. Ramsey M, Berstein R, Zwane E, et al.: XX true hermaphroditism in southern African blacks: an enigma of primary sexual differentiation. Am J Hum Genet 43:4, 1988. 8. Jiminez AL, Kofman-Alfaro S, Berumen J, et al.: Partially deleted SRY gene confined to testicular tissue in a 46,XX true hermaphrodite without SRY in leukocytic DNA. Am J Med Genet 93:417, 2000. 9. Ortenberg J, Oddoux C, Craver R, et al.: SRY gene expression in the ovotestes of true hermaphrodites. J Urol 167:1828, 2002. 10. Aleck KA, Argueso L, Stone J, et al.: True hermaphroditism with partial duplication of chromosome 22 and without SRY. Am J Med Genet 85:2, 1999. 11. Damiani D, Fellous M, McElreavey K, et al.: True hermaphroditism: clinical aspects and molecular studies in 16 cases. Eur J Endocrinol 136:201, 1997.

30.4 Ambiguous Genitalia Definition

Ambiguous genitalia are external genitalia that display characteristics of both male and female sexual development. Chromosomal aneuploidy that leads to external genitalia that are ambiguous are discussed in the earlier sections of this chapter and will not be discussed again here. Diagnosis

In some cases the external genitalia are ambiguous to the point that the sex of the infant is considered indeterminate. In most cases, however, the infant is clearly of a particular sex but has some features that are consistent with the other sex. Features in a female infant that would suggest intersexuality include clitoral hypertrophy, a foreshortened vulva with a single opening, and an inguinal hernia containing a gonad. In apparently male infants the absence of palpable testes bilaterally in a term infant, hypospadias with separation of the scrotal sacs, or undescended tests with hypospadias should prompt an evaluation for intersexuality.1 When ambiguous genitalia are detected in the newborn period, the evaluation is urgent from both the medical and social perspective. All health care personnel involved in such cases need to be sensitive to the language and tone used when discussing the needed evaluations. The infant should be referred to as ‘‘your child’’ or ‘‘your baby’’ rather than using gender-specific pronouns such as ‘‘he’’ or ‘‘she’’ or object pronouns such as ‘‘it.’’ It is helpful to be very specific about the particular differences that are found and, when possible, to examine the infant in the presence of the parents. Stressing the ambiguity of the early developmental stages in all fetuses can also be helpful. Assurances should be made that their child can have surgical correction and/or hormonal treatments that will enable their child to develop as a normal boy or girl. The diagnosis of ambiguous genitalia should begin with a careful family history and maternal and pregnancy history. The

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family history should include any history of relatives in whom there were problems in sex assignment or problems with pubertal development or fertility. In cases in which the child in question has nongenital abnormalities, it is helpful to know whether these occur in any other family members.2 A maternal history should include any exposure to medications, drugs, or other toxins that might be teratogenic to the developing fetus. DES (diethylstilbestrol) is a known teratogen that primarily affects the internal genital structures in female fetuses but can also have an effect on the developing male fetus, causing hypospadias and cryptorchidism that might contribute to ambiguous-appearing genitalia. Exposure to certain anticonvulsants and to alcohol can also cause changes in the external genitalia of male fetuses that might contribute to an appearance of ambiguous genitalia.2 Rarely, maternal ovarian or adrenal androgen-secreting tumors may be present and cause virilization of female fetuses due to the increased androgen levels. Aromatase deficiency is a rare but well-recognized cause of increased androgen levels and virilization of both the mother and the female fetus. Therefore, the mother may need to be examined for evidence of virilization or hirsutism. The detection of associated anomalies is an important goal of the general examination of the newborn. An overall assessment for alertness, irritability, state of hydration, and blood pressure are in order. A history of vomiting, diarrhea, and vaginal discharge or bleeding is significant. Evaluation of the genitalia is then appropriate. A clitoris will generally have paramedian raphes, whereas a penis has a single raphe. A clitoris is often not fully enveloped by the prepuce, the glans being either fully visible or the prepuce forming a hoodlike cover. Lack of midline fusion of a penis may closely mimic a clitoris. The size of the phallus can be determined rolling the corporeal bodies between the fingers to appreciate their true girth and length.1 In full-term infants, the stretched penile length should measure at least 2 cm.3 The urethral meatus is examined for position and relationship to the other openings to determine the extent of closure of the urogenital sinus. The labioscrotal folds are examined for fullness, symmetry, rugation and pigmentation.1 Masses in the genital folds (labia or scrotum) may represent testes, ovotestes, or a uterus. Since ovaries are almost never found in the labioscrotal folds, the presence of a palpable gonad in this area rules out simple virilization of an otherwise normal female. The evaluation of the internal structures is usually postponed until the initial laboratory evaluations are completed. However, an initial evaluation using two catheters is sometimes used in advance of any radiologic studies. The first is placed in the bladder, which is confirmed by urinary return. The second is then introduced in the urogenital sinus. Prompt return of mucus constitutes good evidence of cervical mucus production and therefore of the presence of a uterus. Pelvic ultrasonography and a genitogram can then be used to further delineate the internal structures. Initial laboratory evaluation should include electrolyte measurements as well as a panel of biochemical measurements to identify defects in the steroidogenesis pathway. The most common cause of ambiguous genitalia in a newborn is congenital adrenal hyperplasia (CAH). In these infants, the masculinization is symmetrical and the gonads are nonpalpable (Fig. 30-8). In the most common form of CAH, 21-hydroxylase deficiency, the levels of 17hydroxyprogesterone and androstenedione are greatly elevated. A panel that includes 17-hydroxyprogesterone, androstenedione,

1288

Urogenital System Organs

Fig. 30-8. Ambiguous genitalia in a 46,XX female with virilizing adrenal hyperplasia. The clitoris is enlarged, resembling a short penis with hypospadias, and the labia are regated, resembling the scrotum.

DHEA, cortisol, and ketosteroids is needed to identify the less common forms of CAH.1 Because chromosomal abnormalities, such as sex chromosomal aneuploidy, are also a common cause, a karyotype should be done as part of the initial evaluation as well. In apparently XX individuals with otherwise unexplained ambiguous genitalia, chromosome analysis should be supplemented with fluorescence in situ hybridization or other molecular techniques to detect Y chromosome material. The chromosomal causes of ambiguous genitalia are discussed in the previous section. The degree of genital ambiguity can vary greatly in different individuals, even among those with the same underlying causation. Sometimes, isolated clitoromegaly is the only abnormality. In other cases, it is almost impossible to determine the phenotypic sex of the individual.

The external genitalia evolve in males and females from homologous anlage. The genital tubercle can give rise to the clitoris or to

the penis. The genital folds can give rise to the labia majora and minora or form the scrotum. The full development of the male phenotype requires the presence of androgenic stimulation, particularly in the form of testosterone and dihydrotestosterone. The development of these structures starts at about 10 weeks gestational age, and elevated androgens levels can modify the appearance of the external genitalia at any time in life. Fig. 30-9 represents a graphic summary of key events in the development of external genitalia. By far the most common cause of ambiguous genitalia is a defect in one of the adrenal steroid synthesis pathway enzymes (Fig. 30-10). Nearly every enzyme of the steroid synthesis pathway can give rise to ambiguous genitalia. Defects in steroid enzymes that lead to excess androgen levels will cause masculinization of the female external genitalia but go undetected in the 46,XY individual. In contrast, defects that interfere with normal production of androgens will lead to undermasculinization in a 46,XY individual, whereas it may go undetected phenotypically in a 46,XX subject.

Fig. 30-9. Schematic showing development of the female external genitalia at approximately 4, 6, 9, 11, and 12 weeks of development. Only after about week 9 are there significant differences between male and female genitalia. Lightly stippled labioscrotal swelling develops into

the labia majora, heavily stippled urogenital folds develop into the labia minora, and the dark genital tubercle forms the clitoris. (Adapted from Moore K: The Developing Human, ed 4. WB Saunders Company, Philadelphia, 1988.)

Etiology and Distribution

Female Genital System

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Fig. 30-10. Steroid biosynthesis pathway: The first column contains the pathway for mineralocorticoids (aldosterone), the second for glucocorticoids (cortisol), and the third for androgens (testosterone). The genes encoding the enzymes are indicated in parentheses. (Adapted from Speiser and White.4)

The most common etiology for masculinization of the female external genitalia is congenital adrenal hyperplasia secondary to a 21a-hydroxylase enzyme deficiency. The term classic 21-hydroxylase deficiency refers to a severe salt-wasting type with virilization of female infants and a simple virilizing form. There is also a mild, nonclassic form that may be asymptomatic or associated with signs of postnatal androgen excess.3 Classic 21-hydroxylase deficiency occurs in an estimated one in 16,000 births.4 The nonclassic form occurs in 1–2% of Jews of Eastern European descent, and less commonly (0.2%) in the general Caucasian population.5 In 21-hydroxylase deficiency, the progesterone pathway leading to the production of aldosterone is at least partially blocked and causes an overproduction of androgens and an underproduction of cortisol. Of the patients with the classical type of 21-hydroxylase deficiency, 75% are salt-wasting. That is the defect in the 21-hydroxylation of progesterone causing severely inadequate synthesis of aldosterone, and subsequent alterations in sodium homeostasis cause hypovolemia and hyperreninemia. These individuals can also have varying effects from the lack of cortisol, including poor cardiac function, poor vascular response to catecholamines, a decreased glomerular filtration rate, and increased secretion of antidiuretic hormone.4,7 An overall deficiency of catecholamines may occur as a result of the effect of decreased glucocorticoids on the developing adrenal medulla and can result in shock.8 Blocks in 11b-hydroxylase and 18-hydroxylase activity are less common causes of masculinization.9,10 A defect in androgen synthesis in 46,XY subjects can cause varying degrees of genital ambiguity and must always be considered in the differential diagnosis. Most commonly, 17a-hydroxylase/17,20-lyase deficiency is associated with normal female external genitalia despite a 46,XY karyotype.11 A deficiency of 3b-ol-dehydrogenase can lead to undermasculinization with genital ambiguity at birth.12 Once testosterone is produced, it is metabolized into a more active compound, dihydrotestosterone, through the action of the

enzyme 5a-reductase. Deficiency of this enzyme may obviously lead to ambiguous genitalia.13 Other defects in the testosterone pathway may lead to undermasculinization of the male fetus and are described in the chapter on Male Genitalia (Chapter 29). The next large group of disorders involve chromosomal or gene disorders involving gonadal differentiation. These have been described in the preceding section on mixed gonadal dysgenesis and will not be described again here. Multiple anomaly syndromes associated with ambiguous genitalia are much less frequent in occurrence than are steroid enzyme deficiencies but clearly deserve consideration. The most common of these are listed in Table 30-2.13–29 Because so much attention is usually devoted to endocrine causes in individuals presenting with ambiguous genitalia, a thorough physical examination must be performed to exclude the presence of dysmorphic features suggestive of a syndrome. Disorders of cloacal development have also been associated with ambiguous genitalia.30 Such patients present several concurrent developmental defects. Escobar et al.31 have described a urorectal septum malformation sequence that includes ambiguous genitalia, lack of perineal openings, mu¨llerian and urinary tract anomalies, normal 46,XX karyotype, and normal adrenal function. Belis et al.32 have reported a case of ambiguous genitalia associated with urethral duplication. There are few data on the overall incidence of ambiguous genitalia. A generally accepted figure places the incidence in liveborns at 1.2 per 10,000.33 A study from South America suggests that it may be an isolated finding in about one per 20,000 pregnancies and, overall, may occur in one per 6900 of total births.34 There are significant ethnic variations in some of these disorders, particularly congenital adrenal hyperplasia.5,6 Prognosis, Treatment, and Prevention

Management of infants with ambiguous genitalia should involve a multidisciplinary team that includes professionals in genetics,

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Urogenital System Organs Table 30-2. Syndromes associated with ambiguous genitalia OMIM Number Gene/Locus

Syndrome

Additional Prominent Features

Ablepharon-macrostomia13

Absent eyelids, eyebrows, eyelashes, and external ears; fusion defects of the mouth; absent or rudimentary nipples; parchment skin; expressive language delays

200110

Asplenia-cardiovascular anomalies-caudal deficiency14

Hypoplasia/aplasia of spleen, complex cardiac malformations, abnormal lung lobulation, anomalous position and development of abdominal organs, agenesis of the corpus callosum, imperforate anus, contractures of the lower limbs

208530

Beemer lethal malformation15

Hydrocephalus, dense bones, cardiac malformation, bulbous nose, broad nasal bridge

209970

Fraser16,17

Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactyly

219000 FRAS1, 4q21

Frasier, Denys-Drash18–20

Wilms tumor, male pseudohermaphroditism, gonadal dysgensis, chronic renal failure, nephrotic syndrome, gonadoblastoma, focal and segmental glomerulosclerosis, primary amenorrhea, diaphragmatic hernia

136680, 184080 WT1, 11p13

SCARF21

Skeletal abnormalities, cutis laxa, craniosynostosis, ambiguous genitalia, psychomotor retardation, facial abnormalities

312830

Short rib-polydactyly, Majewski type22,23

Short stature; short limbs; cleft lip and palate; ear anomalies; limb anomalies, including pre- and postaxial polydactyly; narrow thorax; short horizontal ribs; high clavicles

263520

Smith-Lemli-Opitz24,25

Microcephaly, mental retardation, hypotonia, second to third syndactyly of the toes, abnormal facies

270400 DHCR7, SLOS, 11q12-13

Smith-Lemli-Opitz type 2 (Rutledge)26

Joint contractures, cerebellar hypoplasia, renal hypoplasia, urologic anomalies, tongue cysts, shortness of limbs, eye abnormalities, heart defects, gallbladder agenesis, ear malformations

268670 DHCR7, SLOS, 11q12-q13

VATER association

Vertebral, anal, tracheoesophageal, and renal defects; cardiac, ear, and genital defects can also be seen

192350

WAGR27

Wilms tumor, aniridia, genitourinary malformations, retardation of growth and development; microcephaly; aniridia; nystagmus; ptosis; blindness; gonadoblastoma

194072 WT1, 11p13

XLAG (X-linked lissencephaly with ambiguous genitalia)28,29

Lissencephaly, microcephaly, absent corpus callosum, neonatal-onset seizures, hypothalamic dysfunction, prominent forehead, micrognathia

300215 ARX, Xp22.13

urology, and endocrinology. Additional professionals skilled in counseling families should be available to assist the family in handling the social and psychological ramifications. Once the infant is stable, deciding the sex of rearing is of primary importance. This decision is based on a number of factors, including fertility potential, capacity for normal sexual function, endocrine function, the risk for malignant change, and testosterone imprinting.1 The relative impact of each of these factors depends upon the etiology of the ambiguous genitalia. The following discussion will cover only the most common cause, that is, CAH. In classical CAH, the fertility potential should be normal, although there may be a higher risk for oligomenorrhea or amenorrhea in affected females.4 As surgical techniques have improved, the capacity for normal sexual function has improved and many women with the classic form of CAH have successfully completed pregnancies. It is estimated that about 80% of women with the simple virilizing form and 60% of women with the severe

salt-wasting form are fertile.35 With respect to testosterone imprinting, studies have shown that girls with CAH engage in more typically malelike behaviors than their unaffected peers.36 Deciding on the timing of surgical procedures is somewhat controversial. The generally accepted view is that the initial surgery to reduce the clitoral size and externalize the vagina should be done in infancy. Further vaginal reconstruction may wait until adolescence. However, newer surgical techniques have combined these procedures into one surgery. The long-term outcome of the combined methods is still not known.1,4 Prenatal diagnosis and treatment is currently available for CAH. Prenatal genetic counseling of couples at risk is advised so that the risks and benefits of the prenatal treatment can be considered. Maternally administered dexamethasone will ameliorate the masculinization of affected female fetuses.37 There are ethical concerns about unnecessarily exposing unaffected fetuses to steroids, to prevent the virilization of an affected female fetus.

Female Genital System

Therefore, it is recommended that the treatment only be used until the sex and genotype of the infant in question can be determined.4 Newborn screening for CAH is available in many places. The protocols vary from one center to the next. In general, the first measurement is that of 17-hydroxyprogesterone in a neonatal blood spot. If the level is greater than the cutoff level used at that center, either a second measurement of 17-hydroxyprogesterone or genotyping is the next step. A corticotropin stimulation test may also be used to determine the type of CAH. Once the diagnosis is established, replacement steroid therapy is begun.4 References (Ambiguous Genitalia) 1. American Academy of Pediatrics: Evaluation of the newborn with developmental anomalies of the external genitalia. Pediatrics 106:138, 2000. 2. Pinsky L, Erickson RP, Schimke RN: The embryology of normal gonadal and genital development. In: Genetic Disorders of Human Sexual Development. Oxford University Press, New York, 1999. 3. Lee PA, Mazur T, Danish R, et al.: Micropenis 1. Criteria, etiologies and classification. Johns Hopkins Med J 146:156, 1980. 4. Speiser PW, White PC: Congenital adrenal hyperplasia. N Engl J Med 349:776, 2003. 5. Therrell BL: Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 30:15, 2001. 6. Speiser PW, Dupont B, Rubenstein P, et al.: High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37: 650, 1985. 7. Lambers SW, Bruining HA, deJong FH: Corticosteroid therapy in severe illness. N Engl J Med 337:1285, 1997. 8. Merke DP, Chrousos GP, Eisenhofer G, et al.: Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 343:1362, 2000. 9. Rosler A, Lieberman E, Sack J, et al.: Clinical variability of congenital adrenal hyperplasia due to 11b-hydroxylase deficiency. Horm Res 16:133, 1982. 10. Levine LS, Rauh W, Gottesdiener K, et al.: New studies of the 11bhydroxylase and 18-hydroxylase enzymes in the hypertensive form of congenital adrenal hyperplasia. J Clin Endocrinol Metab 50:258, 1980. 11. Yanase T, Simpson ER, Waterman MR: 17-Alpha-hydroxylase/ 17,20lyase deficiency: from clinical investigation to molecular definition. Endocrinol Rev 12:91, 1991. 12. De Peretti E, Forest MG, Feit JP, et al.: Endocrine studies in two children with male pseudohermaphroditism due to 3-b-hydroxysteroid (3bHHSD) dehydrogenase defect. In: Adrenal Androgens. AR Genazzani, JHH Thijssen, PK Siiteri, eds. Raven Press, New York, 1980, p 141. 13. Ferraz VEF, Melo DG, Hansing SE, et al.: Ablepharon-macrostomia syndrome: first report of familial occurrence. Am J Med Genet 94:281, 2000. 14. Rodriguez JI, Palacios J, Omenaca F, et al.: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet 38:99, 1991. 15. Beemer FA, van Ertbruggen I: Peculiar facial appearance, hydrocephalus, double-outlet right ventricle, genital anomalies and dense bones with lethal outcome. Am J Med Genet 19:391, 1984. 16. Greenburg F, Keenan B, DeYanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986. 17. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003. 18. Klamt B, Koziell A, Poulat F, et al.: Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 þ/KTS splice isoforms. Hum Mol Genet 7:709, 1998.

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19. Pelletier J, Bruening W, Kashtan CE, et al.: Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437, 1991. 20. Poulat F, Morin D, Konig A, et al.: Distinct molecular origins for Denys-Drash and Frasier syndromes. Hum Genet 91:285, 1993. 21. Koppe R, Kaplan P, Hunter A, et al.: Ambiguous genitalia associated with skeletal abnormalities, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities (SCARF syndrome). Am J Med Genet 34:305, 1989. 22. Majewski F, Pfeiffer RA, Lenz W, et al.: Polysyndaktylie, verkuerzte Gliedmassen, und Genitalfehlbildungen: Kennzeichen eines selbstaendigen Syndrome? Z Kinderheilk 111:118, 1971. 23. Chen H, Yang SS, Gonzalez E, et al.: Short rib-polydactyly syndrome, Majewski type. Am J Med Genet 7:215, 1980. 24. Cunniff C, Kratz LE, Moser A, et al.: Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet 68:263, 1997. 25. Nowaczyk MJM, Farrell SA, Sirkin WL, et al.: Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G-C genotype. Am J Med Genet 103:75, 2001. 26. Curry CJR, Carey JC, Holland JS, et al.: Smith-Lemli-Opitz syndrometype II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26:45, 1987. 27. Breslow NE, Takashima JR, Ritchey ML, et al.: Renal failure in the Denys-Drash and Wilms’ tumor-aniridia syndromes. Cancer Res 60:4030, 2000. 28. Dobyns WB, Berry-Kravis E, Havernick NJ, et al.: X-linked lissencephaly with absent corpus callosum and ambiguous genitalia. Am J Med Genet 86:331, 1999. 29. Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359, 2002. 30. Karlin G, Brock W, Rich M, et al.: Persistent cloaca and phallic urethra. J Urol 142:1056, 1989. 31. Escobar LF, Weaver DD, Bixler D, et al.: Urorectal septum malformation sequence. Report of six cases and embryological analysis. Am J Dis Child 141:1021, 1987. 32. Belis JA, Hrabovsky EE: Idiopathic female intersex with clitoromegaly and urethral duplication. J Urol 122:805, 1979. 33. Stevenson AC, Johnston HA, Stewart MIP, et al.: Congenital malformations. A report of a study of series of consecutive births in 24 centres. Bull World Health Organ 34(suppl):1, 1966. 34. Castilla EE, Orioli IM, Lugarinho R, et al.: Epidemiology of ambiguous genitalia in South America. Am J Med Genet 27:337, 1987. 35. Lo JC, Grumbach MM: Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am 30: 207, 2001. 36. Hines M, Kaufman FR: Androgen and the development of human sextypical behavior: rough-and-tumble play and sex of preferred playmates in children with congenital adrenal hyperplasia (CAH). Child Dev 65: 1042, 1994. 37. New MI, Carlson A, Obeid J, et al.: Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 86: 5651, 2001.

30.5 Mu¨llerian Aplasia Definition

Mu¨llerian aplasia is the absence or hypoplastic development of the uterus, fallopian tubes, cervix, and upper vagina in a 46,XX individual with normal ovaries and female external genitalia (Fig. 30-11). The Mayer-Rokitansky-Kuster-Hauser syndrome is included in this definition, but vaginal atresia with normal upper vagina and uterus is considered separately.

1292

Urogenital System Organs

Fig. 30-11. Schematic of Mu¨llerian aplasia (A) compared with normal Mu¨llerian development (B). (After Sarto and Simpson2, Alan R. Liss Inc., New York, for the National Foundation-March of Dimes.)

Diagnosis

Most (90%) individuals with ‘‘absence of the vagina’’ have mu¨llerian aplasia. Between 1829 and 1961, Mayer, Rokitansky, Kuster, and Hauser each described patients with defects of the Mu¨llerian system in association with other anomalies.1 The appellation Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is generally applied to cases characterized by a rudimentary uterus and Fallopian tubes with absence of the vagina. The term Rokitansky sequence is used to describe Mu¨llerian aplasia anomalies as they occur in association with other multiple anomaly conditions.2 Individuals with MRKH usually present with primary amenorrhea. Secondary sexual characteristics are normally developed. Physical examination reveals a 1 to 2 cm vaginal pouch. Uterine remnants may or may not be palpable. Ultrasound examination or magnetic resonance imaging (MRI) will demonstrate the presence of hypoplastic uterine structures in some cases and their total absence in others. Both ovarian sex steroids and plasma gonadotropin levels are normal. Testicular feminization (androgen insensitivity) syndrome can be excluded by the presence of normal pubic and axillary hair and a 46,XX karyotype. Associated abnormalities of the urinary tract are common. About 30–40% of patients have ectopic kidneys, agenesis of one kidney, abnormalities of the renal pelvis and ureters, or fused

kidneys.1,3 Skeletal anomalies are also common (12%). Scoliosis and abnormal vertebral bodies are the most prevalent skeletal abnormalities; rib and limb malformations are also found.1 Congenital heart defects and inguinal hernias occur in a small minority of patients. Although most women with Mu¨llerian aplasia do not have a multiple malformation syndrome, Mu¨llerian aplasia has been found to be an occasional component of a number of syndromes and as a part of the MURCS association (Mu¨llerian duct aplasia, unilateral renal agenesis, and cervicothoracic somite anomalies) (Table 30-3).4–13 In addition, in contrast to the normal 46,XX complement found in most patients with Mu¨llerian aplasia, chromosome abnormalities (46,X,i[Xq]; 46,XX,t[12;14]; 45,X/46,XX; 46,XX/ 47,XXX; 47,XXX; 45,X;) have been found in a few affected individuals. Etiology and Distribution

The etiology is absence or aplasia of the mu¨llerian ducts, which normally differentiate into Fallopian tubes, uterus, cervix, and upper vagina. The incidence of ‘‘absence of the vagina’’ is one in 4000 to 5000 female births.1 Ninety percent of females with absent vagina have Mu¨llerian aplasia; the others have vaginal atresia only.2 Of patients with primary amenorrhea, 15–20% have Mu¨llerian aplasia. Families with multiple affected siblings have been documented, suggesting autosomal recessive inheritance. Studies examining the CFTR gene in cases of MRKH have failed to show linkage.14 Lischke et al.15 observed three affected women, each with an unaffected monozygotic twin, making recessive inheritance unlikely as an explanation for all cases. Shokeir16 reported 16 families in which the proband had Mu¨llerian aplasia. Ten of the 16 families had more than one affected member, and eight of 10 had affected paternal relatives. These observations suggested femalelimited autosomal dominant inheritance. Data from these cases are insufficient to determine whether the cases represent the same condition reported by Lindner et al.9 In contrast, a study by Carson et a1.17 of 23 probands with Mu¨llerian aplasia showed not a single affected relative. The latter

Table 30-3. Syndromes associated with Mu¨llerian aplasia OMIM Number Gene/Locus

Syndrome

Additional Prominent Features

Fraser4,5

Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactyly

219000 FRAS1, 4q21

Meckel-Gruber6–8

Microcephaly, posterior encephalocele, eye anomalies, cleft palate, polycystic kidneys, polydactyly

249000 MKS1, 7q22-q23

MURCS association9

M€ u llerian aplasia, renal aplasia, cervical somite dysplasia; Klippel-Feil anomaly; deafness; short stature

601076

Sex-limited AD Mu¨llerian aplasia10

Maturity onset diabetes of the young (MODY V), progressive nondiabetic renal disease

158330 HNF1b, TCF2, 17cen-q21.3

Thalidomide, prenatal11

Nasal hemangioma, neurosensory hearing loss, ear anomalies, limb reduction defects, visceral anomalies

Teratogen

Hereditary urogenital/renal adysplasia12

Oligohydramnios, Potter deformation sequence, pulmonary hypoplasia, unilateral or bilateral absent kidneys, limb deformities

191830

Winter13

Lacrimal duct stenosis, external and middle ear anomalies, renal agenesis

267400

Female Genital System

1293

Fig. 30-12. Creation of a neovagina. McIndoe procedure. A. Incision at the vaginal apex. B. Creation of a space between urethra and rectum. C. Vaginal mold covered with skin graft. D. Vaginal mold in newly developed vaginal space. (After Mattingly and Thompson.18)

authors suggested that in nonsyndromic cases, Mu¨llerian aplasia is inherited in polygenic/multifactorial fashion. Prognosis, Treatment, and Prevention

Patients with Mu¨llerian aplasia are, of course, infertile. However, as these women have normal ovaries, the possibility of oocyte harvesting for in vitro fertilization and gestation in a surrogate uterus exists. Vaginal construction is performed by placing a stent, covered with a split-thickness skin graft taken from the patient’s thigh or buttock, into a cavity created surgically between the urethra and rectum (McIndoe procedure) (Fig. 30-12).18 Functional results are good in almost all patients if the procedure is performed when the woman is mature enough to comply with the requirement for continued use of a vaginal stent until regular sexual intercourse is established.3 An alternative approach to surgical development of a vagina is the Frank method in which the patient repeatedly applies successively larger dilators to the vaginal pouch. Some patients achieve adequate vaginal depth with this method. Laparotomy or laparoscopy are not necessary for diagnosis unless a functioning uterine remnant is suspected. If present, such a remnant must be excised to prevent endometriosis and pain secondary to absence of the outflow tract. Psychological problems related to disturbed body image are not uncommon. Some patients may benefit from counseling. References (Mu¨llerian Aplasia) 1. Griffin JE, Edwards C, Madden JD, et al.: Congenital absence of the vagina. The Mayer-Rokitansky-Kuster-Hauser syndrome. Ann Intern Med 85:224, 1976.

2. Sarto GE, Simpson JL: Abnormalities of the Mu¨llerian and Wolffian duct systems. Birth Defects Orig Artic Ser XIV(6C):37, 1978. 3. Cali RW, Pratt JH: Congenital absence of the vagina. Long-term results of vaginal reconstruction in 175 cases. Am J Obstet Gynecol 100:752, 1968. 4. Greenburg F, Keenan B, DeYanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986. 5. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003. 6. Paavola P, Avela K, Horelli-Kuitunen N, et al.: High-resolution physical and genetic mapping of the critical region for Meckel syndrome and MULIBREY nanism on chromosome 17q22-q23. Genome Res 9:267, 1999. 7. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 8. Paavola P, Salonen R, Weissenbach J, et al.: The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet 11:213, 1995. 9. Duncan PA, Shapiro LR, Stagel JJ, et al.: The MURCS association: Mu¨llerian duct aplasia, renal aplasia and cervicothoracic somite dysplasia. J Pediatr 95:399, 1979. 10. Lindner TH, Njolstad PR, Horikawa Y, et al.: A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1-beta. Hum Mol Genet 8:2001, 1999. 11. Hoffman W, Grospietch G, Kuhn W: Thalidomide and female genital malformation. Lancet 2:794, 1976. 12. McPherson E, Carey J, Kramer A, et al.: Dominantly inherited renal adysplasia. Am J Med Genet 26:863, 1987. 13. Winter JSD, Kohn G, Mellman WJ, et al.: A familial syndrome of renal, genital, and middle ear anomalies. J Pediatr 72:88, 1968.

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14. Timmreck LS, Gray MR, Handelin B, et al.: Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina. Am J Med Genet 120A:72, 2003. 15. Lischke JH, Curtis CH, Lamb EJ: Discordance of vaginal agenesis in monozygotic twins. Obstet Gynecol 41:920, 1973. 16. Shokeir MHK: Aplasia of the Mu¨llerian system: evidence for probable sex-limited autosomal dominant inheritance. Birth Defects Orig Artic Ser XIV(6C):147, 1978.

17. Carson SA, Simpson JL, Malinak LR, et al.: Heritable aspects of uterine anomalies. II. Genetic analysis of Mu¨llerian aplasia. Fertil Steril 40:86, 1983. 18. Mattingly RF, Thompson JD: Te Linde’s Operative Gynecology, ed 6. JB Lippincott, Philadelphia, 1985.

Isolated Anomalies of the Mu¨llerian Structures 30.6 Absence of the Fallopian Tube Partial or complete absence of a Fallopian tube in the presence of a normal uterus (Fig. 30-13) is a rare malformation. In cases of Mu¨llerian aplasia, the Fallopian tube and ipsilateral ovary usually remain. Unilateral absence of a Fallopian tube is most often discovered incidentally. Occasionally, both tubes are absent or present as remnants with either unilateral or bilateral absence of the ovaries. Presentation is as infertility or primary amenorrhea.1 The absence of both the Fallopian tube and the ipsilateral ovary suggests either adnexal torsion or a primary vascular accident as etiology. There is no known genetic basis for this entity.2 References (Absence of the Fallopian Tube) 1. Eustace DL: Congenital absence of the fallopian tube and ovary. Eur J Obstet Gynecol 46:157, 1992. 2. Pinsky L, Erickson RP, Schimke RN: The embryology of normal gonadal and genital development. In: Genetic Disorders of Human Sexual Development. Oxford University Press, New York, 1999.

30.7 ¨ llerian Fusion Incomplete Mu Definition

Incomplete Mu¨llerian fusion is the failure of fusion of the paired Mu¨llerian ducts. Unicornuate uterus, bicornuate uterus, septate uterus, arcuate uterus, and uterus didelphys are manifestations of incomplete Mu¨llerian fusion, but true duplication of the mu¨llerian ducts is not. Fig. 30-13. Schematic of unilateral absence of the Fallopian tube.

Diagnosis

Uterine fusion anomalies most commonly come to medical attention because of poor obstetric performance. Alternatively, if an obstructed hemiuterus or hemivagina coexists, presentation may be shortly after expected onset of menses because retention of menstrual discharge leads to cyclic pelvic pain and hematometra or hematocolpos. If associated renal anomalies are present, Mu¨llerian anomalies may be discovered in childhood during evaluation of the urinary tract. Uterine fusion anomalies are depicted in Fig. 30-14. In the unicornuate uterus, there is a single Fallopian tube; the uterus and cervix open into a normal vagina (Fig. 30-14b). There may also be a blind or communicating rudimentary hemiuterus (Fig. 30-15). Absence of the kidney ipsilateral to the absent or defective uterine horn is common. The arcuate uterus is characterized by a flattened fundus with a midline notch (Fig. 30-14c). In a septate uterus, the external appearance is normal, but a septum extends from the fundus to the cervix (Fig. 30-14d). Absence of the caudal portion of the septum (subseptate uterus) is a common variant. In the bicornuate uterus, two uterine cavities terminate in either a single cervix or two separate cervices. The fundus is deeply notched (Fig. 30-14e). A didelphic uterus has two separate cavities with separate cervices, and in 75% of cases a septate (longitudinal) vagina (Fig. 30-14f). Rarely, separate hemiuteri may be associated with two vaginas with widely separate orifices and duplicated vulva. Diagnosis is made by physical examination of the vagina, cervix, and uterus. Ultrasound examination, magnetic resonance imaging, hysterosalpingography, laparoscopy, and hysteroscopy may also be useful in determining the structure of the internal genitalia. Urinary tract anomalies are not infrequently found in patients with incomplete Mu¨llerian fusion. In one study in which intravenous pyelograms were performed on all patients, three of 13 women with a unicornuate uterus showed renal anomalies: crossed renal ectopy, absent kidney, and moderate hydronephrosis of one kidney. Of three patients with uterus didelphys, two showed unilateral absent kidney. Of 21 patients with septate uterus, four showed unilateral duplication of a collecting system or unilateral atrophy of a kidney.1 Although usually an isolated anomaly (with or without an associated renal anomaly), incomplete Mu¨llerian fusion may also be found as an occasional component of several genetic syndromes (Table 30-4).2–19

Female Genital System

1295

Fig. 30-14. Schematic of uterine fusion anomalies. A. Normal uterus. B. Unicornuate uterus. C. Arcuate uterus. D. Septate uterus. E. Bicornuate uterus. F. Didelphic uterus, septate vagina. (From Simpson.26)

Etiology and Distribution

Prognosis, Treatment, and Prevention

Fusion defects result from failure of the paired Mu¨llerian organs to fuse during embryonic life. If one duct does not contribute to the definitive uterus, a unicornuate uterus and a rudimentary horn result. Family aggregates (sisters; mother and daughter) have been reported10; however, monozygotic twins discordant for uterine malformation are also known. Pedigree analysis of 24 probands with incomplete Mu¨llerian fusion revealed only one of 61 (1.6%) first-degree relatives to be affected, suggesting polygenic/multifactorial causation.20 Retrospective surveys estimate the prevalence of symptomatic incomplete Mu¨llerian fusion to be 0.1%; however, manual exploration of uteri immediately following delivery suggests a prevalence of 2–3%. Many of the latter are asymptomatic. Bicornuate uterus is the most common form of incomplete Mu¨llerian fusion and unicornuate uterus the least; didelphic, septate, and arcuate uteri are intermediate in frequency.21

Obstructive complications can arise in a rudimentary horn. If there is endometrial tissue present and no communication with the normal horn or vagina, cryptomenorrhea and cyclic pain (dysmenorrhea) will occur. Endometriosis is also found with increased frequency in women with obstructed, anomalous uteri. A rudimentary horn with an endometrial cavity should be excised. If pregnancy occurs in either a communicating rudimentary horn or a noncommunicating horn (by transperitoneal migration of sperm), rupture and massive hemorrhage may ensue. Diagnosis during pregnancy can be made by ultrasound. Interruption of the pregnancy is probably unavoidable in most cases. If a longitudinal vaginal septum is present, unilateral cervical and vaginal obstruction may coexist (Figure 30-16). Menstruation will result in unilateral hematocolpos as well as cyclic menstrual flow through the adjacent normal cervix and vagina. Drainage of the hematocolpos and removal of the vaginal septum are required. Renal anomalies should be sought with intravenous pyelography or ultrasound scanning. In nonobstructive forms of incomplete Mu¨llerian fusion, patients are usually fertile but suffer a variety of obstetric complications. In addition, deformations of the fetal skull, face, and limbs, as well as pulmonary hypoplasia, have been reported in the offspring of women with bicornuate or septate uteri.22,23 Spontaneous abortion, premature delivery, abnormal fetal presentations, retained placenta, and dystocia are all increased in frequency. In particular, patients with septate uteri appear to have increased fetal wastage compared to that of women with other forms of incomplete fusion.24 Precise frequencies are unknown because of ascertainment bias in reported pregnancy outcomes, most series consisting of women with poor reproductive histories who have sought medical attention. If one examines pregnancy outcome among women with incidentally discovered uterine anomalies, 93%,

Fig. 30-15. Schematic of unicornuate uterus with communicating rudimentary horn (A) and noncommunicating (blind) horn (B).

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Table 30-4. Syndromes associated with incomplete Mu¨llerian fusion OMIM Number Gene/Locus

Syndrome

Additional Prominent Features

Bardet-Biedl2

Retinitis pigmentosa, adult-onset rod-cone dystrophy, polydactyly, obesity, mental deficiency, congenital heart defects, hepatic fibrosis, Hirschsprung, hypodontia

209900 BBS1, 11q13 BBS2, 16q21 BBS3, 3p13-p12 BBS4, 15q22.3-q23 BBS5, 2q31 BBS6 (MKKS), 20p12 BBS7, 4q27 BBS8 (TTC8), 14q32.1

Beckwith-Wiedemann3–5

Macroglossia, omphalocele, macrosomia, hemihypertrophy, hepatoblastoma

130650 Duplication, 11p15

Donahue (leprechaunism)6,7

Elfin facies with thick lips; large, low-set ears; prominent breasts and external genitalia; hirsutism; abnormal carbohydrate metabolism; failure to thrive; motor and mental retardation

246200 INSR, 19p13.2

Fraser8,9

Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactyly

219000 FRAS1, 4q21

Hand-foot-uterus10,11

Metacarpal and metatarsal anomalies, malformed thumbs, displaced urethral meatus, urinary incontinence

140000 HOXA13, HOX1J, 7p15-p14.2

Johanson-Blizzard12

Deafness, hypoplastic alae nasi, primary hypothyroidism, mental retardation

243800

Meckel-Gruber13–15

Microcephaly, posterior encephalocele, eye anomalies, cleft palate, polycystic kidneys, polydactyly

249000 MKS1, 7q22-q23

Roberts16

Sparse silvery blond hair, midfacial hemangioma, cleft lip with or without cleft palate, limb reduction defect, intrauterine growth retardation

268300

Rudiger17

Bifid uvula, coarse facies, absent ear cartilage, hydronephrosis secondary to ureterovesical stenosis, short digits

268650

Thalidomide, prenatal18

Nasal hemangioma, neurosensory hearing loss, ear anomalies, limb reduction defects, visceral anomalies

Teratogen

Trisomy 18

Microcephaly, prominent occiput, malformed ears, micrognathia, cardiac defects, short sternum, overlapping fingers, intrauterine growth retardation, severe developmental retardation, kidney defects

Chromosomal

Trisomy 13

Microcephaly, microphthalmia, malformed ears, prominent nose, posterior scalp defect, brain malformations, polydactyly, severe developmental retardation

Chromosomal

Urogenital/renal adysplasia, hereditary19

Oligohydramnios, Potter deformation sequence, pulmonary hypoplasia, unilateral or bilateral absent kidneys, limb deformities

191830

Fig. 30-16. Schematic of didelphic uterus with obstructing vaginal septum.

84%, and 78% with didelphic, bicornuate, and septate uteri, respectively, were reproductively successful.25 Plausible pathogenic mechanisms for poor reproductive outcome include poor vascularization or decidualization of the septum, or associated cervical incompetence. Fetal deformations are thought to be secondary to the constraint imposed by a small or asymmetric uterine cavity.22,23 Many surgical procedures have been described for treatment of fusion defects. These include the Strassmann transverse fundal incision (for the bicornuate uterus) and the Jones and Jones wedge metroplasty and the Tompkins median bivalving techniques (for the septate uterus). Recently, hysteroscopic resection of the septum has been favored because it is an outpatient procedure performed through the cervix with good results and low morbidity. Surgical procedures, however, are generally advocated only for women with at least one second or third trimester loss, or for women with multiple early losses with no other explanation. Results of metroplasty are good, 75% of patients subsequently conceiving and

Female Genital System

80% of their conceptions resulting in live births.21,25 Coexistence of cervical competence may require cerclage. References (Incomplete Mu¨llerian Fusion) 1. Buttram VC, Gibbons WE: Mu¨llerian anomalies: a proposed classification (an analysis of 144 cases). Fertil Steril 32:40, 1979. 2. Ross AJ, Beales PL: Bardet-Biedl syndrome. GeneReviews, last revision, October 17, 2003. (Accessed March 28, 2004, at http://www.genetests. org/servlet/access?db¼geneclinics&site¼gt&id¼8888891&key¼ T8qEWAfkqTyc3&gry¼&fcn¼y&fw¼UWdY&filename¼/profiles/bbs/ index.html.) 3. Pettenati MJ, Haines JL, Higgins RR: Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 74:143, 1986. 4. Slavotinek A, Gaunt L, Donnai D: Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet 34:819, 1997. 5. Weksberg R, Nishikawa J, Caluseriu O, et al.: Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 10:2989, 2001. 6. Summit RL, Favara BE: Leprechaunism (Donohue’s syndrome): a case report. J Pediatr 74:601, 1969. 7. Hone J, Accili D, Al-Gazali LI, et al.: Homozygosity for a new mutation (ile119-to-met) in the insulin receptor gene in five sibs with familial insulin resistance. J Med Genet 31:715, 1994. 8. Greenburg F, Keenan B, DeYanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986. 9. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003. 10. Verp MS, Simpson JL, Elias S, et al.: Heritable aspects of uterine anomalies. I. Three familial aggregates with Mu¨llerian fusion anomalies. Fertil Steril 40:80, 1983. 11. Mortlock DP, Innis JW: Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet 15:179, 1997. 12. Gershoni-Baruch R, Lerner A, Braun J, et al.: Johanson-Blizzard syndrome: clinical spectrum and further delineation of the syndrome. Am J Med Genet 35:546, 1990. 13. Paavola P, Avela K, Horelli-Kuitunen N, et al.: High-resolution physical and genetic mapping of the critical region for Meckel syndrome and Mulibrey nanism on chromosome 17q22-q23. Genome Res 9:267, 1999. 14. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997. 15. Paavola P, Salonen R, Weissenbach J, et al.: The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet 11:213, 1995. 16. Freeman MVR, Williams DW, Schimke RN, et al.: The Roberts syndrome. Clin Genet 5:1, 1974. 17. Rudiger RA, Schmidt W, Loose DA, et al.: Severe developmental failure with coarse facial features, distal limb hypoplasia, thickened palmar creases, bifid uvula, and ureteral stenosis: a previously unidentified familial disorder with lethal outcome. J Pediatr 79:977, 1971. 18. Newman CGH: Clinical observations on the thalidomide syndrome. Proc R Soc Med 70:225, 1977. 19. McPherson E, Carey J, Hall JG: Dominantly inherited renal adysplasia. Am J Med Genet 26:863, 1987. 20. Elias S, Simpson JL, Carson SA, et al.: Genetic studies in incomplete Mu¨llerian fusion. Obstet Gynecol 63:276, 1984. 21. Rock JA, Schlatt WD: The obstetric consequences of uterovaginal anomalies. Fertil Steril 43:681, 1985. 22. Miller ME, Dunn PM, Smith DW: Uterine malformation and fetal deformation. J Pediatr 94:387, 1979. 23. Graham JM Jr, Miller ME, Stephan MJ, et al.: Limb reduction anomalies and early in utero limb compression. J Pediatr 96:1052, 1980.

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24. Buttram VC Jr: Mu¨llerian anomalies and their management. Fertil Steril 40:159, 1983. 25. Thompson JA, Smith RA, Welch JS: Reproductive ability after metroplasty. Obstet Gynecol 28:363, 1966. 26. Simpson JL: Disorders of Sexual Differentiation. Academic Press, New York, 1976.

30.8 Cervical Atresia Agenesis or hypoplasia of the distal cervix and cervical canal resulting in closure between the uterine cavity and the vagina constitutes cervical atresia (Fig. 30-17). Absence of menses with cyclic lower abdominal pain indicates an obstructed outflow tract of the uterus. Examination reveals either cervical atresia alone, vaginal agenesis combined with cervical atresia, or cervical atresia and a uterine anomaly. Magnetic resonance imaging or ultrasound scanning is especially useful in evaluation if vaginal agenesis is also present.1 The cervix may also be absent in true hermaphrodites, particularly in South African Bantus. Etiology of cervical atresia involves failure of canalization of the mu¨llerian ducts or local epithelial hyperplasia. The former hypothesis seems more likely in view of the finding of muscle bundles ‘‘extended as a complete, uninterrupted bridge around the closed end of the cervical canal’’ in one case.1 Cervical atresia is rare, fewer than 50 cases having been reported. No familial aggregates are known. Two forms of treatment have been advocated. In several cases a uterovaginal tract has been successfully established, followed by regular menstrual bleeding and even pregnancy.2–5 However, because of the risk of infection ascending from the vagina following surgical fistulization of uterus to vagina, other authors strongly recommend hysterectomy.6,7 Harvesting of oocytes, in vitro fertilization, and gestation in a surrogate uterus could be considered at the appropriate time as a means of reproduction for such patients. Endometriosis, the result of retrograde menstruation, may also require treatment. References (Cervical Atresia) 1. Markham SM, Parmley TH, Murphy AA, et al.: Cervical agenesis combined with vaginal agenesis diagnosed by magnetic resonance imaging. Fertil Steril 48:143, 1987. 2. Cukier J, Batzofin JH, Conner JS, et al.: Genital tract reconstruction in a patient with congenital absence of the vagina and hypoplasia of the cervix. Obstet Gynecol 68:32S, 1986. 3. Farber M, Marchant DJ.: Reconstructive surgery for congenital atresia of the uterine cervix. Fertil Steril 27:1277, 1976.

Fig. 30-17. Schematic of cervical atresia.

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4. Zarou GS, Esposito JM, Zarou DM.: Pregnancy following the surgical correction of congenital atresia of the cervix. Int J Gynaecol Obstet 11:143, 1973. 5. Singh I, Devi YL: Pregnancy following surgical correction of non-fused Mu¨llerian bulbs and absent vagina. Obstet Gynecol 61:267, 1983. 6. Geary WL, Weed JC: Congenital atresia of the uterine cervix. Obstet Gynecol 42:213, 1973. 7. Niver DH, Barrette G, Jewelewicz R: Congenital atresia of the uterine cervix and vagina: three cases. Fertil Steril 33:25, 1980.

30.9 Vaginal Atresia Definition

Vaginal atresia is the absence of the lower third of the vagina with normal external genitalia, upper vagina, cervix, and uterus (Fig. 30-18). Mu¨llerian aplasia is discussed in a preceding section. Diagnosis

The patient typically presents at the time of expected menarche with cyclic abdominal cramping due to obstruction of menstrual outflow. Menstrual blood accumulates in the uterus and upper vagina, producing hematocolpos and hematometra (Fig. 30-19). If

unrecognized, a large pelvic–abdominal mass may develop. The diagnosis should be suspected in a female with normal secondary sexual characteristics, pubic and axillary hair, normal external genitalia, and primary amenorrhea. Pelvic examination reveals a short vaginal pouch terminating in 2 to 3 cm of fibrous tissue. Ultrasound or magnetic resonance imaging demonstrates the presence of a uterus.1 Renal anomalies may also be present. Vaginal atresia may rarely be diagnosed in a newborn who presents with mucocolpos. Usually an isolated anomaly, vaginal atresia also occurs as an occasional component of multiple malformation syndromes (Table 30-5).2–7 Etiology and Distribution

Vaginal atresia results from failure of normal development of the urogenital sinus, which contributes the caudal portion of the vagina. ‘‘Absence of the vagina’’ occurs in one per 4000 to 5000 female births. Only 10% of patients with absence of the vagina have isolated vaginal atresia. The other 90% have Mu¨llerian aplasia. There is no evidence of racial variation. Except for syndromes that include vaginal atresia as one component, family aggregates have not been reported. Prognosis, Treatment, and Prevention

If the disorder is diagnosed soon after menarche and if satisfactory drainage of the uterus and cervix is achieved, damage to the uterus and fallopian tubes and development of endometriosis may be avoided. In many cases, however, endometriosis secondary to retrograde menstruation through the Fallopian tubes into the pelvis is already present at the time of diagnosis. Treatment requires creation of a neovagina. The potential space between the urethra and rectum is surgically dissected, thereby developing a vaginal space between the urogenital sinus and the upper vagina. A split-thickness skin graft is wrapped around a stent and placed in the cavity. Continuing use of the stent is required until regular intercourse is established. Successful pregnancies have been reported in treated women.8 Prenatal diagnosis of vaginal atresia has not been reported but may be possible in the rare situation in which mucocolpos develops prenatally. Fig. 30-18. Schematic of vaginal atresia. (From Sarto GE, Simpson JL: Abnormalities of Mu¨llerian and Wolffian duct systems. BDOAS XIV(6C):37, 1978.)

Fig. 30-19. Schematic showing hematocolpos, hematometra, and hematosalpinx secondary to vaginal atresia.

References (Vaginal Atresia) 1. Togashi K, Nishimura K, Itoh K, et al.: Vaginal agenesis: classification by MR imaging. Radiology 162:675, 1987. 2. Kelley RI, Kratz LE, Glaser RL, et al.: Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. Am J Med Genet 110:95, 2002. 3. Fluck CE, Tajima T, Pandey AV, et al.: Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet 36:228, 2004. 4. Ross AJ, Beales PL: Bardet-Biedl syndrome. GeneReviews, last revision, October 17, 2003. (Accessed March 28, 2004, at http://www.genetests. org.) 5. Greenberg F, Keenan B, DeYanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986. 6. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003. 7. Winter JSD, Kohn G, Mellman WJ, et al.: A familial syndrome of renal, genital, and middle ear anomalies. J Pediatr 72:88, 1968. 8. Bates GW, Wiser WL: A technique for uterine conservation in adolescents with vaginal agenesis and a functional uterus. Obstet Gynecol 66:290, 1985.

Female Genital System

1299

Table 30-5. Syndromes associated with vaginal atresia OMIM Number Gene/Locus

Syndrome

Additional Prominent Features

Antley-Bixler2,3

Craniosynostosis, choanal atresia, humeroradial synostosis, gracile ribs, bowed femora, camptodactyly, renal anomalies

207410 POR (cytochrome P450 reductase), 7q11.2

Bardet-Biedl4

Retinitis pigmentosa, adult-onset rod-cone dystrophy, polydactyly, obesity, mental deficiency, congenital heart defects, hepatic fibrosis, Hirschsprung, hypodontia

209900 BBS1, 11q13 BBS2, 16q21 BBS3, 3p13-p12 BBS4, 15q22.3-q23 BBS5, 2q31 BBS6 (MKKS), 20p12 BBS7, 4q27 BBS8 (TTC8), 14q32.1

Fraser5,6

Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactyly

219000 FRAS1, 4q21

Winter7

Lacrimal duct stenosis, external and middle ear anomalies, renal agenesis

267400

30.10 Transverse Vaginal Septum Definition

Transverse vaginal septum is a suprahymenal membrane with normal external genitalia, uterus, and cervix. Imperforate hymen and vaginal atresia are excluded. Diagnosis

Forty-five percent of transverse septa occur in the upper vagina, 40% in the middle third, and 15% in the lower third.1 These septa are separate from and cephalad to the hymen (Figs. 30-20 and 30-21). Septa are approximately 1 cm thick and may be complete or have a small central or eccentric perforation (incomplete). Absence of a perforation results in retention of menstrual blood and cervical mucus. Hematometra and hematocolpos may develop. Diagnosis is usually made by vaginal examination following detection of a pelvic—abdominal mass in a young woman with primary amenorrhea, cyclic lower abdominal pain, and normal secondary sexual characteristics with pubic and axillary hair. A blind-ending vaginal pouch is found. Rectal examination, ultrasound, or magnetic resonance imaging will reveal a uterus that is usually normal but sometimes bicornuate. Intravenous pyelogram may show urinary tract anomalies (hypoplastic kidney, ureteral duplication, vesicovaginal fistula, caliectasis, and hydronephrosis). Fig. 30-20. Schematic of transverse vaginal septa. a. High septum. b. Midvaginal septum. c. Low septum.

The diagnosis should also be suspected in a newborn female having respiratory difficulty and urinary, intestinal, or circulatory obstruction due to a large abdominal mass (hydro- or mucometrocolpos).1 A woman with a perforate transverse vaginal septum may come to medical attention because of dyspareunia or because of obstructed labor. Fig. 30-21. Low vaginal septum. Urethra is dilated.

1300

Urogenital System Organs

A transverse vaginal septum is distinguished from an imperforate hymen by the identification of the hymen inferior to and separate from the septum. Differentiation from vaginal atresia is by the presence of normal vagina below and above the septum and by the length of the abnormal segment. Transverse vaginal septa are usually isolated defects but are also a component of the McKusickKaufman syndrome. Other features of the latter syndrome are postaxial polydactyly and congenital heart malformation.2 Etiology and Distribution

Transverse vaginal septa are rare defects (one to five per 70,000 females) resulting from either failure of fusion of the urogenital sinus to the mu¨llerian duct derivatives or failure of the initially solid vaginal core to canalize completely. Most cases are sporadic. An autosomal recessive gene, MKKS, is responsible for the McKusickKaufman syndrome, most cases of which have been reported in the Amish.3 Prognosis, Treatment, and Prevention

Excision of the septum soon after onset of menarche will allow drainage of menstrual efflux. In the absence of normal egress, retrograde drainage into the peritoneal cavity may result in damage to fallopian tubes and development of endometriosis on ovarian and peritoneal surfaces. A perforate septum may be surgically removed or manually dilated, depending on the symptomatology and distensibility of the septum. Reproductive function is normal in most affected women; however, infertility appears increased in patients with resected high septa, perhaps secondary to endometriosis.3 Prenatal diagnosis of hydrometrocolpos secondary to a vaginal septum has been made by ultrasound.4 Treatment may be required in the neonatal period if respiratory compromise is present. References (Transverse Vaginal Septum) 1. McKusick VA, Bauer RL, Koop CE, et al.: Hydrometrocolpos as a simply inherited malformation. JAMA 189:813, 1964. 2. Slavotinek AM, Biesecker LG: Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review. Am J Med Genet 95:208, 2000. 3. Slavotinek AM, Searby C, Al-Gazali L, et al.: Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected BardetBiedl syndrome patients. Hum Genet 110:561, 2002. 4. Rock JA, Zacur HA, Olugi AM, et al.: Pregnancy success following surgical correction of imperforate hymen and complete transverse vaginal septum. Obstet Gynecol 59:448, 1982.

30.11 Longitudinal Vaginal Septum A longitudinal vaginal septum can be coronal or sagittal (Fig. 3022). Longitudinal septa may extend the length of the vagina or be restricted to the proximal (cervical) or distal ends of the vagina. Incomplete Mu¨llerian fusion is considered separately in Section 30.7. Visual inspection of the vagina will reveal the presence of a septum. Most longitudinal septa are associated with incomplete Mu¨llerian fusion of the upper genital tract (uterus and cervix). Longitudinal septa may also be found as a component of the Edwards-Gale (camptobrachydactyly) and Johanson-Blizzard syndromes.1,2 In the absence of a syndrome or coexistent incomplete mu¨llerian fusion, somatic anomalies are uncommon. Longitudinal vaginal septa not associated with incomplete mu¨llerian fusion or a genetic syndrome are rare. The etiology is

Fig. 30-22. Schematic of longitudinal vaginal septum.

unknown. Pathogenesis probably involves failure of complete canalization or abnormal mesodermal proliferation of the vagina. Longitudinal vaginal septa rarely cause such clinical problems as dyspareunia or obstruction of the second stage of labor. If symptomatic, the septum can be resected. References (Longitudinal Vaginal Septum) 1. Edwards JA, Gale RP: Camptobrachydactyly: a new autosomal dominant trait with two probable homozygotes. Am J Hum Genet 24:464, 1972. 2. Johanson A, Blizzard R: A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 79:982, 1971.

30.12 Agenesis of the Clitoris Definition

Agenesis of the clitoris is the complete absence of the clitoris with otherwise normal or near-normal external genitalia. There is no evidence of bladder exstrophy, which may give rise to a similar defect. Diagnosis

This defect is rare. Two cases have been reported in which no other major anomalies were detected.1,2 Both instances demonstrated evidence of minor midline fusion failure defects such as absent midline pubic hair or patulous urethra. It is quite likely that there are more patients with this problem but that they go unnoticed and unreported. Del Giudice and Nydorf 3 described agenesis of the clitoris in a patient with the syndrome of cutis marmorata telangiectatica congenita (CMTC). This rare disorder is characterized by persistent livedo reticularis, telangiectases, and superficial ulceration. More than 50% of affected individuals display other somatic anomalies, but the case of Del Giudice and Nydorf is the only one reported thus far with agenesis of the clitoris. Etiology and Distribution

The genital tubercle is the anlagen of the clitoris. Its complete absence seems unlikely. A more likely explanation for this defect appears to be that an event interferes with the development or causes the regression of this midline structure. Falk and Hyman2 suggest that the defect may be a ‘‘forme fruste’’ of bladder exstrophy with an underdeveloped bifid clitoris that is clinically

Female Genital System

undetectable. Agenesis of the clitoris in the context of CMTC may either represent a manifestation of the disorder itself or occur as a malformation from ulceration and healing at the site of a periclitoral hemangioma.

1301

Isolated hypertrophy of the clitoris/clitoromegaly is the isolated enlargement or protrusion of the clitoris without other signs of ambiguity or masculinization of the external female genitalia.

The fetal genital tubercle is the anlage for the clitoris and its male homolog, the penis. The genital tubercle is sensitive to androgen stimulation, and this is a key event in the formation of the penis. Any excess androgenic exposure in utero may result in clitoromegaly. This is the universal pathophysiologic mechanism when an endocrine cause is present. Prolonged androgen exposure postnatally may cause clitoral enlargement as well. Isolated clitoral enlargement can reflect enlargement of the clitoris itself or its surrounding tissue. It is likely that the most common underlying pathology is a variant of the bifid clitoris, where fusion still occurs. Another possibility is that highlighted by the leiomyoma syndrome, in which a growth at the base of the clitoris causes it to protrude. Isolated cysts of the clitoris can produce enlargement and are usually located at the base of the organ but can be found near the tip.4 Clitoral anomalies in the context of multiorgan involvement are usually a reflection of a disorder in the segmentation, fusion, or canalization of embryologic cloacal structures. Several syndromes occasionally display clitoromegaly. They are listed in Table 30-6.5–16 Unfortunately, most reported cases provide little objective description of the clitoral hypertrophy. The clitoromegaly seen with leprechaunism in reality is endocrine mediated. It is thought to reflect insulin-induced androgen secretion from the ovary. A similar process occurs in adults affected with the syndrome. Bonney et al.17 reported a case of complete urethral duplication with hypertrophy of the clitoris and a vaginal urethra. This may reflect a variant of bladder exstrophy with duplication of the clitoris and midline fusion. The clitoromegaly seen in Fraser syndrome may represent the same process.

Diagnosis

Prognosis, Prevention, and Treatment

Clitoral length and breadth vary in proportion at different developmental ages and possibly between races. While several authors have attempted to establish standards for clitoral length and breadth at different gestational and postnatal ages, clinicians rely more on the overall appearance of the individual rather than on any absolute criteria for size.1–3 Three major etiologic categories must be considered in the diagnosis of isolated clitoromegaly: (1) endocrine disorders, (2) isolated clitoral processes, and (3) multisystem disorders. Isolated clitoral hypertrophy can be seen in all the disorders that give rise to ambiguous genitalia. Therefore, these conditions must be considered in the diagnosis. It is important to distinguish hypertrophy of the clitoris itself from hypertrophy of the surrounding tissue. The consistency of the clitoris can also provide important clues. An enlarged clitoris from androgen stimulation feels normal in consistency, whereas localized pathology can give rise to a very firm, indurated organ. Isolated clitoromegaly arising de novo without endocrine pathology should raise the possibility of neurofibromatosis, and the appropriate investigative steps should be taken. This is particularly relevant in an individual with no disorder of pubertal development. Investigations should include abdominal computed tomography or magnetic resonance imaging to rule out intraabdominal neurofibromas.

Clitoromegaly can be diagnosed prenatally, at birth, or later in life. Prenatal diagnosis can be problematic as there is in fact little difference between the size of the fetal penis and clitoris. The clitoris is usually oriented cephalad by contrast to the caudad direction of the penis. Two sets of parallel lines suggest the presence of vulvar tissue, whereas a dome sign is indicative of a scrotal sac. Even in the best of hands, there is only about a 95–97% accuracy for early sex determination. The impact of isolated clitoromegaly is not only cosmetic. The presentation may give rise to confusion about the actual sex of the child. When this is the case, examination to document the presence of vagina and uterus and chromosome analysis may be required. Evaluation should be carried out promptly to permit the sex of rearing to be established early. Counseling of the parents is important to ensure that an understanding of the development of external genitalia is understood. Some suggest that surgical treatment be postponed until the affected person can participate in the decision.18 In most centers, however, this decision continues to lie in the hands of the parents and the physician caring for the child. Treatment first consists of removing the etiologic factor, if possible. Any source of excess androgen must be identified and eliminated. Surgical correction can then be undertaken. If the clitoris is enlarged only and otherwise normal, the preferred procedure is a partial clitoral resection, in which the glans and its neurovascular bundle are preserved. Only the midportion of the shaft of the clitoris is removed and the glans reapproximated to its base. The results have been both cosmetically and functionally effective. If the clitoral tissue itself is abnormal, a clitoridectomy is the more appropriate procedure.

Prognosis, Treatment, and Prevention

The clitoral defect itself is minor, and its main impact is cosmetic in nature. Sexual function could potentially be compromised, but there are no data on this to date. A vulvoplasty could create a midline structure resembling a clitoris, providing a more pleasing external appearance. References (Agenesis of the Clitoris) 1. Russu IG: Absence of clitoris. Endocrinol Ginecol Obstet (Roumania) 5:23, 1938. 2. Falk HC, Hyman AB: Congenital absence of clitoris. A case report. Obstet Gynecol 38:269, 1971. 3. Del Giudice SM, Nydorf ED: Cutis marmorata telangiectatica congenita with multiple congenital anomalies. Arch Dermatol 122:1060, 1986.

30.13 Isolated Hypertrophy of the Clitoris/Clitoromegaly Definition

Etiology and Distribution

As mentioned above, isolated clitoromegaly may be caused by an endocrine disorder, a localized clitoral process, or a multisystem disorder. Precise data on the frequency of this condition are not available.

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Urogenital System Organs

Table 30-6. Syndromes associated with clitoromegaly Syndrome

Additional Prominent Features

OMIM Number Gene/Locus

Beckwith-Wiedemann5–7

Macroglossia, omphalocele, macrosomia, hemihypertrophy, hepatoblastoma

130650 Duplication, pat UPD, 11p15

Bowen8

Failure to thrive, congenital glaucoma, congenital heart defects, agenesis of the corpus callosum, flexion deformities of the fingers

211200

Donahue (leprechaunism)9,10

Elfin facies with thick lips; large, low-set ears; prominent breasts and external genitalia; hirsutism; abnormal carbohydrate metabolism; failure to thrive; motor and mental retardation

246200 INSR, 19p13.2

Fraser11,12

Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactyly

219000 FRAS1, 4q21

Leiomyoma of vulva and esophagus13,14

Lower esophageal leiomyoma with obstruction, leiomyoma at base of clitoris causes enlargement of the clitoris

150700

Neurofibromatosism type I15

Cafe´ au lait spots, neurofibromas, enlargement of the clitoris with significant firmness compatible with neurofibroma, usually appears during adolescence or adulthood

162200 NF1, 17q11.2

Smith-Lemli-Opitz type 2 (Rutledge)16

Joint contractures, cerebellar hypoplasia, renal hypoplasia, urologic anomalies, tongue cysts, shortness of limbs, eye abnormalities, heart defects, gallbladder agenesis, ear malformations

268670 DHCR7, SLOS, 11q12-q13

Long-term physical and psychological follow-up of these patients is important. The works of Masters and Johnson have clearly established that sexual activity can still be pleasurable after a total clitoridectomy. The patients or parents must be advised of this, and any concerns about the external appearance of the genitalia should be discussed in detail. References (Isolated Hypertrophy of the Clitoris/Clitoromegaly) 1. Litwin A, Aitkin I, Merlob P: Clitoral length assessment in newborn infants of 30 to 41 weeks gestational age. Eur J Obstet Gynecol Reprod Biol 38:209, 1991. 2. Oberfield SE, Mondok A, Shavrivar F, et al.: Clitoral size in full-term infants. Am J Perinatol 6:453, 1989. 3. Riley WJ, Rosenbloom AL: Clitoral size in infancy. J Pediatr 96:918, 1980. 4. Teague JL, Angelo L. Clitoral cyst; an unusual cause of clitoromegaly. J Urol 156:2057, 1996. 5. Pettenati MJ, Haines JL, Higgins RR: Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 74:143, 1986. 6. Slavotinek A, Gaunt L, Donnai D: Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet 34:819, 1997. 7. Weksberg R, Nishikawa J, Caluseriu O, et al.: Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 10:2989, 2001. 8. Bowen P, Lee CSN, Zellweger H, et al.: A familial syndrome of multiple congenital defects. Bull Johns Hopkins Hosp 114:402, 1964. 9. Summit RL, Favara BE: Leprechaunism (Donohue’s syndrome): a case report. J Pediatr 74:601, 1969. 10. Hone J, Accili D, Al-Gazali LI, et al.: Homozygosity for a new mutation (ile119-to-met) in the insulin receptor gene in five sibs with familial insulin resistance. J Med Genet 31:715, 1994. 11. Greenburg F, Keenan B, DeYanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986. 12. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003.

13. Schapiro RL, Sandrock AR: Esophagogastric and vulvar leiomyomatosis: a new radiologic syndrome. J Canad Assoc Radiol 24:184, 1973. 14. Wahlen T, Astedt B: Familial occurrence of coexisting leiomyoma of vulva and oesophagus. Acta Obstet Gynec Scand 44:197, 1965. 15. Sutphen R, Galan-Gomez E, Koussef BG: Clitoromegaly in neurofibromatosis. Am J Med Genet 55:325, 1995. 16. Curry CJR, Carey JC, Holland JS, et al.: Smith-Lemli-Opitz syndrometype II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26:45, 1987. 17. Bonney WW, Young HH II, Levin D, et al.: Complete duplication of the urethra with vaginal stenosis. J Urol 113:132, 1995. 18. Diamond M: Pediatric management of ambiguous genitalia and traumatized genitalia. J Urol 162(3 Pt 2):1021, 1999.

30.14 Duplication or Bifidism of the Clitoris/Female Epispadias A bifid clitoris or duplication of the clitoris is usually associated with urethral anomalies, such as female epispadias or urethral duplication, and/or bladder anomalies. Schey et al.1 have reviewed female epispadias, which they consider to be a mild form of bladder exstrophy. The anomaly is rare. The underlying mechanism is that involved with bladder or cloacal exstrophy. It disrupts midline integrity of the lower abdomen and pelvis, including the development of the clitoris. The end result is a bifid clitoris that may be evident or rudimentary. Primary attention must be devoted to repair of the associated exstrophy. Severe cases may be diagnosed in utero. Females with epispadias may present with incontinence, and corrective surgery can be very difficult. Reference (Duplication or Bifidism of the Clitoris/ Female Epispadias) 1. Schey WL, Kandel G, Charles AG: Female epispadias. Report of a case and review of the literature. Clin Pediatr 19:212, 1980.

Female Genital System

30.15 Labial Fusion Definition

Labial fusion is the midline fusion of the labia minora with otherwise normal genitalia. The line of fusion is thin, and the vagina behind it is normal. Diagnosis

Labial fusion is a very common condition. It is usually detected during childhood. The precise etiology is multifactorial, but it usually resolves spontaneously at puberty. This supports the idea that the hypoestrogenic milieu of childhood favors the development of this problem. Labial agglutination at birth is rare and can be confused with masculinized female genitalia with midline fusion. The conditions are distinguished by the presence of a normal vagina behind a thin membrane with a distinct urethral opening in the case of labial fusion. Masculinized genitalia show a thickened perineum and frequently a common urogenital opening. Fraser syndrome can be associated with labial fusion at birth.1 The other features of the syndrome include cryptophthalmia, defects of the auricle, hair growth on the lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, and partial cutaneous syndactyly. Etiology and Distribution

The most common form of labial agglutination is the result of healing secondary to local irritation. The hypoestrogenic environment of childhood favors such conditions. A survey of prepubertal females seen for gynecologic reasons other than sexual abuse showed labial adhesions in close to 40%.2 The defect in Fraser syndrome has been said to reflect the underlying disease process, with slow cell turnover and failure of separation of the labia. While this is a superficially attractive hypothesis, it is flawed since the labia are not initially fused and then separated. Another explanation must be sought. Prognosis, Treatment, and Prevention

The prognosis for labial agglutination is excellent. It can be observed until puberty, at which time it will usually resolve spontaneously. Treatment is indicated when urinary retention occurs from the agglutination or when there is parental anxiety. Topical antibiotic and estrogen therapy will resolve the problem in about 90% of cases. Surgical separation under anesthesia followed by topical estrogen therapy postoperatively is indicated in the other cases. Forceful separation of the labia in the office is clearly contraindicated; the problem rapidly recurs and is more severe in nature. References (Labial Fusion) 1. Ramsing M, Rehder H, Holzgreve W, et al.: Fraser syndrome (cryptophthalmos with syndactyly) in the fetus and newborn. Clin Genet 37:84, 1990. 2. McCann J, Wells R, Simon M, et al.: Genital findings in prepubertal girls selected for nonabuse: a descriptive study. Pediatrics 86:428, 1990.

30.16 Imperforate Hymen A completely imperforate hymen with otherwise normal genitalia is an anomaly that must be distinguished from the other obstruc-

1303

tive conditions of the vagina. The examination of the patient with an imperforate hymen reveals normal labia majora and minora, a completely obstructed vagina on examination, and, very frequently, bulging of the thin membranous hymen during a Valsalva maneuver. If not detected prior to puberty, it may present as hematocolpos. Ultrasound may be of assistance in the diagnosis of this anomaly.1 Cloacal anomalies can be associated with an imperforate hymen.2 Some authors therefore advocate a complete urologic survey in patients presenting with an imperforate hymen. The embryonic vaginal canal is a solid structure that becomes canalized during the second trimester of gestation. Failure of complete canalization can lead to any of a spectrum of anomalies, including imperforate hymen, transverse vaginal septum, and vaginal agenesis. Mor et al.3 report an incidence of imperforate hymen of 0.3% in a survey of female newborns. This is probably an overestimate, as they included all types of hymenal obstruction as opposed to complete imperforate hymen only. Another survey of prepubertal patients presenting with gynecologic complaints showed an incidence of 1.2%.4 Genital trauma, in the context of sexual abuse, can mimic imperforate hymen.5 The prognosis for imperforate hymen is excellent. Recognition is the most important step. Surgical correction is easily accomplished and is not associated with any persistent complications. References (Imperforate Hymen) 1. Blask AR, Sanders RC, Rock JA: Obstructed uterovaginal anomalies: demonstration with sonography. Part H. Teenagers. Radiology 179:84, 1991. 2. Shaw LM, Jones WA, Brereton RJ: Imperforate hymen and vaginal atresia and their associated anomalies. J R Soc Med 76:560, 1983. 3. Mor N, Merlob P, Reisner SH: Types of hymen in the newborn infant. Eur J Obstet Gynecol Reprod Biol 22:225, 1986. 4. McCann J, Wells R, Simon M, et al.: Genital findings in prepubertal girls selected for nonabuse: a descriptive study. Pediatrics 86:428, 1990. 5. Berkowitz CD, Elvik SL, Logan M: A simulated ‘‘acquired’’ imperforate hymen following the genital trauma of sexual abuse. Clin Pediatr 26:307, 1987.

30.17 Absence/Hypoplasia of External Genitalia Hypoplasia or absence of any evidence of development of external genitalia can occur. Hypoplasia of the clitoris is included. This is a relatively rare defect. The external genitalia of the newborn or infant can at times assume a relatively hypoplastic appearance. The obese child may display only the genital fold because of the thick fat pad underlying the labia majora. Chronic inflammatory processes can lead to fusion of the labia majora and minora, giving the perineum a flat, cleftlike appearance leading up to the introitus. It is sometimes difficult to confirm this defect based on the descriptions in the literature. Nonetheless, we relied here on the published descriptions. It is to be noted that we could not find any data about the ‘‘lower limits of normal’’ for size of the female external genitalia. Hypoplasia of the external genitalia may be seen in a number of malformation syndromes. They are listed in Table 30-7.1–11 Hypoplasia of the external genitalia is commonly seen in the context of disorders with cloacal anomalies. It is most important to remember that the normal appearance of the external female genitalia does not depend on any hormonal input until the pubertal phase. While androgen action

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Urogenital System Organs

Table 30-7. Syndromes associated with hypoplasia of the female external genitalia OMIM Number Gene/Locus

Syndrome

Additional prominent features

Antley-Bixler1,2

Craniosynostosis, choanal atresia, humeroradial synostosis, gracile ribs, bowed femora, camptodactyly, renal anomalies

207410 POR (cytochrome P450 reductase), 7q11.2

CHARGE3

Coloboma, heart defects, atresia choanae, retarded growth, genital hypoplasia, ear defects

AD (214800) CHD7, 8q12.1

Fraser4,5

Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactyly

219000 FRAS1, 4q21

Gorlin-Chaudry-Moss6

Craniofacial dysostosis, hypertrichosis, dental and eye anomalies, patent ductus arteriosus

233500

Prader-Willi7

Short stature, obesity, small hands and feet, mental retardation

176270 PWCR(SNRPN), 15q11-q13

Pterygium8

Multiple pterygia and skeletal abnormalities, camptodactyly, syndactyly, facial anomalies, pulmonary hypoplasia

265000

Roberts9

Sparse silvery blond hair, midfacial hemangioma, cleft lip with or without cleft palate, limb reduction defect, intrauterine growth retardation

268300

Robinow10

Short stature, macrocephaly, prominent eyes, short forearms, hemivertebrae

180700, 268310

Schinzel-Giedion11

Severe midface retraction, multiple skull anomalies, heart defect, hydronephrosis, clubfeet, hypertrichosis

233500

is key for normal male sexual phenotype development, such is not the case for the female.

11. Al-Gazali LI, Farndon P, Burn J, et al.: The Schinzel-Giedion syndrome. J Med Genet 27:42, 1990.

References (Absence/Hypoplasia of External Genitalia) 1. Kelley RI, Kratz LE, Glaser RL, et al.: Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. Am J Med Genet 110:95, 2002. 2. Fluck CE, Tajima T, Pandey AV, et al.: Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet 36:228, 2004. 3. Duncan NO III, Miller RH, Catlin FL: Choanal atresia and associated anomalies: the CHARGE association. Int J Pediatr Otorhinolaryngol 15:129, 1988. 4. Greenburg F, Keenan B, DeYanis V, et al.: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986. 5. McGregor L, Makela V, Darling SM, et al.: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 34:203, 2003. 6. Ippel PF, Gorlin RJ, Lenz W, et al.: Craniofacial dysostosis, hypertrichosis, genital hypoplasia, ocular, dental, and digital defects: confirmation of the Gorlin-Chaudhry-Moss syndrome. Am J Med Genet 44:518, 1992. 7. Aughton DJ, Cassidy SB: Physical features of Prader-Willi syndrome in neonates. Am J Dis Child 144:1251, 1990. 8. Chen H, Chang CH, Misra RP, et al.: Multiple pterygium syndrome. Am J Med Genet 7:91, 1980. 9. Freeman MVR, Williams DW, Schimke RN, et al.: The Roberts syndrome. Clin Genet 5:1, 1974. 10. Robinow M, Silverman FN, Smith HD: A newly recognized dwarfing syndrome. Am J Dis Child 117:645, 1969.

30.18 Hyperplasia, Duplication, and Inversion of External Genitalia Hypertrophy of both the labia and clitoris has been described in G syndrome, accompanied by an imperforate hymen.1 Complete duplication of the external genitalia, including the clitoris, has been reported by Kapoor and Saha.2 Their case displayed complete duplication of the bladder, urethra, and external genitalia. Vertical transposition of the external genitalia sometimes occurs such that the urethra exits between the posterior fourchette and the anus.3 This is a rare defect associated with the caudal regression syndrome. The bladder and uterus retain their normal positions relative to each other, but there are often associated cloacal and uterine anomalies. References (Hyperplasia, Duplication, and Inversion of External Genitalia) 1. Arya S, Vieskul C, Gilbert EF: The G syndrome—additional observations. Am J Med Genet 5:321, 1980. 2. Kapoor R, Saha MM: Complete duplication of the bladder, urethra and external genitalia in a neonate—a case report. J Urol 137:1243, 1987. 3. Lage JM, Driscoll SG, Bieber FR: Transposition of the external genitalia associated with caudal regression. J Urol 138:387, 1987.

31 Part VIII Other Systems and Structures

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31 Cutaneous Structures Julie S. Prendiville

T

he skin is a highly complex organ composed of many different structures and cell types. Developmental abnormalities may be isolated to the skin or associated with structural anomalies of the underlying tissues and syndromes involving other organ systems.1–3 Congenital anomalies arise when normal skin development is disrupted by genetic mutations or teratogenic agents. To begin to understand these malformations, a basic knowledge of cutaneous structure and morphogenesis is necessary. Identification of many of the gene mutations associated with inherited cutaneous diseases in recent years has improved our understanding of the molecular basis of skin development.4 The skin is derived from embryonic ectoderm and mesoderm. Development during embryonic and fetal life occurs in overlapping stages of organogenesis (0–60þ days), histogenesis (60 days to 5 months), and maturation (5–9 months).5 Mature skin is composed of three layers: the epidermis, dermis, and subcutaneous fat (Figs. 31-1 and 31-2). The epidermis and dermis interconnect through a complex basement membrane zone at the dermal–epidermal junction. The skin appendages, including hair follicles, nails, sweat glands, and sebaceous glands, have both an epidermal and dermal component. Epidermis

The epidermis derives from the ectoderm, which early in gestation divides into the medial neuroectoderm and a single cell layer of presumptive epidermis on either side. The embryonic epidermis is composed of two cell types: basal cells and the superficial periderm cells adjacent to the amniotic fluid. The epidermis becomes stratified during early fetal development with the formation of a spinous cell layer between the basal layer and periderm. Maturation of the epidermis during late fetal development results in the appearance of the granular cell layer and stratum corneum. Keratinization, a vital step in development of skin barrier function, appears in the hair follicles at weeks 11–15 estimated gestational age (EGA) and in the interfollicular epidermis starting at weeks 22–24 EGA.6 Mature epidermis is composed of four keratinocyte layers at different stages of differentiation (Fig. 31-1). The proliferative basal layer is anchored to the basement membrane at the dermal– epidermal junction by hemidesmosomes. Daughter cells in the spinous layer produce keratin filaments that insert into desmosomes to form interconnections between adjacent keratinocytes.

The granular layer accumulates protein and lipid granules, which are the building blocks of the keratinized stratum corneum and skin barrier function. Terminal differentiation occurs by (1) enucleation of the cell nucleus, (2) aggregation of keratin filaments by the protein filaggrin, (3) cross-linking of protein by transglutaminase to form an insoluble cornified envelope, and (4) extrusion of lipid by lamellar granules. The extruded lipid forms the waterimpermeable ‘‘mortar’’ surrounding the ‘‘bricks’’ of the cornified envelopes in the stratum corneum. The epidermis also contains melanocytes, derived from the neural crest, and Langerhans cells, derived from the mesenchymal bone marrow, as well as small numbers of Merkel cells, a specialized neuroendocrine cell. Neural crest cells destined to become melanocytes migrate though the mesenchyme from the dorsal neural tube to the epidermis, starting in the embryonic period. Melanin production is detected at months 4–5 EGA. Transfer of melanosomes to keratinocytes is detected by 5 months EGA and continues into the first months of postnatal life. Langerhans cells first appear in the epidermis by day 40 EGA. These antigenpresenting macrophages develop their characteristic Birbeck granules and CD1- positive staining properties during the second trimester and reach adult numbers in the third trimester. Dermis and Subcutis

The cell of origin of dermal cells differs depending on body site.5 On the face, dermal cells derive from the neural crest, on the dorsal trunk from the dermatomyotome portion of the differentiated somite, and on the limbs from the lateral plate mesoderm.5 The mesenchymal cells of the embryonic dermis are embedded in a hydrated gel, rich in hyaluronic acid. The early dermis is highly cellular with fine filaments but few fibers. Production and assembly of collagen and elastin fibrils into large fibers occurs during the second and third trimesters. Nerves and blood vessels are evident in the embryo and continue to develop and mature in the fetus and in early postnatal life. Vasculogenesis (formation of blood vessels de novo) is complete by the fifth gestational month. Angiogenesis (budding and migration from existing vessels) continues into postnatal life until definitive vascular patterns are established by approximately 3 months of age.6,7 The mature dermis is composed of collagen and elastin fibrils in a proteoglycan matrix. It contains fibroblasts, mast cells, and 1307

1308

Other Systems and Structures

Fig. 31-1. Schematic figure showing features of normal skin.

macrophages as well as nerve fibers and a horizontal and vertical vascular network. The epidermal appendages are also located within the dermis. Toward the end of the first trimester, the sparse

matrix of the hypodermis can be distinguished from the dermis. Preadipocytes derived from the mesenchyme become evident in the second trimester. Mature adipocytes with fat lobules and fibrous septa develop in the third trimester.

Fig. 31-2. Microscopic section of normal skin. Compare with schematic in Figure 31-1. (A) melanocyte. (B) Rete ridge. (C) Dermal papilla. (D) Horny layer. (E) Squamous cell layer. (F) Basal cell layer. (G) Sebaceous cells. (H) Follicular cells of pilosebaceous follicle. (Courtesy of Dr. A. Benohanian.)

Dermal–Epidermal Junction

A simple basement membrane is apparent at 8 weeks gestational age. Specialized structures appear in early fetal development, and all of the clinically important basement membrane proteins are detectable by the end of the first trimester. These include keratins 5 and 14, plectin, a6b4 integrins, laminin, and types IV, VII, and XVII collagen. The mature dermal–epidermal junction is an integrated structure composed of the basement membrane together with components of the adjacent basal cells and upper dermis. Keratin intermediate filaments in the basal cells attach to hemidesmosomes on the basal surface of these cells. The hemidesmosomes bind to anchoring filaments in the basal lamina. These filaments attach to anchoring fibrils that traverse the lamina densa and mesh with the connective tissue of the underlying dermis. Epidermal Appendages

Hair follicle formation first appears on the head at days 75–80 EGA and spreads caudally and ventrally. An early ectodermal bud proliferates and elongates to form the hair peg. At weeks 12–14, a bulb develops at the base of the hair peg that surrounds a cluster of subjacent mesenchymal cells which become the follicular dermal papilla.5 Two subsequent bulges along the hair follicle develop into the sebaceous gland and the site of insertion of the arrector pili muscle (Fig. 31-1). Maturation of the bulbous hair

Cutaneous Structures

peg results in the outer and inner root sheaths of the hair follicle and development of the hair shaft from matrix cells at the base of the follicle. Fine lanugo hairs are evident from weeks 19–21. A first wave of lanugo hair is shed into the amniotic fluid; a second wave is shed in the perinatal period with subsequent growth of terminal hair shafts on the scalp and vellus hairs elsewhere. Maturation of the sebaceous glands develops in parallel with the hair follicle, and sebum is synthesized and secreted in the second and third trimesters. Nail formation begins at weeks 8–10 EGA. The definitive nail plate is formed within months 4–5 EGA. The glandular portions of palmar and plantar eccrine glands are evident at 16 weeks along the parallel ectodermal ridges of the embryonic volar pads. The epidermal portion of the eccrine ducts is not complete until 22 weeks EGA. Elsewhere, the eccrine and apocrine glands begin to bud in the fifth month of gestation. The apocrine sweat gland, which buds from the upper portion of the hair follicle, functions in the fetus and becomes quiescent in the neonate. Eccrine glands arise independently and do not appear to function in utero. References 1. Sybert VPL: Genetic Skin Disorders. Oxford University Press, New York, 1997. 2. Eichenfield LF, Frieden IJ, Esterly NB: Textbook of Neonatal Dermatology. WB Saunders, Philadelphia, 2001. 3. Schachner LA, Hansen RC: Pediatric Dermatology, ed 3. Mosby, New York, 2003. 4. Pulkkinen L, Ringpfeil F, Uitto J: Progress in heritable skin diseases: molecular bases and clinical implications. J Am Acad Dermatol 47:91, 2002. 5. Loomis CA, Birge M: Fetal skin development. In: Textbook of Neonatal Dermatology, Eichenfield LF, Frieden IJ, Esterly NB, eds. WB Saunders, Philadelphia, 2001, p 1. 6. Eady R, Holbrook K: Structure and function: embryogenesis of the skin. In: Pediatric Dermatology, Schachner LA, Hansen RC, eds. Mosby, New York, 2003, p 3. 7. Brouillard P, Vikkula M: Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340, 2003.

31.1 Skin Cysts, Sinuses, Dimples, Tags, Tails, and Clefts Dermoid cysts are subcutaneous epithelium-lined cysts with epidermal appendages, including hair follicles, and may contain hair, sebum, keratin, and sometimes apocrine glands. They are believed to arise as a consequence of displacement of dermal and epidermal cells into and along embryonic lines of fusion. Sites of predilection are the lateral eyebrow, periorbital region, midline of the nose, and scalp. Dermoid cysts present as an asymptomatic firm or compressible nodule. Lesions on the nose, and occasionally elsewhere, may have a central punctum sometimes containing several fine hairs. Midline nasal lesions may have an accompanying sinus tract, sometimes with intracranial extension.1 Bronchogenic cysts present in the skin in the region of the sternal notch and sides of the manubrium sterni. They are believed to derive from abnormal budding of the ventral segment of the primitive foregut as it divides into tracheal and esophageal components before fusion of the sternum in the early embryonic period. They are lined by pseudostratified columnar epithelium with goblet cells.2 The cyst wall may contain smooth muscle, mucous glands, and rarely cartilage. These cysts may have a central fistula and discharge mucoid material.

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Thyroglossal duct cysts result from a failure to obliterate the embryonic thyroglossal duct. They appear on the skin in the midline of the neck and move upward on swallowing or protrusion of the tongue. They should not be confused with an ectopic thyroid gland, which occurs in the same location. Branchial cleft cysts and sinuses present on the neck and preauricular area (Fig. 31-3). They are believed to be remnants of the pharyngeal pouches and branchial clefts. They are lined with stratified or pseudostratified ciliated columnar epithelium and/or stratified nonkeratinizing squamous epithelium. The most common are defects of the second branchial cleft located along the anterior border of the sternocleidomastoid muscle. These developmental defects are often bilateral. Branchial cleft sinuses may have an associated skin tag containing cartilage. Most are incomplete fistulae, but a true fistula may occur. Secondary infection is a concern. Preauricular pits and sinuses may result from defects of development of the first branchial cleft, which extends from the anterior superior neck to the preauricular area (Fig. 31-4).2 Accessory tragi present as cartilage-containing skin tags in the same distribution. Although usually an isolated finding, they may be associated with other abnormalities in the Goldenhar syndrome.

Fig. 31-3. Bilateral cervical branchial sinuses in branchiootorenal syndrome.

Fig. 31-4. Preauricular pit anterior to the superior helix in branchiootorenal syndrome.

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Other Systems and Structures

Midline cervical clefts on the anterior lower neck are also thought to result from abnormal morphogenesis of the first branchial cleft. They present as a vertical linear atrophic patch, often with a skin tag or sinus. They may be associated with other congenital midline defects. Congenital lip pits commonly occur on the commissures and may be bilateral.3 They are frequently familial with autosomal dominant inheritance. Unilateral and bilateral paramedian cysts of the lower lip may also be sporadic or familial. Midline cysts of the upper lip are rare. In the Van der Woude syndrome, bilateral cysts of the lower lip are associated with cleft lip and palate (Fig. 31-5).3 The gene for this autosomal dominant disorder, IRF6, has been localized to the distal long arm of chromosome 1. Lip pits are also associated with oral-facial-digital syndrome type 1 and popliteal pterygia syndrome. Supraumbilical raphe is a midline cleft above the umbilicus, believed to result from abnormal fusion of the abdominal wall. There may be sternal clefting. This malformation is associated with hemangiomas and other vascular anomalies in the PHACES syndrome (see Section 31.8). Supernumerary nipples are located along embryonic breast lines, which extend from the axilla to the anterior thigh. They are often bilateral and present as a brown macule or papule in the typical distribution.

Fig. 31-5. Lower lip pits and repaired cleft lip associated with the van der Woude syndrome. (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Institute, Wilmington, Delaware.)

Umbilical polyps are remnants of ectopic gastrointestinal mucosa caused by incomplete closure of the omphalomesenteric duct. If the entire duct is patent, the omphalomesenteric fistula will discharge fecal fluid. Non-patent lesions present as a red polypoid lesion in the umbilicus without fecal discharge. They must be distinguished from the more common umbilical granuloma, which represents incomplete epithelialization following separation of the umbilical cord. Median raphe cysts of the penis are flesh-colored papules that appear in a line along the anterior scrotum and undersurface of the penis. They are believed to be the result of abnormal fusion of the urethral or genital folds.2 Accessory digits may occur on any digit but are most common on the lateral aspect of finger 5 (see Section 21.1). They are often bilateral. Amniotic bands resulting from premature rupture of the amniotic sac may cause a variety of disruptions in the fetus (see Section 20.3). The most common cutaneous abnormalities are constriction bands and amputations of the distal limbs. 31.1.1 Cutaneous Markers of Spinal Cord Dysraphism

Congenital skin anomalies overlying the spinal cord, particularly at significant neural tube closure sites such as the lumbosacral area, may be a sign of occult spina bifida and spinal cord tethering. These include dimples and dermal sinuses, congenital scars/aplasia cutis, skin tags and tails, hypertrichosis, lipomas, hemangiomas, and capillary malformations. More than one type of lesion may overlie a spinal cord defect, e.g., a capillary malformation may be associated with a lipoma or hypertrichosis, or a hemangioma may occur in conjunction with a congenital scar or skin tag. Dimples located in the intergluteal cleft are a common normal variant. They are usually small with a visible base. A deeper or larger sacral dimple, and dimples located above the gluteal crease, are suspicious for spinal cord dysraphism and may represent a dermal sinus communicating directly with the spinal canal. Congenital scars, likely representing areas of healed aplasia cutis, are also a marker. Skin tags, tails, or pseudotails are located over the lumbosacral spine in the midline. A skin tag is composed of epidermis and a dermal stalk. A human tail contains a central core of fatty tissue with nerve bundles and vascular structures. A pseudotail is a hamartoma composed of fatty tissue and sometimes cartilage.2 Hypertrichosis in a localized patch over the lumbosacral area may be a normal finding, an isolated area of hypertrichosis, or a sign of underlying spinal cord dysraphism. When associated with a vascular stain or other cutaneous lesion, the incidence of a spinal cord defect is high. Congenital lipomas in this area are virtually always indicative of spina bifida occulta and many represent a lipomeningomyelocele extending into the spinal canal. Hemangiomas associated with spinal cord defects are usually large metameric lesions overlying the midline; they are often associated with other skin lesions such as a scar, dermal sinus, or skin tag.4 Capillary malformations or vascular stains associated with spinal cord dysraphism are usually, but not invariably, associated with other skin malformations or an underlying lipomeningomyelocele. A small isolated vascular stain is a common benign finding in the lumbosacral area. Similar benign vascular stains are frequently seen over neural tube closure sites on the nape of the neck, occiput, and glabella.

Cutaneous Structures

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Table 31-1. Classification of aplasia cutis congenita

References (Skin Cysts, Sinuses, Dimples, Tags, Tails, and Clefts) 1. Pensler JM, Baur BS, Naidich TP: Craniofacial dermoids. Plast Reconstruc Surg 82:953, 1988. 2. Drolet BA: Developmental abnormalities. In: Textbook of Pediatric Dermatology. Eichenfield LF, Frieden IJ, Esterly NB, eds. WB Saunders, Philadelphia, 2001, p 117. 3. Larralde M, Eichenfield LF: Neonatal skin and skin disorders: developmental anomalies. In: Pediatric Dermatology. Schachner LA, Hansen RC, eds. Mosby, St. Louis, 2003, p 223. 4. Goldberg N, Hebert A, Esterly N: Sacral hemangiomas and multiple congenital abnormalities. Arch Dermatol 122:684, 1986.

Type 1. Scalp ACC without associated abnormalities Type 2. Scalp ACC with limb defects: Adams-Oliver syndrome Type 3. Scalp ACC with associated epidermal and organoid nevi Type 4. Scalp or truncal ACC overlying embryologic malformations Type 5. ACC on the trunk associated with fetus papyraceus or placental infarcts Type 6. ACC associated with epidermolysis bullosa Type 7. ACC on the limbs without blistering Type 8. ACC caused by specific teratogens, e.g., methimazole, intrauterine viral infection Type 9. ACC associated with genetic malformation syndromes

31.2 Aplasia Cutis Congenita Aplasia cutis congenita (ACC) is a congenital localized absence of skin. Lesions may be single or multiple and most commonly occur on the scalp but also on the face, trunk, or limbs. ACC may be a solitary finding or associated with other developmental defects and genetic disorders. A classification of the different variants of ACC is outlined in Table 31-1.1 Lesions in the newborn may be ulcerated, covered with a thin membrane of atrophic skin, or may have already healed with scarring. Aplasia cutis congenita of the scalp, most commonly presents as one or multiple small circular lesions on or around the vertex (Fig. 31-6). Although usually sporadic, some cases are inherited as an autosomal dominant trait. A membrane-like surface overlying the defect may result in a bullous or cystic appearance in the newborn. This type of membranous aplasia cutis is often surrounded by a hair collar.2 Both the membranous appearance and the hair collar disappear after the first year of life to leave a circular area of scarring alopecia. These lesions are believed to be related to incomplete closure along embryonic fusion lines and may be a ‘‘forme fruste’’ of a neural tube closure defect. Underlying bone defects may be present at birth and heal spontaneously. Heterotopic brain tissue or meningeal rests are sometimes found in the skin on histologic examination. Aplasia cutis with a hair collar may also occur overlying an encephalocele or meningocele.3

Modified from Frieden.1

Unusual linear or stellate areas of ACC may be associated with underlying venous, arterial, or arteriovenous malformations. Large areas of skin ulceration with underlying bone defects are seen at birth in the Adams-Oliver syndrome. ACC on the scalp is also associated with trisomy 13 (Fig. 31-7), trisomy 18, Opitz syndrome, and the Johanson-Blizzard syndrome.4 Aplasia cutis congenita on the face occurs only rarely. These lesions are located on the lateral forehead and temple and appear along embryonic fusion lines.5 The terms focal facial dermal hypoplasia, Brauer syndrome, and ectodermal dysplasia of the face have been used to describe these lesions, which are sometimes familial. An association with other developmental defects is seen in Setleis syndrome. Linear skin defects with microphthalmia are seen in MIDAS/MLS syndrome and associated with fat herniation and papillomas in focal dermal hypoplasia (Goltz syndrome). ACC-like lesions with skin papillomas are also a feature of the oculocerebrocutaneous (Delleman) syndrome. Aplasia cutis congenita on the trunk and limbs is a distinctive form of ACC seen on the lateral sides of the trunk in the twin survivor of an intrauterine fetal death. A fetus papyraceus may be evident at birth. The etiology is unknown, but is believed to be related to placental infarction. Gastrointestinal abnormalities and other developmental defects may be present in some cases. ACC

Fig. 31-6. Left: single midline circular lesion of aplasia cutis congenita. The patient’s twin sister had a similar lesion. Middle and right: bilateral areas of aplasia cutis congenita of the posterior parietal area in a newborn infant and an adult. At birth, the defects are circular, well circumscribed, and covered with a thin membrane. In adult life, the lesions appear well healed, with opaque, hairless scars.

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Other Systems and Structures

Fig. 31-7. Large, irregular areas of aplasia cutis congenita (arrows) in two infants with trisomy 13.

presenting as a midline skin defect in the lumbosacral area should raise concern about underlying spinal cord dysraphism. Congenital skin ulceration on the anterior aspect of the lower legs is associated with epidermolysis bullosa (EB). Previously known as Bart syndrome, it is usually a manifestation of dominant dystrophic EB. Congenital ulceration or scarring may also be seen with intrauterine blistering from maternal varicella or herpes simplex virus infections. The linear atrophic lesions of focal dermal hypoplasia (Goltz syndrome) commonly involve the trunk and limbs. References (Aplasia Cutis Congenita) 1. Frieden IJ: Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646, 1986. 2. Drolet B, Prendiville J, Golden J, et al.: Membranous aplasia cutis with hair collars: congenital absence of the skin or a neuroectodermal defect? Arch Dermatol 131:1427, 1995. 3. Drolet B, Clowry I Jr, McTigue K, et al.: The hair collar sign: a cutaneous marker for neural tube dysraphism. Pediatrics 96:309, 1995. 4. Evers MJ, Steijlen PM, Hamel BJ: Aplasia cutis congenita and associated disorders: an update. Clin Genet 47:295, 1995. 5. Drolet BA, Baselga E, Gosain AK, et al.: Preauricular skin defects: a consequence of a persistent ectodermal groove. Arch Dermatol 133:1551, 1997.

31.3 Mosaicism and the Lines of Blaschko Many developmental skin disorders and genodermatoses can be explained by genetic mosaicism. Mosaicism occurs when two genetically different populations of cells originate from a single genetically homogeneous zygote.1 The mosaic phenotype may be caused by difference in a single gene, group of genes, or the entire chromosome. Functional mosaicism results from random X inactivation in normal females (the Lyon hypothesis). This becomes clinically apparent in the skin in X-linked dominant disorders that are lethal in the XY male (Table 31-2). It also explains limited disease expression in female carriers of certain non-lethal X-linked recessive disorders, such as anhidrotic ectodermal dysplasia, in which the severity of the disease depends on the degree

of lyonization (Table 31-2). In autosomal mosaicism, with the possible exception of paradominant inheritance, the patterned skin lesions are not familial because the mutation is either lethal if present in every cell of the developing embryo, or is non-lethal and inherited as a generalized, non-mosaic skin disorder. Cutaneous mosaicism is recognized in the skin as distinctive skin patterns, the most familiar of which are the linear and whorled lines of Blaschko (Fig. 31-8). These are believed to correspond to the paths of migration of an abnormal clone of cells during embryogenesis. Happle recognizes two variants of Blaschko lines: (1) narrow bands, as seen in incontinentia pigmenti, and (2) broad bands, as observed in the large segmental areas of pigmentation in the McCune-Albright syndrome.2 Other recognizable skin patterns are the checkerboard pattern, the phylloid pattern, a patchy pattern, and lateralization as seen in CHILD syndrome.2 Mosaicism in X-linked dominant disorders is usually limited to females because the mutation is lethal in the hemizygous male. The occasional occurrence of these diseases in male patients can be explained by an XXY genotype, a gametic half-chromatid mutation, or a post-zygotic mutation early in embryogenesis. Autosomal disorders characterized by mosaicism are seen in both males and females and will be discussed later in relation to disorders of pigmentation, epidermal nevi, and hamartomas. Mosaic forms of generalized skin disorders are described in neurofibromatosis, tuberous sclerosis, Darier disease, and epidermolytic hyperkeratosis.1,2 A linear mosaic pattern following the lines of Blaschko may also be seen in acquired skin diseases such as lichen striatus, lichen planus, and psoriasis. 31.3.1 Incontinentia Pigmenti

Incontinentia pigmenti is an X-linked dominant disorder caused by a mutation in the NEMO (NF-kappa B essential modulator) gene at Xq28.3 Skin lesions are distributed along the lines of Blaschko and occur in four overlapping stages (Fig. 31-9). The first stage is characterized by linear vesicular lesions on an erythematous base in the newborn period and first months of life. The blisters may continue to recur during the first year and, less

Cutaneous Structures Table 31-2. Disorders characterized by X-chromosome mosaicism X-linked dominant disorders (male-lethal) Incontinentia pigmenti Focal dermal hypoplasia MIDAS/MLS syndrome X-linked chondrodysplasia punctata/Conradi-Hunermann syndrome CHILD syndrome Oral facial digital syndrome, type 1 X-linked recessive disorders (mosaicism in female carriers only) Anhidrotic ectodermal dysplasia Hypohidrotic ectodermal dysplasia with immunodeficiency Menkes syndrome Partington syndrome Dyskeratosis congenita Ichthyosis follicularis, atrichia, and photophobia (IFAP) Modified from Happle.2

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and include seizures, developmental delay, spastic diplegia, and quadriplegia. 31.3.2 Focal Dermal Hypoplasia

Focal dermal hypoplasia, or Goltz syndrome, is an X-linked dominant disorder characterized by linear areas of cutaneous atrophy, fat herniation, and telangiectasia.4 Fibrovascular papillomas develop in the mucosa and periorificial areas around the mouth, nose, anus, and genitalia. Alopecia and lesions resembling aplasia cutis congenita are seen in some patients, as well as nail dystrophy and hyperkeratoses on the palms and soles. Non-cutaneous manifestations include developmental abnormalities of the eyes and teeth, and skeletal anomalies. Syndactyly is a common finding, and short stature and other skeletal abnormalities are described. The radiologic finding of osteopathia striata is considered pathognomonic but is not seen in infants and young children. Mental retardation and microcephaly are present in a minority of patients. 31.3.3 MIDAS/MLS Syndrome

Microphthalmia and striking congenital linear areas of cutaneous atrophy characterize this syndrome, which is believed to be inherited as an X-linked dominant trait and may be a variant of Goltz syndrome. The linear lesions follow the lines of Blaschko and are limited to the head and neck. Deletions have been demonstrated at Xp22.3. Corneal opacities and orbital cysts occur in addition to microphthalmia and may be bilateral. Congenital heart disease and neurologic disease may be associated.5 31.3.4 X-linked Dominant Chondrodysplasia Punctata/Conradi-Hunermann Syndrome

Fig. 31-8. Lines of Blaschko. This ‘‘system of lines’’ on the surface of the human body which the linear nevi and dermatoses follow was prepared by Blaschko in 1901.2

commonly, in later childhood and adult life, often precipitated by fever and viral infections. In the second stage, the vesicles are superseded by hyperkeratotic lesions. These are replaced in the third stage by whorls and streaks of hyperpigmentation, corresponding histologically to the dermal pigment incontinence that gives the disorder its name. Finally, there are corresponding lines of hypopigmentation with absence of hair follicles and eccrine glands. Several stages may be present at the same time, and not all stages occur in every patient. Scalp lesions give rise to scarring alopecia, and nail dystrophy may be seen. Non-cutaneous manifestations of incontinentia pigmenti include retinal vascular proliferation in the newborn and infant, which can lead to blindness, and missing and peg-shaped teeth. Neurologic complications occur in a small percentage of patients

The X-linked dominant form of chondrodysplasia punctata is caused by a mutation in EPB (emopamil binding protein) at Xp11.22-p11.23, an important gene in biosynthesis of cholesterol.6 Its name derives from the radiologic finding of punctuate stippling of the epiphyses seen in infancy. Erythematous lesions with a thick adherent scale are evident at birth in a linear and whorled distribution corresponding to the lines of Blaschko. Scaling may persist, or resolve during infancy to leave a patterned follicular atrophoderma and scarring alopecia. Hypopigmentation and hyperpigmentation also occur. Sectorial cataracts are characteristic of this disease and may be unilateral. Skeletal dysplasia is present in many cases; specifically, the epiphyseal abnormality may result in asymmetric shortening of the long bones. 31.3.5 CHILD Syndrome

The CHILD syndrome (congenital hemidysplasia with ichythosiform nevus and limb defects) is an X-linked dominant disorder in which the skin and skeletal abnormalities are limited to one side of the body. The skin lesions are yellowish, wax-like scales and may follow Blaschko lines or involve the entire half of the body, excluding the face. They have a predilection for the flexures, a pattern that Happle has termed ‘‘ptychotrophism.’’7 The skin lesion may partially resolve or persist into adult life. Contralateral lesions may be present. Like X-linked chondrodysplasia punctata, epiphyseal stippling may be seen in infancy. There is striking shortening or absence of limbs on the same side as the nevus. In addition to ipsilateral limb defects, there may be ipsilateral congenital anom-

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Other Systems and Structures

Fig. 31-9. Incontinentia pigmenti. Streaking and ‘‘marble cake’’ pigmentary changes of left chest and lower limb in a 2-year-old girl (A, B). The pigmentary changes were preceded by vesicular and verrucous phases (C, D).

alies of the heart, lungs, brain, and kidneys. A mutation in the NHSDL (NADPH steroid dehydrogenase-like protein) gene at Xq28, important in lipid biosynthesis, has been found in patients with CHILD syndrome.8 The unilateral distribution is hypothesized to occur because X-inactivation interferes with the origin of a clone of organizer cells in the dorsocranial region of the embryo.2 31.3.6 Oral-Facial-Digital Syndrome, Type 1

This X-linked dominant disorder is characterized by oral anomalies, including an abnormal frenulum and cysts, multiple milia on the

face and ears, cleft lip and/or palate, and digital anomalies including polydactyly, syndactyly, and brachydactyly. Polycystic kidneys, mental retardation, and cerebral structural abnormalities are associated. Scarring alopecia occurs in a pattern following the lines of Blaschko on the scalp.9 The gene for OFD1, CXorf5, is located in Xp22.10 References (Mosaicism and the Lines of Blaschko) 1. Bolognia JL, Orlow SJ, Glick SA: Lines of Blaschko. J Am Acad Dermatol 31:157, 1994. 2. Happle R, Ko¨nig A: Cutaneous mosaicism. In: Pediatric Dermatology. Schachner LA, Hansen RC eds. Mosby, New York, 2003, p 368.

Cutaneous Structures 3. Shastry BS: Recent progress in the genetics of incontinentia pigmenti (Bloch-Sulzberger syndrome). J Hum Genet 45:323, 2000. 4. Goltz RW: Focal dermal hypoplasia: an update. Arch Dermatol 128:1108, 1992. 5. Happle R, Daniels O, Koopman RJ: Midas syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. Am J Genet 47:710, 1993. 6. Has C, Bruckner-Tuderman L, Muller D, et al.: The ConradiHunermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet 13:1951, 2000. 7. Happle R: Ptychotropism as a cutaneous feature of the CHILD syndrome. J Am Acad Dermatol 23:763, 1990. 8. Konig A, Happle R, Bornholdt D, et al.: Mutations in the NHSDL gene, encoding for 3-beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet 90:339, 2000. 9. Del C, Boente M, Prime N, et al.: A mosaic pattern of alopecia in the oral-facial-digital syndrome Type 1 (Papillon-Leage and Psaume syndrome). Pediatr Dermatol 16:367, 1999. 10. Ferrante MI, Giorgio G, Feather SA, et al.: Identification of the gene for oral-facial-digital type 1 syndrome. Am J Hum Genet 68:569, 2001.

31.4 Cutaneous Hamartomas A cutaneous hamartoma is a developmental abnormality of the skin in which there is an excess of one or more mature, or nearly mature, tissue structures normally found at that site. The term nevus is often used synonymously, although not all ‘‘nevi’’ are hamartomas, e.g., nevus anemicus, nevus depigmentosus. Whether a lesion is designated a hamartoma or a nevus largely depends on tradition. An organoid nevus or organoid hamartoma refers to a malformation that consists of more than one type of tissue structure and where identification of a single tissue of origin is not possible.1 Most hamartomas are isolated, sporadic malformations. They can be single or multiple, localized or extensive, and may be distributed in a linear or whorled pattern corresponding to the lines of Blaschko. Some arise from a postzygotic mutation in the embryo that leads to somatic mosaicism. Others are manifestations of well-defined genetic disorders such as tuberous sclerosis. Epidermal hamartomas may be associated with underlying abnormalities in the central nervous system, skeleton, or other organs. Rarely, a postzygotic mutation that involves the germ line results in transmission of a generalized skin disease to subsequent offspring.2 Epidermal nevus is a term used to encompass a group of hamartomas of ectodermal origin in which there is clinical and histologic overlap. These include the linear verrucous epidermal nevus, inflammatory linear verrucous epidermal nevus (ILVEN), sebaceus nevus, and nevus comedonicus. Other hamartomas that may be considered epidermal nevi are syringocystadenoma papilliferum, linear porokeratosis, and porokeratotic eccrine nevus. Epidermal nevi occur also as a component of the Proteus syndrome and CHILD syndrome.3 When applied without qualification, the term epidermal nevus usually refers to a linear verrucous, or keratinocytic, epidermal nevus. The keratinocytic epidermal nevus presents at birth or during early childhood and may continue to extend for a variable period of time.3 Rarely, new lesions become apparent in adolescence or adult life. Lesions vary in extent from a small cluster or linear arrangement of pigmented, warty papules to widespread linear and swirled areas of pigmentation following the lines of Blaschko. A

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linear epidermal nevus may involve an entire limb, half of the body in a unilateral distribution, or both sides of the trunk, limbs, and face in a symmetric pattern with demarcation at the midline. Extensive bilateral lesions have been referred to historically as ‘‘systematized epidermal nevus’’ or ‘‘ichthyosis hystrix,’’ and unilateral lesions as ‘‘nevus unius lateris.’’ Epidermal nevi may have a macerated appearance at birth because of prolonged contact with amniotic fluid. During childhood the degree of verrucosity varies from subtle, almost flat pigmentation to a grossly elevated, warty appearance.3 There is a tendency to become more verrucous with age, particularly during puberty. Epidermal nevi involving the head and neck often exhibit the morphology of a nevus sebaceous. Scalp lesions may also be associated with wooly hair nevus and occasional epidermal nevi have overlying hypertrichosis. A linear lesion that impinges on the nail matrix may cause dystrophy of the involved nail. The linear inflammatory verrucous epidermal nevus (ILVEN) is a verrucous, erythematous lesion that can occur at any site but is most often seen on the limbs or perineum in girls. It is extremely pruritic and may simulate linear psoriasis or linear lichen planus. It is rarely present at birth but may appear in the first months of life. The majority of epidermal nevi are isolated lesions with no evidence of extracutaneous disease. Multiple associated anomalies are seen in the so-called ‘‘epidermal nevus syndrome.’’4 Manifestations of this very variable syndrome include developmental abnormalities of the central nervous system, skeleton, eye, and heart as well as tumors of the genitourinary tract, precocious puberty, and vitamin D–resistant rickets.2,3 In the Proteus syndrome, epidermal nevi occur in association with limb overgrowth, lipomatous lesions, cerebriform malformations of the feet, and cutaneous vascular anomalies.3 The CHILD syndrome is characterized by verrucous lesions corresponding to the lines of Blaschko in conjunction with limb reduction defects.3 In phakomatosis pigmentokeratotica (PPK), the coexistence of an epidermal nevus of the non-epidermolytic type and a melanocytic speckled lentiginous nevus is frequently associated with neurologic and musculoskeletal anomalies.3 The distribution of epidermal nevi in patterns following the lines of Blaschko suggests somatic mosaicism. Chromosomal mosaicism has been demonstrated in two patients with linear verrucous epidermal nevi.5 The concept of mosaicism is supported by observation of lesions with the histology of epidermolytic hyperkeratosis in the parents of children with bullous ichthyosiform erythroderma.2 The same keratin 10 gene mutation was identified in lesional skin from parents with epidermal nevi and in their offspring with generalized skin disease.2 This phenomenon has not been observed with other epidermal nevi, suggesting that the genetic defects in these cases may be lethal if inherited.3 Epidermal nevi are now thought to represent a phenotypic expression of several genetic defects due to postzygotic mutations, rather than a single disease. Whether the basic pathogenetic defect of non-epidermolytic lesions lies in the dermal fibroblast or in the keratinocyte is unknown. The nevus sebaceous (of Jadassohn) is an organoid hamartoma of appendageal structures that is usually evident at birth. It occurs where pilosebaceous and apocrine structures are prominent and is considered to be a variant of epidermal nevus on the head and neck. The typical nevus sebaceous is a pink-yellow or yellow-orange plaque with a pebbly or velvety surface that is located on the scalp or face (Fig. 31-10). It varies in size from one to several centimeters and can be round, oval, or linear in shape.

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Other Systems and Structures

Fig. 31-10. Linear sebaceous nevus in a newborn (A, B) and an older child (C, D).

Lesions on the scalp present as a congenital area of circumscribed alopecia. There may be evolution from a slightly raised plaque at birth to a flat, almost macular lesion in infancy and childhood. A verrucous or cobblestone appearance develops in adolescence when the sebaceous and apocrine glands enlarge and proliferate. Some lesions present with an atypical papillomatous or cerebriform morphology. There can be some overlap between the morphology of a sebaceous nevus and an epidermal verrucous nevus on the head and neck. Both types of nevus may coexist at different sites when extensive lesions are present. The nevus sebaceous is usually an isolated lesion with no extracutaneous findings. Rarely, it is associated with other developmental abnormalities in a variable malformation syndrome known as the ‘‘Schimmelpenning-Feuerstein-Mims syndrome,’’ ‘‘linear nevus sebaceous syndrome’’ or ‘‘epidermal nevus syndrome.’’3,4 The nevus sebaceous can be of any size or shape but is often extensive or linear, with a distribution following the lines of Blaschko. Extracutaneous manifestations include mental retardation, seizures, coloboma of the eyelid, lipodermoids of the conjunctiva, choristomas, and other ophthalmologic and central

nervous system abnormalities. Skeletal, cardiac, and genitourinary abnormalities, and vitamin D–resistant rickets are also reported. The pathogenesis of this hamartoma is unknown. There is no racial or gender predilection. There have been rare reports of familial lesions, which may be explained by paradominant inheritance. The linear nevus sebaceous (or epidermal nevus) syndrome occurs sporadically, and an autosomal lethal mutation that survives by mosaicism has been postulated.4 The nevus sebaceous has a propensity to develop neoplastic growths, most of which are benign appendageal tumors such as syringocystadenoma papilliferum, trichilemmoma, trichoblastoma, and apocrine cystadenoma. Malignant tumors include basal cell epithelioma, squamous cell carcinoma, and tubular apocrine carcinoma.3 These tumors are localized to the skin lesion and rarely metastasize, although they may be locally invasive. Basal cell epitheliomas may be confused histologically with trichoblastoma, and it is possible that the incidence of malignant tumors is less than previously reported.3 Nevus comedonicus is a developmental abnormality of the pilosebaceous unit that appears as a grouped or linear arrangement of

Cutaneous Structures

small or large comedones. Lesions present at birth or during infancy in the majority of cases. Groups of enlarged follicular openings containing pigmented, comedone-like keratin plugs may be localized or extensive. Most nevi are unilateral and located on the face or upper trunk. They frequently have a linear arrangement. Extensive lesions are distributed along the lines of Blaschko and are limited at the midline.3 There may be associated white papules representing milia, closed comedones, or deeper follicular cystic structures. Later in childhood or adolescence these lesions may develop painful, inflammatory cystic nodules and acneiform scarring. In most cases there are no extracutaneous manifestations. Rarely, a nevus comedonicus is associated with central nervous system, skeletal, and ocular abnormalities.3 In these cases, unilateral cataract and skeletal abnormalities are found on the same side of the body as the nevus. Porokeratotic eccrine nevus (porokeratotic eccrine and ostial dermal duct nevus) is a congenital hamartoma of the eccrine ducts. Although usually present at birth, lesions may first appear in later childhood or adult life. This hamartoma is characterized clinically by grouped comedo-like keratotic papules or pits on a palm or sole.3 Occasionally, lesions may be more widespread with a linear distribution. Keratotic papules and plaques that are located in sites other than the palms and soles resemble linear verrucous epidermal nevi. There may be associated anhidrosis. There are no recognized systemic manifestations. The pathogenesis is believed to represent a circumscribed disorder of keratinization localized to the acrosyringium. Congenital smooth muscle hamartoma is a benign cutaneous developmental anomaly characterized by an excess of arrector pili muscle within the reticular dermis. It is usually evident at birth or shortly thereafter. Rarely, extensive involvement may be associated with the phenotype of the Michelin tire baby. The typical congenital smooth muscle hamartoma presents as a lightly pigmented plaque or patch with overlying hypertrichosis.6 The trunk, in particular the lumbosacral area, is the site of predilection, but lesions may also occur on the proximal limbs. Perifollicular papules are sometimes evident. The overlying hair is vellus in type. Hypertrichosis is not invariable, and the hamartoma may present as a plaque of perifollicular papules with little or no increase in hair growth. Transient elevation or a rippling movement of the lesion due to contraction of the muscle bundles can sometimes be elicited by rubbing or stroking the surface. Rarely, a congenital smooth muscle hamartoma has a linear configuration or presents with multiple lesions. There are no systemic findings with localized lesions. Associated mental retardation, seizures, and other developmental abnormalities are reported in association with extensive smooth muscle hamartoma as a manifestation of the Michelin tire baby syndrome.5 Unilateral hypoplasia of the breast and other cutaneous, muscular, or skeletal defects may be associated with smooth muscle hamartoma in the Becker nevus syndrome.3,8 Congenital smooth muscle hamartoma is believed to represent aberrant development of pilar smooth muscle during fetal life. It has been suggested that the hamartoma involves other structures such as neural tissue and hair. The hypertrichosis appears to result from increased hair length and diameter rather than from an increase in hair density. Congenital Becker nevus is a hamartoma characterized by a circumscribed area of hyperpigmentation and hypertrichosis. It is commonly located over the shoulder, chest, or scapula and has a predilection for males. Although usually acquired in adolescence,

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a number of congenital cases of Becker nevus have been described.8 Histopathologic examination reveals acanthosis and hyperpigmentation of the basal layer of the epidermis as well as a variable dermal component consisting of smooth muscle bundles that resembles congenital smooth muscle hamartoma. The Becker nevus syndrome refers to an association with unilateral hypoplasia of the female breast and ipsilateral skeletal defects such as hypoplasia of the shoulder girdle or arm. Other reported anomalies include supernumerary nipples, scoliosis, spina bifida occulta, congenital adrenal hyperplasia, and accessory scrotum.4 The syndrome is twice as common in females, possibly because ipsilateral hypoplasia of the breast is easily recognized and reported. A postzygotic mutation that gives rise to mosaicism may explain the location of the nevus and associated anomalies in a similar body region.8 Although both the isolated nevus and the Becker nevus syndrome are generally sporadic, there have been a few reports of familial aggregation.8 Michelin tire baby syndrome is characterized by numerous transverse skin folds on all four limbs. These circumferential ringed creases may be associated with an underlying diffuse nevus lipomatosus or a smooth muscle hamartoma. There have been two reports of autosomal dominant transmission.7 There may be an association with other congenital defects, such as mental retardation, microcephaly, hemiplegia, hemihypertrophy, and chromosomal defects, suggesting a contiguous gene syndrome.7 When associated with an underlying smooth muscle hamartoma, there is often diffuse hyperpigmentation and hypertrichosis. The skin folds usually diminish slowly as the child grows. Nevus lipomatosus cutaneous superficialis is a hamartoma composed of mature fat. Clinically, these lesions present at birth or later in childhood as an asymptomatic, soft or rubbery plaque with a polypoid or cerebriform appearance. A linear arrangement of flesh-colored to yellow lesions in a zosteriform pattern is the most common presentation. They are frequently observed in the lumbosacral or perineal areas but can be located elsewhere. Histologic specimens show mature unencapsulated adipose tissue infiltrating between collagen bundles in the superficial and deep dermis. Similar features may be observed in the lipomatous lesions of encephalocraniocutaneous lipomatosis, focal dermal hypoplasia, or benign fat herniations on the feet of infants. Encephalocraniocutaneous lipomatosis is a neurocutaneous disorder in which lipomatous scalp lesions, often with overlying alopecia, are associated with ipsilateral brain defects.9 Porencephaly, paramedullary lipomas, ventricular dilation, and cerebral atrophy are described. Papules and nodules are seen on the bulbar conjunctiva, and ocular blood vessels may be abnormal. A connective tissue nevus is characterized by excessive deposition of one or both of the collagen or elastin components of dermal connective tissue. These hamartomas may occur sporadically or as a familial disorder with autosomal dominant transmission.10 Connective tissue nevi are also seen as a manifestation of genetic syndromes, notably the ‘‘shagreen patch’’ or collagenoma in tuberous sclerosis and the multiple elastic tissue nevi of Buschke-Ollendorff syndrome. A connective tissue nevus may be present at birth but most become evident during childhood or adolescence. Connective tissue nevi present clinically as asymptomatic, firm, skin-colored to yellowish nodules or plaques located on the trunk or limbs. The surface of the lesion may be smooth or have a ‘‘cobblestone,’’ ‘‘leather grain’’ or ‘‘peau d’orange’’ appearance. They may be solitary or multiple. A linear morphology is sometimes observed.

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Other Systems and Structures

Osteopoikilosis is seen in association with elastic tissue nevi in the Buschke-Ollendorff syndrome. The skin lesions in this condition may rarely be present at birth, but the distinctive bone changes are not reported in infancy. The collagenoma or ‘‘shagreen patch’’ of tuberous sclerosis usually develops in later childhood, although other stigmata of the disease may be present at birth or in early infancy. Cardiomyopathy may occur in association with the multiple lesions of familial cutaneous collagenoma and with collagenomas and hypogonadism.10 A cerebriform collagenoma on the sole of the foot may be an isolated phenomenon or a component of Proteus syndrome. In familial cutaneous collagenoma, the skin lesions are inherited as an autosomal dominant trait. Tuberous sclerosis and Buschke-Ollendorff syndrome are also inherited by autosomal dominant transmission. Somatic mosaicism may be postulated for sporadic lesions. Fibrous hamartoma of infancy is a benign fibrous mass that is present at birth or develops during the first 2 years of life.11 Occasional cases have been described in children between ages 2 and 10 years. Males are affected more frequently than females. Fibrous hamartoma presents as a subcutaneous lesion located around the axillae, shoulders, and upper chest wall. It may involve other sites such as the inguinal region, extremities, head, and neck. It is usually a solitary nodule, measuring 2–5 cm in diameter that feels lumpy to palpation. Occasionally, these lesions are multifocal. There are no symptoms or systemic associations. Proteus syndrome is characterized by multifocal hamartomas of many tissues (Fig. 31-11).3 It occurs sporadically and is believed to result from a lethal autosomal mutation surviving by mosaicism. Epidermal nevi and cutaneous pigmentary anomalies are associated with subcutaneous masses containing lipomatous, collagenous, vascular, and lymphatic tissue. There is a characteristic cerebriform appearance on the palms and soles. Skeletal anoma-

lies include macrocephaly, macrodactyly, and hemihypertrophy. Visceral hamartomas may also occur. Mutations in the PTEN tumor suppressor gene are reported in some patients with Proteus syndrome, but the cases have been questioned.3 There may be genetic heterogeneity.3 References (Cutaneous Hamartomas) 1. Poomeechaiwong S, Golitz LE: Hamartomas. Adv Dermatol 5:257, 1990. 2. Paller AS, Syder AJ, Chan Y-M, et al.: Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 331:1408, 1994. 3. Happle R, Rogers M: Epidermal nevi. Adv Dermatol 18:175, 2002. 4. Happle R: How many epidermal nevus syndromes exist? A clinicogenetic classification. J Am Acad Dermatol 25:550, 1991. 5. Stosiek N, Ulmer R, von den Driesch P, et al.: Chromosomal mosaicism in two patients with epidermal verrucous nevus: demonstration of chromosomal breakpoint. J Am Acad Dermatol 30:622, 1994. 6. Zvulunov A, Rotem A, Merlob P, et al.: Congenital smooth muscle hamartoma: prevalence, clinical findings, and follow-up in 15 patients. Am J Dis Child 144:782, 1990. 7. Schnur RE, Herzberg AJ, Spinner N, et al.: Variability in the Michelin tire syndrome: a child with multiple anomalies, smooth muscle hamartoma, and familial paracentric inversion of chromosome 7q. J Am Acad Dermatol 28:364, 1993. 8. Happle R, Koopman RJJ: Becker nevus syndrome. Am J Med Genet 68:357, 1997. 9. Grimalt R, Ermacora E, Mistura L, et al.: Encephalocraniocutaneous lipomatosus: case report and review of the literature. Pediatr Dermatol 10:164, 1993. 10. Uitto J, Santa Cruz DJ, Eisen AZ: Connective tissue nevi of the skin: clinical, genetic and histopathologic classification of hamartomas of the collagen, elastin, and proteoglycan type. J Am Acad Dermatol 3:441, 1980. 11. Paller AS, Gonzalez-Crussi F, Sherman JO: Fibrous hamartoma of infancy. Arch Dermatol 125:88, 1989.

Fig. 31-11. Facial and limb lipoatrophy in an 8-year-old male with Proteus syndrome. Note massive lipomatous overgrowth of the back and widening of left foot caused by verrucous tumor of the plantar surface. The patient’s identical twin was not affected.

Cutaneous Structures

31.5 Disorders of Keratinization Inherited disorders of keratinization are caused by abnormal epidermal differentiation and are characterized clinically by scaling of the skin or hyperkeratosis (Fig. 31-12).1 They include the ichthyoses, as well as the various types of palmoplantar keratoderma, follicular hyperkeratosis, and erythrokeratoderma. Abnormal keratinization is also involved in a number of other developmental disorders such as epidermolysis bullosa simplex, the X-linked dominant genodermatoses, and the ectodermal dysplasias. Many of the basic molecular defects responsible for these conditions have been identified.1,2 Mutations in genes encoding keratin proteins as well as proteins inherent to the cornified envelope, desmosomes, gap junctions (connexins), and enzymes necessary for epidermal protein and lipid metabolism, DNA repair and transcription, and the calcium ion pump may each result in abnormal development of the epidermis. The gene mutations and the diseases with which they are associated are tabulated in Table 31-3.1 31.5.1 The Ichthyoses

The ichthyoses are a heterogeneous group of disorders characterized by diffuse scaling of the skin. The skin changes are present at birth or in the first year of life. Ichthyosis may be an isolated finding or associated with extracutaneous disease in a number of Fig. 31-12. Hyperkeratosis showing thickening of the horny layer (A) of the epidermis. Granular cell layer (B), squamous cell layer (C), and basal cell layer (D) are normal. Compare with Figs. 31-1 and 31-2.

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defined syndromes.2 In some types of congenital ichthyosis there is underlying generalized erythema. Newborns with ichthyosis may present with erythroderma and scaling, a collodion membrane, or, rarely, the harlequin fetus phenotype. Neonatal erythroderma is seen in Netherton syndrome and in congenital ichthyosiform erythroderma. A collodion membrane is a feature of more than one type of ichthyosis. It is usually a manifestation of autosomal recessive lamellar ichthyosis or congenital ichthyosiform erythroderma but can be seen in Sjo¨gren-Larsson syndrome (Fig. 31-13A), Gaucher syndrome type 2, Conradi-Hunermann syndrome, and trichothiodystrophy. A collodion membrane-like appearance may be seen in newborns with anhidrotic ectodermal dysplasia and the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome. Some infants with a collodion membrane at birth subsequently develop clinically normal skin. The harlequin fetus is an autosomal recessive disorder characterized by thick scaling and fissuring of the skin at birth associated with severe eclabium and ectropion (Fig. 31-13B). The classification, inheritance, and clinical characteristics of the ichthyoses are summarized in Tables 31-4 and 31-5. 31.5.2 Keratoderma

Other disorders of keratinization include the palmar plantar keratodermas, erythrokeratodermas, and follicular keratoses. There are many forms of palmar plantar keratoderma, presenting with diffuse, focal/punctuate, or striate hyperkeratosis of the palms and soles (Tables 31-6 and 31-7).1 Erythrokeratoderma is an autosomal dominant disorder that has two variants, erythrokeratoderma variabilis and progressive symmetric erythrokeratoderma.1,2 Follicular keratosis occurs in the X-linked IFAP (ichthyosis follicularis, alopecia, photophobia) syndrome and in Darier and Hailey-Hailey disease. It is most commonly seen in keratosis pilaris. Severe keratosis pilaris is a feature of Noonan syndrome. Some cases of keratosis pilaris develop scarring alopecia of the eyebrows and, rarely, of scalp hair. References (Disorders of Keratinization) 1. Irvine AD, Paller AS: Molecular genetics of the inherited disorders of cornification: an update. Adv Dermatol 18:111, 2002. 2. Irvine AD, Paller AS: Inherited disorders of keratinization. Curr Probl Dermatol 14:71, 2002. 3. Traupe H: The Ichthyoses: A Guide to Clinical Diagnosis, Genetic Counseling, and Therapy. Springer-Verlag, New York, 1989.

31.6 Epidermolysis Bullosa Epidermolysis bullosa is a clinically and genetically heterogeneous group of blistering disorders caused by defective development of the dermal–epidermal junction. It is classified into three main types, dystrophic, junctional, and simplex, depending on the level of separation within the basement membrane region (Table 31-8).1 The severe recessive dystrophic (Fig. 31-14) and milder dominant dystrophic variants are caused by mutations in the type VII collagen gene COL7A1. Anchoring fibrils in the dermis are composed of type VII collagen, and blistering at this site below the basement membrane heals with scarring and milia formation. In junctional EB (JEB), the level of separation is within the basement membrane zone. The most severe form of JEB is the Herlitz, or lethal, type. This type results from mutations in the laminin 5 gene. Laminin 5

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Other Systems and Structures

Table 31-3. Protein abnormalities and gene mutations associated with developmental disorders of keratinization Class of Protein

Protein

Gene

Disease

Inheritance

Cornified envelope

Loricrin Loricrin

LOR LOR

Progressive symmetric erythrokeratoderma Vohwinkel syndrome

AD AD

Cytoskeleton

Keratin 1 Keratin 1 Keratin 1

KRT1 KRT1 KRT1

AD AD

Keratins 1 & 10 Keratin 2e Keratins 6A & 16 Keratins 6B & 17 Keratin 9

KRT1, KRT10 KRT2e KRT6A, KRT16 KRT6B, KRT17 KRT9

Diffuse non-epidermolytic PPK Ichthyosis hystrix Curth-Macklin Cyclic ichthyosis with epidermolytic hyperkeratosis Bullous ichthyosiform erythroderma Ichthyosis bullosa of Siemens Pachyonychia congenita, type 1 Pachyonychia congenita, type 2 Epidermolytic PPK of Vorner

Plakophilin 1 Desmoplakin 1

PKP1 DSP

AR AR

Desmoplakin 1 Desmoglein 1 Plakoglobulin

DSP DSG1 JUP

Ectodermal dysplasia/skin fragility Dilated cardiomyopathy with wooly hair and striate PPK Striate PPK Striate PPK Naxos disease

Gap junction

Connexin Connexin Connexin Connexin

GJB2 GJB2 GJB6 GJB4

Connexin 31 Metabolic and enzymes

Phytanol-CoA alpha-hydroxylase Fatty aldehyde dehydrogenase Steroid sulfatase b-glucocerebrosidase Transglutaminase Tyrosine transaminase LETKI 3-b-Hydroxysteroid-D8, D7-isomerase Emopamil-binding protein Cathepsin C Cathepsin C CGI-58

CTSC CTSC CGI-58

DNA repair and transcription

Xeroderma pigmentosum Group D protein Group B protein

XPD or ERCC2 ERCC3

Trichothiodystrophy

AR

Ca2þ ion pump

SERCA2 Ca2þ-ATPase P-type Ca2þ-ATPase

ATP2A2 ATP2C1

Darier-White disease Hailey-Hailey disease

AD AD

Secreted proteins

SLURP-1

AMS

Mal de Meleda PPK

AR

Desmosome

26 26 30 30.3

AD AD AD AD AD

AD AD AR

GJB31

Vohwinkel syndrome (classic) KID syndrome Hidrotic ectodermal dysplasia Erythrokeratoderma variabilis with erythema gyratum repens Erythrokeratoderma variabilis

AD AD/sporadic AD AD AD

PAHX or PHYH

Refsum disease

AR

ALDH3A2

Sjogren-Larsson syndrome

AR

ARSC1 BGA TGM1 TAT Spink5 NHSDL

X-linked recessive ichythosis Gaucher syndrome, type 2 Lamellar ichthyosis Richner-Hanhart syndrome Netherton syndrome CHILD syndrome

XR AR AR AR AR XD

EBP

Chondrodysplasia punctata (Conradi-Hunerman) Papillon-Lefevre syndrome Haim-Munk Chanarin-Dorfman (neutral lipid storage disease)

XD AR AR

KID = keratosis, ichythosis, deafness syndrome, PPK = palmar plantar keratoderma. Modified from Irvine and Paller.1

is an essential component of the anchoring filaments that connect the hemidesmosomes of the basal cells to the anchoring fibrils in the dermis. A second severe form of JEB associated with pyloric atresia results from mutations in a6 or b4 integrin genes. Less severe, non-lethal forms of JEB are caused by mutations in laminin 5 or in type XVII collagen genes. All forms of JEB are autosomal recessive disorders. There are three main autosomal dominant types of EB simplex (EBS), each caused by mutations in the basal keratins K5 and K14. These are EBS Dowling-Meara, EBS Koebner, and EBS Weber-Cockayne. A rare form of EBS with mottled pigmentation

is also described. An autosomal recessive variant of EBS is associated with late-onset muscular dystrophy and results from mutations within plectin, a protein that connects keratin filaments in the basal cell to the hemidesmosomal inner plaque. The classification of EB includes many other subtypes, some of which are no longer considered distinct entities.2 References (Epidermolysis Bullosa) 1. Corden LD, McLean WHI, Irvine AD: Skin: hereditary disorders. In: Nature Encyclopedia of the Human Genome. Cooper D, ed. Nature Publishing Group, New York, 2003.

Cutaneous Structures

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Fig. 31-13. (A) Ichthyosis in a male with Sjo¨gren-Larsson syndrome. (B) Ichthyotic plaques and fissures in newborn infant with harlequin ichthyosis.

2. Fine JD, Eady RAJ, Bauer EA, et al.: Revised classification system for inherited epidermolysis bullosa: report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol 42:1051, 2000.

31.7 Developmental Disorders of Connective Tissue Ehlers-Danlos syndrome (EDS) is a heterogeneous group of disorders characterized by abnormal collagen formation. The known gene mutations are summarized in Table 31-9. In EDS types Ia and II, the collagen defect results in hyperextensible skin, easy bruising, fragile skin that heals with scarring, and joint hypermobility (Fig. 31-15). Type III is characterized by hypermobile joints that dislocate easily. In type IV EDS, the skin is thin and translucent rather than hyperextensible, with a prominent subcutaneous venous pattern, thin facial appearance, and acrogeria; the collagen defect in this life-threatening variant causes spontaneous rupture of major blood vessels as well as the uterus and bowel.1 There is skin fragility and easy bruising of the skin in type VI, in which kyphoscoliosis and ocular abnormalities are found, and type VIIA and B, associated with arthrochalasia. Type VIIC, or dermatosparaxis, is characterized by loose, sagging skin. Periodontitis is a hallmark of type VIII EDS. Marfan syndrome is an autosomal dominant disorder caused by mutation in fibrillin-1 and consequent abnormal development of the elastic fiber system. Striae distensae are a common cutaneous finding, and elastosis perforans serpiginosa occasionally occurs in this condition. Cutis laxa is caused by abnormal development of elastic tissue. It is characterized by loose, non-elastic skin as well as abdominal and inguinal hernias. There are three genetically distinct variants. The X-linked form, also known as EDS type IX or occipital horn syndrome, is caused by a defect in copper-transporting ATPase. The milder autosomal dominant form has been linked to mutations in

the elastin gene. An autosomal recessive type is associated with diaphragmatic hernias and early-onset emphysema. Pseudoxanthoma elasticum is associated with mutations in the ATP-binding cassette transporter gene, resulting in calcification of the elastic tissues of the dermis, retina, and systemic arteries.2 Osteoma cutis is caused by heterotopic differentiation of osteoblasts in the dermis and deposition of osteoid tissue. This may occur as a manifestation of Albright hereditary osteodystrophy (AHO). Other variants of primary osteoma cutis are described as progressive osseous heteroplasia,3 congenital plate-like osteoma cutis,4 and familial ectopic ossification or hereditary osteoma cutis.5 AHO is associated with pseudohypoparathyroidism, in which there is an abnormal end-organ response to parathormone, and pseudopseudohypoparathyroidism, in which osteoma cutis and the skeletal anomalies of AHO are seen in the absence of, or prior to development of, metabolic dysfunction. Mutations in the GNAS1 (guanine nucleotide-binding protein, alpha stimulating activity polypeptide) gene on chromosome 20q13.2 have been linked to AHO and progressive osseous heteroplasia (POH).6,7 Paternal inheritance of the gene mutation is associated with the POH phenotype and maternal inheritance with AHO. References (Developmental Disorders of Connective Tissue) 1. Pepin M, Schwarze U, Superti-Furga A, et al.: Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 342:673, 2000. 2. Pulkkinen L, Ringpfeil F, Uitto J: Progress in heritable skin diseases: molecular bases and clinical implications. J Am Acad Dermatol 47:91, 2002. 3. Miller ES, Esterly NB, Fairley JA: Progressive osseous heteroplasia. Arch Dermatol 132:787, 1996. 4. Sanmartin O, Alegre V, Martinez-Aparicio A, et al.: Congenital platelike osteoma cutis: case report and review of the literature. Pediatr Dermatol 10:182, 1993. 5. Gardner RJM, Yun K, Craw SM: Familial ectopic ossification. J Med Genet 25:113, 1988.

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Other Systems and Structures

Table 31-4. The ichthyoses Disorder

Skin Findings

Associated Features

Ichthyosis vulgaris

Fine white scale

Atopy

X-linked recessive ichthyosis

Fine white scale or dark brown scaling

Corneal opacities, may have contiguous gene syndrome with short stature, hypogonadism

Harlequin fetus

Thick scale with fissuring

Ectropion, eclabion

Lamellar ichthyosis

Large adherent scale

Ectropion

Congenital ichthyosiform erythroderma

Fine white scale with erythroderma

Ectropion

Bullous congenital ichthyosiform erythroderma

Scaling, blistering, epidermal fragility

None

Ichthyosis bullosa of Siemens

Flexural hyperkeratosis

None

Ichthyosis hystrix (Curth-Macklin)

Spiky hyperkeratosis

None

Familial peeling skin

Superficial peeling

Koilonychia, onycholysis

Netherton

Erythroderma in infancy, ichthyosis linearis circumflexa

Atopic diathesis, failure to thrive in infancy, trichorrhexis invaginata, alopecia

Ectodermal dysplasia/skin fragility syndrome

Skin fragility, keratotic plaques, PPK

Hypohidrosis

Trichothiodystrophy

May have collodion membrane, variable ichthyosis

Photosensitivity, brittle hair, decreased fertility, short stature

KID

Thick leathery plaques, with stippled hyperkeratosis

Keratitis, sensorineural deafness

CHILD

Unilateral waxy hyperkeratosis

Limb reduction defects Unilateral organ hypoplasia Chondrodysplasia punctata

X-linked chondrodysplasia punctata

Linear, adherent scale with erythroderma

Cataracts Short proximal limbs

CHIME

Erythematous scaling plaques

Colobomas, conductive hearing loss, mental retardation

Sjo¨gren-Larsson

Variable ichthyosis with thickening of skin

Diplegia or tetraplegia Retinal glistening white dots

Refsum disease

Late-onset fine scale

Retinitis pigmentosa

Multiple sulfatase deficiency

Mild scaling

Mental retardation

Neu-Laxova

Variable ichthyosis

Intrauterine growth retardation Sensorineural deafness Cataracts, strabismus, nystagmus Mental retardation

Gaucher syndrome, type 2

Collodion membrane at birth; fine scale afterward

Hepatosplenomegaly, neurologic dysfunction

Chanarin-Dorfman (neutral lipid storage disease)

Fine scale, occasionally erythema

Myopathy, hepatosplenomegaly

Modified from Irvine and Paller.2

6. Patten JL, Johns JR, Valle D, et al.: Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med 322:1412, 1990. 7. Shore EM, Ahn J, de Beur J, et al.: Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. New Engl J Med 246:99, 2002. 8. Corden LD, McLean WHI, Irvine AD. Skin: hereditary disorders. In: Nature Encyclopedia of the Human Genome. Cooper D, ed. Nature Publishing Group, New York, 2003.

31.8 Vascular Malformations Vascular anomalies are subdivided into vascular malformations and vascular tumors.1,2 A vascular malformation is a developmental defect of the blood or lymphatic vessels, whereas a vascular tumor is characterized by endothelial cell hyperplasia. Vascular

malformations are further subdivided into capillary, venous, and lymphatic malformations, all of which are slow-flow lesions, and high-flow arteriovenous malformations. Complex or combined vascular anomalies include capillary-venous, capillary-lymphatic, capillary-venous-lymphatic, venous-lymphatic, and capillary-arteriovenous malformations (Table 31-10). The most common vascular tumor of infancy is the infantile hemangioma. This is a benign tumor that proliferates in infancy followed by spontaneous regression during the first 10 years of life. Other vascular tumors of infancy include the rapidly-involuting congenital hemangioma (RICH), the non-involuting congenital hemangioma (NICH), tufted angioma, kaposiform spindle cell hemangioenthothelioma, and congenital eccrine angiomatous hamartoma. The widespread application of the term hemangioma to all congenital vascular lesions in the past has caused much confusion in the literature. Old terminology such as cavernous hemangioma, capillary hemangioma, and lymphangioma should no longer be used.

Cutaneous Structures

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Table 31-5. Classification of the ichthyoses Disorder

Inheritance

Clinical Diagnosis

Ichthyosis vulgaris

AD

Clinical

X-linked recessive ichthyosis

XR

Decreased levels of WBC arylsulfatase C; elevated plasma cholesterol; abnormal lipoprotein electropheresis

Harlequin fetus

AR

Clinical

Lamellar ichthyosis

AR

Clinical

Congenital ichthyosiform erythroderma

AR

Clinical

Bullous congenital ichthyosiform erythroderma

AD

Characteristic histology shows epidermolytic hyperkeratosis

Ichthyosis bullosa of Siemens

AD

Clinical

Ichthyosis hystrix (Curth-Macklin)

AD

Clinical

Familial peeling skin syndrome

AR

Clinical, characteristic histology

Netherton syndrome

AR

Hair microscopy shows trichorrhexis invaginata: bamboo hairs, golf tee hairs

Ectodermal dysplasia/skin fragility syndrome

AR

Clinical

Trichothiodystrophy

AR

Hair microscopy with polarization shows characteristic tiger-tail pattern

KID syndrome

AD/sporadic

Clinical, hearing test

CHILD syndrome

XD

Clinical

X-linked chondrodysplasia punctata

XD

Clinical

CHIME syndrome

AR

Clinical

Sjo¨gren-Larsson

AR

Fatty alcohol dehydrogenase assay of cultured fibroblasts

Refsum disease

AR

Phytanic acid levels

Multiple sulfatase deficiency

AR

Plasma cholesterol sulfate increased; decreased steroid sulfatase levels

Neu-Laxova syndrome

AR

Clinical

Gaucher syndrome, type 2

AR

Enzyme studies on cultured fibroblasts

Chanarin-Dorfman syndrome (neutral lipid storage disease)

AR

Lipid droplets in granulocytes, characteristic skin histology

Modified from Irvine and Paller.2

31.8.1 Capillary Malformations

Salmon patches, angel kisses, stork bites, and butterfly-shaped marks are fanciful names which refer to midline capillary malformations that are present at birth and often regress spontaneously within the first 2 years of life. They typically occur over the glabella and central forehead, sometimes in a V-shaped distribution, the eyelids, nose, upper lip, occiput and vertex, nape of the neck, and sacral area (Fig. 31-16). Facial lesions affect almost 50% of newborns and almost always disappear. Vascular stains on the nape of the neck and sacral area tend to persist. A persistent midline facial lesion may be inherited as an autosomal dominant trait.4 Persistent forehead lesions are associated with certain syndromes such as Beckwith-Wiedemann syndrome. Craniofacial malformations may underlie a midline facial capillary malformation. The Nova syndrome refers to the association of a glabellar vascular stain with a variety of intracranial malformations, including Dandy-Walker malformation, hydrocephalus, and cerebellar vermis agenesis.5 The butterfly-shaped mark overlying the sacrum, which almost always persists, has been linked to spinal cord dysraphism. However, many authors believe the risk to be low in the absence of other cutaneous signs such as a sinus tract, tuft of hair, or lipoma. The same is true for lesions on the scalp where a vascular

stain associated with an abnormal tuft or collarette of hair may overly a neural tube closure defect. Port-wine stains (or nevus flammeus) are permanent capillary malformations that present as a flat vascular stain in 0.3% of newborns.4 The pink, red, or purple discoloration is usually uniform but may have a reticulated appearance. It occurs most commonly on the head and neck, but may involve any area of the body (Fig. 31-17). Port-wine stains vary in size from small localized lesions to extensive disfiguring malformations. With age, they tend to become darker in color, and there is often overgrowth of the underlying bone and soft tissues. Facial lesions involving the V1 or V1/V2 distribution may be associated with ipsilateral choroidal vascular anomalies, congenital glaucoma, and a vascular malformation of the leptomeninges in the Sturge-Weber syndrome. Limb lesions may be part of a more complex capillary-venous or capillary-venous lymphatic malformation associated with limb overgrowth in the Klippel-Trenaunay syndrome. Limb undergrowth is occasionally found and referred to as the Servelle-Martorell syndrome. Port-wine stains are also seen in Proteus syndrome and in the Bannayan-Riley-Ruvalcaba syndrome. A port-wine stain may be associated with pigmentary anomalies in the various forms of phakomatosis pigmentovascularis. Cutis marmora telangiectatica congenita (CMTC) is characterized by a reticulate purple vascular anomaly present at birth that may become less apparent with time. It occurs most commonly

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Table 31-6. Palmar plantar keratodermas (PPK) Disorder

Distribution

Inheritance

Other Findings

Epidermolytic PPK of Vorner

Diffuse

AD

None

Mal de Meleda

Diffuse

AR

Knuckle pads, digital autoamputation, koilonychias, subungual hyperkeratosis

Hidrotic ectodermal dysplasia (Clouston)

Diffuse

AD

Nail dystrophy, paronychia, alopecia, oral leukokeratoses

Vohwinkel syndrome (classic variant)

Diffuse

AD

Sensorineural deafness, pseudoainhum, digital autoamputation

Vohwinkel syndrome (ichthyotic variant)

Diffuse

AD

Diffuse ichthyosis

Bart-Pumphrey syndrome

Diffuse

AD

Sensorineural deafness, knuckle pads, leukonychia

Keratolytic winter keratoderma (Oodtshoorn syndrome)

Diffuse

AD

Centrifugal peeling of palms, soles, sometimes buttocks and trunk

PPK of Sybert

Diffuse

AD

Pseudoainhum Digital autoamputation

Corneodermatoosseous syndrome

Diffuse

AD

Photophobia, corneal dystrophy, onycholysis, brachydactyly, stort stature, dental decay, medullary narrowing of digits

Naegeli-Francheschetti syndrome

Diffuse

AD

Reticulate hyperpigmentation, nail and dental dystrophy, absent dermatoglyphics

Schopf-Schultz-Passarge syndrome

Diffuse

AR

Hypodontia, hypotrichosis, eyelid cysts, facial telangiectasia, multiple squamous cell carcinomas

Olmstead syndrome

Focal/diffuse

AD

Hypotrichosis, perioral plaques

Pachyonychia congenital, type 1

Focal

AD

Symmetric subungual hyperkeratosis, oral leukokeratoses, natal teeth

Pachyonychia congenita, type 2

Focal

AD

Symmetric subungual hyperkeratoses

Striate PPK

Focal/striate

AD

none

Striate PPK with cardiomyopathy and wooly hair

Focal/striate

AR

Dilated cardiomyopathy

Naxos syndrome

Focal

AR

Arrhythmogenic right ventricular dysplasia, cardiomyopathy

Howel-Evans syndrome

Focal

AD

Esophageal carcinoma, oral leukokeratosis, carcinoma

Papillon-Lefebre syndrome

Focal

AR

Periodontitis, hypotrichosis, nail fragility, calcification of dura mater, eyelid cysts

Richner-Hanhart syndrome

Focal

AR

Photophobia, corneal erosions, mental retardation

Punctate PPK

Punctate

AD

Malignancy

Porokeratosis punctata palmaris et plantaris

Punctate

AD

None

Acrokeratoelastoidalis

Punctate

AD

None

Modified from Irvine and Paller.1

Table 31-7. Follicular keratosis Disorder

Appearance

Inheritance

Other Findings

Keratosis Pilaris

Follicular

AD

Atopy, Noonan Syndrome

Keratosis pilaris spinulosa decalvans

Follicular

AD

Corneal degeneration, alopecia, loss of eyebrows

Ichythosis follicularis (IFAP syndrome)

Spiny follicular

XR

Alopecia, photophobia, nail dystrophy, short stature, psychomotor delay

Darier disease

Yellow-brown, greasy papules

AD

Neuropsychiatric problems, frequent bacterial and herpes simplex superinfection

on the limbs, and there is often hypoplasia of the affected limb. The deep-purple lesions are interspersed with areas of skin and subcutaneous atrophy and sometimes ulceration. Associated neurologic and musculoskeletal developmental anomalies are reported, although most cases are an isolated defect. A widespread variant of CMTC is seen in the Adams-Oliver syndrome associated with limb defects and aplasia cutis congenita of the scalp. CMTC may be difficult to differentiate from a reticulated portwine stain, and both CMTC and port-wine stains sometimes coexist

in the same patient. Widespread reticulate port-wine stains/CMTC can occur in association with macrocephaly and hemihypertrophy. Intracranial vascular anomalies may also be associated. 31.8.2 Venous Malformations

Venous malformations may present at birth or first become apparent in childhood. They are slow-flow lesions with a blue or

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Table 31-8. Gene mutations and developmental defects in epidermolysis bullosa Type of EB

Gene

Developmental Abnormality

EBS Dowling-Meara

KRT5, KRT14

Keratin 5 and 14 in basal cells

EBS Koebner

KRT5, KRT14

Keratin 5 and 14 in basal cells

EBS Weber-Cockayne

KRT5, KRT14

Keratin 5 and 14 in basal cells

EBS with mottled pigmentation

KRT5

Keratin 5 in basal cells

EBS with muscular dystrophy

PLEC1

Plectin in the hemidesomosomal inner plaque

EBS-Ogna

PLEC1

Plectin in the hemidesmosomal inner plaque

JEB Herlitz

LAMA3, LAMB3, LAMC2

Laminin 5 in anchoring filaments

JEB Non-Herlitz

COL17A1, LAMB3

Type 17 collagen in the hemidesmosome, laminin 5

JEB with pyloric atresia

ITGB4, ITGA6

Integrins b4, a6 in the hemidesmosome complex

Dominant DEB

COL7A1

Type 7 collagen in dermal anchoring fibrils

Recessive DEB-Halopeau-Siemens

COL7A1

Type 7 collagen in dermal anchoring fibrils

Recessive DEB-Non-Hallopeau-Siemens

COL7A1

Type 7 collagen in dermal anchoring fibrils

DEB = dystrophic epidermolysis bullosa, EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa. From Corden.

1

Fig. 31-14. Extensive scarring of the limbs in autosomal recessive epidermolysis bullosa. (A,B) Intermediate severity with residual scarring and loss of nails. (C,D) Marked severity loss of tissue and fusion of digits.

purple discoloration.4 They may present as a soft mass or have the appearance of varicosities. They occur both in the skin and subcutaneous tissues and in the mucosa of the mouth and lips. Thrombosis within the dilated vessels results in a painful, hard nodule that may calcify. Venous malformations may involve underlying muscles, joints, and bone structures and cause pain

and deformity. Patients with extensive venous malformations often have a low-grade consumption coagulopathy. The vast majority of venous malformations occur sporadically and are localized lesions. Familial cases with autosomal transmission have been linked to a mutation in the endothelial cellspecific receptor TIE-2 gene on chromosome 9p21.6 Venous

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Other Systems and Structures Table 31-9. Developmental disorders of connective tissue Disorder

Gene

Developmental Defect

Ehlers-Danlos syndrome types I,II

COL5A1, COL5A2

Type 5 collagen

Ehlers-Danlos syndrome type III

COL3A1

Type 3 collagen

Ehlers-Danlos syndrome type IV

COL3A1

Type 3 collagen

Ehlers-Danlos syndrome type VI

PLOD

Lysyl hydroxylase

Ehlers-Danlos syndrome types VIIa and b

COL1A1, COL1A2

Type 1 collagen

Ehlers-Danlos syndrome type VIIc

ADAMST2

Metalloproteinase?

Ehlers-Danlos progeroid form

XGPT1

Xylosylprotein 4-beta-galactosyl transferase

X-linked cutis laxa

ATP7A

Copper transporting ATPase

Pseudoxanthoma elasticum

MRP6

Transmembrane ATP-binding

Marfan syndrome

FBN1

Fibrillin-1

Progressive osseous heteroplasia, Albright hereditary osteodystrophy

GNAS1

Guanine nucleotide-activity stimulating polypeptide

Modified from Corden.7

mal dominant trait. They are distinguished histologically by the presence of glomus cells around the distended venous channels. A mutation in the glomulin gene on 1p21-22 has been identified in kindreds with this disorder.5 31.8.4 Lymphatic Malformations

Lymphatic malformations (LM) may be macrocystic, microcystic, or a combination of both. In the old terminology, a macrocystic LM is often referred to as a cystic hygroma, and a microcystic LM as lymphangioma circumscriptum. A macrocystic LM is usually evident at birth as a large transilluminating mass in the neck or axillary area. A microcystic lymphatic malformation may not become apparent until later in childhood as clear or hemorrhagic vesicles on the skin or mucosa. Large combined LMs in the tongue and oral mucosae may obstruct the airway or interfere with development of the facial bones. Lymphatic malformations are a component of Proteus syndrome, Klippel-Trenaunay syndrome, Bannayan-RileyRuvalcaba syndrome, and Gorham syndrome. In complex malformations, a well-circumscribed ‘‘geographic’’ vascular stain is often present in conjunction with the lymphatic anomaly. Fig. 31-15. Hyperextensible skin in an adult with Ehlers-Danlos syndrome.

malformations may be associated with visceral venous malformations in the so-called ‘‘blue rubber bleb nevus’’ syndrome and with multiple enchondromas in Mafucci syndrome. They are seen in association with capillary and lymphatic malformations in Klippel-Trenaunay syndrome, Proteus syndrome, Gorham syndrome, and Bannayan-Riley-Ruvalcaba syndrome, and with arteriovenous malformations in the Parkes-Weber syndrome. 31.8.3 Glomulovenous Malformations

These are a subtype of venous malformation, previously known as glomangioma or multiple glomus cell tumors. They are single or widespread blue lesions, often painful to palpation, and do not affect the mucosae. They are frequently inherited as an autoso-

31.8.5 Lymphedema

Congenital aplasia or hypoplasia of the lymphatic system results in primary lymphedema. This most commonly involves the lower limbs and can be unilateral or bilateral (Fig. 31-18). It may present at birth or in early childhood (Milroy disease) or in later childhood and adolescence (lymphedema praecox). Some cases are familial with autosomal dominant inheritance. Primary congenital lymphedema or Milroy disease is linked to mutations in the FLT-4 (VEGFR3) gene on chromosome 5q34-35.6 Lymphedema praecox, or Meige lymphedema, is caused by mutations in the FOXC2 gene on chromosome 16q24.3.7 Mutations in the SOX18 gene on 20q have been identified in the dominant and recessive forms of hypotrichosis-lymphedema-telangiectasia syndrome.5 An autosomal recessive form of lymphedema associated with facial anomalies, intestinal lymphangiectasia, and mental retardation is termed Hennekam disease. Congenital lymphedema may also be associated with Turner and Noonan syndromes.

Cutaneous Structures

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Table 31-10. Vascular malformations and associated syndromes Syndrome

Malformation

Associated Findings

Sturge-Weber

Capillary (port-wine stain)

Congenital glaucoma, ipsilateral leptomeningeal vascular malformation

Klippel-Trenaunay

Capillary/venous, or capillary/lymphatic/venous

Limb hypertrophy

Parkes-Weber

Capillary/arteriovenous, or capillary/lymphatic/ arteriovenous malformation

Limb hypertrophy

Proteus

Capillary, lymphatic, capillary lymphatic venous

Hemihypertrophy, macrodactyly, thickened palms and soles, epidermal nevi, visceral lipomas and vascular malformations

Servelle-Martorell

Capillary/venous

Limb undergrowth

Banayan-Riley-Ruvalcaba

Capillary, lymphatic, venous

Macrocephaly, mental retardation, lipomas, pigmented macules on genitalia, intestinal polyposis

Beckwith-Wiedeman

Capillary (midline vascular stain)

Macroglossia, macrosomia, renal disorders, embryonal tumors

Adams-Oliver

Capillary (cutis marmorata telangiectatica congenita)

Aplasia cutis congenita, cranial defects, limb defects

Blue rubber bleb nevus

Venous

Bleeding gastrointestinal vascular malformations, anemia

Wyburn-Mason

Arteriovenous

CNS arteriovenous malformation

Cobb

Arteriovenous

Spinal arteriovenous malformation

HCCVM

Hyperkeratotic Cutaneous Capillary Venous Malformation

Cerebral capillary malformations

Gorham

Venous, lymphatic

Bone

Lymphedema-distichiasis

Lymphatic

Double row of eyelashes, corneal erosions

From Enjolras and Garzon.2

31.8.6 Arteriovenous Malformations

Arteriovenous malformations (AVM) are high-flow malformations that increase in size over time. They may cause considerable disfigurement as well as pain, hemorrhage, and high-output cardiac failure; they can be life-threatening. Trauma or ill-conceived surgical intervention may result in rapid deterioration. AVMs are most common on the head and neck. In infancy, an AVM may be confused with a port-wine stain or hemangioma. They are warm to palpation, and the skin erythema may appear slightly raised or infiltrated. There is often a palpable thrill or audible bruit. More than 50% of lesions are not evident at birth but become apparent in infancy and childhood. A cephalic AVM may be associated with a contiguous lesion in the brain or orbit. The terms Wyburn-Mason syndrome, Bonnetde-Chaume syndrome, and Bregeat syndrome are used to describe this association. The Cobb syndrome refers to the association of a dermatomal truncal skin lesion with an intraspinal AVM. A hemangioma, which is also a high-flow vascular lesion in infancy, should not be confused with an AVM. Unlike an AVM there is a tumor between the arterial feeding vessels and the draining venous vasculature that can be demonstrated by imaging studies. 31.8.7 Infantile Hemangioma

Infantile hemangioma is a common tumor of infancy occurring in 5–10% of infants in the first months of life. It is characterized by rapid benign proliferation of endothelial cells followed by slow spontaneous regression over the next 5–10 years.7 It is more common in females and in premature infants. The pathogenesis is unknown. The proliferative cells stain positively with Glut-1, a cell marker also present in placental blood vessels. Infantile hemangiomas may be superficial and red in color, deep with a blue color and swelling, or mixed, a combination of superficial and deep components. They may arise as a localized lesion (Fig. 31-19) or in a large segmental or metameric pattern. Multiple lesions are

Table 31-11. Vascular tumors and associated malformation syndromes Syndrome

Tumor

Associated Findings

PHACES

Hemangioma of head and neck

Posterior fossa anomalies, cardiac and arterial malformations, ocular anomalies, cleft sternum, median raphe

Sacral Hemangioma of sacral Spinal cord dysraphism, hemangioma area and perineum renal and anal anomalies From Enjolras and Garzon.2

common. Numerous cutaneous hemangiomas may represent benign cutaneous hemangiomatosis, with lesions limited to the skin, or diffuse neonatal hemangiomatosis with associated lesions in the liver and other visceral organs. Infantile hemangiomas may be complicated by ulceration, bleeding, or obstruction of vision or the airway. Large segmental lesions in the so-called ‘‘beard’’ area are often associated with a corresponding subglottic hemangioma leading to respiratory obstruction. A hemangioma may rarely be associated with structural malformations of other organs (Table 31-11). The eponym PHACES refers to a segmental facial hemangioma associated with posterior fossa and other central nervous system malformations, arterial anomalies, coarctation of the descending aorta, cardiac defects, and eye abnormalities. Sternal agenesis and supraumbilical raphe are reported with facial and truncal hemangiomas. A segmental hemangioma in the lumbosacral area may be associated with sacral bony defects, spinal cord dysraphism, and malformations of the anus and rectum, external genitalia, kidneys, and genitourinary tract. 31.8.8 Congenital Hemangiomas

The term congenital hemangioma refers to a fully formed hemangioma that is present at birth. It presents as a firm purple-colored

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Other Systems and Structures

Fig. 31-16. Centrally located vascular stain in infants with prenatal thalidomide syndrome (A) and Roberts syndrome (B).

Fig. 31-17. Laterally located port-wine stain in children with Sturge-Weber syndrome (A) and KlippelTrenaunay-Weber syndrome (B). (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Institute, Wilmington, DE.)

Fig. 31-18. Lower limb lymphedema in newborn with Milroy disease.

mass, sometimes with overlying telangiectasia or a surrounding pale halo. Imaging studies or biopsy may be necessary to exclude other congenital neoplasms such as myofibroma and fibrosarcoma. The congenital hemangioma does not stain with Glut-1, distinguishing it from the common infantile hemangioma. It must also be distinguished from the tufted angioma and spindle-cell hemangioendothelioma, both of which may be present at birth (see following). Most congenital hemangiomas involute in the first year of life and are referred to as rapidly involuting congenital hemangioma (RICH). Bleeding and ulceration are occasional complications. Lesions with a telangiectatic morphology often do not involute with time and may eventually require surgical excision (non-involuting congenital hemangioma or NICH). 31.8.9 Kasabach-Merritt Syndrome

Kasabach-Merritt syndrome (KMS) refers to the association of a vascular tumor with development of platelet trapping, thrombocytopenia, and consumption coagulopathy at birth or shortly

Cutaneous Structures

1329

31.9 Pigmentation Anomalies 31.9.1 Hypopigmentation

Fig. 31-19. Bright red raised infantile hemangioma (strawberry mark) on the cheek of a female infant. The lesion regressed remarkably between 3 and 8 years of age, but ultimately required surgical and laser treatment.

thereafter.4–6 The vascular tumor is not the common hemangioma of infancy but either a tufted angioma or a kaposiform spindle cell hemangioendothelioma. Both tumors show histopathologic evidence of dilated lymphatic spaces in addition to the characteristic vascular tufts or spindle cell endothelial proliferation, respectively. These vascular tumors, possibly of lymphatic endothelial origin, present as a blue or red plaque that becomes inflamed, indurated, and purpuric with development of thrombocytopenia and hemorrhage. Kasabach-Merritt syndrome is a life-threatening condition and requires a multidisciplinary approach to management. Thrombocytopenia usually resolves with or without treatment by 18 months of age. Tufted angiomas may regress spontaneously but sometimes persist. The kaposiform spindle cell hemangioendothelioma also regresses but commonly leaves residual induration, fibrosis, and a port-wine stain–like vascular discoloration of the skin. References (Vascular Malformations) 1. Enjolras O, Mulliken J: Vascular tumors and vascular malformations: new issues. Adv Dermatol 13:375, 1998. 2. Enjolras O, Garzon MC: Vascular stains, malformations, and tumors. In: Textbook of Neonatal Dermatology. Eichenfield LF, Frieden IJ, Esterly NB, eds. WB Saunders Co., Philadelphia, 2001, p 324. 3. Esterly NB: Cutaneous hemangiomas, vascular stains and malformations and associated syndromes. Curr Probl Dermatol 3:69, 1995. 4. Enjolras O, Ciabrini D, Mazoyer E, et al.: Extensive pure venous malformations in the upper and lower limbs: a review of 27 cases. J Am Acad Dermatol 36:219, 1997. 5. Nova HR: Familial communicating hydrocephalus, posterior cerebellar agenesis, mega cisterna magna, and port wine stain nevi. J Neurosurg 51:862, 1979. 6. Brouillard P, Vikkula M: Vascular malformations: localized defects in vascular morphogenesis. Clin Genet 63:340, 2003. 7. Bruckner AL, Frieden IJ: Hemangiomas of infancy. J Am Acad Dermatol 48:477, 2003.

Developmental disorders causing hypopigmentation may be caused by abnormal production and migration of melanocytes (e.g., piebaldism), defective synthesis of melanin (albinism), or disordered function of melanocytes (e.g., tuberous sclerosis, hypomelanosis of Ito). Piebaldism is characterized by pure white patches of skin that are present at birth and inherited as an autosomal dominant gene (Fig. 31-20). Mutations in the c-KIT protooncogene affect migration of melanocytes from the neural crest in the developing embryo.1 The depigmentation is most evident on the forehead, with a white forelock, and on the chest abdomen, and limbs. There may be islands of pigmentation within the affected areas. Occasionally, repigmentation can occur, although the white forelock is usually permanent. Waardenburg syndrome, like piebaldism, is an autosomal dominant disorder caused by defective migration of neural crest cells during embryogenesis. It is associated with heterochromia iridis and sensorineural deafness. In type I Waardenburg syndrome there is dystopia canthorum. A white forelock and areas of depigmentation are variable features and are present in less than 50% of patients (Fig. 31-21). The depigmentation may resemble vitiligo. Early graying of the hair, premature canities, is also seen. Albinism, or oculocutaneous albinism, is caused by absent or defective production of melanin (Fig. 31-22). There are 10 different variants. Most are inherited by autosomal recessive transmission. The patient’s eyes are invariably affected with photophobia, visual loss, and nystagmus. The degree of depigmentation depends on the type of albinism. In oculocutaneous albinism type Ia, tyrosinase activity in melanocytes is absent and the skin and hair are white with pale irides that transilluminate and appear pink in bright light. In other forms of albinism, there is partial tyrosinase activity, and the patient may have pigmented nevi and colored hair. In the Hermansky-Pudlak variant, there is an associated bleeding diathesis. Chediak-Higashi, Griscelli, and Elejalde syndromes are characterized by light skin and a silvery gray hair color at birth. The abnormal pigmentation appears to result from disordered formation of melanosomes and transfer of pigment to adjacent keratinocytes. Chediak-Higashi syndrome is an autosomal recessive condition in which hypopigmentation is associated with abnormal leukocyte function and recurrent infections. Giant lysosomal granules are seen within myeloid cells in the blood and bone marrow. Griscelli syndrome is also inherited as an autosomal dominant condition and is characterized by hypopigmentation and severe combined immunodeficiency. Elejalde syndrome is an autosomal recessive disorder with abnormal melanosomes and central nervous system disease. Pigment mosaicism, or nevoid hypopigmentation, refers to hypomelanosis following the lines of Blaschko and other segmental patterns (Fig. 31-23).2 The term hypomelanosis of Ito (syn. incontinentia pigmenti achromians) was coined to describe a linear and whorled pattern of hypopigmentation analogous to the hyperpigmented streaks of incontinentia pigmenti. Hypomelanosis of Ito is no longer considered to be a distinct disease but a mosaic pattern of hypopigmentation associated with a number of different chromosomal abnormalities. It is a sporadic disorder and is not familial. The hypomelanosis is usually clinically apparent, but

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Other Systems and Structures

Fig. 31-21. White forelock in a 2-year-old girl with Waardenburg syndrome. Note the lateral displacement of the inner canthi and the repaired cleft lip. (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Institute, Wilmington, DE.)

Wood’s lamp examination may be necessary to visualize lesions in lightly pigmented individuals. Melanocytes may be normal or reduced in number and contain less melanosomes than normal. Hypomelanosis of Ito may be an isolated skin anomaly or associated with developmental anomalies of the central nervous system and musculoskeletal defects. Fig. 31-22. Albinism in an African American infant, showing lightly pigmented skin and blond hair.

Fig. 31-20. Piebaldism in South African family members showing irregular hypopigmentation of the skin and hair. Four generations were affected in this family. No other anomalies were present. (Courtesy of Dr. Peter Beighton, University of Cape Town, South Africa.)

Cutaneous Structures

1331

pigmented skin. Hypomelanotic macules can be difficult to discern in light-skinned infants without Wood’s light examination. They are often the only cutaneous manifestation of tuberous sclerosis early in life and are an important diagnostic feature. Facial angiofibromas, collagenomas (the ‘‘shagreen patch’’), forehead plaques, skin tags, and periungual and gingival fibromas usually appear later in childhood. A single, or sometimes more than one, hypomelanotic macule unassociated with tuberous sclerosis is referred to as a nevus depigmentosus or achromic nevus. 31.9.2 Hyperpigmentation

Fig. 31-23. Hypomelanosis of Ito in a child, showing hypopigmentation following lines of Blaschko. Chromosome study results were normal.

Limited pigment mosaicism following the lines of Blaschko, and segmental pigment mosaicism, sometimes referred to as nevus depigmentosus or achromic nevus, are rarely associated with extracutaneous disease. Hypomelanotic macules in tuberous sclerosis are typically oval or lance-ovate (ash-leaf ) in shape, but may have a confetti-like or large segmental morphology (Fig. 31-24). They appear at birth or in early childhood and may be few or numerous. Melanosomes have been shown to be reduced in size and number in the hypo-

The prototype of pigment mosaicism following the lines of Blaschko is incontinentia pigmenti (see previously). A similar pattern of hyperpigmentation in the absence of blistering and other manifestations of IP is found in linear and whorled nevoid hypermelanosis.2 This is evident at birth or shortly thereafter and is not familial. It is usually an isolated cutaneous anomaly, although associated developmental defects have occasionally been reported. Unlike IP, histologic examination of the skin does not show pigment incontinence. The large areas of pigmentation in a segmental distribution present in the McCune-Albright syndrome are also believed to be a manifestation of pigment mosaicism. These lesions are often referred to as large cafe´-au-lait macules. Limited areas of pigment mosaicism following the lines of Blaschko or large isolated patches of pigmentation, often with sharp mid-line demarcation, are not uncommon in otherwise healthy infants without evidence of neurocutaneous disease or McCune-Albright syndrome. Cafe´-au-lait macules are round or oval areas of hyperpigmentation with a distinct border (Fig. 31-25). They vary in size from a few millimeters to several centimeters in diameter. They present at birth or in the first few months of life. Melanin is increased in the skin and melanosomes may have large pigment

Fig. 31-24. Hypomelanotic macule on nose of a 10-year-old girl with tuberous sclerosis. She has cutaneous hamartomas of the face and mental retardation.

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Other Systems and Structures

Fig. 31-25. Cafe´ au lait spots. Smooth-bordered pigmented spots of limbs and trunk in two patients with neurofibromatosis (A, B). Diffuse, irregular pigmentation may also occur and may overlie a plexiform neurofibroma (C). Cutaneous neurofibromas may occur anywhere on the skin but seem to have a predilection for the areolar area (D).

granules on ultrastructural examination. They are usually an isolated finding, but numerous lesions are a marker for neurofibromatosis type 1. Multiple cafe´-au-lait macules may occasionally be inherited as an isolated abnormality with autosomal dominant transmission. The large segmental areas of pigmentation in the McCune-Albright syndrome are often referred to as large cafe´au-lait macules. Small numbers of cafe´-au-lait macules may be seen in tuberous sclerosis and a number of other syndromic disorders.4 Lentigines are characterized histologically by an increase in melanocytes in the basal layer of the epidermis. Whereas most lentigines are acquired and induced by ultraviolet radiation, they are seen as a developmental abnormality in two specific syndromes. The LEOPARD syndrome is an acronym for lentigines associated

with electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retardation of growth, and deafness (Fig. 31-26). The Carney syndrome, also previously described as NAME and LAMB syndrome, is characterized by lentigines, cutaneous myxoid tumors, blue nevi, and atrial myxomas associated with a propensity to develop pituitary adenomas, adrenal tumors, and testicular Sertoli cell tumors. In the LEOPARD syndrome, the lentigines are widespread and do not involve the mucous membranes. In the Carney syndrome, lentigines are also widespread but are particularly concentrated on the central face and may involve the mucosa. In both conditions, lentigines can be present at birth and increase in number with age.

Cutaneous Structures

1333

of melanocytes from the neural crest to the basal layer of the epidermis. It presents with a blue-gray or blue-black appearance in the skin. The most common form of dermal melanocytosis is the macular so-called Mongolian spot, which usually fades with time. It is a frequent finding in infants of African, Asian, or Native American heritage. Permanent areas of macular dermal melanocytosis are seen in the periorbital area and sclera in nevus of Ota, and on the shoulders and upper back in the nevus of Ito. These lesions are more commonly seen in individuals of East Asian descent. Proliferation of dermal melanocytes is seen in congenital blue nevi, which may be considered a type of hamartoma. References (Pigmentation Anomalies) 1. Spritz RA: Piebaldism, Waardenburg syndrome, and related disorders of melanocyte development. Semin Cutan Med Surg 16:15, 1997. 2. Nehal KS, PeBenito R, Orlow SJ: Analysis of 54 cases of hypopigmentation along the lines of Blaschko. Arch Dermatol 132:1167, 1996. 3. Landau M, Krafchik B: The diagnostic value of cafe´-au-lait macules. J Am Acad Dermatol 40:877, 1999. 4. Salmon J, Frieden IJ: Congenital and genetic disorders of hyperpigmentation. Curr Probl Dermatol 7:143, 1995.

31.10 Malformations of the Epidermal Appendages Fig. 31-26. Variably pigmented macules distributed diffusely in LEOPARD syndrome. (Courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Institute, Wilmington, DE.)

Melanocytic nevi are localized proliferations of melanocytes. A congenital melanocytic nevus is present in 1% of newborns. These are usually small or intermediate size lesions but may be large and extensive nevi. Large hamartomatous congenital nevi on the scalp or central back may be associated with leptomeningeal (neurocutaneous) melanosis and have an increased potential for developing malignant melanoma or other tumors. Dermal melanocytosis, in which the melanocytes are located in the dermis, is believed to be caused by arrested migration

The epidermal appendages consist of the hair, nails, and sweat glands. Developmental anomalies may occur as an isolated defect or as a component of a particular syndrome. Developmental abnormalities that encompass more than one of these structures are classified as an ectodermal dysplasia (Fig. 31-27). There are many variants of ectodermal dysplasia, and a broad application of the term to include all disorders with hair and nail anomalies can be exhaustive. Many ectodermal dysplasia syndromes, such as incontinentia pigmenti, with hair, nail, and dental defects, are not traditionally classified under this rubric. Anhidrotic or hypohidrotic ectodermal dysplasia is an X-linked recessive disorder that is fully expressed in males and partially

Fig. 31-27. Hyperkeratosis of soles, nail dystrophy, and anomalies of teeth in a 15-year-old girl with odontoonycho-dermal dysplasia (Fadhil-Ghabra-Deeb type of ectodermal dysplasia).

1334

Other Systems and Structures

expressed in female carriers. The mutated gene, EDA, is located at Xq12-q13.1. In boys, there is marked hypotrichosis present from birth associated with absent sweating, disordered thermoregulation, and dry skin. The nails are normal. The nipples may be absent or hypoplastic. Affected individuals have distinctive facies with a depressed nasal bridge and frontal bossing. Hypohidrotic ectodermal dysplasia associated with immune deficiency has been linked to mutations in the NEMO gene on Xq28, which is the same gene associated with incontinentia pigmenti. Hidrotic ectodermal dysplasia, also known as Clouston disease, is an autosomal dominant disorder characterized by variable hypotrichosis, nail dystrophy, and palmar plantar keratoderma. The nail changes and keratoderma may not become evident until later in childhood. Mutations in a gene encoding connexin-30 have been associated with this disorder. Rapp-Hodgkin syndrome and ankyloblepharon, ectodermal dysplasia, and clefting (AEC) syndrome are characterized by hypo-

Fig. 31-28. Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome. Cleft lip and palate have been repaired (A), and syndactyly of digits 1 and 2 has been released bilaterally (B and C). Fig. 31-29. (A) Thinning of frontal hair in a 5-yearold male with Costello syndrome. (B) Six-year-old male with progeria showing loss of hair and smooth thin skin with visible subcutaneous blood vessels.

trichosis, abnormal nails, and cleft lip and palate. Ankyloblepharon and lacrimal duct atresia are seen in the AEC syndrome. Severe hypotrichosis with crusting and scaling of the scalp is seen at birth in the AEC syndrome. In ectrodactyly, ectodermal dysplasia, and clefting (EEC) syndrome, there are mild hair and nail changes associated with cleft lip and palate and significant limb defects, most notably split hand/foot malformation (Fig. 31-28). The causative gene p63 is located on 3q27. Mutations in p63 have also been reported in Rapp-Hodgkin and AEC syndromes. 31.10.1 Hair Abnormalities

Abnormal hair patterns with absence or multiplication of the normal parietal scalp whorl can be seen in association with structural anomalies of the brain or developmental delay. A low frontal hairline is seen in several syndromes, including Costello (Fig. 31-29A),

Cutaneous Structures

1335

Table 31-12. Diffuse hypotrichosis

Table 31-13. Localized hypertrichosis

Hair shaft abnormalities

Congenital melanocytic nevus

Monilethrix

Congenital smooth muscle hamartoma

Pili Torti

Congenital Becker nevus

Isolated defect

Plexiform neurofibroma

Menkes syndrome, Bazex syndrome, Crandall syndrome, Rapp-Hodgkin syndrome

Nevoid hypertrichosis

Trichorrhexis invaginata (Netherton syndrome) Trichorrhexis nodosa

Spinal cord dysraphism Hair collar associated with aplasia cutis or neural tube defect

Isolated defect

Hemihypertrophy

Menkes and other syndromes, arginosuccinic aciduria

Anterior cervical hypertrichosis

Trichothiodystrophy

Hypertrichosis of elbows

Isolated congenital alopecia Congenital hypotrichosis Atrichia congenita

Hypertrichosis of palms and soles Hairy pinnae Modified from Wendelin et al.1

Marie Unna hypotrichosis Atrichia with papular keratin cysts Congenital atrichia with mila Ectodermal dysplasia Hypohidrotic ectodermal dysplasia Hidrotic ectodermal dysplasia (Clouston syndrome) Rapp-Hodgkin and AEC (ankyloblepharon, ectodermal dysplasia, clefting) syndromes Bazex-Dupre-Christol syndrome Congenital atrichia with nail dystrophy, abnormal facies, and psychomotor retardation

Diffuse congenital alopecia presenting at birth or in early infancy may be caused by reduced or absent hair follicles (hypotrichosis) or by abnormal development of the hair shaft. Hypotrichosis may be an isolated finding or a manifestation of one of the ectodermal dysplasias. It may also be associated with disorders of keratinization such as the KID (keratitis, ichthyosis, deafness) syndrome and the IFAP (ichthyosis follicularis, congenital atrichia, and photophobia) syndrome. Progeria (Fig. 31-29B) and neonatal progeroid syndromes may also present with sparse hair development.

Hypotrichosis with premature aging syndromes Hutchinson-Gilford progeria, neonatal progeroid syndrome, Cockayne syndrome, Rothmund-Thomson syndrome Hypotrichosis with immunodeficiency syndromes Cartilage hair syndrome, Omenn syndrome, and others Hypotrichosis with ichthyosis

Table 31-14. Generalized hypertrichosis Congenital hypertrichosis lanuginosa Congenital generalized hypertrichosis Gingival fibromatosis with hypertrichosis

Keratitis, ichthyosis, deafness (KID) syndrome

Osteochondrodysplasia with hypertrichosis (Cantu syndrome)

Ichthyosis, follicularis, congenital atrichia, photophobia (IFAP) syndrome

Cornelia de Lange syndrome

Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis

Lipoatrophic diabetes

Collodion baby Modified from Rogers.

Berardinelli-Seip syndrome Donohue syndrome (leprechaunism)

2

Laurence-Seip syndrome Mucopolysaccharidoses Hurler syndrome

Cornelia de Lange, Coffin-Siris, Fanconi, and fetal hydantoin syndromes. Congenital hair pigment abnormalities are seen most commonly in piebaldism and overlying congenital nevi, but nevoid patches of abnormally dark or red hair color are sometimes an isolated finding.1 Localized congenital alopecia is a circumscribed area of alopecia at birth that is seen most commonly overlying a nevus sebaceous or aplasia cutis congenita. It may also occur with other developmental scalp lesions such as congenital melanocytic nevi, neural tube closure defects, and hemangiomas. Rarer forms of congenital alopecia include triangular alopecia of the frontotemporal scalp, and circumscribed areas of alopecia associated with nevus of Ota. Localized patches of permanent alopecia are a component of several syndromes including incontinentia pigmenti, focal dermal hypoplasia, X-linked chondrodysplasia punctata, the CHILD syndrome, and Hallermann-Streiff syndrome.

Hunter syndrome Sanfilippo syndrome Stiff skin syndrome Winchester syndrome Congenital porphyrias Barber-Say syndrome Rubinstein-Taybi syndrome Schinzel-Gideon syndrome Coffin-Siris syndrome Teratogens Fetal alcohol syndrome Fetal hydantoin syndrome Modified from Wendelin et al.1

1336

Other Systems and Structures

There are a number of hair shaft defects that present with brittle hair and alopecia (Table 31-12).1 Monilethrix, or beaded hair, has been linked to mutations in the type II hair cortex keratin genes hHb1 and hHb6 on chromosome 12q13. Netherton syndrome is characterized by trichorrhexis invaginata (bamboo hairs) and is associated with mutations in the SPINK5 gene on chromosome 5q32. Pili torti and trichorrhexis nodosa are seen in Menkes syndrome, an X-linked recessive disorder caused by mutations in the ATP7A gene on Xq12-13, which encodes a

copper-transporting ATPase. Pili torti may be seen as an isolated finding or associated with other syndromes. Trichorrhexis nodosa may also be an isolated finding.1 Trichothiodystrophy is characterized by brittle sulfur-deficient hair that has a tiger-tail appearance on polarized light microscopy. Certain hair shaft defects such as pili annulati, uncombable hair syndrome, and woolly hair are rarely associated with alopecia.1 Localized hypertrichosis is a circumscribed patch of increased hair growth that is a common finding overlying a congenital

Fig. 31-30. Nail abnormalities. (A) Hypoplasia of nails and distal phalanges associated with prenatal Dilantin exposure. (B) Nail dysplasia with cutaneous pterygia extending onto nails in nail-patella syndrome. (C and D) Discoloration, pitting, and distortion of nail shape in a child (left) and adult (right) with ectodermal dysplasia. (E) Pitting, irregularity of shape, and distal fraying of nails in dyskeratosis congenita.

Cutaneous Structures

melanocytic nevus, congenital smooth muscle hamartoma, or plexiform neurofibroma. Nevoid hypertrichosis in the lumbosacral area or at other neural tube closure sites may be associated with spinal cord dysraphism. A collarette of hair that is longer and darker than the surrounding hair may surround neural tube closure defects and areas of membranous aplasia cutis on the scalp and face. Localized patches of nevoid hypertrichosis are also described on the anterior neck, the elbows, and the palms and soles (Table 31-13).2 Generalized hypertrichosis is a manifestation of a number of defined syndromes (see Table 31-14).2 Many cases are difficult to classify, and the literature can be confusing. Diffuse retention of fine, silky lanugo hair is characteristic of hypertrichosis lanuginosa, an autosomal dominant disorder. Diffuse overgrowth of coarse terminal hair is a component of multiple syndromes, including Cornelia de Lange (Brachmann-de Lange) syndrome, leprechaunism, Coffin-Siris syndrome, and Barber-Say syndrome. Congenital hypertrichosis may also occur in association with inherited gingival fibromatosis. Maternal drug and alcohol ingestion during pregnancy has been implicated in some cases.2 31.10.2 Developmental Nail Defects

Nail defects are seen in the ectodermal dysplasia disorders and as a component of numerous syndromes (Fig. 31-30).3 Isolated nail defects include congenital malalignment of the great toenails, congenital onychodysplasia of the index fingers, and ectopic nails. Broadened, or racquet nails, are seen with shortening of the terminal phalanges and may be associated with other congenital anomalies. Transverse overcurvature of the nails, or pincer

1337

nails, may be an isolated finding or resemble pachyonychia congenita. Pachyonychia congenita is a keratinization disorder in which keratin accumulates under the nail plate resulting in dystrophy and overcurvature of the nails. Pachyonychia congenita type I is associated with white plaques of leukokeratosis on the tongue and palmar plantar keratoderma. Psoriasiform papular skin lesions and epidermal cysts may also occur. Pachyonychia congenita type II is associated with natal teeth. Mutations in keratins type 16 and 6A are found in type I, and keratins type 17 and 6B in type II. Both are autosomal dominant disorders. Nail-patella syndrome includes micronychia, hemionychia, and occasionally anonychia (Fig. 31-30) of the nails. A triangular shaped lunula, if present, is pathognomonic. The thumbs and index fingers are most commonly affected. Skeletal abnormalities include a small, easily subluxed patella, posterior iliac horns, hypoplasia of the proximal radius and ulna, and scoliosis. There may be associated palmar plantar hyperhidrosis. Chronic renal disease and musculoskeletal symptoms often do not become clinically apparent until early adult life. It is an autosomal dominant disorder linked to a mutation in LMX1B on chromosome 9q34. References (Malformations of the Epidermal Appendages) 1. Wendelin DS, Pope DN, Mallory SB: Hypertrichosis. J Am Acad Dermatol 48:161, 2003. 2. Rogers M: Hair disorders. In: Textbook of Neonatal Dermatology. Eichenfield LF, Frieden IJ, Esterly NB, eds. WB Saunders, Philadelphia, 2001, p 487. 3. Baran R, Dawber RPR, Tosti A, et al.: A Text Atlas of Nail Disorders. Martin Dunitz, London, 1996.

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32 Endocrine Organs Amy Potter and John A. Phillips III

E

ndocrine disorders that are associated with malformations are numerous and include defects of the central nervous system, hypothalamus, pituitary, thyroid, skeleton, and a variety of other endocrine glands, tissues, or organs. These disorders are caused by genetic variations that interrupt different points of the hypothalamic–pituitary axis and other synthetic pathways that are required for normal development. Many metabolic pathways affect growth, and changes in any gene in any of the component pathways can lead to different phenotypes due to decreased or, in some cases, excessive expression of the perturbed gene. The resulting endocrine disorders can be classified by their (1) etiology (mendelian mode of inheritance or chromosomal basis), (2) phenotype (isolated or multiple hormone deficiencies), (3) genetic variations of different alleles at a locus or at different loci and/or (4) the associated biochemical findings. The endocrine disorders selected for inclusion are examples and by no means a comprehensive list of all known genetic diseases that have some effect on endocrine function. Information on each endocrine disorder is summarized and, for most, more detailed information can be obtained through the electronic database Online Mendelian Inheritance in Man (OMIM), which is available at http:// www.ncbi.nlm.nih.gov/Omim.1 While it is not feasible to discuss all of the known genetic disorders related to endocrinology in detail in this chapter, we provide useful information on some of the most commonly seen disorders. In addition, Table 32-1 gives an overview of genetic endocrine disorders, including many not discussed in the text. Table 32-2 lists naturally occurring animal models of human endocrine disorders. Table 32-3 provides a list of known genetic tumor syndromes that include endocrine tumors. Table 32-4 lists mendelian genetic disorders which are not primarily endocrine in nature but may have endocrine features. Table 32-5 lists chromosomal disorders with endocrine features.1 For the disorders discussed, we have focused on the genetic aspects.

How Mutations Affect the Endocrine System

All endocrine systems consist of interacting networks of ligands, receptors, post-receptor signaling molecules, enzymes, and protein products. Each of these proteins is encoded by a gene, and these genes in turn are regulated by networks of transcription factors.

Mutations in any of the involved genes can lead to alterations in the function of a given system and, thus, to disease. Selected endocrine disorders that illustrate particular molecular mechanisms of disease will be discussed here; other disorders are discussed in more detail following. A variety of mutations have been reported in the genes that encode hormones. Deletions of such genes cause complete absence of the corresponding hormone (see section on growth hormone deficiency following), while less drastic mutations will result in a deficiency, rather than absence or, alternatively, in a nonfunctional protein product. Mutations have also been reported that alter processing and packaging of the hormone. One example is the AVP gene (OMIM 192340), which encodes both the hormone arginine vasopressin (AVP) and its packaging protein neurophysin II. Mutations in the neurophysin II domain impair packaging and secretion of AVP, leading to central diabetes insipidus.2 Mutations in cell surface receptors are another important genetic cause of endocrine disorders (see sections on the growth hormone pathway and the calcium sensing receptor following). The severity and manifestations of an illness may vary depending on whether mutations result in no receptor function (null mutations) or in decreased amount of function. Receptor mutations can lead to decreased ligand binding or impaired signaling. For example, null mutations of the insulin receptor lead to leprechaunism (also called Donohue syndrome, OMIM 246200); these patients have nearly absent insulin function and die in infancy.3–6 Less severe mutations in the insulin receptor cause Rabson-Mendenhall syndrome (OMIM 262190), which is associated with survival into late childhood and early adolescence.7 Two groups of hormones (steroid and thyroid) interact with nuclear receptors. In order to function properly, the receptor must be able to bind both its ligand and its appropriate DNA binding site, as well as to interact with other cofactors. For example, androgen insensitivity syndrome is caused by mutations in the androgen receptor (OMIM 313700); the majority of such mutations are in the ligand binding domain, but up to 20% occur in the DNA binding domain.8–9 Mutations in the proteins of post-receptor signaling systems can also cause endocrine disease. The classic example is the McCuneAlbright syndrome (OMIM 174800). This syndrome is caused by

1339

Table 32-1. Selected genetic disorders of the endocrine organs* Disorder/Syndrome

Causation/Gene 

Testingz

Comments

The Adrenal Gland

Adrenal insufficiency

(184757) NR5A1

Res

Sex reversal in 46,XY

Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase type 2 deficiency

AR (201810) HSD3B2

No

Severe salt wasting

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency

AR (202010) CYP11B1

Res

Hypertension

Congenital adrenal hyperplasia due to 17-hydroxylase deficiency

AR (202110) CYP17

No

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

AR (201910) CYP21

Yes

Most common CAH; may or may not have salt wasting

Congenital adrenal hypoplasia

X (300200) DAX1

Yes

Adrenal insufficiency; may have hypogonadism

Congenital hypoaldosteronism

AR (124080) CYP11B2

Yes

Aldosterone deficiency

Familial glucocorticoid resistance

AD (138040) GCCR

No

Homozygotes may have severe hypertension

Familial hyperaldosteronism type 1 (glucocorticoid remediable aldosteronism)

AD (103900) CYP11B2/ CYP11B1 fusion gene

Yes

Increased aldosterone secretion can be suppressed by glucocorticoids

Familial hyperaldosteronism type 2

AD (605635)

No

Increased aldosterone secretion cannot be suppressed by glucocorticoids

Lipoid congenital adrenal hyperplasia

AR (600617) STAR AD (118845) CYP11A

Yes

Adrenal failure, ambiguous genitalia

AR (600414) PXR1 AR (602136) PEX1 AR (602859) PEX10 AR (601789) PEX13

Yes

AR (600228) SCNN1A AD (600760) SCNN1B AD (600761) SCNN1G AD (600983) NR3C2

Res

Defect in sodium channel

Res

Liddle syndrome: hypokalemic metabolic acidosis and hypertension with suppressed aldosterone/rennin Defect in mineralocorticoid receptor

AD (605232) PRKWNK1 AD (601844) PRKWNK4

No

X (300100) ABCD1

Yes

Adrenal insufficiency and neurologic deterioration

AR, AD (173110) POU1F1

Res

AR (601538) PROP1

Yes

Can be due to inactivating mutations or dominant negative mutations; deficiency of TSH, GH, PRL Deficiency of TSH, GH, PRL, LH, FSH

Neonatal adrenoleukodystrophy

Pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 2

X-linked adrenoleukodystrophy

No

Yes Yes Yes

Res Res

No

Hyperkalemia, hypertension; tight junction defect in distal convoluted tubule and collecting duct

The Anterior Pituitary, Hypothalamus, and Disorders of Short Stature

Combined pituitary hormone deficiency

(continued)

1340

Table 32-1. Selected genetic disorders of the endocrine organs* (continued) Disorder/Syndrome

Causation/Gene 

Testingz

Comments

Combined pituitary hormone deficiency with rigid cervical spine

AR (600577) LHX3

No

Deficiency of all pituitary hormones except ACTH with rigid cervical spine

Corticotropin-releasing hormone deficiency

AR (122560) CRH

No

Central adrenal insufficiency

Hypogonadotropic hypogonadism

AR (138850) GNRHR AR (152780) LHB X (300200) DAX1

No

Delayed puberty, hypogonadism

No

Delayed puberty in males

Yes

Mutations in this gene also cause adrenal hypoplasia (see above)

Isolated adrenocorticotropin deficiency

TBX19 (604614)

No

Isolated follicle-stimulating hormone deficiency

AR (136530) FSHB

Res

Primary amenorrhea

Isolated growth hormone deficiency (GHD)

AR, AD (139250) GH1 AR (139191) GHRHR

Res No

Deletions of this gene lead to AR GHD; other mutations cause GHD (dominant negative effect)

Isolated thyrotropin deficiency

AR (188540) TSHB

No

Congenital central hypothyroidism

Kallman

X (308700) KAL1 AR or AD Other genes

Yes

Anosmia and hypogonadotropic hypogonadism

Laron, type 1

AR (600946) GHR

Res

Short stature, lack of response to growth hormone

Laron, type 2

AR (245590)

No

Same phenotype as type 1, due to post-receptor defect

Septo-optic dysplasia (SOD)

AR (601802) HESX1

Res

SOD, varying pituitary insufficiency

SHOX deficiency syndromes

PAD (312865) SHOX

Yes

Idiopathic short stature

Langer mesomelic dysplasia

PAR (312865) SHOX

Yes

Severe mesomelic dwarfism

Leri-Weill dyschondrosteosis

PAD (312865) SHOX

Yes

Mesomelic short stature

Syndrome of obesity, adrenal insufficiency, and red hair

AR (176830) POMC

No

Thyrotropin-releasing hormone resistance

AR (188545) TRHR

No

X-linked hypogammaglobulinemia and isolated growth hormone deficiency

X (300300) BTK

Yes

No

The Gonads and Disorders of Sexual Development

5a-reductase deficiency

AR (607306) SRD5A2

Res

Female genitalia at birth with masculinization at puberty

17-ketosteroid reductase deficiency

AR (605573) HSD17B3

No

Ambiguous genitalia

Androgen insensitivity

XR (313700 AR

Yes

Partial forms also exist

Aromatase deficiency

AR (107910) CYP19

No

Female pseudohermaphroditism, delayed puberty

Azoospermia

Y (400003) DAZ Y (400005) USP9Y

Yes Yes

Azoospermia

(continued)

1341

Table 32-1. Selected genetic disorders of the endocrine organs* (continued) Disorder/Syndrome

Causation/Gene 

Testingz

Comments

Cryptorchidism

AD (146738) INSL3

No

Cryptorchidism

Estrogen resistance

AR (133430) ESR1

No

Tall stature, delayed closure of epiphyses

Frasier

AD (607102) WT1

Yes

Male pseudohermaphroditism, streak gonads, 46,XY karyotype, gonadoblastoma

Gonadal dysgenesis, XY female type

Y (480000) SRY

Yes

Gonadal dysgenesis, XY, with minifasicular neuropathy

AR (605423) DHH

No

Leydig-cell hypoplasia

AR (152790) LHCGR

Res

Inactivating mutations lead to varying degrees of male pseudohermaphroditism

Male-limited precocious puberty (familial testotoxicosis)

AD (152790) LHCGR

Res

Caused by activating mutation of LH receptor

Oligospermia

Y (400006) RBMY1A1

Yes

Oligospermia

Persistent Mu¨llerian duct, type 1

AR (600957) AMH

No

Persistent uterine structures

Persistent Mu¨llerian duct, type 2

AR (600956) AMHR2

No

Same as type 1

Premature ovarian failure, autosomal recessive

AR (136435) FSHR

Yes

Premature ovarian failure with primary or secondary amenorrhea

The Parathyroid Gland and Mineral Metabolism

Albright hereditary osteodystrophy

AD (139320) GNAS

Yes

Loss of function mutations

Familial hypercalciuric hypercalcemia

AR (601199) CASR

Yes

Caused by inactivating mutations

Familial hypocalciuric hypercalcemia (FHH)

AD (601199) CASR

Yes

Caused by inactivating mutations

Familial isolated hyperparathyroidism

AD (607393) HRPT2 AD (131100) MEN1 AD (145000)

No

AD (601199) CASR AD, AR (168450) PTH

Yes

Hyperparathyroidism-jaw tumor syndrome

AD (607393) HRPT2

Res

Hypomagnesemia with secondary hypocalcemia

AR (607009) TRPM6

No

Hypoparathyroidism, sensorineural deafness, and renal dysplasia

AD (131320) GATA3

No

Hypophosphatasia

AR (171760) ALPL

Yes

Juvenile Paget disease

AR (602643) TNFRSF11B

No

Neonatal severe primary hyperthyroidism

AR, AD (601199) CASR

Yes

Familial isolated hypoparathyroidism

Yes

Caused by activating mutation

No

Defect in magnesium absorption

Occurs in severe infantile form, milder childhood and adult forms

Can be caused by compound heterozygosity for FHH mutation or by autosomal recessive mutation (continued)

1342

Table 32-1. Selected genetic disorders of the endocrine organs* (continued) Disorder/Syndrome

Causation/Gene 

Testingz

Comments

Osteopetrosis, autosomal recessive

AR (604592) TCIRG1 AR (602727) CLCN7 AR (607649) GL

No

Severe osteopetrosis

Primary hypomagnesemia

AR (603959) CLDN16

No

Renal magnesium wasting, hypocalcemia, hypercalciuria, nephrocalcinosis

Pycnodysostosis

AR (601105) CTSK

Yes

AD (605380) FGF23

Yes

Renal phosphate wasting

X-linked hypophosphatemic rickets

X (307800) PHEX

Yes

Altered phosphate transport

Vitamin D-dependent rickets type 1

AR (264700) CYP27B1

Yes

Defective 1a hydroxylation of vitamin D

Vitamin D-dependent rickets type 2

AR (601769) VDR

Yes

Resistance to vitamin D

Rickets Autosomal dominant hypophosphatemic rickets

The Posterior Pituitary and Water Metabolism

Familial central diabetes insipidus

AD (192340) AVP

Yes

Mutations in either the AVP portion or neurophysin portions of the gene can cause DI

Nephrogenic diabetes insipidus

AR, AD (107777) AQP2

Yes

Defective water channel

X-linked nephrogenic diabetes insipidus

X (304800) AVPR2

Yes

Lack of response to ADH

Abnormal thyroglobulin

AR (188450) TG

No

Autosomal dominant hyperthyroidism

AD (603372) TSHR

Res

Caused by activating mutations of TSHR

Bamforth-Lazarus

AR (602617) FOXE1

Res

Thyroid agenesis with cleft palate, choanal atresia, bifid epiglottis, spiky hair

Familial non-medullary thyroid carcinoma

AD (188550) PTC fusion genes

Res

Impaired iodide uptake

AR (601843) SLC5A5

Yes

Iodide transport defects

Organification defects

AR (606765) TPO AR (606759) DUOX2

No

Impaired synthesis of thyroid hormone

Pendred

AR (605646) SLC26A4

Yes

Thyroglobulin synthesis defect

AR (600635) TITF1

No

Thyroid dysgenesis

AD (167415) PAX8

Yes

Thyroid hormone resistance

AD, AR (190160) THRb

Yes

Thyroid stimulating hormone resistance

AR (603372) TSHR

Yes

The Thyroid

No Deafness and goiter, usually euthyroid

Some mutations have dominant negative effect

(continued)

1343

1344

Other Systems and Structures Table 32-1. Selected genetic disorders of the endocrine organs* (continued) Disorder/Syndrome

Causation/Gene 

Testingz

Comments

Disorders Involving Multiple Endocrine Systems

McCune-Albright

SM (139320) GNAS

Res

Caused by somatic mosaicism for activating mutation of the stimulatory G-protein; characterized by polyostotic fibrous dysplasia, cafe´-au-lait spots, multiple endocrine oversecretion syndromes

Autoimmune polyendocrinopathy, type 1

AR (607358) AIRE

Yes

Chronic mucocutaneous candidiasis, Addison disease, hypoparathyroidism; may have other autoimmune endocrinopathies

Autoimmune polyendocrinopathy, type 2 (Schmidt)

(269200)

No

Addison disease plus autoimmune thyroid disease and/or type 1 diabetes

Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked (IPEX)

X (300292) FOXP3

No

Neonatal diabetes due absence of pancreatic islets, thyroid autoimmunity

Obesity and endocrinopathy due to impaired processing of prohormones

AR (162150) PCSK1

No

Obesity, secondary hypocortisolism, hypogonadotropic hypogonadism, abnormal glucose homeostasis

*Selected non-endocrine disorders are included where they are important in differential diagnosis.  

Modes of inheritance: autosomal dominant (AD), autosomal recessive (AR), pseudoautosomal dominant (PAD), pseudoautosomal recessive (PAR), X-linked (X), Y-linked (Y), mitochondrial (MT), sporadic (S). à

Testing: Yes—clinical testing available; Res—testing available on research basis only; No—testing not available. Data obtained from GeneTests web site, http://www.geneclinics.org/ (information up to date as of November 9, 2003). The reader should consult this web site for the most up-to-date information. Modified from Potter A, Phillips JA III: Genetic disorders in pediatric endocrinology. In: Pediatric Endocrinology: Mechanisms, Manifestations, and Management. Pescovitz OA, Eugster E, eds. Lippincott Williams & Wilkins, Philadelphia, 2004, pp 1–23.

post-zygotic somatic mutations in the alpha subunit of the adenylate cyclase stimulatory G protein (Gsa, encoded by GNAS1, OMIM 139320). Gsa is a key regulator of the hormone responsive adenylate cyclase system and is involved in intracellular signaling by many endocrine receptors, including those for adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), parathyroid hormone (PTH), leuteinizing hormone (LH), and follicle stimulating hormone (FSH). Activating GNAS1 mutations lead to constitutive activity of these receptors. The classic triad of McCuneAlbright syndrome consists of polyostotic fibrous dysplasia, precocious puberty, and cafe´-au-lait spots, but hyperfunction of multiple endocrine systems can occur, including hyperthyroidism, hypercortisolism, growth hormone excess, and hyperprolactinemia. The timing of the somatic mutation causes variation in the type and extent of manifestations. The majority of patients have a point mutation in exon 8 of the GNAS1 gene (Arg201His or Arg201Cys), although individuals with other mutations have been reported. Molecular analysis is best done on affected tissue, as unaffected tissue may not show the mutation.10–12 Finally, many endocrine disorders are caused by defects in the enzymes that synthesize the respective hormones. For example, deficiencies in any of the several enzymes involved in adrenal steroid hormone biosynthesis can result in congenital adrenal hyperplasia, while defects in thyroid hormone biosynthesis can result in congenital hypothyroidism. Because these defects can occur at different steps in the corresponding synthetic pathway,

the associated phenotypes may differ in subtle or striking ways so that the associated malformations and related anomalies can be locus, or even allele, specific. These differences in phenotypes will almost certainly increase with time as the contribution of rare and common genetic variations at each locus are known and their effects on development are understood. From the material presented in this chapter, it is obvious that many endocrine disorders are caused by congenital anomalies of endocrine glands or defects in the enzymes that constitute different steps in hormone biosynthesis. Thus, deficiencies in a variety of enzymes involved in adrenal steroid and thyroid hormone biosynthesis can cause congenital adrenal hyperplasia or hypothyroidism. For example, in the case of thyroid hormone biosynthesis, specific mutations in SLC26A4 cause developmental anomalies in the cochlea, deafness, and goiter in Pendred syndrome. Knowledge of the potential for such rare as well as common genetic variations throughout the human genome to cause pleiotropic effects will almost certainly increase with time. With this knowledge will come better understanding of the contribution of genetic variation to human malformations and related anomalies. References 1. Online Mendelian Inheritance in Man, OMIM (TM). McKusick Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information,

Endocrine Organs

1345

Table 32-2. Selected naturally occurring animal models of genetic disorders of the endocrine organs Human Disorder

Animal Model

Disorder/Syndrome

OMIM

Gene

Model

Gene

Description

Abnormal thyroglobulin

188450

TG

Cog/cog mouse

Tg

Autosomal recessive congenital hypothyroidism

WIC-rdw rat

Tg

Autosomal recessive congenital hypothyroidism

Blepharophimosis, ptosis, and epicanthus inversus, type 1 (BPES 1)

605597

FOXL2

Polled intersex goat

FOX12

Suppression of horn formation and abnormal sexual differentiation

Combined pituitary hormone deficiency

173110

POU1F1

Snell dwarf (dw) mouse

Pit1

Missense mutation results in pituitary dwarfism with absence of GH, TSH, and PRL

Jackson dwarf (dw) mouse

Pit1

Gene rearrangement results in pituitary dwarfism with absence of GH, TSH, and PRL

601538

PROP1

Ames dwarf (df ) mouse

Prop1

Pituitary dwarfism with absence of GH, TSH, and PRL

Familial central diabetes insipidus

192340

AVP

Brattleboro rat

Avp

Autosomal recessive DI due to single base deletion

Gardner

175100

APC

Min mouse

Apc

Autosomal dominant multiple intestinal neoplasia

Gonadal dysgenesis, XY female type

480000

SRY

XY female cow

Sry

XY sex reversal

Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked (IPEX)

300292

FOXP3

Scurfy (sf) mouse

Foxp3

X-linked recessive lethal lymphoproliferative disorder

Isolated growth hormone deficiency (IGHD)

139250

GH1

Spontaneous dwarf rat

Gh

Isolated growth hormone deficiency

139191

GHRHR

Little mouse

Ghrhr

Dwarfism due to GH deficiency

Klinefelter

N/A

47,XXY

Male tortoise-shell cats

39,XXY or 39,XXY/38, XY mosaic

Tortoise-shell coat color, infertility

Laron

600946

GHR

Sex-linked dwarf chicken

Ghr

Dwarfism with GH resistance

Osteopetrosis, autosomal recessive

607649

GL

Gray-lethal (gl) mouse

Gl

Autosomal recessive lethal osteopetrosis and gray coat color

604592

TCIRG1

Osteosclerotic (oc) mouse

Mnuoc116

Autosomal recessive lethal osteopetrosis

Primary hypomagnesemia

603959

CLDN16

Japanese black cattle

Paracellin-1

Autosomal recessive renal tubular dysplasia with renal failure and growth retardation

Tuberous sclerosis

191092

TSC2

Eker rat

Tsc2

Hereditary renal carcinoma

X-linked hypogammaglobulinemia and isolated growth hormone deficiency

300300

BTK

X-linked immunodeficiency (xid) mouse

Btk

X-linked immunodeficiency

X-linked hypophosphatemic rickets

307800

PHEX

Hyp mouse

Pex

X-linked hypophosphatemia

National Library of Medicine (Bethesda, MD), 2003. http://www.ncbi .nlm.nih.gov/omim/ Accessed 9/3/2002 through 10/04/2003. 2. Ito M, Mori Y, Oiso Y, et al.: A single base substitution in the coding region for neurophysin II associated with familial central diabetes insipidus. J Clin Invest 87:725, 1991. 3. Kadowaki T, Bevins CL, Ojamaa K, et al.: Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science 240:787, 1988. 4. Krook A, Brueton L, O’Rahilly S: Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism. Lancet 342:277, 1993.

4. Wertheimer E, Lu SP, Backeljauw PF, et al.: Homozygous deletion of the human insulin receptor gene results in leprechaunism. Nat Genet 5:71, 1993. 5. Hone J, Accili D, Psiachou H, et al.: Homozygosity for a null allele in a patient with leprechaunism. Hum Mutat 6:17, 1995. 6. Longo N, Wang Y, Smith SA, et al.: Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 11:1465, 2002. 7. Lubahn DB, Brown TR, Simental JA, et al.: Sequence of the intron/ exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci USA 86:9534, 1989.

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Other Systems and Structures Table 32-3. Genetic tumor syndromes with endocrine features Syndrome

Carney complex type 1

Causation* Gene

Endocrine Features

AD (188830) PRKAR1A

Pituitary adenomas (ACTH or GH secreting), pheochromocytoma

Carney complex type 2

AD (605244)

Same as type 1

Cowden disease

AD (601728) PTEN

Thyroid adenomas

Familial medullary carcinoma of the thyroid

AD (164761) RET AD (191315) NTRK1

MTC without other features of MEN

Familial pheochromocytoma

AD (164761) RET AD (185470) SDHB AD (602690) SDHD

Pheochromocytoma without other evidence of MEN Extra-adrenal pheochromocytoma

Gardner

AD (175100) APC

Adrenal carcinoma, papillary thyroid carcinoma

Li-Fraumeni

AD (191170) P53 AD (604373) CHEK2

Adrenal carcinoma, germ cell tumors

Multiple Endocrine Neoplasia 1 (MEN1)

AD (131100) MEN1

Parathyroid adenomas, entero-pancreatic adenomas (most commonly gastrinoma), pituitary adenomas

Multiple Endocrine Neoplasia 2A (MEN2A)

AD (164761) RET

Pheochromocytoma, medullary carcinoma of the thyroid, parathyroid tumors

Multiple Endocrine Neoplasia 2B (MEN2B)

AD (164761) RET

Mucosal neuromas, pheochromocytoma, medullary carcinoma of the thyroid

Neurofibromatosis

AD (162200) NF1

Pheochromocytoma

Nijmegen breakage

AR (602667) NBS1

Primary ovarian failure, short stature

Peutz-Jeghers

AD (602216) STK11

Sertoli cell and ovarian tumors

Von Hippel-Lindau

AD (193300) VHL

Pheochromocytoma

Paragangliomas

Less likely to have childhood onset of tumors

*Modes of inheritance: autosomal dominant (AD), autosomal recessive (AR). From Online Mendelizen Inheritance in Man.1

8. McPhaul MJ: Molecular defects of the androgen receptor. Recent Prog Horm Res 57:181, 2002. 9. Weinstein LS, Shenker A, Gejman PV, et al.: Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. New Engl J Med 325:1688, 1991. 10. Schwindinger WF, Francomano CA, Levine MA: Identification of a mutation in the gene encoding the a subunit of the stimulatory G protein of adenyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA 89:5152, 1992. 11. Lumbroso S, Paris F, Sultan C: McCune-Albright syndrome: molecular genetics. J Pediatr Endocrinol Metab 15:875, 2002.

32.1 Congenital Adrenal Hyperplasia Definition

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by a deficiency of one of several enzymes involved in adrenal steroid synthesis.

Diagnosis

Because of defective cortisol synthesis, ACTH levels increase, resulting in overproduction and accumulation of cortisol precursors, particularly 17-OHP, proximal to the block. The diagnosis is made by detecting cortisol deficiency and 17-OHP accumulation. Etiology and Distribution

Adrenal gland development begins about 6 weeks post fertilization. The adrenal cortex and medulla develop from the mesoderm and neural crest cells, respectively. Cells forming the cortex are derived from the mesothelium lining the posterior abdominal wall. Cells that form the medulla are derived, as are the adjacent sympathetic ganglia, from trunk neural crest cells. The neural crest cells are surrounded by the fetal cortex and become the secretory cells of the medulla. More mesenchymal cells then enclose the fetal cortex and become the permanent cortex. Differentiation of the zones of the cortex continues for several years after birth. The adrenals of the fetus are 10 to 20 fold larger in proportion to body weight than in the adult. Congenital anomalies of the adrenal gland occur in CAH.

Table 32-4. Selected other genetic syndromes with endocrine features Disorder/Syndrome

Causation/Gene

Testing 

Economic Features

Achondroplasia

AD (100800) FGFR3

Yes

Short stature

Ataxia-telangiectasia

AR (208900) ATM

Yes

Delayed puberty, diabetes mellitus

Bardet-Biedl

AR (209901) BBS1 AR (606151) BBS2 AR (600374) BBS4 AR (604896) MKKS

Yes

Obesity, hypogonadism

AD (600856) CDKN1C AD (130650) Duplications/ deletions at 11p15.5

Yes

Blepharophimosis, ptosis, and epicanthus inversus, type 1 (BPES 1)

AD (605597) FOXL2

Yes

Premature ovarian failure

Bloom

AR (604610) RECQL2

Yes

Non-insulin dependent diabetes mellitus, impaired growth

Borjeson-Forssman-Lehmann

X (300414) PHF6

Res

Obesity, hypogonadism

Campomelic dysplasia

AD (114290) SOX9

Yes

Sex reversal in karyotypic males

Cerebellar ataxia and hypogonadotropic hypogonadism

AR (212840)

No

Hypogonadotropic hypogonadism

CHARGE

AD, S (214800) CHD7, 8q12.1

Res

Growth hormone deficiency, parathyroid hypoplasia, hypogonadotropic hypogonadism

Ectrodactyly, ectodermal dysplasia, and cleft lip/palate

AD (129900) 7q AD (602077) Chromosome 19 AD (603273) TP63

Res

Growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus

Fahr disease

AR (213600)

No

Hypoparathyroidism

Friedreich ataxia

AR (606829) FRDA1

Yes

Diabetes mellitus

Hemochromatosis

AR (235200) HFE AD (604653) SLC11A3 AR (604720) TFR2 AR (606464) HAMP

Yes No

Hypogonadotropic hypogonadism, diabetes mellitus Same

No

Same

No

Same, juvenile onset

Hyperglycerolemia

X (307030) GK

Yes

Poor growth, osteoporosis, adrenal hypoplasia, adrenal insufficiency

Hypoparathyroidism-retardationdysmorphism (Sanjad-Sakati)

AR (604934) TBCE

No

Congenital hypoparathyroidism

Johanson-Blizzard

AR (243800)

No

Hypothyroidism

Mental retardation/ alpha-thalassemia

X (300032) ATRX

Yes

Cryptorchidism, small penis, shawl scrotum, hypospadias in males

Nephropathic cystinosis

AR (606272) CTNS

Yes

Hypophosphatemic rickets, primary hypothyroidism, insulin dependent diabetes mellitus, delayed puberty

Beckwith-Wiedemann

Yes Yes Yes

Yes

Res

Overgrowth, adrenocortical cytomegaly, adrenal carcinoma, neonatal hypoglycemia due to islet hyperplasia

Yes

(continued)

1347

1348

Other Systems and Structures Table 32-4. Selected other genetic syndromes with endocrine features (continued) Disorder/Syndrome

Causation/Gene

Testing 

Economic Features

Noonan

AD (176876) PTPN11

Yes

Short stature, delayed puberty

Pallister-Hall

AD (165240) GLI3

Yes

Panhypopituitarism due to pituitary hypoplasia/aplasia; thyroid dysplasia/ aplasia; adrenal gland hypoplasia

Rieger

AD (601542) PITX2

Res

Hypospadias, growth hormone deficiency

Rothmund-Thomson

AR (603780) RECQL4

Res

Hypogonadism

Russell-Silver

S (180860) Heterogeneous

Yes

Short stature, growth hormone deficiency, fasting hypoglycemia

Tuberous sclerosis

AD (605284) TSC1 AD (191092) TSC2 AD (191091) TSC3 AD (191090) TSC4

Yes

Precocious puberty, hypothyroidism

Ulnar-mammary

AD (181450) TBX3

Yes

Delayed puberty

Werner

AR (604611) RECQL2

No

Diabetes mellitus, hypogonadism, short stature

Wilson disease

AR (606882) ATP7B

Yes

Hypoparathyroidism

Wolcott-Rallison

AR (604032) EIF2AK3

No

Insulin dependent diabetes

Wolfram

AR (606201) WFS1

Yes

DIDMOAD syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness)

Wolfram, mitochondrial form

MT (598500) mtDNA deletions/ mutations

No

Same as above

Yes No No

*Modes of inheritance: autosomal dominant (AD), autosomal recessive (AR), X-linked (X), mitochondrial (MT), sporadic (S).  

Testing: Yes—clinical testing available; Res—testing available on research basis only; No—testing not available. Data obtained from GeneTests web site, http://www.geneclinics.org/ (information up to date as of November 9, 2003). The reader should consult this web site for the most up-to-date information. Modified from Potter A, Phillips JA III: Genetic disorders in pediatric endocrinology. In: Pediatric Endocrinology: Mechanisms, Manifestations, and Management. Pescovitz OA, Eugster E, eds. Lippincott Williams & Wilkins, Philadelphia, 2004, pp 1–23.

Table 32-5. Selected chromosomal disorders with endocrine features1 Syndrome

Chromosomal Defect

OMIM

Endocrine Features

Chromosome 18q deletion

Del 18q

601808

Short stature, growth hormone deficiency

DiGeorge

Del 22q11.2

188400

Hypoparathyroidism

Down

Usually, trisomy 21; rarely mosaic or unbalanced translocation

190685

Predisposed to autoimmune endocrinopathies including hypothyroidism, type 1 diabetes mellitus

Klinefelter

47,XXY

N/A

Small testes, hypogonadism

Prader-Willi

Uniparental maternal disomy 15q, Del 15q11-q13

176270

Short stature, obesity, hypogonadotropic hypogonadism

Turner

45,X

N/A

Short stature, ovarian failure, mosaicism common, autoimmune hypothyroidism

Williams

Del 7q11.23

194050

Infantile hypercalcemia

Endocrine Organs

1349

In CAH an abnormal increase in cells of the adrenal cortex occurs and excess androgen is produced, causing female pseudohermaphroditism with masculinized external genitalia. Affected males have normal external genitalia. In both cases, deficiencies of cortisol and aldosterone occur secondary to the block in steroid biosynthesis and lead to salt-losing adrenal insufficiency crises that can be fatal.1 In CAH, 21 hydroxylation by CYP21 is impaired in the adrenal cortex so that 17-hydroxyprogesterone (17-OHP) is not converted to 11-deoxycortisol. CAH affects about 1 in 5000 births, and about 95% of cases are due to 21-hydroxylase deficiency (OMIM# 201910). Prognosis, Prevention, and Treatment

The block in cortisol biosynthesis causes excessive production of androgens, resulting in virilization. Patients may have either a simple virilizing or a salt wasting form of the disease. 21-hydroxylase deficiency can be caused by a variety of CYP21 mutations, of which the most common are gene deletions and an intron 2 splice site change.2,3 Compound heterozygotes are common, and phenotypic severity may vary widely depending on the severity of mutations in a given patient. Testing for CYP21 mutations is available and can be used for prenatal testing as well as for diagnostic confirmation. Other, much rarer forms of CAH include deficiency of CYP11B1 (OMIM# 202010), CYP17 (OMIM# 202110), and HSDB3 (OMIM# 201810).4–6 In CYP11B1 deficiency, patients may have hypertension due to accumulation of 11-deoxycorticosterone. Fusion of the CYP11B1 and CYP11B2 (aldosterone synthase) genes leads to the syndrome of glucocorticoid remediable hypertension.4 Patients with CYP17 deficiency have hypertension and absent sexual development, while those with HSDB3 deficiency have severe salt wasting.5,6 References (Congenital Adrenal Hyperplasia) 1. Moore KL, Persaud TVN: The Developing Human: clinically oriented embryology, ed 6. WB Saunders Company, Philadelphia, 1998. 2. Keegan CE, Killen AA: An overview of molecular diagnosis of steroid 21-hydroxylase deficiency. J Mol Diagn 3:49, 2001. 3. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (201910), (11/25/2002). http://www.ncbi.nlm.nih.gov/omim/ Accessed 12/12/2002. 4. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (202010), (3/12/02). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/12/2002. 5. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (202110), (8/8/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/12/2002. 6. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (201810), (3/2/2001). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/12/2002.

32.2 Anterior Pituitary, Hypothalamus, and Disorders of Short Stature The growth hormone (GH) pathway is comprised of a series of interdependent genes whose products are required for normal growth. The GH pathway genes include ligands (GH, insulin-like growth factor 1), transcription factors (Prophet of PIT1 or PROP1 and PIT1), agonists (GH releasing hormone or GHRH), antagonists (somatostatin or GH1F), and receptors (GH-releasing hormone receptor or GHRHR and the GH receptor or GHR)(see Fig. 32-1). These genes are expressed in different organs and tissues including the hypothalamus, pituitary, liver, and bone.

Fig. 32-1. Growth hormone (GH) biosynthetic pathway (for details see text).

Diagnosis

Short stature, delayed growth, and delayed skeletal maturation occur with GH pathway defects. Since these signs can also be associated with systemic illnesses, individuals suspected to have GH deficiency (GHD) should be evaluated for systemic diseases before having complicated tests to detect GHD. Provocative tests for GHD include GH stimulation tests. Deficient GH peak responses range from 7–10 ng/ml. Testing for concomitant deficiencies of LH, FSH, TSH, and/or ACTH should be done on GHD cases to detect CPHD, provide a complete diagnosis, and enable planning of optimal treatment.2,3 Etiology and Distribution

Pituitary gland development begins about 4.5 weeks post fertilization. The gland develops from two different sources. One is a growth upward of the ectodermal roof of the stomodeum called Rathke’s pouch, and the other is growth downward from the neuroectoderm (neurohypophyseal bud). The adenohypophysis or anterior lobe of the pituitary gland arises from oral ectoderm, whereas the neurohypophysis or posterior lobe arises from the neuroectoderm. Congenital anomalies can arise from persistence of the stalk of Rathke’s pouch in the roof of the oropharynx. Also, pituitary hypoplasia or aplasia can occur, which causes panhypopituitary dwarfism.1 Abnormal pituitary development and hypopituitarism occurs in ~5% of cases of cleft palate. Estimates of the frequency of GHD range from 1/4,000 to 1/ 10,000 in various studies. Causes of GHD include central nervous system insults or defects such as cerebral edema, chromosome anomalies, histiocytosis, infections, radiation, septo-optic dysplasia, and trauma or tumors that affect the hypothalamus or pituitary. While most GHD patients are the only affected member of their family, estimates of the proportion of cases that have an affected parent, sibling, or child range from 3–30% in different studies. This familial clustering suggests that having a close affected relative conveys substantial relative risk and that a significant proportion of GHD cases may have a genetic basis.2,3 Our current understanding of the genetic contributions to a series of familial defects in the GH pathway will be discussed in the following sections.

1350

Other Systems and Structures

Familial isolated growth hormone deficiency (IGHD) can be caused by at least six different mendelian disorders. These include four autosomal recessive disorders (IGHD 1A and 1B, Bioinactive GH, and GHRHR defects) (OMIM#s 262400, 139250, 262650, and 139191, respectively). In addition, there is an autosomal dominant (IGHD II, OMIM 173100) and an X-linked form of IGHD (IGHD III, OMIM# 307200)(see Tables 32-1, 32-2 and Fig. 32-1). IGHD IA

The most severe form of IGHD, called IGHD IA (OMIM 262400 and139250), has an autosomal recessive mode of inheritance. Affected neonates occasionally have mildly decreased birth lengths and hypoglycemia in infancy. All develop severe dwarfism by 6 months of age. While replacement therapy with exogenous GH gives a good initial growth response in individuals with IGHD IA, this response is often temporary because GH resistance develops due to anti-GH antibodies. IGHD IA is usually caused by a deletion of the GH1 genes. At a molecular level, these DNA deletions are 6.7, 7.0, or 7.6 kb in length with ~3/4 being 6.7 kb.2,3 DNA sequence analysis of the fusion fragments associated with these recurring deletions has shown that the deletions arise from homologous recombination between repeated sequences that flank the GH1 gene.4 Multiple studies indicate that ~15% of individuals with severe IGHD (>4.5 SD in height) have GH1 gene deletions. Since gene deletions, as well as frameshift and nonsense mutations, have been found to cause the IGHD IA phenotype, this disorder is best described as complete GHD due to heterogeneous GH1 gene defects, rather than gene deletions alone (see Tables 32-1, 32-2, and Fig. 32-1).2,3 IGHD IB

This milder form of IGHD, IGHD IB, also has an autosomal recessive mode of inheritance. These cases differ clinically from IGHD IA in their having low but detectable levels of GH and a continued growth response due to immunologic tolerance to treatment with exogenous GH. IGHD IB cases are caused by GH gene defects that result in a mutant GH protein that may not be detected by RIA. The presence of these mutant GH protein molecules may explain the good responses that are seen to GH therapy because their presence mitigates against the production of anti-GH antibodies. IGHD 1B is caused by mutations that affect splicing of the GH1 gene. This altered splicing causes loss of amino acids that affect the stability and biologic activity and reduce secretion of the mutant GH protein.2,3 IGHD II

IGHD II has an autosomal dominant mode of inheritance due to dominant-negative mutations of the GH1 gene, and it responds well to GH treatment. Almost all the GH1 gene defects reported in IGHD II are mutations that alter splicing of GH mRNA and cause skipping or deletion of exon 3. The mechanism by which these dominant negative mutations prevent expression of GH protein from the other, normal GH1 gene is poorly understood. Other IGHD II mutations cause skipping of exon 3 by disrupting splicing enhancer sequences (SEs) that regulate the splicing pattern of GH mRNA and, when these SEs are perturbed, exon 3 skipping occurs.2,3 An IGHD II mutation that does not cause abnormal splicing is a G to A transition which results in an Arg to His substitution at residue 183 (Arg183His) of the GH molecule. This substitution is thought to alter the intracellular processing of the GH molecule by binding to zinc, thereby deranging the zinc associated presecretory packaging of GH.5

IGHD III

A third form of IGHD called IGHD III (OMIM 307200) has an X-linked mode of inheritance and distinct clinical findings in different families. In some families, all cases have agammaglobulinemia associated with their IGHD, whereas in other families, all cases have only IGHD. This suggests that contiguous gene defects on the long arm of the X chromosome may cause some IGHD III cases. Duriez et al. reported that X-linked agammaglobulinemia and IGHD is caused by mutation in the Bruton’s tyrosine kinase or BTK gene.6 Laumonnier et al. studied the SOX3 gene in families with Xlinked mental retardation where the causative gene had been mapped to Xq26-q27.7 They showed that the SOX3 gene maps to Xq26.3 and was involved in a large family in which affected individuals had mental retardation and IGHD (OMIM 300123 and 313430, Table 321). The mutation was an in-frame duplication of 33 bp encoding 11 alanines in a polyalanine tract of the SOX3 gene. The expression pattern during neural and pituitary development suggested that dysfunction of the SOX3 gene caused by this polyalanine expansion might disturb transcription pathways and the regulation of genes involved in pituitary development. Biodefective GH

A number of patients have been described with the clinical features of IGHD who achieved normal plasma immunoactive GH levels following GH provocative or stimulation tests, but low levels of somatomedin (OMIM 139250, Table 32-1). Less GH was detected by radioreceptor assay than by RIA analysis in some studies. In view of their clinical syndrome of IGHD, apparently normal plasma concentrations of GH, low basal somatomedin levels, and their normal response to exogenous GH, individuals with bioinactive GH are thought to secrete a biologically inert GH. Takahashi et al. identified a C to T transition in codon 77 which results in an Arg to Cys substitution in the GH1 gene of a subject diagnosed with bioinactive GH.8 GHRH Receptor (GHRHR) Defects

A variety of mutations have been detected in the human GHRHR gene in individuals with IGHD (OMIM 139191) (Fig. 32-1). In a kindred with a nonsense mutation, affected family members had poor growth since infancy and were extremely short. They failed to produce GH in response to standard provocative tests and had good responses to GH replacement. Cases were homozygous for a G to T transversion that caused a premature termination mutation (Glu72Stop). A large Brazilian family was reported by Salvatori et al. who had many family members with IGHD due to an intronic G to T transition that destroys the 5’ splice site of IVS 1 of the GHRHR gene.9 GH Receptor (GHR) Defects

To be biologically active, GH (OMIM 139250) must bind to a transmembrane receptor (GHR) (OMIM 60094), the GHR must form a dimer, and an intracellular signal-transduction pathway must be activated which causes the synthesis and secretion of insulin-like growth factor I (IGF1) (OMIM 147440). This factor, which in serum is bound to members of a family of binding proteins, binds to the IGF1 receptor (IGF1R) (OMIM 147370) and activates its own signal-transduction pathways, resulting in mitogenic and anabolic responses that lead to growth. It is uncertain whether GH has any anabolic actions independent of IGF1. Disruptions in GHR or IGF1 can cause GH resistance characterized by phenotypic features of GHD associated with normal or high GH levels.

Endocrine Organs

Growth Hormone Receptor (GHR) Dysfunction or Laron Dwarfism I

This an autosomal recessive disorder caused by GH resistance due to defects in the GH receptor (GHR) gene (OMIM 262500). While at the clinical level Laron syndrome cases are indistinguishable from GHD cases, they differ at the biochemical level because they have low levels of IGF1, despite their having normal or increased levels of GH. This contrasts with the low levels of both IGFI1 and GH that are seen in GHD. Importantly, exogenous GH does not induce an IGF1 response or restore normal growth in Laron dwarfism I cases because their GHR dysfunction prevents the synthesis and secretion of IGF1. While plasma levels of the GH binding proteins (GHBP) that are derived from the extracellular domain of GHR are usually low in Laron dwarfism I , Woods et al. reported a homozygous point mutation in the intracellular domain of the GHR that caused Laron syndrome with elevated GHBP levels.10 These authors predicted that the mutant GHR would not be anchored in the cell membrane but would be measurable in the serum as GHBP, thus explaining the phenotype of severe GH resistance combined with elevated circulating GHBP. Studies of the GHR genes of Laron dwarfism I patients (OMIM 262500) have identified a variety of exon deletions and base substitutions. While treatment with exogenous GH is ineffective in those with GHR dysfunction, replacement therapy with recombinant IGFI1 has been shown to be effective (see Fig. 32-1 and Table 32-1). Laron Dwarfism II

This form of GH resistance is caused by post-GHR defects (see OMIM 245590 and Table 32-1). Patients with Laron dwarfism II have elevated serum GH, normal GHBP levels, and respond well to treatment with IGF1, indicating that their growth deficiency is due to a post-GHR defect (see Fig. 32-1). Woods et al. described a patient with severe growth failure, sensorineural deafness, and mental retardation who was homozygous for a partial deletion of the IGF1 gene.11 Combined Pituitary Hormone Deficiency (CPHD)

Cases with combined pituitary hormone deficiency (CPHD) vary in their clinical findings because they have deficiencies of varying severity of one or more of the other pituitary trophic hormones (ACTH, FSH, LH, or TSH) in addition to GHD (OMIM 262600). While most cases of CPHD are sporadic, a variety of familial forms are known that can have autosomal recessive, autosomal dominant, or X-linked modes of inheritance. HESX1 Mutations

HESX1 is expressed in the thickened layer of oral ectoderm that gives rise to Rathke’s pouch, the primordium of the anterior pituitary. Down regulation of HESX1 coincides with the differentiation of pituitary-specific cell types (see Table 32-1 and Fig. 32-1). Dattani et al. found a homozygous missense HESX1 mutation (ARG53CYS) in a brother and sister with septooptic dysplasia, agenesis of the corpus callosum, and CPHD (OMIM 182230).12 LHX3 Mutations

Murine Lhx3 mRNA accumulates in Rathke’s pouch, the primordium of the anterior pituitary, and may be involved in differentiation of pituitary cells (see Table 32-1 and Fig. 32-1). Netchine et al. identified two families with CPHD (OMIM 262600) caused by mutations in the LHX3 gene.13 The phenotype associated with these mutations included the following: (1) severe growth retardation,

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(2) complete deficiency of all but one of the anterior pituitary hormones (ACTH), (3) elevated and anteverted shoulders with a short neck associated with severe restriction of rotation of the cervical spine, and (4) an enlarged anterior pituitary. The authors concluded that LHX3 is required for the proper development of all anterior pituitary cell types except corticotropes and that the rigid cervical spine phenotype is consistent with a function of LHX3 in the proper development of extrapituitary structures as well. PIT1 Mutations

Defects in the PIT1 gene causes familial CPHD cases which have a different phenotype (OMIM 173110). PIT1 is an anterior pituitary– specific transcription factor, which regulates the expression of GH, PrL, and TSH. PIT1 is also required for pituitary cellular differentiation and function. PIT1 has functional domains that enable transactivation of other genes including GH, PrL, and TSH or binding to these genes. At least six different PIT1 mutations causing autosomal recessive and two others causing autosomal dominant CPHD have been found in humans in a subtype of panhypopituitary dwarfism associated with GH, PrL, and TSH deficiency (see Tables 32-1 and 32-2, and Fig. 32-1). PROP1 Mutations

PROP1 or Prophet of PIT1 is a pituitary-specific homeodomain factor that is required for development of somatotropes, lactotropes, thyrotropes of the anterior pituitary, and for expression of PIT1. Multiple PROP1 gene mutations cause an autosomal recessive CPHD that has a third phenotype in humans (OMIM 601538, Tables 32-1 and 32-2, and Fig. 32-1). In addition to deficiencies of GH, PrL, and TSH as are seen in those with PIT1 defects, subjects with PROP1 defects also have deficiencies of LH and FSH, which prevent the onset of spontaneous puberty and, in some cases, ACTH deficiency in later life. The various PROP1 mutations include (1) a C to T transition in codon 120 which encodes a TGC (Arg) to CGC (Cys) substitution, (2) a T to A transversion that encodes a TTC (Phe) to ATC (Ile) substitution at codon 117, and (3) 2 bp AG deletion in codon 101 (101delAG) that causes a frameshift and results in a premature stop at codon 109. The resulting protein products from all three of these different PROP1 mutations have greatly reduced DNA binding and transactivation abilities.14 The 101delAG is a recurring mutation that is estimated to occur in about 55% of familial and 12% of sporadic CPHD cases.15 A fourth PROP1 mutation is a 2 bp GA deletion in codon 51 (51delGA).16 Like the 101delAG mutation, the 51delGA mutation causes a frameshift that results in a premature stop codon. This mutation was found in 12% of familial and 21% of sporadic CPHD cases. X-linked CPHD

Lagerstrom-Fermer et al. reported a family that included affected males suffering from variable degrees of CPHD (OMIM 312000, Table 32-1).17 Some affected males who died during the first day of life had postmortem findings of hypoadrenalism, presumed to be due to CPHD. Others had variable combinations of hypothyroidism, delayed pubertal development, and short stature due to GHD. All surviving patients exhibited mild to moderate mental retardation. They found linkage with markers in the Xq25-q26 region. Furthermore, they found an apparent extra copy of the marker DXS102 in affected males and heterozygous carrier females, suggesting that a segment including this marker was duplicated.

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SHOX Mutations

The short stature homeobox gene, or SHOX (OMIM #312865, Table 32-1), is a transcription factor which is important in skeletal development.18 The gene is located in the pseudoautosomal regions of the X and Y chromosomes and escapes inactivation in XX females. It encodes 2 isoforms, SHOX a and b, with protein products of 292 and 225 amino acids, respectively. SHOX variants have been associated with multiple short stature phenotypes, including idiopathic short stature (ISS), Turner syndrome (TS), Leri-Weill syndrome (LWS, also called Leri-Weill dyschondrosteosis), and Langer mesomelic dysplasia (LMD). Patients with TS are, by definition, missing at least part of the X chromosome, and it has been established that the loss of one SHOX allele contributes, at least in part, to the short stature seen in TS, as well as skeletal manifestations such as Madelung deformity (distal radioulnar deformity) which are sometimes a part of TS.19,20 Deletions or mutations of one SHOX allele are also linked to ‘‘idiopathic’’ short stature in approximately 2.4% of short children with normal karyotypes and no other features of TS or the other SHOX-associated syndromes.21 Leri-Weill syndrome and Langer mesomelic dysplasia represent, respectively, heterozygous and homozygous SHOX mutations. LWS is characterized by disproportionate short stature with mesomelic shortening of the forearms and lower legs and Madelung deformity of the forearm. At least 60% of LWS patients have either a deletion or a mutation of one SHOX allele,22–26 resulting in haploinsufficiency. LMD is characterized by severe mesomelic limb shortening and dwarfism, and results from either homozygous or compound heterozygous deletions or mutations in the SHOX gene.27 Testing for SHOX deletions and mutations is now commercially available. It should be considered in patients with features suggesting either LWS or LMD, or in patients with otherwise ‘‘idiopathic’’ short stature who have isolated Madelung deformity, mild forelimb shortening, or other features suggesting possible SHOX deficiency. Prognosis, Prevention, and Treatment

The prognosis and prevention of various endocrine deficiencies associated with these various disorders depends on their etiology and associated findings (see Table 32-1). In some cases, malformations of the pituitary and cervical spine and/or mental retardation may be associated, while in others only delayed growth retardation occurs. Tests are available for a number of these disorders, and they can be applied both prenatally and postnatally to enable early treatment and prevention of the various complications associated with the disorder. Treatment by replacing the corresponding deficient hormone is indicated for these disorders. Recombinant-derived GH is widely available but must be given by subcutaneous injection. To obtain an optimal outcome, children with GHD should be started on replacement therapy as soon as their diagnosis is established. The dosage increases with increasing body weight to a maximum during puberty. Disorders in which GH treatment is of proven efficacy include GHD, either isolated or in association with CPHD, and Turner syndrome. The clinical responses of individuals with IGHD or CPHD to GH replacement therapy varies depending on (1) the severity and age at which treatment is begun, (2) recognition and response to treatment of associated deficiencies such as thyroid hormone deficiency, and (3) if treatment is complicated by the development of anti-GH antibodies. The outcome of Turner syn-

drome subjects varies with the severity of their short stature, chromosomal complement, and age when treatment began.3 References (Anterior Pituitary, Hypothalamus, and Disorders of Short Stature) 1. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, ed 6. WB Saunders Company, Philadelphia, 1998. 2. Rimoin DL, Phillips JA III: Genetic disorders of the pituitary gland. In Principles and Practice of Medical Genetics, ed 3. Rimoin DL, Connor JM, Pyeritz RE, eds. Churchill Livingstone, New York, 1997, p 1331. 3. Cogan JD, Phillips JA III: Inherited defects in growth hormone synthesis and action. In: The Metabolic and Molecular Bases of Inherited Disease, ed 8. Scriver CR, Beaudet AL, Sly WS, et al., eds. McGraw-Hill, New York, 2001, p 4159. 4. Vnencak-Jones CL, Phillips JA III, Chen EY, et al.: Molecular basis of human growth hormone gene deletions. Proc Natl Acad Sci 85:5615, 1988. 5. Wajnrajch MP, Gertner JM, Mullis PE, et al.: Arg183His, a new mutational ‘‘hot-spot’’ in the growth hormone gene causing isolated GH deficiency type II. J Endocr Genet 1:125, 2000. 6. Duriez B, Duquesnoy P, Dastot F, et al.: An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett 346:165, 1994. 7. Laumonnier F, Ronce N, Hamel BCJ, et al.: Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 71:1450, 2002. 8. Takahashi Y, Kaji H, Okimura Y, et al.: Brief report: short stature caused by a mutant growth hormone. N Engl J Med 334:432, 1996. 9. Salvatori R, Gondo RG, de Aguirar Oliveira MH, et al.: Familial isolated growth hormone deficiency due to a novel mutation in the growth hormone-releasing hormone receptor. J Clin Endocrinol Metab 84:917, 1999. 10. Woods KA, Fraser NC, Postel-Vinay MC, et al.: A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab 81:1686, 1996. 11. Woods KA, Camacho-Hubner C, Savage MO, et al.: Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor 1 gene. New Engl J Med 335: 1363, 1996. 12. Dattani MT, Martinez-Barbera J-P, Thomas PQ, et al.: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125, 1998. 13. Netchine I, Sobrier M-L, Krude H, et al.: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25:182, 2000. 14. Wu W, Cogan JD, Pfaffle RW, et al.: Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 18:147, 1998. 15. Cogan JD, Wu W, Phillips JA III, et al.: The PROP1 2-bp deletion is a common cause of CPHD. J Clin Endocrinol Metab 83:3346, 1998. 16. Fofanova O, Takamura N, Kinoshita E, et al.: Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency. J Clin Endocrinol Metab 83:2601, 1998. 17. Lagerstrom-Fermer M, Sundvall M, Johnsen E, et al.: X-linked recessive panhypopituitarism associated with a regional duplication in Xq25-q26. Am J Hum Genet 60:910, 1997. 18. Rao E, Blaschke RJ, Marchini A, et al.: The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Hum Molec Genet 10:3083, 2001. 19. Rao E, Weiss B, Fukami M, et al.: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54, 1997. 20. Clement-Jones M, Schiller S, Rao E, et al.: The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Molec Genet 9:695, 2000. 21. Rappold GA, Fukami M, Niesler B, et al.: Deletions of the homeobox gene SHOX (Short Stature Homeobox) are an important cause of

Endocrine Organs

22.

23.

24.

25. 26. 27.

growth failure in children with short stature. J Clin Endocrinol Metab 87:1402, 2002. Shears DJ, Vassal HJ, Goodman FR, et al.: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet 19:70, 1998. Schiller S, Spranger S, Schechinger B, et al.: Phenotypic variation and genetic heterogeneity in Leri-Weill syndrome. Eur J Hum Genet 8:54, 2000. Grigelioniene G, Eklo¨f O, Ivarsson SA, et al.: Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia. Hum Genet 107:145, 2000. Huber C, Cusin V, Le Merrer M, et al.: SHOX point mutations in dyschondrosteosis. J Med Genet 38:323, 2001. Falcinelli C, Iughetti L, Percesepe A, et al.: SHOX point mutations and deletions in Leri-Weill dyschondrosteosis. J Med Genet 39:e33, 2002. Zinn AR, Wei F, Zhang L, et al.: Complete SHOX deficiency causes Langer mesomelic dysplasia. Am J Med Genet 110:158, 2002.

32.3 Parathyroid Gland: Calcium Sensing Receptor Defects Embryology

The superior parathyroid gland develops by week 6 from the fourth pharyngeal pouch. The parathyroid glands derived from the third pouches descend with the thymus and are eventually located inferior to those derived from the fourth pharyngeal pouch. The chief cells differentiate and become functional in regulating fetal calcium metabolism. In contrast, the oxyphil cells differentiate several years after birth. Congenital anomalies of the parathyroid glands occur in DiGeorge sequence, in which congenital thymic aplasia also occurs.1 The calcium sensing receptor (CASR, OMIM# 601199, Table 32-1) is a large protein of 1084 amino acids. It contains seven transmembrane spanning helices and is part of the superfamily of G protein coupled receptors. CASR functions as a calcium sensor in parathyroid and kidney cells, and its activation suppresses PTH secretion and enhances urinary calcium excretion.2 Diagnosis

These disorders are associated with hypocalcemia, hypercalcemia, hypocalciuria, and inappropriate PTH levels. Etiology and Distribution

To date, three disorders have been associated with CASR mutations. The first, familial hypocalciuric hypercalcemia (FHH), is caused by heterozygous inactivating mutations. In this autosomal dominant syndrome, the calcium ‘‘set point’’ is altered, leading to mild hypercalcemia, hypocalciuria, and inappropriately normal PTH levels.3 Patients are usually asymptomatic; many are not diagnosed until they have a chemistry panel done for other purposes which reveals the hypercalcemia. No treatment is necessary. The second disorder, neonatal severe hyperparathyroidism (NSHPT), occurs in neonates who are homozygous for inactivating mutations.4 Patients with NSHPT have hyperplasia of all parathyroid glands and severe elevations of serum calcium, which may be lifethreatening if not treated by parathyroidectomy. The third disorder, autosomal dominant hypocalcemia (ADH), is caused by activating mutations of the CASR.5–8 As with FHH, patients with ADH have an altered set point for calcium homeostasis. The hypocalcemia is usually mild, and most patients are asymptomatic. Over 53 mutations in CASR have been documented. The majority

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of mutations are in the extracellular and transmembrane domains. Most are missense or nonsense mutations.9 Prognosis, Prevention, and Treatment

These disorders vary in their severity, prognosis, and need for treatment. References (Parathyroid Gland: Calcium Sensing Receptor Defects) 1. Moore KL, Persaud TVN: The Developing Human: clinically oriented embryology, ed 6. WB Saunders Company, Philadelphia, 1998. 2. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (601199), (12/4/2002). http://www.ncbi.nlm.nih.gov/omim/ Accessed 12/10/2002. 3. Fuleihan, GE: Familial benign hypocalciuric hypercalcemia. J Bone Miner Res 17:N51, 2002. 4. Pollak MR, Brown EM, Chou YW, et al.: Mutations in the human Ca2þ-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297, 1993. 5. Pollak MR, Brown EM, Estep HL, et al.: Autosomal dominant hypocalcemia caused by a Ca2þ-sensing receptor gene mutation. Nat Genet 8:303, 1994. 6. Perry YM, Finegold DN, Armitage MM, et al.: A missense mutation in the Ca-sensing receptor gene causes familial autosomal dominant hypoparathyroidism. Am J Hum Genet 55(Suppl):A17, 1994. 7. D’souza-li L, Yang B, Canaff L, et al.: Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia. J Clin Endocrinol Metab 87:1309, 2002. 8. Nagase T, Murakami T, Tsukada T, et al.: A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser820Phe) in the calcium-sensing receptor. J Clin Endocrinol Metab 87:2681, 2002. 9. Hendy GN, D’Souza-Li L, Yang B, et al.: Mutations of the calciumsensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 16:281, 2000.

32.4 Parathyroid Gland: Albright Hereditary Osteodystrophy Albright hereditary osteodystrophy (AHO), also called pseudohypoparathyroidism, is a clinical syndrome of short stature and short 4th and 5th metacarpals associated with hypocalcemia and ectopic calcification. Diagnosis

AHO is diagnosed on the basis of the above findings or detection of characterized changes in the GNAS1 gene. Etiology and Distribution

AHO is caused by inactivating mutations in the GNAS1 gene (OMIM 139320, Table 32-1), which leads to impaired parathyroid hormone action. The GNAS1 gene is paternally imprinted, meaning that normally only the maternal copy is expressed and the paternal copy is not. Prognosis, Prevention, and Treatment

Patients with AHO exhibit variable severity due to a combined effect of tissue-specific imprinting and haploinsufficiency (Fig. 32-2). Thus, patients who inherit an abnormal GNAS1 gene from

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Fig. 32-2. Variation in the severity of Albright hereditary osteodystrophy due to imprinting of paternally transmitted GNAS1 gene. Note mild phenotype when GNAS1 mutation is paternally transmitted and severe when maternally transmitted.

their mother are more severely affected (the normal paternal allele is imprinted and suppressed), and patients who inherit the gene from their father are less severely affected (the abnormal paternal allele is suppressed, and the normal maternal allele is expressed). See Fig. 32-2 for an example pedigree showing the effect of imprinting on the severity of the clinical expression of AHO.1,2 References (Parathyroid Gland: Albright Hereditary Osteodystrophy) 1. Levine MA, Ahn TG, Klupt SF, et al.: Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy. Proc Natl Acad Sci USA 85:617, 1988. 2. Farfel Z, Bourne HR, Iiri T: The expanding spectrum of G protein diseases. New Engl J Med 340:1012, 1999.

cause accumulation of the AVP-NPII precursors, which then damage the cells producing them, eventually leading to loss of these cells and central diabetes insipidus. An autosomal recessive form due to a mutation in the AVP moiety of the AVP gene has also been reported.1 The clinical syndrome of NDI is the same as that of CDI, except that patients with NDI do not respond to exogenous AVP. In type 1 NDI (OMIM #304800, Table 32-1), there is a defect in the AVP receptor (AVPR2), resulting in inability of the kidney to resorb water in response to AVP. Numerous mutations in AVPR2 causing NDI have been described including missense mutations, small deletion/insertions, tandem duplications, large deletions, and nonsense mutations leading to a truncated receptor. These mutations can lead to binding impairment at the cell surface, blocked intracellular transport, ineffective biosynthesis, and/or accelerated degradation of AVPR2.2 Patients with type II NDI have normal AVPR2, but have a defect in the water channel AQP2 (OMIM# 107777, Table 32-1) such that they do not respond to signaling through AVPR2. AQP2 mutations can be autosomal dominant (via a dominant negative effect) or recessive.3 Prognosis, Prevention, and Treatment

The prognosis, prevention, and treatment depend on the genetic basis and responsiveness to AVP. References (Posterior Pituitary and Water Metabolism) 1. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (192340), (7/25/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002. 2. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (304800), (7/23/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002. 3. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (107777), (10/28/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002.

32.5 Posterior Pituitary and Water Metabolism

32.6 Thyroid and Thyroid Biosynthetic Defects

Abnormalities in water homeostasis can be caused by deficiency of or peripheral resistance to arginine vasopressin (AVP).

Genetic defects in the thyroid axis include those that cause hyperthyroidism or hypothyroidism. Included are mutations in thyroidstimulating hormone (TSH) or thyroid-stimulating hormone receptor (TSHR) as well as multiple defects in thyroid hormone synthesis, secretion, and effect.

Diagnosis

The diagnosis of central diabetes insipidus (CDI) depends on detection of absent or defective AVP. The diagnosis of nephrogenic diabetes insipidus (NDI) depends on demonstration of refractory renal response to AVP. Etiology and Distribution

Hereditary CDI (OMIM# 125700, Tables 32-1, 32-2) is a syndrome characterized by absent or ineffective AVP leading to polyuria, polydipsia, and dehydration. It can have autosomal dominant negative or autosomal recessive modes of inheritance. The AVP gene contains AVP in exon 1 and its carrier protein (neurophysin or NPII) in exons 2 and 3. Heterogeneous mutations including Ala-1Thr in AVP and Gly57Ser in NPII cause DI. The Ala-1Thr mutation prevents cleavage of AVP from its precursor by signal peptidase, and the Gly57Ser mutation is speculated to perturb NPII’s ability to transport AVP or protect it from proteolytic degradation. These processing defects are thought to

Diagnosis

These disorders are caused by defects in the TRHR, TSH, TSHR, and SLC26A4 genes. Their diagnosis is made by detecting defects in each gene or their products. Etiology and Distribution

The thyroid gland is the first endocrine gland to appear during embryonic development. The thyroid begins to develop about 3.5 weeks post fertilization from a thickening of the pharyngeal endoderm. This tissue descends as the diverticulum. The definitive thyroid gland has right and left lobes that are connected by the isthmus. Additionally, a remnant of tissue, the thyroglossal duct, is commonly present in the path of the gland’s descent. Congenital anomalies of the thyroid include thyroglossal duct cysts and sinuses in the tongue or anterior to the laryngeal cartilages, respectively; ectopic thyroid glands high in the neck or just inferior to the hyoid

Endocrine Organs

bone; and accessory thyroid tissue in the tongue or in the neck above the thyroid gland.1 Thyrotropin-releasing hormone receptor (TRHR) deficiency causes central hypothyroidism due to deficient TSH secretion. Rare mutations of the TRHR (OMIM 188545, Table 32-1) leading to central hypothyroidism in humans have been reported.2,3 Thyroid-stimulating hormone (TSH) deficiency was found in a family with two affected sisters born of consanguineous parents.4 Hayashizaki et al. found homozygosity for a G to A transition in exon 2 in codon 29 of the TSH-beta subunit (OMIM 188540, Table 32-1).4 This transition encoded a Gly29Arg substitution in the center of the so-called CAGYC region, which represents an amino acid sequence conserved among all known glycoprotein hormone beta subunits.5 Thyroid-stimulating hormone receptor (TSHR) deficiency can be associated with both familial non-autoimmune autosomal dominant hyperthyroidism (activating mutations) or hypothyroidism due to TSH insensitivity (inactivating mutations) (OMIM 603372, Table 32-1).4.6 Pendred syndrome (PDS) is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). PDS is caused by mutations in the SLC26A4 gene (OMIM# 605646, Table 32-1).7 Thyroid hormone resistance is characterized by elevated free thyroxine and tri-iodothyronine levels in the presence of a normal serum thyroid stimulating hormone level. The majority of cases are due to autosomal dominant mutations in the thyroid hormone receptor, THRb (OMIM# 190160, Table 32-1). Most mutations affect the ligand-binding site, with intact DNA binding. This leads to a dominant negative effect, with mutant receptor molecules occupying DNA binding sites and preventing binding of the normal receptor. The mutant molecules may also interfere with the normal dimerization of the receptor. One kindred has been reported with autosomal recessive inheritance and a complete deletion of the THRb gene.8 Prognosis, Prevention, and Treatment

The prognosis, prevention, and treatment depend on the genetic defect in thyroid hormone biosynthesis. Clinically, Pendred syndrome should be considered in individuals with early onset hearing loss. References (Thyroid and Thyroid Biosynthetic Defects) 1. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology, ed 6. WB Saunders Company, Philadelphia, 1998. 2. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (188545), (2/5/2001). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002. 3. Collu R, Tang J, Castagne J, et al.: A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 82:1361, 1997. 4. Hayashizaki Y, Hiraoka Y, Endo Y, et al.: Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. EMBO J 8:2291, 1989. 5. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (188540), (7/31/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002. 6. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (603372), (5/16/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002. 7. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: (605646), (12/4/2002). http:// www.ncbi.nlm.nih.gov/omim/ Accessed 12/13/2002.

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8. Refetoff S, Weiss RE, Usala SJ: The syndromes of resistance to thyroid hormone. Endocr Rev 14:348, 1993.

32.7 Endocrine Tumor Syndromes MEN1, MEN2, and familial medullary thyroid carcinoma (FMTC) are autosomal dominant disorders that are associated with development of tumors in endocrine tissues (Table 32-2). Diagnosis

Testing for MEN1 mutations is commercially available. Such testing will identify approximately 80–90% of mutations. Once a mutation has been identified in an index patient, at-risk relatives should be tested. Identification of carrier status can single out those patients who require regular screening for the manifestations of MEN1 and relieve patients who are not carriers of the burden of regular medical testing. For families where a mutation cannot be identified, 11q13 haplotype testing may identify carriers. All three MEN2 disorders (MEN2A, MEN2B, and FMTC) are caused by mutations in the RET gene (see OMIM# 164761). Most mutations associated with the MEN2 syndromes occur in exons 10, 11, 13, 14, 15, and 16. Testing of these exons is commercially available and will detect the majority of mutations. Etiology and Distribution

MEN1 is an autosomal dominant disorder with marked intrafamilial variability, characterized by multiple tumors or hyperplasia of endocrine glands (see OMIM # 131100, Table 32-3). MEN1 is defined by the presence of two of the following three endocrine tumors: parathyroid adenoma or hyperplasia, enteropancreatic endocrine tumors, and pituitary adenomas. Other possible manifestations include carcinoid tumors, adrenal adenomas, and lipomas. The MEN1 gene was identified through analysis of large kindreds with MEN1. It is located on chromosome 11q13 (65). The gene product, menin, appears to function as a tumor suppressor gene, with germline mutations leading to a ‘‘first hit.’’ In some tissues, loss of the second allele through somatic mutations (‘‘two hits’’) leads to tumor formation. MEN2A is an autosomal dominant disorder defined by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenomas (OMIM# 171400, Table 32-3). Ninety percent of MEN2A patients will have medullary thyroid carcinoma, 50% will have pheochromocytomas, and 20–30% will have parathyroid tumors. MEN2B consists of medullary thyroid carcinoma and pheochromocytomas in association with marfanoid body habitus and intestinal and mucosal ganglioneuromatosis alone. FMTC can occur in isolation. Hirschsprung disease can be seen in association with either MEN2A or FMTC. As stated previously, all three MEN2 disorders (MEN2A, MEN2B, and FMTC) are caused by mutations in the RET gene (see OMIM# 164761 and Table 32-3). RET is located on chromosome 10 and encodes a membrane-bound tyrosine kinase. A limited number of mutations are associated with the MEN2 syndromes, mainly in exons 10, 11, 13, 14, 15, and 16. Testing of these exons is commercially available and will detect the majority of mutations. Prior to the availability of RET testing, patients who were possible carriers were monitored for MTC by following basal and stimulated calcitonin levels; however, these have higher false-positive and false-negative rates than mutation testing (66). Determining RET carrier status in children at risk is particularly important because

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Other Systems and Structures

prophylactic thyroidectomy may be life saving. In one study, 67% of juvenile RET mutation carriers subsequently shown to have MTC or C-cell hyperplasia (a premalignant lesion) at thyroidectomy had normal basal calcitonin levels (67). MTC has been reported in infancy, highlighting the need for early testing and decisions about prophylactic thyroidectomy. Prognosis, Prevention, and Treatment

The MEN syndromes are a group of conditions in which molecular genetic testing guides therapy and can be life-saving. Testing for MEN1 or RET mutations can confirm the diagnosis in affected patients and, in the case of RET mutations, guide optimal timing of thyroidectomy. For unaffected patients at risk, testing can identify carriers who will need life-long surveillance for the manifestations of these syndromes and can exclude non-carriers from costly and invasive testing. References (Endocrine Tumor Syndromes) 1. Guru SC, Manickam P, Crabtree JS, et al.: Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene. J Intern Med 243:433, 1998. 2. Brandi ML, Gagel RF, Angeli A, et al.: Consensus: guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658, 2001. 3. Sanso GE, Domene HM, Rudaz MCG, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children. Cancer 94:323, 2002.

32.8 Mendelian Disorders with Endocrine Abnormalities A variety of mendelian disorders have among their pleiotropic effects endocrine abnormalities. These disorders include some, such as achondroplasia, that have a single common mutation and others, such as hemoglobinopathies, that are caused by heterogeneous mutations. See Table 32-4 for additional single-gene disorders with associated endocrine features. Diagnosis

The diagnosis of these various mendelian disorders is based on clinical, biochemical, radiologic, and/or molecular testing. Etiology and Distribution

Achondroplasia with obstructive sleep apnea. Achondroplasia is a common skeletal dysplasia in which the dwarfism is due to an abnormality in endochondral ossification (see OMIM 100800, Table 32-4). Up to 10% of patients with achondroplasia have been reported to have serious respiratory complications. Goldstein et al. studied a 9-year-old boy with achondroplasia and obstructive sleep apnea who had low-growth hormone secretion during sleep1 (68). Following tracheotomy, his GH secretion during sleep normalized, and his growth rate almost doubled. This case suggests that short patients with craniofacial syndromes associated with obstructive sleep apnea may have diminished sleep entrained GH secretion as a contributing cause to their growth retardation. Bo¨rjeson-Forssman-Lehmann syndrome. The X-linked Bo¨rjesonForssman-Lehmann syndrome is characterized by short stature, hypogonadism, hypotonia, severe mental deficiency, and coarse facial appearance with a prominent brow ridge and large ears in affected males (see OMIM 301900, Table 32-4). Robinson et al. documented markedly deficient GH responses to arginine and

L-dopa, as well as low somatomedin C levels in a severely affected male and two of his mildly affected twin sisters.2 The growth deceleration in this syndrome, however, may not begin until age 8–10 years, and therefore the pituitary deficiency may be progressive. Indeed, the associated hypogonadism has been reported to be both primary and secondary, and may also evolve with age. CHARGE syndrome. CHARGE is an acronym that describes a nonrandom association of anomalies: colobomas of the eye; heart disease; atresia of the choanae; retarded growth, development, and/ or CNS anomalies; genital hypoplasia; and ear anomalies or deafness (see OMIM 214800, Table 32-4). Growth retardation, which is usually of postnatal onset, and hypogonadism are prominent features of the CHARGE syndrome and may well be due to hypothalamic defects. August et al. documented GH and gonadotropin deficiencies in a girl with the CHARGE syndrome who also had a delayed peak TSH response to TRH.3 Boys may have cryptorchidism, microphallus, and/or hypospadias. Adult males were also reported to have genital hypoplasia and no secondary sexual characteristics. Arrhinencephaly and holoprosencephaly have been reported, suggesting a hypothalamic cause for the pituitary deficiencies. Although most cases are sporadic, a few familial occurrences suggestive of both dominant and recessive inheritance have been reported. Fanconi anemia. Fanconi anemia is an autosomal recessive disorder characterized by chronic pancytopenia with bone marrow hypoplasia, abnormal pigmentation, upper limb malformations, kidney anomalies, growth retardation, small genitalia, and increased frequency of chromosomal breaks in cultured lymphocytes (see OMIMs 227650, 227660, 227645, 227646, 600901, Table 32-4). Nilsson found that 38/68 (56%) of patients with Fanconi anemia in published reports had stunted growth, and 24/ 68 (35%) had genital anomalies.4 Cussen reported a child with Fanconi anemia who appeared to be a pituitary dwarf and pointed out that small pituitary glands, adrenocortical atrophy, and atrophic testis have been described in this syndrome.5 A number of investigators have now documented GHD in patients with Fanconi anemia, most of whom had no other endocrine dysfunction. Administration of GH resulted in excellent short-term and long-term responses in most of these patients. In view of the intrauterine growth retardation commonly associated with this syndrome, it appears that both cellular factors and GHD probably contribute to the short stature. Hemochromatosis. Male hypogonadism and pituitary hemosiderosis can both occur in hemochromatosis (see OMIMs 235200 and 602390, Table 32-4), and abnormalities have also been found in gonadotropin, cortisol, GH, PrL, and TSH secretion. Stocks and Martin found that functional pituitary insufficiency of varying degree occurs in 60% of patients with hemochromatosis.6 Signs and symptoms of gonadal dysfunction included depressed sexual function, testicular atrophy, absent urinary gonadotropins, decreased plasma levels of LH, and low plasma testosterone levels, indicating that the hypogonadism in hemochromatosis is secondary to a deficiency of pituitary gonadotropin. The testes of hypogonadal hemochromatosis patients usually show evidence of secondary atrophy without iron deposition, documenting the hypogonadotropic nature of the hypogonadism in this disease. Most studies have reported testicular atrophy with low levels of gonadotropins that is unresponsive to gonadotropin-releasing hormone. Hemochromatosis is an autosomal recessive trait tightly linked to the HLA loci. Hemoglobinopathies. There are well-documented cases of acquired pituitary insufficiency occurring in adults with

Endocrine Organs

hemoglobinopathies, presumably secondary to infarction of the gland (see OMIM 141900, Table 32-4). In one instance, a 41-yearold black American with sickle-cell trait (hemoglobin SA) developed fatigue, weight loss, decreased libido, impotence, polyuria, and polydipsia a few months after a prolonged high-altitude flight.7 Endocrinologic evaluation revealed evidence of both anterior and posterior pituitary insufficiency. Among 130 autopsied cases of sickle trait (SA), McCormick found two instances of pituitary infarction, and abnormal GH secretion has been found in thalassemic patients on clinical transfusion therapy.8 Histiocytosis X (Letterer-Siwe disease, Hand-Schuler-Christian disease, eosinophilic granuloma). Histiocytosis X is characterized by foamy histiocyte infiltration in many areas of the body, including the hypothalamus. When the histiocytic infiltration involves the hypothalamus, prepubertal growth retardation associated with GHD and diabetes insipidus frequently occur (see OMIM 246400, Table 32-4). Delayed puberty and hypogonadism are also frequent accompaniments of this syndrome. Autopsy reports in adults with histiocytosis X suggest that the pituitary insufficiency is secondary to hypothalamic destruction. Diabetes insipidus and GHD frequently occur together, but either endocrine abnormality may exist alone. In contrast to a previous suggestion of GH unresponsiveness, Braunstein et al. documented a significant increment in growth rate in response to GH therapy in these individuals.9 Neurofibromatosis type 1 (NF1). A variety of endocrine disturbances have been reported in patients with neurofibromatosis that has an autosomal dominant mode of inheritance (see OMIM 162200, Table 32-4). The most common associated endocrine disorder in children with NF1 is sexual precocity, whereas pheochromocytoma is the most common associated disorder in adults. Marked growth retardation unrelated to skeletal anomalies has also been reported. Andler et al. documented a variety of pituitary dysfunctions in affected children, including GHD, both diminished and elevated TSH response to TRH, and hyperprolactinemia.10 All of their patients with neurofibromatosis and pituitary dysfunction had a suprasellar tumor. Pallister-Hall syndrome. Hall et al. described this neonatal lethal malformation syndrome which consists of hypothalamic hamartoblastoma, hypopituitarism, postaxial polydactyly, and imperforate anus (see OMIM 146510, Table 32-4).11 Variable features include laryngeal cleft, abnormal lung lobulation, renal agenesis and/or renal dysplasia, short 4th metacarpals, nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus, congenital heart defect, and intrauterine growth retardation. The anterior pituitary gland was absent in all cases. The posterior pituitary was absent in the majority. The adrenal hypoplasia, small thyroid, and microphallus are presumably secondary to pituitary insufficiency. Most cases have been sporadic, but several instances of father to son transmission have been reported, suggesting autosomal dominant inheritance. Rieger syndrome (iris dental dysplasia). The Rieger syndrome is an autosomal dominant disorder associated with malformation of the iris, pupillary anomalies and hypoplasia of the teeth, with or without maxillary hypoplasia. Sadeghi-Nejad and Senior reported a large family in which multiple individuals had both Rieger syndrome and IGHD (see OMIM 180500, Table 32-4).12 Siblings of the proband had Rieger syndrome with normal pituitary function, but GHD was not found in any member of the family who did not have Rieger syndrome. Affected individuals had insulin hypersensitivity, but normal plasma insulin responses to arginine and glucose. One subject who was treated with GH exhibited substantial enhancement of his rate of growth. It is postulated that the basic pathogenetic mechanism in this autosomal

1357

dominant disorder is maldevelopment of the neural crest, resulting in ocular and dental abnormalities. Primary empty sella with normal pituitary function has also been reported in association with dominantly inherited Rieger syndrome in multiple members of a large kindred. Prognosis, Prevention, and Treatment

The prognosis, prevention, and treatment depend on the mendelian disorder, and the frequency and severity of the associated endocrine abnormality. References (Mendelian Disorders with Endocrine Abnormalities) 1. Goldstein S, Wu R, Thorpy M, et al.: Reversibility of deficient sleep entrained growth hormone secretion in a boy with achondroplasia and obstructive sleep apnea. Acta Endocrinol 116:95, 1987. 2. Robinson L, Jones K, Culler F, et al.: The Bo¨rjeson-Forssman-Lehmann syndrome. Am J Med Genet 15:457, 1983. 3. August G, Rosenbaum K, Friendly D, et al.: Hypopituitarism and the CHARGE association. J Pediatr 103:424, 1983. 4. Nilsson LR: Chronic pancytopenia with multiple congenital abnormalities. Acta Paediatr 49:518, 1960. 5. Cussen LJ: Primary hypopituitary dwarfism with Fanconi’s hypoplastic anaemia syndrome, renal hypertension and phycomycosis: report of a case. Med J Aust 2:367, 1965. 6. Stocks AE, Martin FIR. Pituitary function in haemochromatosis. Am J Med 45:839, 1968. 7. Pastore RA, Anderson JW, Herman RH: Anterior and posterior hypopituitarism associated with sickle cell trait. Ann Intern Med 71:593, 1969. 8. McCormick WF: Abnormal hemoglobins II. The pathology of sickle cell trait. Am J Med Sci 91:329, 1961. 9. Braunstein GD, Raiti S, Hansen JW, et al.: Response of growth-retarded patients with Hand-Schu¨ller-Christian disease to growth hormone therapy. N Engl J Med 292:332, 1975. 10. Andler W, Roosen K, Kohns U, et al.: Endokrine Storungen bei Kindern mit Neurofibromatose von Recklinghausen. Monatsschr Kinderheilk 127:135, 1979. 11. Hall JG, Pallister PD, Clarren SK, et al.: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly—a new syndrome? Part 1. Am J Med Genet 7:47, 1980. 12. Sadeghi-Nejad A, Senior B: Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger’s syndrome). J Pediatr 85:644, 1974.

32.9 Chromosomal Disorders with Endocrine Features A large variety of chromosomal abnormalities are associated with endocrine disorders. These chromosomal anomalies can affect autosomes or sex chromosomes. See Table 32-5 for information on selected chromosomal disorders with endocrine features. Diagnosis

These disorders are diagnosed by karyotype analysis, or in the case of Prader-Willi syndrome, FISH studies to detect intersitial deletions or DNA methylation or other studies to detect uniparental disomy. Etiology and Distribution

Down syndrome. Down syndrome is caused by trisomy for chromosome 21, specifically duplication trisomy of 21q22. Down syndrome has an overall prevalence of 1/704 births and can also

1358

Other Systems and Structures

occur due to inheritance of an unbalanced translocation of chromosome 21. Some patients may be mosaic, and have variable phenotypic features. Endocrine disorders associated with Down syndrome include decreased growth rate, with adult height being 2 to 4 SD below average. Patients have a general predisposition to autoimmune disease. Hypothyroidism occurs in 20–40% of those with Down syndrome, whereas hyperthyroidism is reported in 2.5%.1 Type 1 diabetes also occurs at an increased rate relative to the general population (see Table 32-5). Prader-Willi syndrome. Prader-Willi syndrome is caused by the lack of expression of normally active paternally inherited genes on 15q11-q13 (Table 32-5). Maternal homologues are normally inactive due to imprinting. In about 75% of individuals with Prader-Willi syndrome, there is a deletion of the paternal allele. Most of the remainder have two maternal 15 homologues (uniparental disomy). The frequency of Prader-Willi syndrome is 1 in 10–15,000. Endocrine features include short stature, obesity, and hypogonadism from birth with genital hypoplasia. Treatment may include hCG for testicular descent in childhood as well as testosterone in males and estrogen in females for delayed secondary sex characteristics. Growth hormone treatment has been shown to have beneficial effects on body composition and growth.2–5 Turner syndrome (45, X). Turner syndrome was first described in 1938 and consists most commonly of short stature and gonadal dysgenesis. Other features include lymphedema, webbed neck, coarctation of the aorta, and renal anomalies; however, the phenotype may be variable, and can be limited to short stature and primary amenorrhea. The overall incidence is about 1/2000 live births. Approximately 50% of patients have a 45,X karyotype; the remainder have mosaic karyotypes.6–8 Because Turner patients have only one copy of the X chromosome, they have haploinsufficiency of the genes in the pseudoautosomal region of the X chromosome (which are not inactivated during lyonization). It is thought that one of these genes, SHOX, contributes significantly to the short stature and to some of the skeletal features which are sometimes seen in Turner syndrome (see previous section on SHOX, Tables 32-1 and 32-5).

Klinefelter syndrome (47,XXY). Klinefelter syndrome is caused by nondisjunction of the X chromosome, either during meiosis (gamete formation) or during mitosis after the zygote has formed. Nondisjunction occurring after formation of the zygote will lead to somatic mosaicism. Typically, patients with mosaicism have a 46,XY/47,XXY karyotype (Table 32-5). Higher multiples of the X chromosome (48,XXXY) can occur.8 Patients with Klinefelter syndrome can present with a spectrum of clinical features from isolated hypogonadism and infertility to the classic phenotype described by Klinefelter et al. in 1942: eunuchoid body habitus, decreased secondary sexual hair, gynecomastia, and small testes. Patients with Klinefelter syndrome typically have hypergonadotropic hypogonadism.8 Prognosis, Prevention, and Treatment

The prognosis, prevention, and treatment depend on the chromosomal disorder and the frequency and severity of the associated endocrine abnormality. References (Chromosomal Disorders with Endocrine Features) 1. Hunter AGW: Down syndrome. In: Management of Genetic Syndromes. Cassidy SB, Allanson JE, eds. Wiley-Liss, New York, 2001, p 103. 2. Lindgren AC, Hagena¨s L, Mu¨ller J, et al.: Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favorably. Acta Paediatr 87:28, 1998. 3. Carrel AL, Myers SE, Whitman BY, et al.: Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: a controlled study. J Pediatr 134: 215, 1999. 4. Myers SE, Carrel AL, Whitman BY, et al.: Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome. J Pediatr 137:42, 2000. 5. Carrel AL, Myers SE, Whitman BY, et al.: Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab 87:1581, 2002. 6. Ranke MB, Saenger P: Turner’s syndrome. Lancet 358:309, 2001. 7. Chu CE, Connor JM: Molecular biology of Turner’s syndrome. Arch Dis Child 72:285, 1995. 8. Smyth CM, Bremmer WJ: Klinefelter syndrome. Arch Intern Med 158:1309, 1998.

33 Asymmetry and Hypertrophy Omar Abdul-Rahman and H. Eugene Hoyme

A

symmetry of various body structures results from normal and pathologic developmental processes. Handed asymmetry refers to consistent left/right differences in structure, such as the dextral looping of the heart, variations in the number of lobes vis-a`-vis the two lungs, and abdominal visceral situs. Handed asymmetry must be differentiated from random asymmetry and from the differences that arise between the right and left sides due to mirror symmetry.1 Mirror symmetry refers to the fact that the slightly asymmetric development of many paired structures does not require differences in morphogenesis between the two sides, but simply reflects the sides developing in mirror symmetry to the midline of the embryo.2 Multiple groups2–4 have hypothesized three sequential processes necessary for the development of handed asymmetry in bilaterally symmetric animals, including humans. First, a mechanism must exist for converting the handedness of asymmetry at the molecular level to handedness at the cellular and multicellular levels to establish left/right polarity. In addition, a mechanism must exist for the random generation of handedness or asymmetry at the cellular and multicellular levels, which can be biased by the mechanism converting molecular to cellular asymmetry. Finally, a mechanism must exist for interpreting the asymmetry at the multicellular level, so that particular organs develop on one side and not on the other with respect to the midline. Mutations altering handed asymmetry must occur either at the level of conversion from the molecular level to the cellular and multicellular levels or at the level of interpretation whereby asymmetry at the multicellular level results in the handed asymmetry of organs. This loss of control of determination of handed asymmetry would result in random asymmetry of structure. Handed asymmetry requires a special mechanism for distinguishing ‘‘leftness’’ from ‘‘rightness’’ during embryogenesis. Left and right are not independent relationships within the embryo, but are defined with respect to the anteroposterior or dorsoventral axes of the embryo.1 The exact developmental processes by which the molecular determinants of handed asymmetry are translated into asymmetry at the cellular and multicellular levels are unknown. However, studies of chick and mice embryos have revealed the existence of a node on the ventral surface of the embryo, the equivalent of the early embryonic organizer region of Xenopus responsible for the asymmetric disposition in that species. In the

mouse embryo, the node is equipped with a specialized cluster of monocilia that rotate in a vortical manner.5 The result is the generation of leftward flow of the surrounding extraembryonic fluid. This flow has been termed ‘‘nodal flow’’ and is presumed to create a biased distribution of extracellular signals leading to the initiation of further downstream pathways. Ultimately, distinct gene expression patterns are observed within the lateral plate mesoderm (LPM) to the right and left of the node. Several genes involved in this mechanism have been identified and include sonic hedgehog (SHH), FGF8, activin bB, and activin receptor IIA (ActRIIA). Further downstream targets include members of the TGF-b superfamily, Nodal and lefty-1. Evidence supporting the monocilia-nodal flow theory has been obtained from studies of the inversus viscerum (iv) mouse. The iv mutation in mice in its homozygous state results in the normal handed asymmetry of embryonic development being converted to random asymmetry. Thus, iv/iv mice are found to have situs solitus 50% of the time and situs inversus (complete reversal of the position of organs in relation to the midline) 50% of the time.1 The product of the iv gene is an axonemal-type dynein heavy chain important for normal function of the cilia within the nodal cells. Okada et al.6 demonstrated that mice homozygous for the iv mutation have absent nodal flow. Additional studies demonstrated that mice deficient for other components of nodal cilia, such as the kinesin molecules KIF3A and KIF3B, also exhibit abnormal asymmetry patterns.7–9 The establishment of asymmetric expression patterns within the node and the surrounding area leads to the production of inhibitory signals that influence ubiquitously expressed proteins. An example in the chick model is the Cerberus-related gene Caronte (Car).10–12 Car is initially transcribed after induction by SHH in the left domain of the node, and subsequently binds and inactivates members of the TGF-b-related ligands known as bone morphogenetic proteins (BMPs).13 BMPs themselves are repressors of Nodal; therefore, with left-sided expression of Car and inactivation of BMPs, Nodal expression is unhindered within the left LPM, but is inhibited in the right LPM. Other mechanisms using both activators and repressors may exist, but the common pathway appears to involve asymmetric expression of Nodal. As diffusion of the left-handed signals spreads, a mechanism whereby prevention of these signals from reaching the right LPM 1359

1360

Other Systems and Structures

must exist. It has been noted that among conjoined twins, laterality defects can extend for significant distances, yet these defects are unable to cross the embryonic midline in the neighboring twin. Additionally, in mouse and zebra fish embryos with midline defects (such as SHH-deficient mice), alterations in sidedness have been observed.14–17 These findings have encouraged the concept of the ‘‘midline barrier’’ which serves to prevent left-sided signals from affecting the right LPM.18,19 The barrier seems to utilize several mechanisms including silencer ligands to Car in the right LPM, negative feedback loops to Car within the right LPM, and competitive inhibition of Nodal by lefty-2 proteins.10,11,20–24 With differential expression achieved within the right and left LPM, and prevention of signal spread from one side to the other, a number of downstream gene targets are either induced or suppressed. The details of how genes such as Pitx2, SnR, and Nkx3.2 affect organogenesis to produce asymmetric development and structure have yet to be elucidated. The development of normal handed asymmetry not only affects organs such as the heart, spleen, and liver, but may also play a role in the determination of sidedness of unilateral defects in morphogenesis. In investigations by Brown and colleagues,2 it was determined that the visceral situs of the embryo determines the laterality of drug-induced limb defects. Acetazolamide usually causes unilateral forelimb anomalies on the right side of treated mouse embryos. However, in iv/iv mice (with 50% exhibiting situs solitus, and 50% situs inversus), acetazolamide caused forelimb anomalies on the left in 50% of cases and on the right in 50% of cases. The side of the forelimb anomaly correlated with visceral situs.2 A number of defects in human morphogenesis show similar preferential laterality (Table 33-1).25 It has been speculated that the preferential laterality of such defects is influenced by the handedness of the embryo.2

Table 33-1. Asymmetry of selected single primary defects in development Predominant Side Percent Left

Percent Right

Cleft lip

68

32

Agenesis of maxillary lateral incisor

55

45

First and second branchial arch defects

38

62

Renal agenesis

56

44

Supernumerary nipples

55

45

Poland sequence

32

68

Pulmonary agenesis

43

57

Cryptorchidism

40

60

Inguinal hernia

33

67

Postaxial polydactyly

77

23

Congenital hip dislocation

62

38

Clubfoot

45

55

Defect

Radial aplasia

42

58

Fibular aplasia

35

65

Adapted from Cohen.25

References 1. Brown NA, Wolpert L: The development of handedness in left/right asymmetry. Development 109:1, 1990. 2. Brown NA, Hoyle CI, McCarthy A, et al.: The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice. Development 107:637, 1989. 3. Capdevila J, Vogan KJ, Tabin CJ, et al.: Mechanisms of left-right determination in vertebrates. Cell 101:9, 2000. 4. Cohen MM: Asymmetry: Molecular, biologic, embryopathic, and clinical perspectives. Am J Med Genet 101:292, 2001. 5. McGrath J, Somlo S, Makova S, et al.: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61, 2003. 6. Okada Y, Nonaka S, Tanaka Y, et al.: Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 4:459, 1999. 7. Marszalek JR, Ruiz-Lozano P, Roberts E, et al.: Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc Natl Acad Sci 96:5043, 1999. 8. Takeda S, Yonekawa Y, Tanaka Y, et al.: Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by KIF3A null mice analysis. J Cell Biol 145:825, 1999. 9. Nonaka S, Tanaka Y, Okada Y, et al.: Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95:829, 1998. 10. Rodriguez-Esteban C, Capdevila J, Economides AN, et al.: The novel Cer-like protein Caronte mediates the establishment of embryonic leftright asymmetry. Nature 401:243, 1999. 11. Yokouchi Y, Vogan KJ, Pearse RV, et al.: Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98:573, 1999. 12. Zhu L, Marvin MJ, Gardiner A, et al.: Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr Biol 9:931, 1999. 13. Hsu DR, Economides AN, Wang X, et al.: The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell 1:673, 1998. 14. Chen JN, van Eeden FJ, Warren KS, et al.: Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development 124:4373, 1997. 15. Dufort D, Schwartz L, Harpal K, et al.: The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis. Development 125:3015, 1998. 16. King T, Beddington RS, Brown NA: The role of the brachyury gene in heart development and left-right specification in the mouse. Mech Dev 79:29, 1998. 17. Lohr JL, Danos MC, Yost JH: Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development 124:1467, 1996. 18. Levin M, Roberts DJ, Holmes LB, et al.: Laterality defects in conjoined twins. Nature 384:321, 1996. 19. Meno C, Shimono A, Saijoh Y, et al.: Lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94:287, 1998. 20. Bisgrove BW, Essner JJ, Yost HJ: Regulation of midline development by antagonism of lefty and nodal signaling. Development 126:3253, 1999. 21. Cheng AMS, Thisse B, Thisse C, et al.: The lefty-related factor Xatv acts as a feedback inhibitor of Nodal signaling in mesoderm induction and L-R axis development in Xenopus. Development 127:1049, 2000. 22. Meno C, Gritsman K, Ohishi S, et al.: Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol Cell 4:287, 1999. 23. Saijoh Y, Adachi H, Mochida K, et al.: Distinct transcriptional regulatory mechanisms underlie left-right asymmetric expression of lefty-1 and lefty-2. Genes Dev 13:259, 1999. 24. Thisse C, Thisse B: Antivin, a novel and divergent member of the TGF beta superfamily, negatively regulates mesoderm induction. Development 126:229, 1999. 25. Cohen MM Jr: The Child with Multiple Birth Defects. Raven, New York, 1982, p 112.

Asymmetry and Hypertrophy

33.1 Laterality Sequences Definition

Laterality sequences are abnormalities in determination of normalhanded asymmetry during embryogenesis. In addition to reversal of sides, right for left, with partial to complete situs inversus, bilateral left-sidedness or right-sidedness can occur.1 Simple agenesis of the spleen, accessory spleens, and splenogonadal fusion are not included. The immotile cilia syndrome is discussed in Section 33.2. Diagnosis

A spectrum of abnormalities in determination of visceral situs can be observed (Fig. 33-1). The position of the organs as normally encountered is termed situs solitus. If the asymmetries are reversed, the condition is termed situs inversus. A mixture of normal and reversed asymmetries is termed partial situs inversus or situs ambiguus.2,3 In total situs inversus, the heart lies in the right side of the thorax with the position of the cardiac chambers reversed. The left lung has three lobes and the right lung two. The liver and stomach are transposed, and the spleen is on the right. The cecum is in the left lower quadrant; the hepatic flexure is located on the left, and the splenic flexure is located on the right. In males, the right testis is positioned lower in the scrotum than the left. All asymmetric blood vessels are reversed.3 Approximately 25% of individuals with total situs inversus are found to have the immotile cilia syndrome (Kartagener syndrome).3 In situs ambiguus, the reversal of organs may be limited to the thorax or to the arrangement of cardiac chambers only. The

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heart appears to be particularly sensitive to laterality defects, as most individuals with situs ambiguus have congenital heart defects. However, the pathogenesis of congenital heart disease is beyond the scope of this chapter. Alternatively, there may be partial degrees of inversion of the position of abdominal and/or thoracic organs.3 Defects of the liver and biliary tract, intestinal malrotation, and abnormal lung lobulation are also included. Two other types of situs ambiguus have been postulated by Moller et al.4 In one, both sides of the body are right sides; in the other, both sides are left sides. These have been termed bilateral right-sidedness and bilateral left-sidedness, respectively.4 The full clinical spectrum of these conditions is set forth in Table 33-2.1 Suspicion of total or partial situs inversus should lead to further physical examination and diagnostic imaging studies. The apex of the heart may be found on the right instead of the left side of the chest, and palpation and percussion of the abdomen may reveal transposition of the liver and the stomach. Plain radiographs of the chest and abdomen may reveal reversal of situs of the heart and/or stomach. Barium studies of the intestine will aid in the diagnosis of malrotation and prompt prophylactic surgery. Nuclear medicine scans of the liver and spleen will reveal the position of the involved organs as well as document the presence or absence of asplenia or polysplenia. Ultrasonographic, magnetic resonance, and computerized tomographic imaging modes have been useful adjuncts in the determination of visceral and cardiovascular situs.2,3 In the case of asplenia, examination of the peripheral blood smear will reveal Howell-Jolly and/or Heinz bodies.

Fig. 33-1. Positions of organs in situs solitus, total situs inversus, and bilateral right- and left-sidedness.

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Other Systems and Structures Table 33-2. Clinical features of the laterality sequences Pattern of Malformation

Pulmonary anomalies Cardiovascular anomalies

Bilateral Left-sidedness

Bilateral Right-sidedness

Bilateral bilobed (60%)

Bilateral trilobed (95%)

No eparterial bronchus (70%)

Bilateral eparterial bronchus (90%)

Bilateral left atria

Bilateral right atria

Azygos return of inferior

Aorta/IVC juxtaposed (100%)

vena cava (IVC) (70%) Right cardiac apex (37%)

Right cardiac apex (40%)

Right aortic arch (35%)

Right aortic arch (20%)

Anomalous pulmonary venous return (70%)

Anomalous pulmonary venous return (88%)

Venous return of lung to ipsilateral atrium (50%)

Anomalies of abdominal viscera

Bilateral IVC (50%)

Bilateral IVC (75%)

Single ventricle (10%)

Single ventricle (60%)

Endocardial cushion defect (40%)

Endocardial cushion defect (85%)

Pulmonary stenosis/atresia (10%)

Pulmonary stenosis/atresia (75%)

Transposition of great vessels (17%)

Transposition of great vessels (75%)

Polysplenia

Asplenia

Bilateral liver (25%)

Bilateral liver (50%)

Right-sided stomach (65%)

Right-sided stomach (65%)

Intestinal malrotation and aberrant mesentery

Intestinal malrotation and aberrant mesentery

Adapted from Jones.1

Etiology and Distribution

Total or partial situs inversus may be the end result of disturbances in left-right patterning during early embryogenesis. This anomaly may be caused by single gene abnormalities, teratogenic effects, and/or multifactorially determined factors.5–7 Although once considered etiologically distinct entities, it is now understood that polysplenia (bilateral left-sidedness) and asplenia (bilateral right-sidedness) are examples of phenotypic variation of a single developmental process.6 Bilateral right-sidedness and bilateral left-sidedness have been described with autosomal dominant, autosomal recessive, and X-linked modes of inheritance.7–12 In addition, siblingships have been reported with bilateral rightsidedness in one child and bilateral left-sidedness in the other.10,13 Familial forms of laterality defects have been reported in the literature. Variability ranging from isolated congenital heart lesions to situs ambiguus to situs inversus within the same family among four kindreds was reported by Casey.14 More recently, mutations in the zinc finger transcription factor ZIC3 have been associated with X-linked forms of familial laterality disorders. In a study of 194 unrelated patients with laterality defects, five novel mutations in ZIC3 were discovered.15 Three of the mutations were among different kindreds, and the other two were discovered in sporadic cases of congenital heart defects typically seen among individuals with laterality defects. The pathogenesis of the laterality sequences has not been clearly delineated. However, the primary defect is thought to be a failure in the development of normal-handed asymmetry prior to 30 days of embryonic development.1,4 In some instances, bilateral rightsidedness or bilateral left-sidedness is part of the spectrum of Kartagener syndrome. In those cases, morphogenetic abnormalities in ciliary structure or function lead to disruption of the development of

normal-handed asymmetry in the embryo, with random asymmetry the end result, as described in the introduction to this chapter. Although much is known about the genetics of left-right patterning in animal models, the list of genes involved in human laterality defects remains short. Four genes have been clearly associated with abnormal familial asymmetry in man including ZIC3, activin receptor type IIB (ACVR2B), CRYPTIC, and LEFTYA.15,16 Additionally, mutations in CRELD1 and NKX2.5 have recently been identified as possible candidates in a few families.17,18 Most of the genes identified to date function within the transforming growth factor-b (TGFb) signaling pathway, playing a critical role in left-right patterning within the embryo.19 Several chromosomal anomalies have been discovered in individuals with laterality defects. The chromosomes involved are numerous and include chromosomes 2, 3, 4, 6, 7, 10, 11, 13, 18, and 22.3 Investigations into the molecular defects responsible for abnormal asymmetry in these patients is ongoing. Complete situs inversus is a rare disorder. Significant ascertainment bias exists because many individuals with complete situs inversus are likely never identified in the absence of other features of Kartagener syndrome. In addition, a number of people may have mild forms of situs ambiguus with no clinical consequences. Nevertheless, several studies have attempted to evaluate the prevalence of laterality defects. A review of records at the Mayo Clinic from 1910 through 1947 revealed 76 affected patients (0.005%).20 No apparent sex predilection has been reported.3 Bilateral left-sidedness and bilateral right-sidedness are also uncommon disorders. Ivemark21 found 11 cases of bilateral rightsidedness among 7032 autopsies of children at the Boston Children’s Hospital during a 33-year period (0.16%). Brandt and Liebow22 have suggested that bilateral left-sidedness occurs three times as frequently as bilateral right-sidedness. The bilateral right-sidedness

Asymmetry and Hypertrophy

sequence is two to three times more common in males than in females, whereas the bilateral left-sidedness sequence affects males and females equally.3 Prognosis, Treatment, and Prevention

In patients with total situs inversus, no treatment may be necessary, many cases being discovered serendipitously at autopsy. However, situs inversus may present a hazard during abdominal and thoracic surgery if it remains unrecognized. Although dextrocardia is the usual finding in total situs inversus, levocardia can occur. Cardiac anomalies, potentially requiring surgical correction, are almost always present in patients with levocardia, but are infrequent in patients with dextrocardia.1–3 Patients with bilateral right-sidedness have increased neonatal mortality related to accompanying complex cardiac anomalies, including common atrioventricular canal, single ventricle, pulmonic stenosis or atresia, transposition of the great arteries, or anomalous venous connections. Most patients present in the newborn period with cyanosis and early cardiac failure. Early recognition of visceroatrial situs is important so that prognosis and proper surgical palliation or correction can be determined. Affected children are also at a greater risk of sepsis; therefore, prophylactic use of antibiotics preoperatively should be considered. The possibility of coexisting gastrointestinal anomalies must be recognized, especially aberrant mesenteric attachments. Renal anomalies have also been described in 25% of affected patients. Survivors beyond the newborn period have had an increased frequency of skin, bronchopulmonary, and other infections, possibly related to the asplenia.1–3 Bilateral left-sidedness is generally associated with cardiac anomalies less severe than those noted in bilateral right-sidedness. Five to ten percent of affected children with polysplenia have no heart defects. As in bilateral right-sidedness, varying degrees of incomplete rotation of the intestine and aberrations of mesenteric attachment have been noted with bilateral left-sidedness. The prognosis for patients with bilateral left-sidedness is better than that for those with bilateral right-sidedness.1–3 Careful genetic evaluation and counseling are indicated in all patients with laterality sequences. As noted previously, autosomal dominant, autosomal recessive, and X-linked families have been described.7–12 Affected infants have been successfully diagnosed prenatally with fetal ultrasonography during the second trimester of pregnancy.23,24 References (Laterality Sequences) 1. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 602. 2. Winer-Muran HT, Toukin ILD: The spectrum of heterotaxic syndromes. Radiol Clin North Am 27:1147, 1989. 3. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001. 4. Moller JH, Nakib A, Anderson RC, et al.: Congenital cardiac disease associated with polysplenia, a developmental complex of bilateral ‘‘leftsidedness.’’ Circulation 36:789, 1967. 5. Opitz JM, Gilbert EF: CNS anomalies and the midline as a ‘‘developmental field.’’ Am J Med Genet 12:443, 1982. 6. Opitz JM: Editorial comment on paper by de la Monte and Hotchins on familial polysplenia syndrome. Am J Med Genet 21:175, 1985. 7. Distefano G, Romeo MG, Grasso S, et al.: Dextrocardia with and without situs viscerum inversus in two sibs. Am J Med Genet 27:929, 1987. 8. Arnold GL, Bixler D, Girod D: Probable autosomal recessive inheritance of polysplenia, situs inversus, and cardiac defects in an Amish family. Am J Med Genet 16:35, 1983. 9. Simpson J, Zellweger H: Familial occurrence of Ivemark syndrome with splenic hypoplasia and asplenia in sibs. J Med Genet 10:303, 1973.

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10. Niikawa K, Kohsaka S, Mizumoto M, et al.: Familial clustering of situs inversus totalis and asplenia and polysplenia syndromes. Am J Med Genet 16:43, 1983. 11. Calabro A, Taraschi A, Lungarotti MS, et al.: Familial situs inversus and congenital heart defects. Am J Med Genet 31:698, 1988. 12. Matthias RS, Lacro RV, Jones KL: X-linked laterality sequence: situs inversus, complex cardiac defects, and splenic defects. Am J Med Genet 28:111, 1987. 13. Zlotogara J, Elian E: Asplenia and polysplenia syndromes with abnormalities of lateralization in a sibship. J Med Genet 18:301, 1981. 14. Casey B: Two rights make a wrong: human left-right malformations. Hum Mol Gen 7:1565, 1998. 15. Ware SM, Peng J, Zhu L, et al.: Identification and functional analysis of ZIC3 mutations in heterotaxy and congenital heart defects. Am J Hum Genet 74:93, 2004. 16. Bamford RN, Roessler E, Burdine RD, et al.: Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26:365, 2000. 17. Robinson SW, Morris CD, Goldmuntz E, et al.: Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 72:1047, 2003. 18. Watanabe Y, Benson DW, Yano S, et al.: Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD. J Med Genet 39:807, 2002. 19. Ware SM, Belmont JW: Tgfb signaling in midline and laterality defects. In: Inborn Errors of Development: the Molecular Basis of Clinical Disorders of Morphogenesis. Wynshaw-Boris A, ed. Oxford University Press, New York, 2003. 20. Mayo CW, Rice RG: Situs inversus totalis: statistical review of data on seventy-six cases, with special reference to diseases of the biliary tract. Arch Surg 58:724, 1949. 21. Ivemark BI: Implications of agenesis of the spleen on the pathogenesis of conotruncus anomalies in childhood. Acta Paediatr 44(Suppl 104):1, 1955. 22. Brandt HM, Liebow AA: Right pulmonary isomerism associated with venous, splenic, and other anomalies. Lab Invest 7:469, 1958. 23. DeVore GR, Sarti DA, Siassi B, et al.: Prenatal diagnosis of cardiovascular malformations in the fetus with situs inversus viscerum during the second trimester of pregnancy. J Clin Ultrasound 14:454, 1986. 24. Stoker AF: Ultrasound diagnosis of situs inversus in utero: a case report. S Afr Med J 64:832, 1983.

33.2 Kartagener Syndrome Definition

Classically, Kartagener syndrome is a triad including total or partial situs inversus, bronchiectasis, and structurally abnormal paranasal sinuses leading to chronic sinusitis. Chronic nasal polyposis is a frequent accompaniment.1 Kartagener syndrome (KS) is one member of a category of ciliary disorders known as primary ciliary dyskinesis (PCD). Although the term ‘‘immotile cilia syndrome’’ has been synonymously used with KS in the past, it currently refers to any abnormality of the ciliary machinery that results in decreased motility. The presence of laterality sequences distinguishes KS from other types of PCD. Laterality sequences are discussed in the preceding section. Diagnosis

Kartagener syndrome should be considered in any patient with thick nasal secretions since infancy, pansinusitis, and partial or complete situs inversus.2 A variety of upper respiratory tract and bronchopulmonary abnormalities have been noted in affected patients. Approximately 20% have nasal polyps. Agenesis or hypoplasia of the frontal sinuses

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Other Systems and Structures

is common, and ethmoidomaxillary sinusitis is prominent. Affected individuals complain of thick purulent nasal secretions and chronic hyperplastic rhinitis. In early infancy, in addition to the chronic nasal discharge, frequent colds, chronic bronchitis, and bouts of pneumonia are observed. Bronchiectasis is found in 30% of older children and adults. Occasionally, asthma, hemoptysis, and pulmonary osteoarthropathy are observed.2 Fifty percent of patients with PCD have partial or complete situs inversus. In fact, 20–25% of patients with complete situs inversus are found to have KS. Dextrocardia without other evidence of situs inversus has been frequently described.2 Case reports have documented families with KS manifesting components of the bilateral left-sidedness and/or bilateral right-sidedness sequences. Other families have been described in which an individual with KS had first-degree relatives with only total situs inversus. Additionally, a pair of monozygotic twins was recently described in which both exhibited PCD, but only one had situs inversus.3 These data imply that, in many instances, laterality sequences and KS are a heterogeneous group of disorders that share a single developmental pathogenesis.4–6 Most males with KS are infertile. However, normal fertility has also been described.7 Female patients with KS have fewer problems with infertility than do affected males.8 Rheumatoid arthritis has been described in a few patients.9 Other associated anomalies include anomalous subclavian artery, cardiac and renal anomalies (particularly those associated with polysplenia or asplenia), turricephaly, thyrotoxicosis, arteriovenous malformations, mesangiocapillary glomerulonephritis, extrahepatic biliary atresia, and Paterson-Brown-Kelly syndrome (postcricoid web dysphagia, anemia, glossitis, cheilosis, and koilonychiasis).2 Chronic otitis media leading to significant hearing loss may be an additional component.8 In a patient with suggestive signs and symptoms, the diagnosis can be achieved by studying mucociliary clearance or by light and electron microscopic examination of cilia from samples obtained by nasal and bronchial brushings.2 Occasionally, low serum IgA levels have been documented, although this is not believed to be the primary cause of bronchopulmonary problems in affected patients.8

Fig. 33-2. Ultrastructural comparison between spermatozoa from a normal male (A) and from a patient with the immotile cilia syndrome (B). Note the following normal structures in cross sections of flagellum: outer and inner dynein arms, nexin links, central sheath, radial spokes, and a 9 þ 12 microtubular pattern (A). The outer and inner dynein arms are completely absent in the flagellum from the patient with immotile cilia syndrome (B). (Courtesy of Claire Payne, University of Arizona, Tucson.)

Ultrastructural studies of ciliated cells, including respiratory epithelium, sperm, and tissue from fallopian tubes, reveals a variety of structural and functional abnormalities of ciliary arms. Deficiencies in dynein arms on the outer microtubular doublets of cilia are the most frequently found abnormalities (Fig. 33-2). However, a host of other ultrastructural abnormalities have been reported, including deficiencies in radial spokes, abnormal random orientation of cilia, cilia with supernumerary or absent microtubules, and lack of central core structures.2,6,10,11 Observations of ciliary motility in many patients reveal that the structures are not immotile but rather have dysfunctional or dyskinetic movement.6,12 Etiology and Distribution

Kartagener syndrome is a genetically determined disorder, inherited in an autosomal recessive fashion.2,6,8,13 However, autosomal dominant and X-linked forms have also been reported in individuals with PCD.14 As set forth previously, the disorder may have considerable variability within females, some individuals manifesting the full-blown syndrome, and others having features of laterality sequences.4,5 The developmental pathogenesis of KS relates to the intrinsic ultrastructural abnormalities in ciliary structure and function, which have been well described. Some of the pathogenetic causes that have been identified include absent dynein arms, absent radial spokes, and disturbed ciliary orientation.6 The abnormal motility of the cilia leads to sinus blockage, eustachian tube dysfunction, and decreased bronchopulmonary clearance of secretions. The affected structures become recurrently infected. The ciliary dysmotility likewise leads to infertility in both males and females, with males far more frequently affected.2 It has been hypothesized that unimpaired ciliary function and cell movement of embryonic epithelial tissues play an important role in the development of normal body-handed asymmetry. As previously described in the introduction to this chapter, one mechanism that may be responsible for the establishment of asymmetry is the monocilia-nodal flow theory. According to this theory, vortical motion of monocilia within the embryonic organizer node leads to leftward flow that initiates a cascade of events resulting in differential expression of genes within the left and right lateral plate mesoderm. When normal ciliary structure is altered, the consistent leftward flow is affected. Therefore, normal-handedness does not develop, and random asymmetry is the result. This explains the 50% incidence of total or partial situs inversus in affected individuals with PCD.15 Multiple gene loci have been implicated in familial cases of KS. The regions that demonstrate consistent linkage include 8q, 16p, and 19q.6 Pennarun et al.16 identified homozygosity for mutations in DNAI1 in an individual with PCD. The patient had absent outer dynein arms in the respiratory cilia on electron microscopy. The DNAI1 gene was identified as a candidate gene based on its homology with a gene in the algae, Chlamydomonas reinhardtii, encoding for outer dynein arms in this ciliated organism. Zariwala et al.17 subsequently found two more families with PCD and mutations in DNAI1. The frequency of KS has been estimated to be 1/120,000 to 1/ 40,000 individuals.13 There is no apparent racial predilection, and males and females are equally affected.2,18 Since ciliary abnormalities result in an equal distribution of handedness, some authors have suggested that half of all cases would result in KS.6,19 Therefore, it has been inferred that the estimated prevalence of PCD is roughly double that of KS. However, the clinical heterogeneity of PCD has been a significant obstacle to classifying this group of

Asymmetry and Hypertrophy

disorders. Further molecular studies may assist greatly in properly categorizing the different types of PCD. Prognosis, Treatment, and Prevention

Life expectancy is normal unless there are severe accompanying malformations of the spleen, heart, and/or biliary tree. Many patients, however, have significant respiratory pathology, including polyposis (20%), bronchiectasis (30%), chronic rhinitis, wheezing, and rales. Deafness may occur in later life secondary to recurrent and chronic otitis media. Some individuals eventually require partial lung resection because of chronic bronchiectasis.2,8 To date, prenatal diagnosis for this disorder has not been reported. Genetic counseling is indicated in families of all affected individuals.18 References (Kartagener Syndrome) 1. Gray SW, Skandalakis JE: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Anomalies, ed 2. WB Saunders, Philadelphia, 1994. 2. Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001, p 883. 3. Noone PG, Bali D, Carson JL, et al.: Discordant organ laterality in monozygotic twins with primary ciliary dyskinesia. Am J Med Genet 82: 155, 1999. 4. Gershoni-Baruch R, Gottfried E, Pery M, et al.: Immotile cilia syndrome including polysplenia, situs inversus, and extrahepatic biliary atresia. Am J Med Genet 33:390, 1989. 5. Schidlow DV, Katz SM, Turtz MG, et al.: Polysplenia and Kartagener syndromes in a sibship: association with abnormal respiratory cilia. J Pediatr 100:41, 1982. 6. Aylsworth AS: Clinical aspects of defects in the determination of laterality. Am J Med Genet 101:345, 2001.

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7. Jonsson MS, McCormick JR, Gillies CG, et al.: Kartagener’s syndrome with motile spermatozoa. N Engl J Med 307:1131, 1982. 8. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 604. 9. Mastaglia GL, Goatcher P: Rare association of rheumatoid arthritis and Kartagener’s syndrome: a common denominator? Med J Aust 2:400, 1980. 10. Afzelius BA: Genetic and ultrastructural aspects of the immotile-cilia syndrome. Am J Hum Genet 33:852, 1981. 11. Rutland Veerman AJP, van Delden L, Fienstra L, et al.: The immotile cilia syndrome: phase contrast, microscopy, scanning and transmission electron microscopy. Pediatrics 65:698, 1980. 12. Rutland J, Cole P: Ciliary dyskinesia. Lancet 2:859, 1980. 13. Afzelius BA, Mossberg B, Bergstrom SE: Immotile-cilia syndrome (primary ciliary dyskinesia), including Kartagener syndrome. In: The Metabolic and Molecular Basis of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, et al., eds. McGraw-Hill, New York, 1995, p 3943. 14. Narayan D, Krishnan SN, Epender M, et al.: Unusual inheritance of primary ciliary dyskinesia (Kartagener’s syndrome). J Med Genet 31: 493, 1994. 15. Afzelius BA: A human syndrome caused by immotile cilia. Science 193:317, 1976. 16. Pennarun G, Escudier E, Chapelin C, et al.: Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet 65:1508, 1999. 17. Zariwala M, Noone PG, Sannuti A, et al.: Mutations within the IC78 (DNAI1) gene in patients with primary ciliary dyskinesia (PCD). Am J Hum Genet 67(Suppl 2):403, 2000. 18. Holmes LB: Dextrocardia-bronchiectasis-sinusitis syndrome. In: Birth Defects Encyclopedia. ML Buyse, ed. Blackwell Scientific, Cambridge, MA, 1990, p 521. 19. Cowan MJ, Gladwin MT, Shelhamer JH: Disorders of ciliary motility. Am J Med Sciences 321:1, 2001.

Patterns of Asymmetric Growth Although humans are bilaterally symmetric organisms, visceralhanded asymmetry reflects normal morphogenetic processes. External asymmetry is also the rule rather than the exception when exact anthropometric measurements are employed. Among normal external asymmetries are the following: the left half of the skull and the left side of the face are larger than the right; the right halves

Fig. 33-3. A diagnostic approach to asymmetric growth.

of the vertebral bodies, the sternum, the right upper extremity, and the right ribs are larger than their left counterparts; the left testis is lower in the scrotum than the right; and the ears, eyes, and nipples are found at slightly different levels.1,2 A number of patterns of pathologic asymmetric growth also exist. Pathologic asymmetric growth may be an isolated problem in development or one feature of a variety of multiple malformation syndromes (Sections 33.3, 33.4). These pathologic growth patterns may become manifest either prenatally or postnatally. One can conceptualize these patterns as either reflecting overgrowth or atrophy/underdevelopment of body parts. A case of complete absence of one half of the body has been described.3 A flow chart depicting a diagnostic approach to the child with asymmetric pathologic growth is set forth in Figure 33-3. References 1. Warkany J: Congenital Malformations: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 162. 2. Skandalakis JE, Gray SW: Embryology for Surgeons: The Embryologic Basis for the Treatment of Congenital Anomalies, ed 2. Lippincott Williams and Wilkins, Philadelphia, 1994. 3. Carranza A, Gilbert-Barness E, Modrigal F, et al.: Complete absence or deficiency of one half of the body. Am J Med Genet 76:97, 1998.

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33.3 Hemihyperplasia (Hemihypertrophy) Definition

Hemihyperplasia (hemihypertrophy) is asymmetric overgrowth of one or more external body parts. The overgrowth may involve an entire half of the body, a single limb, one side of the face, or combinations thereof.1,2 Generalized overgrowth, hemihypoplasia, and hemiatrophy are discussed in Section 33.4. Diagnosis

The process that has traditionally been termed hemihypertrophy is more correctly referred to as hemihyperplasia. The pathologic growth process leading to asymmetric overgrowth usually involves an abnormal proliferation of cells (hemihyperplasia) rather than an increase in size of existing cells with no increase in cell number (hemihypertrophy).1,2 Hemihyperplasia has been discussed in a confusing body of literature. This relates to the fact that many authors have combined a variety of malformation syndromes of varied etiology and pathogenesis into an overall diagnosis of hemihypertrophy. Thus, the existing literature must be scrutinized carefully in attempting to interpret data as they relate to a single patient with asymmetric overgrowth. Hemihyperplasia may be partial (e.g., involving the face, the tongue, or one or more extremities) or may involve an entire half of the body.1,2 Rowe3 has proposed a classification of hemihyperplasia according to anatomical site of involvement: (1) Complex hemihyperplasia involves an entire half of the body, or at least one arm and one leg. The enlarged parts may be ipsilateral or contralateral to one another. (2) Simple hyperplasia involves a single limb. (3) Hemifacial hyperplasia involves one side of the face. Hemihyperplasia is congenital, but may become more noticeable after birth or with puberty and may become less pronounced with increasing age. It can be found on either side of the body, but is more frequent on the right side than the left. Hemihyperplasia of the limb implies a discrepancy in both length and circumference of the affected limb as compared with the contralateral side. However, instances of isolated length or circumference discrepancy are frequently seen. The affected hyperplastic body parts may appear swollen or edematous, and the skin may be thickened on the larger side. There may be differences in temperature and perspiration between the two sides. Supernumerary nipples or enlargement of one breast may be present on either the larger or smaller side.4 Asymmetry of the face (hemifacial hyperplasia) may be the only manifestation or may be a part of complex hemihyperplasia. Usually a bulging cheek is noticeable and the lips of the involved side are enlarged, with lowering of the angle of the mouth on the same side. Nasal, external ear, and palpebral fissure asymmetry may be striking. The tongue may be hyperplastic on the affected side, with sharp demarcation at the midline and enlargement of the fungiform papillae. The palate and alveolar ridges may be enlarged on the affected side. Enlargement of the maxilla and the mandible may contribute to a swollen appearance on the affected side of the face. Enlargement of the teeth and jaws may result in malocclusion.4 Recently, bilateral retinal telangiectasia and exudative retinopathy were described in an individual with complex hemihyperplasia.5 When limbs and/or digits are involved, overgrowth of long bones on the affected side can be demonstrated by roentgenogra-

phy and has been demonstrated at autopsy. In children, the ossification centers and corresponding bone age may appear quite advanced on the affected side in relation to the unaffected side. Conversely, some instances of idiopathic hemihyperplasia were not found to have advanced bone age in the affected limbs.6 Scoliosis, chest asymmetry, pelvic tilt, and resultant limping are frequent symptoms and signs.4,7 Enlargement of abdominal organs may accompany hemihyperplasia. Enlargement of one kidney, adrenal gland, testis, or ovary has been observed.4 Medullary sponge kidney has also been described in affected patients.8 Nervous system involvement may be present, including unilateral enlargement of peripheral nerves, sciatica, and intermittent attacks of pain and swelling.4 Hemimegalencephaly may be a complication; neurodevelopmental prognosis is guarded in such cases.9 The diagnosis of hemihyperplasia is based on clinical observation and documentation of asymmetric overgrowth. Diagnostic adjuncts include careful anthropometric measurements of the face and limbs, scoliosis screening, radiographs of the cranium, spine, and long bones, ultrasonography of the abdominal viscera, and/or computerized tomographic or magnetic resonance imaging of the cranium or abdomen. If patients are developmentally delayed and have pigmentary abnormalities of the skin, a karyotype of the peripheral blood or skin fibroblasts should be considered to rule out chromosomal mosaicism.10 Isolated congenital hemihyperplasia is a diagnosis of exclusion. A careful history, physical examination, and/or appropriate diagnostic imaging studies will serve to differentiate isolated congenital hemihyperplasia from the malformation syndromes associated with asymmetric overgrowth (Table 33-3). This differentiation is essential for the accurate counseling of families regarding prognosis, treatment, complications, and recurrence risks with future pregnancies. Etiology and Distribution

The pathogenesis of hemihyperplasia is unknown. In syndromes with generalized overgrowth, it has been hypothesized that the time for cells to complete a cell cycle is decreased, thereby leading to prenatal embryonic and fetal cellular hyperplasia. This has been documented in a striking disorder of prenatal onset overgrowth, Elejalde syndrome (acrocephalopolydactylous dysplasia).11 In that disorder, cells cultured in vitro have been shown to complete a cell cycle in 63% of the time usually observed.4 Pollock and colleagues12 have hypothesized that hemihyperplasia is the result of asymmetric enlargement of one neural fold, with derivatives of the enlarged side being overgrown in comparison to their counterparts. This theory does not, however, account for cases of crossed hemihyperplasia. Another possibility is that patients with isolated hemihyperplasia may represent somatic mosaicism for single gene disorders which result in overgrowth syndromes.13 In this circumstance, a spectrum ranging from complete overgrowth to isolated hemihyperplasia may correlate with the degree of mosaicism. Hemihyperplasia may accompany a number of malformation syndromes (Fig. 33-4, Table 33-3). Although the etiology and pathogenesis of many of these disorders remain undetermined, some cases are the result of single gene or chromosomal anomalies. For example, patients with hemihyperplasia and organomegaly similar to that seen in Beckwith-Wiedemann syndrome may represent mosaicism for abnormalities of the BWS critical region. Previous authors have suggested that isolated hemihyperplasia represents a single gene disorder, asymmetric twinning, or human chimerism.4,14,15 However, no increased incidence of monozygotic twinning has been demonstrated, and karyotypic analysis of

Asymmetry and Hypertrophy

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Table 33-3. Syndromes associated with hemihyperplasia (hemihypertrophy) Causation Gene/Locus

Syndrome

Prominent Features

Beckwith-Wiedemann

Omphalocele, generalized overgrowth, macroglossia, adrenal cytomegaly, hyperplastic visceromegaly, ear creases and pits, neoplastic predisposition

(130650) CDKN1C, KCNQ1OT1, and others, 11p15.5 Multiple genes and mechanisms including deletions, uniparental disomy, and imprinting defects

Klippel-TrenaunayWeber

Hemangiomata (various), arteriovenous fistulae, lymphatic anomalies, polydactyly, syndactyly, oligodactyly, microcephaly, glaucoma, cataracts (Fig. 33-4)

Unknown

Neurofibromatosis

Caf
e-au-lait spots, axillary freckling, neurofibromas, Lisch nodules, microcephaly, scoliosis, hypertension, CNS tumors

AD (162200) Neurofibromin, 17q11.2

Langer-Giedion

Multiple exostoses, bulbous nose, tented nares, loose skin in infancy, microcephaly, long and simple philtrum, sparse scalp hair, cone-shaped epiphyses, deafness, dental anomalies

AD (150230) Contiguous microdeletion TRPSI and EXT1, 8q24

Endochondromatosis

Enchondromas, fractures, digital enlargement, bowing of long bones, development of osteosarcoma in adulthood (low risk)

AD (166000) variable penetrance PTHR1, 3p22

Maffucci

Enchondromas, bowing of long bones, hemangiomata (various types, especially ectasia), fractures, chondrosarcoma (15%)

AD (166000) variable penetrance PTHR1, 3p22

McCune-Albright

Fibrous dysplasia of bones, irregular hyperpigmentation, precocious puberty, hyperthyroidism, hyperparathyroidism, other endocrinopathies

AD (174800) somatic mosaicism GNAS1, 20q13.2

Proteus

Lipomas, hemangiomas, microcephaly, scoliosis, macrodactyly, soft tissue hypertrophy, gyriform changes of soles of feet

(176920) Sporadic, possibly due to somatic mosaicism, germline mutation of PTEN (10q23) reported in 1 patient

Epidermal nevus

Epidermal nevi, alopecia, hypoplastic or hyperplastic sebaceous glands, hyperpigmentation, hyperkeratosis, mental retardation, seizures, bony cysts, kyphoscoliosis, ocular anomalies

Sporadic (163200) possibly due to somatic mosaicism

Triploid/diploid mixoploidy

Large placenta with hydatidiform changes, incomplete calvarium ossification, microretrognathia, microphthalmia, colobomas, cataracts, irregular skin pigmentation, 3,4 finger and 2,3 toe syndactyly

Somatic mosaicism for diploidy/triploidy

Data from Cohen,2 Fraumeni,7 and Gorlin.10

chromosomal markers from various body parts has demonstrated no evidence of chimerism. Future investigations into the molecular differences between affected and unaffected body parts utilizing techniques such as comparative genomic hybridization may reveal causative mechanisms. It has been estimated that hemihyperplasia occurs with a frequency of 1/14,300 live births followed to age 6 years, as reported by the Registry of Malformations in Birmingham, England.7 These data include isolated hemihyperplasia as well as those multiple malformation syndromes associated with asymmetric overgrowth. Isolated congenital hemihyperplasia has been estimated to occur with a frequency of 1/86,000 live births.8 Isolated hemihyperplasia

also reflects a sex differential, with females twice as often affected as males.16 Prognosis, Treatment, and Prevention

The exact prognosis for children with asymmetric overgrowth is dependent on the underlying diagnosis. One of the interesting observations in many, but not all, disorders associated with asymmetric overgrowth is the predisposition to neoplasia. Such neoplastic potential also pertains to many disorders of generalized overgrowth. Among these disorders are isolated congenital hemihyperplasia, Beckwith-Wiedemann, Sotos, Bannayan-RileyRuvulcaba, Weaver, and Proteus syndromes.1,2 The nature of the

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Fig. 33-4. Hemihyperplasia of right lower limb associated with hemangioma as part of Klippel-Trenaunay-Weber syndrome (top left). Hemihyperplasia of right upper and lower limbs in a 6-month-old infant (top right) and of right lower limb only in a 3-year-old male

(bottom right). Neither had other abnormalities. Hemihyperplasia of the left side of the face in an 11-year-old female with neurofibromatosis (bottom left). (Courtesy of Dr. Charles I. Scott, Jr., A. I. duPont Institute, Wilmington, Delaware.)

risk of neoplasia in children with asymmetric overgrowth is critically dependent on a proper diagnosis having been made, since the types of tumors and risks for their development may vary considerably depending on the underlying disorder. In isolated congenital hemihyperplasia, the overall risk for tumor development has been found to be 5.9%.16 Among tumors described in these cases, tumors of embryonal origin such as Wilms tumor, hepatoblastoma, adrenal cell carcinoma, and leiomyosarcoma of the small bowel predominate.10 Thus, the greatest risks for tumor development are in early life.10 Hoyme et al. found that the majority of these embryonal tumors were diagnosed before age 6 years. This has led to the recommendation that affected children be

monitored with ultrasonographic scanning of the abdomen every 3 months up to age 6 years. Such scans should be accompanied by regular medical examination at least every 6 months during the period of greatest tumor incidence, followed by annual evaluations after age 6 years. Since the likelihood of tumors occurring after age 6 years is extremely low, current protocols recommend scanning thereafter every 6 months from ages 6 to 12 years.17 Embryonal tumors identified after puberty are exceedingly rare. Hence, routine ultrasonography after age 12 years is not recommended. Serum afetoprotein (AFP) screening for hepatic tumors every 6 months has been studied as a possible screening adjunct. However, most clinicians feel that the cost and anxiety created by an abnormal AFP level

Asymmetry and Hypertrophy

are not outweighed by the potential benefit of an early diagnosis. This is especially true among children undergoing routine ultrasonography, the diagnostic test of choice. Leg length discrepancy may accompany hemihyperplasia, with resultant pelvic tilt and scoliosis. Affected children should receive careful orthopedic examination and scoliosis screening every 6 months. Medullary sponge kidney and other genitourinary defects may impair renal function.4,10 Examinations of the urinary tract should be performed at the discretion of the clinician on a case by case basis. Treatment of hemihyperplasia is symptomatic and may involve a variety of orthopedic procedures, such as epiphysiodesis for leg length discrepancy. If a tumor is discovered during periodic screening, appropriate surgical and/or chemotherapeutic intervention must be taken. The prognosis in children in whom tumors have been discovered is dependent on the nature of the tumor; many embryonal tumors have an excellent prognosis with aggressive and timely treatment.10 Children with isolated congenital hemihyperplasia may be expected to have an average life span. However, serious associated anomalies, such as renal defects, hamartomas, and neoplasia, can modify prognosis for long-term survival.4,10 Developmental abnormalities and mental retardation may occur in individuals with hemimegalencephaly accompanying hemihyperplasia.9 Limb asymmetry can affect mobility and motor function. Orthopedic surgical procedures can modify attendant disabilities from bony overgrowth.4,10 Based upon the theory that isolated hemihyperplasia is the result of a somatic mutation, most geneticists agree that the recurrence risk to couples with an affected child is very low. However, it should be noted that familial cases have been described in the literature. Slavotinek et al. recently reviewed reports of kindreds affected by non-syndromic hemihyperplasia.18 All affected individuals demonstrated inheritance through a maternal relative. This suggests either X-linked or mitochondrial inheritance, or that loci that contribute to hemihyperplasia may be subject to imprinting. Additionally, no differences were identified upon physical examination to distinguish between familial and isolated congenital hemihyperplasia. References (Hemihyperplasia) 1. Cohen MM, Jr: The Child with Multiple Birth Defects. Raven, New York, 1982, p 112. 2. Cohen MM, Jr: A comprehensive and critical assessment of overgrowth syndromes. Adv Hum Genet 18:181, 1989. 3. Rowe HN: Hemifacial hypertrophy: review of the literature and addition of four cases. Oral Surg 15:572, 1962. 4. Warkany J: Congenital Malformation: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 163. 5. Haritoglou C, Schmidt H, Rudolph G, et al.: Bilateral retinal telangiectasia and exudative retinopathy associated with isolated hemihyperplasia. Retina 23:549, 2002. 6. Viljoen D, Pearn J, Beighton P: Manifestations and natural history of idiopathic hemihypertrophy: a review of eleven cases. Clin Genet 26:81, 1984. 7. Fraumeni JF, Jr: Hemihypertrophy. In: Birth Defects Encyclopedia. ML Buyse, ed. Blackwell Scientific, Cambridge, 1990, p 885. 8. Tomooka Y, Onitsuka H, Goya R, et al.: Congenital hemihypertrophy with adrenal adenoma and medullary sponge kidney. Br J Radiol 61:851, 1988. 9. Dean JCS, Cole GF, Appleton RE, et al.: Cranial hemihypertrophy and neurodevelopmental prognosis. J Med Genet 27:160, 1990. 10. Gorlin RJ, Cohen MM, Jr, Levin LS: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001, p 329.

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11. Elejalde BR, Giraldo C, Jiminez R, et al.: Acrocephalopolydactylous dysplasia. BDOAS XIII(3B):53, 1977. 12. Pollock RA, Newman MH, Burdick AR, et al.: Congenital hemifacial hyperplasia: an embryologic hypothesis and case report. Cleft Palate J 22: 173, 1985. 13. Itoh N, Becroft DM, Reeve AE, et al.: Proportion of cells with paternal 11p15 uniparental disomy correlates with organ enlargement in Wiedemann-Beckwith syndrome. Am J Med Genet 92:111, 2000. 14. Gesell A: Hemihypertrophy and twinning: further study of the nature of hemihypertrophy with report of a new case. Arch Neurol Psychiatry 6:400, 1921. 15. Burchfield D, Escobar V: Familial facial asymmetry (autosomal dominant hemihypertrophy?). Oral Surg Oral Med Oral Pathol 50:321, 1980. 16. Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): Report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79:274, 1998. 17. Shah KJ: Beckwith-Wiedemann syndrome: role of ultrasound in its management. Pediatr Radiol 34:313, 1983. 18. Slavotinek AM, Collins MT, Muenke M: Non-syndromic hemihyperplasia in a male and his mother. Am J Med Genet 121A:47, 2003.

33.4 Hemihypoplasia and Hemiatrophy Definition

Hemihypoplasia and hemiatrophy are body asymmetry accompanying undergrowth or atrophy of one or more external body parts. The growth deficiency or atrophy may involve an entire half of the body, a single limb, one side of the face, or combinations thereof.1 Isolated congenital hemihyperplasia and generalized growth excess are discussed in Sections 33.3 and 33.5, respectively. Diagnosis

In children with significant asymmetry, care must be taken to differentiate undergrowth or atrophy from hemihyperplasia. The child with hemihypoplasia or hemiatrophy frequently has generalized growth deficiency accompanying asymmetry. This growth deficiency is usually, but not always, of prenatal onset. Conversely, the child with hemihyperplasia has a normal or accelerated general growth rate.2 Hemihypoplasia and hemiatrophy are diagnosable by careful physical examination, including the use of detailed anthropometric methods. Additional diagnostic adjuncts may include radiographs of the cranium, spine, and extremities and ultrasonographic, computerized tomographic, and/or magnetic resonance imaging of the brain or viscera.2,3 Hemihypoplasia has been associated with a number of multiple malformation syndromes (Table 33-4). In these disorders, as noted previously, the asymmetric undergrowth is usually a reflection of a more generalized disorder in body growth.2 The term hemiatrophy is reserved for disorders accompanying progressive atrophic processes (Table 33-5). Parry-Romberg syndrome or isolated progressive hemiatrophy is the most common of these disorders. Although the Parry-Romberg syndrome may involve atrophy of an entire half of the body, it is usually confined to the face and is often termed progressive hemifacial atrophy. The atrophy usually begins within the first two decades of life. It represents a slowly progressive atrophy of the subcutaneous tissue and fat on one side of the face.2–4 Progressive hemifacial atrophy is associated with ophthalmic findings in 10–35% of cases. Usually there is progressive endophthalmos. Other abnormalities that have been described include

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Other Systems and Structures Table 33-4. Syndromes associated with hemihypoplasia Causation Gene/Locus

Syndrome

Prominent Features

Silver-Russell

Intrauterine growth retardation, immature osseous development, short incurved 5th finger, triangular facies, bluish sclerae, cafe´-au-lait spots, 2,3 syndactyly of toes

AD (180860) GRB10, 7p11.2 Chromosomal rearrangements, maternal uniparental disomy, and GRB10 mutations explain only 10% of cases

Poland

Hypoplasia of pectoralis major muscle, nipple, and/or areola; rib defects; hypoplastic upper limb with syndactyly, brachydactyly, oligodactyly; gluteal hypoplasia with ipsilateral toe brachysyndactyly

AD (173800) Vascular disruption of subclavian or external iliac artery

Hemifacial microsomia

Asymmetric hypoplasia of malar, maxillary, mandibular regions; macrostomia; preauricular rags; deafness; epibulbar dermoid; cleft lip/palate; vertebral anomalies; renal anomalies; cardiac defects

AD (164210), AR (?) 14q32 Vascular disruption sequence

CHILD

Unilateral hypomelia; webbing of joint spaces; unilateral skin erythema and scaling; unilateral renal agenesis; hypoplasia of clavicle, scapula, ribs, vertebrae

XLD (308050) with lethality in males NSDHL, Xq28

Focal dermal hypoplasia

Focal dermal hypoplasia, telangiectasia, lipomatous nodules herniating through hypoplastic dermis, dystrophic nails, syndactyly, strabismus, coloboma, heart defects, polydactyly, oligodactyly, ectrodacyly

XLD (305600) with lethality in males

Oromandibular limb hypoplasia

Small mouth, micrognathia, hypoglossia, Mo¨bius sequence, aberrant attachments of tongue, hypoplastic limbs, oligodactyly, ectrodactyly, syndactyly

Sporadic AD (103300)

Data from Cohen,1 Warkany,2 Gorlin et al.,3 Lewkonia and Jorgenson,4 and Jones.12

iris heterochromia (with the iris on the affected side of the face the lighter), uveitis, iridocyclitis, restrictive strabismus, refractive changes, and pigmentary changes of the retina.5,6 A variety of neurologic changes may accompany progressive hemifacial atrophy. Ipsilateral Horner syndrome and trigeminal neuralgia have been noted, and migraine is much more common in affected patients. Seizures may occur, including partial, generalized, sensory, and Jacksonian seizures. The brain may show hemiatrophy or may be diffusely atrophic.3,4,6,7 Dermatologic involvement is common, and skin hypo- or hyperpigmentation may be present. Scalp involvement often leads to blanching of the hair or alopecia. Involvement of the upper face gives rise to the ‘‘coupe de sabre’’ appearance (a sharply demarcated area between normal and abnormal facial skin (Fig. 33-5).2–4 Patches of skin hyperpigmentation may also be found on the trunk and limbs. Biopsy tissue of affected skin taken during the active phase of the process may show thickening of collagen bundles and inflammatory cellular infiltrates.2–4 Etiology and Distribution

The etiology of hemihypoplasia in most instances is unknown. However, consideration of the specific diagnosis is essential in

assigning prognosis and recurrence risk during genetic counseling of families of affected patients. The pathogenesis of this disorder involves a decrease in cell number, usually accompanying a generalized process of growth deficiency of prenatal onset.2 Hemiatrophy is likewise of heterogeneous etiology. Causes may include trauma, infection, and/or neurologic damage.1 The pathogenesis of hemiatrophy involves varying degrees of progressive cell death over time. Speculation abounds regarding the etiology and pathogenesis of the Parry-Romberg syndrome (progressive hemifacial atrophy). Theories have included an irritative lesion affecting the sympathetic system, a slow viral infection of the tissues of the craniofacial area, a hereditary degenerative disorder, endocrine disturbances, and the late effects of trauma. The identification of monozygotic twins discordant for hemiatrophy provides further support for environmental causes.8 It should be noted that differentiation between this condition and linear scleroderma is difficult.3,5,9 The presence of anti-dsDNA antibodies in patients with hemiatrophy reinforces the association with scleroderma. Damage to the sensorimotor cortex during fetal life, infancy, or childhood may lead to thickening of the skull on the side of the cortical injury and body hemiatrophy on the contralateral side,

Asymmetry and Hypertrophy

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Table 33-5. Syndromes associated with hemiatrophy Causation Gene/Locus

Syndrome

Prominent Features

Parry-Romberg

Progressive hemifacial atrophy, endophthalmos, iris heterochromia, Horner syndrome, trigeminal neuralgia, seizures, skin hypoor hyperpigmentation, body hemiatrophy

Sporadic (141300)

Dyke-Davidoff-Masson

Hypertrophic thickening of cranium ipsilateral to cortical injury, body hemiatrophy contralateral to cortical injury

Sporadic following cortical brain injury

Sturge-Weber

Flat facial hemangiomas (most commonly a port-wine stain) in the ophthalmic distribution of the trigeminal nerve, buphthalmos, glaucoma, hemangiomas of brain with secondary atrophy and calcification, seizures, hemiplegia, mental deficiency

Sporadic (185300)

Incontinentia pigmenti

Bullous or vesicular skin lesions progressing to hyperpigmentation or hypopigmentation and atrophy, hypodontia, patchy alopecia, mental deficiency, seizures (33%), strabismus, retinal dysplasia, hemivertebrae, kyphoscoliosis

XLD (308300) NEMO, Xq28

Data from Cohen,1 Warkany,2 Gorlin et al.,3 Lewkonia and Jorgenson,4 and Jones.12

a collection of findings termed the Dyke-Davidoff-Masson syndrome.10 Sagild and Alving11 reported on a 13-year-old boy with a long-standing history of hemiplegic migraine affecting the right extremities, global dysphasia, and left-sided headache. Over time, this child developed left progressive hemifacial atrophy. In this case, the authors theorized that small infarcts of the left cerebral hemisphere caused by complicated migraine led to adverse effects on the central sympathetic nervous system leading to hemifacial atrophy. Ipsilateral facial atrophy and contralateral limb and truncal atrophy have also been described in a 39-year-old man with a large cerebral arteriovenous malformation.12

Disorders accompanying hemihypoplasia are uncommon. Progressive hemifacial atrophy is also a rare occurrence; an exact incidence figure is not available. There is a slight excess of affected females, with a sex ratio 2:3. Prognosis, Treatment, and Prevention

The prognosis for children with hemihypoplasia is dependent on the overall diagnosis of the disorder of which the undergrowth is a part. In general, if significant facial asymmetry exists, plastic surgical reconstructive procedures of the affected side are indicated to improve psychological adaptation and orthognathic

Fig. 33-5. Seven-year-old boy with progressive hemifacial atrophy (Parry-Romberg syndrome). Note the sharp demarcation between the atrophic hyperpigmented areas and normal skin.

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Other Systems and Structures

function. If significant asymmetry of limbs is present, pelvic tilt and scoliosis may be accompaniments. In those cases, orthopedic intervention, including epiphysiodesis, is indicated to improve leg length outcome.2–4 In progressive hemifacial atrophy, the natural history reflects a self-arresting disorder. Therefore, no treatment should be initiated until the process has stopped and the full extent of the deformity is apparent. Plastic and maxillofacial surgical procedures may then be performed as indicated. Subcutaneous silicone implantations or more extensive forms of plastic surgery have been used to augment areas of atrophy. Treatment of ocular and neurologic complications is indicated based on signs and symptoms.4 References (Hemihypoplasia and Hemiatrophy) 1. Cohen MM Jr: The Child with Multiple Birth Defects. Raven, New York, 1982, p 112. 2. Warkany J: Congenital Malformation: Notes and Comments. Year Book Medical Publishers, Chicago, 1971, p 167. 3. Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001, p 329. 4. Lewkonia RM, Jorganson RJ: Hemifacial atrophy, progressive. In: Birth Defects Encyclopedia. ML Buyse, ed. Blackwell Scientific, Cambridge, 1990, p 854. 5. Miller MT, Sloane H, Goldberg MF, et al.: Progressive hemifacial atrophy (Parry-Romberg disease). J Pediatr Ophthalmol Strabismus 24:27, 1987. 6. Paradise JE, Raney RB, Whitaker LA: Progressive facial hemiatrophy: report of a case with Ewing’s sarcoma. Am J Dis Child 134:1065, 1980. 7. Asher SW, Berg BO: Progressive hemifacial atrophy: report of three cases, including one observed over 43 years, and computerized tomographic findings. Arch Neurol 39:44, 1982. 8. Larner AJ, Bennison DP: Some observations on the aetiology of progressive hemifacial atrophy (Parry-Romberg syndrome). J Neurol Neurosurg Psychiatr 56:1035, 1993. 9. Adebajo AO, Crisp AJ, Nicholls A, et al.: Localized scleroderma and hemiatrophy in association with antibodies to double-stranded DNA. Postgrad Med J 68:216, 1992. 10. Wyler AR, Ward AA: Cranial asymmetry secondary to unilateral hemispheric damage during late childhood. J Neurosurg 52:423, 1980. 11. Sagild JC, Alving J: Hemiplegic migraine and progressive hemifacial atrophy. Ann Neurol 17:620, 1985. 12. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997.

33.5 Generalized Overgrowth Definition

Generalized overgrowth is symmetric overgrowth of body parts, with weight and/or length exceeding the 97th percentile.1,2 Diagnosis

Generalized growth excess may represent a variation of normal or pathologic processes. A flow chart approach to the diagnosis of growth excess is depicted in Figure 33-6. Normal variants of excessive growth may present prenatally or postnatally. About 5% of all newborns weigh greater than 4000g at birth.3 Although this degree of macrosomia may be an accompaniment of the effects of maternal diabetes, in many instances it represents normal variation. Nondiabetic fetal macrosomia is associated with several predisposing factors: family history

Fig. 33-6. A diagnostic approach to generalized overgrowth. (Adapted from Cohen.1)

of fetal macrosomia; excessive prepregnancy maternal weight (obese women have macrosomic infants four times more frequently than do underweight women); maternal multiparous state; male fetal sex; and higher socioeconomic status of the mother.1,2,4 Normal variants of growth excess include familial tall stature and familial rapid maturation. In familial tall stature, there is genetic predisposition toward growth excess, with adult first-degree relatives having tall stature. In these individuals, the onset of rapid growth is in early infancy; they have a normal bone age for chronologic age, normal onset of puberty, and eventual tall stature consistent with other family members. In familial rapid maturation, the height of adult first-degree relatives is normal. However, there is advanced growth beginning in early infancy accompanied by an advanced bone age in comparison with chronologic age. The onset of puberty is early, and final height is attained prematurely. Eventual adult stature is normal, consistent with other family members. These variant growth patterns present no particular medical problems to affected individuals.2 Pathologic overgrowth may be of prenatal or postnatal onset. Prenatal onset overgrowth may result from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of fetal cells, an increase in interstitial spaces, or a combination of the above. Most prenatal onset overgrowth is the result of excessive cellular proliferation, i.e., primary growth excess.1,2,5 A number of multiple malformation syndromes associated with prenatal onset primary growth excess have been described (Table 33-6). These pathologic syndromes share several characteristics: the overgrowth is present at birth, persisting into postnatal life; excessive growth affects weight as well as length; the overgrowth is associated with multiple characteristic anomalies; mental deficiency is a usual accompaniment; and a neoplastic predisposition is frequently noted.1,6 Humorally mediated (secondary) overgrowth of prenatal onset is typified by diabetic macrosomia. In these infants, maternal hyperglycemia has led to excessive fetal pancreatic function and hyperinsulinemia, resulting in fetal overgrowth.1 The cellular components comprising the overgrowth in diabetic macrosomia include adipose tissue as well as nonadipose cellular constituents. Inspection of organs in affected infants reveals an increased number of cellular nuclei, suggesting increased protein synthesis.7,8 In animal experiments, maternal administration of streptozotocin (to produced glucose intolerance) or insulin to fetuses results in fetal cellular hyperplasia, not hypertrophy. In these animals, an increased number of

Table 33-6. Syndromes associated with prenatal onset primary growth excess Causation Gene/Locus

Syndrome

Prominent Features

Beckwith-Wiedemann

Omphalocele, generalized overgrowth, macroglossia, adrenal cytomegaly, hyperplastic visceromegaly, ear creases and pits, neoplastic predisposition

(130650) 11p15.5 Multiple genes and mechanisms including deletions, paternal uniparental disomy, and imprinting defects

Sotos

Macrocephaly, advanced bone age, ocular hypertelorism, prominent mandible, neoplastic predisposition

Sporadic AD (117550) NSD1, 5q35

Nevo

Dolichocephaly, advanced bone age, large hands and feet, incoordination, mental deficiency, generalized edema at birth, hypotonia, contracted feet, malformed ears, cryptorchidism

Sporadic AR (601451)

Bannayan-Riley-Ruvalcaba

Macrocephaly, mental deficiency, intestinal polyposis, pigmented penile macules, multiple lipomas and hemangiomas, other mesodermal hamartomas, myopathy (60%)

Sporadic AD (153480) PTEN, 10q23.31 Mutations in PTEN account for 60% of cases

Weaver

Macrocephaly, advanced bone age, broad forehead, thin hair, large ears, widened distal long bones, camptodactyly, some neoplastic predisposition

AR (277590) NSD1 mutations (5q35) found in some cases

Marshall-Smith

Postnatal growth failure, advanced bone age, mental deficiency, respiratory distress, early lethality (50%), prominent forehead, frontal ridging, low nasal bridge, choanal stenosis/atresia, laryngomalacia, umbilical defect, cardiac defect

Sporadic (602535)

Elejalde

Early lethality, globular body, omphalocele, short limbs, redundant neck skin, craniosynostosis, hypoplastic nose, rudimentary pinnae, enlarged cystic kidneys

AR (256710)

Simpson-Golabi-Behmel

Mental deficiency, broad nose, wide mouth, cleft palate, large cystic kidneys, large square hands, postaxial polydactyly, hypoplastic nails, neoplastic predisposition

XLR (300209, 312870) GPC3, Xq26

Proteus

Lipomas, hemangiomas, microcephaly, scoliosis, macrodactyly, soft tissue hypertrophy, gyriform changes of soles of feet

(176920) Sporadic possibly due to somatic mosaicism, germline mutation of PTEN reported in 1 patient

Carpenter

Craniosynostosis, preaxial polydactyly of feet, short fingers, clinodactyly

AR (201000)

Cranioectodermal dysplasia

Sagittal craniosynostosis, dolichocephaly, sparse hair, hypodontia, narrow thorax, short limbs, brachydactyly

AR (218330)

Hypertrichotic osteochondrodysplasia

Generalized hypertrichosis, narrow thorax, cardiomegaly, wide ribs, platyspondyly, hypoplastic ischial and pubic bones, small obturator foramen, coxa valga, Erlenmeyer flask-shaped long bones, generalized osteopenia

Sporadic AR (239850)

Pallister-Killian

Hypotonia, mental deficiency, seizures, coarse facies, prominent forehead, sparse hair, ocular hypertelorism, flat nasal bridge, macrostomia, macroglossia, ear anomalies

(601803) Mosaic tetrasomy 12p

Trisomy 8 mosaicism

Scaphocephaly, mental deficiency, prominent forehead, broad nose, small mandible, contractures of hands and feet, scoliosis, rib and vertebral anomalies, prominent interdigital pads, vertical sole creases

Mosaic trisomy 8

Beare-Stevenson

Craniosynostosis, ear defects, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, and prominent umbilical stump

Sporadic AD (123790) FGFR2, 10q26

Data from Cohen,2 Elejalde et al.,9 and Jones.17

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Other Systems and Structures Table 33-7. Syndromes associated with postnatal-onset obesity Causation Gene/Locus

Syndrome

Prominent Features

Albright hereditary osteodystrophy

Short metacarpals, short metatarsals, short stature, mental deficiency, short neck, cataracts, cone-shaped epiphyses, variable hypocalcemia and hyperphosphatemia

AD (103580) GNAS1, 20q13.2

Alstrom

Blindness (accompanying retinitis pigmentosa), nystagmus, hypogenitalism, deafness, hyperuricemia, hypertriglyceridemia, insulin-resistant diabetes mellitus

AR (203800) ALMS1, 2p13

Bardet-Biedl

Mental deficiency, retinitis pigmentosa, syndactyly, polydactyly, hypogenitalism, renal defects

AR (209900) Mutations have been found in genes at several BBS loci: BBS1, BBS2, BBS4, BBS6, BBS7, and BBS8

Biemond II

Iris coloboma, mental deficiency, hypogenitalism, postaxial polydactyly

AR (210350)

Borjeson-ForssmanLehmann

Severe mental deficiency, seizures, hypotonia, microcephaly, coarse facies, prominent supraorbital ridges, deeply set eyes, retinal/optic nerve dysplasia, hypogenitalism, kyphosis, hypoplastic distal and middle phalanges

XLR (301900) PHF6, Xq26.3

Carpenter

Craniosynostosis, preaxial polydactyly of feet, short fingers, clinodactyly

AR (201000)

Prader-Willi

Hypotonia, almond-shaped eyes, narrow bifrontal diameter, tapering fingers, hypogenitalism, small hands and feet

(1762709) SNRPN, necdin, possibly others, 15q11-q13 Multiple genes and mechanisms including deletions, uniparental disomy, and imprinting defects

Urban-Rogers-Meyer

Prader-Willi habitus, osteopenia, contractures of fingers

AR (264010)

Data from Cohen2 and Jones.17

cells is noted in the liver, spleen, and heart. No hyperplastic processes are noted in the brain or kidneys.1 Postnatal onset growth excess is nearly always secondary in nature, i.e., involving humorally mediated factors. Such growth excess is usually associated with disorders exhibiting early production of estrogens, androgens, or both, leading to sexual precocity accompanying an increased growth rate. Obesity may also be considered to be a form of postnatal onset growth excess. Obesity may be exogenous (secondary to increased caloric intake) or one component of several multiple malformation syndromes. Some of these disorders may reflect a defect in hypothalamic development. In these conditions, obesity is usually accompanied by short stature rather than tall stature (as in exogenous obesity).2 Syndromes associated with postnatal onset obesity are listed in Table 33-7. Diagnosis of disorders associated with generalized overgrowth is accomplished by application of clinical criteria, after synthesis of data from a careful history and physical examination. It is essential to have inquired about growth patterns of other family members during the clinical evaluation. Radiographs for bone age determination and a skeletal survey may prove useful. Chromosome analysis of blood or fibroblasts may be indicated if associated structural defects are present.1,2

Etiology and Distribution

As described previously, growth excess may be considered to be primary or secondary in nature. In disorders associated with primary growth excess, intrinsic cellular hyperplasia has been documented.1,2,5 Theoretically, cells cultured from affected individuals should manifest this growth excess in vitro. Preliminary data from one disorder, Elejalde syndrome, indicate that cultured fibroblasts complete the cell cycle in 63% of the usual time.9 The molecular genetics of disorders associated with primary overgrowth of prenatal onset continues to be elucidated, and a detailed discussion of the genes identified is beyond the scope of this chapter. The current body of knowledge is summarized in Table 33-6. Secondary (humorally mediated) growth excess accompanies pathologic states in which excess hormone production is the initiating event. Tumors or inborn errors in steroid synthesis account for many of these secondary growth excess states.2 Prognosis, Treatment, and Prevention

The prognosis for overgrowth associated with normal variation is excellent. Concerned members of such families may be offered reassurance.2 The prognosis and treatment of pathologic states accompanying prenatal onset overgrowth is dependent on the nature of the

Asymmetry and Hypertrophy

underlying condition. Careful genetic evaluation and counseling are indicated in all cases. A serious complication of many primary overgrowth disorders of prenatal onset is a predisposition to neoplasia. In overgrowth syndromes, the normally increased mitotic activity of prenatal life is even more increased. Cells in such individuals are theoretically more vulnerable to structural changes in DNA, disrupted transcription to RNA, and altered protein translation during mitotic activity. The increased mitotic activity may lead to production of clones of altered cells, contributing to neoplasms.1,2 Additionally, some tumors may be explained by the ‘‘two-hit hypothesis.’’ For example, in Sotos syndrome, haploinsufficiency for the NSD1 gene has been found to be causative in most cases.10 NSD1 presumably functions as a tumor suppressor gene, regulating components involved in cellular maturation and division. Haploinsufficiency leads to decreased regulation of cell growth. Subsequently, loss of the normal allele post-zygotically would account for tumor formation. The neoplastic predisposition of generalized overgrowth syndromes is given in Table 33-8. Previous studies have documented an association between increased body size and the development of neoplasms. Children with Wilms tumor and infants with leukemia have both been observed to have increased birth weight in comparison to controls.11– 13 Fraumeni has documented that osteosarcoma tends to arise in bones that grow rapidly and produce taller individuals.14 Some overgrowth syndromes of prenatal onset have not been associated with neoplasia. This may be accounted for by the fact that many of these disorders are very rare; thus, insufficient data may exist to rule out malignant predisposition. In addition, some prenatal onset overgrowth syndromes are associated with secondary growth excess, such as diabetic macrosomia. In these infants, the aspects of increased cellular mitotic activity, which might lead to neoplasia in primary growth excess, do not play a role.2 Three disorders associated with overgrowth have welldocumented associations with neoplastic potential: BeckwithWiedemann syndrome, hemihyperplasia (hemihypertrophy), and Sotos syndrome (Figs. 33-7 and 33-8). In hemihyperplasia, pa-

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Table 33-8. The neoplastic potential of prenatal-onset generalized overgrowth syndromes Syndrome

Neoplasms Reported

Type of Overgrowth

Diabetic macrosomia

No

Secondary

Beckwith-Wiedemann

Yes

Primary

Sotos

Yes

Primary

Nevo

No

Primary

Bannayan-Riley-Ruvalcaba

Yes

Primary, hamartoneoplastic

Weaver

Yes

Primary

Marshall-Smith

No

Primary

Elejalde

No

Primary

Simpson-Golabi-Behmel

Yes

Primary

Proteus

Yes

Primary, hamartoneoplastic

Adapted from Cohen.2

tients have asymmetric, rather than generalized, overgrowth. In Beckwith-Wiedemann syndrome (Fig. 33-7), affected individuals have generalized overgrowth, but, in addition, may have elements of asymmetric overgrowth. The malignant tumors observed in all three of these syndromes are similar and are thought to be of embryonal origin. Tumors of the kidney and liver occur in all three conditions; adrenal neoplasms are found in BeckwithWiedemann syndrome and hemihyperplasia. In all disorders of overgrowth associated with neoplasms, periodic screening to rule out tumor development is indicated. The greatest risks for tumor development are in early life, the majority being diagnosed before age 6 years.15 This has led to the recommendation that affected children be monitored with ultrasonographic scanning of the abdomen every 3 months up to age 6 years. Such scans should be accompanied by regular medical examination at least every 6 months during the period of greatest tumor incidence,

Fig. 33-7. Features of the Beckwith-Wiedemann syndrome, including macroglossia, ear creases, and omphalocele. (Courtesy of Dr. Charles I. Scott, Jr., A. I. duPont Institute, Wilmington, Delaware.)

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Fig. 33-8. Generalized overgrowth in an infant with Sotos syndrome.

followed by annual evaluations after age 6 years. Since the likelihood of tumors occurring after age 6 years is extremely low, current protocols recommend scanning thereafter on an every 6 months basis from ages 6 to 12 years.16 Embryonal tumors identified after puberty are exceedingly rare. Hence, routine ultrasonography after age 12 years is not recommended. Serum AFP screening for hepatic tumors every 6 months has been studied as a possible screening adjunct. However, most clinicians feel that the cost and anxiety created by an abnormal AFP level are not outweighed by the potential benefit of an early diagnosis. This is especially true among children undergoing routine ultrasonography, the diagnostic test of choice. References (Generalized Overgrowth) 1. Cohen MM Jr: The Child with Multiple Birth Defects. Raven, New York, 1982, p 107. 2. Cohen MM Jr: A comprehensive and critical assessment of overgrowth syndromes. Adv Hum Genet 18:181, 1989. 3. Hellman LM, Pritchard JA, eds: Williams Obstetrics, ed 14. AppletonCentury-Crofts, New York, 1971, p 1026. 4. Niswander JR, Singer J, Westphal M: Weight gain during pregnancy and prepregnancy weight. Obstet Gynecol 33:482, 1969. 5. Al-Okail MS, Al-Attas OS: Histological changes in placental syncytiotrophoblasts of poorly controlled gestational diabetic patients. Endocr J 41:355, 1994.

6. Cohen MM: Mental deficiency, alterations in performance, and CNS abnormalities in overgrowth syndromes. Am J Med Genet 117C:49, 2003. 7. Fee SA, Weil WB Jr: Body composition of infants of diabetic mothers by direct analysis. Ann N Y Acad Sci 110:869, 1963. 8. Naeye RL: Infants of diabetic mothers: a quantitative, morphologic study. Pediatrics 35:980, 1965. 9. Elejalde BR, Giraldo C, Jiminez R, et al.: Acrocephalopolydactylous dysplasia. BDOAS XIII(3B):53, 1977. 10. Kurotaki N, Imaizumi K, Harada N: Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365, 2002. 11. Irving I: The EMG syndrome. In: Progress in Pediatrics, vol 1. RP Rickham, WC Hacker, J Prevolt, eds. Urban and Schwarzenberg, Munich, 1970, p 1. 12. Wertelecki W, Mantel N: Increased birth weight in leukemia. Pediatr Res 7:132, 1973. 13. Peshan AF: Birth weight and the incidence of childhood cancer. J Natl Cancer Inst 72:1039, 1984. 14. Fraumeni JF Jr: Stature and malignant tumors of bone in childhood and adolescence. Cancer 20:967, 1967. 15. Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head and Neck, ed 4. Oxford University Press, New York, 2001, p 329. 16. Shah KJ: Beckwith-Wiedemann syndrome: role of ultrasound in its management. Pediatr Radiol 34:313, 1983. 17. Jones KL: Smith’s Recognizable Patterns of Human Malformation, ed 5. WB Saunders, Philadelphia, 1997, p 150.

34 Twins Mary C. Phelan and Judith G. Hall

The rarity of a plural birth in woman, and the increased danger to both mother and offspring in these circumstances, render such an event, in a certain limited sense, an abnormity. —J. Matthews Duncan, 1865

T

he increased frequency of pregnancy complications, prematurity, anomalies, and neonatal morbidity and mortality associated with multiple births has long been recognized. As noted by Duncan,1 twinning itself may be viewed as an ‘‘abnormity’’ or abnormality of development; viewed as such, twinning is among the most common human malformations. With an incidence of about 1 in 80 births, twinning affects approximately 1 in 40 individuals. Historically, multiple births have been greeted with interest, excitement, and often, suspicion. In many societies, elaborate myths and superstitions have surrounded the occurrence of multiple births. In some areas of Africa twins were welcomed, while in other areas twins were considered a threat to the community so that both mother and children were banished, or one or both of the twins were killed.2 Fear and distrust of twins were reflected in the fact that, although multiple births were accepted as normal in animals, they were considered extremely abnormal in humans. Multiple births were considered to be a degrading event, suggesting that the mother had been unfaithful to her spouse and had consorted with another man or with an evil spirit.3 Fortunately, social attitudes toward multiple births have changed and twins are often welcomed and their births celebrated.3 Although the existence of two classes of twins, so-called ‘‘fraternal’’ and ‘‘identical’’ twins, was well known, it was not until Sir Francis Galton, cousin of Charles Darwin, proposed the use of twins as models for studying disease that twin research became an active field.4 Galton proposed that through the study of development and diseases in twins, understanding of the complex interaction between environmental and genetic factors, the ‘‘nature vs. nurture’’ concept, might be achieved.5 The use of twins in genetic analysis is based on the existence of two types of twins who differ in their origin and in their degree of genetic similarity. Monozygotic (MZ) twins arise from a single fertilized ovum and thus will be alike for all of their genetically determined characters. Dizygotic (DZ) twins originate from two independently fertilized ova and will be no more alike genetically

than any pair of siblings.6 Classical twin studies exploit the genetic distinction between MZ and DZ twins by assuming that any differences observed within an MZ pair are attributable to environmental influences, whereas differences within DZ pairs are due to both genetic and environmental factors. Despite criticism of the statistical and biological limitations, the twin method provides valuable information concerning the relative contributions of genetic and environmental factors to normal and abnormal development. Zygosity and Placentation Human twins are subject to a variety of prenatal influences that do not affect singletons. The most important factor that is unique to twins and exerts a profound effect on their intrauterine environment is the form of placentation. The developmental stage at which the twinning event occurs determines the type of placentation.7 Normally, several ovarian follicles begin to ripen in each ovary during the menstrual cycle, although only one will develop into a mature graafian follicle destined to ovulate.8 In DZ twinning, two ovarian follicles mature resulting in the release of two separate ova.6 The two ova may be released from the same ovary, or one ovum may be released from each ovary. After fertilization, the two zygotes traverse either the same or opposite fallopian tubes to implant in the uterine wall. Each of these zygotes will develop its own placenta with a chorionic and amniotic membrane, although the two placental discs may show varying degrees of fusion depending on the proximity of the implantation sites.8 This form of placentation is called dichorionic diamniotic (Figs. 34-1 and 34-2) and is found in all DZ twin pregnancies. DZ twinning is characterized by the simultaneous development of two conceptuses which have arisen from two ova fertilized by two separate sperm. As such, DZ twinning has been regarded as a duplication of the normal development of a single zygote. That DZ twins arise from two independently developing zygotes implies that DZ twins might result from more than one act of coitus, either during a single ovarian cycle or during different cycles.8 Superfecundation refers to the fertilization of two or more ova of the same estrous cycle by sperm from different coitions. Superfecundation is 1377

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Fig. 34-1. Separate dichorionic diamniotic placenta. Dichorionic diamniotic placentation is observed in all dizygotic twin pregnancies and in monozygotic twin pregnancies resulting from separation of the blastomeres within 3 days post fertilization. If the twin zygotes implant at sites distant from each other on the uterine wall, the placental discs remain completely separate.

common in lower animals and has been reported in man, although it can only be proven in cases involving more than one father.9,10 An ancient example of superfecundation is the legend of the conception of Hercules. According to the legend, the Greek god Zeus seduced Alcmene by disguising himself as Alcmene’s husband, Amphitryon. The following day, Amphitryon returned home and visited his wife. Subsequently, Alcmene gave birth to twins, one of whom was Hercules, son of Zeus, and the other Iphicles, son of Amphitryon.11 A more complex story of superfe-

Fig. 34-2. Fused dichorionic diamniotic placenta. If the twin zygotes implant close together on the uterine wall, the placental discs may show varying degrees of fusion.

cundation, also involving Zeus, is the birth of the Gemini twins, Castor and Pollux.12 The beautiful Leda was wed to Tyndareus, King of Sparta. On her wedding night Leda was visited by Zeus, disguised as a swan. Leda subsequently bore two eggs. The first egg hatched to reveal Castor and Clytemnestra, mortals fathered by Tyndareus. Hatched from the second egg were Pollux and Helen, later queen of Sparta, who were immortals fathered by Zeus. Despite heteropaternity, Castor and Pollux were said to be physically identical. Castor and Pollux became great athletes and warriors. After Castor was killed in battle, Pollux was so despondent that he implored Zeus to let him join his brother in death. Zeus compromised by placing the brothers always together in the heavens as the constellation Gemini, or The Twins. Superfetation is the fertilization of multiple ova released during different ovarian cycles. Twins arising as a result of superfetation may be markedly discordant in size and development due to different gestational ages.13,14 Superfetation was reported in a 20-year-old primigravida with a uterus pseudo didelphys. The twins were delivered by cesarean section at gestational week 35.15 MZ twinning involves an abnormal series of events during which a single zygote divides, giving rise to two embryos. The division of the zygote may occur at variable times after fertilization. The earliest stage at which MZ twinning might occur is at the two-cell stage. When division of the zygote occurs within about 3 days of fertilization, each of the two daughter cells, or blastomeres, will pass down the fallopian tube and implant independently in the wall of the uterus.6 In such cases, each conceptus will have its own placenta with chorionic and amniotic membranes. Dichorionic diamniotic placentation is observed in about 25% of MZ twin pregnancies and is indistinguishable from the placentation of DZ twins. As in DZ pregnancies, the dichorionic placentas of MZ twins may be completely separate or may show some degree of fusion, depending on whether the zygotes implant at adjacent or distant sites on the uterine wall. Dichorionic placentas are separate when they have easily distinguished placental masses that can be readily parted. Fused placentas occur when the two placental discs of a dichorionic mass are adherent to each other.16 MZ twins may occur more often among twins with fused dichorionic placentas than those with separate placentas, since the zygotes of an MZ pair pass down the same fallopian tube and may be more likely to implant at adjacent, rather than remote, sites in the uterus.17 In contrast, the two zygotes of a DZ twin pair may pass through either the same or different fallopian tubes; thus, the proximity of their implantation sites is a matter of chance. When twinning takes place between about days 4–8 post fertilization, after the inner cell mass has developed and the chorionic membrane has been established, the twins will share a single placental disc with one chorionic membrane and two amniotic membranes.8 This form of placentation is termed monochorionic diamniotic (Fig. 34-3) and is the most common type observed in MZ twins, occurring in 70–75% of monozygotic pregnancies. During the second week post fertilization, the primitive streak forms and both the chorionic and amniotic membranes have been established. If twinning occurs at this late stage, the twin embryos will be contained within a single amniotic cavity and the placentation, which occurs in about 1–2% of MZ pregnancies, is designated monochorionic monoamniotic (Fig. 34-4). At later stages of development, ‘‘incomplete’’ twinning may result if the twin embryos fail to separate completely, giving rise to conjoined twins.4 The temporal relationship between MZ twinning and X chromosome inactivation has led to speculation that MZ twinning

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Fig. 34-3. Monochorionic diamniotic placentation is observed when the monozygotic twinning event occurs between 4 and 8 days post fertilization.

and X-inactivation may be etiologically related. According to the Lyon hypothesis,18 one X chromosome of normal females is randomly inactivated in each cell. X-inactivation occurs early in embryonic life when the embryo consists of about 10–20 cells.19 As a consequence of X-inactivation, or Lyonization, females heterozygous for X-linked traits are effectively mosaic at the cellular level, resulting in considerable phenotypic variability among carriers of X-linked disorders. In extreme cases, preferential inactivation of a particular X chromosome may lead to the full expression of X-linked disorders in carrier females. Preferential Xinactivation has been invoked to explain the discordant expression in female monozygotic twins of X-linked traits including

Fig. 34-4. Monochorionic monoamniotic placentation is observed when twinning occurs after 8 days post fertilization. The twin fetuses are contained within the same amniotic cavity.

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Duchenne muscular dystrophy, hemophilia, color blindness, and glucose-6-phosphate dehydrogenase variants.20–29 James30 speculated that the link between X-inactivation and MZ twinning may include a relationship between X-inactivation and neural tube defects, as suggested by Hall.31 If anomalous Xinactivation were causally related to MZ twinning and to neural tube defects, then a number of epidemiologic features of neural tube defects could be explained.21,30,32 These features include the excess of anencephaly among MZ but not DZ twins, the increased risk of anencephaly in monoamniotic and conjoined twins compared to dichorionic MZ pairs, the greater concordance rate for anencephaly among MZ compared to DZ pairs, and the low sex ratio of spina bifida cases that occur in twins. A possible mechanism by which X-inactivation might lead to monozygotic twinning was proposed by Burn et al.21 Aberrant Xinactivation in females may occasionally lead to clumping of cells that bear the same inactive X. The resulting cell aggregates would have opposite or discordant inactivation patterns. Each aggregate may view cells with the opposite inactivation pattern as foreign and may repulse them. Separation or splitting of the cell aggregates based on the X-inactivation pattern may ultimately lead to MZ twinning. Among twin pairs arising in this way, one would expect an excess of females, as this mechanism would be unique to female zygotes. A preponderance of females among MZ twins has been reported, with the excess being greater in later-forming twins. This trend is most notable among conjoined twins in which the female to male ratio is 2:1. Nonetheless, studies of Xinactivation patterns in MZ twins have failed to show contrasting, non-random X-inactivation patterns.33,34 To investigate the timing of the twinning event relative to X-inactivation, Montiero et al35 examined the X-inactivation patterns of monochorionic MZ (MC-MZ) and dichorionic MZ (DC-MZ) twins. An extremely similar pattern of X-inactivation was observed in cord blood from MC-MZ twins, while DC-MZ twins showed large differences.36 Traditionally, such similarities within MC-MZ twins pairs have been attributed to vascular anastomoses within the monochorionic placenta which lead to shared circulation of hematologic factors. Alternatively, the high correlation between X-inactivation patterns could result from the occurrence of the twinning well after the inactivation of the X chromosome. To exclude the possibility that shared blood supply caused the similarity in MC-MZ pairs, X-inactivation was examined in buccal mucosa—a non-circulating ectodermal tissue that would not be affected by shared circulation. X-inactivation patterns were also examined in peripheral or cord blood. Again, MC-MZ twins had a highly similar pattern while DC-MZ twins had a dissimilar pattern of X-inactivation. Montiero et al., 1992,35 simulated embryo splitting and concluded that MC-MZ twins typically occurred 3–4 rounds of replication after X-inactivation while DC-MZ twinning preceded or coincided with the time of inactivation. The simulation assumed that the embryo splitting resulted in a fairly equal distribution of cells to the co-twins. Despite the high correlation within MC-MZ twins, the patterns were not as closely correlated as repeated assays within the same individual. The slight differences between the patterns of monochorionic twins may reflect heterogeneity in the timing of MC-MZ twinning. Subsequent analysis of monoamniotic MZ (MA-MZ) twins revealed virtually identical X-inactivation patterns analogous to the pattern expected for studies within a single individual.37 These results indicate that MC twinning occurs over a broad spectrum of time following X-inactivation. Monochorionic pairs that split soon after X-inactivation have a greater

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intrapair difference than monoamniotic pairs who have identical patterns of X-inactivation. Although X-inactivation and MZ twinning are temporally related, they do not appear to be etiologically related. Despite speculation that extreme skewing may be associated with the twinning process, a higher degree of skewed X-inactivation has not been found in MZ twins versus singleton females.34,35 Extreme skewing of X-inactivation does not occur commonly within MZ twin pairs and is not known to play a direct role in the twinning process, but could easily account for the excess of female MZ twins. Polar Body Twinning Although all non-identical twins are generally considered to be dizygotic, it has been postulated that a third type of twin might result from the fertilization of two ova that have developed from the same primary oocyte.6,14 Normally, in the first meiotic division the primary oocyte divides unequally to give rise to the secondary oocyte and to a much smaller cell, the first polar body. As a result of the unequal division, the secondary oocyte contains nearly all the cytoplasm from the primary oocyte; the first polar body is a small, nonfunctional cell that soon degenerates.38 At ovulation, the secondary oocyte begins the second meiotic division that is completed only if fertilization occurs. This second unequal division results in formation of the mature oocyte and the smaller second polar body. The first polar body may also undergo division. Theoretically, fertilization of either of these polar bodies can produce a zygote in which either would have been fertilized by a different sperm than the normal zygote. If the first polar body were fertilized, there would be a triploid zygote. If the second were fertilized, the difference in genetic material would be contributed by the sperm since the maternal genetic contributions would be more or less identical. The zygote’s development depends upon the cytoplasm of the egg, and the polar bodies might be deficient in cytoplasm since they are set aside and may not have any cytoplasm associated with them. Danforth39 first postulated the existence of a third type of twin to explain results obtained when plotting the frequency distribution of differences between twins for various physical characteristics. Thorndike40 found that when plotting the degree of similarity between two members of different twin pairs, the resulting curve was unimodal rather than bimodal, with the mode falling above that obtained for comparisons of ordinary siblings, but below the point representing identity. Danforth39 suggested that the unimodal curve might be explained by (1) the leveling effect of shared environment on DZ twins together with somatic variation affecting monozygotic twins, or (2) the existence of a third type of twin. Citing work on the eggs of bees and sea urchins, Danforth39 noted that the entry of the sperm into the egg sometimes stimulates the egg pronucleus to divide precociously so that the sperm pronucleus unites with only half of the original egg nucleus. If a similar condition arose in man, each half of the egg nucleus might be fertilized by a separate sperm, leading to a pair of twins derived from one egg and two sperm. Bulmer6 proposed three mechanisms to give rise to the ‘‘third type’’ of twins: (1) the primary oocyte may divide equally at the first meiotic division to produce two secondary oocytes, thus two ova; (2) the secondary oocyte may divide equally at the second meiotic division to give rise to two ova; or (3) the ovum itself may divide before fertilization. This third type of twin would be neither MZ nor DZ: unlike MZ twins, two different sperm

fertilize the ova and, unlike DZ twins, the ova are not independently released from the ovaries.8 If meiosis proceeds normally with unequal divisions leading to production of the first and second polar bodies, the question arises as to whether fertilization of a functional second polar body might lead to viable twins. Such twins could have independent paternal contributions, but the maternal genes would differ only if they were far enough from the centromere for crossing over to have occurred.14 Nance41 suggested that examination of nonidentical twins with marked phenotypic discordance may permit identification of so-called ‘‘polar body’’ twins. He described a pair of non-identical male twins who were markedly discordant for birth weight, motor development, and bone age. The smaller twin had developmental delay, and the twins showed a 6-month difference in bone age. The mother had intentionally delayed conception until the end of her fertile period, believing that this would increase the likelihood of conceiving a male. Nance14 postulated that since over-ripeness of the egg may contribute to MZ twinning, this mechanism may also result in abnormalities of the second meiotic division, leading to polar body twinning. Mosaic individuals have been shown to arise from the fertilization of a single ovum by two sperm, leading to speculation that this mechanism might also lead to viable twins.42 Analysis of blood group markers has been used to investigate the possible existence of polar body twins.6 An increased incidence of concordance among non-identical twins, particularly for genes located near the centromere, would be expected in polar body twins.14 In fact, no excess concordance for blood groups was shown in non-identical twins, leading Bulmer6 to conclude that if a third type of twin does exist, such individuals must be very rare. There have been no reports of a polar body twinning since the time when molecular techniques would enable identification of the source of genetic material. Animal Models of Twinning The earliest stage at which MZ twinning might occur is at the two-cell stage when two blastomeres separate to produce two identical individuals. Studies of early mammalian development have confirmed that blastomeres separated at the two-cell stage are capable of further development.43 Based on observations in rat, rabbit, mouse, pig, and sheep, Moore44 suggested that cellular specialization does not occur until after the eight-cell stage of development. Prior to specialization, the cells of the blastomere are totipotent—capable of full development into normal young. After several cell divisions, the blastocyst begins to form and the cells begin to specialize. The trophoblast will form placenta and supporting structures while the inner cell mass will form the embryo. The cells from the inner cell mass are pluripotent— capable of forming many cell types but not a completely functional organism since they lack the ability to form the placental structures. The pluripotent stem cells become further specialized and become committed to give rise to specific cells with specific functions. These cells are now called multipotent stem cells. Methods to isolate pluripotent stem cells have been used to manipulate human cells. Inner cell mass cells from human embryos and fetal gonadal cells have been cultured to produce pluripotent cell lines.45,46 Such cell lines are of great interest for the study of human development, for pharmacologic research and drug development, and for stem cell therapy for diseases arising due to cellular dysfunction. Ethicists, scientists, and politicians debate the

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development of stem cell research, with a great concern being attempted cloning of a human being. Many animals including sheep, cats, mice, and goats have been cloned, but the potential cloning of a human being raises emotional and controversial issues. At present, MZ twinning is said to be the only natural form of cloning in humans. However, MZ twins are obviously not completely similar to each other or to animals which have been cloned. While many species of animals produce litters of two or more offspring, only one mammal—the nine-banded armadillo in the genus Dasypus—is known to produce litters of identical quadruplets. Six species of armadillo found from northern Argentina to the southern United Stated reproduce routinely by polyembryony. Polyembryony is a type of reproduction that combines features of sexual and asexual reproduction. Parthenogenesis is a means of asexual reproduction in which an unfertilized ovum develops into a new individual genetically identical to the mother. Sexual reproduction relies on genetic contributions from both parents to produce genetically diverse offspring, thereby increasing the probability of survival in adverse environments. In polyembryony, a single sexually produced embryo splits to form two or more genetically identical embryos.47 Monozygotic twinning in man is an example of polyembryony. Because genetic variability within litters is eliminated, the nine-banded armadillo is a useful animal model for studying physiologic traits during development.48 Despite their utility in research, litters produced by polyembryony lack the advantages conferred by either asexual or sexual reproduction. Polyembryonic litters do not benefit from replication of the mother’s genotype that has already been proven ‘‘fit’’ or successful for survival in a given environment. Unlike offspring resulting from sexual reproduction, the genetic variability within polyembryonic litters is essentially zero with none of the littermates having an advantage over the others in terms of survival. Compared to other reproductive processes, polyembryony seems inefficient and risky, yet its evolution in the armadillo has caused investigators to question the possible benefits of this reproductive strategy. After extensive field studies found no evidence that polyembryony exerted a positive impact on behavior or ecology, the anatomy and embryology of the armadillo were examined in an attempt to explain this reproductive process.47,49 The result was two conflicting theories regarding the evolution of polyembryony. Based on anatomic studies of the reproductive tract of the female ninebanded armadillo, Loughry et al.47 concluded that polyembryony evolved as a way for females to bypass reproductive constraint imposed by an unusual uterine shape. The female armadillo has a uniquely shaped uterus with a small implantation site that can accommodate only a single blastocyst, a situation that, in ordinary circumstances, limits females to a single offspring per mating season. Although a single blastocyst implants in the uterus, it subsequently splits into four identical littermates, thus increasing the likelihood that one or more individuals will survive. In contrast, Enders et al.49 studied conceptuses of the nine-banded armadillo between the beginning of implantation to primitive streak formation and concluded that the formation of identical quadruplets was related to trophoblast differentiation. Early blastocysts show precocious exocelom formation, a single epiblastic plate, and a single amniotic cavity. During trophoblast differentiation, the exocelom expands extensively to permit enlargement of the epiblastic plate. The elongated epiblastic plate has sufficient surface for the development and separation of four embryonic shields that eventually develop into identical quadruplets.

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Although MZ twinning in most species is considered an anomaly, the formation of MZ quadruplets in the nine-banded armadillo is the norm. Despite controversy surrounding its origins, polyembryony has evolved as an efficient mechanism to increase the reproductive success in the armadillo.

Determination of Zygosity Zygosity determination is essential for the accurate study of twins. The classical twin method utilizes the differences within MZ and DZ twin pairs to estimate the relative influences of genetic and environmental factors on phenotype. Incorrect assignment of twin zygosity may lead to invalid estimates of the contribution of heritable vs. non-heritable factors to development. There are several techniques to establish twin zygosity. A statistical approach to determine zygosity utilizes ‘‘Weinberg’s differential method’’ to estimate the number of MZ and DZ twin pairs.50 Weinberg’s method assumes that there should be an equal number of like-sexed and opposite-sexed DZ twin pairs. The possibility that the number of males and females at conception was not equal was disregarded by Weinberg, as any inequality was considered too small a factor to affect the calculation. The total number of DZ pairs is obtained by doubling the number of opposite-sexed pairs. The proportion of dizygotic pairs equals 2U N where U ¼ the number of unlike-sexed twins and N ¼ the total number of maternities.51 The number of MZ pairs is equal to the difference between the number of like-sexed and unlike-sexed pairs. The proportion of MZ pairs is LU N where L ¼ the number of like-sexed twins.51 Critics of Weinberg’s method observe that because there is, in fact, an excess of like-sex over unlike-sex DZ twin pairs, this formula results in an overestimation of the frequency of MZ twinning.52,53 Once the twinning rate in a population is known, the incidence of higher multiple births can be calculated by using Hellin’s law.54 Hellin’s law states that if the frequency of twinning is n, the frequency of triplets will be n2, quadruplets will be n3, and so on. This method of estimating the incidence of higher multiple births makes no distinction between monozygotic and DZ twins. There is one consistent flaw in the statistics on multiple gestations that makes it impossible to test the accuracy of Hellin’s law: vital statistics consider viable births rather than total pregnancies, so that spontaneous abortions are not included among records of multiple gestations.55 Since spontaneous abortions are more common in multiple pregnancies than in singleton pregnancies, the incidence of twin pregnancies is greater than the incidence of twin births. The discrepancy between the number of fetuses conceived and the number of fetuses delivered is even more marked for higher multiple gestations, thus making it difficult to test Hellin’s law. The ‘‘placenta method’’ depends on the examination of fetal membranes to determine twin zygosity. Monochorionic twins are monozygotic with very rare exceptions. Dizygotic monochorionic twins could form by fusion of separately fertilized embryos at the late-morula (12–16 cell) stage just before blastocyst

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formation.55a,55b Dichorionic twins may be either monozygotic or dizygotic. While the majority of MZ twins will have monochorionic placentation, 20–25% of identical pairs will have dichorionic placentas. Unlike-sexed twins are virtually always dizygotic, and the majority of like-sexed dichorionic twins will be dizygotic. A small proportion of like-sexed dichorionic twins will be monozygotic. In practice, the zygosity of approximately 55% of twins can be determined by examination of their sex and placentation; further testing will be necessary to determine the zygosity of the remaining 45%.52 The ‘‘questionnaire method’’ assumes that reliable information regarding zygosity of twins can be obtained by posing only a few simple questions.56 In particular, monozygosity could be established with a high degree of accuracy when based solely on questions regarding the similarity of twins, such as ‘‘When growing up, were you and your twin ‘as like as two peas’ or only of ordinary family likeness?’’ The ‘‘similarity method’’ compares traits for which MZ twins are expected to be more alike than DZ twins. Siemens57 diagnosed twin zygosity by comparing several genetically determined physical characteristics, including hair color and texture, eye color and structure, and skin color. Unfortunately, these comparisons proved to be limited value due to the complex inheritance of some of the selected features and to the fact that many of the selected characteristics were not well developed at birth. Additional criticism of such a subjective method focused on examiner bias, such that diagnosis of zygosity would be influenced by features that greatly impressed the examiner.58,59 Typically, the similarity diagnosis of twin zygosity has been accomplished on the basis of blood or serum examinations, anthropometric measurements, PTC taster status, dermatoglyphic patterns, and other traits. Smith and Penrose60 presented the theoretical and practical implications of zygosity determination. They provided reference tables for several blood group systems, dermatoglyphic characteristics, and specific physical measurements to simplify the calculations involved in estimating the probability of dizygosity and monozygosity. Overall, zygosity determinations based on blood and serum markers have proven very reliable. It has been estimated that 98% of dizygotic twin pairs can be identified on the basis of the ten most common serological markers.61 Despite its accuracy, zygosity testing using anthropometric measures, serologic typing, and genetic markers is time consuming and labor intensive. Since 1980, DNA markers have been used to determine twin zygosity. DNA ‘‘fingerprinting’’ utilizes multi-locus minisatellite probes to detect genetic polymorphisms. Typically, DNA is cut using a restriction enzyme to produce fragments of variable lengths. Following electrophoresis, the patterns of restriction fragment polymorphisms (RFLPs) of a twin pair are compared to determine zygosity. Twins with identical patterns of RFLPs are classified as MZ while those with dissimilar patterns are classified as DZ. One of the pitfalls of this method is that incomplete digestion of DNA could introduce additional fragments, causing MZ pairs to be misdiagnosed as DZ. As advances have been made in molecular genetic technology, VNTR (variable number of tandem repeat) markers and PCR conditions have been incorporated into zygosity testing. Becker et al.62 used five highly polymorphic short tandem repeat loci coamplified by PCR to test 132 pairs of MZ and DZ twins. The probability that any twin pair was MZ if all markers were concordant was 99%.

Among the advantages of using DNA polymorphisms for zygosity determination are the following: (1) placental tissue rich in DNA can be stored for long periods of time; (2) the accuracy of zygosity diagnosis can be increased due to the vast number of polymorphic sites that can be tested; and (3) DNA typing can still be performed in the event of fetal death, even when the tissue is macerated.63 Incorporating PCR microsatellite markers into zygosity testing adds the further advantage that extremely small samples are sufficient for analysis.62 One of the pitfalls of using DNA polymorphisms for determining zygosity is that rarely the bone marrow of one DZ twin can be taken over by hematogenous spread from the other twin, and consequently other tissues (fibroblast, cord, placenta) should be used. Incidence of Twinning The past 30 years have witnessed a dramatic rise in the incidence of multiple births. From 1971 to 1998, the twinning rate increased from 1.8–2.8% of all births, and twins now represent about 3% of births. During the same time period, the triplet rate has increased 5.9-fold, the quadruplet rate 1.91-fold, and the quintuplet rate 5.3-fold.64 Two major factors contribute to the increase in multiple births: (1) the use of assisted reproductive technologies (ARTs) and (2) the trend toward increasing maternal age. Since the first successful birth following in vitro fertilization (IVF) in 1978,65 the use of ARTs has rapidly increased in the U.S. and elsewhere.66 Also between 1973 and 1990, the proportion of births to women over age 30 doubled. The risk of multiple birth is increased for older mothers, and older women, who experience a natural decrease in fecundity, may be more likely to seek infertility therapies than younger women.64,66 Advanced technologies that aid in achieving pregnancy include IVF, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), pronuclear stage transfer (PROST), and intracytoplasmic sperm injection (ICSI). These procedures involve the use of drugs to induce ovulation so that multiple eggs can be retrieved from the ovaries. The eggs are fertilized outside of the body and then introduced into the uterus or fallopian tube at the designated stage of development. It is common practice to introduce more than one fertilized egg or embryo in order to optimize the chances of achieving pregnancy; thus, pregnancies that result from ARTs are at a higher risk of resulting in multiple birth than spontaneous pregnancies.67 Among pregnancies resulting from ARTs, the incidence of twinning may be as high as 25% and triplets as high as 3%.68 Although the majority of multiple births resulting from ARTs develop from multiple zygotes, the incidence of MZ pregnancies is also increased. It has been speculated that the zona pellucida may become hardened or damaged due to biochemical or mechanical trauma employed during ARTs. The blastocyst may fail to hatch completely so that it is trapped partly inside and partly outside the zona. Such a trapped blastocyst may herniate through the opening in the zona and become bisected. The separation or splitting off of a portion of the inner cell mass could thus result in the development of two distinct zygotes—MZ twins. This theory suggests that all MZ twin pairs may arise at or after the blastocyst stage and that the differences in placentation may reflect whether the twin zygotes were physically separate upon implantation.69,70 Because an increased rate of MZ twinning has also been reported with zona-free blastocyst transfer, mechanisms other than herniation of

Twins

the blastocyst through the zona pellucida must be operative as well.71 Historically, MZ twinning rates have been remarkably constant throughout the world at about 4/1000 births, comprising about one-third of twin births in the U.S and Europe. Thus, any variation in twinning rates has been attributed almost exclusively to changes in the DZ rates.55,72 Derom et al.73,74 first reported an increase in MZ twinning after the use of ovulation induction therapy. MZ twins were found in about 1% of all pregnancies compared to about 0.4% in the general population. Subsequently, a number of factors associated with ARTs have been reported to increase the incidence of MZ twinning. These include prolonged time in culture,75–77 blastocyst transfer as opposed to early cleavage-stage transfer,76,78 and micromanipulation of the zona pellucida with assisted hatching.78,79 Estimates of the incidence of monochorionic pregnancies resulting from ARTs vary from 1.2– 8.9% of all pregnancies.68,77,79 The estimates are based on the identification of monochorionic placentation, thus resulting in an underestimation of the incidence of monozygosity associated with ARTs, since MZ twins with dichorionic placentas are excluded. DZ twinning results from multiple ovulations due to overstimulation by FSH and the surge of LH. Higher levels of FSH have been found in women who had delivered twins compared to women who had delivered singletons.80 Exogenous gonadotropins, clomiphene, and similar drugs used in the treatment of infertile women cause a rise in serum FSH levels and induce multiple ovulation, leading to increased risk of multiple pregnancy. As stated earlier, multiple pregnancies are fairly common following the use of ARTs, and most of the twins are DZ since two or more embryos are generally implanted. Causes of Twinning There has always been a fascination with twins, since two children are born when one is expected. They are the makings of myths, legends, and old wives’ tales. There are both recognized and hypothesized causes for twinning. In DZ twinning, the maturation and subsequent release of more than one dominant ovarian follicle occur during the same menstrual cycle. While most mammals are multi-ovulatory, humans are usually not. The cause of multiple ovulation and spontaneous DZ twinning in humans seems to be related entirely to an increased FSH level in the mother. Mothers of twins have been shown to have higher FSH levels than mothers of singletons.80 Several factors—ethnicity, age, parity, height, and weight— that are related to variations in FSH have also been shown to influence the occurrence of DZ twinning. The twinning rate among Asians is generally lower than the rate in the U.S and Europe,81 and the highest twinning rate in the world is in the Yoruba tribe in Southwestern Nigeria, where twins represent over 4% of all births. About 92% of these twins are DZ.82 Variation in the twinning rate between specific ethnic groups suggests that genetic factors play a role in the etiology of DZ twinning. Maternal age and parity affect the twinning rate, although independent of each other. The incidence of DZ twins rises with maternal age to a peak at 35 to 39 years.55 The twinning rate also increases with birth order, regardless of maternal age.83 Tall women are more likely to have DZ twins than short women, and normal to heavy women are more likely to have DZ twins than thin women. In that increased gonadotropin production is likely

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to be associated with obesity, thin women who have lower gonadotropin production may have a lower twinning rate.84 Spontaneous DZ twinning runs in families. The repeat frequency of spontaneous twinning in mothers who have previously given birth to twins is about 3%.85 Mothers of MZ twins are no more likely to give birth to a second set of twins than any women in the population, while a woman who has had DZ twins is at an increased risk for subsequent twinning. The tendency to DZ twinning has variously been described as having autosomal recessive and autosomal dominant inheritance and even having a paternally derived inheritance pattern. It is postulated that between 7–15% of the population carry a gene leading to DZ twinning. One such gene has been linked to chromosome 3. Women with a gene for DZ twinning could have a selective advantage to have a successful twin pregnancy by virtue of a suitable physical capacity to carry a multiple gestation.86 The causes of MZ twinning are much more tenuously understood than the causes of DZ twinning. Many suggestions as to the cause of MZ twinning have been developed. These include (1) damage to the inner cell mass leading to two points of regrowth. There are many examples in animal studies of temperature, oxygen supply, and various teratogenic agents artificially inducing MZ twinning, but no such effect has been seen in humans.87,88 (2) Physical splitting of the zygote mass at the time of hatching may cause the sharp edge of the zona pellucida to cut the early zygote in two. This obviously must happen early enough for a complete inner cell mass to form in each MZ twin. This has been observed in in-vitro fertilization and may occur spontaneously in MZ twinning in an ‘‘old egg’’ or one treated with gonadotrophins where the zona has hardened. (3) Abnormalities of the zona pollucida proteins could lead to early hatching. This would be anticipated to have an effect early in embryonic development prior to implantation and probably prior to the 8–16 cell stage when intracellular connections have not been established. (4) Another possible mechanism would be the origin of two discordant cell masses either through X-inactivation or through mosaicism arising from mutation, loss of imprinting, and discordance within other epigenetic phenomena. MZ twinning is generally considered to be a chance occurrence, unaffected by maternal age, parity, height, weight, or other factors that affect DZ twinning. Likewise, MZ twinning appears to be unaffected by hereditary factors, although there have been reports of families with recurrent MZ twins.6,84,89–91 Despite repeated efforts to identify conditions that might influence MZ twinning, assisted reproductive technology is the first factor proven to increase the MZ twinning rate. Sex Ratio Sex ratio is the ratio of males to females. In general, there is an excess of males at birth, and the sex ratio for DZ twins is equivalent to that excess of males seen among singletons. However, James noted some time ago that there is an excess of females among spontaneous MZ twins.92,93 This excess of females occurs in spontaneous triplets and quadruplets, as well. James and subsequently Derom94 noticed that the excess of females (producing a decreasing sex ratio) increased with what would be thought to be late MZ twinning events. As discussed earlier, spontaneous MZ twinning may occur at many different times in early preimplantation embryogenesis, and the timing is thought to be reflected

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Other Systems and Structures Table 34-1. Sex ratio in twins M/M þ F

Type of Twin

DZ and singletons

0.514

All MZ

0.484

All monoamniotic twins

0.231

Conjoined twins

0.230

Sacral teratomas After James

92,93

0.250 and Derom, et al.

94

in the placental membranes. Thus, when the MZ twinning event occurs very early, there would be expected to be two separate placentas. A little later (3–7 days of embryogenesis), as the chorion has begun to form, a monochorionic diamniotic placenta would be expected. At an even later period (8–14 days of human embryonic development), a single chorion and a single amnion would be expected (i.e., a monochorionic, monoamniotic placenta). Conjoined twinning and even later forms of ‘‘twinning’’ such as teratomas are thought to originate later on in embryonic development (Table 34-1). There does not seem to be an excess of males among spontaneously aborted twins. The excess of females among MZ twins suggests that females may be more predisposed to MZ twinning than males. Several explanations have been suggested for the excess of females among MZ twins. The first relates to the observation that the female rate of early embryonic development is slower than that for males. It would follow that something about being slow during the course of early embryonic development may predispose to a MZ twinning event. Data from several studies in mice suggest that females are as much as a day behind in embryologic developmental time in early embryonic development.95 The reasons for this are unclear, but it has been suggested that females may grow like other aneuploids, i.e., much slower than normal until they inactivate their second X chromosome.96 X-inactivation occurs as tissues differentiate; therefore, the process of early embryogenesis in females may slow down to allow for X-inactivation as tissue differentiation occurs, putting females behind males in their early development. This may also be reflected in the fact that on average, males weigh slightly more at birth than females. Growth Both MZ and DZ twins have compromised growth. This first becomes obvious in the early part of the third trimester but may well have been programmed during the second trimester. Compared to singletons, the growth of twins falls off for their gestational age (Fig. 34-5); however, their combined weight greatly exceeds the normal weight for a singleton, and maternal weight gain in a twin pregnancy is normally greater than that for a singleton.97 In addition, if one twin has a specific genetic disorder, syndrome, disease, or intrauterine compromise, that twin may well be smaller than the unaffected twin at birth. Twin-to-twin transfusion is such an example, with the pump twin usually being significantly smaller than the recipient twin. A twin with a neural tube defect, a chromosome abnormality such as trisomy 21, or achondroplasia is likely to be smaller than its normal co-twin. Many twin pregnancies are delivered early, contributing to the perception that twins are small at birth. Discordance in birth weight is often seen in both MZ and DZ twins. However, approximately 10% of MZ twins have greater

Fig. 34-5. Growth curve showing mean weights of infants from single and multiple pregnancies by gestational age.97

than 10% discordance in weight at birth. This is a larger disparity than would be expected. In at least one-third of these twin pregnancies with discordance of birth weight, more than a 10% disparity in size also persists into adulthood. The decrease in growth seen among twins may represent an adaptive pattern of growth. For instance, it has been observed that the smaller of both DZ and MZ twins does not appear to be more predisposed to cardiovascular disease, diabetes, and hypertension than their co-twin, in spite of the observation that singletons with intrauterine growth retardation (IUGR) are more predisposed to these disorders than singletons with normal birth weight. There is some evidence to suggest that the process of down-regulating growth occurs in the second trimester since if one twin dies, the remaining twin will also be smaller than expected. Maternal physiologic changes may play some role in this down-regulation. Mothers of twins have lower hematocrit levels, greater cardiac output, lower glucose levels, greater weight gain, and develop gestational diabetes more frequently than the mothers of singletons. Alternatively, Machin98 has suggested that the average decreased birth weight observed in twins may actually reflect the increased number of IUGR twin infants, and the remaining twins may be of normal birth weight for gestational age. OFC and length have not been studied well enough to know how much discordance in size occurs in MZ twins. The reasons that twins and particularly MZ twins are on average small for gestational age are not clear. MZ twins live off the cytoplasm of one egg until implantation. Normally, it is thought that implantation occurs at about day 8 of embryologic development (22 days after the last menstrual period). It is possible that in MZ twinning, the clock of embryologic development is somewhat delayed. Critical nutritional requirements for growth and gene regulation in these earlier stages may slow down the rate of development when half the normal cytoplasm is available. Machin98 has also suggested that in some MZ twin pairs, the two cell masses that go on to form the MZ twins may differ in size, so that one twin may start with more cells than the other. MZ twin individuals theoretically have at least one less cell division at birth as compared to singletons, which could be represented by

Twins

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the smaller size at birth. Machin98 also points out that a difference in blood flow in monochorionic placentas usually exists. Thus, even when twin-to-twin transfusion does not occur, there may be different nutritional flows to each of the MZ twins. Spontaneous Abortions It is estimated that 10–15% of clinically recognized pregnancies end in spontaneous abortion. The fetal loss rate is greater among twin and higher-order pregnancies than among singletons. Twins occur among spontaneous abortions at a frequency 2 to 3 times higher than the frequency of twins among live births. Higher multiple births are at greater risk of loss, with about 20% of triplet pregnancies ending in spontaneous abortion before 24 weeks gestation.99 MZ twins are associated with a higher fetal loss rate than are DZ twins. The ratio of MZ to DZ twins among abortuses of known zygosity is 17.5 to 1 compared to a ratio of 0.3 to 1 among liveborns.100,101 Studies that examine the chorion type of twins have determined that it is chorionicity rather than zygosity that accounts for the excess of twins over singletons among spontaneous pregnancy losses.102 Using ultrasound at 10 to 14 weeks gestation, Sebire et al.103 identified 365 dichorionic and 102 monochorionic twin pregnancies in which both fetuses were alive at presentation. Before 24 weeks of gestation, the fetal loss rate in monochorionic twins was 12.2% compared to a rate of 1.8% among dichorionic twins. After 24 weeks gestation, the loss rate was 2.8% in monochorionic placentas and 1.6% in dichorionic pregnancies. The proportion of losses involving both fetuses was three times higher in monochorionic pregnancies than in dichorionic pregnancies. The increased risk of fetal loss associated with monochorionic placentation is likely to result from vascular anastomoses within the placenta, potentially leading to severe twin–twin transfusion.103,104 The rates of anomalies among spontaneously aborted twin embryos and fetuses were comparable to overall anomaly rates determined for all abortuses.101 The overall rate of anomalies for embryos was 84% compared to 88% for twin embryos and 26% for fetuses compared to 21% for twin fetuses. The increased incidence of twins among spontaneous abortions suggests that twinning occurs with greater frequency than expected based on the observed frequency of twin births. In addition, embryonic and fetal mortality is higher among twins than among singletons.101 Vanishing Twin The use of first trimester ultrasonography confirms that the number of twins observed at delivery is significantly less than the number of twin conceptions. The term ‘‘vanishing twin’’ refers to the death and resorption early in gestation of one fetus from a multiple pregnancy. Fetal loss can be documented by serial ultrasound showing the ‘‘disappearance’’ of at least one gestational sac (Fig. 34-6). Mechanisms for the vanishing twin include resorption, formation of a blighted ova or anembryonic pregnancy, and formation of a fetus papyraceus.105 Finberg and Birnholz106 described three different ultrasonic patterns of the vanishing twin prior to complete disappearance: (1) a second sac, usually smaller than the normal sac, with irregular margins and often having an incomplete decidual response; (2) a crescent-shaped gestational sac outlining a portion of the normal amniotic cavity; and (3) septation of the amniotic cavity, with the smaller compartment empty.

Fig. 34-6. Top: Ultrasound at 10 weeks of gestation showing gestational sac containing a fetus (F) and a second sac with no fetus (O). Bottom: Diagram of the ultrasound showing the two gestational sacs.

The resorption of a deceased co-twin generally occurs during the latter half of the first trimester, and early second trimester of pregnancy. The most common complication of a vanishing twin is slight vaginal bleeding, and the prognosis for carrying a coexisting twin to term is generally good.107,108 Another possible complication of the vanishing twin is the occurrence of cerebral palsy (CP) in the surviving co-twin. Pharoah and Cooke109 proposed that spastic CP of prepartum origin may be due to the death of a monochorionic co-twin during the first half of gestation. It is well known that the death of a co-twin late in gestation is associated with an increased risk of neurologic damage in the survivor. According to this hypothesis, early death resulting in vanishing twin may also lead to CP in the co-twin. Apparent singletons with CP of prepartum origin may be survivors of twin pregnancies in which the co-twin died between 8–14 weeks of gestation. Because the dead twin was resorbed, the birth is classified as a singleton yet the survivor is at increased risk of CP. The misinterpretation of the surviving twin as a singleton falsely deflates estimates of the twinning frequency and contributes to the underestimation of spontaneous abortion rates.110 Estimates of twin disappearance rates vary depending on the patient population, the time of the ultrasound examination, and the number of scans performed. Generally, higher rates of vanishing twin are found for women whose scans were performed before week 10 of gestation compared to those performed after weeks 10–14. Levi111 reported that only 29% of women with twin pregnancies diagnosed before 10 weeks gestation ultimately gave birth to twins. Table 34-2 lists previous studies in which multiple gestation was diagnosed early in pregnancy and gives the outcomes and estimated ‘‘disappearance’’ rates derived from these studies. In

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Other Systems and Structures Table 34-2. Estimates of the ‘‘disappearance’’ rate in multiple gestations Reference

Number of Multiple Gestations Detected

113

28

114

3

Disappearance Rate

Outcome

5 twins; 13 singletons; 14 SAB 3 singletons

77% 100%

111

28 (<10 wk) 11 (10–15 wk) 79 (>15 wk)

4 twins; 10 singletons; 14 unknown 3 twins; 5 singletons; 3 unknown 77 twins; 1 triplets; 1 fetus papyraceous

71% 62% 0%

107

30

14 twins; 10 singletons; 6 SAB/blighted

53%

112

47 (4–9 wk) 23 (10–14 wk) 89 (>14 wk)

6 multiple births; 26 singletons; 15 unknown 14 multiple births; 8 singletons; 1 unknown 89 multiple births

81% 36% 0%

115

41

28 singletons; 13 SAB

108

30

13 twins; 1 triplet; 5 singletons; 11 SAB

53%

116

21 twin 1 triplet 1 quadruplet

3 twins; 18 singletons 1 twin 1 singleton

87%

130 twins; 73 singletons; 24 AB 13 triplets; 22 twins; 5 singletons; 3 AB

43% 70%

116

227 twin (<8 wk) 43 triplet (<8 wk)

a study of 6990 women, 118 were found to have multiple gestational sacs.111 Among 28 women having ultrasound scan before 10 weeks of gestation, follow-up data were available for 14. Among these 14, only 4 sets of twins (28.6%) were delivered. Of 11 women found to have multiple pregnancies between weeks 10–15, 8 were followed through delivery. Of the eight, only three sets of twins (37.5%) were delivered. In 79 women, multiple pregnancy was diagnosed after week 15. These 79 pregnancies resulted in 77 sets of twins, 1 set of triplets, and 1 normal infant accompanied by a fetus papyraceous. On the basis of these studies, a ‘‘disappearance’’ rate of 71% was determined for twin gestation diagnosed prior to week 10. In a subsequent study, Levi and Reimers112 found an 81% disappearance rate for multiple pregnancy diagnosed prior to week 10. Landy et al.118 reviewed sonographic findings of 1000 viable gestations in the first trimester and found a minimum incidence of twinning of 3.29%. Among 54 suspected multiple pregnancies, 26 resulted in multiple births and 28 showed evidence of a vanishing fetus. The latter pregnancies were divided into three groups according to whether the diagnosis of multiple pregnancy was documented, suspected, or doubtful. The ‘‘documented’’ diagnoses consisted of seven pregnancies in which fetal heart motion was documented in two gestational sacs but subsequent scan revealed one viable fetus. The ‘‘suspected’’ diagnoses group was composed of 17 patients whose initial ultrasound scan showed one or more viable gestations with an additional empty or abnormal sac. The ‘‘doubtful’’ diagnoses consisted of four pregnancies with a viable fetus within a bi-lobed gestational sac such that the possibility of a twin gestation could not be excluded. The overall disappearance rate for one fetus was 21.2% when only the documented diagnoses group was considered. The rate of disappearance increased to 48% and 51.8%, respectively, if the suspected and doubtful groups were included. The incidence of multiple gestation was 3.29% when only those with documented diagnoses were included, but increased to 4.99% and 5.39%, respectively, if suspected and doubtful diagnoses were considered. The disappearance rate for those pregnancies with a documented diagnosis of multiple gestation (21.2%) is comparable to the reported spontaneous fetal loss rate for singleton pregnan-

100%

cies.118 The pregnancies with suspected diagnoses may represent cases of vanishing fetus after disappearance has already begun. As for the group with doubtful diagnoses, these may in fact represent twin pregnancies; alternatively, they may represent false interpretation of physiologic conditions or artifactual error. Physiologic cavities that are present early in pregnancy and may be misinterpreted on an early ultrasound include the amniotic cavity, chorionic sac, extraembryonic coelom, and yolk sac. The intrauterine collection of blood at the trophoblast, hydropic changes in chorionic villi, or changes in a bicornuate uterus may also be misinterpreted as representing multiple gestation.105,119,120 Furthermore, artifactual errors such as distortion due to excessive pressure from the transducer on the patient’s abdomen, compression from a full bladder, myoma, transient uterine contraction, or normal variation in the shape of the sac may lead to misdiagnosis of the number of gestational sacs present. Sulak and Dodson121 presented the first histologic evidence of a vanished twin at term following in vitro fertilization. Ultrasonographic examination 4 weeks after transfer of five fertilized eggs revealed three gestational sacs. Upon genetic amniocentesis at 18.5 weeks, a singleton pregnancy was observed and ultimately a single infant was delivered at term. Careful examination of the placenta revealed histologic evidence of a vanished twin. A chorion-lined sac containing amorphous material and surrounded by degenerated chorionic villi was compressed against the surviving twin’s amniochorionic membrane. No histologic evidence of the third gestational sac was found. Subsequently, Jaunaiux et al.122 reported pathologic findings from ten multiple gestations complicated by the disappearance of one twin. Five of the pregnancies resulted from in-vitro fertilization and embryo transfer, and five conceptions were spontaneous. Repeat ultrasound examinations were performed between 5–12 weeks gestation, and first-trimester bleeding was the only clinical sign of the vanishing twin. At birth, the placentas were examined macroscopically then processed for routine histologic examination. In five cases, placental evidence of the vanishing twin consisted of well-delineated plaques of perivillous fibrin deposition, associated in one case with embryonic remnants. Macroscopically visible perivillous fibrin deposition occurs in about 25% of

Twins

placentas from uncomplicated term pregnancies and may be the only clue as to the disappearance of one conceptus. There have been numerous reports of discrepancies between results of prenatal chromosome analyses (amniocentesis and chorionic villus sampling, CVS) and newborn karyotypes or phenotypes. Many of these reports describe prenatal diagnosis of apparent mosaicism for numerical or structural abnormalities, followed by the delivery of a chromosomally normal infant. When the sex chromosome constitution is concordant between prenatal and postnatal studies, confined placental mosaicism has been invoked as an explanation. However, when the sex chromosome constitutions are discordant, resorption of a dead co-twin has been proposed to explain the discrepancies. Table 34-3 lists nine cases in which a vanishing twin may be responsible for discrepancies between prenatal and postnatal studies. Possible XX/XY chimerism was detected prenatally in five cases.123–127 Three of the cases with sex chromosome discordance also had a numerical or structural chromosome defect: case 2 had an apparently balanced 13;14 translocation in the female cell line,124 case 3 had a supernumerary marker chromosome in the male cell line,125 and case 5 had trisomies 8 and 10 in the male cell line.127 In case 6, nonmosaic trisomy 16 was found in direct cytotrophoblast preparations and cultured mesenchymal cells while amniotic fluid and cord blood revealed 46,XX.128 In situ cultures from three sites of fetal membranes and from a placental nodule revealed 46,XX/47,XX,þ16 mosaicism. The trisomy 16 cells most likely originated from a degenerated co-twin represented as the placental nodule. Villi from the deceased co-twin retained intervillous circulation and were cultured in CVS preparations. In case 7, normal female cells were found in direct CVS cultures, while mosaicism for trisomy 9 was found in cultured villi.129,130 Cultured amniocytes, neonatal blood, and umbilical vessel also revealed a 46,XX karyotype, and a normal female was delivered. Direct and cultured CVS in case 8

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found triploidy, 69,XXY.131 The majority of placental cells also showed triploidy, whereas the cord blood revealed a normal female karyotype. In this case, the triploid placenta of a vanishing twin persisted and provided the majority of the functional term placenta. Each of the cases 1 through 8 resulted in the delivery of a phenotypically normal infant, although case 5 died of hypertrophic cardiomyopathy during the neonatal period. Finally, case 9 had a normal female chromosome constitution in direct and cultured CVS.132 Intrauterine fetal demise occurred subsequently and resulted in the delivery of a macerated fetus at 20 weeks gestation. Because autopsy revealed a male phenotype, DNA studies using a Y specific probe (DYZ1) were performed on fetal skin and confirmed the presence of a Y chromosome. The undetected presence of a female vanishing twin would explain the discrepancy between the prenatal chromosome analysis and the DNA results. Although the causes of embryonic disappearance in multiple gestation may be similar to the causes of fetal loss in singleton pregnancies, intrauterine factors related to placentation and cord placement may place multiple pregnancies at greater risk than singletons.122,133 Cord complications and marginal or velamentous cord insertion are more common in multiple pregnancy. Marginal insertion of the cord is observed in 5.6% of singleton pregnancies compared with 10.6% of dichorionic and 22.1% of monochorionic twin gestations.122,134 Other conditions that contribute to high fetal mortality, such as the twin–twin transfusion syndrome (TTTS), are unique to twin gestations. Blickstein135 presented the following evidence that early-onset TTTS may lead to vanishing twin: (1) An extremely high prevalence of velamentous insertion of the umbilical cord is found in the placentas of TTTS as well as in the placentas of vanishing twins. The occurrence of the same rare placental anomaly in these two conditions may suggest a common etiology. (2) TTTS may develop during the first trimester, coinciding with the timing of the vanishing twin. Echocardiogram has

Table 34-3. Discrepancy in CVS results possibly attributable to a resorbed co-twin Case

Chromosome Constitution

Tissue

Phenotype

1

46,XX/46,XY 46,XX

Amniocytes Neonatal blood

NF

2124

45,XX,der(13;14)(q10;q10) 45,XX,der(13;14)/46,XY

Direct CVS; amniocytes Cultured CVS

NF

3125

46,XX/47,XY,þmar 46,XX

Direct CVS Amniocytes

NF

4126

46,XX/46,XY 46,XX/46,XY

Amniocytes Neonatal blood

NM

5127

46,XX/48,XY,þ8,þ10 46,XX

Amniocytes Fetal blood

NF*

6128

47,XX,þ16

Direct/cultured CVS, fetal membranes, placental nodule Amniocytes, neonatal blood, placenta, cord

NF

NF

123

46,XX 7129,130

46,XX 46,XX/47,XX,þ9

Direct CVS, amniocytes, neonatal blood, umbilical vessel Cultured CVS, amnion, placental nodule

8131

69,XXY 46,XX/69,XXY 46,XX

Direct/cultured CVS, chorion Placenta Cord blood, amnion

NF

9132

46,XX Y chromosome probe

Direct/cultured CVS Fetal skin (DYZ1þ)

IUFD-M

*Newborn died of hypertrophic cardiomyopathy. IUFD-M ¼ intrauterine fetal demise, male fetus; NF ¼ normal female; NM ¼ normal male.

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Other Systems and Structures

demonstrated fetal cardiac decompensation of the recipient twin as early as 12–13 weeks gestation, indicating that TTTS may not always occur in mid-gestation as commonly believed. (3) There is a paucity of information about the placentation in vanishing twin. Therefore, the possibility exists that some cases of vanishing twin occur in monochorionic placentas, consistent with the placentation of TTTS. (4) Current information about TTTS, including the type of placentation, is obtained from cases identified during midtrimester. Vascular anastomosis may occur in dichorionic placentas, leading to the vanishing twin syndrome. At term, the birth is identified as a singleton, and the placenta is not examined carefully for vascular anomalies or for remnants of a resorbed cotwin. Fetus Papyraceus A fetus papyraceus, or fetus compressus, is a mummified, dead fetus usually occurring in association with a viable twin (Fig. 34-7).136,137 The surviving infant is generally healthy and unaffected by the coexistence of a fetus papyraceus, although the Fig. 34-7. Fetus papyraceus in one of like-sex monozygous twins. The larger twin survived to 23 weeks gestation and imposed a mild degree of compression on the smaller twin, who died at 11 weeks gestation based on morphometry. When one twin survives to term gestation, the remains of the smaller twin are often flattened and the tissues mummified, hence the term papyraceus. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

eventual death of the co-twin has been observed.138 Skelly et al.139 reported a triplet pregnancy with fetus papyraceus, death of a second fetus prior to 35 weeks, and delivery of a normal infant. While the death of one twin has been associated with malformations in the co-twin, in the majority of cases the surviving twin develops normally in the presence of a fetus papyraceus. There have been only a few reports of congenital anomalies in the surviving infant. These include congenital aplasia of the skin, intestinal atresia, gastroschisis, amputation of the limbs, bilateral cleft lip, tracheal stricture, and hypoplastic right heart with pulmonic valve stenosis.136,137,140–144 The birth of a viable twin accompanied by a compressed twin is not a recent observation, as it was mentioned in the writings of Pliny in 23 A.D. and is referred to in handbooks of midwifery as early as 1594.145,146 Fetus papyraceus occurs in about 1 in 200 twin gestations or 1 in 12,000 live births and has also been reported in triplet pregnancies and higher multiple gestations.139,140,147 Death usually occurs in the second trimester, although cases have been reported with survival into the third trimester.145,146 A twin fetus dying very early in gestation may be completely absorbed (‘‘vanishing twin’’); late fetal death usually results in a macerated but not compressed fetus.147 The distinction between a ‘‘vanished twin’’ and a fetus papyraceus relies on the method of diagnosis and the gestational age at time of death. The diagnosis of a vanished twin is a sonographic diagnosis based on the presence of two or more gestational sacs, often representing blighted (anembryonic) gestations, which disappear during the first trimester. In fetus papyraceus, death occurs during the middle part of pregnancy, and a fetus is recognized at delivery, although after death it undergoes flattening, necrosis, atrophy, and sometimes mummification.147 The cause of single fetal death leading to fetus papyraceus is usually unknown. No correlation of fetus papyraceus with maternal age, parity, or gravidity has been found. Both monochorionic and dichorionic placentations are seen in pregnancies associated with fetus papyraceus. Kindred145 reported that 93 of 141 (66%) cases, in which sufficient information was available concerning the placenta, were dichorionic. Possible etiologies include TTTS, cord problems, hemolytic disease, decidual vascular disease, and various fetal anomalies.147 Daw144 reviewed 11 cases of fetus papyraceus and suggested that cord complications increase the chances of intrauterine death and formation of fetus papyraceus. In his series, velamentous insertion of the cord was observed in two of the compressed fetuses and in one surviving MZ twin; one fetus papyraceus had the cord tightly around its neck. The mechanism of papyraceus formation involves compression of the blighted fetus between the amniotic sac or the structures of the surviving fetus and the uterine wall.140 As the surviving twin continues to grow, the dead co-twin shrinks and flattens, becoming incorporated by pressure into the surface of the placenta. The size and shape of the fetus papyraceus depends upon the time of death. The compressed fetal structures resemble yellow, necrotic decidua and may be found in a separate, atrophied sac.147 Nance41 described two unusual cases of fetus papyraceus and suggested that vascular abnormalities play an important role in the etiology of this condition. In the first case, fetal hydrops was diagnosed in one twin upon evaluation at 28 weeks gestation due to sudden onset of polyhydramnios. The large hydropic twin with marked polyhydramnios was compressing the co-twin, who subsequently died. The pregnancy ended with the cesarean delivery of a large, stillborn fetus with resolving hydrops and a smaller fetus showing evidence of intrauterine compression. The initial event in this case may have been development of TTTS, giving rise to

Twins

hydrops and progressive polyhydramnios in one twin, leading to compression and eventual death of the co-twin. In the second case, discordance in head size was documented at 24 weeks of gestation. The smaller twin died at 27 weeks followed by marked decrease in uterine size as the amniotic fluid was resorbed. The phenotypically normal surviving twin was delivered at 37 weeks accompanied by a stillborn fetus papyraceus. The region of the placenta supplying the compressed twin was thin, avascular, and fibrotic. Based on these two instances, Nance41 suggested that true fetal compression may arise from transient hydrops in the surviving co-twin related to polyhydramnios due to vascular and other abnormalities. Formation of a fetus papyraceus does not usually cause major complications during gestation or delivery, although premature labor, obstruction of labor necessitating cesarean section, infection, and postpartum hemorrhage have been reported.138,144,146,148–150 The diagnosis of fetus papyraceus is often made only at delivery, following the birth of the viable twin. The following clinical signs are suggestive of a fetus papyraceus: (1) rapid uterine enlargement between 12 and 24 weeks of gestation followed by slow to normal growth; (2) sudden appearance or subsidence of toxemia of pregnancy; (3) unexplained vaginal bleeding; and (4) amniotic fluid leakage which suddenly ceases.140,144 Twin pregnancies with a fetus papyraceus have been associated with elevated serum and amniotic a-fetoprotein (AFP) levels. Lange et al.150 described three twin pregnancies, each with one fetus papyraceus and abnormal AFP levels. In two cases the co-twin was liveborn, whereas in the third case the co-twin died in utero at 31 weeks gestation. Stirrat et al.151 described a twin pregnancy with a fetus papyraceus and repeated raised amniotic fluid AFP levels. The pregnancy was not identified as a twin gestation, and was terminated at 17 weeks. One fetus was apparently normal, and the other was a fetus papyraceus. Perinatal Morbidity and Mortality Twin pregnancies have a higher frequency of perinatal morbidity and mortality than singleton pregnancies. The perinatal mortality rate in twins is 4 to 10 times that of singletons, ranging from 9– 20% compared to less than 2% for single births.152 While twins comprise only 2.6% of all fetuses, they account for 9.6% of stillbirths, 15.4% of neonatal deaths, and 12.2% of perinatal deaths.152 Premature delivery is the most significant factor leading to the adverse outcome of twin pregnancies, with low birth weight, discordant growth, zygosity, type of placentation, and birth order also contributing to the poor outcome.153 Premature delivery is 3 to 4 times higher in multiple births than in singleton deliveries, with approximately 12% of all premature infants resulting from twin pregnancies.154 Spontaneous labor is the most frequent cause of premature delivery in twins. Twin pregnancy is associated with three times the normal incidence of preeclampsia, polyhydramnios, and placental abruption, all of which predispose to spontaneous labor.109,152 Low birth weight is also an important factor in the poor perinatal outcome of twin pregnancies. The mean birth weight of twins is significantly less than that of single infants, with the average twin weighing 2400 grams compared to a weight of 3400 grams for singletons.97,155,156 At mid-gestation, the body weight of twins is close to the mean body weight for singletons.157 Early in the third trimester of pregnancy, the weight of twins begins to deviate from normal by singleton standards, so that by 42 weeks gestation, the

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median weight of twins is just above the tenth percentile for singletons. For higher multiple births, the weight discrepancy is greater: the more fetuses present in a multiple pregnancy, the lower the birth weight of each fetus (Fig. 34-5).97,158 Comparison of perinatal mortality rates of twins with that of single infants as a function of birth weight reveals that the mortality risk among multiple births is actually lower than among single infants at weights below 2500 g.159 At higher birth weights, the relationship is reversed and singletons are at a definite advantage in terms of neonatal survival.159,160 The higher mortality in singletons with low birth weight is commonly attributed to the fact that single births below 2500 g are often associated with complications such as congenital malformations, toxemia, and placental previa, which may predispose to early death.161 Twins of comparable weights are common and are not particularly associated with pathologic conditions of the fetus or the mother. Furthermore, low birth weight twins have a greater gestational age than singletons of the same birth weight. To explore the paradoxical relationship between better survival at lower birth weight in twins versus singleton, Buerkens et al.162 compared birth weight distributions and weight-specific mortality of singletons and twins after converting the birth weights to a standardized z score. Weight-specific mortality rates were then plotted on the z scale and compared. Results indicated that the mortality rates of singletons were lower than that of twins at every weight, and that the mortality rates of the second-born twin was greater than that of the firstborn at all but the lowest measure. Comparison of twins and singletons at similar relative weights showed that twins had a higher mortality than singletons at each weight. Victoria et al163 have shown that twins with severely discordant birth weights (>25% difference between co-twins) are a greater risk of perinatal mortality and morbidity than are concordant (<5% difference) or mildly discordant (5–25% difference) twins. Severe discordance was found more frequently in monochorionic than dichorionic twins, and discordant monochorionic twins were more likely to be born before 36 weeks gestation than were discordant dichorionic twins. Among severely discordant pairs with dichorionic separate placentas, the placental weight of the smaller fetus was significantly less than the placental weight of their concordant or mildly discordant counterparts. Likewise, the total placental weight of severely discordant monochorionic twins was significantly less than the placental weight of concordant or mildly discordant monochorionic twins. Furthermore, the smaller member of a severely discordant pair was more likely to have cord anomalies such as velamentous insertion and single umbilical artery. Overall, severely discordant pairs had a greater risk of pre-term birth, perinatal asphyxia, malpresentation, and prolonged hospitalization. MZ twins have an increased risk of premature birth and perinatal mortality compared with DZ twins. MZ twins with monochorionic placentation are at risk for problems associated with placental vascular anastomoses, such as TTTS. The perinatal mortality among dichorionic MZ twins is similar to that of DZ twins, suggesting that the increased mortality is associated with chorionicity rather than zygosity. In the 1–2% of MZ twins with monoamniotic placentation, a perinatal mortality rate of 40–50% has been reported due to such complications as cord entanglement and fetal interlocking.164,165 Newton166 classified the causes of perinatal mortality in twins into four main groups: (1) mortality related to abnormal genetics or development, including congenital defects, complications associated with monochorionic

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placentation, and multifetal gestations; (2) complications of prematurity such as respiratory distress, intraventricular hemorrhage, or necrotizing enterocolitis; (3) uteroplacental insufficiency associated with small for gestational age infants, fetal distress, or abruptio placenta; and (4) trauma at delivery. Birth order contributes to the poor outcome of twin pregnancies in that there is a two-fold increase in neonatal death among second-born twins compared with the firstborn. Secondborn twins tend to have a lower birth weight than firstborn and are at an increased risk of asphyxia associated with malpresentation, reduced placental circulation, or placental separation.162 Likewise, higher mortality has been shown for triplets born second and third than for the firstborn. This higher mortality of second and third triplets may be due to less favorable position in the uterus during labor, making them more susceptible to direct trauma from the contracting uterus during delivery.155,159 Botting159 observed that reduced uterine capacity following delivery of the first triplet may alter the blood flow in the placenta, leading to anoxia in the remaining infants; this effect could be aggravated by prolonged anesthesia. Cesarean section is an option when difficulties are encountered during delivery of second twins, or second or third triplets, even after successful vaginal delivery of the firstborn.167 Attempts to reduce the incidence of preterm labor in twin gestations have included the prophylactic use of tocolytic agents, cervical cerclage, and bed rest. Tocolytic agents are drugs administered to inhibit uterine contractions thereby prolonging pregnancy. The efficacy of prophylactic tocolysis has been questioned in that evidence suggests that it does not prevent preterm labor and delivery.166 Besides the failure to produce the desired effect of prolonging gestation, the use of tocolytics may be accompanied by additional adverse effects. Maternal cardiovascular and respiratory complications as well as increased fetal and neonatal problems have been associated with the certain tocolytic agents.168 With little data to suggest that tocolytics actually improve outcome and mounting evidence of morbidity to mother and fetus, caution should be exercised when administering these potent agents. Prophylactic cervical cerclage has been used to provide mechanical support for the cervix stressed by multiple gestation.166 However, cerclage is associated with a 1–4% risk of chorioamnionitis, premature rupture of membranes, and bleeding—all factors that may increase the risk of premature delivery. Because prophylactic cerclage has not been shown to improve pregnancy outcome in multiple gestation, its use should be limited to patients with a history of cervical incompetence.166,169 As early as 1939, Hirst170 recommended hospitalization of the mother at 36 weeks with bed rest and a good diet to reduce the risk of prematurity and possible perinatal death in twin pregnancies. The rationale for recommending bed rest is to improve uterine blood flow and to relieve mechanical pressure on the cervix, resulting in increased fetal growth. However, prospective studies of routine hospitalization for bed rest in multiple gestations found no difference in gestational or fetal outcomes in women treated with bed rest compared to untreated women. Bed rest was actually associated with an increase in preterm labor and delivery.169,171–175 The only obvious advantage of bed rest was the reduction of maternal hypertension.169 As the number of fetuses in a multiple pregnancy increases to three or more, there is a concomitant increase in maternal complications, perinatal mortality, and morbidity. As in twin pregnancies, the primary problem encountered in multifetal gestations is prematurity with the associated increased risk of perinatal mortality and morbidity.176 Early diagnosis of multifetal gesta-

tion is important for the implementation of management strategies aimed at prolonging the pregnancy. Meticulous antenatal care, early hospitalization, frequent and comprehensive evaluation of fetal well-being, cesarean delivery, on-site availability of a trained neonatologist for each neonate, and a highly functional neonatal intensive care unit (NICU) have been associated with improved perinatal outcome in multifetal gestations.177,178 Although the survival of all or some of the fetuses in quadruplet and quintuplet pregnancies is possible, there is significant risk of long-term morbidity; with six or more fetuses, the chance of survival of any of the infants decreases. To enhance the survival of infants from higher-order multiple gestations, multifetal termination has been performed to reduce the number of fetuses present. Since 1978, selective termination has been successfully performed in twin pregnancies discordant for genetic disease.179 Reduction in quadruplet and higher-order pregnancies leads to increased birth weight and longer gestational age at delivery.180 The benefit of reducing triplets is less clear and remains controversial. The outcome of triplet pregnancies managed expectantly with specialized prenatal and neonatal care programs has improved considerably in recent years. In contrast, twin pregnancies resulting from reduced triplets are often complicated by premature rupture of membranes, fetal growth restriction, and premature delivery.181,182 Nonetheless, the perinatal mortality of triplets is about 20.5%, whereas the fetal loss rate for twins reduced from triplets is 8–10%. As such, the risks associated with multifetal reduction must be weighed against the risk to the fetuses and to the mother if the procedure is not performed.183,184 The widespread use of ARTs and the increasing number of multifetal gestations has been accompanied by an increase in low birth weight and prematurity. Efficient protocols are needed to reduce the complications that multifetal gestations cause for mother and fetus. One strategy is to reduce the number of higherorder multiple pregnancies by more judicious use of ARTs. It has been speculated that this may be the most efficient way to avoid the complications that accompany higher multifetal gestation.185 Vascular Anastomoses in Twin Placentas The timing of the twinning event and the form of placentation may have far-reaching implications, both structurally and functionally, for the twin infants. A major distinction between monochorionic and dichorionic placentas that may profoundly affect the intrauterine environment of twins is that almost all monochorionic placentas demonstrate vascular anastomoses between the two fetal circulations, whereas dichorionic placentas do not.16,186 Although exceptions to this situation exist, they are rare; it can generally be assumed that the majority of MZ pairs who have monochorionic placentation will show some degree of vascular connection, whereas DZ twins and a minority of MZ twins with dichorionic placentas will have completely independent circulations. Differing environmental influences may affect individual members of twin pairs with dichorionic placentation, but such influences are likely to be related to sites of implantation or to discordant response to intrauterine insult.16 In contrast, differences between twin pairs with monochorionic placentas may result from a unique cause: inequalities of the common placental circulation.187,188 Although virtually all monochorionic placentas have some form of vascular anastomoses, these connections vary considerably in type, number, size, and function.189 Two major types of anastomoses are found in monochorionic placentas: those which are

Twins

superficial and easily identified on the fetal surface of the placenta, and those which lie deep within the substance of the placenta.16 In 1900, the German obstetrician Friederich Schatz190 observed that vessels linking artery to artery or vein to vein remained on the chorionic surface, while those linking artery to vein disappeared into a villus within the placental mass. The areas of villous transfusion served as a ‘‘third circulation’’ common to both twins; the other two circulations were the circulatory systems of each twin. Direct artery-to-artery communication is the most commonly observed form of anastomosis within monochorionic placentas.58,190–192 Second in frequency are artery-to-vein anastomoses. Typically, artery-to-vein connections occur as an umbilical artery from one twin supplies a placental cotyledon which, in turn, is drained by a vein from the other twin.146 Within the shared cotyledon, the blood flow is unidirectional, thus bringing blood from the left side of the heart of the first twin to the right side of the heart of the second twin. Several shared cotyledons may be present within a monochorionic placenta, and the direction of the blood flow may or may not differ from one cotyledon to another. Direct anastomoses of very fine arteries to veins, without interposition of villous tissue, are rarely found within monochorionic placentas.146 Vein-to-vein anastomoses occur less frequently than artery-to-artery or artery-to-vein communications and are generally found in the presence of one or both of the other forms of anastomoses.58,191 Anastomoses between blood vessels within fused dichorionic placentas of DZ twins have been reported to result in blood chimerism and, rarely, to TTTS.193 In Greek mythology, a chimera was a fire-spouting creature with a lion’s head, a goat’s body, and a serpent’s tail. In medical usage, a chimera is an individual who possesses tissues derived from two non-identical zygotes. There are two types of human genetic chimeras: DZ twin blood group chimeras, which result from transplacental passage of hematologic precursors via vascular anastomoses, and dispermic or tetragenetic chimeras, arising from early fusion of two separate and genetically distinct zygotes. Human chimeric twins are difficult to recognize and are most likely underreported. They most often present as problems in ABO blood typing due to the mixture of two cell types and absence of expected agglutinin.4,42 Blood group chimerism in twins may not be as rare as previously believed. Using a sensitive fluorescent technique for detecting very subtle red cell populations, van Dijk et al.194 found that 8% of twins and 21% of triplets were blood group chimeras. Other potential consequences of placental vascular anastomoses in DZ twins are acquired immune tolerance and freemartinism. Acquired immune tolerance refers to the phenomenon by which an individual becomes tolerant of antigens to which it was exposed in fetal life, and will not produce antibodies to such antigens.195 Studies in cattle have shown that chimeras acquire tolerance to their twin’s genotype and will not reject skin grafts from their twin as foreign.196,197 When placentas of opposite sexed twin calves are fused, the female twin will be sterile, called a freemartin.198 Lillie199 suggested that the transplacental passage of male hormones, secondary to fusion of the chorions and anastomoses between the fetal circulations, inhibits normal female organogenesis. Freemartinism has not been documented in man. The various forms of placentation have tremendous impact on the intrauterine environment of twins. Examination of the placenta for the condition of the membranes, the existence of vascular communications between the twins, and evidence of a deceased twin may extend the current understanding of the role of the placenta in multiple pregnancy.

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Twin–Twin Transfusion Syndrome The twin–twin transfusion syndrome (TTTS) is a complication of multiple gestation, resulting from imbalanced blood flow through placental vascular communications such that one twin is compromised and the other is favored. TTTS usually develops during the second trimester of pregnancy and often results in spontaneous rupture of the membranes or spontaneous labor leading to premature delivery.200 At birth, twins affected by the transfusion syndrome may be markedly dissimilar in weight, skin color, and hemoglobin levels. Prognosis is poor, with the perinatal mortality rate ranging from 60–100%.4,201–204 Vascular communications occur in most, if not all, monochorionic placentas but rarely in dichorionic placentas; thus, TTTS is almost exclusively found in monochorionic MZ twins (Fig. 34-8). It is estimated to occur in 5–15% of monochorionic twin pregnancies.4,203,205 Two theories exist concerning the significance of placental vascular anastomoses in twin gestations. One view is that vascular anastomoses represent one of many malformations frequently found in twin placentas, with the prevalence depending on the type of placentation. The other view holds that vascular anastomoses are an inherent feature of monochorionic placentas, but signify a congenital malformation in dichorionic placentas.206,207 Vascular anastomoses within twin placentas have long been recognized. Strong and Corney58 provide a detailed historical background of the placenta in twin gestation, noting that the earliest description of TTTS may have been in the Book of Genesis. At the birth of Esau and Jacob, it was recorded that ‘‘the first one came out red,’’ possibly describing the birth of a plethoric twin. As early as 1685, Portal208 advised his students to tie a knot in the umbilical cord of the firstborn twin to prevent exsanguination of the second. In 1751, Smellie209 reported the injection of an umbilical artery of one twin with the injection material flowing out the vessel of the co-twin. Research in the area of vascular anastomoses in twin placentas was dominated by the German obstetrician Friederich Schatz,210 who was also a harsh critic of other researchers in the field. He proposed four types of vascular connections within monochorionic placentas: (1) superficial connections between capillaries. (2) superficial arterial communications between large vessels, (3) superficial venous connections between large vessels, and (4) vascular communications between capillaries in the villi. Schatz210 described three circulatory systems in monochorionic twins: the first two comprised the circulations of each twin, and the ‘‘third circulation’’ consisted of the arteriovenous communications joining the two fetal circulations below the placental surface. The superficial artery-toartery and vein-to-vein anastomoses serve as a compensatory mechanism for the deep arteriovenous connections. Superficial anastomoses are present in the majority of monochorionic placentas; but when they are absent or inadequate, imbalances in blood flow may occur, leading to functional changes in the bodies of the twins.58,186,191 Such imbalances, favoring the transfer of blood from one twin (the donor) to the other twin (the recipient), result in TTTS.4,191,192 Other factors, such as torsion of the cord, primary defects of the fetal heart, and problems at delivery, may also compromise the common circulation of the twins, so that the deleterious effects may not be solely due to the presence of anastomoses.16,210 Assuming that the umbilical vessels of the twins have identical blood pressures, a ‘‘balanced’’ placental circulation can result from artery-to-artery or vein-to-vein connections. A balanced circulation

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Fig. 34-8. Diagrams of vasculature observed in monochorionic twin placentas. (A) Monochorionic placenta showing no apparent vascular anastomoses between the circulations of the co-twins. (B) Twin placenta with deep artery-to-vein and superficial artery-to-artery anastomoses. This is the most common combination of vascular connections observed in monochorionic placentas. The superficial artery-to-artery anastomoses act as a compensatory mechanism for the

deep artery-to-vein connections. (C) Monochorionic placenta demonstrating deep arteriovenous communications. Absence of compensatory superficial anastomoses leads to an imbalance of blood flow and may result in the twin transfusion syndrome. (D) Monochorionic placenta showing artery-to-artery and vein-to-vein anastomoses as seen in acardia. Such connections may lead to reversed perfusion of one twin, destined to become the acardiac twin.

can also be maintained by an arteriovenous anastomosis compensated by a venoarterial communication in the opposite direction. It is the ‘‘unbalanced’’ arteriovenous communications that are not compensated by superficial anastomoses or by venoarterial connections that are associated with TTTS.207 Bajoria et al.211 compared the fetoplacental angioarchitecture in monochorionic placentas with and without TTTS and observed marked differences in the type and number of anastomoses in pregnancies with TTTS compared to unaffected pregnancies. The vascular anastomoses found in monochorionic placentas of midtrimester TTTS were fewer in number, more likely to be solitary, and more likely to be of the arteriovenous type than those in monochorionic placentas without TTTS. The anastomoses in TTTS always ran in one direction, from donor to recipient, and the placentas lacked superficial artery-to-artery and vein-to-vein anastomoses. In contrast, unaffected placentas had anastomoses of all three types—arteriovenous, artery to artery, and vein to vein— and the anastomoses ran in both directions. These results confirm the protective role of superficial vascular anastomoses in maintaining the hemodynamic balance between monochorionic twins. TTTS was first characterized by Herlitz,212 who noted anemia in one twin and polycythemia in the other. Two types of TTTS have been proposed: the ‘‘chronic’’ form and the ‘‘acute’’ form. The sudden transfer of blood from one twin to the other has been classified as the acute transfusion syndrome. In early pregnancy, the acute transfusion syndrome may result in the vanishing twin syndrome; later in pregnancy it may cause death of one or both twins.

In some cases, the rapid transfer of blood from one twin to the other occurs not during intrauterine life, but at delivery.213–217 In such cases, the twins are similar in weight and length, but one is polycythemic and hypervolemic, while the other is anemic and hypovolemic.217 Seip215 theorized that the polycythemia resulted from an increased amount of blood given from the placenta after the first cord was clamped, so that the polycythemic twin would always be born second. In contrast, Klebe et al.216 postulated that the timing at which the umbilical cord of the first-born twin is clamped would influence which twin developed polycythemia: early clamping of the cord would result in polycythemia of the twin born second, while late clamping would lead to polycythemia in the firstborn. In the chronic form, the transfusion of blood from one twin to the other occurs slowly, over an extended period of the pregnancy.212 As a result of chronic transfusion, the donor twin is generally hypovolemic and anemic, showing varying degrees of growth retardation (Table 34-4).217 In severe cases, the donor may die in utero, resulting in a fetus papyraceus at birth. The recipient twin is hypervolemic, is often larger than the donor, and may develop cardiac hypertrophy and congestive heart failure (Fig. 34-9). Because of increased urine output, severe polyhydramnios frequently develops in the amniotic sac of the polycythemic twin, often leading to premature delivery, whereas oligohydramnios is associated with the donor twin.218 In some cases, the smaller donor twin is pushed against the uterine wall in an oligohydramnic sac secondary to compression from the polyhydramnic sac of the larger recipient; this situation has been referred to as the ‘‘stuck

Twins Table 34-4. Characteristics of the twin transfusion syndrome Donor Twin

Recipient Twin

Anemia

Polycythemia

Hypovolemia

Hypervolemia

Growth retardation

Organomegaly

Oligohydramnios

Polyhydramnios

Pale, swollen, atrophic placenta

Congested, enlarged placenta

twin’’ phenomenon and complicates up to 35% of monochorionic twin pregnancies.219,220 The stuck twin phenomenon has also been seen in dichorionic MZ and DZ pregnancies, suggesting that causes other than TTTS must also contribute to its occurrence.220 Traditionally TTTS was diagnosed or confirmed at birth by demonstration of a difference in hemoglobin greater than 5 g/dl and a difference in birth weight greater than 20% between the twins.203,221 However, a definitive diagnosis of TTTS cannot be made by these criteria. Some twins with TTTS do not show such a marked discordance in hemoglobin levels or in weight, whereas other twin pairs without TTTS may have large discrepancies in weight and/or hemoglobin level. The diagnosis of TTTS is currently based on ultrasound findings: (1) the presence of a single placenta, (2) like-sex twins, (3) significant discordance in weight, typically greater than 20%, and (4) significant discordance in amniotic fluid volume that has led some investigators to call TTTS the polyhydramnios-oligohydramnios syndrome.222 Still, these features are not unique to TTTS. Discordance within twin pairs for a number of conditions may give similar sonographic findings and must be ruled out. These include discordance for placental insufficiency, fetal bladder obstruction, isolated growth retardation, aberrant cord placement, chromosome abnormality, fetal infection, and other fetal anomalies.223,224 Echocardiogram is helpful in characterizing TTTS by detecting complications such as decreased ventricular function, tricuspid regurgitation, and cardiomegaly.223 Fetoplacental vasFig. 34-9. Monozygotic twins with the twin transfusion syndrome at 30 weeks of gestation. The larger (recipient) twin weighed 1160 g and the smaller (donor) twin weighed 500 g.

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cular Doppler studies on both fetuses are indicated and, although the results are variable, absent end-diastolic umbilical artery flow is often seen in donor twins.225 Based on severity, Quinterro et al.225 classified TTTS into five stages: stage I: discordance in amniotic fluid volume with polyhydramnios in one twin and oligohydramnios in the other; stage II: features of stage I plus absence of a urine-filled bladder in the donor twin; stage III: the features of stages I and II plus critically abnormal Doppler umbilical artery studies with either absent or reversed end diastolic flow in the umbilical artery or reversed ductus venosus flow or pulsatile umbilical venous flow; stage IV: all of the above plus the presence of hydrops in one or both twins; and, stage V: in utero demise of one or both twins. As expected, the increased severity of TTTS at the time of diagnosis is highly correlated with increasing perinatal mortality. Both the gestational age at diagnosis and the severity of disease at the time of diagnosis will impact the success of intervention therapies. Without intervention, the perinatal mortality of TTTS is 90– 100% for both twins.223 The typical course in untreated TTTS is premature labor due to premature rupture of the membranes and fetal death related to prematurity, congestive heart failure, and/or IUGR. The obvious goals of antenatal management strategies are to prolong pregnancy and to reduce perinatal mortality. Conservative antenatal management of TTTS has included bed rest, use of prophylactic tocolysis, digoxin therapy, and weekly ultrasound surveillance. Bed rest and tocolysis do not appear to improve outcome.202 Digoxin has been used with some success to treat congestive heart failure in the recipient, but this treatment is somewhat controversial due to adverse maternal side effects.226 Weekly ultrasound surveillance is warranted to assess cardiac function, amniotic fluid volume, and fetal size discordance, but more aggressive management strategies are necessary to reduce perinatal mortality. Among these are therapeutic amnioreduction, amniotic septostomy, laser ablation of placental vascular anastomoses, and selective feticide. Umbilical cord ligation for selective feticide is not recommended as a treatment for TTTS because of the risk of embolization to the surviving twin.223 In amnioreduction, excess amniotic fluid is removed from the polyhydramniotic sac. Duncombe et al.227 recommend this procedure when the maximum vertical pocket of fluid exceeds 8 cm on sonographic assessment. Fluid is aspirated from the sac of the recipient twin until the maximum vertical pocket is reduced to 4 cm or less. The procedure is repeated as often as necessary to keep the fluid volume within the normal range, thereby reducing the risks associated with polyhydramnios and improving the placental blood flow by reducing the intrauterine pressure.226 Duncombe et al.227 reported an overall perinatal survival rate of 67.6% in pregnancies treated with amnioreduction vs. 55.6% survival in pregnancies without amnioreduction. Unfortunately, this procedure is not without complications, including premature rupture of membranes, preterm delivery, chorioamnionitis, and placental abruption. Because amnioreduction does not treat the underlying cause of TTTS, the risk for long-term neurologic damage is still present. Neurologic abnormalities have been reported in 18–26% of TTTS pregnancies treated with amnioreduction. Mari et al.228 found cerebral palsy in 4.7% of twins treated by amnioreduction. The etiology of the neurologic damage is not certain, but it may be due to decreased cerebral perfusion and ischemic brain injury.229 In septostomy, the dividing membrane is pierced or torn to allow amniotic fluid to equilibrate between the two sacs.227 In earlier applications, the membrane was torn to artificially create a monoamniotic pregnancy. Unfortunately, the risks associated with

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monoamniotic gestation—fetal interlocking, cord entanglement— were also present. Another theoretical complication is the production of amniotic bands from the torn membrane. More recently, microseptostomy has been used to puncture, but not tear, the dividing membrane. This allows fluid to flow from one sac to the other without the inherent risks of monoamniotic pregnancy. Amniotic septostomy has been found to prolong pregnancy by 8 weeks with an overall survival rate of 67–83%.230 Fetoscopic laser ablation of the placental vessels, followed by amnioreduction, interrupts the arteriovenous shunting from one fetus to the other. In early attempts, all vessels crossing the dividing membrane were coagulated. More recently, selective laser ablation has been performed in which only the arteriovenous anastomoses resulting in imbalanced blood flow are treated. Selective coagulation reduces the rate of intrauterine death of the donor twin and offers an effective alternative to amnioreduction alone.226 The overall survival rate ranges from 53–69%, with survival of at least one twin in 70–82% of pregnancies following selective ablation.223,226,231 Because laser occlusion of the twin–twin shunt treats the source of the problem, it has the great advantage of reducing the risk of neurologic damage to 4–6% of pregnancies.231 The disadvantages of laser ablation are that is it more invasive than amnioreduction, it may require general anesthetic, and it has been associated with premature rupture of membranes.229 Despite the use of aggressive strategies to manage TTTS, the risks of neonatal mortality and morbidity persist. After delivery, the surviving twins may require mechanical ventilation, exogenous surfactant, prophylactic antibiotics, blood transfusion and prolonged stay in the neonatal nursery.227 In addition, the procedures used to treat TTTS are associated with significant risks of fetal and maternal complications.

Acardia Acardia is an anomaly of MZ twins in which one twin has an absent, rudimentary, or nonfunctioning heart (Figs. 34-10 and 34-11). The circulation of the acardiac twin is supported by the heart of the unaffected co-twin. Acardiac twinning is a rare malformation with an incidence of about 1/100 MZ twin pairs, or 1/35,000 births.232,233 Acardia has only been described in multiple births, usually occurring in MZ twins, although it is also seen in triplet and quadruplet births.234,235 Acardia has also been described in lower animals.236 Multiple gestation is a prerequisite for this condition, since the acardiac fetus relies on the functioning heart of the normal fetus for maintenance of its circulation. Acardia is associated with monochorionic placentation, suggesting the MZ derivation of the acardiac and its co-twin. The MZ origin of acardia is further supported by sex chromatin studies and by karyotypic analysis showing concordant sex chromosome constitution in the acardiac and its co-twin.237,238 Acardia was first mentioned in 1533 by Benedetti,239 who reported an amorphous mass which contained no viscera and was thought to represent a hydatidiform mole. The term ‘‘fetus amorphus’’ was first used by Gurlt240 in 1832 to describe two cases of asymmetrical amorphous masses found in cattle. Geoffrey Saint Hilliare241 is credited with the first full description of acardia. Acardia has been classified as follows: Acardius acephalus: This is the most frequent variety, responsible for 60–75% of cases.242 The head is absent but the trunk and limbs are more or less well developed.236,243,244

Fig. 34-10. Acardia in a twin pregnancy. Note the relatively wellformed lower limbs compared with upper torso and head.

Acardius acormus: This is a very rare type of acardia in which there is development of the fetal head only.244 The head is usually directly attached to the placenta via a cord arising in the cervical region.234,236,243 Acardius amorphus, or anideus: This type of acardia occurs in about 20% of cases.242 The defect consists of an irregular skin-covered mass of bone, muscle, fat, and connective tissue without the external form of a fetus.234,243 The umbilical cord is inserted anywhere on the surface. Acardius anceps or paracephalus: The head is poorly formed but the trunk and limbs are fairly well developed.236,237 This form is sometimes included with the acephalus group. Acardius mylacephalus: This form consists of an amorphus mass with some development of one or more limbs.234,236 The more general terms holocardius and hemicardius have also been used to indicate when no trace of myocardial elements exist (holocardius), or when some functional structure is present (hemicardius).234,242 Three primary theories have been advanced for the pathogenesis of acardia.236 The first theory suggests that a primary deficiency in the development of the germinal layers, rather than imperfect circulation, leads to acardia. The heart fails to develop and the acardiac fetus is sustained in cases where anastomoses exist between the vessels of the two umbilical cords. This theory was supported by Meckel,245 Darest,246 and Panum.247

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Fig. 34-11. Posterior view (left) of acardiac twin at 29 weeks of gestation showing partially collapsed and fused cervical hygromas. Face and cranium (right) with distorted anatomy secondary to inadequate cephalic blood supply and massive fetal hygromas (H). M, mouth; N, external nares; E, right ear; AEC, anterior encephalocele. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

The second theory acknowledged the existence of artery-toartery and vein-to-vein anastomoses within the acardiac placenta, but proposed that an interfering factor, such as small blood vessels in one cord, impeded the return flow of blood from the placenta to one twin, leading to reversal of circulation. This theory was supported by Schatz,248 who suggested that an omphalocele, frequently seen in acardia, might be responsible for the obstructed blood flow resulting in the development of acardia.237,249 The third theory, supported by Claudius,250 Ahlfeld,251 and Hunziker,252 is the favored explanation for acardia.236 According to this theory, the primary defect in acardia is the presence of artery-toartery and vein-to-vein anastomoses which lead to reversal of blood flow in one twin.236,252 As a consequence of reversed circulation, the affected twin is perfused with poorly oxygenated blood from the cotwin, leading to hypoxia, poor nutrition, and abnormal development. The heart and other organs in the acardiac fail to develop or regress secondary to aberrant hemodynamic factors.232 As a consequence of the reversed flow and pressure gradients, the structure of the aortic wall, particularly the distribution of elastin lamellae, is severely deranged in the acardiac.253 Acardia is also referred to as the twin reversed arterial perfusion (TRAP) sequence, a name which reflects the third pathogenetic mechanism mentioned above.254 Artery-to-artery anastomoses within the monochorionic placenta develop early in the first trimester of pregnancy. The twin with the hemodynamic advantage becomes the pump twin and retrogradely perfuses the co-twin, who is destined to become the acardiac. Through the common umbilical artery, the perfused twin receives poorly oxygenated blood, which would normally enter the placenta for oxygenation, nutrition, and waste disposal. The blood flows into the affected twin through the umbilical artery to the iliac arteries

and abdominal aorta.254 Cardiac and other organs fail to develop, or there is regression of previously formed organs.255 There is variable development of external structures. Organs supplied by the iliac arteries and abdominal aorta receive a better blood supply and are generally more developed than structures of the upper body.254 In some cases, the acardiac twin is of equal size or larger than the pump twin.232,256,257 Major malformations occur in 10% of pump twins. Congestive heart failure occurs in 50% of cases.254,256,258 Cardiomegaly, hepatomegaly, and IUGR of the pump twin have also been noted. The true incidence of acardia may be greater than the 1% of MZ twins generally estimated, as affected twin pairs could be missed if the TRAP sequence is lethal early and leads to spontaneous abortion or vanishing twin.254 Fetal or neonatal death of the pump twin has been reported in 50% of cases, associated with premature delivery, congestive heart failure, and hydramnios.254,256 Hydramnios is the major maternal complication, occurring in about 40% of pregnancies.256 Close proximity of the developing umbilical arteries of the twins, allowing the establishing of arterial anastomoses, may be a prerequisite for development of the TRAP sequence.254 An increased frequency of monoamniotic placentas has been reported among acardiac twins compared to other MZ twins, supporting the requirement of close proximity of umbilical arteries.259 The observation that the TRAP sequence is about three times more common among MZ triplets than among MZ twins also supports the requirement of close proximity of developing arteries, as the crowded surface of an MZ triplet placenta may favor the formation of arterial anastomoses necessary to produce acardia.254,259 A second factor which may be necessary for the TRAP sequence is the discordant development of twin embryos, which

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may increase the chance of reversed blood flow in the presence of arterial anastomoses.254 Discordant development between twins is well described, particularly in MZ twins with monochorionic placentation.260 Twins discordant for a chromosome abnormality (post-zygotic error) or a malformation syndrome may also demonstrate discrepant development.261,262 Discordance for karyotypic abnormalities has been described in association with acardia, with the perfused twin having an abnormal karyotype and the pump twin having a normal chromosome constitution.249,254,255,263–265 No consistent karyotypic abnormality has been found; thus, chromosome abnormalities cannot be considered the primary defect leading to acardia. Nonetheless, an abnormal karyotype may predispose to the discordant development of the twins, which in turn favors the reversal of blood flow in the presence of placental anastomoses.254 Nance41 suggested that a cellular or cytoplasmic deficiency of the zygote, rather than a vascular defect, may be the primary cause of acardia. Such a defect could result from fertilization of a polar body, from asymmetric twinning, or from a chromosomal error arising in an early cell division. The vascular malformations may then be a secondary event that permits the survival of the acardiac twin. Kaplan and Benirschke266 investigated the possibility that acardia could arise from fertilization of a polar body. However, chromatin studies of specimens failed to identify any unlike-sexed pairs among the acardiacs and their co-twins as would be expected to occur by chance if an ovum and polar body were fertilized by separate sperm. There have been reports of acardia in unlike sex twins, although chromosome studies were not always performed to confirm the discordant phenotypic findings.243,259,263,267 In the absence of karyotype analysis, internal examination, or microscopic analysis, it seems likely that aberrant external structures may have led to the misdiagnosis of the sex of the acardiac. Bieber et al.263 reported a triploid 70,XXX,þ15 karyotype in an acardiac fetus with a normal male (46,XY) co-twin. The placenta was monochorionic diamniotic. The discordant sex suggested that the twins arose from independent fertilizations involving different sperm. The finding of two maternally derived chromosome complements suggested that the acardiac arose from fertilization of the diploid first polar body by an X-bearing sperm. Acardia has also been observed in unlike-sex DZ twins among domestic animals.268 Chromosome analysis performed on a bovine acardiac and its normal co-twin revealed that the acardiac had a female sex chromosome constitution with an extra acrocentric autosome. The male co-twin had an XY constitution with no evidence of chimerism, suggesting that the acardiac and the normal male were DZ twins of unlike sex without blood chimerism. The observation of acardia in dizygotic cattle implicates vascular anastomoses rather than monozygosity itself as the underlying causative factor in the development of this anomaly. In man, vascular connections are virtually limited to monochorionic twin placentas, whereas anastomoses occur commonly in fused placentas of bovine twins.259 Prenatal diagnosis of the TRAP sequence is often made in the second trimester, although acardia may be missed or confused with an anencephalic twin or with fetal demise of one twin.256,269 Serial ultrasonography, elevated maternal serum and amniotic fluid AFP concentrations, and Doppler velocimetry studies may aid in the diagnosis.270–272 Elevated maternal serum AFP concentrations, with or without elevated amniotic fluid concentrations, have been detected in association with acardia, although this is not a universal finding.270,271,273 Pulsed Doppler studies

have been used to show reversed blood flow through the umbilical artery of the perfused twin.272 Ultrasonographic features that are useful in the diagnosis of acardia include absent cardiac movement in one twin in the presence of limb movement, failure in fetal growth, gross hydropic changes, single umbilical artery, reversed blood flow in umbilical vessels detected by Doppler studies, and polyhydramnios.269 Other sonographic features include the identification of monochorionic placentation, discordant size of the two cords inserted close together on the placental surface, cardiomegaly and hydrops in the pump twin, and occasional polyhydramnios in the sac of the pump twin.269 Considering the 100% mortality of the perfused fetus, the management of acardiac pregnancies has been directed toward enhancing survival of the co-twin. Strategies for managing acardiac pregnancies include serial ultrasound scans to assess fetal growth and cardiovascular status of the pump twin, therapeutic amniocentesis to relieve polyhydramnios, steroid administration to achieve lung maturation of the unaffected twin, and digitalis administration to treat fetal cardiac failure and reverse subcutaneous edema in the pump twin.256,269 More aggressive measures used for selective fetocide of the acardiac twin have been met with variable success.274 The injection of various thrombogenic substances has been attempted but carries the risk of embolizing the non-affected twin through placental vascular anastomoses.275 Hysterotomy with selective delivery of an acardiac fetus has been successful in allowing continuation of the pregnancy while eliminating the risks of embolic phenomena and intrauterine disseminated intravascular coagulation in the unaffected co-twin.244,276 Techniques implemented to occlude the umbilical cord of the acardiac include clamping, ligation, laser coagulation, placement of thrombogenic coils, and radiofrequency ablation.275,277–279 Conjoined Twins Conjoined twins result from a defect in the MZ twinning process in which the embryonic disc fails to separate completely prior to week 3 of development. Complete separation of the embryonic disc during week 2 post fertilization results in monochorionic monoamniotic MZ twins. By this stage, the chorionic and amniotic membranes have been established and the primitive streak has formed. Subsequent splitting may be incomplete, giving rise to twins that show varying degrees of fusion. Conjoined twins range from those with only a thin connection between two more or less completely formed individuals to those with a single trunk and duplication of only the head or only the caudal part of the body. Numerous systems have been proposed for the classification of conjoined twins. Schwalbe’s280 classification separates conjoined twins into duplicatas completa for two complete twins and duplicatas incompleta for twins in which only a part or region is duplicated. Conjoined twins have also been classified on the basis of whether they are equal in growth (symmetric disomata) or unequal (asymmetric disomata).281 Symmetric disomata are rare, and asymmetric disomata are even less common.282 Symmetric disomata may be attached longitudinally or laterally. In longitudinal attachment, the axes of the bodies make a straight line as in craniopagus (head to head) and ischiopagus (rump to rump) twins. In lateral junction, the union may be side to side, back to back, or face to face. The union may be in the cephalic region only (syncephalus) or in the cephalic and thoracic

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Fig. 34-12. Diagram of various types of conjoined twins: craniopagus (A, B); ischiopagus (C, D); dicephalus (E); thoracopagus (F); syncephalus (G); and cephalothoracopagus (H).

regions (cephalothoracopagus); both types of junction are associated with duplication of the caudal end. Conversely, the caudal end may be joined with duplication of the cephalic region (dicephalus). In thoracopagus twins, the mid-part of the body is joined with duplication of both cephalic and caudal ends (Figs. 34-12 to 34-14).281 Asymmetric disomata are characterized by very unequal growth and development, such that one member of the pair is small and only partially formed. The smaller twin, or ‘‘parasite,’’ is attached to the body of the co-twin, or ‘‘autosite,’’ as a dependent growth.284 Patten283 classified parasitic twins as cephalopagus parasiticus, consisting mostly of a head which is fused to the head of the autositic twin; epignathus parasiticus, attached to the jaws of the larger twin; pygopagus parasiticus, joined to the rump of its co-twin; thoracopagus parasiticus, connected to the thorax of the larger twin; and, those parasitic twins attached to the epigastric region of the co-twin. Whenever the sex of the parasitic twin is apparent, it is the same as that of the autosite. It has been proposed that parasitic/autositic twins result from the unequal division of the inner cell mass or from inequalities in the relationship

between conjoined twins, such as an unequal vascular supply, leading them to develop asymmetrically. The fetus-in-fetu, or ‘‘inclusion twin,’’ is a parasitic twin that is encased in the body of the autosite. The fetus-in-fetu ranges in development from a shapeless mass of tissue to a fairly wellformed fetus, and may occur at any number of sites within the cotwin, including the abdominal or thoracic cavity, cranial cavity, spinal canal, scrotum, or urinary bladder.284 Fetus-in-fetu is thought to occur when one member of a conjoined twin pair lags behind early in development and is entirely encased in the body of the co-twin.283,285 Saint Hilaire’s241 detailed classification of conjoined twins was modified by Fisher,286 then by Hirst and Piersol.287 The major morphological types are defined as the following: 290 I. Terata catadidyma—A pair of twins joined by some lower part of the body; or, twins that are single in the lower part of the body and double in the upper portion of the body. A. Pygopagus—Union of the lateral and posterior surfaces of the coccyx and sacrum, which are single; the rest of the

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Fig. 34-13. Conjoined twins (craniopagus) at 26 weeks of gestation showing multiple deformations in association with fetal compression. Potter facies is noted in each twin; the ears are low set. Each twin shows a clubfoot deformation, and muscular atrophy is present in the ipsilateral lower leg (arrows). The kidneys of each twin were dysplastic, and oligohydramnios was noted clinically. (Courtesy of Dr. Will Blackburn and Nelson Reede Cooley, Jr.)

two bodies are duplicated with the twins positioned almost back to back. B. Ischiopagus—Union of the inferior margins of the coccyx and sacrum, with the two separate spinal columns lying in the same axis. C. Dicephalus—Two distinct heads, usually having separate necks and one body. D. Diprosopus—Two faces with one head and one body. II. Terata anadidyma—Conjoined twins that are single in the upper portion of the body and double below, or a pair of twins joined by some upper portion of the body. A. Cephalopagus or craniopagus—United at some point of the cranial vault. B. Syncephalus—Union at the face; the twins may be separate below the face or may be joined by the thorax and separate from the umbilicus down (cephalothoracopagus). In the janiceps type there are two faces, each a composite of both twins, facing opposite to each other on the anterior and posterior sides of the head. Janiceps is named for Janus, the Roman god of doors and gates, who had two heads, one facing the past and one facing the future.288 C. Dipygus—One head, thorax, and abdomen with duplication of the pelvis, external reproductive organs and legs; one, two, or all three of the duplications may be present.

Fig. 34-14. Conjoined twins (dicephalus) at 16 weeks of gestation. Two well-formed heads were attached to one broad thorax. Two complete spines were present and two hearts were partially fused. Four lungs, two esophaguses, two stomachs, two duodenums, one common ileum, and one colon were present.

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III. Terata anacatadidyma—Conjoined twins united at the midpoint of the body. A. Thoracopagus—Twins sharing part of the thoracic wall; may have abnormalities of the chest organs and upper abdominal viscera. B. Omphalopagus—Twins united from the umbilicus to the xiphoid cartilage. C. Rachipagus—Twins united by the vertebral column above the sacrum. The incidence of conjoined twins is about 1/50,000 births.289 Thoracopagus is the most common type, with an incidence of 1/82,000 births, while craniopagus is the rarest type occurring in 1 in 2–4 million births.289 Among conjoined twins, 70–75% are thoracopagus, 20% pygopagus, 6% ischiopagus, and 2% craniopagus.282,290 Conjoined twins have also been reported among higher multiple births.291–294 In that conjoined twins are derived from a single fertilized ovum, they are virtually always of the same sex and same chromosome constitution. Apparent differences in phenotypic sex have been attributed to pseudohermaphroditism, such that the phenotypic sex differs from the genotypic sex in one twin.8 An excess of females has been observed among conjoined twins, with females comprising 70–80% of cases. The preponderance of females has led to speculation that abnormal X-inactivation may play a role in conjoined twinning. However, Zeng et al.295 found no evidence that skewed inactivation contributed to conjoined twinning or to the female excess among conjoined twins. Other genetic or environmental influences may place females at higher risk of being conjoined than males, or may make females less likely to be spontaneously aborted than males. Various theories have been proposed for the etiology and mechanism of formation of conjoined twins. Ambroise Pare,296 a 16th century surgeon, listed 13 causes of single and double monsters, attributing multiple births and monstrous children with duplicated body parts to an excessive quantity of seed (semen). This view has been referred to as ‘‘the principle of excess and defect.’’284 Maternal impression was cited as the cause of craniopagus twins, as their birth followed an accident in which their mother bumped heads with a second woman.297 Another popular concept was that double monsters resulted from the fertilization of one ovum by two or more spermatozoa.209 The uniovular origin of conjoined twins was supported by Dareste,298 Fisher,286 and Galton.299 A common notion was that complete separation of the first two blastomeres followed by partial fusion led to conjoined twins. The so-called ‘‘fusion theory’’ recalls the Aristotelian concept that conjoined twins arose from two separate embryos growing together.280 A variation of the fusion theory proposed that conjoined twins arose from the coalescence of two originally separate embryos, as in the fusion of fraternal twins. Such fusion would require two independent abnormal events: the rupture of the amniotic membrane so the twins would develop within the same sac, followed by the fusion of the two embryos.300 In addition, the symmetrical relationship exhibited by conjoined twins would argue against random fusion of two independent embryos. With possible exception of parasitic conjoined twins, the junction between conjoined twins conforms to the ‘‘teratological law of the union of like to like.’’ Thus, although diverse sites and degrees of union are observed among conjoined twins, within each pair ‘‘the same parts only unite with the same parts.’’301

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The origin of conjoined twinning has also been explained by the ‘‘fission theory,’’ which suggested that incomplete separation of the first two blastomeres gave rise to conjoined twins, with duplication of only those parts which had become completely separated.284 Sobotta302 proposed that separation occurred at later stages of blastocyst formation, observing that it was unknown whether human blastomeres were equipotent or how they became separated within the zona pellucida. The late fission of the embryo is the basis of the current explanation for conjoined twinning. Incomplete separation of the embryonic disc, occurring near the end of week 2 of development, results in partially joined twins. The degree and origin of the separation determines the type of conjoined twins. While this is the accepted mechanism to explain conjoined twinning, it has been speculated that a subset of conjoined twins may form secondary to the action of the disorganization gene.303 Experimental studies have revealed a number of factors which influence the occurrence of conjoined twinning in lower forms: hypoxia and water temperature in fish, delayed fertilization in frogs, and various teratogens in hamsters.304–307 Factors that have been postulated to influence the formation of conjoined twins in man include a defect in the primitive streak, aging of the ovum, and environmental factors.308 Aging of the ovum could result in gradual decline and inability of the ovum to differentiate normally, forming two centers of differentiation, neither able to suppress the other.306 Maternal factors such as poor obstetric history may also be important in conjoined twinning; an excess of stillbirths has been reported among previous pregnancies of women who gave birth to conjoined twins.309 A positive family history of twinning has been reported in some cases, but is not common.282 No seasonal or temporal clustering of cases has been found, although epidemics of conjoined twinning in southern Africa and Sweden have been reported.310–312 The clustering of cases in these regions may be due to chance or to bias in reporting several occurrences of conjoined twins rather than individual cases.313 There have been numerous historical accounts describing various types of conjoined twins, many of whom lived until adulthood. An interesting case cited by Shrewsbury314 was a female dicephalus born in 961 A.D. One account states that the twins died 2 days apart, while a more fanciful account claims that one head survived the other by 3 years.281 Most conjoined twins who survive to adulthood consist of two complete conjoined twins, such as thoracopagus twins. The earliest known English conjoined twins are the Biddenton Maids, born at Biddenton, Kent in 1100. They survived for 34 years and are generally depicted as joined at the shoulder and the hip.280 More likely, they were united at the hip alone but kept their medial arms around each other’s shoulder, leading artists to depict them as joined at the shoulder.315 Perhaps the most famous conjoined twins were Chang and Eng Bunker, born in Siam in 1811.316 Exhibited by P.T. Barnum as his famous ‘‘Siamese twins,’’ Chang and Eng were thoracopagus twins joined by a thin band of tissue containing a bridge of liver. At the age of 42, they married sisters and produced a total of 22 children (Fig. 34-15).301 Although they lived 63 years, separation was never attempted, and Eng died within hours of discovering Chang’s death. Postmortem examination revealed that Chang had died of pneumonia, and Eng had died of fright. Further examination of the band of tissue joining the twins demonstrated that they could have been successfully separated.316

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Fig. 34-15. Photograph of Chang and Eng Bunker at age 59 shown with James Montgomery, Eng’s 21-year-old son, and Albert, Chang’s 12-year-old son. Eng and wife Sallie Yates had 12 children; Chang and wife Adelaide Yates had 10 children. The band of tissue uniting the twins is visible.

The routine use of ultrasonography has dramatically improved the prenatal detection of conjoined twins. Ultrasonographic features suggestive of conjoined twinning include the lack of a dividing membrane between the fetuses; the presence of more than three vessels in the umbilical cord; the inability to separate fetal bodies or fetal contours; the observation of the heads at the same level or body plane; the unusual extension of the spines; the close proximity of the limbs; and, the failure of the fetuses to change their relative positions to each other after movement or manipulation, or over time.317 Examination of the fetuses for anatomic joining, assessment of fetal movement, evaluation of gestational age, identification of congenital abnormalities, and monitoring of fetal heart motion is facilitated by the use of realtime ultrasonography.318 Once conjoined twinning has been confirmed, parents should be counseled regarding prognosis and opportunities for intervention including pregnancy termination, preterm cesarean section, and possible postnatal separation. The identification of shared organs and the presence or absence of congenital malformations have major implications for the prognosis of the twins. Serial ultrasound scans in the late second trimester may aid in defining the anatomic relationship between the twins and in evaluating the pregnancy for complications such as polyhydramnios and hydrops.319 Polyhydramnios is common complication, occurring in over 75% of conjoined twins compared to 10% of normal twins.320 Multiple amnioreductions may be required to reduce the severity of polyhydramnios in an effort to prolong gestation. The development of hydrops may necessitate early delivery if the survival of one or both twins is possible, or for maternal indications.319 Premature delivery of conjoined twins is frequent, with the mean gestational age at delivery between 33 and 36.4 weeks.282,309

Despite the increased use of ultrasound, conjoined twins may be undiagnosed until labor or delivery. During labor, the presence of conjoined twins may be suggested by radiologic evidence of conjunction; the presentation of two breech infants in the pelvis with the impossibility of moving one fetus up or down relative to the cotwin; and dystocia, when traction on the presenting part fails to advance it.282 The presence of conjoined twins can be excluded if a second amniotic sac can be felt vaginally, since conjoined twins are always monoamniotic. The second amniotic sac rarely ruptures before the birth of the first twin, so if limbs from two fetuses are apparent on vaginal examination, the presence of monoamniotic twins or conjoined twins must be considered. Cesarean section has been advocated for the delivery of viable conjoined twins to reduce the risk of fetal and maternal complications.321 The incidence of congenital malformations is higher among MZ twins than among DZ twins and singletons, with conjoined twins having a higher rate of malformations than separate MZ twins. The increased incidence of congenital malformations among conjoined twins suggests that a common factor may be responsible for MZ twinning, conjoined twinning, and some malformations.258 The interaction of multiple factors, including conjoined twinning itself, crowding in utero, and dysgenetic development, has also been invoked to explain multiple abnormalities in conjoined twins.288 Many of the malformations observed in conjoined twins are associated with the site of union, while others are anatomically unrelated to the junction site.322,323 Neural tube defects are frequently observed in conjoined twins, particularly among pairs united in the cephalic region. Lateral cephalothoracopagus twins have associated neural tube defects in 64% of cases.324,325 The high incidence of anencephaly in diprosopus and lateral cephalothoracopagus twins has been attributed to difficulties in closing the rostral neuropore in conjoined twins with laterally fused heads.326 Concordance for cardiac defects is frequently observed in thoracopagus twins.327 The degree of union in thoracopagus can range from a thin band of tissue to a complete union of the liver and heart. The high incidence of congenital heart disease in thoracopagus twins seems to be related to the degree of union.327,328 Cardiac fusion has been associated with laterality defects in conjoined twins. If conjoined twinning itself predisposed to situs inversus, the right and left twin should be equally affected, and laterality defects would not be limited to conjoined pairs with cardiac fusion. Early investigators proposed the rotation of the heart as the initiating event in determining normal visceral asymmetry and suggested that the laterality defects observed in conjoined twins with cardiac fusion could result from abnormal cardiac rotation.329,329a Studies from the mouse and other vertebrates indicate a complex series of events underlying the development of laterality. Asymmetric gene expression in the early embryo, ciliary motility, directional fluid flow at the embryonic node, and other factors play a role in left-right axis specification.329b,329c Defects in the mechanisms that establish left-right sidedness can lead to mirror imaging, situs inversus, and other abnormalities of organ placement. Discordance for congenital anomalies, including neural tube defects, acardia, omphalocele, and cleft lip and palate, has also been reported among conjoined twins.308,323,330,331 Discordance may be more likely than concordance for malformations distant to the site of union.323 Discordance for congenital anomalies in conjoined twins has been attributed to unequal partitioning of nutrients and oxygen, leading to anomalies in the deprived

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twin.308 Alternatively, the MZ twinning process itself may predispose to the development of structural malformations. MZ twinning may lead to developmental asynchrony between the embryos, rendering one or both fetuses susceptible to the action of subtle environmental agents.332 Conjoined twins are at a disadvantage in terms of cell number and biochemical timing, such that agents which would be non-teratogenic or only mildly teratogenic in DZ twins and singletons have a more severe effect on MZ twins. One twin may become retarded in development and therefore unable to complete normal morphogenetic processes successfully, resulting in the discordant expression of various malformations.323 Because of their high malformation rate, conjoined twins should be carefully examined for major anomalies at sites related and unrelated to the point of junction. Fetal death in conjoined twins is associated with prematurity and with cardiac, gastrointestinal, and genitourinary anomalies. Despite expectant prenatal care, conjoined twins are often stillborn. In the United States, about 40% of conjoined twins are stillborn, and 35% die within the first day.322 Emergency cesarean section under suboptimal conditions may be related to the high stillbirth rate among conjoined twins.333 In the event of liveborn conjoined twins, surgery to separate the twins should be delayed, except in lifethreatening emergencies, until an accurate assessment of shared structures has been made.290 Even in the most experienced hands, the surgical separation of conjoined twins is an extremely complex process that involves a wide range of medical and surgical specialists. With the availability of CT scans, MRIs, and other imaging and diagnostic techniques, along with advances in surgical procedures, the rate of survival of separated twins continues to improve.334

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Structural Defects Twins have an increased risk of structural anomalies compared to singletons. The excess is attributable to MZ twins, with structural defects occurring two to three times more frequently in liveborn MZ twins than among DZ twins or singletons.258,335,336 Twins are susceptible to the same genetic (chromosome and gene) influences and the same prenatal environmental factors (maternal metabolic disturbance, infection, drug exposure) as singletons. In addition, factors unique to the twinning process contribute to the increased incidence of defects observed in multiple pregnancies.258,.335,337 Structural defects occurring in twins can be classified as follows: 1. Malformations: defects that are part of the twinning process itself, including conjoined twinning, individual malformations, and malformation sequences. 2. Disruptions: defects secondary to the twinning process as a result of shared placental circulation, including TTTS, acardia, and vascular disruptive defects. 3. Deformations: defects secondary to in-utero fetal constraint, including positional defects resulting from intrauterine crowding. Malformations. Single localized malformations and malformation complexes are the most commonly observed defects among twins. Chromosome abnormalities and single gene disorders occur less frequently (Table 34-5).258 Only 5–20% of MZ pairs are concordant for structural malformations, and in some

Table 34-5. Structural defects in twins Malformations 258,335,338,341

Anencephaly

Sirenomelia258,335,342 258,335,343

Holoprosencephaly

258,335

Disruptions

Deformations

Twin-twin transfusion

Bowing of limbs337

Acardia

Head molding332

Secondary to in utero death 258,344–348

Exstrophy of the cloaca

Microcephaly

Renal agenesis258

Porencephalic cyst258,335,344,345

Anal atresia258

Hydrocephaly258,345

258

Hydranencephaly191,258,345,348

TE fistula

258,335

VATER association

258

Intestinal atresia140,355

Asplenia, situs inversus

Cutis aplasia136,335

Saccrococcygeal teratoma258

Terminal limb defects142,258,335

Unique to twinning process

Gastroschisis258,335,349

Conjoined twinning

Disseminated intravascular coagulation332,346 Hemifacial microsomia258,350 Multicystic encephalomalacia3487,351,352 Renal cortical necrosis191,353,354 Horseshoe kidney345 Splenogonadal fusion355 Renal agenesis258 Bilateral anorchia258 Cerebellar necrosis346 Spinal cord transection345 Colonic atresia345 Appendiceal atresia345

Clubfoot332,338

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cases one twin is severely affected with a particular malformation, while the co-twin is affected to a lesser degree.121,335 Defects involving midline structures such as holoprosencephaly, symmelia, exstrophy of the cloaca, and neural tube defects are more common in like-sexed than unlike-sex twins, suggesting a higher incidence in MZ versus DZ twins.41,343 For example, the overall incidence of symmelia is about 1/60,000 births, with about 50% of cases occurring in twins, suggesting that the incidence of symmelia may be 100 times higher in MZ twins than in singletons.41 The excess of neural tube defects in twins appears to be due to an increased incidence of anencephaly, with spina bifida rates in twins similar to those in singletons. Encephalocele may also be increased in twins. An increased incidence of anencephaly has also been reported in conjoined twins, particularly those involving the cephalic region.324,339 Schinzel et al.258 presented two possible explanations for the excess of malformations in MZ twins. First, while many defects are lethal in singletons, the presence of a normal co-twin may allow survival of an affected twin. Second, and more likely, the MZ twinning process and the early structural malformations may be etiologically related. Experimental evidence for the causal relationship between MZ twinning and early malformations was provided by Stockard,304 who proposed that MZ twinning was a teratogenic event and that associated early malformations could be induced by the same teratogenic insult. Both MZ twinning and early malformations could be produced in developing minnows by altering environmental conditions such as oxygen level and temperature. Discordant expression for numerous structural disorders has been observed in MZ twins (Fig. 34-16).357 Post-zygotic events such as single gene mutations, mitochondrial mutations, nondisjunction, structural chromosomal alterations, and skewed Xinactivation have long been acknowledged as causing discordance

in MZ twins. In recent years, other epigenetic mechanisms— uniparental disomy, genomic imprinting, loss of imprinting,358 and telomere crossing over359—have been shown to result in discordance in MZ twins. Discordant expression of genetic information in the cells of a single zygote may be an under-recognized cause of MZ twinning.357 Disruptions. Placental vascular communications are unique to multiple pregnancy, occurring in monochorionic placentas but rarely in dichorionic placentas. About 75% of MZ twins share a monochorionic placenta and show some degree of vascular anastomoses between the circulations of the twins. Consequently, abnormalities resulting from placental vascular communications are almost exclusively observed in monochorionic vs. dichorionic twin pairs. TTTS and TRAP sequence are examples of disruptive events unique to the twinning process.360 Acardia is caused by reversed perfusion due to artery-to-artery and vein-to-vein placental anastomoses. TTTS results from uncompensated artery-to-vein anastomoses favoring blood flow to one twin at the expense of the co-twin. Single fetal death is more common in twins with monochorionic placentation than those with dichorionic placentas and may lead to vascular disruptive defects in the survivor. In 1961, Benirschke191 first noted the association between in-utero death of one twin and vascular disruptions in the co-twin. The transfer of thromboplastin-rich blood from a dead twin to the surviving cotwin could cause embolization and infarction of various tissues and organs. The consequence of single fetal death in twin pregnancies differs depending on the time at which death occurs.345 In over 50% of twin pregnancies, death of one twin occurs prior to 10 weeks postmenstrual age. Pregnancy generally continues without complication, with resorption of the dead fetus resulting in the vanishing twin phenomenon. In some cases, however, early death may lead to

Fig. 34-16. Infant with sirenomelia (left) and normal monozygous twin (right). (Courtesy of Dr. H. G. Kohler, Leeds, England.)

Twins

Fig. 34-17. Two and one-half-year-old female with right side weakness and muscular atrophy. Computed tomography scan shows porencephaly of left parietal region. A macerated stillborn twin was presumably the source of emboli to this child’s nervous system.

Fig. 34-18. Mechanically induced deformations observed in twins: head molding (left) and clubfoot (right).

1403

1404

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vascular disruptions in the co-twin. Infarcted tissue from the vascular disruption may be resorbed, leading to absence of structures or atresia. Defects consistent with early death of one MZ twin are colonic atresia, appendiceal atresia, and intestinal atresia.345 Death of one fetus after 20 weeks gestation is reported to occur in 0.5–6.8% of multiple gestations.191,358,346–348,351 Risks to the mother and surviving twin are increased when fetal death occurs in the late second or third trimester. Late death of one MZ twin may result in evidence of tissue necrosis in the survivor. Cerebral necrosis, spinal cord transection, and renal cortical necrosis secondary to disseminated intravascular coagulation occurring late in gestation have been reported (Fig. 34-17).345 A rare case of vascular disruption was observed in the surviving male of unlike-sex DZ twins with dichorionic placentation.361 The 510 g male, delivered by cesarean section at 25 weeks gestational age, had amelia, cutis aplasia of the scalp, and XX/XY blood chimerism. The autolyzed female co-twin appeared grossly normal. Injection studies of the fused dichorionic placenta revealed superficial artery-to-vein anastomoses between the vessels of the twins. Various disruptive defects including congenital skin defects, small bowel atresia, colonic and appendiceal atresia with horseshoe kidney, hemifacial microsomia, and necrotic limbs have also been reported following single twin death.136,140,142,258,345 The inutero death of one twin should prompt a careful evaluation for disruptive structural defects in the surviving co-twin. Deformations. Twins are more susceptible than singletons to intrauterine crowding, which may lead to growth deficits and to deformations secondary to constraint. Twins generally grow at the same rate as singletons up to about 34 weeks of gestation. Thereafter, uterine constraint limits the rate of growth and may result in mechanically induced deformations. Constraint molding of the head and positional defects of the foot are examples of defects attributable to intrauterine crowding. These defects tend to be transient, usually returning to normal growth and form after birth.258 Defects secondary to uterine constraint are expected to occur with the same frequency in MZ and DZ twins (Fig. 34-18).258,337 Mirror Image Twinning Early investigators thought MZ twins to be mirror image duplicates of each other: if one twin was right-handed, the other was expected to be left-handed; if one twin had a clockwise hair whorl, the other was expected to have a counterclockwise whorl. In fact, the majority of MZ twins show no reversal of asymmetry, although some pairs do show mirror imaging for traits such as handedness, palm patterns, hair whorl patterns, ear shape, and dental patterns.284,362 The mirror-imaging phenomenon has been attributed to late division of the embryo, after differentiation into right and left sides has begun. According to this view, twins resulting from early cleavage would show no mirror imaging, as the embryo had not begun right-left differentiation when splitting occurred.362 That conjoined twins, thought to result from late, incomplete splitting of the embryo, frequently show mirror-imaging supports this view.363 Other factors must contribute, however, as mirror imaging has also been described in DZ twins.362 Mirror image twinning occurs in about 10–15% of otherwise normal MZ twins. Mirror-image MZ twins have inverse laterality, but not usually situs inversus. Inverse laterality means that minor structural features are on the opposite sides, such as the side on which the first tooth erupts. The first tooth to erupt is usually the right lower incisor. In mirror image twins, one twin erupts the first

tooth on the right side while the other erupts on the left. There are many other minor features that are on opposite sides, such as side of a hair whorl or cowlick, asymmetric smile, irregular eyebrow, wrinkles, even the positioning of warts. Occasionally, mirror-image twins also have differences in handedness. There is an excess of mirror-image twins among monochorionic twins and, thus, it is suggested that these twins are the latest in separating among MZ twins. It would be expected that the separation of this kind of MZ twins would occur after the formation of the embryonic plate has begun to lateralize but prior to the formation of the primitive streak. It is not known whether mirror-image twins have an increased risk for congenital anomalies or an excess of females. Discordance Discordance for syndromes, diseases, and physical, intellectual, and psychological features are frequently noted in MZ twins. These differences are in addition to size differences. MZ twinning is two to five times more frequent among ARTs liveborn offspring than among naturally conceived offspring. These offspring also have greater predisposition to congenital anomalies than has been seen in spontaneous MZ twinning. DZ twins are expected to be as different as singleton siblings are, but it has always been anticipated that MZ twins would be very similar, hence the outdated name, ‘‘identical twins.’’ Increasingly, there are a number of potential mechanisms for discordance among MZ twins. As more is learned about reproductive cloning of mammals, it has become clear that the products of cloning lack normal control of epigenetic phenomenon, and those mammalian clones that survive to be born do not go through reprogramming of genomic imprinting in a normal way. Genomic imprinting appears to occur in a stochastic manner in cloned mice.364 Data from intracytoplasmic sperm injection (ICSI) types of in-vitro fertilizations suggest that such errors in imprinting are likely to occur in very early embryonic development. An increased occurrence of discordance has been observed in MZ twins where there is an excess of disorders (Beckwith-Wiedemann and RussellSilver syndromes) known to be related to genomic imprinting errors in one twin. Thus, in some twins, there may be loss of normal control of imprinting phenomenon. Perhaps these are the very early-separating MZ twins. More importantly, however, as with any large multi-cellular organism, somatic mutations that lead to differences between the two MZ twins may be anticipated. Discordance for chromosomal abnormalities and autosomal dominantly expressing genes has been described repeatedly in MZ twins. In addition, the nature of immunologic response and possibly neuronal growth suggests that there will be, by chance alone, differences in the immunologic response and neurologic patterning between MZ twins. In addition, fetal-maternal microchimerism occurs on a regular basis during pregnancy,365 particularly in complicated pregnancies such as twin pregnancies. It can be anticipated that the amount of fetal-maternal microchimerism between the two MZ twins may be quite different. This might be anticipated to lead to differences in autoimmunity and other characteristics. Caution for Complex Disorders In the last few decades, a number of large collections of twins have been established in order to study the genetic basis of complex

Twins

traits and diseases.366 The studies depend on the concept that MZ twins originate from one fertilized egg and thus have a genetic make-up that is identical, and that differences between the MZ twins would be due to environmental factors. Because DZ twins originate from two ova, their differences would be due to both genetic and environmental factors. The concordance rates in MZ and DZ twins with various disorders have been used in many studies to identify the heritability of the particular trait. In general, this is a very useful approach, and many variables can be analyzed simultaneously. However, there are a number of reasons for caution including the fact that the mother’s metabolism is different in twin pregnancies compared to singleton pregnancies; MZ twins may be discordant for genetic traits, and there are rare examples in which apparent DZ twins are actually MZ twins, and vice versa. As mentioned previously, 10% of MZ twins have markedly discordant birth weights. Intra-pair differences in OFC and length are not as well documented as the differences in weight. Nonetheless, it has been reported that about 3% of older MZ twins continue to have obvious discordance in size. Surprisingly, the smallest of these discordant MZ twins are not predisposed to the types of adult diseases (cardiovascular disease, hypertension, and diabetes)367 that are seen in low birth weight singletons.368 This suggests that twins, particularly those with IUGR, are less susceptible to disorders typically associated with prenatal growth deficiency in singletons. Twinning appears to be a risk factor in a number of disorders including autism,369,370 schizophrenia, testicular cancer,371 and breast cancer.372–374 Although the reason for this relationship is unclear, it is possible that the intrauterine environment of twins leads to nutritional or other deficiencies that are critical for normal embryonic development. Studies have yet to determine whether the type of placenta (i.e., the stage at which twinning occurred) predisposes twins to disorders that are less common in singletons. Because of their unique intrauterine environment, twins are exposed to prenatal influences distinct from those experienced by singletons. As a result, prenatal factors related to the development of complex disorders in twins may not be representative of etiological influences associated with the same disorders in singletons. While this distinction between twins and singletons may be problematic in some cases, twin studies provide valuable information regarding the etiology and expression of complex disorders. References 1. Duncan JM: On some laws of the production of twins. Edinburgh Med J 10:767, 1865. 2. MacGillivray I: Epidemiology of twin pregnancy. Semin Perinatol 10:4, 1986. 3. Corney G: Mythology and customs associated with twins. In: Human Multiple Reproduction. I MacGillivray, PPS Nylander, G Corney, eds. WB Saunders, London, 1975, p 1. 4. Benirschke K, Kim CK: Multiple pregnancy. New Eng J Med 288:1276, 1329, 1973. 5. Benirschke K: Origin and clinical significance of twinning. Clin Obstet Gynecol 15:220, 1972. 6. Bulmer MG: The Biology of Twinning in Man. Clarendon Press, Oxford, 1970. 7. Corner GW: The observed embryology of human single-ovum twins and other multiple births. Am J Obstet Gynecol 70:933, 1955. 8. Corney G, Robson EB: Types of twinning and determination of zygosity, in Human Multiple Reproduction, I MacGillivray, PPS Nylander, G Corney, eds. WB Saunders, London, 1975, p 16.

1405 9. Terasaki PI, Gjertson D, Bernoco D, et al.: Twins with two different fathers identified by HLA. New Eng J Med 299:590, 1978. 10. Phelan MC, Pellock JM, Nance WE: Discordant expression of fetal hydantoin syndrome in heteropaternal dizygotic twins. N Eng J Med 307:99, 1982. 11. Thijssen JM: Twins as monsters: Albertus Magnus’s theory of the generation of twins and its philosophical context. Bull Hist Med 61:237, 1987. 12. Howe G, Harrer GA: A Handbook of Classical Mythology. Gale Research Company, Detroit, 1970, p 86, 153. 13. Scrimgeour JB, Baker TG: A possible case of superfetation in man. J Reprod Fert 36:69, 1974. 14. Nance WE: The use of twins in clinical research. BDOAS XIII(6):19, 1977. 15. Singhal SR, Agarwal U, Sharma D, et al.: Superfetation in uterus pseudo didelphys: an unreported event. Arch Gynecol Obstet 268:243, 2003. 16. Corney G: Placentation. In: Human Multiple Reproduction, I MacGillivray, PPS Nylander, and G Corney, eds. WB Saunders, London, 1975, p 40. 17. Fujikura T, Froehlich LA: Twin placentation and zygosity. Obstet Gynec 37:34, 1971. 18. Lyon MF: Sex chromatin and gene action in mammalian X chromosome. Am J Hum Genet 14:135, 1962. 19. Puck J, Stewart CC, Nussbaum RL: Maximum likelihood analysis of human T-cell X chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet 50:742, 1992. 20. Gomez MR, Engel AG, Dewald G, et al.: Failure of inactivation of Duchenne dystrophy X-chromosome in one of female identical twins. Neurol 27: 537, 1977. 21. Burn J, Povey S, Boyd Y, et al.: Duchenne muscular dystrophy in one of monozygotic twins girls. J Med Genet 23:494, 1986. 22. Chutkow JG, Hyser CL, Edwards JA, et al.: Monozygotic twin carriers discordant for the clinical manifestations of Duchenne muscular dystrophy. Neurol 37:1147, 1987. 23. Pena SDJ, Karpati G, Carpenter S, et al.: The clinical consequences of X chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins. J Neurol Sci 79:337, 1987. 24. Jongbloet PH: Duchenne muscular dystrophy in one of monozygotic twin girls. J Med Genet 25:214, 1988. 25. Richards CS, Watkins SC, Hoffman EP, et al.: Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy. Am J Hum Genet 46:672, 1990. 26. Lascari AD, Hoak JC, Taylor JC: Christmas disease in a girl. Am J Dis Child 117:585, 1969. 27. Ingerslev J, Schwartz M, Lamm LU, et al.: Female haemophilia A in a family with seeming extreme bidirectional lyonization tendance: abnormal premature X-chromosome inactivation. Clin Genet 35:41, 1989. 28. Philip J, Vogelius Anderson CHV, Dreyer V, et al.: Color vision deficiency in one of twins with secondary amenorrhea. Ann Hum Gen 33:185, 1969. 29. Phelan MC, Morton CC, Swensen BA, et al.: Evidence for lyonization of G-6-PD in a monozygotic twin pair. Am J Hum Genet 32:123A, 1980. 30. James WH: Anomalous X chromosome inactivation: the link between female zygotes, monozygotic twinning, and neural tube defects. J Med Genet 25:213, 1988. 31. Hall JG: Neural tube defects, sex ratios, and X inactivation. Lancet 2:1334, 1986. 32. Derom C, Vlietinck R, Derom R, et al.: Population-based study of sex proportion in monoamniotic twins. New Engl J Med 319:119, 1988. 33. Goodship J, Carter J, Burn J: X-inactivation patterns in monozygotic and dizygotic female twins. Am J Med Genet 61:205, 1996. 34. Jarvik GP, Motulsky AG: Low frequency of skewed X-inactivation in identical female twins. Am J Hum Genet Suppl 61:A102, 1997. 35. Montiero J, Derom C, Vlietinck R, et al.: Commitment to X inactivation precedes the twinning event in monochorionic twins. Am J Hum Genet 63:339, 1998.

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234. Kappelman MD: Acardius amorphus. Am J Obstet Gynecol 47:412, 1944. 235. Wylin R: Acardiac monster in a triplet pregnancy. J Reprod Med 6:270, 1971. 236. Simonds JP, Gowen GA: Fetus amorphus: report of a case. Surg Gynecol Obstet 41:171, 1925. 237. Benirschke K: Nuclear sex of holoacardii amorphi. Obstet Gynecol 14:72, 1959. 238. Richart R, Benirschke K: Holoacardius amorphus. Am J Obstet Gynecol 86:328, 1963. 239. Benedetti: De Morborum a Capite de Pedis Signis, Lector Studioso Hox Volumine, Lucaeantonii Juntai, Venice, 1533. 240. Gurlt: Lehrbuch der Pathol Anatomic di Haussaugetiere. A Hirchwald, Berlin, 1832, p 130. 241. Geoffroy Saint-Hilaire I: Histoire Ge´ne´rale et Particulie`re des Anomalies ou Traite de Teratologie. Bailliere, Paris, 1836. 242. Lachman R, McNabb M, Furmanski M, et al.: The acardiac monster. Eur J Pediatr 134:195, 1980. 243. Das K: Acardius anceps. Br J Obstet Gynaecol 2:341, 1902. 244. Robie GF, Payne GG, Morgan MA: Selective delivery of an acardiac, acephalic twin. N Eng J Med 320:512, 1989. 245. Meckel H: Uber die Verhaltnisse des Geschlechts, der Lebensfahigkeit und der Eihaute bei ein fachen und Mehrgebunten. Arch Anat Physiol Wissensch Med, 1850, p 234. 246. Dareste C: Recherches sur la Production Artificielle des Monstrosities, ed 2. C Reinwald, Paris, 1891. 247. Panum PL: Bidrag til Kundskab om Misfostrenes Physiologiske Betyding. Copenhagen, 1877. 248. Schatz F: Die Acardii und ihre Verwadten. Arch Gynakol 55:485, 1989. 249. Benirschke K, Harper VDR: The acardiac anomaly. Teratology 15:311, 1977. 250. Claudius M: Die Entwicklung der herzlosen Missgeburten. Schwers, Kiel, 1859. 251. Ahlfeld F: Beitrage zur Lehre von den Zwillingen. Arch Gynaeol 14:321, 1885. 252. Hunziker H: Beitrag zur Lehre vom Acardius amorphus. Beitr Geburtsh Gynaekol 11:385, 1906. 253. Park YW, Kapur RP, Shepard TH: Reversed circulation in acardiac fetuses is associated with anatomic inversions in the aortic wall. Teratology 49:267, 1994. 254. Van Allen MI, Smith DW, Shepard TH: Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Sem Perinatol 7:285, 1983. 255. Deacon JS, Machin GA, Martin JME, et al.: Investigation of acephalus. Am J Med Genet 5:85, 1980. 256. Moore TR, Gale S, Benirschke K: Perinatal outcome of forty-nine pregnancies complicated by acardiac twinning, Am J Obstet Gynecol 163:907, 1990. 257. Simpson PC, Trudinger BJ, Walker A et al.: The intrauterine treatment of fetal cardiac failure in a twin pregnancy with an acardiac acephalic monster, Am J Obstet Gynecol 147:842, 1983. 258. Schinzel AAGL, Smith DW, Miller JR: Monozygotic twinning and structural defects. J Pediatr 95:921, 1979. 259. James WH: A note on the epidemiology of acardiac monsters. Teratology 16:211, 1977. 260. Babson SG, Philips DS: Growth and development of twins dissimilar in size at birth. New Eng J Med 289:937, 1973. 261. Nylander PPS, Osankoya BO: Unusual monochorionic placentation with heterosexual twins. Obstet Gynecol 36:621, 1970. 262. Nielsen J: Inheritance in monozygotic twins. Lancet 2:717, 1967. 263. Bieber FR, Nance WE, Morton CC, et al.: Genetic studies of an acardiac monster: evidence of polar body twinning in man. Science 213:775, 1981. 264. Scott JM, Ferguson-Smith MA: Heterokaryotypic monozygotic twins and the acardiac monster. J Obstet Gynaecol Br Commonw 80:52, 1973. 265. Kerr MG, Rashad MN: Autosomal trisomy in a discordant monozygotic twin. Nature 212:726, 1966. 266. Kaplan C, Benirschke K: The acardiac anomaly: new case reports and current status. Acta Genet Med Gemellol 28:51, 1979.

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267. Buxbaum H, Wachsman DV: A case of acephalus holoacardius. Am J Obstet Gynecol 36:1055, 1938. 268. Dunn HO, Lein DH, Kenney RM: The cytologic sex of a bovine anidian (amorphous) twin monster. Cytogenet 6:412, 1967. 269. Borrell A, Pesarrodona A, Puerto B, et al.: Ultrasound diagnostic features of twin reversed arterial perfusion sequence. Pren Diagn 10:443, 1990. 270. Harger JH, Doshi N, Marchese S, et al.: Increased amnionic fluid alphs-fetoprotein due to a holoacardium amorphous twin. Clin Genet 19:257, 1981. 271. Read AP, Donnai D, Tracey J, et al.: Increased amniotic alphafetoprotein due to a holoacardium amorphus twin. Clin Genet 21:382, 1982. 272. Pretorius DH, Leopold GR, Moore TR, et al.: Acardiac twin: report of Doppler sonography. J Ultrasound Med 7:413, 1988. 273. Platt LD, DeVore GR, Bieniarz A, et al.: Antenatal diagnosis of acephalus acardia: a proposed management scheme. Am J Obstet Gynecol 146:857, 1983. 274. Seeds JW, Herbert WNP, Richards DS: Prenatal sonographic diagnosis and management of a twin pregnancy with placenta previa and hemicardia. Am J Perinatol 4:313, 1987. 275. Deprest JA, Audibert F, Van Schoubroeck D, et al.: Bipolar coagulation of the umbilical cord in complicated monochorionic twin pregnancy. Am J Obstet Gynecol 182:340, 2000. 276. Ginsberg NA, Applebaum M, Rabin SA, et al.: Term birth after midtrimester hysterotomy and selective delivery of an acardiac twin. Am J Obstet Gynecol 167:33, 1992. 277. Tsao KJ, Feldstein VA, Albanese CT: Selective reduction of acardiac twin by radiofrequency ablation. Am J Obstet Gynecol 187:635, 2002. 278. Arias R, Sunderji S, Gimpelson R, et al.: Treatment of acardiac twinning. Obstet Gynecol 91:818, 1998. 279. McCurdy CM, Childers JM, Seeds JM: Ligation of the umbilical cord of an acardiac-acephalus twin with an endoscopic intrauterine technique. Obstet Gynecol 82:708, 1993. 280. Guttmacher AF, Nichols BL: Teratology of conjoined twins. BDOAS III(1):3, 1967. 281. Badawy AH, Shehata R: Cephalothoracopagus: clinical and anatomic study of a case. Obstet Gynecol 18:106, 1961. 282. Rudolph AJ, Michaels JP, Nichols BL: Obstetric management of conjoined twins. BDOAS III(1):28, 1967. 283. Patten BM: Human Embryology, ed 3. McGraw-Hill, New York, 1968, p 157. 284. Wilder HH: Duplicate twins and double monsters. Am J Anat 3:387, 1904. 285. Grosfeld JL, Stepita DS, Nance WE, et al.: Fetus-in-fetu: an unusual cause for abdominal mass in infancy. Ann Surg 180:80, 1974. 286. Fisher GJ: Diploteratology. Trans NY State Med Soc 268:207, 1866. 287. Hirst BC, Piersol GA: Human Monstrosities, vol 1. Lea Brothers, Philadelphia, 1891, p 17. 288. Baron BW, Shermeta DW, Ismail MA, et al.: Unique anomalies in cephalothoracopagus janiceps conjoined twins with implications for multiple mechanisms in the abnormal embryogenesis. Teratology 41:9, 1990. 289. Robertson EG: Craniopagus parietalis: report of a case. Arch Neurol Psychiatr 70:189, 1953. 290. Filler RM: Conjoined twins and their separation. Sem Perinatol 10:82, 1986. 291. Foster PM: Conjoined fetuses (thoracopagus) in a dizygotic triplet pregnancy. Am J Obstet Gynecol 56:799, 1948. 292. Ripman JA: Conjoined twins as an obstetric problem. Guy’s Hosp Rep 107:173, 1958. 293. Tan KL, Goon SM, Salmon Y et al.: Conjoined twins. Acta Obstet Gynec Scand 50:373, 1971. 294. Apuzzi KK, Gahesh VV, Chervenak J, et al.: Prenatal diagnosis of dicephalous conjoined twins in a triplet pregnancy. Am J Obstet Gynecol 159:1214, 1988. 295. Zeng SM, Yankowitz J, Murray JC: Conjoined twins in a monozygotic triplet pregnancy: prenatal diagnosis and X-inactivation. Teratol, 66:278, 2002

296. Pare A: On Monstrosities and Marvels (trans by JL Pallister). University Chicago Press, Chicago, 1982. 297. Munster S: Cossmographie. H Pierre, Basel, 1552. 298. Dareste C: Memoire sur l’origine et le mode de formation des monstres doubles. Arch Zool 3:73, 1874. 299. Galton F: The history of the twins, as a criterion of the relative powers of nature and nurture. J Anthropol Inst, 1875. 300. Aird I: Conjoined twins - further observations. Br Med J 2:1313, 1959. 301. Simpson JY: A lecture on the Siamese and other viable united twins. Br Med J 1:139, 1869. 302. Sobotta J: Neurre Anschauungen uber die Entstehung der Doppelbildungen mit besonderer Berucksichtigung der menschlichen Zwillingsgeburten. Wurzburger Abbandilg Gesamtgebiet Prakt Medi 4:1, 1901. 303. Petzel MA, Erickson RP: Disorganization: a possible cause of apparent conjoint twinning. J Med Genet 28:712, 1991. 304. Stockard CR: Developmental rate and structural expression: an experimental study of twins, ‘‘double monsters’’ and single deformities and the interaction among embryonic organs during their origin and development. Am J Anat 28:115, 1921. 305. Ingalls TH, Philbrook FR, Majima A: Conjoined twins in zebra fish. Arch Environ Health 19:344, 1969. 306. Witschgi E: Teratogenic effects from overripeness of the egg, In: Congenital Malformations, FC Fraser, VA McKusick, eds. Exerpta Medica, New York, 1970, p 157. 307. Ferm VH: Conjoined twinning in mammalian teratology. Arch Environ Health 19:353, 1969. 308. Ornoy A, Navot D, Menashi M, et al.: Asymmetry and discordance for congenital anomalies in conjoined twins: a report of six cases. Teratology 22:145, 1980. 309. Milham S: Symmetrical conjoined twins: an analysis of the birth records of twenty-two sets. J Pediatr 69:643, 1966. 310. Bhettay E, Nelson MM, Beighton P: Epidemic of conjoined twins in Southern Africa. Lancet 2:741, 1975. 311. Viljoen DL, Nelson MM, Beighton P: The epidemiology of conjoined twinning in Southern Africa. Clin Genet 24:15, 1983. 312. Kallen B, Rybo G: Conjoined twinning in Sweden. Acta Obstet Gynecol Scand 57:257, 1978. 313. Hanson JW: Incidence of conjoined twins. Lancet 2:1257, 1975. 314. Shrewsbury JFD: A contribution to the historical record of monstrous births. J Obstet Gynaecol Br Emp 56:67, 1946. 315. Ballantyne JW: Manual of Antenatal Pathology and Hygiene. The Embryo. William Green and Sons, Edinburgh, 1904, p 641. 316. Guttmacher AF: Biographical notes on some famous conjoined twins. BDOAS III(1):10, 1967. 317. Van den Brand SFJJ, Nijhuis JG, van Dongen PWJ: Prenatal ultrasound diagnosis of conjoined twins. Obstet Gynecol Survey 49:656, 1994. 318. Wood MJ, Thompson HE, Roberson FM: Real-time ultrasound diagnosis of conjoined twins. J Clin Ultrasound 9:195, 1981. 319. MacKenzie TC, Crombleholme TM, Johnson MP: The natural history of prenatally diagnosed conjoined twins. J Pediatr Surg 37: 303, 2002. 320. Compton HL: Conjoined twins. Obstet Gynecol 37:27, 1971. 321. Sorosky J, Ingardia CJ, Burchell RC, et al.: Intrapartum fetal heart monitoring in conjoined twins: a case report. J Reprod Med 27: 107, 1982. 322. Edmonds LD, Layde PM: Conjoined twins in the United States, 19701977. Teratology 25:301, 1982. 323. Seller MJ: Conjoined twins discordant for cleft lip and palate. Am J Med Genet 37:530, 1990. 324. Moerman P, Fryns JP, Goddeeris P, et al.: Aberrant twinning (diprosopus) associated with anencephaly. Clin Genet 24:252, 1983. 325. Herring SW, Rowlatt UF: Anatomy and embryology in cephalothoracopagus twins. Teratology 23:159, 1981. 326. Marin-Padillo M: Notochordalbasichondrocranium relationships: abnormalities in experimental (dysraphic) disorders. J Embryol Exp Morphol 53:15, 1979. 327. Noonan JA: Twins, conjoined twins, and cardiac defects. Am J Dis Child 132:17, 1978.

Twins 328. Izukawa T, Kidd BSL, Moes CAF, et al.: Assessment of the cardiovascular system in conjoined thoracopagus twins. Am J Dis Child 132:19, 1978. 329. Cunniff C, Jones KL, Jones MC, et al.: Laterality defects in conjoined twins: implications for normal asymmetry in human embryogenesis. Am J Med Genet 31:669, 1988. 329a. Gilbert-Barness E, Debich-Spicer D, Opitz JM: Conjoined twins: Morphogenesis of the heart and a review. Am J Med Genet 120A:568, 2003. 329b. Tabin CJ, Vogin KJ: A two-cilia model for vertebrate left-right axis specification. Genes Dev 17:1, 2003. 329c. Burdine RD, Schier AF: Conserved and divergent mechanisms in leftright axis formation. Genes Dev 14:763, 2000. 330. Benirschke K, Temple WW, Bloor CM: Conjoined twins: nosology and congenital malformations. BDOAS XIV(6A):179, 1978. 331. Kim CK, Barr RJ, Benirschke K: Cytogenetic studies of conjoined twins: a case report. Obstet Gynecol 38:877, 1971. 332. Melnick M, Myrianthopoulos NC: The effect of chorion type on normal and abnormal developmental variation in monozygotic twins. Am J Med Genet 4:147, 1979. 333. Marin-Padilla M, Chin AJ, Marin-Padilla TM: Cardiovascular abnormalities in thoracopagus twins. Teratology 23:101, 1981. 334. Spitz L, Kiely E: Success rate for surgery of conjoined twins. Lancet 356:1765, 2000. 335. Jones KL: Smith’s Recognizable Patterns of Human Malformations. ed 5. WB Saunders, Philadelphia, 1997, p 652. 336. Myrianthopoulos NC: Congenital malformations in twins: epidemiologic survey. BDOAS XI(8):1, 1975. 337. Gericke GS: Genetic and teratological considerations in the analysis of concordant and discordant abnormalities in twins. S Afr Med J 69:111, 1986. 338. Hay S, Wehrung DA: Congenital malformations in twins. Am J Hum Genet 22:662, 1970. 339. Windham GC, Bjerkedal T, Sever LE: The association of twinning and neural tube defects: studies in Los Angeles, California and Norway. Acta Genet Med Gemellol 31:156, 1982. 340. James WH: Twinning and anencephaly. Ann Hum Biol 3:401, 1976. 341. Riccardi VM, Bergmann CA: Anencephaly with incomplete twinning (Diprosopus). Teratology 16:137, 1977. 342. Davies J, Chazen E, Nance WE: Symmelia in one of monozygotic twins. Teratology 4:367, 1971. 343. Suslak L, Mimms GM, Desposito F: Monozygosity and holoprosencephaly: cleavage disorders of the ‘‘midline field’’. Am J Med Genet 28:99, 1987. 344. Durkin MV, Kaveggia EG, Pendelton E, et al.: Analysis of etiologic factors in cerebral palsy with severe mental retardation. I. Analysis of gestational, parturitional and neonatal data. Eur J Pediatr 123:67, 1967. 345. Hoyme HE, Higginbottom MC, Jones KL: Vascular etiology of disruptive structural defects in monozygotic twins. Pediatrics 67:288, 1981. 346. Melnick M: Brain damage in survivor after in-utero death of monozygotic co-twin. Lancet 2:1287, 1977. 347. Hughes HE, Miskin M: Congenital microcephaly due to vascular disruption: in utero documentation. Pediatrics 78:85, 1986. 348. Jung JH, Graham JM, Schultz N, et al.: Congenital hydranencephaly/ porencephaly due to vascular disruption in monozygotic twins. Pediatrics 73:467, 1984. 349. Bugge M, Petersen MB, Christensen MF: Monozygotic twins discordant for gastroschisis: case report and review of the literature of twins and familial occurrence of gastroschisis. Am J Med Genet 52:223, 1994.

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350. Lawson K, Waterhouse N, Gault, et al.: Is hemifacial microsomia linked to multiple maternities? Br J Plastic Surg 55:474, 2002. 351. D’Alton ME, Newton ER, Cetrulo CL: Intrauterine fetal demise in multiple gestation. Acta Genet Med Gemellol 33:43, 1984. 352. Yoshioka H, Kadomoto Y, Mino M, et al.: Multicystic encephalomalacia in liveborn twin with a stillborn macerated co-twin. J Pediatr 95:798, 1979. 353. Reisman LE, Pathak A: Case reports: bilateral renal cortical necrosis in the newborn associated with feto-maternal transfusion and hypermagnesemia. Am J Dis Child 111:541, 1966. 354. Moore CM, McAdams AJ, Sutherland J: Intrauterine disseminated intravascular coagulation: a syndrome of multiple pregnancy with a dead twin fetus. J Pediatr 74:523, 1969. 355. Johnson GF, Robinow M: Aglossia-adactylia. Radiology 128:127, 1978. 356. Little J, Bryan E: Congenital anomalies in twins. Sem Perinatol 10:50, 1986. 357. Hall JG: Twins and twinning. In: Emory and Rimoin’s Principles and Practice of Medical Genetics, ed 3. DL Rimoin, JM Connor, RE Pyeritz, BR Korf, eds. NS Churchill Livingstone, New York, 2002, p 501. 358. Hall JG: Twinning: mechanisms and genetic implications. Curr Opin Genet Devel 6:343, 1999. 359. Shafer LG, Kashorek C, Bacino CA, et al.: Caution: telomere crossing. Am J Med Genet 87:278, 1999. 360. Van Allen MI: Fetal vascular disruptions: mechanisms and some resulting birth defects. Pediatr Ann 10:219, 1981. 361. Phelan MC, Geer JS, Blackburn WR: Vascular anastomoses leading to amelia and cutis aplasia in a dizygotic twin pregnancy. Clin Genet 52:126, 1998. 362. Newman HH: The question of mirror imaging in human one-egg twins. Hum Biol 12:21, 1940. 363. Keeler CE: On the amount of external mirror imaging in double monsters and identical twins. Proc Natl Acad Sci USA 15:839, 1929. 364. Jaenisch R: DNA methylation and imprinting: why bother? Trends Genet 13:323, 1997. 365. Bianchi D: Fetomaternal cell trafficking: a new cause of disease? Am J Med Genet 91: 22, 2000. 366. Boomsma D, Busjahn A, Peltonen L: Classical twin studies and beyond. Nature Rev Genet 3:872, 2002. 367. Barker DJ: Fetal origins of coronary heart disease. Br Med J 311:171, 1995. 368. Phillips DIW, Davies MJ, Robinson JS: Fetal growth and the fetal origins hypothesis in twins—problems and perspectives. Twin Res 4:327, 2001. 369. Greenberg DA, Hodge SE, Sowinski J, et al.: Excess of twins among affected sibling pairs with autism: implications for the etiology of autism. Am J Hum Genet 69:1062, 2001. 370. Hallmayer J, Glasson EM, Bower C, et al.: On the twin risk in autism. Am J Hum Genet 71:941, 2002. 371. Lambalk CB, Boomsma DI: Genetic risk factors in tumours of the testis: lessons from twin studies. Twin Res 1:154, 1998. 372. Swerdlow AJ, De Stavola BL, Swanwick MA, et al.: Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet 350:1723, 1997. 373. Verkasalo PK, Kaprio J, Pukkula E, et al.: Breast cancer risk in monozygotic and dizygotic female twins: A 20-year population-based cohort study in Finland from 1976 to 1995. Cancer Epidemiol Biomarkers Prev 8:271, 1999. 374. Peto J, Mack TM: High constant incidence in twins and other relatives of women with breast cancer. Nature Genet 26:411, 2000.

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35 Umbilical Cord Will Blackburn

T

he umbilical cord is composed of elements derived from the primitive (primary) yolk sac (allantois and vitelline duct), the connecting (body) stalk, and the amnion. The primary yolk sac is lined with endoderm and forms the central portion of the embryonic gut (Fig. 35-1). In the caudal part of the embryonic gut, the allantois appears as an outpouching (evagination) that extends ultimately as a small duct into the connecting stalk mesenchyme (Fig. 35-1). Along its course, a portion of the allantois develops into the urinary bladder; the portion between the bladder and the connecting stalk will become the urachus, and the attending ‘‘allantoic blood vessels’’ will become the left and right umbilical arteries. After contributing to the embryonic gut, the remains of the primary yolk sac elongate ventrally, an alteration that narrows its connection with the midgut. This area of narrowing between the midgut and the remaining yolk sac (now termed the secondary yolk sac) is the entrance to the ‘‘vitelline duct’’ (Fig. 35-1). The endoderm lining the yolk sac is surrounded by mesenchyme, a portion of which differentiates into the vitelline arteries and veins. The yolk sac mesenchyme also contributes pluripotential stem cells which ultimately migrate to target sites within various organs (lungs, bone marrow, liver, etc). With further development, the entire connecting stalk is covered with amnion. As development proceeds, the yolk sac tissues fuse with the more caudally placed connecting stalk tissues: the latter include the allantois and its attending vessels (umbilical arteries and veins). The umbilical cord is thus formed by the fusion of yolk sac derivatives and connecting stalk mesenchyme. Initially, the umbilical cord is short and relatively large in diameter (week 6 ). By week 8 the organ is more elongated, and surface deformations characteristic of vascular spiraling are obvious (Fig. 35-2). In humans, the secondary yolk sac is small and ‘‘rudimentary’’ even quite early in development. It ultimately becomes sandwiched between the amnion and the chorion on the surface of the placental plate very near the insertion of the umbilical cord. Therefore, remnants of the vitelline (omphalomesenteric) duct may be found throughout the length of the umbilical cord. These are usually present, however, near the fetal body wall (proximal one-third of the umbilical cord). The same may be said of the delicate, thin-walled vitelline vessels (arteries and veins). The allantois arises more caudally from yolk sac endoderm, taking its apparent origin in the region of the hind gut. Portions of the allantois give rise to the urinary bladder from which it extends as a tiny duct (the ‘‘urachus’’) within the median

ligament to the umbilical ring; it is accompanied by (allantoic) blood vessels, which ultimately become the left and right umbilical arteries. Allantoic duct remnants may persist at any site within the umbilical cord but most often are confined to the proximal 10–15 cm. Wharton’s jelly, a special thixotropic packing jelly, is apparently derived from mesenchyme residing within the splanchnopleure and the connecting stalk. Once the contents of the connecting stalk and the yolk sac structures fuse and form the definitive umbilical cord, Wharton’s jelly begins to accumulate rapidly, surrounding the elongating and spiraling umbilical arteries and veins. At term gestation, about 76% of the umbilical cord cross-sectional area is composed of Wharton’s jelly. Little is known of the influences that limit the confines of Wharton’s jelly at either the body wall or at the placental plate. A unique spiraling of the umbilical arteries and vein develops early in gestation (week 8), such that by weeks 12–14, most umbilical cords contain rather tightly spiraled blood vessels. All vessels spiral in the same direction, and the vessels are spatially organized so as to prevent kinking or lumen occlusion when the cord is deformed by ordinary bends, loops, kinks, torsions, and knots, or linear stretching. The morphologic organization of the umbilical vessels is much like that of a spiral telephone cord, which allows stretch without true kinking or obstruction. This unique organizational plan is best demonstrated in latex casts of the umbilical cord vessels at term gestation (Fig. 35-3). To emphasize further the unique structural organization of the umbilical cord, mention of the organization of the surface amnion epithelium is justified. These cells are somewhat cuboidal early in development; however, by about week 16 the surface epithelium becomes more squamous and tight intercellular bonds are formed. The arrangement of the cells is such that when tension is applied in a linear manner the diameter of the cord decreases, Wharton’s jelly moves both proximally and distally within the amnionic sheath, and the coiled vessels are stretched. Scanning electron micrographs of the amnionic sheath covering the umbilical cord suggest that the amnion cells accommodate linear stretch (tension) in a manner similar to that noted in the child’s toy ‘‘Chinese hand cuff’’ or ‘‘finger puzzle’’ (Fig. 35-4). The tensile strength of the umbilical cord reaches maturity by 30 weeks gestation. At this point, and thereafter, the cord will rupture only when a force greater than 2.9 times the fetal body weight is applied. This unique structural arrangement of the 1413

Bivesicular embryo with formation of the embryonic disk at junction between the primary yolk sac (YS) and the amnion cavity (AC). The vesicles are surrounded by extraembryonic mesenchyme (EM).

During day 17 or early day 18, the allantois appears as an evagination from the primary yolk sac that invades the connecting stalk (CS) mesenchyme. During this period, the extraembryonic celom (EC) develops and surrounds the embryo.

During day 22, the extraembryonic celom is reduced in size due to expansion and counterclockwise growth of the amnionic cavity. The primary yolk sac forms much of the midgut and the residual component, the secondary yolk sac (SYS), projects into the extraembryonic celom.

By the end of the first month, the extraembryonic celom is greatly reduced in size due to expansion of the amnionic cavity, which now surrounds the developing embryo except for the region of the connecting stalk mesenchyme. The secondary yolk sac is considerably reduced in size and lies near the surface of the developing placental plate, and the vitelline duct or yolk stalk (V) remains connected to the embryonic midgut. The allantoic duct (A) extends deep into the connecting body stalk.

By day 38, the connecting stalk containing the vitelline duct, the allantoic duct, and the umbilical vessels (not shown) becomes ensheathed by the amnion (Am). The developmental complex is now referred to as the ‘‘umbilical cord.’’ Fig. 35-1. Schematic series depicting the embryonic development of the umbilical cord (days 13–38). 1414

Umbilical Cord

Fig. 35-2. Day 30 postconception. Longitudinal schematic of developing embryo showing vascular system accompanying umbilical cord development. The vitelline arteries (VA) and veins (VV) surround the vitelline duct (yolk stalk) and the secondary yolk sac (SYS). The umbilical veins (UV) and arteries (UA) accompany the allantoic duct, developing from angiogenic mesenchyme surrounding the duct. With vascularization of the developing trophoblast, chorioallantoic placentation is achieved. AC, amnion cavity; Am, amnion epithelium; EM, extraembryonic mesenchyme; EC, extraembryonic celom.

umbilical vessels (the umbilical arteries spiraling around a similarly directed spiraled umbilical vein) allows the blood vessels to extend their length during fetal heart systole. This phenomenon promotes arterial blood flow in the direction of the placenta and, at the same time, umbilical venous (oxygenated) blood flow toward the fetal heart. This anatomic complex is thus a unique pump enhancing fetal blood flow to and from the placenta. This anatomic complex has been referred to as the ‘‘pulse pump.’’1 Understanding the developmental events leading to the establishment of the umbilical cord allows one to explain the various types of cystic malformations and their distributions within the human umbilical cord. Most such cysts are derived from the covering sheath (amnion) or from ductal elements (allantois and vitelline). The same may be said of neoplasms, most of which originate from vascular elements (allantoic, vitelline) or from cells with pluripotential capacities (e.g., yolk sac origin). The latter consideration explains why teratomas of the placenta are usually located between the amnion and the chorion on the placental plate surface near the insertion of the umbilical cord. Normal Growth and Development of the Umbilical Cord

Although few carefully designed studies have been reported which evaluate factors controlling umbilical cord growth, studies of cord

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Fig. 35-3. (A) Latex injection of umbilical cord vessels at term gestation showing relatively few vascular spirals. The arteries are darker and smaller in caliber than the single umbilical vein. (B) Latex-injected umbilical arteries and vein in term human umbilical cord showing tightly spiraled vessels. Note that the umbilical vein spirals in the same direction as the arteries. (C) Cast of latex-injected umbilical cord at term gestation with cord parenchyma digested away. The vascular spiral arrangement allows the cord to stretch and grow without vascular kinking or obstruction. Helical spiraling of the umbilical blood vessels allows the cord to undergo torsion (360o twisting) without great risk for vascular obstruction.

morphometry during normal and abnormal fetal development suggest that fetal movement, traction, and blood pressure stimulate the linear growth of the cord.2–6 In our experience, the human umbilical cord grows continually throughout pregnancy (Fig. 35-5); its rate of growth decreases after 24 weeks gestation. Relatively little is known of the factors that govern Wharton’s jelly production and its level of hydration and hence umbilical cord caliber (diameter). Umbilical cord hydration is closely related to its circumference. The latter dimension (growth) diminishes after 30 weeks gestation. In an attempt to establish normal morphometric data concerning umbilical cord dimensions, we have constructed growth curves for its length and mean diameter at weekly intervals throughout gestation (Figs. 35-5 and 35-6). Other workers have offered similar data.7 Umbilical Cord Anomalies

Umbilical cord anomalies are common (incidence is 26–35%), and about 1.2% of cords contain two or more anomalies. The incidence of umbilical cord anomalies is considerably higher if one includes an analysis of tissues from spontaneous abortions.8 The cords of electively aborted fetuses are abnormal much less frequently (4– 5%). In general, anomalous umbilical cord development includes abnormalities in dimensions (diameter, length), vascular spiraling,

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Fig. 35-4. Scanning electron microscope views of the amnionic surface of the human umbilical cord at term gestation. A. Longitudinal (side) view of cord showing rather flat, squamoid, amnion cells with vertical cell surface creases due to drying. B. End view of freeze-fractured cord

Fig. 35-5. Normal human umbilical cord linear growth during 20–42 weeks gestation. Mean values are plotted as solid line curves with ±2 SD in hatched areas. (From Blackburn et al.4)

showing circumferential arrangement (arrows) of umbilical cord mesenchyme and Wharton’s jelly region. C. Higher magnification of umbilical cord amnion showing diamond-shaped cells arranged (arrows) in a manner resembling the surface of a ‘‘Chinese handcuff ’’ toy.

and composition (too many or too few vessels), cysts, neoplasms (hemangiomas, teratomas), aberrations of Wharton’s jelly (too much or too little), and distortional abnormalities (knots, loops, torsions, and twists). In this chapter we have attempted to refine the nomenclature, using the simplest and clearest terms and avoiding the more classic Latin terms with which few clinicians are familiar. A few entries have been included that may not, in the strictest sense, be regarded as developmental malformations; these require attention so as to enable differentiation of the true developmental abnormalities. In summary, while the umbilical cord is one of the most intriguing of the human organs, it is one of the least investigated. At the cellular and molecular levels, little is known of the normal or abnormal biology of the umbilical cord. The only sign that most humans have of umbilical cord existence is a shallow pit-like scar—the umbilicus. Cullen’s statement5 regarding the nature of the umbilicus deserves an honorable mention: In anatomy, then, it [the umbilicus] is little better than a mere landmark. When we assume the spectacles of the embryologist, however, it takes on great importance. If one may be allowed a poetical image, it is all that remains of the stem that bound us to the parental stalk. It is a reminder that we have been plucked and must sooner or later die. It might be said that when the stem is severed, we cease to live in any true sense. We may be ornamental like roses or useful like cabbages, but only for a little while. Our dissolution has begun. References 1. Reynolds SRM: The umbilical cord. Scientific Am 187:70, 1952. 2. Mills JL, Harley EE, Moessinger AC: Standards for measuring umbilical cord length. Placenta 4:423, 1983. 3. Soernes T, Bakke T: The length of the human umbilical cord in twin pregnancies. Am J Obstet Gynecol 157:1229, 1987.

Umbilical Cord

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Fig. 35-6. Normal human umbilical cord diameter growth during weeks 16–42 gestation. Values are plotted as a mean of three caliper measurements (mm), and individual growth curves are plotted for males and females. (Blackburn and Cooley, unpublished data.)

4. Blackburn WR, Cooley NR Jr, Manci EA: Correlations between umbilical cord structure-composition and normal and abnormal fetal development. Proc Greenwood Genet Center 7:180, 1988. 5. Cullen TS: Embryology, Anatomy, and Diseases of the Umbilicus Together With Diseases of the Urachus. WB Saunders, Philadelphia, 1916. 6. Naeye RL: Umbilical cord length: clinical significance. J Pediatr 107: 278, 1985. 7. Patel D, Dawson M, Kalyanam P, et al.: Umbilical cord circumference at birth. Am J Dis Child 143:638, 1989. 8. Javert CT, Barton B: Congenital and acquired lesions of the umbilical cord and spontaneous abortion. Am J Obstet Gynecol 63:1065, 1952.

35.1 Umbilical Cord Calcifications Definition

Umbilical cord calcifications are the presence of calcium deposits within the umbilical cord. Calcification of the yolk sac and calcification in teratomas are not included in this entry. Diagnosis

When large deposits of calcium are present within the umbilical cord, the lesions may be detected by radiograph or ultrasonography. Most often, these yellow-white, gritty deposits are detected during routine examination, including histologic studies. In certain conditions, calcium is deposited within systemic arteries in stillborn fetuses or in liveborn infants with idiopathic infantile arterial calcifications, including the umbilical arteries.1,2 Radiologic examination of the umbilical cord will also identify calcium deposits but does not accurately identify the exact tissues involved. Etiology and Distribution

Umbilical cord calcium deposition is most often associated with funisitis with vasculitis. In a few cases, the calcium deposits are within the vascular lumen and are associated with previous thrombosis; calcium may also be deposited within the intramural or adventitial regions of the umbilical blood vessels (Fig. 35- 7). Occasionally, foci of calcium may be detected within Wharton’s jelly, as in ‘‘sclerosing funisitis,’’ or within a focus of old hemorrhage (Fig. 35-8).3–6

Fig. 35-7. Umbilical cord artery with calcium deposition (arrows) within lumen.

Ivemark et al.1 reported two stillborn infants with generalized arterial calcification and hydramnios. Two additional, similar cases were referred to in the literature. These authors suggest that hydramnios leads to a drastic alteration in ion and fluid exchange Fig. 35-8. Umbilical cord showing focus of calcium deposition (arrows) within Wharton’s jelly in an area of recent hemorrhage.

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between the mother and the developing fetus and that this leads to altered fetal homeostasis and to the precipitation of mineral salts in predisposed tissues, particularly the elastic membranes of blood vessels. In our experience with cases of hydramnios with associated fetal loss, calcification is rare. The presence of umbilical cord calcification is rare. The condition is most common in stillborn infants or in infants with funisitis or those with a history of umbilical cord hemorrhage. The lesion can be associated with iatrogenic umbilical cord venipuncture. Umbilical cord calcification has been associated with Salla disease, fetal nephrocalcinosis, macerated stillborns, and has even been found in normal liveborn infants. Prognosis, Prevention, and Treatment

Umbilical cord calcifications are often associated with fetal death. In liveborn infants, the prognosis is variable because of the likelihood of active or previous fetal infection. In cases in which calcium deposition is present in the systemic fetal arteries, the prognosis has uniformly been poor. No treatment is available once the lesion is established. Prevention is associated with the control of prenatal infection. References (Umbilical Cord Calcifications) 1. Ivemark BI, Lagergren C, Ljungqvist A: Generalized arterial calcification associated with hydramnios in two stillborn infants. Acta Paediatr (Suppl) 135:103, 1962. 2. Van Dyck M, Proesmans W, Van Hollebeke E, et al.: Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement. Eur J Pediatr 148:374, 1989. 3. deSa DJ: Diseases of the umbilical cord. In: Pathology of the Placenta. EVDK Perrin, ed. Churchill Livingston, New York, 1984, p 128. 4. Perrin EV, Bel JK: Degeneration and calcification of the umbilical cord. Obstet Gynecol 26:371, 1965. 5. Khong TY, Dilly SA: Calcifications of umbilical artery: two distinct lesions. J Clin Pathol 42:931, 1989.

6. Schiff I, Driscoll SG, Naftolin F: Calcification of the umbilical cord. Am J Obstet Gynecol 126:1046, 1976.

35.2 Umbilical Cord Amnion (Inclusion) Cysts Definition

Umbilical cord amnion (inclusion) cysts are inclusions (infoldings) of the amnionic surface of the umbilical cord or placental plate. Inclusion cysts are lined by amnionic cells and are fluid filled. Cystic anomalies of the umbilical cord from yolk sac or allantois, cysts associated with teratomas, pseudocysts (mucoid degeneration of Wharton’s jelly), and edema of the umbilical cord are discussed in Sections 35.3 through 35.5. Diagnosis

Umbilical cord cysts of amnionic origin are readily identified by gross inspection. The cysts are thin walled, fluid filled, and appear as subamnionic accumulations of straw-colored or clear serous fluid. Diagnosis is established by histologic section showing an intact epithelial lining identical to that of the surface amnion. There is little or no discernible collagen or fibroid layer within the cyst wall. Usually the cysts are quite small; however, relatively large (6 cm in diameter) amnion inclusion cysts have been described (Fig. 35-9). Occasionally, the large cysts are associated with elevated a-fetoprotein levels. Etiology and Distribution

Virtually all organs ensheathed by serous membranes (e.g., ovary, pancreas, lung) have been shown to develop cysts lined by the covering serosa. The umbilical cord is no exception. Umbilical cord amnion cysts are relatively rare in our experience. We have observed 4 in 10,000 cord examinations. Amnion inclusion cysts are

Fig. 35-9. A. Umbilical cord showing conspicuous enlargement (arrows) of the proximal region due to herniation of small bowel. A small cyst (C) is present on the right. B. At higher magnification, the cyst wall is thin (arrows) and contains clear fluid. Histologic studies revealed a single layer of amnion-like cells composing the inner lining of the cyst.

Umbilical Cord

the least common cystic abnormality of the umbilical cord. Usually, cysts of this sort are more common in the proximal or distal extremes of the cord. Prognosis, Prevention, and Treatment

Although amnion inclusion cysts are seen with increased frequency in stillborn fetuses, most such cysts are, in reality, focal areas of umbilical cord edema rather than true cysts.1 In a few examples in which amnion inclusion cysts are associated with elevated levels of amnionic fluid a-fetoprotein and abortion was elected, no associated fetal anomalies were detected at necropsy. Treatment or preventive measures are not indicated.

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umbilical arteries and, hence, the umbilical cord has a single umbilical artery. In these cases, the median ligament will contain only a single umbilical artery. If both vessels fail to differentiate, the umbilical cord and the placenta may be vascularized by vessels derived from the vitelline blood vessels, whose origin will be from or near the superior mesenteric artery. In rare instances, the median ligament may contain two arteries, while distally the umbilical cord may contain only one artery. In such instances, the anomaly most likely resulted from atresia of a preexisting, presumably normal vessel. Nevertheless, these lesions are, by definition, developmental anomalies; but in reality a few may be ‘‘secondary’’ in nature, e.g., the atrophy and loss of the vessel following embolization or possibly another catastrophic event.

Reference (Umbilical Cord Amnion Cysts) 1. Browne FJ: On the abnormalities of the umbilical cord which may cause antenatal death. J Obstet Gynaecol Br Emp 32:17, 1925.

35.3 Umbilical Cord Cysts and Remnant Anomalies of Allantoic Duct Origin Definition

Cystic and ductal remnants of the allantoic duct originally present as lesions within the umbilical cord (usually the proximal segment), the umbilicus, or within the median ligament (urachus) between the umbilical ring and the apex of the urinary bladder. The latter lesions are extraperitoneal and are usually attached to the dome of the urinary bladder. Umbilical cord allantoic cysts, umbilical cord urinary retention cysts (‘‘giant umbilical cord’’), urachal cysts, patent urachus, ectopic urinary bladder, short urachus (urachal band), and urachal agenesis are included in this entry. The allantois is (by day 13) a ductal evagination from the caudal portion of the primary yolk sac. This duct-like structure arises in a portion of the yolk sac that will become the hindgut. The allantois initially serves as an extraembryonic urinary bladder. The proximal segment of the allantois gives rise in part to the cloaca, a portion of which becomes the urinary bladder; the middle allantoic duct segment extends from the superior apex of the urinary bladder to the umbilicus, where it then enters the connecting (body) stalk. The middle allantoic segment lies in the midline; it extends superiorly within the median ligament, lying between the left and right umbilical arteries (Fig. 35-10). This segment will become the urachus. The distal allantoic segment extends from the umbilical ring for several centimeters into the proximal umbilical cord. By about 15 weeks gestation, the middle and distal allantoic segments become an atretic cord without a discernible lumen. Persistence of a patent allantoic duct or portions thereof may give rise to a variety of developmental anomalies. These usually present as cystic structures. Less commonly, the duct may remain patent and drain urine into the proximal umbilical cord prenatally or from the umbilicus postnatally (Table 35-1). Rarely, the allantois fails to differentiate in toto and is associated with agenesis of the urinary bladder. In these cases, the middle and distal segments are also agenic, as are the allantoic blood vessels. In such cases, the human placenta is vascularized by vitelline vessels and, by definition, is ‘‘choriovitelline’’ in nature. It should be emphasized that the allantoic blood vessels are derived from mesenchymal condensations accompanying the migrating allantoic duct. A unilateral failure of mesenchymal differentiation of this sort leads to agenesis of one (left or right) of the

Diagnosis

Cysts and ductal remnants that are present in the proximal umbilical cord and lie between the umbilical arteries are usually of allantoic (urachal) origin. It is important to determine whether such lesions are indeed of allantoic or vitelline duct origin in order to determine the direction of further surgical exploration of the abdomen, which is always indicated (Table 35-1). All umbilical cords should be examined at delivery. Histologic examination of labeled cross sections of the proximal, middle, and distal cord will identify persistent, patent ducts and/or cysts. Obviously, the proximal section of the umbilical cord is most important in that it gives a clue as to the structures left behind in the umbilicus that are continuous with the fetal gastrointestinal, urinary, and vascular systems. Although many authors state that ducts and cysts of urachal origin are lined by ‘‘urothelium’’ rather than the traditional ‘‘cuboidal endothelium’’ seen in vitelline (yolk) duct remnants or cysts, in our experience the histologic differentiation is not totally reliable. Usually, but not always, cysts and ductal remnants of allantoic origin are devoid of smooth muscle. A thin layer of smooth muscle often surrounds cysts and ductal remnants of vitelline origin. More reliable is the subsequent evaluation of the infant’s abdomen by ultrasonography and by radiology using contrast media injection into the duct at the umbilicus.1 Almost always, surgical exploration definitively establishes the etiologic nature of the persistent duct. The presence of a cyst or duct filled with urine may lead to ‘‘giant umbilical cord.’’ Such umbilical cords should be ligated several centimeters away from the abdominal wall and dissected using transillumination. Fluid-filled structures should be aspirated and tested for urine. The dilated duct or cyst can then be further examined by the injection of contrast media.2 Rarely, the urine-filled, dilated allantoic duct may be surrounded by smooth muscle cells and show histologic organization resembling that of the urinary bladder. Rarely, intra-abdominal urachal cysts and/or patent urachal ducts may persist into adulthood and present with symptoms of recurrent infection or urine leaking from the umbilicus.3 A rare anomaly involving the allantoic duct is the formation of the short ‘‘urachal band.’’ In this situation, the urachal lumen is properly obliterated; however, the atretic cord (urachus) left behind appears to be too short, and during micturition the umbilicus is inverted. Often, pain is present and described as ‘‘terminal dysuria.’’ Examination reveals an unusually short urachus, and often a small, dome-shaped diverticulum is present at the junction between the urachus and urinary bladder. The urachus normally extends for several centimeters into the proximal umbilical cord. At times, these segments may form cysts that do not communicate into the umbilicus or the fetal

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Fig. 35-10. A collage of the normal anatomy and the anomalies of the abdominal segment of the allantoic duct (urachus). A. Posterior peritoneal view of the umbilicus (U), median ligament containing the umbilical arteries (UA), and the urachus extending from the dome of the urinary bladder (B). B. Patent urachus (Ur) in association with urethral stenosis (arrow). C. Patent urachus forming the urachal diverticulum anomaly (UD) immediately above the urinary bladder (B).

D. Patent distal urachus with cyst (UC) and an open sinus tract (arrow) entering the umbilicus. E. Multiple isolated urachal cysts (UC) within the proximal urachal segment. The distal urachus is atretic, and the umbilicus (UM) is normal. F. Massive dilation of the urachus (undescended bladder, ‘‘B’’) with open fistula at umbilicus (Um). Cullen’s case showed a valve-like structure at the apex of the urinary bladder (arrow). (Redrawn and modified from Cullen.8)

abdomen. If communication continues into the umbilicus or to the level of the median ligament, surgical exploration and treatment are indicated.

anomalies are presented in Figure 35-10. In most cases, the pathogenesis of allantoic duct anomalies is thought simply to be the result of incomplete involution during normal development. Patent urachus has been described in fetuses exposed to methimazole and carbimazole during development. The incidence of urachal anomalies is not well documented in the literature. The overall impression is that the incidence of allantoic-derived anomalies is less than those of vitelline duct derivation. Steck and Helwig4 stated that some degree of patency of the urachal lumen could be demonstrated in 30–50% of all patients. In our experience in which the median ligament is histologically examined in all pediatric and perinatal necropsies, patency is rarely demonstrated (less than 5.0%). Our results are

Etiology and Distribution

The allantois is derived from the primary yolk sac as a ductal evagination. It arises near the ‘‘hindgut region’’ of the embryonic gut and extends anteriorly and superiorly where it gives rise to the urinary bladder en route and then to the urachus. Finally, the migrating duct extends through the umbilical ring and into the proximal umbilical cord, where it terminates usually within 10 cm of the umbilical ring. Cystic and ductal remnants may originate at any site distal to the urinary bladder apex. The variations of these

Umbilical Cord

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Table 35-1. Clinical manifestations of allantoic duct remnant anomalies Anomaly

Umbilical Cord

Umbilicus

Urachus (Median Ligament)

Patent urachus

Giant umbilical cord (urine filled)

Wet-moist umbilicus, chronic omphalitis

Thick urachal cord

Allantoic cyst

Focally enlarged umbilical cord

Umbilical cystic mass

Midline cystic mass (space of Retzius), infection-peritonitis, prostatism, obstructive uropathy

Urachal cyst

Usually none

Leaky-wet umbilicus, sinus tract ostium, recurrent omphalitis

Thick urachal cord, recurrent cystitis

Urachal diverticulum

None

Inversion during urination

Recurrent cystitis

Short urachus (urachal band)

None

Umbilical inversion during urination

Terminal dysuria, bladder distortion during urination

Allantoic remnants may undergo neoplastic transformation. Benign and malignant neoplasms of allantoic derivation have been reported in infants, children, and adults.

similar to those of Mahoney and Ennis,5 who reported the incidence of a completely patent urachus to be extremely low. Prognosis, Prevention, and Treatment

Isolated umbilical cord cysts and ductal remnants of allantoic duct origin are usually of no clinical significance; however, their presence should initiate a more thorough evaluation of the embryologically related structures (umbilicus, median ligament, and urinary bladder). A patent urachus may produce recurrent urinary infections resembling cystitis.6 Usually, when the patent urachus begins to leak urine from the umbilicus in the adult, infection plays a role in the process. Pregnancy may also aggravate such persistent patent ducts. The clinical complications and expressions of allantoic anomalies confined to the median ligament (i.e., abdomen) include chronic infection, peritonitis, benign and malignant neoplasms, prostatism and, rarely, obstructive uropathy (hydroureter and hydronephrosis). Adenocarcinoma (mucinous type) of urachal origin is rare but may present as early as the second year of life. Benign tumors of urachal origin include mesenchymoma and histocytoma.7 Treatment is surgical ligation and excision. No relevant preventive measures are known. References (Umbilical Cord Cysts and Remnant Anomalies of Allantoic Duct Origin) 1. Avni EF, Matos C, Van Regemorter G, et al.: Symptomatic patent urachus in children: The contribution of ultrasound. Ann Radiol 30:482, 1987. 2. Ente G, Penzer PH, Kenigsberg K: Giant umbilical cord associated with patent urachus. An external clue to internal anomaly. Am J Dis Child 120:82, 1970. 3. Neilson TP, Nelson RM, Lee-Green B, et al.: Patent urachus complicating pregnancy: a review and report of a case. Am J Obstet Gynecol 143:61, 1982. 4. Steck WD, Helwig EB: Umbilical granulomas, pilonidal disease and the urachus. Surg Gynecol Obstet 120:1043, 1965. 5. Mahoney PJ, Ennis D: Congenital patent urachus. N Engl J Med 215: 193, 1936. 6. Newman BM, Karp MP, Jewett TC, et al.: Advances in the management of infected urachal cysts. J Pediatr Surg 21:1051, 1986. 7. Avni EF, Matos C, Diard F, et al.: Midline omphalovesical anomalies in children: contribution of ultrasound imaging. Urol Radiol 10:189, 1988. 8. Cullen T: Embryology, Anatomy, and Diseases of the Umbilicus Together With Diseases of the Urachus. WB Saunders, Philadelphia, 1916.

35.4 Umbilical Cord Cysts and Remnants of Vitelline (Omphalomesenteric Duct) Origin Definition

Cysts, ductal remnants, and patent segments of the vitelline (omphalomesenteric) duct present as anomalies within the abdomen, umbilicus, or the umbilical cord (Fig. 35-11). Umbilical enteric fistulas, umbilical sinus, vitelline cysts and/or ductal remnants, omphaloileal fistula, Meckel diverticulum, congenital (vitelline) band, umbilical cord hernia, and yolk sac remnants are included in this entry. As emphasized in the embryology review in the chapter introduction, the umbilical cord is derived by the fusion of two yolk sac derivatives (the allantois and the secondary yolk sac with its associated vitelline duct) with the embryonic mesenchyme of the connecting body stalk. These three components are ultimately ensheathed in amnion. The resulting organ, the umbilical cord, is surrounded by amnionic fluid. In the human, the umbilicoplacental vessels are of allantoic derivation and, hence, the term chorioallantoic placentation. In certain other animals (e.g., rodents) and occasionally in humans (Section 35.21), the umbilicoplacental vessels are derived from those accompanying the vitelline duct and, hence, the term choriovitelline placentation. Most of the primary yolk sac is incorporated into the embryonic gut and the allantois; the remaining portion resides outside of the embryonic body wall and ultimately is referred to as the secondary yolk sac. The latter is attached to the embryonic midgut by the vitelline (omphalomesenteric) duct. When the embryonic gut rotates and becomes established within the abdominal cavity, the vitelline duct extends throughout the length of the umbilical cord, terminating in a dilated cul-de-sac, the secondary yolk sac. The vitelline duct begins to narrow after placental nutrition begins (week 5); during week 7, the vitelline duct normally is obliterated. The secondary yolk sac in the human reaches its maximum size at about 7 weeks gestation. At this time it measures only 8–10 mm in maximum diameter. Thereafter, it shrinks and will ultimately form a flattened, discoid, pale yellow tissue mass (5–17 mm diameter) sandwiched between the amnion and the chorionic plate. The secondary yolk sac remnant contains

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Fig. 35-11. Collage of drawings showing variations in anomalies involving the abdominal segment of the vitelline (omphalomesenteric) duct. A. Meckel diverticulum without attachment to the anterior abdominal wall at the umbilicus. B. Vitelline cyst without communications with the gut or the umbilicus. C. Umbilical sinus formed by tiny

patent tract in distal vitelline duct remnant. D. Patent vitelline duct communication between ileum and umbilicus. E. Telescopic herniation of the intestinal mucosa into the patent duct and through the umbilicus leads to ‘‘umbilical polyp’’ which may later become isolated as the duct closes.

paracrystalline materials rich in phosphates, lipids, and calcium. Thus, the vitelline duct, at one time during development, extends from the small intestine to the surface of the placental plate. Although often depicted as such, the vitelline duct and secondary yolk sac are never structures floating freely within the amnionic cavity. These structures reside within the extra-embryonic celom and are always surrounded by embryonic mesenchyme. Ultimately, the secondary yolk sac is compressed onto the chorionic surface of the placental plate by the expanding amnion. After week 7, the vitelline duct undergoes regression with obliteration of its lumen and forms a solid cord that, in time, normally undergoes complete resorption. This process is not always complete, and remnants of the duct may remain within the fetal abdomen, the umbilicus, and/or the umbilical cord. The regression of the duct usually leads to partial or complete obliteration of the lumen, but at times the lumen may persist. These irregular failures in vitelline duct resolution lead to a variety of developmental anomalies described within this section. At the distal end of the vitelline duct, the secondary yolk sac also progressively shrinks in size and usually disappears. On close inspection of the amnionic surface (fetal side) of the placental plate immediately surrounding the insertion site of the umbilical cord, a discrete, pale yellow, discoid tissue mass may be identified that represents the remnant of the secondary yolk sac. Cells from the latter structure may at times survive and give rise to hamartomatous and/or teratomatous neoplasms. These are discussed below.

with contrast media and its association with the fetal abdominal organs (e.g., urinary bladder or ileum) determined and proper surgical treatment implemented. Ducts that are shown to communicate via the median ligament with the urinary bladder are almost certainly of allantoic origin. Ducts communicating with the gastrointestinal tract are almost certainly of vitelline origin. All umbilical cords should be examined in cross section at the proximal, middle, and distal regions. With practice and the use of a hand lens, most umbilical cord anomalies can be readily identified or at least suspected. In histologic section, ductal remnants of vitelline origin usually show cuboidal, vacuolated, epithelial lining cells and occasionally gastrointestinal mucosal linings. Such ducts (in contrast to those of allantoic origin) often have a thin, smooth muscle sheath surrounding the lumen mucosa. Although umbilical polyps, umbilical cord polyps, and hamartomatous umbilical cord polyps are anomalies that are derived from the vitelline duct, this group of anomalies is discussed separately (see Section 35.14). The yolk sac remnant is not a true anomaly, but is a normal residual tissue mass that continually confuses examiners. The remnant consists of a small, yellow, discoid, flattened tissue mass lying sandwiched between the amnion and the chorion near the insertional site of the umbilical cord (Fig. 35-12). Careful dissection often discloses a small, duct-like structure leading toward the base of the umbilical cord (the vitelline duct remnant). Histologic sections show abundant frothy epithelial cells, paracrystalline materials (phosphates, calcium), and numerous lipid droplets. The importance of a knowledge of the development and composition of the (secondary) yolk sac remnant lies in its relationship to the development of umbilical cord hamartomas (ectopic masses of normal tissues such as liver, pancreas, intestinal mucosa) and teratomas of both the umbilical cord and placenta. In the authors’ opinion, these lesions are all derived from pluripotential cells of yolk sac origin. This topic is further explored in Section 35.20. Symptoms relating to anomalies of the vitelline (omphalomesenteric) duct are quite variable. Moore2 noted that the most frequent presentations were intestinal obstruction (28%), abdominal pain (28%), melena and anemia (26%), and herniation of the ileum into a patent persistent duct (10%).

Diagnosis

Anomalies of the vitelline duct are relatively common and consist of cysts and patent or atretic duct segments.1–8 Because of the pluripotential (stem cell) nature of yolk sac-derived cells, ectopic masses of normal-appearing tissues (e.g., liver, pancreas, intestinal mucosa) also constitute aberrations in vitelline duct development. Establishing the vitelline nature of such anomalies, if possible, is usually achieved by gross dissection and histologic sampling. The presence of patent ductal structures within the umbilicus or within the proximal umbilical cord stump is an indication for evaluation of the newborn abdomen using either ultrasonography or radiography in combination with injected contrast media.6,9 An evaluation of the proximal umbilical cord should be a part of all prenatal ultrasonographic examinations.10 Cords that are enlarged in this region should, at delivery, be clamped several centimeters from the abdominal wall. Closer clamping, for example, may result in iatrogenic obstruction of the small intestine (e.g., in cases of umbilical cord hernia). The attached, enlarged, proximal umbilical cord can then be surgically explored and the vessels individually ligated. A patent duct can then be injected

Etiology and Distribution

The various cystic, ductal, and remnant anomalies discussed in this section are derived from the yolk sac. Their formation is inherent in the development of the umbilical cord by the fusion of the yolk sac elements (vitelline duct and secondary yolk sac), the allantois, and the attending vitelline and allantoic blood vessels. Umbilical cord

Umbilical Cord

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umbilical cord polyp. The most infrequent vitelline duct anomaly is the complete, patent duct (omphalomesenteric sinus), having been noted in only 2/30,000 newborns.1 This anomaly also shows a predilection for males (8:1). Prognosis, Prevention, and Treatment

Fig. 35-12. Top: Yolk sac remnant (arrows) on surface of placenta. Bottom: Histologic section shows crystalline materials within the remnant lumen lying between the amnion (Am) and chorion (C) along the surface of the placental plate.

anomalies of vitelline duct origin are most often localized in the proximal umbilical cord (usually within 15 cm of the fetal abdominal wall). Anomalies of this type may, however, occur at any site within the umbilical cord, and those derived from the secondary yolk sac may in fact appear to represent placenta anomalies (e.g., heterotopic tissue masses and teratomas). Umbilical cord anomalies of yolk sac origin account for about 7% of remnant anomalies; this group accounts for about 12% of all umbilical cord anomalies. Umbilical cord cysts of vitelline origin are more common in males (4:1). Vitelline duct cysts within the abdomen account for only 0.24% of vitelline duct anomalies. Umbilical cord cysts of vitelline duct origin are, according to Heifetz and Rueda-Pedraza,4 extremely rare. These authors noted only six cases in the world’s literature and reported three additional cases. Complications occur more commonly in vitelline duct anomalies that occur within the intraabdominal segment of the vitelline duct than in those appearing elsewhere. Steck and Helwig5 noted that vitelline duct remnants may appear within the abdominal skin and that these lesions were most common in males (6:1). These anomalies, like those in the umbilical cord, were also associated with an increased incidence of intraabdominal vitelline duct anomalies. The incidence of vitelline (mesoumbilical) bands or cords is rare; we have encountered three bands in 1400 pediatric necropsies. The incidence of Meckel diverticulum is about 2.5% of the American population. Clinical studies suggest that Meckel diverticulum is frequently (19.5%) joined to the umbilicus by granulation tissue or by a fibrous band.8 Our experience at necropsy suggest a much lower incidence of connections of this sort. About 5% of patients with Meckel diverticulum have a history of umbilical polyp and very rarely an

Anomalies of vitelline (omphalomesenteric) duct origin that are located within the fetal abdomen are important because of their high risk for catastrophic complications. A persistent patent vitelline duct or sinus tract produces a chronically moist, weeping umbilicus and ultimately leads to local infection. The persistently patent vitelline duct is at great risk for subsequent herniation of the small intestine and ultimately vascular compromise, perforation, intestinal obstruction, and infection.3,6,7 The persistence of an atretic band of tissue (vitelline cord) connecting the ileum with the posterior wall of the umbilicus places the newborn infant at risk for subsequent intestinal obstruction due to volvulus. Meckel diverticulum is well known as a source of clandestine gastrointestinal bleeding in infants and children and even adults. Ectopic mucosa (e.g., gastric) in persisting segments of vitelline duct lead to ulceration and hemorrhage. Gastrointestinal radioisotopic scans using 99mTC pertechnetate are useful in localizing ectopic gastric glands in vitelline ducts and their remnants. Rarely, pancreatic tissue masses in vitelline duct remnants account for hyperinsulinemia. Cysts developing within abdominal segments of the vitelline duct must be considered in diagnostic evaluations of intraabdominal masses. Rarely, cysts of vitelline origin appear within the umbilicus or within the abdominal wall. Anomalies of the vitelline duct that are confined to the umbilical cord are usually of little clinical significance; while these lesions may cause enlargement of the proximal umbilical cord and hence require careful evaluation at birth, their clinical significance is minimal. The presence of such anomalies in the proximal section of the umbilical cord mandates further evaluation of the infant immediately after birth. Since remnants of the intraabdominal portions of the vitelline duct may give rise to certain malignant neoplasms (e.g., sarcomas, carcinoids, and adenocarcinomas) these tissues should be removed from the infant in toto at the time of initial surgery. The treatment of vitelline duct anomalies that reside within the abdomen or the umbilicus is surgical resection and repair. Vitelline duct anomalies of the umbilical cord that are isolated and do not extend into the umbilicus or the abdomen require no further treatment. The presence of hamartomatous tissue masses within the umbilical cord are also thought to be of no clinical significance. Lesions of this type, which are designated teratomas, are discussed in Section 35.20. Although no manipulative measures are known that prevent yolk sac anomalies in the developing human or experimental animals, a knowledge of the origin and nature of these anomalies allows one to order surgical and roentgenographic exploration of the newborn infant intelligently and in turn to prevent more serious, and even life-threatening, complications (e.g., intestinal obstruction, infection, herniation, and intussusception). References (Umbilical Cord Cysts and Remnants of Vitelline Origin) 1. Brown KL, Glover DM: Persistent omphalomesenteric duct anomalies; incidence relative to Meckel’s diverticulum. Ann J Surg 83:680, 1952.

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2. Moore TC: Omphalomesenteric duct anomalies. Surg Gynecol Obstet 103:569, 1956. 3. Vane DW, West KW, Grosfeld JL: Vitelline duct anomalies: experience with 217 childhood cases. Arch Surg 122:542, 1987. 4. Heifetz SA, Rueda-Pedraza ME: Omphalomesenteric duct cysts of the umbilical cord. Pediatr Pathol 1:325, 1983. 5. Steck WD, Helwig EB: Cutaneous remnants of the omphalomesenteric duct. Arch Dermatol 90:463, 1964. 6. Petrikovsky BM, Nochimson DJ, Campbell WA, et al.: Fetal jejunoileal atresia with persistent omphalomesenteric duct. Am J Obstet Gynecol 158:173, 1988. 7. Delorimier AA, Fonkalsrud EW, Hays DM: Congenital atresia and stenosis of the jejunum and the ileum. Surgery 65:819, 1969. 8. Soderlund S: Meckel’s diverticulum, a clinical and histological study. Acta Chir Scand Suppl 248:1, 1959. 9. Vidal J, Cortina H, Alonso A, et al.: Indications for pneumoperitoneum in the diagnosis of congenital anomalies in the umbilical region. Pediatr Radiol 6:147, 1977. 10. Samuel N, Dicker D, Feldberg D, et al.: Ultrasound diagnosis and management of fetal intestinal obstruction and volvulus in utero. J Perinat Med 12:333, 1984.

Diagnosis

Cystic spaces within the Wharton’s jelly region of the umbilical cord that are not lined by epithelium may be observed by prenatal ultrasonography. No echogenic structures are seen within umbilical cord pseudocysts. Such structures may be quite large (5 cm) and may be single or, as is most often the case, present as a cluster of nearby smaller cystic spaces. Ultrasonographers consider pseudocysts in the differential diagnosis of various other umbilical cord lesions (e.g., omphalocele, gastroschisis, umbilical cord hernia, and cystic structures derived from both vitelline and allantoic ducts). The diagnosis requires histologic examination to confirm the absence of an organized cellular cyst lining (Fig. 35-13). Collagen fibers, often concentrically arranged, may be noted in the wall of the cyst. An increased number of umbilical cord mast cells have been reported in association with umbilical cord pseudocysts. The umbilical cord diameter is usually enlarged in the region of the pseudocyst. Histologic cross sections should be harvested from the areas of umbilical cord enlargement. Etiology and Distribution

35.5 Umbilical Cord Pseudocyst (Cystic Mucoid Degeneration) Definition

Umbilical cord pseudocysts are single or multiple fluid-filled spaces within the Wharton’s jelly region of the umbilical cord that by histologic analysis show no lining epithelium (hence the term pseudocyst). Often these spaces show peripheral, concentrically arranged collagen fibers that form a thin connective tissue rind about the more central lumen. These pseudocysts are also called Wharton’s jelly cysts, cystic or mucoid degeneration of Wharton’s jelly, and giant focal cord edema.1–4

Bergman et al.1 and Iaccarino et al.2 suggested that an increased quantity of Wharton’s jelly results in pseudocyst formation and/or foci of mucoid degeneration. Others have postulated, with good reason, that ‘‘mucoid degeneration’’ of Wharton’s jelly is related to the accumulation of edema fluid. In our experience, cystic degenerations of Wharton’s jelly are most common in edematous umbilical cords (e.g., those with demonstrable increase in water/ gram wet weight). In such cords, the cystic spaces appear to be related to the accumulation of unbound water (e.g., water residing outside the complex binding molecules comprising Wharton’s jelly) within the connective tissue compartment of the umbilical cord. Further supporting this concept is the fact that cross sections of the normal umbilical cord do not freely release fluid; cross

Fig. 35-13. A. Umbilical cord (UC) showing large, fluid-filled, thin-walled pseudocyst (PC) near the body wall of fetus. B. Histologic studies revealed no internal cellular lining of the cyst.

Umbilical Cord

sections of an area of cystic mucoid degeneration rapidly release fluid. Although pseudocysts are rather common lesions in the umbilical cord, the exact incidence is not well documented. The lesions are most often seen in the umbilical cord of premature infants and are especially associated with edematous cords. The lesions are most common in the proximal umbilical cord but are by no means confined to this region. About 8–10% of umbilical cords have been described as edematous.4 Prognosis

Umbilical cord pseudocysts are associated with increased fetal morbidity and mortality; however, this observation may be misleading due to the fact that such lesions are associated with prematurity and edematous umbilical cords attached to stillborn fetuses. In liveborn fetuses, umbilical cord pseudocysts are not generally accompanied by fetal abnormalities other than immaturity, and usually the clinical outcome is normal. Umbilical cord pseudocysts have been associated with omphaloceles, trisomy 18 and other chromosomal abnormalities,3,5–7 abnormal umbilical cord blood vessels,2 fetal growth retardation, respiratory distress,4 hydramnios, and increased numbers of mast cells within the umbilical cord connective tissue compartment.8 Treatment for umbilical cord pseudocysts is not indicated, nor are preventive measures known. Knowledge of the pathogenesis and associations between pseudocysts and other conditions is valuable in considering the diagnostic possibilities of cord masses and their prenatal monitoring. References (Umbilical Cord Pseudocyst) 1. Bergman P, Lundin P, Malmstrom T: Mucoid degeneration of Wharton’s jelly. Acta Obstet Gynecol Scand 40:372, 1961. 2. Iaccarino M, Baldi F, Persico O, et al.: Ultrasonographic and pathologic study of mucoid degeneration of the umbilical cord. J Clin Ultrasound 14:127, 1986. 3. Jauniaux E, Donner C, Thomas C, et al.: Umbilical cord pseudocyst in trisomy 18. Prenat Diagn 8:557, 1988. 4. Coulter JBS, Scott JM, Jordan MM: Oedema of the umbilical cord and respiratory distress in the newborn. Br J Obstet Gynaecol 82:453, 1975. 5. Kuwata T, Matsubara S, Izumi A, et al.: Umbilical cord pseudocyst in a fetus with trisomy 18. Fetal Diagn Ther 18:8, 2003. 6. Ross Ja, Jurkovic D, Zosmer N, et al.: Umbilical cord cysts in early pregnancy. Obstet Gynecol 89:442, 1997. 7. Sepulveda W, Gutierrez J, Sanchez J, et al.: Pseudocyst of the umbilical cord: prenatal sonographic appearance and clinical significance. Obstet Gynecol 93: 377, 1999. 8. Howarka E, Kapczynski W: Unusual thickness of the fetal end of the umbilical cord. J Obstet Gynaecol Br Commonw 78:283, 1971.

35.6 Umbilical Cord Disruption (Linear) Definition

Linear rupture or dissolution of the amnionic sheath covering the umbilical cord results in long expanses of freely exposed umbilical vessels (arteries) devoid of Wharton’s jelly. The exposed vessels may extend throughout the entire length of the umbilical cord, or within focal areas, or only at the distal most aspect of the cord. Smaller, helical ulcerations of the umbilical cord surface which follow the vascular spiral pattern are discussed as a separate entity in Section 35.19.

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Diagnosis

Inspection of the umbilical cord reveals umbilical arteries devoid of amnionic covering and Wharton’s jelly (Fig. 35-14). The vessels hang free like garlands surrounding the remaining substance of the cord (e.g., the umbilical vein surrounded by various quantities of Wharton’s jelly). The abnormality is such that visualization by ultrasonography appears possible. Histologic studies of the exposed vessels reveal a loss of the amnionic cover and, to varying degrees, the Wharton’s jelly surrounding the exposed arteries. In all carefully studied cases, the umbilical vein continues to be surrounded by Wharton’s jelly; however, its amnionic covering sheath is either absent or shows extensive areas of disruption. Murdoch1 reported a case described as ‘‘umbilical cord doubling’’ in which the middle portion of the cord appeared to be duplicated. One portion was of the usual diameter and contained a normal three-vessel composition and was ensheathed normally by amnion, while a smaller duplicated segment contained a persistent (right) umbilical vein and also was apparently ensheathed in amnion. Umbilical cord duplication must therefore be differentiated from linear disruptions of the umbilical cord as described here. While this differentiation would seem difficult by ultrasonography, direct inspection or histologic examination should easily distinguish duplicated cords with both segments covered with normal amnion from linear disrupted cords, which show rupture and dissolution of the amnionic sheath. Etiology and Distribution

Abnormalities of this type have been thought to be due to either ‘‘agenesis’’ or degeneration of Wharton’s jelly.2 Other explanations include incomplete fusion of the amnionic covering and the connecting stalk mesenchyme during umbilical cord embryologic development or to ‘‘hypoplasia’’ of the amnionic covering with secondary loss of Wharton’s jelly.3,4 In our experience these lesions result from rupture or dissolution of the umbilical cord amnionic sheath with secondary loss of Wharton’s jelly into the amnionic fluid. Our experience suggests that the amnionic sheath remains intact in focal areas and is almost always intact where the cord’s integrity is preserved. The passage of meconium (a substance rich in bile acids and other digestive enzymes) may play a role in amnionic disruption with exposure of the fetal

Fig. 35-14. Linear disruption of the umbilical cord showing ‘‘naked’’ umbilical arteries (UA) without supporting Wharton’s jelly. The umbilical vein (UV) continues to be surrounded by considerable Wharton’s jelly and matrix material (arrows).

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arteries. (see Umbilical cord helical ulcerations, Section 35.19). The tendency for the umbilical vein to retain Wharton’s jelly in the adventitial zones remains unexplained. Similar lesions may be produced in umbilical cords treated in vitro with weak solutions of trypsin. Linear disruptions of the umbilical cord in utero are extremely rare. Labarrere et al.4 observed only three cases in 10,450 deliveries. Prognosis, Prevention, and Treatment

Thus far, all cases of linear umbilical cord disruption have been associated with acute fetal distress, meconium staining, and perinatal death. Labarrere et al.4 suggest that fetal death is due to ‘‘compression of the unprotected vessels.’’ These authors also entertain the view that such abnormalities result from digestion of the amnionic sheath by enzymatic components present in meconium; hence, the abnormality may develop after extreme stress in the fetus or even death. No treatment or preventive measures are known. References (Umbilical Cord Disruption) 1. Murdoch DE: Umbilical-cord doubling: report of a case. Obstet Gynecol 27:555, 1966. 2. Bergman P, Lundin P, Malmstrom T: Mucoid degeneration of Wharton’s jelly. An umbilical cord anomaly threatening foetal life. Acta Obstet Gynecol Scand 40:372, 1961. 3. Fox H: Pathology of the Placenta. WB Saunders, London, 1978, p 426. 4. Labarrere C, Sebastiani M, Siminovich M, et al.: Absence of Wharton’s jelly around the umbilical arteries: an unusual cause of perinatal mortality. Placenta 6:555, 1985.

35.7 Umbilical Cord Dimensional Abnormalities Collection and analysis of morphometric data from the umbilical cord were initiated as early as the 12th century. Physicians and midwives thereafter have often discussed the significance of abnormally long or short umbilical cords, but only recently have begun to evaluate umbilical cord caliber (diameter) and its significance. In spite of this interest, few carefully controlled studies have been conducted. A national perinatal collaborative study reported on the significance of umbilical cord length involving some 35,000 umbilical cord measurements.1 The data from this study have limited value because the measurements were made by a number of investigators using different techniques and included cords severed at variable distances from the fetus and stored under variable conditions. In spite of these problems, the consensus is that the abnormally long or short umbilical cord is often associated with significant abnormalities in fetal growth and development and pregnancy outcome. We now appreciate how abnormalities within the fetal habitat and altered fetal kinetics (e.g., hypokinesia, hyperkinesia) affect umbilical cord growth. Although relatively little detailed information is available concerning fetal factors that influence umbilical cord growth, there is a consensus that reduced fetal activity (whether by mechanical constraint, e.g., oligohydramnios, or by fetal diseases that suppress or inhibit motor activity in utero) is associated with reduced umbilical cord linear growth. Certain genetic diseases (e.g., trisomy 21, Prader-Willi syndrome) associated with reduced fetal motor activity also produce similar degrees of umbilical cord

linear growth suppression. The mechanical constraint of fetal activity generally suppresses umbilical cord linear growth; the suppression is most severe during the first two trimesters of pregnancy. Experimental models of fetal hypokinesia and/or mechanical constraint in a variety of animals produce similar inhibitory influences of umbilical cord linear growth. Fetal hyperkinesia, on the other hand, tends to enhance, but with less consistency, umbilical cord linear growth. Significant increase in umbilical cord linear growth has been reported in association with polyhydramnios and in situations in which the fetal CNS is stimulated to produce increased motor activity. Examples of the latter include maternal amphetamine, caffeine, and cocaine addictions. In certain experimental models, linear umbilical cord growth stimulation appears to be associated with increased fetal cardiac activity and blood pressure. In experimental models, polyhydramnios may be associated with fetal hypokinesia (e.g., fetal curare administration); in this association, umbilical cord growth is generally suppressed rather than increased. Abnormalities in umbilical cord diameter are rarely studied. In most instances, enlargement of the proximal umbilical cord is due to abnormalities related to vitelline duct and/or allantoic duct development. Localized enlargements of the umbilical cord diameter are also related to neoplasms, vascular aberrations, hamartomatous tissue masses, and edema. Variations in umbilical cord water content, as expected, are generally only minimally reflected in umbilical cord diameter. Significant alterations in umbilical cord water content in various fetomaternal disease states are listed in Table 35-2. Coulter et al.2 have defined umbilical cord edema in relation to a cross-sectional area greater than 1.3 cm at term gestation. About 10% of all umbilical cords are edematous. The diameter of the umbilical cord is generally smaller in female than in male fetuses at any stage of gestation (Figs. 35-15 and 35-16). Because umbilical cords are often sectioned and segments removed and/or lost prior to formal examination by the physician, we have studied umbilical cord weight/length ratios and have established a normal curve for normal fetal umbilical cord growth (Fig. 35-17). In addition, we have evaluated umbilical cord weight/ length ratio in certain disease states (Table 35-3). The value of umbilical cord weight/length ratio in predicting umbilical cord length, umbilical cord age, or associations with certain common diseases is limited. The umbilical cord weight/length ratio is significantly decreased in Turner syndrome, in triploidy, and in fetuses with oligohydramnios. The umbilical cord weight/length ratio is increased in nonmacrosomic infants born to diabetic mothers. No significant changes in the ratio were noted in Potter syndrome, renal dysplasia, trisomy 13 and 18 syndromes, anencephaly, and in umbilical cords containing a single umbilical artery. In our experience, a more valuable assessment of umbilical cord edema in third trimester cords is the umbilical cord weight/ length ratio; a ratio greater than 1.1 g/cm strongly suggests umbilical cord edema.

Table 35-2. Umbilical cord water content and fetomaternal disease No Change

Increased

Fetal distress

Abruptio placenta

Neonatal asphyxia

Maternal diabetes

Maternal hypertension

Intrauterine fetal death

Maternal edema

Rh incompatibility

Fig. 35-15. Human umbilical cord diameters in male fetuses at various stages of gestation. Hashed zone represents ±1 SD of the mean.

Fig. 35-16. Human umbilical cord diameters in female fetuses at various stages of gestation. Hashed zone represents ±1 SD of the mean.

Fig. 35-17. Human umbilical cord weight/length ratios in male (M) and female (F) fetuses at various stages (16–42 weeks gestation).

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Other Systems and Structures Table 35-3. Abnormalities in umbilical cord weight/length ratio in various fetomaternal disease states No Change

Long, short, and single umbilical artery cords Short umbilical cord syndrome Anencephaly Trisomies 13 and 18 Renal dysplasia and Potter syndrome Decreased

Triploidy Turner syndrome Oligohydramnios Increased

Infants of diabetic mothers

The most useful morphometric values for human umbilical cord development are presented in Figures 35-5, 35-6, and 35-15 through 35-17. These data represent values collected by the authors over a period of about 10 years and include length, diameter, weight/length ratio, and water content.3 In the following sections, major abnormalities in umbilical cord morphometry are discussed in detail. 35.7.1 Umbilical Cord Agenesis (Acordia)

Acordia is the complete absence of the formed umbilical cord. This anomaly is also called umbilical cord aplasia and dysplasia umbilico fetalis. Failure in the development of the umbilical cord may be considered in three, somewhat imperfect, categories (Fig. 35-18). Type I umbilical cord acordia is the most common variety and consists of an ‘‘empty gestational sac’’ without discernible body stalk, formed umbilical cord, or organized embryo or fetus. This type is most common and accounts for about 40–45% of acordia cases. Type II umbilical cord acordia is a condition in which a stunted or nodular embryo lies freely within a fluid-filled (chorionic) sac without evidence of an attached or severed umbilical cord. This variety accounts for about 10% of cases of acordia. If development is beyond that of the early embryo (e.g., early fetus), careful examination will usually lead to the recognition of a severed, macerated, but formed umbilical cord (Section 35.16). Type III umbilical cord acordia is a condition in which the fetal blood vessels communicate directly with the placental plate and with no portion of the true, ‘‘formed’’ umbilical cord being present. The amnion does not encase the umbilical vessels, and Wharton’s jelly is absent. The fetus is directly tethered to the placental plate, and a massive abdominal wall defect is present. The open abdominal wall results from a defect in the lateral folds.4,5 The fetal abdominal organs reside outside the abdominal cavity and within a fluid-filled sac, which is most likely of chorionic rather than amnionic origin. As the tethered fetus develops, the vertebral (spinal) axis becomes progressively distorted; ultimately, a pleurosomus or cyllosomus type defect of the body axis appears. Type III umbilical cord acordia is, at first glance, quite similar to both ruptured amnion (ADAM) sequence and to short um-

bilical cord syndrome. In each of these latter conditions, however, a segment of normally formed umbilical cord is present; the segment is quite short (under 10 cm) and on histologic examination contains the umbilical vessels (usually only one umbilical artery) surrounded by Wharton’s jelly and ensheathed by amnion. During normal development, the umbilical cord is formed by the fusion of the secondary yolk sac with the more caudally placed body stalk and its contents (the allantois and its associated blood vessels). A third component, the amnion, ensheathes the fused elements in such a manner as to provide a single-cell–layer covering for the formed cord. Umbilical cord agenesis may result from a failure of fusion of any or all of the fusion components. Type I acordia appears to be related to embryonic growth failure prior to the embryogenesis of the umbilical cord. Failures of this type are most often due to chromosomal anomalies precluding embryonic differentiation. In type II acordia, the embryo proceeds in development until nutritional limitations are imposed; the associated acordia most likely results from improper vascular penetration of the chorion and vascularization of the trophoblastic tissues. A likely explanation for type III acordia is a failure of either mesenchymal elements within the body stalk connective tissues or a proper interaction between amnion and these elements. In support of the idea of amnion failure in type III acordia are Gruenwald and Mayberger’s studies6 showing the absence of an amnion sac in a human case. In cases such as these, the abdominal viscera resides within a sac formed or lined by chorion. One may also argue that umbilical cord acordia may result from primary amnion failure; in this case, the sac containing the embryonic viscera extends all the way from the body to the chorion, and no true umbilical cord is formed. Acordia is almost always associated with severe deformation of the developing body axis and with disruption of the body wall as well as additional anomalies. In only one case has umbilical Fig. 35-18. Schematic classification of umbilical cord agenesis.

Umbilical Cord

cord acordia been described in which no associated anomalies were detected, and this was in a cat.7 The incidence of umbilical cord agenesis is considered rare; however, the condition is considerably more frequent when careful examination of early abortuses is included. The studies of Javert and Barton8 clearly support the latter conclusion. Type III acordia was rare in our autopsy population (3/1400 examinations). The anomalies associated with umbilical cord agenesis are invariably lethal, usually due to fetal hemorrhage at either vaginal or cesarean section delivery.8,9 The associated abnormalities of fetal body axis as well as gastroschisis-like features are most often deformations rather than malformations. The abdominal wall is incompletely formed, and hence the abdominal organs remain outside the peritoneal cavity. Severe kyphoscoliosis is present, and diaphragmatic hernia and pulmonary hypoplasia are often present. Since fetuses with type III acordia may reach term gestation, the utilization of their organs for transplantation is a worthy consideration. Umbilical cord agenesis is, at present, an untreatable condition. No known preventive measures exist. 35.7.2 Short Umbilical Cord

An umbilical cord that measures less than 2 SD below the mean at any given point during gestation is considered short. At or near term (37–40 weeks gestation), the short umbilical cord measures less than 35.0 cm in length, but more than 10 cm. The length of the fresh umbilical cord is determined at birth and, using developmental growth (length) curves established for gestational age, sex, and race, a percentile position is determined. Cord lengths at or below the 10th percentile are considered ‘‘short.’’ If a length of normally formed cord is present at birth and measures 10 cm or less and certain additional malformations/deformations are present, the ‘‘short cord syndrome’’ should be considered (vide infra). The umbilical cord is derived by a fusion of the yolk sac and associated tissues (yolk stalk and vitelline vessels, portions of the allantois and its attending allantoic vessels), the body stalk with its attending tissues (mesenchyme), and the amnion that forms its external covering. The mechanisms by which the umbilical cord increases in length are incompletely understood, but are believed to include (1) torsion tension imposed by expansion of the amnionic fluid volume; (2) fetal movement, especially extremity movements; and (3) rising blood pressure with the associated pulsatile and spiral movements of blood flow within the umbilical arteries.10,11,13,17 Short umbilical cords are associated with a variety of developmental anomalies (Table 35-4), most of which are also associated with varying degrees of fetal hypokinesia, severe abdominal body wall defects (including cyllosomus, pleurosomus, omphalocele), and monozygotic twinning (e.g., acephalus-acardia and TRAP sequence).10,11,13,17 In general, conditions characterized by mild or moderate degrees of fetal hypokinesia (e.g., Down syndrome, Prader-Willi syndrome) produce only mild or moderate degrees of umbilical cord growth suppression and hence do not usually produce a true ‘‘short cord.’’ Significantly short umbilical cords may be produced in experimental animals using agents known to inhibit fetal movement (e.g., b-blocking agents, atenolol, curare).14 In studies of umbilical cord length in 59 sets of twins (118 cords), the length was significantly shorter (p < 0.001) than in 9601 singletons. The umbilical cord length of a twin averaged 7.9 cm shorter than that of the average singleton. 15 In our experience with

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Table 35-4. Short umbilical cord (SUC) syndrome and similar anomaly constellations* Group 1

Group 4

SUC þ amnion bands

SUC þ acephalus-acardia

ADAM sequence

Abnormal twinning

Variable clefts Variable amputations

Group 5

SUC þ fetal hypokinesia Group 2

Neuromuscular disorder

SUC þ abdominal wall defect

Arthrogryposis

Severe SUC (<10 cm) Abdominal wall defect Bent fetal body axis (pleurosomus, cyllosomus) Missing limb Group 3

Limb defect Group 6

SUC primary defect Abdominal wall defect Omphalocele

SUC þ severe midline field schisis defect *Anomaly groups are modified from those proposed by Grange et al.18 and by Drs. John Opitz and Enid Gilbert-Barness (personal communications).

diamnionic monochorionic twinning, the umbilical cord length in twin pregnancies was considerably variable and correlated more with individual amnionic fluid volume than with the phenomenon of twinning alone. Examples of isolated short umbilical cord without attending anomalies in the fetus or fetal membranes are rare if not nonexistent. A short umbilical cord is noted in 0.8–7.0% of all deliveries. The sex ratio is variable due to associations with diverse and sometimes sexually skewed conditions (e.g., TRAP sequence, triploidy). The presence of a short umbilical cord indicates, at best, a guarded prognosis.12,13,16 In the absence of serious associated anomalies, as appraised by ultrasonography, and in the absence of oligohydramnios, the prognosis is greatly improved. When a short umbilical cord is present in association with abnormalities in the body axis (e.g., scoliosis, cyllosomus, pleurosomus), the prognosis is poor. The short umbilical cord in association with omphalocele offers a serious, but more favorable prognosis. Short umbilical cords are also associated with complications in 14% of patients (vs. 24%, normal cord length; 62%, long cord length). As would be expected, short umbilical cords are not often associated with knots, loops, or prolapse. Short umbilical cords have been associated with delay (inadequate descent) in second-stage labor, irregular fetal heart tones, placental abruption, umbilical cord avulsion, uterine inversion, fetal asphyxia, and umbilical cord herniation. At present, there are no established treatment methods for the short umbilical cord. For vaginal delivery to be achieved at term without avulsion of the cord, a length (fundal implantation) of about 35.5 cm is necessary; for low-lying placentas, a 20.0 cm umbilical cord is required. When umbilical cord length is less than these values at 37 or more weeks gestation, cesarean section delivery is indicated. In cases of short umbilical cord due to oligohydramnios associated with obstruction of the lower urinary tract (e.g., posterior urethral bands, urethral stenosis, or agenesis), the placement of a catheter to drain fetal urine continuously into the amnionic

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cavity prevents progressive renal degeneration and enhances lung growth by expanding the amnionic fluid volume. Counseling for recurrence risk in future pregnancies requires knowledge of the etiology and pathogenesis of short umbilical cords. 35.7.3 Short Umbilical Cord Syndrome

Short umbilical cord syndrome involves an umbilical cord that measures 10 cm or less at or near term gestation and is, at least in part, fully formed with an intact amnionic sheath. The associated fetus appears tethered to the surface of the placental plate, and the spinal axis is bent in the direction of umbilical cord tethering. The amnionic sac is intact, and amnionic bands are absent. An abdominal wall defect is present (gastroschisis or omphalocele), and the fetal abdominal organs in part lie outside the abdominal cavity. Deformations of the limbs (clubfoot, abnormal leg rotation, asymmetry) commonly accompany the defect, and the fetus has been described as assuming a ‘‘flying’’ position (Figs. 35-19 and 35-20). The fetus is in close approximation with the chorioamnionic surface of the placental plate, and 10 cm or less of fully formed umbilical cord is present (Fig. 35-19).17 An abdominal wall defect is present (usually involving the cranial or caudal fold), allowing the abdominal organs to reside freely within the intact amnionic sac. The fetus appears to be tethered to the surface of the placenta and maintains this position throughout pregnancy. The spinal axis is sharply bent in the direction of umbilical cord tethering. Deformations of the limbs are present (e.g., clubfoot, abnormal extremity rotation, asymmetry). Internal anomalies are always present (e.g., diaphragmatic hernia, gastrointestinal and genitourinary anomalies). Infants with short umbilical cord syndrome look alike, whereas infants with amnion rupture (ADAM) sequence, who also have very short umbilical cords, show variable phenotypic features.17 Clinical signs appear by the end of the first trimester and include decreased fundal height, decreased fetal growth, and reduced amnionic fluid volume. Ultrasonography reveals a bent

Fig. 35-19. Fetus with lateral bending of the spinal axis with tethering onto the placental surface due to short umbilical cord (5.8 cm).

Fig. 35-20. Placenta (P) with attached, well-formed, but short umbilical cord (UC) and portions of the fetal abdominal wall (Aw) containing abdominal segments of the umbilical blood vessels.

fetus consistently in close apposition to the placental surface. Reduced fetal movements (hypokinesia) are present. Sirenoid malformations have been reported in a few cases. At birth, the fetus and the placenta are delivered together, but occasionally the placenta may be avulsed from the fetus. Inspection reveals an extremely short, but fully formed, umbilical cord, which may give rise to ‘‘furcate’’-like changes (‘‘naked’’ branched vessels) prior to their entrance into the placental plate. An omphalocele may be present in addition to the aforementioned gastroschisis.10 There are no signs of amnionic band formation, and hence amputations and clefting defects are absent. Histologic studies of the fetal membranes reveal a characteristic fine, uniform vacuolation of the amnionic epithelial cells. The latter changes are also seen in gastroschisis with or without short umbilical cord syndrome. Several etiologic considerations for short umbilical cord syndrome have been proposed,4,9,10,18 including an abnormality involving the embryonic body folds, namely, the cephalic and caudal folds.4 Abnormal development of the cephalic fold leads to anomalies similar to those of the ‘‘pentalogy of Cantrell.’’ Abnormal development of the caudal body fold leads to anomalies such as bladder exstrophy, hypogastric omphalocele, imperforate anus, short colon, and unilateral umbilical artery agenesis. Several cases of short umbilical cord syndrome have been reported that seem to point to the body fold concept.5,8,9 Other etiologic considerations include a massive midline developmental defect, extreme fetal hypokinesia (as in neuromuscular disorders and arthrogryposis) and abnormalities in

Umbilical Cord

twinning (acephalus-acardia). In 1986, Grange et al.18 considered short umbilical cord syndrome as embracing six separate groups of infants with umbilical cords shorter than 30 cm. Group determination was based on similarities in the constellation of anomalies and the proposed pathogenesis (Table 35-4). From this study it is apparent that infants with short umbilical cord syndrome show vastly different anomaly patterns. While we appreciate this approach and recognize the complexity of the subject, we feel that the syndrome best embraces infants in the Grange et al. groups 2 and 6 as modified in the definition above. In our experience, patients with the short umbilical cord syndrome tend to appear in a cluster. We see several cases clustered in time and then see few if any cases for several months or even years. This phenomenon alone raises certain etiologic considerations (e.g., infectious, toxic). A national reporting center would be helpful in further evaluating the etiologic nature of the syndrome. Patients with the short umbilical cord syndrome show rather remarkable development except for the abdominal wall defect and the extreme deformation of body axis. The anomalies, nevertheless, preclude life for more than a very short period. In our opinion, several of the vital organs (e.g., heart, liver, pancreas) are normally formed and should be considered in transplant programs. Death is almost always caused by respiratory insufficiency due to extreme pulmonary hypoplasia. There are no known treatment programs or established preventive measures. 35.7.4 Long Umbilical Cord

An umbilical cord with a length exceeding 80 cm at term gestation is considered long. Umbilical cords measuring more than 300 cm have been reported. In abortuses, a long umbilical cord measures in excess of 2.5 times the crown-rump length. In preterm infants, a long umbilical cord measures
2 SD above the mean length as corrected for sex (Fig. 35-5). Umbilical cords of excessive length are detected by direct examination and measurement. In aborted materials, the crownrump and umbilical cord lengths are determined using calipers. The umbilical cord is considered long if it exceeds the crown-rump length by 2.5 or more times. Later in development, excessive umbilical cord length can be determined using umbilical cord ‘‘growth curves’’ established for various gestational ages (Fig. 35-5). Long umbilical cords should be suspected in all cases of umbilical cord looping or encirclement as observed by prenatal ultrasonography or at delivery. Patients with suspected long umbilical cords during the prenatal period can be further evaluated by using the ‘‘nuchal cord’’ test described by Mendez-Bauer et al.19 The incidence of excessively long umbilical cord is extremely variable. In our experience, and using strict morphometric guidelines, about 7% of umbilical cords qualify as being ‘‘long.’’ In abortuses, the incidence of long umbilical cord is about 11%. In Javert and Barton’s studies,8 13.4% of the umbilical cords displayed excessive length. Long umbilical cords are associated with looping (nuchal cord) and with deformations of the fetus (vide infra) as well as with knots and entanglements. Rayburn et al.16 noted that ‘‘cord accidents’’ were more common (62%) with long cords than with normal or short cords. In our experience, long umbilical cords are more common in singletons than in twins. Factors that mediate umbilical cord growth have only recently been explored. In general, long umbilical cords have been associated with traction, as in polyhydramnios and in abdominal pregnancy.13 These associations have led to the ‘‘stretch’’ or

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traction hypothesis. Fetal hyperkinesia has also been thought to stimulate umbilical cord growth; however, we have not been able to establish this relationship in many cases of maternal cocaine and/or amphetamine abuse, conditions thought to induce fetal hyperkinesia. Recently, we reviewed the subject of fetal blood pressure and its possible role in umbilical cord growth. Only a weak association between fetal hypertension and excessive umbilical cord growth was noted. We studied by direct examination 98 long umbilical cords in 12,077 deliveries.20 Long umbilical cord was associated with several conditions (Table 35-3), the most common of which were fetal infection, maternal cigarette smoking, fetal macrosomia, and maternal obesity. Long umbilical cords, at autopsy (n ¼ 36), were associated with fetal cardiomegaly (14%). We attributed this finding to a progressive increase in perfusion pressure due to excessive length of the cord vessels and, in time, compensation by increased cardiac rate and output and, ultimately, cardiomegaly (14%). Signs of overt heart failure were present in 14%. When a long umbilical cord is present, the prognosis (fetal outcome) is guarded because of the high rate of complications (i.e., loops and encirclements, prolapse, knot formation, torsion) and fetal hypoxia associated with cord accidents. Nuchal cord (neck encirclement) is more common with long cords (53%) than with normal (23%) and short (14%) cords. True knots are more common in long cords (3%) than in normal (1%) and short (0.0%) cords. Prolapsed cords are more common in long cords (6%) than cords with normal length (0.4%) and short cords (0.0%). Excessive vascular spiraling and twisting have been reported to be associated with long umbilical cords (vide infra). When long umbilical cords are detected during the prenatal period, monitoring by ultrasonography seems prudent insofar as intervention may be required if persistent body loops or encirclements are encountered. Treatment is not generally necessary except during delivery, when efforts should be directed toward preventing compromise of the fetal vascular supply.21 Fetal monitoring during delivery is indicated. No preventive measures are available at this time except for protection of the fetus from conditions which promote fetal hyperkinesia. 35.7.5 Abnormalities of Umbilical Cord Diameter

Large or small umbilical cord diameter (circumference) due either to a decreased or an increased quantity of Wharton’s jelly and/or edema fluid can occur. Using standard morphometry growth curves, such abnormalities are more than 2 SD above the mean or 2 SD below the mean for any given gestational period (Figs. 35-15 and 35-16). Abnormal umbilical cord caliber may involve the entire cord (e.g., ‘‘thin cord syndrome’’) or only focal areas of cord (e.g., umbilical cord stricture, focal areas of umbilical cord edema). Thick cord, ‘‘megacord,’’ mucoid degeneration (focal or complete), umbilical cord edema, thin cord syndrome, and umbilical cord stricture are included in this entry. Focal enlargement of the cord due to cysts, tumors, hernias, hematomas, and urinefilled or patent urachus are not included here. Also, umbilical cord edema associated with vascular occlusion and/or torsion, umbilical cord disruption, insertio funiculi furcata, and umbilical cord coarctation are excluded. Umbilical cord diameter (circumference) is normally greater in the male than in the female at any stage of gestation; however, the difference is not significant at any given stage of development (Fig. 35-6). The umbilical cord diameter is abnormally enlarged when the mean diameter (or circumference) exceeds 2 SD above

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Other Systems and Structures

the mean at any given gestational age; conversely, the umbilical cord diameter (circumference) is abnormally small when the mean diameter is less than 2 SD below the mean value at any given gestational age (Figs. 35-15 and 35-16). Cord diameter is determined with a precision caliper. Three individual measurements are made at separate sites within the proximal, middle, and distal cord regions. The mean umbilical cord diameter is the average of these three measurements. Inspection of an enlarged cord will usually differentiate between edema, abnormally large accumulations of Wharton’s jelly, foci of mucoid degeneration, and enlargements due to herniated organs or materials (e.g., umbilical cord polyps, urine accumulation due to patent urachus, and hematomas). Edematous cords, when sectioned, ooze a watery, jelly-like fluid, whereas cords with normal or excessive amounts of Wharton’s jelly release little or no free fluid. Edematous cords are more translucent than those with normal quantities of Wharton’s jelly. Hemorrhage into the cord parenchyma is easily discerned in cross sections examined with a hand magnifier. Rarely, the umbilical cord may appear enlarged due to umbilical vein dilation associated with stenosis or occlusion. Such lesions may appear anywhere along the cord or within the fetal abdomen. In the latter cases, the fetus is usually stillborn. Small-caliber umbilical cords (‘‘thin cord syndrome’’) may be due to autolysis (fetal death in utero) and the loss of water from Wharton’s jelly (Fig. 35-21). We have noted small-caliber umbilical cords in association with triploidy and Turner syndrome. Thin cords may also be present with a normal fetus and show no specific change other than an apparent, generalized reduction of Wharton’s jelly. In such cords, it is important to establish the presence of an intact amnionic surface sheath in order to rule out umbilical cord disruption. Linear disruption of the cord may result from chemical digestion of the amnionic layer with subsequent loss of Wharton’s jelly. In such cases, meconium is often the culprit; it apparently is capable of lysing the umbilical cord amnionic covering. In these cords, the umbilical arteries appear ‘‘naked’’ and unsupported by Wharton’s jelly, while the vein continues to be surrounded by a thin collection of Wharton’s jelly (see Section 35.6). Umbilical cords that show a localized area of extreme narrowing without evidence of torsion (twisting) are referred to as

Fig. 35-21. Actual size of umbilical cords at term gestation showing small cord from stillborn fetus (A), normal-caliber cord (B), and large cord from fetus delivered to a mother with diabetes mellitus (C).

Fig. 35-22. Stillborn fetus showing attached umbilical cord with a focal area of stricture (S) near the abdominal wall.

having umbilical cord stricture (Fig. 35-22). These lesions are most often associated with stillborn macerated fetuses; in a few instances, umbilical cord stricture has been reported in a normal liveborn infant. Almost always the area of stricture is near the fetal abdomen. Weber described umbilical cords with more than one site of stricture and with stricture occurring near the placental end of the cord.22 Histologic studies of umbilical cord stricture sites reveal a virtual absence of Wharton’s jelly and ‘‘fibrosis’’ in the connective tissues surrounding the blood vessels. Narrowing of the lumens of the umbilical vessels may or may not be present. The etiology of umbilical cord stricture is not well established. We have produced very similar lesions in the umbilical cords of experimental animals by partial ligation. Within 48 hr, the area of stricture will remain if the ligature is removed; histologic studies show little Wharton’s jelly in the narrowed area, and, because of concentration of mesenchymal cells and fibers, the area resembles ‘‘fibrosis.’’ Thus, one concept is that strictures of the cord can be produced by external circumferential pressure (e.g., ligation). Other workers feel that umbilical cord stricture represents postmortem artifact due to autolysis beginning at the fetal end of the cord.23 Another concept is that umbilical cord stricture represents a focal, congenital lack of Wharton’s jelly. It seems possible, in summary, that umbilical cord stricture may well result from more than one etiologic mechanism. In all cases of abnormal umbilical cord caliber, histologic sections of the abnormally thin or thick regions must be examined. Such sections establish the etiologic basis of the anomaly. Umbilical cord edema is expressed histologically as a dispersal of the mesenchymal cells residing within the Wharton’s jelly area (Fig. 35-23). The water apparently binds to the jelly and uniformly expands the extracellular compartment. Umbilical cord mucoid degeneration appears in histologic sections as clusters of tiny cystlike, empty-appearing spaces (pseudocyst formation); the spaces are devoid of a cellular lining. Mucinous degeneration of Wharton’s jelly may be accompanied by edema in nearby areas, and hence the lesions may appear mixed. Surprisingly little information is available regarding the biology and pathobiology of Wharton’s jelly. This unique, waterbinding jelly is thought to be secreted by mesenchymal cells that, during early stages of development, are arranged in a concentric manner about the umbilical cord vessels. In older cords, this arrangement is less conspicuous. Our morphometric studies of umbilical cord cross sections have shown that the proportion of the area occupied by jelly and by blood vessels does not significantly

Umbilical Cord

Fig. 35-23. Photomicrograph of umbilical cord showing edema as multiple fluid-filled spaces surrounded by displaced connective tissue and Wharton’s jelly (arrows).

change after 24–28 weeks gestation. Wharton’s jelly is unique in that it demonstrates thixotropy, the ability of the jell to liquify when pressure is applied and then become semisolid again. It provides a mechanically supporting jell surrounding the spiraled umbilical vessels. Other less well-documented properties of the jelly include anticoagulation, bacteriocidal, bacteriostatic, and water-binding and -releasing properties. Abnormalities in the quantity of Wharton’s jelly are thought to result in either enlarged or thin umbilical cords. The factors regulating such quantitative changes are not clearly understood. Umbilical cords containing increased quantities of Wharton’s jelly also contain increased quantities of water. Thin, delicate umbilical cords contain less water per unit of weight. Hence, hydration is known to be one mechanism that significantly alters umbilical cord cross-sectional diameter. Although no studies have been reported, it seems logical to suggest that amnionic fluid osmolarity would influence umbilical cord water content and cross-sectional caliber. After birth, we have documented the rapid dehydration of normal umbilical cords drying in air at 228C. Under these conditions, the normal umbilical cord loses 50% of its water by 7.2 hr; no significant acceleration of this process is noted at a higher (body) temperature (378C). Dehydration of the normal umbilical cord in saline or amnionic fluid at body temperature is greatly retarded. The umbilical cord contents are confined by a single, thin layer of amnion cells with little underlying fibrillar (collagen) material. The cells are arranged in a manner so as to allow stretch in both linear and cross-sectional directions (Fig. 35-4). The arrangement between the amnion surface and the encased Wharton’s (thixotropic) jelly that surrounds the spiraled vessels allows the cord to expand or shrink without greatly increasing the risk for vascular obstruction due to kinking. The umbilical cord may accommodate exceptionally large volumes of edema fluid without significant vascular compromise. Umbilical cord edema is a relatively common condition (incidence, 10%) and is not regularly associated with specific abnormalities of the fetus. Umbilical cord edema is most commonly associated with normal fetal outcome. In viewing this subject in another manner, we have not noted umbilical cord caliber enlargement in fetuses with hydrops fetalis and fetal heart failure, nor in fetal macrosomia unrelated to maternal diabetes. Umbilical cord caliber enlargement has been described in infants delivered to diabetic mothers; we have not confirmed this observation, although increased umbilical cord

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glycogen content may occur in infants delivered to mothers with poorly controlled diabetes mellitus. Coulter et al.2 reported a careful evaluation of umbilical cord edema and its associations. These workers noted a statistical correlation between umbilical cord edema and a variety of conditions, including prematurity, respiratory distress syndrome, Rh isoimmunization, abruptio placenta, macerated stillbirth, and infants born to mothers with diabetes mellitus. No correlation was noted between umbilical cord edema and asphyxia, ‘‘fetal distress,’’ or maternal hypertension with or without edema. Three general etiologic mechanisms for umbilical cord edema have been postulated: (1) low plasma oncotic pressure due to reduced fetal plasma proteins or the actual leakage of protein from the vessels with build up of the oncotic pressure within the extracellular space; (2) raised hydrostatic pressure within the placental and umbilical cord vascular systems, which in turn leads to transfer of fluid into the cord connective tissue space; and (3) increased total water content of the fetoplacental unit. Each of these mechanisms has been closely associated with umbilical cord edema in the human.2 Extremely thin umbilical cords (‘‘thin cord syndrome’’) have been consistently seen in association with fetal death in utero (Fig. 35-21). The cord, being a fetal organ, dies when the fetal heart ceases to pump blood. It slowly loses its diameter, and, in time, much of the Wharton’s jelly disappears; ultimately the vessels collapse. Excessive twisting of the cord in the direction of the vascular spiral is also associated with a significant decrease in diameter. Rarely, small-caliber umbilical cords have been described in which the umbilical arteries are devoid of Wharton’s jelly and are not surrounded by the amnionic sheath. Labarrere et al.24 described three cases in which the arteries were devoid of Wharton’s jelly and apparently the amnionic covering as well. In such latter instances, we refer to the disorder as umbilical cord disruption because of the loss of the amnionic sheath. Most often, the disruption is due to autolytic digestion of the sheath after meconium passage (see Section 35.6). In rare cases, the diameter of the umbilical cord is small and the organ is nearly devoid of Wharton’s jelly, yet the amnionic sheath is intact. No satisfactory explanation for the etiologic deficiency in jelly has as yet been offered. Bergman et al.25 suggested that the defect was due to a degeneration of the embryonal mesenchyme responsible for Wharton’s jelly production. Fox26 suggested that the anomaly might be due to incomplete fusion of the amnionic covering with the mesenchyme of the body stalk during early development or to a hypoplasia of the amnion with secondary loss of Wharton’s jelly. Both bile and meconium are apparently capable of digesting the amnionic layer, which results in the subsequent loss of Wharton’s jelly. Cords with little or no jelly should be carefully examined and the intact nature of the amnionic sheath fully established. A focal, localized absence of Wharton’s jelly may produce what appears to represent a focal constriction (or umbilical cord stenosis or stricture).8 Most often these areas of extreme external narrowing are located at the proximal end of the cord near the fetal abdominal wall (Fig. 35-22). More distally, the caliber of the cord is normal. Histologic comparisons of the normal and the constricted regions show normal-caliber vessels in the proximal segment and vessels with reduced lumens at the site of stricture. Little or no Wharton’s jelly is present in the constricted zone. In our experience, such localized strictures of the cord are not true foci of intrinsic vascular narrowing, but more likely represent a focus of external constriction (the nature of which is unknown), resulting

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in reduction of the lumen area in all three vessels. Usually, the lesion is associated with a macerated, stillborn fetus, and often the umbilical cord is twisted in the area of stenosis. The latter lesion is referred to as umbilical cord torsion. Twisting of the cord occurs most likely after fetal death in utero rather than before. Obviously, patients with this lesion should be carefully evaluated in order to determine the true significance of this lesion and its relationship, if any, to the attending fetal death. Only a few careful studies of abnormally large umbilical cords have been made. Coulter et al.2 studied umbilical cord edema and noted the anomaly in 10% of all deliveries. Other workers (including ourselves) note a much less common incidence. Coulter et al. noted an increased frequency in prematurity, cesarean sectiondelivered infants, abruptio placenta, infants born to mothers with diabetes mellitus, Rh isoimmunization, and macerated stillbirth. Abnormally thick umbilical cords are fairly common and most often result from focal areas of liquefaction of Wharton’s jelly, edema, or possibly an abnormal distribution of the jelly (since it has been described as a thixophilic jell). Abnormally smallcaliber umbilical cords are rare in the presence of liveborn fetuses. In our experience, the incidence of the latter abnormality is about 1/5000 livebirths. Cords devoid of Wharton’s jelly and an absence, or near absence, of amnionic covering are very rare (1/3483, or 0.03%). Abnormally large-diameter umbilical cords are not usually associated with increased fetal morbidity and mortality. Smallcaliper umbilical cords in which Wharton’s jelly is present but in short supply are associated with both stillborn fetuses and an increased fetal mortality due to vascular occlusion and/or thrombosis. In cords in which little or no Wharton’s jelly surrounds the umbilical vessels, increased perinatal mortality has been described. Labarrere et al.24 described three cases in the latter category; all cases with little or no Wharton’s jelly were associated with acute fetal distress and perinatal death. Apparently death was due to vascular compromise of the unprotected vessels. Although no known preventive measures have as yet been described, cesarean section delivery appears the route of choice in the presence of naked umbilical arteries or an unusually thin umbilical cord. References (Umbilical Cord Dimensional Abnormalities) 1. Naeye RL: Umbilical cord length: clinical significance. J Pediatr 107: 278, 1985. 2. Coulter JBS, Scott JM, Jordan MM: Oedema of the umbilical cord and respiratory distress in the newborn. Br J Obstet Gynaecol 82:453, 1975. 3. Blackburn WR, Cooley NR Jr, Manci EA: Correlations between umbilical cord structure-composition and normal and abnormal fetal development. Proc Greenwood Genet Center 7:180, 1988. 4. Jauniaux E, Vyas S, Finlayson C, et al.: Early sonographic diagnosis of body stalk anomaly. Prenat Diagn 10:127, 1990. 5. Lockwood CJ, Scioscia AL, Hobbins JC: Congenital absence of the umbilical cord resulting from maldevelopment of embryonic body folding. Am J Obstet Gynecol 155:1049, 1986. 6. Gruenwald P, Mayberger HW: Differences in abnormal development of monozygotic twins. Arch Pathol 70:685, 1960. 7. Gruenwald P: Aplasia of the umbilical cord. J Morphol 73:103, 1943. 8. Javert CT, Barton B: Congenital and acquired lesions of the umbilical cord and spontaneous abortions. Am J Obstet Gynecol 63:1065, 1952. 9. Brown FJ: On the abnormalities of the umbilical cord which may cause antenatal death. J Obstet Gynaecol Br Emp 32:17, 1925. 10. Grange DK, Arya S, Opitz JM, et al.: The short umbilical cord. BDOAS XXIII(1):191, 1987. 11. Moessinger AC, Mills JL, Harley EE, et al.: Umbilical cord length in Down’s syndrome. Am J Dis Child 140:1276, 1986.

12. Miller ME, Higginbottom M, Smith DA: Short umbilical cord: its origin and relevance. Pediatrics 67:618, 1981. 13. Moessinger AC, Blanc WA, Marone PA, et al.: Umbilical cord length as an index of fetal activity: experimental study and clinical implications. Pediatr Res 16:109, 1982. 14. Katz V, Blanchard G, Dingman C, et al.: Atenolol and short umbilical cords. Am J Obstet Gynecol 156:1271, 1987. 15. Soernes T, Bakke T: The length of the human umbilical cord in twin pregnancies. Am J Obstet Gynecol 157:1229, 1987. 16. Rayburn WF, Beynen A, Brinkman DL: Umbilical cord length and intrapartum complications. Obstet Gynecol 57:450, 1981. 17. Blackbum W: Umbilical cord, short umbilical cord syndrome. In: Birth Defects Encyclopedia. ML Buyse, ed. Blackwell Scientific, London, 1990, p 1732. 18. Grange DK, Arya S, Opitz J, et al.: The short cord syndrome. Pediatr Pathol 5:96, 1986. 19. Mendez-Bauer C, Troxell RM, Roberts JE, et al.: A clinical test for diagnosing nuchal cords. J Reprod Med 32:924, 1987. 20. Blackburn W, Cooley Jr NR, Hudson J: Umbilical cord overgrowth (long umbilical cord): etiologic considerations, associations, and pathophysiologic implications. Proc Greenwood Genet Ctr 18:119, 1999. 21. Katz K, Shosham Z, Lancet M, et al.: Management of labor with umbilical cord prolapse: a 5-year study. Obstet Gynecol 72:278, 1988. 22. Weber J: Constriction of the umbilical cord as a cause of foetal death. Acta Obstet Gynecol Scand 42:259, 1963. 23. Edmonds HW: The spiral twist of the normal umbilical cord in twins and in singletons. Am J Obstet Gynecol 67:102, 1954. 24. Labarrere C, Sebastiani M, Siminovich M, et al.: Absence of Wharton’s jelly around the umbilical arteries: an unusual cause of perinatal mortality. Placenta 6:555, 1985. 25. Bergman P, Lundin P, Malmstrom T: Mucoid degeneration of Wharton’s jelly. An umbilical cord anomaly threatening foetal life. Acta Obstet Gynecol Scand 40:372, 1961. 26. Fox H: Pathology of the Placenta. WB Saunders, Philadelphia, 1978, p 426.

35.8 Umbilical Cord-to-Cord Entanglements Definition

Umbilical cord-to-cord entanglements are most often seen in monoamnionic twinning and occur when separate umbilical cords become entangled. The entanglement may or may not produce vascular obstruction, fetal growth retardation, or death. Diagnosis

The condition is to be suspected and monitored in monoamnionic twinning where the umbilical cords become interwound as evidenced by ultrasonography and where one or both twins show signs of reduced umbilical cord vascular flow and/or restricted movement. At delivery, the umbilical cords show various kinds of entanglement, forming knotted and twisted masses (Fig. 35-24) with or without obvious signs of vascular obstruction. Perfusion studies using radio-opaque materials may demonstrate foci of vascular lumen constriction and/or increased perfusion pressures. Careful reduction of the twisted masses and histologic sectioning of cord regions showing signs of torsion or constriction of the normal caliber are helpful in further delineating and documenting the lesion(s). Etiology and Distribution

With rare exception, cord-to-cord entanglements involve monoamnionic twin pregnancies.1,2 Monoamnionic twins result from division of the ovum on days 7–13 after conception and hence after the formation of the bilaminar germ disc and yolk sac.3 Signs

Umbilical Cord

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Fig. 35-24. Collage of cord-to-cord entanglements showing complexity of lesions. A. Entanglement of small-caliber cord (arrowhead) from stillborn twin and normal-caliber cord from liveborn twin. B. Entanglement of cords where one fetus passed through loop in cord

of sibling. C. Simple twist entanglement of cords with signs of vascular obstruction in one (dark) cord. D. Complex entanglement of thin (arrows) and normal-caliber cords. The small-caliber cord was associated with stillbirth.

of cord-to-cord entanglement result from fetal movements within a single amnionic sac. Usually the cords are not greatly unequal in length except when one twin has serious developmental anomalies. The distance between the sites of cord insertion into the placental plate does not seem to influence the frequency of cordto-cord entanglements. Variable decelerations on nonstress test are usually regarded as a sign of abnormal cord position, and in monoamnionic twinning, cord-to-cord entanglements are most common. Benirschke and Driscoll4 discuss the possibility of cordto-cord entanglements in the rare condition in which diamnionic sacs are converted into a seemingly monoamnionic sac by rupture and dissolution of the partition initially separating the once in-

dependent amnionic sacs. Rarely, a furcate (forked) cord is present in a monoamnionic pregnancy. A single cord arises from each fetus and then fuses into a single cord near the placental insertion (i.e., ‘‘funiculopagus twinning’’).5 Monoamnionic twin pregnancies account for about 1% of twin pregnancies and are attended by high (40%) risk for both fetal anomalies and death. Fetal loss in pregnancies in which two fetuses are present within a single gestation sac is due primarily to cord-to-cord entanglements. Although vascular communications are almost universally present in monochorionic placentas, twintwin transfusion syndrome is a rather infrequent complication. There is also a poor correlation between the degree of cord-to-cord

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entanglement and fetal outcome. Cord-to-cord entanglements are more common between male fetuses and when one or both cords are abnormally long. Prognosis, Prevention, and Treatment

The careful monitoring of monoamnionic twin pregnancies for umbilical cord entanglement by ultrasonography and for fetal heart rate aberrations is important in the management of such pregnancies. Cesarean section delivery is indicated in cases in which nonstress tests with variable decelerations are detected. Cesarean section delivery is indicated in all cases of cord-to-cord entanglement so as to prevent cord avulsion, hemorrhage, and/or vascular flow obstruction during a vaginal delivery. References (Umbilical Cord-to-Cord Entanglements) 1. Lyndrup J, Schouenborg L: Cord entanglement in monoamnionic twin pregnancies. Eur J Gynecol Reprod Biol 26:275, 1987. 2. Nyberg DA, Filly R, Golbus MS, et al.: Entangled umbilical cords: a sign of monoamnionic twins. J Ultrasound Med 3:29, 1984. 3. Corner GW: Observed embryology of human single ovum twins and other multiple births. Am J Obstet Gynecol 70:933, 1955. 4. Benirschke K, Driscoll SG: The Pathology of the Human Placenta. Springer-Verlag, New York, 1967. 5. Larson SL, Kempers RD, Titus JL: Monoamnionic twins with a common umbilical cord. Am J Obstet Gynecol 105:635, 1969.

35.9 Umbilical Cord Hematoma Definition

An umbilical cord hematoma is an area of hemorrhage (focal or diffuse) within the confines of the umbilical cord with or without extension into the placental plate or amnionic sac or fetal abdomen. Diagnosis

Hemorrhages into the tissues of the umbilical cord are most often observed at delivery or shortly thereafter by direct examination. A few cases have been detected by ultrasonography, either serendipitously, or when studying an umbilical cord with an unusually large diameter, or during an evaluation for complications attending amniocentesis (e.g., fetal tachycardia followed by bradycardia).1 Diagnostic accuracy requires the visual examination of each umbilical cord and histologic sampling of suspected areas of hemorrhage (Fig. 35-25). In the absence of funisitis, inflammatory changes are not usually associated with hemorrhage into the umbilical cord parenchyma. Etiology and Distribution

Only a few careful studies of umbilical cord hemorrhage and/or hematoma have been reported.1–6 Dippel2 reviewed the subject in 1940, and subsequently several case reports have been published. The etiology is variable, but is often unknown. Cases have been associated with funisitis (especially of syphilitic origin), cord trauma (after amniocentesis, cord prolapse, loop or knot formations, and iatrogenic crush injuries such as clamping), and umbilical cord aneurysms associated with postmaturity. Hemorrhage most often involves the proximal one-third of the umbilical cord and most often involves the vein (90%). Only a few cases of umbilical cord hemorrhage/hematoma have involved umbilical arteries.4,5 Factors predisposing to umbilical cord hemorrhage include velamentous umbilical cord insertion, short

Fig. 35-25. Equal length segments of umbilical cord in normal (A) and hematoma (B) regions. Differences in weight between such segments may be used to estimate fetal blood loss (see text). (C and D) Corresponding cross sections for each cord. (E) Note histologic profile of cord hemorrhage (H) associated with thin-walled, vitelline vessels (arrows).

Umbilical Cord

umbilical cord, prolapsed umbilical cord, umbilical cord loops, encirclements or entanglements, neoplasms (e.g., hemangioma), amniocentesis, and a deficiency of Wharton’s jelly leading to exposed or poorly supported umbilical cord vessels. Some studies (including our own) suggest funisitis as a predisposing factor. The incidence of umbilical cord hematoma is not firmly established and varies with the methods of detection. Dippel’s study2 suggests umbilical cord hemorrhage to be a rather rare lesion (1/5050 deliveries). In our medical service where all umbilical cords are examined both by direct visual inspection and histologically, the incidence of umbilical cord hemorrhage is 8% (406/5000). In routine histologic samples (three cross sections: proximal, middle, and distal), care must be taken so as to exclude hemorrhages associated with umbilical cord clamping at delivery. Prognosis, Prevention, and Treatment

The prognosis in umbilical cord hemorrhage depends on the volume of fetal blood loss expressed as a fraction of total blood volume. A quick method for calculating fetal blood loss in a cord hematoma is to tie off the hemorrhagic area with silk sutures and excise and weigh the segment of cord (Fig. 35-25). Then tie, excise, and weigh an exact length of cord in a normal nonhemorrhagic area. The volume of blood lost corresponds to the difference in equal segment weights (1 g blood ¼ 1 ml blood). Small hemorrhages, as are often seen histologically in the adventitial zones of umbilical cord blood vessels, are most often associated with a favorable clinical outcome. When the umbilical cord diameter is significantly enlarged due to hematoma formation, the prognosis is adversely affected. In Dippel’s study,2 umbilical cord hematomas were associated with a fetal mortality rate of about 47%. Ruvinski et al.1 reported a 50% mortality rate in similar cases. The treatment objective is to restore the fetal blood volume to normal. Prevention of umbilical cord hemorrhage is based on identifying high-risk patients (e.g., those with short cords, velamentous insertions, looped or entangled cords, cords with arterial or venous aneurysms) and planning delivery so as to preclude cord traction or trauma. Antibiotic therapy is indicated in cases of suspected funisitis. References (Umbilical Cord Hematoma) 1. Ruvinski ED, Wiley TL, Morrison JC, et al.: In utero diagnosis of umbilical cord hematoma by ultrasonography. Am J Obstet Gynecol 140:833, 1981. 2. Dippel AL: Hematomas of the umbilical cord. Surg Gynecol Obstet 70:51, 1940. 3. Farb HF, Rowlatt U, Spellacy WN: Spontaneous umbilical cord hematoma. A rare cause of fetal death. Minn Med 66:287, 1983. 4. Love WC, Bucklin R: Rupture of umbilical arteries; report of a case. Obstet Gynecol 11:459, 1958. 5. James JD, Nickerson CW: Laceration of umbilical artery and abruptio placentae secondary to amniocentesis. Obstet Gynecol 48 (Suppl):44, 1976. 6. Summerville JW, Powar JS, Ueland K: Umbilical cord hematomas resulting in intrauterine fetal demise, a case report. J Reprod Med 32:213, 1987.

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Diagnosis

The proximal involved segment of the umbilical cord is enlarged (Fig. 35-9); careful examination reveals the presence of the normal umbilical components (Wharton’s jelly and blood vessels) along with the herniated organ (usually the small intestine with or without an associated vitelline duct component). Certain types of ‘‘umbilical cord polyps’’ are, in reality, umbilical cord hernias, which develop as a result of mucosal eversion of a patent vitelline duct into the parenchyma of the umbilical cord. The wall of the umbilical cord in the area of enlargement is thicker and less transparent than that of an omphalocele. The histologic organization of the wall of the umbilical cord is not lost; these features are not present in histologic sections of the omphalocele sac. Histologic examination of the wall of the umbilical cord in the region of umbilical cord enlargement (proximal region) reveals amnion covering the external surface. The amniocutaneous junction remains at the site of umbilical cord origin from the abdominal wall. In the case of omphalocele (which can be confused with umbilical cord hernia), in which the defect is in body fold development, histologic studies of the junction between umbilical cord and omphalocele reveals an abrupt cessation of the amnionic sheath, which is considerably displaced from the skincovered abdominal wall. The internal lining of the umbilical cord hernia sac and of the omphalocele is peritoneum (serosal cells) (Fig. 35-26). Between embryonic weeks 6 and 10, a loop of small bowel may be seen normally herniating into the base of the umbilical cord. The presence of intestine within the proximal umbilical cord after the beginning of week 11 is abnormal. Examination reveals an enlarged proximal segment of umbilical cord which by ultrasonography, transillumination, or careful surgical dissection reveals the presence of a segment of intestine, vitelline duct, or urachus herniating through the umbilical ring and into the parenchyma of the umbilical cord. Patel et al.1 noted crepitus with manipulation of an enlarged umbilical cord containing a gas-filled segment of small bowel. Needle aspiration of the herniated organ may reveal meconium (gut herniation). If urine is retrieved by aspiration, usually a patent urachal fistula is present and disruption or stenosis of the distal urinary tract is present. Injection of a radioopaque material reveals communication between the herniated organ and the gastrointestinal or genitourinary tract. Histologic examination differentiates between umbilical cord hernia and omphalocele. The wall of the umbilical cord hernia consists of umbilical cord tissues, and hence its external surface is covered with amnion; the amniocutaneous junction is at the fetal body wall. In omphalocele (an abdominal wall defect), the surface of the sac is an eosinophilic, fibrous material, and amnion is absent. Sections taken at the umbilical cord-omphalocele junction reveal an abrupt cessation of amnion at the cord’s junction with the omphalocele sac. Both the umbilical cord hernia sac (Fig. 35-26) and the omphalocele sac are lined by peritoneum. Etiology and Distribution

35.10 Umbilical Cord Hernia Definition

An umbilical cord hernia is a displacement of abdominal organs through the umbilical ring and into the proximal formed umbilical cord after 10 weeks gestation.

Umbilical cord hernias are almost always derived from telescoping (herniation) of a segment of a persisting, patent vitelline duct into the proximal umbilical cord. Less commonly, but of more serious import, is the complete prolapse of the vitelline duct and the ileum into the proximal umbilical cord. The variations of this process depend on the degree of prolapse and whether the vitelline duct alone is involved or whether the duct and the ileum are

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Other Systems and Structures

Fig. 35-26. Cross section of umbilical cord hernia (see also Fig. 35-9) showing loops of small bowel (G) within peritoneum-lined cavity (arrows) in parenchyma of cord. The umbilical arteries (A) and vein (V) are displaced laterally. The wall of the hernia sac is composed of compressed, normal components of the umbilical cord. Amnion (Am) covers the surfaces of the hernia sac.

from failure of the intestines to return to the abdomen at the end of the first stage of rotation of the midgut loop. More recently, the anomaly is being considered an abdominal wall defect. Congenital umbilical cord hernia is also an abnormality of the anterior abdominal wall. In this condition, the gut returns normally to the abdomen during week 10 of gestation and then is herniated back into the umbilical ring and proximal umbilical cord during the fetal period. In umbilical cord hernia, the wall of the cord is greatly thinned but continues to show the external amnion layer overlying a thin compressed connective tissue layer, which in turn surrounds the peritoneum (hernia sac) and herniated organ (gut loop). Omphaloceles are closely associated with short umbilical cords and possible abnormal umbilical cord tension during development. Umbilical cord hernias are not, in our experience, associated with abnormally short umbilical cords. Umbilical cord hernia may rarely, however, be associated with an omphalocele. In the latter situation, the cord and its herniated organ(s) arise directly from the wall of the omphalocele. Extremely large umbilical cord hernias have been described that contain most of the abdominal viscera; the latter anomalies have been referred to as ‘‘eventration’’ of the abdominal viscera and have been described in association with abnormalities of the caudal abdominal fold (e.g., exstrophy of the urinary bladder). The incidence of umbilical cord hernia is approximately 1/3000 livebirths; umbilical cord hernias involving the vitelline duct are more common than those involving the allantoic duct (5:1). Umbilical cord hernias are associated with patency of either the vitelline or the allantoic ducts. Usually, careful exploration will reveal abnormalities in intestinal fixation (mesenteric) or, in the case of a hernia involving the allantoic duct, obstructive anomalies in the distal urinary outflow tract (e.g., urethral atresia, stenosis, or urinary bladder obstruction as in sacrococcygeal teratoma). Both umbilical cord hernias and umbilical hernias are associated with imperforate anus in females. Prognosis, Prevention, and Treatment

involved (Fig. 35-26). Rarely, prolapse of the patent urachus (allantoic duct) may produce an umbilical cord hernia. The etiologic mechanism is identical to those described above which involve the vitelline (omphalomesenteric) duct. Recently Chandavasu and Deposito2 described umbilical cord hernia in association with chondrodysplasia punctata. The authors emphasize the role of mechanical deformation in producing umbilical cord hernia and present arguments in favor of external mechanical forces acting on a malformed fetus leading to the extrusion of abdominal organs into the area of least resistance, the umbilical cord. We agree that mechanical factors most likely play a role in the development of umbilical cord hernia. It is obvious from the foregoing discussion that the herniation of a segment of the vitelline or allantoic duct or of the ileum or urinary bladder into the umbilical cord, by way of these ducts, leads to umbilical cord hernia. The actual herniation takes place in utero prior to ligation of the umbilical cord. The ligation of the umbilical cord in the presence of a hernia may lead to the ‘‘umbilical polyp’’ anomaly. The herniation of these organs into the umbilicus after the ligation of the umbilical cord may lead to umbilical polyp or umbilical hernia. The omphalocele is an abdominal wall defect that involves the lateral abdominal folds (plates) and the umbilical ring. For many years, the omphalocele (exomphalos) was thought to result

The prognosis is generally good but depends on the nature of associated anomalies. Occasionally, the birthing attendant may ligate the enlarged proximal umbilical cord and, in the case of ileal herniation, occlude the intestine.3 Delayed recognition of this condition may lead to intestinal perforation, peritonitis, and death. Examination of the proximal segment of the umbilical cord by prenatal ultrasonography should detect those fetuses with significant enlargement. Such cords should be carefully examined at birth, and ligation should be performed in the most distal normal segment of the cord. The enlarged proximal segment may then be surgically explored and the nature of the hernia determined prior to definitive surgical treatment. Abdominal exploration should include an evaluation of the mesenteric attachments of the gut and of the urinary outflow tract in the case of hernias associated with patent urachus. Measures that prevent umbilical cord hernias are not known. References (Umbilical Cord Hernia) 1. Patel D. Dawson M. Kalyanam P, et al.: Umbilical cord circumference at birth. Am J Dis Child 143:638, 1989. 2. Chandavasu O, Deposito F: Umbilical cord hernia in a child with autosomal recessive chondrodysplasia punctata. J Med Genet 23:84, 1985. 3. Landor JH, Armstrong JH, Dickerson OB, et al.: Neonatal obstruction of bowel caused by accidental clamping of small omphalocele: report of two cases. South Med J 56:1236, 1963.

Umbilical Cord

35.11 Anomalies of Umbilical Cord Insertion Diagnosis

Normally, over 90% of pregnancies are associated with a central or pericentral insertion of the umbilical cord (Fig. 35-27). When one collates the many studies of this anatomic fidelity, it is obvious that only about 9% of insertions are abnormal, and, in these, the umbilical cord inserts onto the placental plate within 3 cm of the margin, or the cord inserts into the membranes remote from the placental plate. In the latter condition, the umbilical blood vessels course in the absence of Wharton’s jelly and may or may not undergo branching. About 7% of cords insert into the placental margin, and only about 1% insert in a velamentous manner. When one examines aborted conceptions at week 12 or earlier, the incidence of abnormally inserted umbilical cords is greatly increased.1 Monie,2 for example, reported the incidence of velamentous insertions to be equal to that of marginal insertions (15.3% and 14.7%, respectively). With the advent of in vitro fertilization, the incidences of marginal and velamentous insertions have greatly increased.3,4 Although few studies have been reported, as many as 60% of in vitro fertilized eggs are associated with marginal umbilical cord insertion. In the interest of an orderly discussion, we address each of these anomalies individually in this section. Umbilical cord insertion is referred to as marginal when the cord inserts within 3 cm of the placental plate margin, velamentous when the umbilical cord terminates prior to reaching the placenta and its vessels course within the membranes to reach the placenta,

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and furcate when the formed cord terminates and the blood vessels course without membranous coverings onto the placental plate (Figs. 35-27 and 35-28). A rare form of velamentous insertion in which the cord ends and the vessels course without branching but within the membranes onto the placental plate is referred to as velamentous interposition insertion (Table 35-5). As indicated in the introduction, umbilical cord insertion anomalies are more commonly encountered in aborted conceptions. The diagnosis in these specimens is established by direct inspection, using, when necessary, a hand lens or a dissecting microscope. In our experience, careful dissection is best carried out in a petri dish with a wax-filled bottom containing Eagle’s or another suitable culture medium. The wax bottom allows one to use insect-mounting pins to anchor the embryo or early fetus while dissecting. In older specimens (after week 12) the diagnosis is again established by direct observation; ultrasonography has been employed with some degree of success in establishing abnormal umbilical cord insertions. In general, direct inspection at birth of the fetus with attached cord and placenta allows one to determine anomalous umbilical cord insertion readily. Because of the extremely high incidence of marginal and velamentous insertion associated with in vitro fertilized pregnancies, careful ultrasonographic monitoring for this anomaly is recommended. Vasa previa may be seen in association with velamentous insertion or in association with placental succenturiate lobes or bilobed placentas. At times, vasa previa may occur as aberrant vessels arising from a marginally inserted cord. The designation

Fig. 35-27. Collage of umbilical cord insertions: A. Central. B. Eccentric. C. Marginal. D. Velamentous.

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Other Systems and Structures Table 35-5. Umbilical cord insertion anomalies Type

Delineating Characteristic

I. Marginal insertion plate

Cord inserts within 3.0 cm of placental plate margin

II. Velamentous insertion*

Cord ends a few centimeters from the placental plate, and vessels course through membranes and display branching prior to reaching placenta

III. Velamentous interposition insertion*

Cord ends and vessels course unbranched within the membranes and without Wharton’s jelly until reaching the placental plate

IV. Insertio funiculi furcata (furcate insertion)*

The organized cord ends, and the vessels course individually onto the placenta with several orders of branching. Each vessel is apparently encased in amnionic sheath, but Wharton’s jelly is not present between the end of the cord and the placenta

*Vasa previa may or may not be present.

Fig. 35-28. ‘‘Interposition’’ variety of velamentous insertion showing vessels coursing within the membranes and parallel to the placental surface before branching. UC, umbilical cords.

vasa previa refers to vessels arising from the distal end of the umbilical cord that course within the fetal membranes and in so doing encroach upon or overlay the internal cervical os, hence the risk for fatal fetal hemorrhage.5,6 Umbilical cord vasa previa by definition involves velamentous umbilical cord insertion and requires that the vessels traverse the lower uterine segment in front of the presenting part. In this context, the condition represents an umbilical cord insertion anomaly in association with umbilical cord prolapse. Manual examination of the dilated cervical area allows one to feel the cord-like vessels but not usually their pulsations. If after manual examination vasa previa is suspected, direct visualization of the vessels using an amnioscope can confirm the diagnosis. Cesarean section delivery is then indicated. Umbilical cord vasa previa may be associated with fetal hemorrhage before the onset of labor. Most often, however, the hemorrhage develops as an intrapartum complication. Vaginal bleeding in pregnancies at high risk for vasa previa (velamentous insertion, bilobed placenta and succenturiate placenta, and in vitro fertilization pregnancies) should be further investigated in order to determine the origin of the blood (fetal vs. maternal). The Kleihauer and Apt tests are commonly used and are based on resistance of fetal hemoglobin to alkylating agents. Hemoglobin electrophoresis may also be used, but is time-consuming.4,5 Etiology and Distribution

Velamentous and marginal cord insertions have been explained by a disturbance in orientation of the blastocyst (the polarity theory)

and by limitation of space (the trophotropism theory). The polarity theory implies that the blastocyst is abnormally rotated at nidation and does not face the endometrium. Thus, when the connecting stalk becomes vascularized and seeks penetration with the future area of placentation, it is obliquely oriented, and hence the vessels must become membranous in location.7 Strassman8 presented organized observations supporting the case for trophotropism. Most strongly supporting this idea is the high incidence of velamentous and marginal cord insertions in twinning, in higher multiple births, in the case of intrauterine foreign bodies (intrauterine devices) and tumors, and, more recently, in ultrasonographic studies of ‘‘placental migration.’’ Recently it has been noted that when eggs are fertilized in vitro and then implanted into the uterus the rates of marginal and velamentous insertion soar. Because of the haphazard and uncontrolled orientation of the blastocysts during mechanical implantation it seems likely that abnormal polarity might indeed occur and hence be responsible for umbilical cord insertion anomalies. Another etiologic consideration, at least for velamentous insertion, is ‘‘competition for space’’ at the site of implantation. The increased incidence of velamentous insertion in twinning seems to imply that such a competition leads both to velamentous insertion of the cord and subsequently to deformations (structural ‘‘anomalies’’) of normally formed organs. Hanley et al.9 evaluated abnormalities of umbilical cord insertion onto the placenta and birth weight discordancy in twins. Monochorionic-diamnionic twins with velamentous cord insertion exhibited an increased risk (13 fold) for birth weight discordancy (present in 46%) as compared to similar type twins with normal umbilical cord insertion. No increased risk of birth weight discordancy was detected in dichorionic-diamnionic twins with velamentous cord insertion. The frequency with which one sees umbilical cord insertion anomalies depends, as one would expect, on the nature of the materials being examined. Insertion anomalies are much more frequent in early abortuses. Monie2 noted about equal frequencies of velamentous (15.3%) and marginal cord (14.7%) insertions in 9–13 weeks abortuses. Other studies1 as well as our own support this general conclusion. In our experience, however, marginal

Umbilical Cord

insertions are significantly more common in early abortuses than are membranous insertions. Although the experience is rather limited, in vitro fertilized eggs show marginal and velamentous insertions in as many as 60% of cases. In third-trimester placentas, velamentous insertion occurs in 0.2–1.2% of singleton pregnancies and in over 10% of multiple pregnancies. Marginal insertion is noted in about 10% of second- and third-trimester deliveries. The incidence of velamentous insertion in third-trimester in vitro fertilized pregnancy is not established at this time but is thought to be significantly higher than in all other pregnancies. Vasa previa by definition requires that velamentous insertions be present and that the vessels traverse the lower uterine segment and present in advance of the fetal presenting part. The incidence of vasa previa remains low in spite of the fact that many cases are not diagnosed. The incidence is about 1/3000–5000 deliveries. The incidence is, because of its association with membranous insertion, increased greatly in multiple pregnancies. Only about 1 in 50 velamentous insertions are further complicated by vasa previa. Prognosis, Prevention, and Treatment

There is a significant association between velamentous insertion and anomalies within the fetus. This association is less strong for marginal insertions.2 Robinson et al.10 noted that structural ‘‘anomalies’’ associated with velamentous umbilical cord insertion were actually most often deformations of normally formed organs. The prognosis is less favorable in cases of umbilical cord insertion anomalies associated with additional fetal anomalies. The major risk in umbilical cord insertion anomalies is fetal hemorrhage. The risk for fatal fetal hemorrhage is greater in umbilical cord vasa previa in which the mortality rate ranges between 33–100%.11 If fetal hemorrhage occurs before delivery, the mortality rate is as high as 73%; if the hemorrhage is encountered during delivery, fetal loss is 58%. Since in vitro fertilization pregnancies show a marked increase in umbilical cord insertion anomalies (particularly for vasa previa), all such deliveries are at high risk for hemorrhage. The key to management of umbilical cord insertion anomalies is early recognition by ultrasonography. All in vitro fertilization pregnancies should be carefully screened for abnormal umbilical cord insertion. As indicated above, delivery should, in the case of vasa previa, be achieved by caesarean section rather than vaginally. Vasa previa may rarely be in association with bilobed placenta or succenturiate placental lobe, and hence similar precautions should be taken. A means of preventing umbilical cord insertion anomalies is not well defined at this time. Since the incidence of these anomalies is increased in situations in which the uterine environment is abnormal (e.g., in the presence of an intrauterine device or foreign body or tumor), one preventive approach is to institute corrective measures prior to conception. References (Anomalies of Umbilical Cord Insertion) 1. Hathout H: The vascular pattern and mode of insertion of the umbilical cord in abortion material. J Obstet Gynaecol Brit Commonw 71: 963, 1964. 2. Monie IW: Velamentous insertion of the cord in early pregnancy. Am J Obstet Gynecol 93:276, 1965. 3. Burton E, Saunders DM: Vasa praevia: cause for concern in in vitro fertilization pregnancies. Aust NZ J Obstet Gynecol 28:180, 1988. 4. Daniel Y, Schreiber L, Geva E, et al.: Do placentae of term singleton pregnancies obtained by assisted reproductive technologies differ from those of spontaneously conceived pregnancies? Hum Reprod 14:1107, 1999.

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5. Kouyoumdijian A: Velamentous insertion of the umbilical cord. Obstet Gynecol 56:737, 1980. 6. Dougall A, Baird CH: Vasa previa-report of three cases and a review of literature. Br J Obstet Gynaecol 94:712, 1987. 7. Hertig AT: The placenta: some new knowledge about an old organ. Obstet Gynecol 20:859, 1962. 8. Strassman P: Placenta praevia. Arch Gyna¨kol 67:112, 1902. 9. Hanley ML, Ananth CV, Shen-Schwarz S, et al.: Placental cord insertion and birth weight discordancy in twin gestation. Obstet Gynecol 99:477, 2002 10. Robinson LK, Jones KL, Bernirschke K: Structural defects associated with velamentous and marginal insertion of the umbilical cord. Proc Greenwood Genet Center 2:99, 1983. 11. Tollison SB, Huang PH: Vasa previa, a case report. J Reprod Med 33:329, 1988.

35.12 Umbilical Cord Knots Definition

The presence of a ‘‘true’’ (‘‘overhand,’’ ‘‘granny,’’ or ‘‘figure eight’’) knot within the umbilical cord that required, in its formation, the complete passage of the fetus through a loop or cord encirclement is an umbilical cord knot. Umbilical cord loops, encirclements, and false knots caused by varices and aneurysms should not be considered umbilical cord knots. Diagnosis

The presence of a true umbilical cord knot may be established prenatally by ultrasonography or, most commonly, at the time of birth by direct inspection. Diagnosis by ultrasonography is the exception, because difficulty is often encountered in differentiating umbilical cord knots from localized umbilical cord enlargements due to multiple vascular loops (Fig. 35-29) and cysts of allantoic or vitelline duct origin. Pulsations in the cord as evidenced by Doppler examination help to differentiate these lesions. The umbilical cord knot is almost invariably that of a simple ‘‘overhand’’ type (Fig. 35-30).1–3 Rarely (11–19%) a ‘‘figure eight’’ knot is produced (Fig. 35-30B). Signs of vascular obstruction (Fig. 3530C,D) may or may not be present. False knots (Fig. 35-29) are focal aneurysmal (arterial) or varicose (vein) elongations of the umbilical vessels within a segment of the cord. The aneurysms produce a ‘‘U-shaped,’’ knot-like deformation of the cord surface. False knots do not require for their formation the passage of the fetus through a cord loop. Etiology and Distribution

Umbilical cord knots are associated most often with long umbilical cords (length at term gestation
75 cm).1,2 Umbilical cord knots are always associated with the previous presence of an umbilical cord encirclement or loop through which the fetus has passed. The incidence of true knots at term delivery is about 0.4–4.6% of all pregnancies. True umbilical cord knots represent about 5% of all cord complications. Although the data are conflicting, umbilical cord true knots are more common in mothers with increased parity and in male fetuses. Since umbilical cord length is not thought to increase significantly after 28 weeks gestation and because umbilical knots are found in aborted fetuses, Walker and Pye3 have suggested that the knots are formed after 9, and probably before 28, weeks gestation. Recent studies have suggested that the location of the umbilical cord knot is not correlated with other variables. Umbilical cord knots are rarely, if

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Other Systems and Structures

Fig. 35-29. ‘‘False knot’’ in cord at term (A) that is composed of dilated loops of umbilical vein. (B) The umbilical arteries (arrows) rarely take part in false knot formation.

Fig. 35-30. ‘‘True’’ overhand umbilical cord knot (A), loose ‘‘figure-eight’’ knot (B), and true cord knots without (C) and with (D) signs of vascular obstruction.

ever, seen in short umbilical cords. The presence of more than one umbilical cord knot is rare and when present is associated with an excessively long umbilical cord. A fetal body part rarely may reside within a knot (Fig. 35-31). Prognosis, Prevention, and Treatment

Most true umbilical cord knots do not impose a significant degree of vascular obstruction to bring about clinically detectable vascular compromise. In 1925 Browne4 reported vascular perfusion data that implied significant venous vascular resistance was associated with a single, snug, umbilical cord knot. The presence of such a knot doubled the required perfusion pressure within the umbilical cord (from 10 to 20 mm Hg). Two true umbilical cord knots required 60 mm Hg perfusion pressure for similar venous flow. Recently Chasnoff and Fletcher5 challenged Browne’s data.

Their studies conclude that true knots in umbilical cords of normal diameter (and hence containing normal quantities of Wharton’s jelly) should not normally compromise fetal blood flow. Their studies indicated that abnormally thin (thin-caliber) umbilical cords required significantly less tension to restrict blood flow adversely. Chasnoff and Fletcher5 implied that Wharton’s jelly protected the umbilical cord vessels from collapse in true knots. Our own studies suggest that umbilical vascular spiraling is unique and, like a spiral telephone cord, prevents actual vascular kinking and collapse. Wharton’s jelly is thixotropic (e.g., liquifies with pressure), as suggested by McKay et al.,6 and simply allows the umbilical cord to undergo significant degrees of tension (stretch) before allowing actual vascular collapse (see chapter introduction). In situations in which less Wharton’s jelly is packed within the amnionic confines of the cord, a thin (small-diameter)

Umbilical Cord

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trasonography for the development of umbilical cord loops and/ or knots. Once a true umbilical cord knot is identified, the fetal cardiovascular system should be monitored for signs of vascular flow compromise, and cesarean section delivery is recommended. It would seem wise to deliver all fetuses by cesarean section if an umbilical cord knot was present in an abnormally thin cord. The prevention of umbilical cord knots lies in the management of those conditions known to predispose the umbilical cord overgrowth, namely, polyhydramnios and fetal hyperkinesia (e.g., maternal drug addiction to cocaine, amphetamines, or caffeine). References (Umbilical Cord Knots) 1. Blickstein I, Shoham-Schwartz Z, Lancet M: Predisposing factors in the formation of true knots of the umbilical cord-analysis of morphometric and perinatal data. Int J Gynaecol Obstet 25:395, 1987. 2. Dippel AL: Maligned umbilical cord entanglements. Am J Obstet Gynecol 88:1012, 1964. 3. Walker CW, Pye BG: The length of the human umbilical cord: a statistical report. Br Med J 1:546, 1960. 4. Browne FJ: On the abnormalities of the umbilical cord which may cause antenatal death. J Obstet Gynaecol Br Commonw 32:17, 1925. 5. Chasnoff IJ, Fletcher MA: True knot of the umbilical cord. Am J Obstet Gynecol 127:425, 1977. 6. McKay DG, Roby CC, Hertig AT, et al.: Studies of function of early human trophoblast. II. Preliminary observations on certain chemical constituents of chorionic and early amnionic fluid. Am J Obstet Gynecol 69:735, 1955. 7. Blackburn W, Cooley Jr NR, Hudson J: Umbilical cord overgrowth (long umbilical cord): Etiologic considerations, associations, and pathophysiologic implications. Proc Greenwood Genet Ctr 18:119, 1999.

35.13 Umbilical Cord Loops (‘‘Encirclements’’) Fig. 35-31. Stillborn fetus with ‘‘true’’ knot encompassing fetal neck. Signs of vascular obstruction are noted in the cord but not within the fetal neck or head.

umbilical cord is produced. Such cords, when distorted by a true umbilical cord knot, are most likely to impose vascular occlusion and pathophysiologic fetal responses. Obviously, the clinical importance of a true umbilical cord knot is whether vascular (particularly venous) compromise is present. This can be determined by simple inspection. When venous obstruction is present, the umbilical vein is dilated and congested within the segment between the knot and the placental plate. The umbilical vein as it courses away from the knot (toward the fetus) shows no obvious sign of dilation or congestion. The presence of a true umbilical cord knot during the prenatal period should be monitored by evaluating fetal heart rate and growth. Since the risk for vascular obstruction is greatest in thin, small-diameter cords, cord diameter might prove a valuable risk indicator. Some obstetricians feel that in such cases delivery should be by cesarean section. The great majority of umbilical cord knots are of no clinical significance except that their presence signals the possibility of an abnormally long umbilical cord. Long umbilical cords are in turn at risk for encirclements (loops), fetal deformations and entanglements, and prolapse during vaginal delivery. Long cords are also associated with fetal cardiomegaly and heart failure.7 In conditions in which umbilical cord elongation is known to occur (see Section 35.7), the fetus should be monitored by ul-

Definition

Encirclement (3608) of a fetal body part by the umbilical cord with or without vascular obstruction in either the umbilical cord or the encircled fetal part is considered an umbilical cord loop. Significant deformation of the encircled fetal part may or may not be present. Diagnosis

Umbilical cord encirclements may be detected prenatally by ultrasonography or at delivery by direct inspection. Umbilical cord loops should be considered when fetal hypokinesia, fetal hypoxia, and/or bradycardia are detected. Umbilical cord loops should also be considered in the differential evaluation of oligohydramnios, placental abruption, and maternal amnionic fluid embolization.1–4 Rarely, umbilical cord loops may be responsible for varying degrees of fetal deformation (especially of the limbs and head-neck region) and growth retardation (Fig. 35-32 and 35-33). Etiology and Distribution

Encirclement of the fetal body or limbs results from fetal movements either during normal intrauterine development or during exaggerated or agonal movements (e.g., during a severe or lethal hypoxic event).1,2 Most umbilical cord loops are single, but as many as five nuchal loops have been reported. Most umbilical cord loops surround the fetal neck (92%); only a few (6%) surround the neck and a fetal limb. Umbilical cord loops around the trunk alone or a limb alone account for only 2%. Rarely an umbilical cord fetal entanglement may involve the introduction of

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Other Systems and Structures

a body part into an umbilical cord knot (Fig. 35-31). Umbilical cord loops are associated with a long umbilical cord (
80 cm), polyhydramnios, fetal hyperkinesia (e.g., after certain types of maternal drug exposures or addictions), and twins with a single amnionic sac. Prognosis, Prevention, and Treatment

Fig. 35-32. Profile of right face and cranium showing deformation by a single umbilical cord loop. The cord coursed from the umbilicus superiorly over the right neck and over the cranial vault (arrow heads) and descended over the left cranium and encircled the neck before reaching the placenta. A conspicuous cleft was produced in the cranium, along with a deep groove in the left neck (arrow).

Fig. 35-33. Single umbilical cord loop (arrows) around fetal neck without signs of vascular obstruction within either the fetal neck or cord.

While most umbilical cord loops do not produce obstruction of the umbilical vascular flow or blood flow within the encircled fetal part, compression of the umbilical cord venous flow is the single most important factor associated with fetal depression at birth. Complications of umbilical cord blood flow are the most common factors associated with stillbirths, being present in about 15% of cases. Compromised umbilical cord blood flow can be held accountable for about 3% of perinatal deaths.5,6 When umbilical cord blood flow (usually flow within the umbilical vein) is significantly reduced, intermittent hypoxia develops. The pathophysiologic chain of events that follows includes fetal hypertension, fetal bradycardia (‘‘decelerations’’), and reduced fetal cardiac output. If the fetal heart rate falls below 80/min, the prognosis becomes more ominous. In cases in which prolonged intermittent bouts of fetal hypoxia are associated with cord compression, several complications have been observed, including myocardial conduction defects and myocardial arrest. Atropine may prevent the latter effect. Intermittent fetal hypoxia may lead to elevated levels of vasopressin and loss of solute (sodium) in the fetal urine. Fetal hypovolemia results from blood accumulating within the placental vascular space and within the umbilical arteries. Vasopressin elevations and fetal hypovolemia reduce fetal urine production, which in turn is associated with oligohydramnios.7,8 Significant umbilical artery acidemia is associated with a nuchal loop in 20% of cases (p < 0.05). In newborns with nuchal loop(s), umbilical artery acidemia is usually mixed (68%) or respiratory (23%) in origin. Pure metabolic acidemia is infrequent (9%). Nuchal cord may persist and may in a few cases result in fetal growth retardation, deformation (Fig. 35-32), or fetal death.1,5,6 In the uncommon case in which deformation is produced, the underlying fetal skin is usually grooved, and an ecchymotic band is present most often around the neck or around a limb. Umbilical cord loops may rarely produce traction on the placenta and initiate placental abruption and amniotic fluid embolism (Fig. 3534). Usually the umbilical cord loop involves the neck and a limb. Careful examination in such cases reveals a tear in the membranes and a separation of the placenta in the lower margin. Amnionic fluid is now free to enter the exposed maternal venous system producing maternal amnionic fluid embolism. Nuchal cords are associated with posterior location of the uterus and are least common with fundal uterine placement.9 When umbilical cord loops are detected prenatally (e.g., by ultrasonography), the pregnancy must be carefully monitored for signs of umbilical cord compression and/or fetal deformation. A cesarean section is the delivery route of choice, and immediate resuscitative measures should be employed. When umbilical cord loops are present in a stillborn, the clinician is wise to leave the loop(s) in place until proper photographic documentation can be established, preferably in the presence of the perinatal pathologist. When a liveborn is delivered with an umbilical cord entanglement, the loop should be unwound by manipulating the fetus rather than by cutting the cord. This technique offers a chance at restoring the fetal blood volume prior to cord clamping. As much as 20% of the fetal blood volume may be entrapped within the umbilical cord and placenta distal to the loop. Once the entrapped

Umbilical Cord

1445

diagnosed prior to delivery and in cases in which the fetus shows signs of vascular impairment (e.g., increased heart rate, decreased fetal movements, or growth failure of the encircled part). References (Umbilical Cord Loops)

Fig. 35-34. Schematic drawing of opened uterus showing fetus with intact fetal membranes and with umbilical cord loop surrounding posterior neck and containing arm. Placental marginal separation is present; arrow indicates portal of entry of amnionic fluid into subplacental decidual venous sinuses, resulting in maternal death due to amnionic fluid embolization. (Redrawn from Corridan et al.4)

fetal blood has been restored to the main fetal reservoir, the cord should be clamped in the usual manner. Ultimately, the cord length should be determined and recorded. Control of factors that tend to produce excessive umbilical cord length (Section 35.7) might well prevent both umbilical cord knots and umbilical cord loops. These include control of polyhydramnios and fetal hyperkinesia (e.g., protection of the fetus from drugs known to produce fetal hyperkinesia, such as theophylline, cocaine, and amphetamines). Cesarean section delivery should be considered in cases in which umbilical cord loops are

1. McLennan H, Price E, Urbanska M, et al.: Umbilical cord knots and encirclements. Aust NZ J Obstet Gynecol 28:116, 1988. 2. Dippel AL: Maligned umbilical cord entanglements. Am J Obstet Gynecol 88:1012, 1964. 3. Adinma JI: Effect of cord entanglement on pregnancy outcome. Int J Gynaecol Obstet 32:15, 1990. 4. Corridan M, Kendall ED, Begg JD: Cord entanglement causing premature placental separation and amnionic fluid embolism. Br J Obstet Gynaecol 87:935, 1980. 5. Hankins GDV, Snyder RR, Hauth JC, et al.: Nuchal cords and neonatal outcome. Obstet Gynecol 70:687, 1987. 6. Bruce S, James LS, Bowe E, et al.: Umbilical cord complications as a cause of perinatal morbidity and mortality. J Perinat Med 6:89, 1978. 7. Dunn PM: Tight nuchal cord and neonatal hypovolemic shock. Arch Dis Child 63:570, 1988. 8. Vanhaesebrouck P, Vanneste K, DePraeter C, et al.: Tight nuchal cord and neonatal hypovolaemic shock. Arch Dis Child 62:1276, 1987. 9. Collins JH, Geddes D, Collins CL, et al.: Nuchal cord: a definition and a study associating placental location and nuchal cord incidence. Am J Obstet Gynecol 167: 570, 1992.

35.14 Umbilical and Umbilical Cord Polyp Definition

An umbilical or umbilical cord polyp is a tissue mass derived almost always from everted mucosa of the vitelline (omphalomesenteric or yolk) duct and/or occasionally from everted mucosa of the small intestine. Usually the polyp-like mass is present within the umbilicus or, less commonly, within the proximal umbilical cord. Polyps of this type are derived in part by herniation of the vitelline duct or fetal gut into the umbilicus or proximal umbilical cord (Fig. 35-35). The lesion may therefore be seen in the fetus (i.e., within the umbilical cord or on its surface),

Fig. 35-35. Schematic drawings of umbilical cord polyp formation due to progressive degrees of telescoping of the mucosa from a patent vitelline duct (abdominal segment) into the umbilicus or proximal umbilical cord. Similar lesions developing after the umbilical cord has been clamped and excised lead to ‘‘umbilical polyp.’’

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newborn (umbilicus or umbilical cord), or infant (umbilicus). Rarely, an umbilical polyp may appear within the umbilicus of a child or even an adult. The surface of the button-like tissue mass is covered with moist, everted, red-pink intestinal or vitelline duct mucosa and resembles the common colonic ‘‘polyp.’’ Most often, the mass appears as a granular, red tissue mass within the umbilicus. Less often, the polyp appears as a sausage-like tumor within the proximal umbilical cord. In the latter condition, the diameter of the proximal umbilical cord is enlarged, and histologic study reveals a mass composed of a dilated segment of vitelline duct into which a segment of small bowel has herniated (telescoped). The mass appears as a ‘‘polyp’’-like structure with everted intestinal (ileal) mucosa covering the surface. As discussed above, most polyp-like lesions that appear within the umbilical cord of the fetus at birth, or within the umbilicus of the infant or child, are derived from mucosal eversions of a patent vitelline duct and may or may not involve the mucosa of the distal small intestine. A very rare form of umbilical cord polyp is attached to the surface of the proximal cord by a thin, mucosa-covered pedicle containing blood vessels and smooth muscle. Umbilical cord polyps of this type are bathed in amnionic fluid. Histologic studies of such polyps reveal a mucosal surface typical of the small intestine. Rarely, the mucosa is mixed, showing both small intestinal and colonic forms. Umbilical cord polyps attached to the surface of the cord are, in our opinion, best referred to as ‘‘umbilical cord hamartomatous polyps’’ (Figs. 3536 and 35-37) and are derived from pluripotential stem cells originating from pluripotential stem cells within the yolk sac or stalk rather than from mechanical eversions or herniations of the vitelline or intestinal mucosas.1–3 Recently, Guschmann et al.4 reported a polyp of this type on the surface of the cord. Its histology was similar to a polyp of the small bowel. The authors attributed its origin as arising from a remnant of the omphalomesenteric duct. The definition of umbilical cord polyp includes the inverted, herniated vitelline duct (or a segment of ileum) remnants within the proximal (2–10 cm) umbilical cord, umbilical mucosal remnants, and hamartomatous polyps. Umbilical enteric fistula, umbilical sinus, and other vitelline duct-derived anomalies (i.e., cyst, Meckel diverticulum, congenital umbilicoenteric band) are not considered in this section. Diagnosis

The condition is to be suspected when a mass of red, weeping tissue (which resembles that of a gastroenterostomy site) is noted to reside at the base of the umbilicus or when similar tissue masses reside within the proximal umbilical cord and appear to emanate from the abdominal wall. The diagnosis is confirmed by histologically identifying intestinal mucosa covering the surface of the tissue mass. If a lumen is identified, fistulography (using radiopaque materials) should be performed in order to rule out a communication with the intestine (e.g., umbilical enteric fistula). Hamartomatous umbilical cord polyps appear on the surface of the proximal umbilical cord and resemble those commonly seen in the colon. A nodule of tissue covered by intestinal mucosa is attached to the umbilical cord by a thin pedicle (Figs. 35-36 and 35-37). Histologic studies reveal intestinal mucosa overlying a central mass of lamina propria-like tissue. Rarely a pilonidal cyst or sinus may appear in the umbilicus that might be misinterpreted as a ‘‘polyp.’’ These lesions consist of a cystic structure (which may be a part of a sinus tract of vitelline origin) lined by stratified squamous epithelium within which hair

Fig. 35-36. Surface of the umbilical cord (UC) showing a ‘‘hamartomatous polyp’’ attached to the surface of the cord by a thin, delicate stalk (S). The polyp’s surface is covered with a mucosa identical to that of the small intestine (M). (Courtesy of Dr. Kurt Aterman, Halifax, Canada).

follicles, hair shafts, and chronic inflammatory and giant cells are present. Only about 40 cases are well documented in the literature, and almost all patients are adult males. The etiology is not well established, but because of location, the possibility of these lesions representing hamartomatous changes involving pluripotential cells of vitelline duct origin needs consideration and evaluation.5 Etiology and Distribution

Early in embryonic development, the primary yolk sac is converted in large part to the embryonic midgut. The segment remaining outside the developing embryo becomes the secondary yolk sac. The latter is connected to the gut by the yolk stalk or duct. With further embryonic growth, this connection becomes elongated and narrowed and is now referred to as the yolk, vitelline, or omphalomesenteric duct. With continued fetal growth, the vitelline duct continues to elongate, and finally the lumen obliterates, forming an atretic cord-like structure. By the end of intrauterine weeks 5 or 6, the attenuated cord becomes detached from the intestines, and a few remaining segmental remnants reside within the umbilical cord. If a short segment of the patent vitelline duct persists as it passes through the fetal abdominal wall, it usually everts after birth, forming a mucosal-covered button (polyp) at the base of the umbilicus. Less

Umbilical Cord

1447

Fig. 35-37. A. Cross section of umbilical cord (UC) with ‘‘hamartomatous polyp’’ (P) attached to the amnionic surface. B. At higher magnification, the mucosa covering the polyp’s surface is mostly of the small intestine type but contains foci (arrow) of colonic mucosa. The lamina propria contains smooth muscle (Sm) and numerous tiny blood vessels (V). (Courtesy of Dr. Gerard H. Hilbert, Sacred Heart Hospital, Pensacola, Florida.)

commonly, a longer segment of the vitelline duct persists and extends from the abdominal wall distally into the umbilical cord, where again it may evert, forming an intestinal polyp-like structure within the proximal umbilical cord (Fig. 35-35). Very rarely, pluripotential cells become stranded within the umbilical cord connective tissues. These cells may at times further differentiate into intestinal mucosa and may form hamartomatous polyp-like structures on the surface of the proximal cord.6 The incidence of a polyp within the umbilicus is more common than a polyp arising from the surface of the umbilical cord. No true incidence for either type of polyp has thus far been published. In our experience, the incidence of umbilical cord polyps is 1/15,000 births. Umbilical polyps and/or umbilical cord polyps may occur in the absence of other visceral malformations. In some cases, a polyp may be present in association with a fibrous band, Meckel diverticulum, umbilical sinus, and/or umbilical enteric fistula. About 5% of patients with Meckel diverticulum have a history of umbilical or umbilical cord polyp. If one excludes hemangiomas, the remaining ‘‘hamartomatous’’ polyps on the surface of the umbilical cord are extremely rare; we have seen one lesion in some 10,000 umbilical cord examinations. The differential diagnosis includes umbilical granuloma, which is usually dry and velvety in appearance and displays no lumen. Lesions developing later in infancy and early childhood should be studied as possible pyogenic granulomas or benign tumors (angiomas, pigmented nevi, and molluscum contagiosum). In adults, the differential diagnoses should include melanomas and metastases to the umbilicus (St. Joseph nodule).7 Prognosis, Prevention, and Treatment

The prognosis is usually good, especially when there is no communication with the gut. If a fibrous band is present, so is an inherent risk for intestinal obstruction (volvulus or strangulation).

If an associated fistula is present, a search for other underlying embryonic anomalies (e.g., ectopic mucosa, abnormal gut rotation, and anomalous mesenteric fixation of the gut) should be made. A few cases have been reported in which the heterotopic intestinal mucosa contained gastric mucosa and/or pancreas tissues. Internal ulceration of the proximal umbilical cord may result from the secretions of gastric heterotopias. Treatment of isolated umbilical polyps is surgical resection and suturing. If associated lesions (fistula, fibrous cord, Meckel diverticulum) are present, appropriate additional surgical treatment is indicated. No known preventive measures exist. The presence of an umbilical cord polyp discovered during the routine histologic examination of the proximal umbilical cord at birth requires that the infant be further evaluated for umbilical polyp and that appropriate surgical repair be performed. Hamartomatous umbilical cord polyps require no treatment other than routine umbilical cord clamping and an evaluation of the newborn for possible associated vitelline duct remnant anomalies. References (Umbilical and Umbilical Cord Polyp) 1. Nix TE, Jr, Young CJ: Congenital umbilical anomalies. Arch Dermatol 90:160, 1964. 2. Steck WD, Helwic EG: Cutaneous remnants of the omphalomesenteric duct. Arch Dermatol 90:463, 1954. 3. Hejazi N: Umbilical polyp: a report of two cases. Dermatologica 150:111, 1975. 4. Guschmann M, Janda J, Wenzelides K, et al.: Der intestinale nabelschnurpolyp (Intestinal polyp of the umbilical cord). Zentralbl Gynakol 124: 132, 2002. 5. Gupta S, Sikora S, Singh M, et al.: Pilondial disease of the umbilicus-a report of two cases. Jpn J Surg 20:590, 1990. 6. Lee MCL, Aterman K: An intestinal polyp of the umbilical cord. Am J Dis Child 116:320, 1968. 7. Shetty MR: Metastatic tumors of the umbilicus: a review 1830–1989. J Surg Oncol 45:212, 1990.

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35.15 Abnormalities of Umbilical Cord (Abdominal Wall) Position Definition

A high, low, or eccentric position of the umbilical cord (or its cicatrix, the umbilicus) on the surface of the anterior abdominal wall is considered an abnormality of umbilical cord (abdominal wall) position. The eccentric umbilical cord or umbilicus is located away from the midline. High and low cords are usually midline. Diagnosis

During the past decade, we have recorded a series of measurements that were designed to express mathematically the position of the umbilical cord (or the umbilicus) at its origin on the surface of the abdominal wall. The measurements were taken in the midline and included (1) the length of the sternum, (2) the distance from the xiphoid tip inferiorly to the upper margin of the umbilical cord surface or upper rim of the umbilicus, (3) the vertical diameter of the umbilicus or umbilical cord, and (4) the distance between the lower margin of the umbilical cord surface or rim of the umbilicus to the superior edge of the symphysis pubis in the midline. Umbilical cord position was expressed as a ratio between the measurement from the upper edge of the manubrium to the center of the umbilical cord and the measurement from the center of the umbilical cord (or umbilicus) to the upper rim of the symphysis Fig. 35-38. A. Fetus with occipital encephalomyelocele, low-set umbilicus, and demarcations for measurements required for formulating umbilical cord position ratio. MNU ¼ distance between sternal notch and upper margin of umbilical ring; ud ¼ umbilical cord diameter at body wall; US ¼ distance between lower umbilical ring margin and upper margin of symphysis pubis

pubis in the midline. A normal developmental curve for mean umbilical cord position ratio at various stages of development from 20 to 40 weeks gestation is presented in Figure 35-38. A linear plot of these ratios reveals a nearly straight line. Values beyond 2 SD of the mean at any stage of development are considered abnormal, and cord position is considered either high (ratio below 2 SD) or low (ratio above þ2 SD). In analyzing our data, we detected 64 abnormal umbilical cord positions. Low umbilical cords were twice as common as were high cords. Cuniff et al.1 reported a similar method of expressing umbilical cord position. Their data were confined to newborn infants at term gestation for whom they reported a normal ratio of 3.32 ± 0.86 (mean ± 2 SD). Their values are consistent with those we found (ratio of 2.8 ± 0.26) at term gestation. Etiology and Distribution

The position of the umbilical cord is established at the time of umbilical ring formation. It is located at the junction of the four body folds comprising the anterior body wall, namely, the two lateral folds, the caudal fold, and the cranial fold. Abnormalities relating to a deficiency of mesodermal derivatives from the septum transversum may result in superior displacement of the umbilical cord position (decreased ratio). An excess in these derivatives would in turn result in inferior displacement of the umbilical cord position (increased ratio). Our data indicate that renal agenesisdysplasia is the most commonly associated major anomaly complex associated with low umbilical position and that a single umbilical in midline. B. Umbilical cord position expressed as a mathematical ratio (manubrium-umbilical margin length þ ½ umbilical diameter/symphysis-lower umbilical margin length þ ½ umbilical diameter) at various stages of development (20–40 weeks). The hatched shaded areas represent ± SDs for each gestational period.

Umbilical Cord

artery is often an accompanying finding. The observations imply that factors common to the inferior body fold (vascular supply, nutrition) may influence umbilical position. Although trisomies 13 and 18 are most commonly associated with high placement of the umbilicus in our data, we have not been able to identify salient processes within these syndromes that might explain an elevated placement of the body stalk or its derivatives. Although clinicians have repeatedly described ‘‘high-set’’ and ‘‘low-set’’ umbilical cords and ‘‘belly buttons,’’ most of these judgments have been subjective. Table 35-6 lists the various clinical conditions in which abnormal positions of the umbilicus have been found in our necropsy data. Abnormal position is determined on the basis of the criteria outlined above. Our studies indicate that inferior displacement of the umbilical position is associated with bilateral renal agenesis or dysplasia (13%) and with generalized intrauterine fetal growth retardation (12%). Other conditions that tend to displace the umbilical position inferiorly include those that expand the surface area of the anterior body wall (e.g., macro-

Table 35-6. Anomalies associated with abnormal umbilical position Anomaly

Percent

High-Set Umbilicus (37 cases)

Chromosome abnormality (7) Trisomy 13 (5)

11.0

Trisomy 18 (1)

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somia, fetal ascites). Curiously, monozygous twinning accounted for 6% of the low umbilical position; in each case, only one twin was involved. The latter observation implies that mechanical factors associated with amnionic fluid volume, pressure, or possibly umbilical cord tension may also be etiologically involved in this process. Low placement of the umbilicus has been reported in achondroplasia.1 High umbilical position is associated with certain chromosomal abnormalities (11% of cases of abnormal cord placement had trisomy 13, trisomy 18, or 3pþ syndrome) and with infants delivered to mothers with diabetes mellitus (3.2%). Robinow syndrome and the pentalogy of Cantrell have been reported to include high location of the umbilicus.1,2 As the measurement of umbilical position is used more widely, additional conditions with aberrant displacement of the umbilicus may be found. Prognosis, Prevention, and Treatment

The prognostic value of abnormal umbilical placement is not known. Our data reflect only an experience with necropsy specimens and hence the prognosis is abnormally skewed; until a broader database is generated using a more normal population, the predictive value of umbilical position as it relates to abnormal development of certain organ systems remains limited. Obviously, similar data generated by ultrasonographic morphometry from a large pool of fetuses would be of great value in expanding this area of interest. Specific treatment of abnormal umbilical position seems not to be indicated. Treatment directly related to the anomalies is indicated on an individual basis. No known preventive measures have been established.

3pþ syndrome (1) Multiple anomalies (4) Hydranencephaly-Potter syndrome (1)

6.3

References (Abnormalities of Umbilical Cord Position) 1. Cuniff C, Beaton S, Pippenger J: Determinants of umbilical cord position in the newborn. Proc Greenwood Genet Center 10:90, 1991. 2. Friedman JM: Umbilical dysmorphology. The importance of contemplating the belly button. Clin Genet 28:343, 1985.

Holt-Oram syndrome (1) Hemivertebrae (1) Encephalocele (1) Infants of diabetic mother (2) Macrosomic (1)

35.16 Antenatal Separation of the Umbilical Cord

Nonmacrosomic (1) Cantrell pentalogy*

Definition

Robinow syndrome*

Renal agenesis-dysplasia (8)

12.5

Antenatal separation of the umbilical cord is spontaneous detachment of the umbilical cord from the fetal abdominal wall or the placental plate before or during delivery.

Fetal growth retardation (8) Unexplained (6)

12.5

Diagnosis

Low-Set Umbilicus (27 cases)

Maternal drug abuse (2) Monozygous twinning (4)

6.3

Fetal hydrops (4) Congenital heart disease (1)

6.3

Turner phenotype (2) Infection (CMV) (1) CNS anomalies (3) Anencephaly (2)

4.7

Encephalocele (1) Achondroplasia* *Reported by Cuniff, et al.1 or by Friedman.2 Short-limb skeletal dysplasias were not found to have abnormal umbilical placement in our necropsy series.

Antenatal umbilical cord separation from the fetal abdominal wall (umbilicus) or from the placenta in the absence of traction avulsion is a rare event and is associated with fetal death.1,2 Incomplete detachment of the umbilical cord is also rare, but most infants (62%) survive. The diagnosis is established either in utero or at the time of delivery by observing the fetus detached from the umbilical cord (usually within 4 cm of the abdominal wall) or the placental plate. Etiology and Distribution

The process by which the umbilical cord normally separates from the abdominal wall leaving the umbilicus is poorly understood. Most studies suggest that normal umbilical cord separation is influenced by environmental and other factors (e.g., method of delivery, infections, gestational age, bilirubin levels).1–3 Leukocytes

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Table 35-7. Factors predisposing to antenatal umbilical cord detachment Major

Minor

Velamentous insertion

Vasa previa

Short umbilical cord

Marginal attachment

Umbilical cord venous varicosities

Postmaturity

2. Malpas P: A case of constrictive sclerosis of Wharton’s jelly associated with detachment of the placenta. J Obstet Gynaecol Br Commonw 75:678, 1968. 3. Novack AH, Mueller B, Ochs H: Umbilical cord separation in the normal newborn. Am J Dis Child 142:220, 1988. 4. Dippel AL: Hematomas of the umbilical cord. Surg Gynecol Obstet 70:51, 1940.

Umbilical venous aneurysms Trauma Funisitis, especially syphilis

35.17 Abnormalities of Postnatal Umbilical Cord Separation

Umbilical cord structure Umbilical cord torsion

Definition

Vascular thrombi

Abnormalities of postnatal umbilical cord separation are early or late separation of the umbilical cord from the abdominal wall leaving the umbilicus following birth. Cord separation may be said to be delayed when it occurs later than 14 days and is clearly delayed when separation occurs after 21 days.1,2 Little or no information or standards are available regarding accelerated umbilical cord separation after birth. It is noted, however, that cord separation requires a shorter time period in Third World countries apparently due to variations in cord care and the incidence of infections.3

Umbilical cord sclerosis Wharton’s jelly Umbilical cord calcifications, especially intravascular Amnionic bands

infiltrating the umbilical cord at the level of the umbilicus are thought to elaborate lysosomal components that lead to the autolytic separation of the umbilical cord. Supporting this concept is the fact that umbilical cord separation after birth is delayed in certain genetically determined disorders (e.g., deficiency of leukocyte adherence glycoproteins). Opposition to the role of funisitis with leukocyte infiltration playing a role in umbilical cord separation is the fact that intrauterine umbilical cord maceration and/ or separation are rare, whereas funisitis is a common lesion. Anatomic studies suggest that special morphologic structures (e.g., spiral valves of Hoboken) within the umbilical arteries bring about obliteration of the umbilical arteries at the umbilicus soon after birth and, ultimately, ischemic autolysis and cord separation. Supporting this view is the fact that autolysis is a universal tissue phenomenon that does not require leukocyte components such as lysosomes. The incidence of spontaneous antenatal umbilical cord separation is rare, the exact incidence not having been established at this time. A variety of associated umbilical cord lesions have been suggested as predisposing risk factors (Table 35-7). Maceration or sclerosis of Wharton’s jelly seems to be a common component, a process leaving the umbilical cord vessels clearly exposed to occlusion by minimal traction or by torsion or twisting.1,2 Prognosis, Prevention, and Treatment

Complete spontaneous umbilical cord separation in utero is associated with fetal death. If partial separation occurs during the antenatal period, a fetal mortality rate of 38% has been observed.4 Obviously, the prognosis depends on the timing of the separation and the associated risk factors (Table 35-7). In those cases in which funisitis (e.g., syphilis) leads to sclerosis and umbilical cord separation, antibiotic therapy is indicated. In other conditions in which the umbilical cord is short or the vessels exposed and unsupported by Wharton’s jelly (e.g., velamentous insertion, vasa previa), umbilical cord separation during delivery may be precluded by cesarean section.

Diagnosis

Studies of the time required for the separation of the umbilical cord from the abdominal wall following birth reveal considerable variation in the mean time of separation that depends on climate, socioeconomic conditions, and cord care regimens (Table 35-8). Most studies suggest a mean time of separation of about 7.4 days (SD ± 3.3). Other studies have found a somewhat longer mean time (e.g., 12.9 days).1 Vaginal delivery is associated with a shorter time of umbilical cord separation (12.9 days) than is cesarean section delivery (15.9 days). In twins, cord separation is more rapid in the first born (mean ¼ 9.2 days) than in the second born (mean ¼ 10.0 days).4 In general, cord separation is delayed in singletons with serious infections and in certain disorders of neutrophil function (e.g., deficiency of leukocyte adherence glycoprotein). Etiology and Distribution

The process by which normal umbilical cord separation occurs after birth is not fully understood. Drying, necrosis, granulocyte activity, and collagenase activity may all play a role. Hayward et al.2 reported an association between delayed cord separation, severe widespread infections, and familial defective neutrophil mobility. Subsequent studies have indicated that 50% of patients with a genetically determined deficiency in leukocyte adherence Table 35-8. Factors altering umbilical cord separation Accelerating

Delaying

Genetic Factors

None reported

Leukocyte adherence glycoprotein deficiency

Other Factors

References (Antenatal Separation of the Umbilical Cord) 1. Lurie S, Fenakel K, Gorbacz S: Antenatal maceration of umbilical cord: a case report. Eur J Obstet Gynecol 35:271, 1990.

Hyperbilirubinemia

Severe infection

Postmaturity

Prematurity

Umbilical Cord

glycoproteins display delayed cord separation.5 Genetic factors in normal cord separation have not, as yet, been identified except that separation is earlier in females. Cord separation is influenced, however, by a variety of factors, including environment, mode of delivery, the presence or absence of infections, and gestational age (see Table 35-8). Recently Razvi et al.6 have described delayed cord separation in association with retrograde urine flows through the umbilical stump due to a urachal anomaly. Collectively, the data indicate that umbilical cord separation is determined by the interaction of multiple factors. Most data indicate that cord separation is mediated normally by the migration of leukocytes into the cord stump and release of lysosomal enzymes, bringing about autolytic maceration and, ultimately, separation of the cord from the abdominal insertion site. Prognosis, Prevention, and Treatment

The incidence of abnormal cord separation (either accelerated or delayed) has not been established. Prognosis is detrimentally affected by neutrophil mobility disorders, widespread neonatal infections, and deficiencies in leukocyte adherence. Treatment and preventive measures are associated with control of infection due to abnormal neutrophil mobility and/or leukocyte adherence. Conditions that promote umbilical cord separation (postmaturity, hyperbilirubinemia) also tend to diminish a favorable prognosis. References (Abnormalities of Postnatal Umbilical Cord Separation) 1. Novack AH, Mueller B, Ochs H: Umbilical cord separation in the newborn. Am J Dis Child 142:220, 1988. 2. Hayward AR, Leonard J, Wood CBS, et al.: Delayed separation of the umbilical cord, severe widespread infections, and defective neutrophil mobility. Lancet 1:1099, 1979. 3. Guala A, Pastore G, Garipoli V, et al.: The time of umbilical cord separation in healthy full-term newborns: a controlled clinical trial of different cord care practices. Eur J Pediatr 162: 350, 2003. 4. Oudesluys-Murphy AM, Hop W, de Groot C: Umbilical cord separation in twins. Early Hum Dev 19:241, 1989. 5. Berkinshaw CJ, Weemaes CMR, Roos D, et al.: Congenital deficiency of leukocyte-adherence glycoproteins: a familial defect. Neth J Med 31:158, 1987. 6. Razvi S, Murphy R, Shlasko E, et al.: Delayed separation of the umbilical cord attributable to urachal anomalies. Pediatrics 108: 493, 2001.

35.18 Umbilical Cord Torsion (Twist) Abnormalities Definition

Umbilical cord torsion (twist) abnormalities are one or more complete rotations (3608) of the fetus and cord about its longitudinal axis, which may result in compression deformation of the cord contents. In this condition, the deformation is imposed due to fixation of the cord at the placental end; umbilical cord torsion of clinical significance results in partial or complete obstruction of blood flow within the umbilical vein, the arteries, or both. Umbilical cord torsion may occur during life as well as after fetal death. The remarkable structural organization of the umbilical cord allows the fetoplacental circulation to be achieved without imposing great restraint on fetal movement during development. Fetal movement is intimately associated with the normal development of many organ systems and is vitally important for the normal development of fetal respiration, hearing, and range of

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joint motion. To allow fetal motion without vascular compromise, the umbilical cord blood vessels are dispersed in a helical manner and are surrounded by protective jelly with thixotropic properties. In spite of these safeguards, umbilical cord vascular flow may be compromised when the cord, fixed to the placental plate, becomes twisted when the fetus rotates within the amnionic cavity. Unfortunately, considerable confusion exists in regard to the nomenclature relating to torsion (twist) deformation of the cord and its contents. Vascular spiraling is independent of cord torsion, and both are often present within the same cord. The term umbilical cord coarctation is confusing in that coarctation usually refers to narrowing of a vascular lumen due to intrinsic lesions rather than to extrinsic forces. Umbilical cord stricture seems to imply nothing more than a severely narrowed region in the cord; the term does not imply pathologic narrowing of the blood vessel lumen, nor does it imply a rotational ‘‘twist’’ as being responsible for the narrowing. Umbilical cord torsion deformations, which we feel are independent of vascular spiraling, and abnormalities that lead to a localized narrowing of the cord’s caliber with or without coarctation (lumen constriction) of the umbilical blood vessels are discussed in this section. Diagnosis

In abortuses, examination of the umbilical cord using a hand lens or stereomicroscope allows one to suspect umbilical cord torsion. Although torsion may occur at any region of the cord, it is most common at or near the amniosquamous junction in close

Fig. 35-39. Stillborn fetus showing umbilical cord torsion (arrow) near the abdominal wall and with associated vascular obstruction, cord congestion, and dilation distally.

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approximation with the abdominal wall (Fig. 35-39). Only rarely has umbilical cord torsion of clinical importance been reported near the placental end of the cord.1 In examination of larger fetuses, direct inspection of the cord will identify twists. Usually the torsion occurs in a narrowed area of the cord near the abdominal wall (Fig. 35-39), and numerous twists may be present in other regions of the cord as well. In our experience, umbilical cord torsion produces signs of vascular obstruction (dilation of the umbilical vein and, less commonly, arteries) in only about one-half of the specimens (Fig. 35-40). Cross sections of the umbilical cord should be harvested at the level of suspected vascular compromise and at levels both proximal (fetal side) and distal (placental side) to the site of narrowing. A final evaluation of the degree of vascular compromise can then be made using morphometric techniques at the microscopic level. Often signs of vascular thrombosis are present, as are signs of more chronic vascular obstruction (calcification and vascular mural hyalinization). Inflammatory changes are not present in most cases of umbilical cord torsion. As indicated above, it is important to differentiate normal vascular spiraling in the umbilical cord from twisting. This is done simply by rotating the free (fetal) end of an umbilical cord attached to the placenta and observing the resulting deformation as superimposed upon a normal umbilical cord with normal vascular spirals. It is important to determine the direction of torsion as it is related to the direction of vascular spiraling. For example, when a normal, term umbilical cord is twisted (20 full rotations) in the same direction as that of the vascular spiral (e.g., left rotations with left-handed spirals), the resulting deformations of the cord are rather uniform and consist of numerous twists (Fig. 3541). This is the deformation pattern usually described in the literature of umbilical cord torsion. If the same cord is now brought back to the normal position, and rotated 20 full turns in the opposite direction of vascular spiraling, the deformation pattern in the umbilical cord is more conspicuous and is more irregular (Fig. 35-41). The force required to impose 20 rotations in a direction opposite that of the vascular spiraling is considerably greater than that required to impose the same number of twists in the same direction as that of the vascular spiral. For this reason, we believe that the direction of twisting in most reported cases of umbilical cord torsion is the same as that of the normal direction of vascular spiraling. This simple experiment demonstrates that the distortion imposed on the umbilical cord during torsion is dramatically influenced by the direction of vascular spiraling. We have not, at this time, fully explored the influences of this process on vascular flow within the umbilical cord blood vessels. Most umbilical cords with clinically significant torsion are relatively long and have vascular spirals made prominent by vascular dilation and congestion due to flow obstruction. After histologic sections are harvested, the remaining cord can then be counterrotated in such a manner as to remove the twists; the vascular spirals will remain. Umbilical cord coarctation usually occurs in the absence of umbilical cord twists and is diagnosed from histologic sections that demonstrate a localized narrowing of the vascular (arterial) lumen due to an intrinsic lesion.2 Umbilical cord stricture is a term used to describe a focal area of serious reduction in umbilical cord diameter that is not associated with umbilical cord torsion.3,4 Histologic studies of such areas usually show patent vessels and an absence or serious reduction in the quantity of Wharton’s jelly. No inflammatory reaction or scarring is present. True scarring is not observed in the umbilical cord or, for that matter, in other fetal tissues.

Fig. 35-40. Variations in umbilical cord (UC) torsion. (A) Most commonly, UC torsion (T) occurring after fetal death involves the cord in the proximalmost segment near the umbilicus. (B) Rarely, torsion occurs in a segment of cord distal to the umbilicus. UC torsion occurring after fetal death is not associated with vascular congestion and discoloration of the cord as in A and B. (C) Torsion with vascular obstruction prior to fetal death is associated with cord enlargement and signs of vascular congestion (especially involving the umbilical vein).

Umbilical Cord

Fig. 35-41. Photocomposition showing difference in umbilical cord surface deformation when cord is twisted 20 complete revolutions in the same and opposite direction as those of the vascular spiral. A. Cord twisted 20 times in opposite direction of vascular spiral shows coarse kinks and deformations. B. Cord at neutral position showing only

Etiology and Distribution

Umbilical cord torsion results from 3608 rotations of the fetus within the amnionic cavity that appear in the umbilical cord as areas of twisting. Umbilical cord torsion is most often observed in association with fetal death, regardless of whether umbilical cord vascular compromise was present or absent. This observation seems to imply that once a fetus dies in utero, it may continue to change position (rotate) within the amnionic cavity. Studies of this phenomenon need to be carried out using experimental models. Little or no information is available concerning the importance of blood pressure in spiraled umbilical cord vessels as a rotational force. It is possible that, once the fetal blood pressure ceases, intrinsic forces may tend to rotate the cord and fetus after death. If this is the case, it would explain why excessively long umbilical cords, which contain a greater number of vascular spirals, are significantly associated with an increased incidence of umbilical cord torsion. Since long umbilical cords are associated with polyhydramnios, the increased space available for fetal rotation may also play a role in this process. The incidence of cord torsion is not fully established due to nomenclature problems. In the literature, the incidence appears to be about 1/1000 births. In pediatric-perinatal pathology studies, the incidence is higher because of the increased numbers of stillborns and early pregnancies. Javert and Barton2 observed umbilical cord torsion in 15.3% of 297 umbilical cords harvested from fetuses weighing 500 g or less. Prognosis, Prevention, and Treatment

Unfortunately, umbilical cord torsion has, at least in the past, been most often observed in abortuses or stillborns.5 With the advent of ultrasonography, it appears possible that soon the lesions and conditions that predispose to torsion may be identified

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surface deformations due to normal vascular spiraling (left handed). C. Cord twisted 20 revolutions in same direction as that of the vascular spiral shows smooth regular twist deformations. This simple experiment shows that vascular obstruction is most likely to occur when the cord is twisted in the direction opposite that of the vascular spiral.

and more critical fetal monitoring employed. Predisposing lesions include long umbilical cord, polyhydramnios, multigravid pregnancies, and umbilical cord stricture. Umbilical cord torsion is most common in male infants and in pregnancies at risk for fetal hyperkinesia (e.g., certain maternal drug addictions and in mothers receiving asthma medications). No practical treatment protocol has as yet been instituted. Although counterrotation of the fetus with reduction of the umbilical cord twist causing vascular obstruction is an obvious treatment, such a procedure is not yet available. Prevention of umbilical cord torsion lies in the recognition of the factors that predispose to the deformation (long cord, polyhydramnios, fetal hyperkinesia, umbilical cord stricture) and controlling or modifying these risk factors. References (Umbilical Cord Torsion Abnormalities) 1. Glanfield PA, Watson, R: Intrauterine death due to umbilical cord torsion. Arch Pathol Lab Med 110:357, 1986. 2. Javert CT, Barton B: Congenital and acquired lesions of the umbilical cord and spontaneous abortion. Am J Obstet Gynecol 63:1065, 1952. 3. Corkill TF: The infant’s vulnerable life-line. Aust NZ J Obstet Gynecol 1:154, 1961. 4. Browne FJ: On the abnormalities of the umbilical cord which may cause antenatal death. J Obstet Gynaecol Br Empire 32:17, 1925. 5. Weber J: Constriction of the umbilical cord as a cause of foetal death. Acta Obstet Gynecol Scan 42:259, 1963.

35.19 Umbilical Cord Helical Ulceration Definition

Ulcerations of the umbilical cord that develop in a linear and helical fashion and overlie the helical spiral of either an umbilical

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artery or vein are referred to as umbilical cord helical ulcerations. (See also Section 35.6, Umbilical Cord Disruption.) Diagnosis

Examination of the umbilical cord reveals intermittent areas of ulceration that follow the pattern of the vascular spirals (Fig. 3542). Signs of hemorrhage may be present (blood clot) along the surface of the cord or within the amnionic fluid at delivery. Perinatal signs of fetal anemia may be present, and hydropic changes have been reported in one case.1 Bile staining of the umbilical cord and fetal membranes is present. Congenital small bowel atresia has been associated with helical ulcerations of the umbilical cord. The atresias may be single or multiple and have been reported in the duodenum and in the jejunum. Histologic studies reveal necrotic debris within the ulcer beds but little or no inflammation; no evidence of infection by bacteria, fungi, or viruses has been detected. Occasionally, multinucleated giant cells and or ‘‘activated macrophages’’ have been reported within the ulcer bed. Numerous pigment-filled macrophages may also be present within the fetal membranes. Etiology and Distribution

The pathogenesis of these unusual ulcerations is unknown. Bendon et al.1 have suggested three possible etiologic mechanisms that could account for the ulcers and the intestinal atresia association: vascular reactivity, gastric reflux, and a primary epithelial abnormality. The possibility of prolonged vascular spasm might well account for both the helical ulcers and ischemic intestinal atresia.1 Serious vascular spasm has been associated with abnormal smooth muscle reactivity and might well be mediated by vasoconstrictor substances (e.g., maternal cigarette smoking). Gastric reflux may occur in utero due to duodenal or jejunal atresia. Supporting this hypothesis is the presence of hemosiderinnegative, green-brown pigment in the amnionic and chorionic

Fig. 35-42. Umbilical cords showing linear ulcerations following the direction of arterial vascular spiraling (arrows). (Courtesy of Dr. Robert W. Bendon, Cincinnati Medical Center, Cincinnati, Ohio.)

macrophages that suggest the phagocytosis of bilious materials. Components of bile are known to disrupt the amnionic sheath of the umbilical cord (see Section 35.6). Finally, the possibility of a primary epithelial defect has been considered because of the association between intestinal atresia and epidermolysis bullosa, and hence such a defect could produce lesions in both the amnionic sheath of the cord and the intestine.2 Ulcerations of the umbilical cord arranged in a helical fashion are rare, and only nine cases have been reported.3 A few other unreported cases have been observed. The incidence of the lesion is unknown, as is the frequency with which the ulcers are associated with high intestinal atresia. Prognosis, Prevention, and Treatment

An accurate prediction of fetal outcome is not possible because of the few reported cases. Because of the association between helical ulcerations of the umbilical cord and fetal hemorrhage in association with fetal regurgitation of gastric and bilious materials, the risk for in utero exsanguination appears high (about 25%). One of the cases described by Bendon et al.1 was stillborn, and two others were anemic but survived after surgical correction of the small bowel atresias. Ohyama et al.3 described six cases of umbilical cord ulceration in 23 fetuses with upper intestinal atresia below the ampulla of Vater. Although these lesions are uncommon, all fetuses with intestinal atresia, especially in the proximal small bowel, should be considered possible candidates for helical ulcerations of the cord. The presence of physiologic signs of fetal anemia (abnormal heart rate) and/or heart failure are indications for immediate delivery provided adequate vital organ development is present. Although no known preventive measures have been proposed, the presence of bile within the amnionic fluid of a fetus with signs of intestinal atresia is indication for careful monitoring for signs of subsequent umbilical cord ulceration and hemorrhage. Bilious reflux into the amnionic fluid is suggested by increased optical density of the fluid at 450 nm in cases of duodenal atresias. References (Umbilical Cord Helical Ulceration) 1. Bendon RW, Tyson RW, Baldwin VJ, et al.: Umbilical cord ulceration and intestinal atresia: a new association? Am J Obstet Gynecol 164:582, 1991. 2. Chang CH, Perrin EV, Bove KE: Pyloric atresia associated with epidermolysis bullosa: special reference to pathogenesis. Pediatr Pathol 1:449, 1983. 3. Ohyama M, Itani Y, Yamanaka M, et al.: Umbilical cord ulcer: a serious in utero complication of intestinal atresia. Placenta 21: 432, 2000.

35.20 Umbilical Cord Neoplasms When one considers the embryologic derivation of the umbilical cord and placenta, it is not surprising that neoplasms of these organs are most likely derived from these pluripotential (stem) cell lines. Such cells are present in yolk sac endoderm, splanchnic mesenchyme, and trophoblast. A variety of neoplasms originate from remnants of both the vitelline and allantoic ducts. These may give rise to symptoms leading to clinical detection in the newborn or at any time thereafter. Almost always, the neoplasm arises within abdominal remnants of the vitelline (omphalomesenteric) or allantoic ducts, and, like testicular neoplasms, this phenomenon may be related to prolonged exposure of

Umbilical Cord

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the cellular remnants to high body temperature.1 Neoplasms may also be derived from mesenchymal (e.g., vascular) elements that accompany vitelline and allantoic differentiations. The umbilical cord at birth rarely contains neoplasms. Primary neoplasms of the cord are most always benign and of the vascular variety (hemangiomas). While hemangiomas of the placental plate are associated (10%) with similar lesions in the fetus, umbilical cord hemangiomas rarely, if ever, are similarly associated. The remaining primary neoplasm of the umbilical cord is the teratoma; this tumor is also benign and is thought to be derived from pluripotential cell arrests of yolk sac origin. Umbilical cord teratomas are composed of multiple tissue types, most of which are not native to the umbilical cord (e.g., cartilage, neural tissue, skin, skin appendages). Closely related to umbilical cord teratomas are umbilical cord hamartomas. The latter are nodular overgrowths of normalappearing tissues that are common to the umbilical cord such as mesenchyme, blood vessels, and endodermally derived tissues. Secondary (metastatic) tumors of the umbilical cord are extremely rare. The ‘‘giant pigmented nevus’’ may invade the umbilical cord.2 Extension to the cord appears most likely to result from direct surface-to-surface contact spread. While congenital neuroblastoma is fairly common, it is usually confined to the fetal truncal viscera. Jennings et al.3 report a case with metastatic spread to the umbilical cord. Metastatic spread of congenital neoplasm to the umbilical cord remains an esoteric subject with life-threatening implications. 35.20.1 Umbilical Cord Hemangiomas

An umbilical cord hemangioma is a tumor composed of thinwalled blood vessels lined by endothelium and arising from angiogenic buds derived from either allantoic (umbilical) or vitelline (yolk sac) vessels or their progenitors, the umbilical cord angiogenic mesenchyme (Fig. 35-43). These tumors have been considered umbilical cord angiomyxomas, cavernous hemangiomas, myxoangiomas, capillary hemangiomas, hemangiofibromyxomas, telangiectatic myxosarcomas, and angiohamartomas. The vessels are variable in size and are supported by relatively little connective tissue. Pathologic studies of umbilical cord hemangiomas reveal a lack of acidic mucin and a minimal degree of cellularity within the surrounding edematous Wharton’s jelly; these findings confirm the true nature of the lesion as a hemangioma rather than an angiomyxoma. Umbilical cord hemangiomas may be suspected by ultrasonography. The tumor appears as a hyperechogenic mass usually (75%) in the distal one-third of the umbilical cord near the placental plate. In virtually all cases the surrounding Wharton’s jelly is edematous, and the cord appears enlarged. Occasionally collections of edematous fluid may suggest umbilical cord pseudocyst. Maternal serum and amniotic fluid a-fetoprotein concentrations have been elevated in a few cases. Umbilical cord hemangiomas, unlike those of the placental plate, are not associated with polyhydramnios. By ultrasonography, the differential diagnosis includes umbilical cord teratoma, umbilical cord hematoma, and one of several varieties of umbilical cord cysts. Teratomas usually contain calcium; hematomas by ultrasonography are hyperechogenic septated masses. An umbilical cord hemangioma may be associated with a positive Kleihauer-Betke assay and with fluctuating maternal serum afetoprotein levels. The diagnosis is ultimately established by histologic examination (Fig. 35-43). In a few cases, histologic study

Fig. 35-43. Small hemangioma of the umbilical cord composed of numerous small capillary-like vessels (arrows) near three larger vessels of apparent vitelline origin (V).

failed to show the presence of the umbilical arteries at the level of the tumor. These statements implicate the umbilical arteries as the source of the neoplasm. In our experience, the umbilical arteries have always been present. Hemangiomas of the umbilical cord are thought to arise from ‘‘angiogenic mesenchyme’’ from vitelline vessels or accompanying yolk sac-derived elements. This is especially true of those hemangiomas that appear in the proximal one-third of the umbilical cord (20%). In other cases, these vascular tumors are thought to have arisen from the umbilical vein or one of the umbilical arteries. Remnants of vitelline vessels, while more commonly seen in the proximal umbilical cord, may also be present in the distal cord. The yolk sac remnants (and hence vitelline vessel remnants) are at term gestation most often found in the distal-most portion of the umbilical cord or near the base of the umbilical cord lying sandwiched between the amnion and the chorion covering the fetal surface of the placental plate. Umbilical cord hemangiomas, while the most common true neoplasm of the umbilical cord, are rare. Only 24 cases have been reported in the literature as of 1990.4–8 Most lesions are discovered at delivery; only four cases were identified prenatally. The neoplasm may be recognized as early as 17 weeks gestation. The incidence of umbilical cord hemangiomas is unknown. The lesions vary in diameter from 0.2–17 cm. In our experience involving 8000–10,000 histologic examinations, umbilical cord hemangiomas are more numerous than the incidence suggested in the literature. Because of the small number of cases, careful studies of morbidity and mortality are not available. A significant fetal mortality rate (64%) is noted, however, in the reported cases. Most often,

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fetal death in utero occurs in association with exsanguination due to hemorrhage or hematoma formation. Umbilical cord hemangiomas may be associated with torsion of the cord and acute fetal hypoxia. Nonimmune hydrops is also associated with these lesions, the etiologic basis of which is apparently arteriovascular shunts and ‘‘high-output’’ fetal heart failure. Associated fetal anomalies are rare. These include hypoplasia of the umbilical artery, patent vitelline intestinal duct, and ileal atresia. Unlike placental plate hemangiomas, in which 10% are associated with similar lesions within other fetal organs, umbilical cord hemangiomas are only rarely similarly associated.6 Umbilical cord hemangiomas are associated with platelet trapping, extensive thrombosis, fetal thrombocytopenia, and fetal morbidity and mortality due to hemorrhage. A prenatal diagnosis of umbilical cord hemangiomas warrants cesarean section delivery to preclude accidental trauma and fetal hemorrhage. The genetic aspects of the lesions are unknown. 35.20.2 Umbilical Cord Teratoma

An umbilical cord teratoma is a benign tumor composed of disorganized tissues derived from the three primary germ layers which are not normally native to the umbilical cord. Umbilical cord ‘‘dermoid’’ and umbilical cord fetus in situ are considered teratomas. Usually, calcified materials are present as well as mixtures of tissues such as skin, intestinal mucosa, smooth muscle, neural elements, and vascular elements. Usually teratomas display foci of mineralization and show cystic chambers as well. Umbilical cord hamartomas, on the other hand, are nodular masses of normally differentiated tissues that are common to the umbilical cord (e.g., mesenchyme, smooth muscle, and endodermal elements such as pancreas, liver, and intestinal mucosa).9 The latter tissues are apparently derived from pluripotential cells of yolk sac origin. Umbilical cord teratomas are diagnosed by pathologic examination, and the various tissue types are identified by histologic analysis or in situ hybridization (Fig. 35-44 and 35-45).4,10–12 The tumors are to be suspected in all forms of irregular, nodular deformations of the umbilical cord within which cysts and calcified materials are noted by either radiographic or ultrasonographic methods. When unusually large teratomatous masses are present in close association with the cord (a few have been attached by a Fig. 35-44. Umbilical cord with large, irregularly shaped tumor mass attached by a narrow stalk and displaying a smooth (nonmucosal) surface. Histologic studies confirmed the teratomatous nature of the tumor. (Courtesy of Dr. Bhagirath Majmudar, Grady Memorial Hospital, Atlanta, Georgia.)

Fig. 35-45. Low-power photomicrograph of the umbilical cord teratoma in Figure 35-44 showing a stratified squamous covering resembling skin (S), nodular masses of intestinal epithelium (arrows) surrounded by smooth muscles, and a few thin-walled blood vessels (V). (Courtesy of Dr. Bhagirath Majmudar, Grady Memorial Hospital, Atlanta, Georgia.)

stalk-like connection), careful analysis is required to exclude such conditions as acardiac fetus and other types of twinning.13 Umbilical cord teratomas are most likely derived from pluripotential cell masses or remnants of yolk sac. Such cells have been described as ‘‘displaced germ cells’’ that have differentiated into such diverse tissues as skin, skin appendages, cartilage, central nervous system tissues, muscle, cartilage, and bone. We believe that errors in twinning (e.g., acardiac twin) can be eliminated by careful dissection and histologic examination of the tumor mass.13 Umbilical cord teratomas are extremely rare benign neoplasms; only about a dozen cases have been described.4,10–12,14,15 Teratomas of the placental plate, also rare, are more common and share similar derivations from pluripotential yolk sac elements. Little or no information is available concerning the incidence or racial or sex distributions associated with umbilical cord teratomas. A few cases of umbilical cord teratoma have been described in association with additional severe fetal anomalies (e.g., anencephaly, abdominal wall defects, and intestinal anomalies). Umbilical cord teratomas have also been associated with apparently normal infants. In the latter category, no further treatment is indicated. No known preventive measures have been suggested. References (Umbilical Cord Neoplasms) 1. Moses WR: Meckel’s diverticulum. Report of 2 unusual cases, N Engl J Med 237:118, 1947.

Umbilical Cord 2. Reed WB, Snyder W, Horowitz RE: A giant pigmented nevus with invasion into umbilical cord. Acta Derm Venereol 53:318, 1973. 3. Jennings RW, LaQuaglia MP, Leong K, et al.: Fetal neuroblastoma: prenatal diagnosis and natural history. J Pediatr Surg 28:1168, 1993. 4. Browne FJ: On the abnormalities of the umbilical cord which may cause antenatal death. J Obstet Gynaecol Br Empire 32:17, 1925. 5. Dombrowski MP, Budev H, Wolfe HM, et al.: Fetal hemorrhage from umbilical hemangioma. Obstet Gynecol 70:439, 1987. 6. Seifer DB, Ferguson JE, Behrens CM, et al.: Nonimmune hydrops fetalis in association with hemangioma of the umbilical cord. Obstet Gynecol 66:283, 1985. 7. Heifetz SA, Rueda-Pedraza ME: Hemangiomas of the umbilical cord. Pediatr Pathol 1:385, 1983. 8. Mishriki YY, Vanyshelhaum Y, Epstein H, et al.: Hemangioma of the umbilical cord. Pediatr Pathol 7:43, 1987. 9. Preminger A, Udassin R, Pappo O, et al.: Ectopic liver tissue within the umbilical cord. J Pediatr Surg 36:1085, 2001. 10. Smith D, Majmudar B: Teratoma of the umbilical cord. Hum Pathol 16:190, 1985. 11. Heckmann U, Cornelius HV, Freudenberg V: Das Teratom der Nabelschnur. Ein kasuisticher beltrag zu den tumoren der nabulschnur. Geburt Frauenheilkd 32:605, 1972. 12. Wagner H, Baretton G, Wisser J, et al.: Teratoma of the umbilical cord. Case report with literature review (German). Pathologe 14: 395, 1993. 13. Kreyberg L: A teratoma-like swelling in the umbilical cord possibly of acardic nature. J Pathol Bacteriol 75: 109, 1958. 14. Kreczy A, Alge A, Menardi G, et al.: Teratoma of the umbilical cord. Case report with review of the literature. Arch Pathol Lab Med 18:934, 1994. 15. Satge DC, Laumond MA, Desfarges F, et al.: An umbilical cord teratoma in a 17-week-old fetus. Prenat Diagn 21:284, 2001.

35.21 Vascular Anomalies of the Umbilical Cord During the early period of umbilical cord organogenesis, blood vessels begin to appear within the connective body stalk; they are derived from angiogenic mesenchyme accompanying the vitelline and allantoic ducts. Initially, the vitelline vessels are far more numerous and prominent than are those of allantoic origin. Later, however, as the secondary yolk sac and the vitelline duct are converted into remnant structures, the vitelline arteries and veins disappear. A few small, thin-walled vitelline vessels are present in about 5–8% of human umbilical cords at term gestation. In the human, the allantoic vessels predominate in establishing the vascular system within the trophoblastic mass. These vessels ultimately constitute the left and right umbilical arteries, which originate from the left and right internal iliac arteries, respectively. The umbilical arteries course along the allantoic duct within the median ligament and enter the extraembryonic segment of the umbilical cord. These vessels begin to form conspicuous vascular spirals by 8 weeks gestation; the arteries branch and form anastomotic communications near the site of insertion at the placental plate. Monie1 describes the development of the umbilical arteries in human embryos as consisting of three phases. First (stage 11, 2.9 mm embryo), vascular buds appear along the emerging allantoic duct, and together these structures enter the connecting body stalk. Here the angiogenic mesenchyme surrounding the allantoic duct produces a rich, vascular plexus with many anastomoses. Later, during the second phase (early stage 12, 3.4 mm embryo), the plexus forms a single umbilical artery that is continuous with the initial left and right umbilical arteries in the trunk of the embryo. During the third phase (stage 13, 5.0 mm embryo), the

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single artery appears to ‘‘advance distally within the body stalk,’’ and the paired umbilical arteries grow in from the trunk (Fig. 3546). With variations, this developmental scheme is described by others who have studied human embryos. Unfortunately, large numbers of human embryos at various stages of development have not as yet been studied. The umbilical veins are initially paired structures that carry blood from the placental villi through the umbilical cord to the sinus venosus which provides blood flow via the common cardinal vein to the heart. The umbilical veins within the umbilical cord form vascular helices (‘‘spirals’’) in the same direction and number as those described in each umbilical artery. Development of the venous return (oxygenated blood) from the placenta in the early embryo is considerably more complex than is the arterial development.2–4 A left and a right umbilical vein develop in the embryonic connecting stalk and drain into the respective lateral horns of the sinus venosus. The vitelline and common cardinal veins lie medial to two umbilical veins. As the liver develops within the transverse septum, the vitelline veins are incorporated into the hepatic sinusoidal and the portal venous systems. With further liver growth, portions of the umbilical veins are also converted. The proximal part of the right umbilical vein is incorporated into the liver sinusoidal system, along with portions of the right vitelline vein. The proximal portion of the left umbilical vein and a part of the right vitelline vein (the future inferior vena cava) unite to form a shunt (the ductus venosus) within the liver (Fig. 35-47B). This allows oxygenated blood from the placenta to be shunted directly through the liver and into the sinus venosus of the heart. Immediately before regressing, the right umbilical vein merges with the terminal portion of the proximal right vitelline vein. Later, drainage is into the left umbilical vein in the ventral body wall, and finally the distal portions of the two umbilical veins fuse. Thus, when the development and remodeling of the umbilical venous system are complete, most of the right umbilical vein and the portion of the left umbilical vein between the liver and the sinus venosus degenerate. The remains of the left umbilical vein carry all of the blood from the placenta to the fetus. Long after birth, remnants of both the left and right umbilical veins can still be identified. The ductus venosus becomes the ligamentum venosum, while the portion of the left umbilical vein Fig. 35-46. Normal embryologic development of human umbilical arteries. The arteries are shown in black and the veins in white; the body stalk is stippled. Development progresses from left to right; A. Stage 11 embryo (2.9 mm greatest length-GL). The umbilical arteries develop within the stalk mesenchyme, forming an anastamosing plexus surrounding the allantois. B. Stage 12 embryo (3.4 mm GL). A single arterial vessel is present. C. Stage 13 (5.0 mm GL). Single vessel separates into left and right umbilical arteries. D. Stage 14–15 (7.0 mm GL). Normal pattern of unequal arteries persisting until term gestation. (Redrawn from Monie.1)

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Fig. 35-47. Embryologic development of the normal human umbilical venous system during early (A) and middle (B) stages of development and at birth (C). RA, LA, right and left atria; ACV, PCV, anterior and posterior cardinal veins; RUV, LUV, umbilical veins (right

and left); IVC, inferior vena cava; PV, portal vein; SMV, superior mesenteric vein; SpV, splenic vein; DV, venous duct; SHA, subhepatic anastamosis; RVV, LVV, right and left vitelline veins; L, liver; SV, sinus venosus; S, stomach; D, duodenum. (Redrawn from Bell et al.3)

that courses between the umbilicus and the liver within the falciform ligament becomes the ligamentum teres. These developmental events are schematically presented in Figure 35-47. A comparison of the variations in umbilical cord blood vessels among the various vertebrate species can be found in the text of Benirschke and Kaufman.5 Identification of the vessels can usually be made clinically by inspection of the cut surface of the umbilical cord. The arteries are thick walled and have constricted ostia. The larger vein(s) have thinner walls and gaping ostia. These distinguishing features are, however, not invariable. Likewise, the position of the vessels in the cord is an unreliable basis for vessel identification. If the cord is cut at its attachment to the abdomen, the vein usually has a more cephalic location than the arteries. While a few investigators insist that the veins and arteries within the umbilical cord can be identified easily by histologic evaluation, this is often not the case. An experienced pathologist may suspect the presence of two umbilical veins and a single artery within the routine cross sections of the umbilical cord; the walls of the arteries tend to be thicker than those of veins, and the lumens of arteries tend to collapse after ligation whereas those of veins tend to remain more or less patent. Umbilical veins display a few thin, elastic lamellae in the subintimal regions, whereas these are generally absent in umbilical arteries (Fig. 35-48). In our experience, the latter differentiating feature is not absolute and may be confusing. Finally, recent investigations suggest that umbilical cord veins may be distinguished by immunostaining for prostacyclin metabolites; the latter are absent in umbilical cord arteries.6 Another differentiating feature is type I collagen, which is not present in venous endothelial connective tissues, but is present in these tissues of the umbilical cord arteries. In short, histologic evaluations of umbilical cord vasculature may only suggest the presence of a persistent right umbilical vein; confirmation is left to techniques actually delineating the vascular course within the abdomen. Anomalies involving the derivation of the umbilical cord and the placental vascular system have long been subject to argument, mainly because of impatience, poor dissection technique, or both. With the advent of low-density latex vascular casting materials mixed with radiopaque substances and radiographic techniques, it is now possible to define accurately anomalous vascular circuits in perinatal pathology. These latter techniques have recently

demonstrated that in certain conditions (e.g., sirenomelia) the vascularity of the umbilical cord and the placenta is derived from a branch of the superior mesenteric arterial arcades, and hence placentation is choriovitelline rather than chorioallantoic.7,8 It now seems likely that interruptions of the allantoic vascular system may promote the development of the vitelline vascular system and thereby allow survival of the embryo. Interruptions of the superior mesenteric arterial arcade, on the other hand, may lead to abortion and/or certain selected developmental anomalies. Hoyme et al.9 have implicated interruption of the omphalomesenteric artery in gastroschisis; interruptions in other members of the arcade lead to intestinal atresia, gallbladder agenesis and/or atresia, and possibly other developmental anomalies.10 It is imperative that the vascular components of the umbilical cord be carefully evaluated when gastrointestinal and genitourinary anomalies occur. When one evaluates the origin of blood vessels within the human umbilical cord, it is obvious that single umbilical artery (SUA) cords represent a mixture of conditions. The presence of an SUA within the umbilical cord may be due to one of four possible conditions, and for this reason we propose that ‘‘SUA cords’’ be referred to as type I, type II, type III, or type IV (Table 35-9). In type I SUA cords, the surviving umbilical artery is of allantoic origin (hence the term single umbilical (allantoic) artery cord); in type II SUA cords, the surviving umbilical artery is of vitelline origin, hence the term single umbilical (vitelline) artery cord; in type III SUA cords, three vessels are present within the cord due to a persistent right umbilical vein, and the surviving artery usually (but not always) is of allantoic origin. The type IV SUA cord contains two vessels, a persistent right umbilical vein and a single (allantoic) umbilical artery. The importance of being able to distinguish between the different types of arterial vascularizations of the umbilical cord resides in the vastly different types of anomalies accompanying each condition. In the literature, considerable confusion and controversy exist in regard to the associations of anomalies with SUA cords. Much of this controversy arises from the inability in the past to distinguish between umbilical cords containing different SUA types. While we will surely not resolve all of the controversy, we hope in this section to present a different approach to the subject of anomaly patterns associated with three types of SUA cords.

Umbilical Cord

Fig. 35-48. Collage showing various types of umbilical cord vasculature. A. Normal three-vessel cord showing two arteries and a single vein. The latter vessel is larger than either of the arteries, and delicate elastic lamella can be identified within the subintimal zones (Verhoeffvan Gieson). B. SUA cord (type I) showing a single (allantoic) artery

35.21.1 Type I SUA Cords: Single Umbilical (Allantoic) Artery

The umbilical cord in type I SUA contains two vessels, the umbilical vein and a single umbilical artery. The latter vessel develops, as is normal, from the allantoic arterial system. Investigation of the arterial source of the umbilical cord in the fetus or newborn reveals a single umbilical artery arising as a branch of either the left or right internal iliac artery. The median ligament at birth may contain two patent arteries, one patent artery plus one atretic remnant of one artery, or complete agenesis of either the left or the right umbilical artery. When two arteries are present within the median ligament

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and a single umbilical vein (Verhoeff-van Gieson). C. Type III SUA containing two veins (left umbilical vein and right persistent umbilical vein) and a single (allantoic) derived artery. Inset: Intimal region of persistent right umbilical vein showing delicate, elastic lamellae (arrows, Verhoeff-van Gieson, 120).

and the extraembryonic umbilical cord contains only one vessel, a focus of thrombosis and/or lumen obliteration may be present within one umbilical artery in the region of the median ligament at the level of the umbilicus or nearby. Rarely, the abdominal segments of the umbilical (allantoic) arteries fuse, and only a single artery is present within the umbilical cord. The vascular composition of all umbilical cords should be evaluated by inspection of cord cross sections at three (proximal, middle, and distal) widely separated regions. Histologic evaluation of each cross section from each cord region should be routine. When SUA is noted, further examination of the fetus or newborn is indicated either by ultrasonography or by inserting radiopaque catheters. Catheterization of the umbilical stump

Table 35-9. Anomaly patterns associated with different types of umbilical cords containing a single artery Type

Cord Vessels

Distinguishing Feature

Associated Anomalies

I

2 vessels

Single umbilical artery, allantoic origin Single umbilical vein, left

CNS anomalies: Anencephaly-iniencephaly Spina-bifida Lower GU tract anomalies Short umbilical cord syndrome Acardia

II

2 vessels

Single umbilical artery, vitelline origin Single umbilical vein, left Absent urachal remnants

Sirenomelia* Reduction defect or hypoplasia of lower limb Caudal agenesis or regression Anal atresia

III

3 vessels

Single umbilical artery, allantoic or vitelline Left umbilical vein Right umbilical vein, persistent

Variable, depending on origin of umbilical artery Has been described in ectopia cordis and in Klinefelter and Noonan syndromes

IV

2 vessels

Single umbilical artery, vitelline or allantoic Single umbilical vein, right

Unknown

*Anomalies variable due to varying degrees of vitelline ‘‘vascular steal.’’

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Other Systems and Structures

vessels usually will clearly identify SUA cords when the persisting artery is of allantoic origin. In the type I SUA cord, the abdominal course of the single artery is inferior toward the urinary bladder and within the median ligament. If the surviving artery is of vitelline origin, the course is superior and toward the root of the superior mesenteric artery near the midline. In those rare cases in which a single surviving umbilical artery is in association with two umbilical veins (persistent right umbilical vein), the artery may be of either allantoic or vitelline origin. The latter cases are extremely rare, and usually the single artery is thought to be of allantoic origin. Differentiation between umbilical veins and arteries may be achieved by employing elastin stains that identify elastic lamella within umbilical veins and their absence within umbilical arteries. In our opinion, the fetus is abnormal in all cases of SUA cord. At a minimum, the fetus will be growth retarded. In the study of Bryan and Kohler,11 major anomalies were detected in 18% of infants with SUA cord. In our studies, major anomalies were present in 34% of 1741 SUA cords. Leung and Robson12 found anomalies of varying severity in 45% of 159 infants with SUA cords. Much controversy exists within the literature concerning whether certain anomaly patterns are associated with SUA cords. Benirschke and Kaufman5 state that ‘‘It can now be said that there is no predilection for any specific type of anomaly’’ in SUA cords. We believe that this unpredictability is related to a failure in the past to differentiate between the different types of SUA cords. In our experience, certain anomaly patterns are strongly associated with type II single umbilical (vitelline) artery cords. It also appears that type I single umbilical (allantoic) artery cords are associated with less severe anomalies of the caudal body region. These associations, as they appear at this time, are outlined in Table 35-9. Anomalies of the lower genitourinary tract (e.g., urinary bladder agenesis, agenesis of the median ligament, sirenomelia, and lower extremity amelia) are most often (but not always) associated with single umbilical (vitelline) artery (type II SUA cord). Anomalies of the central nervous system (anencephaly, spina bifida) tend to be associated with single umbilical (allantoic) artery cords (type I SUA cord). In virtually all studies of SUA cords in the past, no distinction was made as to the nature of the surviving arterial system in the umbilical cord, and this, we suspect, accounts for the highly variable and unpredictable nature of the anomalies and clinical conditions associated with SUA cords. The loss of one of the umbilical arteries derived from the allantoic system is thought to be due either to primary agenesis or to atrophy of an existing vessel. Unfortunately, careful studies of the nature of the vessels and remnants within the median ligament have not been carried out in large numbers of necropsy studies of infants with single umbilical (allantoic) arteries. Benirschke and Kaufmann5 believe that agenesis of one of the allantoic-derived arteries is rare and that most cases of surviving single (allantoic) artery are due to atrophy of an existing artery. In our experience, in which we evaluated both the umbilical cord and the median ligament for the presence of SUA, 57% of 52 type I SUA cords were due to agenesis of one vessel. While atrophy of an existing artery appears slightly less common than agenesis, the mechanisms leading to atrophy are not clearly documented. Thrombosis apparently accounts for many atrophied arteries. Monie1 has studied the development of umbilical arteries in young human embryos and has proposed that SUA may result from the persistence of a normally present SUA (stage 12, 3.4–4.0 mm embryo) in association with degeneration of the abdominal portion of either the right or left umbilical artery. Benirschke and Kaufmann5 state that SUA cord ‘‘has no familial or genetic tendency.’’ In our opinion, this issue needs further

evaluation. Rudd and Klimek13 recently reported the consistent presence of SUA in association with familial caudal dysgenesis. Other workers have also reported rare cases of familial SUA cord.14,15 SUA cord has been noted in association with certain chromosomal errors (vide infra). Experimentally, retinoic acid can produce SUA in rat fetuses.16 The possibility of thalidomide producing SUA cord has also been raised.11 The information in the literature does not discriminate between the different types of SUA cords. In Table 35-10, the data relating to umbilical cords containing a single umbilical artery without regard to the nature of the existing or agenic artery are summarized. Overall, about 0.7% of cords contain a single artery; this incidence is much higher in the necropsy population and in twin deliveries (3.9%). The incidence of SUA cords is much higher in whites than in blacks or Asians. Although the incidence is very variable, about 45% of SUA cords are associated with other fetal anomalies. Although much cumulative data indicate that the SUA cord is associated with major anomalies in about 18% of patients, we believe that in certain SUA cord types this incidence is much higher. In a recent evaluation of our own data, 34% of infants with

Table 35-10. Associations of various conditions with single artery umbilical cords (all types) Population or Condition

Percent

Incidence*

General (all births)

0.7

Necropsy population

2.0

Twin deliveries

3.9

Twin infants

2.3

Whites

1.5

Blacks

0.5

Asians

0.2

Associations

Hydramnios Oligohydramnios Fetal growth retardation Premature birth Spontaneous abortion Low-set umbilicus (not proven) Anomalies

44.7

Major Anomalies

18.0{

Placenta Anomalies

16.4

Marginal-velamentous insertion

12.0

Circumvallate placenta Chorangioma Maternal Complications

Diabetes mellitus Epilepsy Preeclampsia *Incidence based on review by Benirschke and Kaufman5 and includes the data of Heifetz.18 {

Thirty-four percent in our necropsy series.

Umbilical Cord

SUA were noted to have major structural anomalies. In type II and type III SUA cords, we believe that the incidence of serious associated anomalies is much higher and approaches 100%. SUA cords are associated with placental anomalies (16%), especially abnormalities associated with cord insertion (e.g., marginal and velamentous insertion). The latter association is almost certainly influenced by twinning. In our necropsy studies, SUA cords were significantly associated with acardia; sirenomelia; trisomies 13, 15, and 18; cloacal extroversion; and prenatal thalidomide and hydantoin exposures. A significant association between SUA and decreased fetal birth weight and placental weight is acknowledged. SUA cords (without type distinction) are associated with a high rate of fetal mortality (
20%). Bryan and Kohler11 reported a mortality rate of 17.5% in their careful study. Obviously, when severe major malformations are present (18–45%), the prognosis is poor. When SUA is diagnosed in the fetus (e.g., with ultrasonography), the risk for serious life-threatening complications at or during delivery is greatly increased. Aside from the morbidity and mortality associated with major malformations, increased risk for poor fetal outcome in SUA is related to associated placental anomalies (16%), including umbilical cord insertion anomalies (marginal or velamentous, 12%) and placental neoplasm (chorangioma, 0.65%). In infants with SUA cord but without obvious signs of major malformations, the prognosis is also significantly worse than in normal-appearing infants with three-vessel cords. The latter observation is most likely related to the fact that infants born with SUA cords are small for gestational age (34%), premature (16.5%), and may harbor occult anomalies. When SUA is noted in one of twins, the risk for abnormal outcome for that twin is greatly increased. Bryan and Kohler17 carried out a long-term follow-up study of 96 apparently normal infants born with SUA cords. This study revealed abnormalities in 18% of the children at the time of followup. Ten children were shown to have developmental abnormalities at follow-up; the anomalies tended to be mild and did not reflect a distinct pattern. In a group of children who originally were normal except for retarded growth and body weight, all were now normal except for two who were found to have anomalies. Follow-up studies such as this have tended to dispel certain impressions associated with SUA cords. For example, there does not appear to be an increased incidence of inguinal hernia in infants born with SUA cords, nor has it been proven that urogenital tract anomalies are increased in infants with SUA cords. These issues must be reevaluated and correlation made with the type of SUA cord. There are no known preventive measures for SUA cord except the avoidance of exposures thought to produce the lesion (e.g., retinoic acid, thalidomide). Optimally, planning for medical and surgical management of infants with life-threatening anomalies should begin prior to delivery. Although some workers feel that in the absence of obvious major anomalies no further evaluation of the newborn is indicated, our experience suggests that such infants deserve at least a simple exploration of the etiologic nature of the surviving umbilical artery by ultrasonography and radiopaque catheterization with radiographs of the abdomen. Insofar as about 10% of malformed fetuses and about 15–16% of fetuses with chromosomal abnormalities (trisomy 13 and trisomy 18) have SUA cords, karyotyping of such fetuses is advised.18 35.21.2 Type II SUA Cord: Single Umbilical (Vitelline) Artery

The artery or arteries in type II SUA cord derives from the vitelline arterial system rather than, as is normal, from the allantoic

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arterial system. Examination of the umbilical cord reveals two vessels, one of which is a normally distributed umbilical vein and the other is identified as a branch of the superior mesenteric artery. Although it is possible that two umbilical arteries could be present and both could arise from the superior mesenteric artery or from the aorta, this variation has not as yet been described. Examination of the freshly cut umbilical cord reveals only two vessels. Remnants of the allantoic (urachal) duct are absent. Further examinations either using injection techniques (arteriographic) or inserting radiopaque catheters reveal a normally distributed umbilical vein and an artery that arises as a branch of the superior mesenteric artery. When the arterial supply to the umbilical cord (and placenta) arises as a branch of the superior mesenteric artery, the inserted arterial catheter courses superiorly, whereas in the usual situation (i.e., umbilical arteries arising from the allantoic system) the catheter’s abdominal course is inferiorly and alongside the urinary bladder. Since the single umbilical (vitelline) artery cord is almost invariably associated with severe anomalies of the caudal body trunk (e.g., sirenomelia, lower limb amelia or other limb reduction, OEIS complex, sacral regression or agenesis, anal agenesis, and agenesis of the lower urinary tract, including the urinary bladder and median ligament structures; see Table 35-11), it is imperative to determine accurately the origin of the arterial supply to the umbilical cord and placenta in all such cases. This can be done by exploratory arteriographic procedures (as outlined above), surgical exploration, and by dissection at necropsy. Normally, the first organ to form from the primary yolk sac in humans is the allantois. In conditions in which the allantois does not develop or is lost early in embryogenesis, the allantoic arteries do not develop within the connecting stalk. Survival then depends on the persistent and further development of the vitelline arteries in such a manner as to provide arterial supply via the connecting stalk to the developing placenta. Although many investigators strongly deny the existence of choriovitelline placentation in humans, the condition not only exists but also is probably far more common than originally expected.19 When one becomes familiar with the nature of the vascular systems accompanying allantoic and vitelline duct development, it is not surprising that nature has provided a ‘‘fail-safe mechanism’’ that provides vascular supply for the embryo via the vitelline system when the allantoic vascular system fails. Stevenson et al.20 have provided insight into the relationship of a persistent vitelline artery and anomalous development of the caudal body structures. Their studies suggest that the pathogenetic mechanisms causing sirenomelia, for example, involve nutritional deficiency due to vascular steal via the persistent vitelline artery. Similar considerations (‘‘nutritional want’’) regarding the etiology of sirenomelia were offered as early as 1878 in a paper delivered by Weigert before the Physiological Society in Leipzig. These and other historically important papers regarding type II SUA cords are summarized by Kampmeier.19 The insult most likely occurs prior to 23 days gestation. Recently Rudd and Klimek13 described familial caudal dysgenesis in which umbilical cords with a single artery were common. The anomaly pattern (e.g., renal agenesis, single lower extremity, agenesis of the urinary bladder, ureters, and kidneys) in several of the cases were such that a single existing umbilical artery was almost certainly of vitelline origin. In our experience, when the urinary bladder is agenic, the median ligament and its contents (allantoic duct and the left and right umbilical arteries) are also absent. In these cases, a SUA is present and arises as a branch of the distal mesenteric artery arcade or directly

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Other Systems and Structures Table 35-11. Anomaly patterns associated with single vitelline artery umbilical cord Caudal Defects

Caudal regression-dysgenesis Sirenomelia OEIS complex VATER association Urorectal septum malformation sequence Anal atresia Urinary bladder exstrophy Exstrophy of the cloaca Mu¨llerian aplasia Cloacal dysgenesis Urogenital Anomalies

Complete Urogenital agenesis Renal agenesis, bilateral Ureteral agenesis, bilateral Urinary bladder agenesis Agenesis of the urethra Urachal-median ligament agenesis Umbilical artery agenesis, bilateral Agenesis of external genitalia Incomplete Urinary bladder agenesis (isolated anomaly) Urachal agenesis (isolated anomaly) Umbilical artery agenesis, bilateral Vascular Anomalies

Agenesis-hypoplasia Abdominal aorta (below superior mesenteric artery) Iliac arteries and branches Umbilical arteries

from the aorta. Chaurasia21 has reported a similar experience in three specimens with severe caudal regression. Umbilical cords containing two vessels are noted in about 0.7% of third-trimester deliveries. In about 1.5% (or more) of these cords, the single artery present is derived from a persistent vitelline artery, which in turn arises from the aorta or the superior mesenteric artery. The incidence of single umbilical (vitelline) artery cord is extremely high in fetuses that show serious anomalous development of the caudal body structures and lower extremities (see Table 35-11).19 The type II SUA cord, because of its strong association with sirenomelia, is considerably more common in males (2.7:1). Because of the association of type II SUA cord with serious anomaly complexes involving the caudal body structures, the overall prognosis is poor. Only rarely has the type II SUA cord been associated with normal development.22 In infants with loss of the allantoic system somewhat later in development (e.g., urinary bladder agenesis, urachal and umbilical artery agenesis), the prognosis seems better. In most fetuses with type II SUA, death occurs either in utero or shortly after birth and is associated

with pulmonary insufficiency (hypoplasia) due to oligohydramnios and agenic components of the urinary tract. 35.21.3 Type III SUA Cord: Single Umbilical (Allantoic or Vitelline) Artery with Persistent Right Umbilical Vein

The type III SUA cord has a single artery (of either allantoic or vitelline origin) and two umbilical veins, one of which is a persistent right umbilical vein. At first glance, the vascular composition of the cord appears normal insofar as three vessels are present (Fig. 35-48). Further evaluations (histologic, ultrasonography, catheterization with angiography, and dissection) reveal the presence of both the left and right umbilical veins within the umbilical cord and the fetal abdomen. In three-vessel umbilical cords in which a single artery is present, confirmation of the venous nature of two of the vessels is most often identified serendipitously at the time of umbilical vein catheterization.2,23 When the right umbilical vein is persistent in the umbilical cord, insertion of the catheter into this vessel reveals an unusual right-sided course within the abdomen.2 With catheter placements in the other vessels, the abdominal course of the normally present left umbilical vein is established and finally that of the SUA is established. In the experience to date, the SUA has been of allantoic origin. Although most cases of type III SUA cord are now being diagnosed by ultrasonography, the condition was most often discovered in the past at abdominal exploration at either laparotomy or necropsy.2–4 In the latter procedures, a routine evaluation of the vessels entering the abdomen from the posterior surface of the anterior abdominal wall at the level of the umbilicus is crucial; also, connections between these vessels and the liver is equally important. When the right umbilical vein persists in the umbilical cord, it also persists (at least in part) within the abdomen. In the latter area, it courses from the peritoneal surface of the umbilicus inferiorly and then superiorly along the right side of the spine, where it may either enter directly into the inferior vena cava24 or bypass the liver and enter the right cardiac atrium. Other variations are also possible and have been described.3 Although a type III SUA umbilical cord with persistent right umbilical vein contains three vessels and may on cursory inspection appear normal, it in fact consists of two anomalies. First, one umbilical artery is missing; the remaining artery is almost always of allantoic origin. The second anomaly is the persistence of the right umbilical vein. Persistence of the complete (umbilical cord and abdominal segments) right umbilical vein is thought to be due to a failure in the processes of obliteration and regression of the primary symmetric anlage of the vitelline and umbilical veins during weeks 4–5 of gestation.25 It is possible that hemodynamic factors (e.g., increased pressure within the developing vitelline and umbilical venous system during early development, as in certain forms of heart disease) may override the obliterative and regressive processes. In support of the latter consideration is the rather high incidence of ectopic cordis associated with persistence of the right umbilical venous system either in part or in toto.25 Another explanation for the persistence of the right umbilical vein is related to normal liver growth within the transverse septum. As the liver volume expands, it is thought to compress components of the right umbilical vein and bring about its ultimate regression. In support of this idea is the fact that, in cases of ectopic cordis in which the liver also resides outside, the right

Umbilical Cord

umbilical vein persists.25 Finally, it should also be pointed out that in certain species (e.g., armadillos, cattle) persistence of the right umbilical venous system is the rule; these animals regularly develop a ‘‘four-vessel’’ umbilical cord. The incidence of type III SUA cord is not established, and only a few cases have been published.2,24,25 Our experience involves three cases in 30 years of active perinatal pathology practice. This may indicate the extreme rarity of the anomaly complex. During a 10-year period, we routinely examined the vessels in the abdominal segment of the umbilical cord and have detected 2 cases in approximately 1250 necropsies. With the development of perinatal ultrasonography and with a growing awareness of these anomalies, the detection rate will undoubtedly increase. The persistence of any segment or all of the right umbilical vein is associated most often with serious additional developmental abnormalities. When the right umbilical vein is persistent and in association with a single umbilical artery (type III SUA cord), the prognosis is generally poor. In one of our cases, the infant male had a Klinefelter karyotype (47,XXY) and was one of triplets delivered to a mother with treated infertility. Rehder’s case25 had severe malformations, including ectopic cordis; Bell et al.3 reported a case that most likely was type III SUA cord with associated serious anomalies including anomalous pulmonary venous return, unilateral renal agenesis, ipsilateral limb reduction, and unicornate uterus. Leonidas and Fellows24 reported a case in association with Noonan syndrome. Fliegal and Nars23 reported a case that they described as being similar to that of Leonidas and Fellows. The course of the persistent vein was to the right and made direct connection to the inferior vena cava. The infant had hydranencephaly, but no other anomalies. While the number of patients studied is admittedly small, the associations with anomalous development (particularly the cardiovascular system) is such as to warrant a careful evaluation of any infant with type III SUA cord. Persistence of the right umbilical vein (abdominal segments) warrants umbilical phlebography, the delineation of the abdominal connections particularly in the liver and heart, and surgical correction, if indicated.

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35.21.4 Anomalies of the Umbilical Vein(s)

In early embryogenesis, the chorionic veins unite to form a single umbilical vein within the body stalk. The single vein bifurcates in the middle of the body stalk ultimately forming the left and right umbilical veins. Until week 4, the left and right umbilical veins are paired structures. The right vein normally regresses after week 4. Several vitelline veins arise during the early stages of fetal life. Two of the veins will become the initial umbilical veins. These vessels initially traverse the peritoneal cavity and drain to the sinus venosus. As the liver develops within the transverse septum, several of the remaining vitelline veins become disrupted and take part in the formation of the hepatic sinusoids. Portions of the vitelline venous system then regress, while others persist and take part in the formation of the portal venous system. The vitelline vein between the umbilicus and the portal system disappears by the end of week 8. The embryologic development of both the umbilical and the vitelline veins is schematically displayed in Figures 35-46 and 35-47. Anomalies of the umbilical venous system are described somewhat confusingly in the literature primarily due to errors in dissection or the failure to delineate vascular connections clearly using injection techniques. In general, the anomalies can be considered in two categories: anomalies of umbilical venous drainage limited to the truncal regions of the fetus and those within both the umbilical cord and the truncal regions. This approach may be used to classify umbilical vein anomalies into four groups (Table 35-12). In group I anomalies, the umbilical vein or veins are attached normally at the umbilicus and at the liver; however, the vessels are not ensheathed within the falciform ligament and appear as ‘‘naked,’’ cord-like structures that during their course to the liver pass either anterior or posterior to the transverse colon. Group II anomalies are most frequent and consist of an abnormal persistence of the right umbilical vein within the umbilical cord. In most cases, four vessels are present within the cord; the right umbilical vein persists both within the umbilical cord and within the abdomen, where it makes variable connections with the systemic venous

Table 35-12. Classification of anomalies of the umbilical venous system Group I

A. Umbilical vein (left/right) B. Normal attachments

Normal

Group II

A. Umbilical vein (left/right) Persistent right vein in umbilical cord and abdomen

Posterior umbilicus

4-Vessel cord

Liver (porta hepatis)

3-Vessel type III SUA

C. Cord-like structure free of falciform ligament Group III

2-Vessel type IV SUA B. Variable attachment C. Cord-like structure in/out falciform ligament

A. Umbilical vein (left or right) B. Abnormal attachments

Group IV

Posterior umbilicus

A. Vitelline vein

Liver (porta hepatis)

B. Normal attachments Posterior umbilicus

C. Anomalous venous course UV-Right atrium UV-Portal vein UV-Inferior vena cava UV-Superior vena cava

Portal vein C. Cord-like structure coursing freely to portal vein area near duodenum

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Other Systems and Structures

return. In a few cases, the right umbilical vein persists within the umbilical cord along with the normally present left umbilical vein and a single umbilical artery. This arrangement forms the type III SUA cord. When only the right umbilical vein is present within both the cord and the abdomen and is associated with an SUA, a type IV SUA cord is formed.27 Group III anomalies include those cases in which the course of one (usually the right) or both umbilical veins is abnormal within the abdomen. Thereafter, the venous drainage most often bypasses the liver and connects directly with either the right atrium,27–30 portal vein,4 inferior vena cava,23,24,31 or superior vena cava.26 Group IV anomalies include those of the umbilical venous system that involve the vitelline vein. This group includes those anomalies in which the vitelline vein or its remnant persists as a cord-like structure lying free and independent of the falciform ligament and courses from the peritoneal surface of the umbilicus to the region of the portal vein near the midline. Anomalies of the umbilical venous drainage in group I are characterized by a normal attachment at the peritoneal surface of the umbilicus and a normal attachment with the porta hepatis. The vein, however, is not encased within the falciform ligament and appears as an independent cord-like structure. During its course to the liver, it may pass either posterior or anterior to the transverse colon and the terminal ileum (Fig. 35-49). The diagnosis is most often established during surgical exploration, when the inferior and superior attachments are established by inspection; the cord is resected and its venous nature confirmed by histologic study. Umbilical vein anomalies in group I are most often diagnosed during a work-up for clinical signs of bowel obstruction. These include chronic recurrence of symptoms suggesting partial bowel obstruction, rapid abdominal distention particularly after large meals, and pain localized in the right upper quadrant. The patients range from infants to adults.32–34 Group II venous anomalies are most often detected by routine examination of the umbilical cord which reveals four vessels in cross sections (when vascular loops are excluded). Catheterization of the umbilical stump with subsequent dye injections delineates the course of the umbilical arteries and veins. In most

Fig. 35-49. Group I type umbilical vein anomaly showing the vein (UV) as a cord-like structure free of the falciform ligament and passing posterior to both the distal ileum (DI) and the transverse colon. Partial obstruction of the transverse colon is noted (arrow), with associated dilation of the cecum and ascending colon. L, Liver. (Redrawn from Svendsen et al.34)

cases in which four vessels were identified within the umbilical cord, the courses and connections of the veins within the abdominal cavity have not been fully established.35–38 Also within group II umbilical vein anomalies are those cases in which a single umbilical artery and two umbilical veins are present and hence the cord looks like a normal ‘‘three-vessel’’ cord; anomalies of this sort and their associations have been described above (see type III SUA umbilical cord). Group III umbilical vein anomalies include those in which abnormal connections or courses are noted in the abdominal segments of one or both umbilical veins. While only a few cases have been reported, the most common vascular course is one in which the umbilical vein bypasses the liver to make a direct connection with the right atrium.25,27–30 In a few other cases, the umbilical vein (usually right or left designation has not been specified) courses abnormally within the abdomen to connect with the portal vein,4 the inferior vena cava,23,24 or the superior vena cava.26 Most often the diagnosis is made at necropsy and the connections delineated by direct dissection. A few cases have been discovered during the course of umbilical vein cathertization.25 It would appear that such cases might also be suspected at laparotomy when an anomalous course of the umbilical vein is suspected by inspection of the intraabdominal surface of the umbilicus. It should be emphasized that, when one explores the nature of ‘‘congenital bands’’ (vascular remnants) within the abdomen, considerable confusion may exist as to their exact nature. If the band extends from the peritoneal surface of the umbilicus to terminate in the region of the anti-mesenteric surface of the distal ileum, it most likely represents a remnant of the omphalomesenteric (vitelline) duct; if the band terminates in the mesentery (left or right) of the distal small bowel and courses toward the superior mesenteric artery, the structure is most likely a remnant of the vitelline artery. Congenital bands or cords that course from the peritoneal surface of the umbilicus toward the portal vein are most likely vitelline vein remnant anomalies; those that terminate near the region of the ductus venosus, portal vein, or inferior vena cava may represent umbilical vein remnants. Histologic examination of carefully oriented cross sections of such ‘‘bands’’ is also very helpful in confirming the etiology of such anomalies. Anomalies of the umbilical vein (group I) in which the attachments are normal at the umbilicus and at the liver and with the vein coursing independent of the falciform ligament are most likely due to abnormalities involving the development of the ventral mesentery. Anomalies within group II in which the right umbilical vein persists within both the cord and the abdomen are most likely due to a failure of ‘‘critical anastomosis’’ or fusion of the omphalomesenteric and umbilical venous systems, which in turn leads to a persistence of the right umbilical vein and at times the development of aberrant vessels and anastomoses (e.g., caput medusae).26 A failure in the establishment of anastomoses between the left umbilical vein and the omphalomesenteric system leads to a block in the venous return from the placenta, which in turn leads to the development of new vascular channels or the persistence of venous channels that would otherwise normally regress (i.e., persistence of portions of the right umbilical vein).24 Experimental studies in rats have indicated that folic acid deficiency leads to the persistence of the right rather than the left umbilical vein.39 Exposure of developing rat embryos to retinoic acid produces an identical anomaly.40 The frequency with which anomalies of the umbilical vein occur cannot be accurately stated at this time. In the literature it appears that persistence of the right umbilical vein (all or part) is

Umbilical Cord

the most common anomaly (19 cases). A persistence of the right umbilical vein in the presence of a normal left umbilical vein and a single umbilical artery (type III SUA cord) most often goes undetected insofar as the umbilical cord contains three vessels and hence appears normal. Umbilical vein anomalies in group I and group III are quite rare, with only three and four cases having been described, respectively. Because of the strong association between anomalies of the umbilical vein and SUA (62%), patients with this anomaly should be further explored for possible anomalies in umbilical venous return. Individuals with group I umbilical vein anomalies appear to be at significant risk for recurrent signs and symptoms of intestinal obstruction. The prognosis for patients with group II umbilical vein anomalies is considerably worse than for those in either group l or group III. In 10 well-documented cases, 6 males and 4 females, anomalies were present in 9. No anomalies were detected in one infant, while in another only a complete duplication of the umbilical cord was noted. The most common anomalies associated with group II patients were agenesis of the ductus venosus (n ¼ 5), single umbilical artery (n ¼ 7), and congenital heart disease (n ¼ 4). Ductus venosus agenesis is a rare anomaly which manifests itself in two separate morphologic patterns. In the first group, the liver is completely bypassed (the umbilical vein draining into the inferior vena cava or directly into the right atrium). In the second group, the umbilical vein drains into the left branch of the intrahepatic portal vein. In both groups, the flow of oxygenated, umbilical, venous blood toward the foramen ovale is distrubed.41 The fetuses of both groups show an increased vulnerability to hypoxia, the development of hydrops fetalis, growth retardation, and death. The prognosis for patients with umbilical vein anomalies in group III is not well established in that only four patients have been reported. Two showed no evidence of additional anomalies; one was stillborn without anomalies, and one was described as having sirenomelia with situs inversus. Surgical ligation and resection of the cord-like remnants noted in group I anomalies is recommended because of the likelihood of intestinal obstruction. Patients with group II umbilical vein anomalies that are detected by examination of the umbilical cord at birth require further delineation of the vascular anomalies with catheterization and phlebograms and or arteriograms. The therapeutic approach to those infants with serious associated anomalies must be individualized and directed toward correction of life-threatening conditions. It should be pointed out that a few infants with group II anomalies displayed signs of a failure of ‘‘critical anastomosis’’ between the left umbilical vein and the ductus venosus within the liver (e.g., caput medusae, agenesis of the ductus venosus); these patients require no further treatment in that these vascular systems are no longer needed after birth. A treatment regimen for infants with group III anomalies has not as yet been developed due to the few patients involved and to the variable nature of the associated conditions. 35.21.5 Remnants of the Vitelline Arteries and Veins

Remnants of the vitelline artery (the terminal branch of the superior mesenteric artery) may be found in the mesentery of the terminal ileum, along the course of the abdominal segment of the vitelline (omphalomesenteric) duct, or within the umbilical cord. Atretic remnants of the vitelline artery resemble a fibrous band that extends from the peritoneal surface of the umbilicus to the anterior or to the posterior leaf of the small bowel mesentery (Fig. 35-50). The exact location of the fibrous attachment onto the posterior

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Fig. 35-50. Schematic of a cord-like vitelline artery (VA) remnant originating as a distal branch of the superior mesenteric artery (SMA) and extending over and obstructing the ileum (I) as it courses to the peritoneal surface of the umbilicus (U). (Redrawn from Kleinhaus et al.45)

surface of the abdominal wall may vary from the level of the umbilicus to the symphysis. Rarely, the band may attach itself to or near a Meckel diverticulum.42 Atrophy with detachment of either end of the band may result in a strand hanging free within the abdomen. Histologic sections of the fibrous band may reveal a small, patent artery surrounded by fibrolipomatous connective tissue. In many bands, the artery is atretic and without a discernible lumen. Remnants of the vitelline veins may also produce band-like structures coursing from the posterior surface of the umbilicus to the vicinity of the pancreas and ultimately to the region of the portal vein (Fig. 35-51). Vitelline vein remnants are extremely rare and may produce intestinal obstruction in a manner similar to that noted in vitelline artery or umbilical vein remnants.42 Vitelline artery remnants, including a small, persistently patent artery, are identified by the anatomic course of the vessel or

Fig. 35-51. Schematic showing cord-like (peritoneal band) remnant of the vitelline vein (VV) extending from the umbilicus (U) superiorly to disappear in the region of the portal vein (PV) and pancreas (P) near the midline. The small intestine is obstructed (arrow) by compression in an anteroposterior direction. (Redrawn from Kleinhaus et al.45)

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Other Systems and Structures

fibrous band (remnant). In general, the course is between the peritoneal surface of the umbilicus and the mesentery of the ileum; if it courses on the left side of the gut, the remnant or vessel involved is the left branch of the vitelline artery; if it courses to the right side of the gut, the involved vessel is the right branch of the vitelline artery. At times, it courses between a Meckel diverticulum and the ileal mesentery. Remnants of the vitelline artery may be completely or segmentally patent, or the remnant may be an atretic fibrous arterial remnant covered with peritoneum. Peritoneal bands derived from remnants of the vitelline vein can be differentiated from those derived from the vitelline artery by noting the band insertion. In the former case, the band extends from the posterior abdominal wall at the level of the umbilicus to an area near the midline in the vicinity of the pancreas and/or the portal vein. Histologic sections of such bands usually show little or no evidence of an identifiable vascular remnant. Peritoneal bands extending from the posterior abdominal wall at the level of the umbilicus and the antimesenteric surface of the distal ileum, usually within 40–45 cm of the cecum, represent remnants of the vitelline duct rather than remnants of either vitelline arteries or vitelline veins. Evaluations of the embryologic origins of peritoneal bands that end freely depend on knowledge of the embryologic anatomy of the vitelline duct and the vitelline vessels as discussed above. Histologic analysis of the band’s contents may be helpful. Peritoneal bands due to vitelline artery remnants or to a persistent vessel usually are detected at laparotomy because of signs and symptoms of acute bowel obstruction. In some cases, the signs of obstruction are partial, intermittent, and episodic. A few cases have been discovered after ligation or cauterization of umbilical polyps or granulomas. Our cases were discovered at necropsy and were unrelated to clinical signs or symptoms. Congenital peritoneal bands were first shown to be related to involutional remnants of the vitelline vessels by Neumann in 1891; subsequently, the subject was addressed by Leichtenstein and Fix (1894). Wilms43 summarized the early historical literature dealing with the etiologic nature of peritoneal bands of this type (1906) and referenced the aforementioned cases. Peritoneal bands relating to involution of the vitelline artery are rare. We have detected three instances in about 1600 carefully performed necropsies. We have identified 31 cases in the literature. Most cases have involved infants and children, but several cases were undetected until adolescence or adulthood.44–46 Peritoneal bands arising from remnants of the vitelline artery are not usually associated with additional developmental anomalies. Exceptions are those rare cases in which the vitelline vessels provide vascularization of the placenta (choriovitelline placentation); the prognosis in such patients is poor because of lifethreatening anomalies. The prognosis in cases in which small bowel mechanical obstruction is present is usually good unless perforation, peritonitis, and sepsis have occurred. Intestinal obstruction caused by vascular remnants of either vitelline veins or vitelline arteries is due to direct pressure on the adjacent bowel rather than by volvulus. Hence, the prognosis is generally better. It should be emphasized that patent vitelline arteries and/or veins can exist within the umbilical cord at the time of birth. Usually the vessels are in association with umbilical polyps (which may be present at or shortly after birth). Considerable bleeding has been encountered during the surgical treatment of such anomalies.44 Many of the complications (hemorrhage, bowel obstruction, and perforation) arising from remnants of the vitelline artery may be prevented by early surgical intervention. Identification of a

peritoneal band usually requires laparoscopic examination of the posterior abdominal wall in the region of the umbilicus. Treatment is complete surgical excision of the ligated peritoneal band throughout its course. This restores patency of the small intestine. 35.21.6 Umbilical Cord Vascular Helix Anomalies

The umbilical vessels (arteries and vein) develop cylindrical helices (‘‘spirals,’’ coils) as early as 42 days gestation; by about 8 weeks, the helical vascular spiral is well established and most often takes a counterclockwise (left) direction.47,48 While the number of spirals within an individual umbilical cord is quite variable (usually 10–11 are present), the number of spirals seem to be fully established and possibly fixed by the end of the first trimester.49,50 The concentration of vascular spirals is greatest in the proximal cord. As the cord grows in length, the length of the pitch between each turn of its helix increases, while the number of turns remains unchanged.50,51 The factors that dictate the direction or the number of helical turns of the vessels within the cord are not well understood. The evidence suggests that fetal activity plays a role in this process, as do structural factors inherent to the umbilical vessels. Lacro et al.47 offered indirect evidence that suggested hemodynamic factors (such as the spiral nature of blood flow, blood pressure, and so forth) are not significantly influential. We believe that the latter hypothesis is not settled. About 5% of umbilical cords show no evidence of vascular spiraling. Occasionally, an umbilical cord may show a change of direction of vascular spiral within the same cord. Umbilical cords containing a single umbilical artery are most likely to develop few or no vascular helical spirals compared with normal, three-vessel cords. When spirals are present in umbilical cords with a single umbilical artery, the incidence of helical direction (left vs. right) is nearly equal. Whereas in three-vessel umbilical cords, the left helix predominates (7:1). Little or no information is available concerning the nature of vascular spiraling within individual types (I–IV) of SUA or within ‘‘four-vessel’’ umbilical cords. As indicated above (see 13.18, Umbilical Cord Torsion), the vascular helix is a unique anatomic configuration that tends to protect the patency of the vessels when the cord is stretched or when the developing fetus rotates in the same direction as the spiral. We believe that the living (as well as the dead) fetus rotates within the amnionic cavity and that once established, the umbilical cord’s vascular spiral influences the direction of such rotation. Umbilical vascular helical (‘‘spiral’’) anomalies include those umbilical cords that show little or no helical spiraling of the vessels. When corrected for gestational age, cords with diminished vascular spirals are noted in about 5% of cords after 14 weeks gestation. Umbilical cords with excessive vascular spirals (age 14 weeks gestation and older) are noted in about 10% of cords. As would be expected, both under- and overspiraled cord vessels are associated with significant fetal complications (e.g., fetal death, ‘‘intolerance to labor,’’ growth retardation, and infection).52 Inspection of the underspiraled umbilical cord by the end of the first trimester reveals either a total absence of vascular helical spirals or only one or two spirals within the entire umbilical cord. An absence or marked paucity of vascular spirals within the umbilical cord may also be observed by ultrasonography (Fig. 3552). The umbilical vein spirals in a manner that is identical to that of each umbilical artery (Fig. 35-53). The direction of the vascular helix within the umbilical cord can be determined by direct inspection. The direction of the anterior portion of a left helix will parallel the left limb of the letter

Umbilical Cord

Fig. 35-52. Ultrasonographic image of umbilical cord vascular helix (arrows).

V; the direction of the anterior portion of a right helix will parallel the right limb of the letter V. This will remain true whether or not the umbilical cord is rotated 1808.50 The factors that influence or dictate the direction or the number of vascular helical spirals within the umbilical vein and arteries are not well identified.50 In the past, the helix was thought to be due to factors inherent to the cord itself or to forces that bring about rotation of the fetus. The studies of Lacro et al.47 suggest that both factors are important. The structure of blood vessels such as the orientation of the cellular and fibrous components of the mural regions may, in the presence of hydrostatic pressure and blood flow, impose a helical twist to the vessels that is in the direction opposite to that of the structural helix of the fibrocellular materials.51 Others have proposed that asymmetric size between the left and right umbilical arteries might well influence the direction of helical spiraling.49–51 In our studies of SUA cords, we noted that if the vascular spiral was counterclockwise (left), the left umbilical artery was agenic; the converse was true as well. SUA cords also showed a significant increase in the number with right-handed spirals compared to cords containing two arteries. In our experience, normal monozygotic twins always showed the same direction of vascular spiraling. Other workers have noted exceptions and this issue is not entirely settled.47,50 In monozygotic Fig. 35-53. Uncoiled latex cast of human umbilical artery (top and bottom) and umbilical vein (center) demonstrating identical vascular helices (arrows) in each vessel.

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twins in which one twin was acardiac and the direction of blood flow within the SUA cord is reversed, we have noted that the direction of vascular spiral was either absent or the same as that of the more normal twin. While the number of acardiacs examined is small, the observations indicate that flow reversal or a marked decrease in umbilical cord blood pressure (as is the case for the acardiac twin) does not influence the direction of vascular spiral. Lacro et al.47 point out that fetal activity influences the number of spirals and the total length of the umbilical cord. Animals developing within the confines of an elongated uterine cavity and humans who develop in the presence of intrauterine constraint often have short umbilical cords with few vascular spirals. Our experience supports this conclusion; however, when one examines the frequency of umbilical vascular helices in cords from fetuses exposed to drugs likely to produce fetal hyperkinesia (e.g., amphetamines, cocaine, caffeine), the data are extremely variable.48 An absence or paucity of vascular helical spiraling is noted with increased frequency in umbilical cords containing a single umbilical artery. This association alone imposes a very guarded prognosis for the patient because of the high incidence of lifethreatening birth defects in such patients. Lacro et al.47 noted frequently an absence of vascular spiraling in the umbilical cords of fetuses dying in utero and in the cords of twins. They suggested that the observation was related to decreased fetal movement and concluded that an absence of umbilical vascular spiraling is associated with an ‘‘adverse prognosis.’’ We agree with this prediction and suggest that the adverse prognosis may be related also to the fact that such cords are at great risk for vascular occlusion during normal fetal rotational movements. In studying umbilical cords containing single arteries, we noted that, if the vascular spiral was counterclockwise, the left umbilical artery was agenic; when the spiral was clockwise, the right umbilical artery was agenic. This observation allows one to predict the laterality of the ‘‘vascular steal’’ that may be operational in such fetuses. In the latter group, subtle asymmetries of lower limb development may be present. Lacro et al.47 found no relationship between umbilical vascular spiral direction and development of hand preference in a group of 3- and 4-year-old children. In our studies of normal cords at term gestation, we observed an average of one complete helical spiral per 2.7 cm of umbilical cord length. About 5% of umbilical cords demonstrate no evidence of vascular helical spiral. 35.21.7 Vitelline (Omphalomesenteric) Artery Disruption

Blood flow within the umbilical cord segment of the right vitelline artery may be interrupted in such a manner as to lead to infarction and necrosis of the proximal base of the umbilical cord and the medial portion of the right lateral body wall plate. This can result in a hole in the abdominal wall and herniation of intestine (and often other organs) into the amnionic sac, a defect referred to as gastroschisis. The defect is to the right (96%) of the umbilical cord.9,53 Necrosis of the base of the umbilical cord leaves the structural integrity of the rectus muscles intact. When healing occurs, skin usually bridges across the area between the abdominal wall defect and the umbilical cord base. No covering sac is present over the herniated intestine (Fig. 35-54), and the proximal umbilical cord and ring usually appear normal. Rarely, the amnionic covering of the proximal umbilical cord is interrupted (Fig. 35-55), and the vascular components appear naked (devoid of Wharton’s jelly).

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Other Systems and Structures

Fig. 35-54. Fetus (18 week gestation) showing typical gastroschisis (G) defect with herniation of the small bowel through an abdominal wall defect to the immediate right of the umbilical cord (UC). A membranous sac is absent. In this case, the amnionic sheath of the UC is absent in the proximal-most region, and the umbilical arteries (A) and vein (V) appear ‘‘naked’’ and devoid of Wharton’s jelly. (Compare with Fig. 35-55 showing defect after removal of small bowel.)

Early disruption of the blood flow within the right vitelline artery is at present only diagnosed by exclusion of other causes of defects similar to gastroschisis (e.g., omphalocele, umbilical cord hernia, short umbilical cord syndrome, acordia). In about 28% of patients with gastroschisis, other organs in addition to the bowel are herniated (e.g., stomach, urinary bladder, ovaries, testes, omentum). In contrast to omphalocele, the liver is not commonly herniated in gastroschisis and no covering sac is present.54 The small intestine in such situations is usually hyperemic, and the intestinal loops feel thick and somewhat leathery. Occasionally, foci of small bowel volvulus and/or segments of infarction are present. Histologic studies of the herniated loops of small intestine reveal edema and thickening of the mural regions and at times foci of hemorrhage. The overall degree of mural thickening correlates directly with gestational age and hence the duration of exposure to amnionic fluid. The mesenteric attachments are virtually always incomplete. As with omphalocele, the abdominal cavity is small. Most commonly, the only recognizable abnormality in gastroschisis is the abdominal wall defect containing herniated loops of small bowel (61%); in the remaining cases, additional structural defects are present. These include nonduodenal intestinal atresia or stenosis, atresia of the vermiform appendix, ‘‘apple peel’’ bowel, porencephaly, atresia or agenesis of the gallbladder, defects in the dorsal mesentery, and unilateral renal agenesis.9,53,55 There is a strong correlation between these defects and arterial vascular disruption.

Fig. 35-55. Abdominal wall and attached umbilical cord structures (UC) from early fetus (18 weeks gestation) with gastroschisis. Notice the abdominal wall defect (D) bridges across the umbilical ring and that the amnionic sheath covering the proximal umbilical cord (UC) is disrupted, a lesion that allows the umbilical arteries (A) and vein (V) to appear ‘‘naked’’ and devoid of Wharton’s jelly.

In evaluating the fetus with suspected vitelline artery disruption, it is important to differentiate other defects that on cursory inspection simulate gastroschisis, namely, omphalocele (especially with ruptured sac) and umbilical cord hernia. The features differentiating these lesions are outlined in Table 35-13. Failure to recognize the independent nature of these defects has led to considerable confusion. As late as 1998, the Index Medicus failed to include gastroschisis as a unique and independent body wall defect. In the past, it was believed that failure of the musculature migrating from the dorsal myotomes to invade completely the somatopleure of the lateral fold of the abdominal wall was responsible for gastroschisis. This etiologic consideration failed to explain rather consistent placement of the abdominal wall defect to the right of the umbilical ring and did not explain the presence of other structural defects (e.g., small bowel atresia or stenosis, porencephaly, gallbladder atresia) present in about 40% of fetuses with gastroschisis. Another earlier belief was that gastroschisis resulted from the intrauterine rupture of an incarcerated umbilical cord hernia. This consideration did not account for the presence of a normal rectus muscle between the defect and an intact umbilical ring or the associated structural anomalies noted above. Hoyme et al.53 proposed that interruption of the blood supply to structures supplied by the omphalomesenteric (vitelline) artery led to gastroschisis and, at times, to additional structural defects. A vascular insult or disruption involving the right vitelline artery, they suggest, could lead to necrosis of the base of the umbilical cord and apical portions of the right lateral body wall plate. Subsequently, the gut herniates through the necrotic zone, healing of the margins of the defect takes place, and the typical smooth-bordered body wall defect characteristic of gastroschisis is formed. Only rarely are early fetuses discovered that demonstrate the unhealed

Umbilical Cord

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Table 35-13. Differentiating features of gastroschisis, omphalocele, umbilical cord hernia, and umbilical hernia M:F ratio

Time of Development

1:6000

1:1

Week 5 of embryogenesis

About 30% have vascular disruption types of anomalies: gut atresias, gallbladder atresia, gallbladder agenesis, porencephaly (chromosome aberrations 1%)

Abdominal wall defect at right of umbilical ring, no covering sac, cord usually normal, amniocutaneous junction normal

Omphalocele

1:4000

1:1

After week 10 of embryogenesis

About 67% have multiple malformations in unrelated organ systems, short umbilical cord (chromosome aberrations in 40%)

Abdominal wall defect involving umbilical ring, organs herniate into ring, covering sac (lined by peritoneum and covered by fibrous materials without amnion surface) is present, amniocutaneous junction absent

Umbilical cord hernia

1:3000

1:1

After week 12

About 30% have normal umbilical cord length, patent vitelline or allantoic duct

Dilated umbilical cord containing herniated bowel loops, amniocutaneous junction normal

Umbilical hernia

18% in whites 42% in blacks

1:1

Postnatal

About 1–2% have long umbilical cord59

Skin-covered herniation of abdominal wall at umbilicus, peritoneal lining, amniocutaneous junction absent

Anomaly

Incidence

Gastroschisis

state, namely, the presence of umbilical cord disruption at its base with aseptic necrosis and loss of the medial portion of the right abdominal plate. In Figure 35-54, a fetus with these features is presented. Most dysmorphologists currently accept the vitelline artery disruption concept, as it seems to explain more logically the unique anatomic features of gastroschisis and its accompanying organ defects. In a few cases (less than 1%), gastroschisis may be familial and, hence, a genetic variety may also exist56; too few of these cases have been reported to make accurate comparisons with the sporadic variety of gastroschisis. The incidence of gastroschisis is about 1/6000 to 1/10,000 live births. A recent survey of gastroschisis revealed a mean gestational age of 36.9 weeks gestation and a mean birth weight of 2453 g in 23 infants with gastroschisis.57 In this study, the average maternal age and gravidity were 21.9 years and 2.1, respectively. The prognosis for isolated gastroschisis is quite good with the application of modern surgical therapy and is further improved when the diagnosis is secured during the prenatal period. Currently, over 80% of affected infants survive. About 10% of fetuses with gastroschisis are stillborn. The death rate for gastroschisis is 7% (vs. 22% for omphalocele), and the long-term mortality rate is about 9% (vs. 14.5% for omphalocele).54 Premature birth, which is present in about 26%, adversely affects the prognosis in gastroschisis. The prognosis is less favorable when additional structural defects are present (e.g., small gut atresia or stenosis, porencephaly, apple peel bowel) or when the herniated bowel shows areas of volvulus or ischemic infarction at the time of birth. The presence of meconium staining is common in patients with gastroschisis (74%), as is meconium aspiration (47%). Physicians should be mindful of the latter, potentially life-threatening complication.57 Recent studies suggest that the outcome is not affected by delivery route (vaginal or cesarean) but is influenced by other perinatal events (e.g., presence of additional anomalies, prematurity,

Associated Anomalies

Distinguishing Anatomic Features

meconium aspiration, and umbilical cord ulceration with hemorrhage).54,57 Surgical treatment is essentially the same as that for ruptured omphalocele with closure of the abdominal wall defect either primary or in staged procedures using silastic prostheses.58 Fluid and electrolyte imbalance and serum protein deficiency are associated with prolonged exposure (dialysis) of the small bowel to amnionic fluid. These pathophysiologic defects are treated by replacement therapy in association with analytical monitoring. Occasionally, infants with gastroschisis may display signs of malabsorption due to structural changes in the herniated gut. This process is transient. 35.21.8 Arteriovenous Malformation (Fistula)

Umbilical cord arteriovenous fistulas (AVF) are malformations within the proximal umbilical cord that divert blood from an umbilical artery to an umbilical vein. AVFs of this type almost always produce signs of high-output cardiac failure in the fetus or newborn.67–72 Such infants show signs of increased precordial activity, tachypnea, and hypotension. All four cardiac chambers are dilated and are usually normally formed, as evidenced by ultrasonography or cardiac catheterization. Pulmonary hypertension is usually present.69 Dilation and tortuosity of the aortic arch, main pulmonary artery, and descending aorta are virtually always present.69 The liver is enlarged. In all cases thus far examined, the fistula is located near the umbilical ring and allows blood flow from one of the umbilical arteries to a single large umbilical vein. A periumbilical bruit is usually not detected. Flow between the artery and vein can be demonstrated by aortography. In the case reported by Graham et al.,70 the fistula connected to a persistent right umbilical vein. The differential diagnoses for congenital high-output heart failure in the fetus or newborn should include AV malformations

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Other Systems and Structures

in both tumors (e.g., hemangiomas) and AVFs in various organs (especially the brain, umbilical cord, heart, and legs). In our experience, arteriovenous malformations producing congenital heart failure are most often present in hemangiomas of the liver and less commonly in those of the placenta. Isolated arteriovenous malformations with fistulous shunting of blood are most common in the brain, proximal umbilical cord, and between the abdominal segments of the umbilical arteries and umbilical venous elements within the abdominal wall. A few cases of congenital AVFs have been described in the vessels of the legs and liver (portal vein and hepatic artery). Rarely, fistulous shunts between the pulmonary arteries and the atrial chambers of the heart may also produce heart failure in the fetus and/or newborn. Mechanisms that lead to arteriovenous malformations of the umbilical cord are not well known. Anomalous umbilical vein development and fistulas have been noted in folate-deficient rats and in fetal rats exposed to retinoic acid (vitamin A). Graham et al.70 speculated that umbilical cord AVFs result from abnormal anastomoses between unresorbed portions of the ventral segmental arteries (umbilical allantoic arteries) and the right umbilical vein. Spatenka et al.72 reported an AVF between both umbilical arteries and the umbilical vein in a male who developed signs of heart failure 11 days after birth. The authors assumed that the lesion was iatrogenic due to trauma associated with ligation of the umbilical cord; however, a congenital etiology could not be excluded.

The incidence of umbilical cord AVFs is extremely low; the true incidence is not known. In a fetus or newborn with signs of rapidly advancing cardiac failure, the prognosis is poor. Early recognition of signs of high-output heart failure associated with arteriovenous shunting in and around the umbilical region can lead to surgical cure by ligation of the fistula. 35.21.9 Aneurysms and Varicosities

Abnormal regional dilation(s) of the umbilical arteries or vein may be large enough to be detected by visual examination and grossly distort the surface of the umbilical cord (Fig. 35-56). Such dilations are referred to as aneurysms or varicosities when they involve an umbilical artery or vein, respectively. Aneurysms or varicosities may be suspected prenatally by the regional enlargements of the umbilical cord vessels on ultrasonography. The diagnosis is confirmed by dissection of the cord with demonstration of pathologic dilation of the umbilical artery or vein or both. Varicosities are more common than aneurysms. Each lesion tends to be associated with more or less separate perinatal conditions and abnormalities (Table 35-14). False knots, localized areas of venous or arterial elongation that form a loop or mass of loops along the cord, may be confused with aneurysms or varicosities. Histologic studies of the cord in the region of a false knot will reveal multiple vessels of normal caliber in cross section.

Fig. 35-56. Left: umbilical cord aneurysm (arrows) diagnosed prenatally by ultrasonographic methods. The fetus died suddenly due to an apparent kink in the cord just distal to the aneurysm. Right: arteriogram of an umbilical cord aneurysm showing partially calcified thrombus (arrows). (Courtesy Dr. Robert W. Bendon, University of Cincinnati Medical Center.)

Umbilical Cord Table 35-14. Features associated with aneurysms and varicosities of the umbilical vessels Aneurysms

Varicosities

Abnormal umbilical cord insertion*

Meconium

Arterial smooth muscle lesions

Necrosis of venous wall

Single umbilical artery*

Thrombosis of vein

Fetal growth retardation

Extramedullary hepatic hematopoiesis (hemolytic anemia){

Other placental anomalies*

Segmental thin wall veins

*Data from Lemtis.65 {

Data from DeVore et al.64

Aneurysms of the umbilical artery are usually ‘‘saccular’’ in nature, appearing as a round to oval, sharply localized, dilation of the vessel (Fig. 35-56). Histologic studies may reveal foci of smooth muscle degeneration characterized by a spherical transformation of the smooth muscle cell shape and with eosinophilia of the sarcoplasm.60 Calcification within partially thrombosed aneurysms is common (Fig. 35-56). Varicosities of the umbilical vein may be fusiform or, at times, localized, round, or oval dilations of the vessel.61 Histologic examination usually reveals partial thrombosis of the lumen, and often the wall of the vein in the involved area is uncommonly thin. It should be pointed out that histologic studies of large numbers of umbilical cord veins reveal unusual degrees of venous mural thinning in about 1–2%.61 No inflammatory changes or other abnormalities accompany the lesion. Umbilical cord varicosities are often attributed to a rather striking degree of anatomic thinning of the mural regions of the vein.61 Wentworth62 has pointed out that, while the wall may appear unusually thin, such veins are able to resist rupture even after a considerable rise in intraluminal pressure. Altshuler and Hyde63 have attributed umbilical cord varicosities to meconium exposure with attending mural necrosis. Recently, Devore et al.64 described marked saccular dilation of the umbilical cord vein in association with increased venous pressure due to increased extramedullary hematopoiesis in the liver (e.g., hemolytic anemia). In most cases, an etiologic basis for varicosities of the cord has not been established or considered. Bender et al.60 have described ‘‘degenerating myocytes’’ within the mural regions of umbilical arteries displaying aneurysmal changes. Although little direct evidence is available, increased intraarterial pressure has also been considered an etiologic factor. In support of this phenomenon is the alleged increased incidence of umbilical cord aneurysms with single umbilical artery.65 In our experience, umbilical cord aneurysms are not known to be associated with cases of systemic connective tissue disease such as osteogenesis imperfecta.66 Varicosities of the umbilical vein within the cord are fairly common, being present in 1–2% of specimens. Aneurysms, on the other hand, are quite rare. No reliable incidence rate has as yet been published. Both varicosities and aneurysms are more common in the distal umbilical cord, particularly near the insertion site onto the placental plate.62 Little information is available concerning fetal outcome when umbilical cord varicosities or aneurysms are present. Obviously, varicosities associated with hemolytic anemia (Rh incompatibility) and liver hematopoiesis are associated with increased fetal risk. Aneurysms or varicosities with thrombosis seem also to put the

1471

fetus at increased risk. No reliable data regarding these associations are available at this time. References (Vascular Anomalies of the Umbilical Cord) 1. Monie IW: Genesis of single umbilical artery. Am J Obstet Gynecol 108:400, 1970. 2. Jeanty P: Fetal and funicular vascular anomalies: identification with prenatal US. Radiology 173:367, 1989. 3. Bell AD, Gerlis LM, Variend S: Persistent right umbilical vein-case report and review of the literature. Int J Cardiol 10:167, 1986. 4. Ricklan DE, Collett TA, Lyness SK: Umbilical vein variations: review of literature and a case report of a persistent right umbilical vein. Teratology 37:95, 1988. 5. Benirschke K, Kaufman P: Pathology of the Human Placenta, ed 2. Springer Verlag, New York, 1990, p 180. 6. Harold JG, Siegal RJ, Fitzgerald GA III, et al.: Differential prostacyclin production by human umbilical vasculature. Arch Pathol Lab Med 112:43, 1988. 7. Stevenson R, Jones KL, Phelan MC, et al.: Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the visceral and soft tissues. Pediatrics 78:451, 1986. 8. Ballantyne JW: The occurrence of a non-allantoic or vitelline placenta in the human subject. Trans Edinb Obstet Soc 23:54, 1898. 9. Hoyme HE, Higgenbottom MC, Jones KL: The vascular pathogenesis of gastroschisis: intrauterine interruption of the omphalomesenteric artery. J Pediatr 98:228, 1981. 10. Louw J, Barnard CN: Congenital intestinal atresia: observations on its origin. Lancet 2:1065, 1955. 11. Bryan EM, Kohler HG: The missing umbilical artery. I. Prospective study based on a maternity unit. Arch Dis Child 49:844, 1974. 12. Leung AK, Robson WL: Single umbilical artery. a report of 159 cases. Am J Dis Child 143:108, 1989. 13. Rudd NL, Klimek ML: Familial caudal dysgenesis: evidence for a major dominant gene. Clin Genet 38:170, 1990. 14. Lewenthal H, Alexander DJ, Ben-Adereth N: Single umbilical artery. A report of 50 cases. Isr J Med Sci 3:899, 1967. 15. Papadatos C, Paschos A: Single umbilical artery and congenital malformations. Obstet Gynecol 26:267, 1965. 16. Monie IW, Khemmani M: Absent and abnormal umbilical arteries. Teratology 7:135, 1973. 17. Bryan EM, Kohler HG: The missing umbilical artery II. Paediatric follow-up. Arch Dis Child 50:714, 1975. 18. Heifetz SA: Single umbilical artery. A statistical analysis of 237 autopsy cases and review of the literature. Perspect Pediatr Pathol 8:345, 1984. 19. Kampmeier OF: On sirenoform monsters, with a consideration of the causation and the predominance of the male sex among them. Anat Rec 34:365, 1927. 20. Stevenson RE, Phelan MC, Harley RA, et al.: Vascular steal: a proposed mechanism for certain skeletal, visceral, and soft tissue malformations. Proc Greenwood Genet Center 4:16, 1985. 21. Chaurasia BD: Single umbilical artery with caudal defects in human fetuses. Teratology 9:287, 1974. 22. Gisel A: Persistenz der arteria omphalomesaraica und fhelen der nabelarterien bei einer neugeborenen. Ein beltrag zurlehre von der kombination und korrelation anatomisher varietaten. Ztscher Anat 108:686, 1938. 23. Fliegal CP, Nars PW: Aberrant umbilical vein. Pediatr Radiol 14:55, 1984. 24. Leonidas JC, Fellows RA: Congenital absence of the ductus arteriosus with direct connection between the umbilical vein and the distal inferior vena cava. Am J Roentgenol 126:892, 1976. 25. Rehder H: Anomalien der portalen und umbilicalen venen. Virchows Arch [Pathol Anat] 352:50, 1971. 26. White JJ, Brenner H, Avery ME: Umbilical vein collateral circulation: the caput medusae in a newborn infant. Pediatrics 43:391, 1969. 27. Monie IW: Umbilical vein entering the right atrium: comments on a previously reported case. Teratology 4:461, 1971.

1472

Other Systems and Structures

28. Theander G, Karlson S: Persistent right umbilical vein. Acta Radiol 19:268, 1978. 29. Shryock EH, Jansen J, Barnard MC: Report of a newborn human presenting sympus dipus, anomalous umbilical vein, transposition of the viscera and other anomalies. Anat Rec 82:347, 1942. 30. Putschar W: Rare anomaly of umbilical vein combined with other congenital anomalies. J Tech Methods 18:23, 1938. 31. Blackburn WR, Cooley Jr NR: Unpublished data. 32. Hoffert PW, Strachman J: Intestinal obstruction due to an aberrant umbilical vein, and hypertrophic pyloric stenosis in a two weeks old infant. Bull NY Acad Med 36:475, 1960. 33. Prust FW, Eskandari F: Intestinal obstruction due to an aberrant umbilical vein: a case report. Ann Surg 165:464, 1967. 34. Svendsen LB, Johansen TS, Kristenson P: Intestinal obstruction caused by an aberrant umbilical vein. Acta Chir Scand 143:191, 1977. 35. Rodrigues MA: Four-vessel umbilical cord without congenital anomalies. South Med J 77:539, 1984. 36. Murdoch DE: Umbilical cord doubling: report of a case. Obstet Gynecol 27:555, 1966. 37. Painter D, Russell P: Four vessel umbilical cord associated with multiple congenital anomalies. Obstet Gynecol 50:505, 1977. 38. Von Wunderlich M, Sandig T: Persistenz der vena umbilicalis dextra eine seltene gefa¨ssanomalie der nabelschnur. Zbl Gynakol 99:891, 1977. 39. Monie IW, Nelson MM, Evans HM: Persistent right umbilical vein as a result of vitamin deficiency during gestation. Circ Res 5:187, 1957. 40. Khemmani M: Facial and Other Malformations Induced in Fetal Rats by Retinoic Acid. MA Thesis, University of California, San Francisco, 1967. 41. Siven M, Ley D, Ha¨gerstrand I, et al.: Agenesis of the ductus venosus and its correlation to hydrops fetalis and the fetal hepatic circulation: case reports and review of the literature. Pediatr Path Lab Med 15:39, 1995. 42. Prust FW, Abouatme J: Vitelline artery causing small bowel obstruction in the adult. Surgery 65:716, 1969. 43. Wilms M: Der Ileus. Ferdinand Enke Verlag, Stuttgart, 1906. 44. Cullen TS: Embryology, Anatomy and Diseases of the Umbilicus Together With Diseases of the Urachus. WB Saunders, Philadelphia, 1916. 45. Kleinhaus S, Cohen MI, Boley SJ: Vitelline artery and vein remnants as a cause of intestinal obstruction. J Pediatr Surg 9:295, 1974. 46. Fitz RH: Persistent omphalomesenteric remains: their importance in the causation of intestinal duplication, cyst formation, and obstruction. Am J Med Sci 88:30, 1884. 47. Lacro RV, Jones KL, Benirschke K: The umbilical cord twist: origin, direction, and relevance. Am J Obstet Gynecol 157:833, 1987. 48. Blackburn WR, Cooley NR Jr, Manci EA: Correlations between umbilical cord structure-composition and normal and abnormal fetal development. Proc Greenwood Genet Center 7:180, 1988. 49. Chaurasia BD, Agarwal BM: Helical structure of the human umbilical cord. Acta Anat 103:226, 1979. 50. Edmonds HW: The spiral twist of the normal umbilical cord in twins and in singletons. Am J Obstet Gynecol 67:102, 1954. 51. Malpas P, Symonds EM: Observations on the structure of the human umbilical cord. Surg Gynecol Obstet 123:746, 1966.

52. Machin GA, Ackerman J, Gilbert-Barness E: Abnormal umbilical cord coiling is associated with adverse perinatal outcomes. Pediatr Develop Path 3:462, 2000. 53. Hoyme HE, Jones MC, Jones KL: Gastroschisis: abdominal wall disruption secondary to early gestational interruption of the omphalomesenteric artery. Semin Perinatol 7:294, 1983. 54. Moretti M, Khoury A, Rodriques J, et al.: The effect of mode of delivery on the perinatal outcome in fetuses with abdominal wall defects. Am J Obstet Gynecol 163:833, 1990. 55. Ramenofsky ML, Cooley NR Jr, Blackburn WR: Agenesis of the gallbladder: a classification based on associated anomalies. Teratology 25:69A, 1982. 56. Salinas CF, Bartoshesky L, Otherson HB, et al.: Familial occurrence of gastroschisis. Four new cases and review of the literature. Am J Dis Child 133:514, 1979. 57. Superneau DW, Falterman KW: Gastroschisis: ten years experience. Proc Greenwood Genet Center 11:150, 1992. 58. Sherman NJ, Ash MJ: Gastroschisis: current concepts. J Calif Perinatal Assoc 1:74, 1981. 59. Woods GE: Some observations on umbilical hernia in infants. Arch Dis Child 28:450, 1953. 60. Bender HG, Werner C, Karsten C: Zum einflub der Nabelschnur-struker auf schwangerschafts-und geburtsverlauf. Arch Gynakol 225:347, 1978. 61. Leinzinger E: Varixthrombose der Nabelschnur. Z Geburtshilfe Gynakol 171:82, 1969. 62. Wentworth P: Some anomalies of the foetal vessels of the human placenta. J 99:273, 1965. 63. Altshuler G, Hyde S: Meconium-induced vasoconstriction: a potential cause of cerebral and other fetal hypoperfusion and of poor pregnancy outcome. J Child Neurol 4:137, 1989. 64. DeVore GR, Mayden K, Tortora M, et al.: Dilation of the fetal umbilical vein in Rhesus hemolytic anemia: a predictor of severe disease. Am J Obstet Gynecol 141:464, 1981. 65. Lemtis H: Uber aneurysmen im fetalen gefabapparat der menschlicken plazenta. Arch Gynakol 206:330, 1968. 66. Wheeler VR, Cooley NR Jr, Blackburn WR: Cardiovascular pathology in osteogenesis imperfecta type IIA with a review of the literature. Pediatr Pathol 8:55, 1988. 67. Murray DE, Meyerowitz BR, Hutter JJ: Congenital arteriovenous fistula causing congestive heart failure in the newborn. JAMA 209:770, 1969. 68. Hager J, Gschnitzer F, Hammerer I, et al.: Die angeborene epigastnischumbilicale A V-fistel. Langenbecks Arch Chir 357:269, 1982. 69. Sapire DW, Costa A, Donner RM, et al.: Dilatation of the descending aorta: a radiographic and echocardiographic diagnostic sign of arteriovenous malformations in neonates and young infants. Am J Cardiol 44:493, 1979. 70. Graham SM, Seashore JH, Markowtiz RI, et al.: Congenital umbilical arteriovenous malformation: a rare cause of congestive heart failure in the newborn. J Ped Surg 24:1144, 1989. 71. Reagen LC, James FW, Dutton RV: Umbilical artery-vein fistula. Am J Dis Child 119:363, 1970. 72. Spatenka J, Hucin B, Tuma S, et al.: Umbilical arteriovenous fistula-a rare case of congestive failure in neonates. Cs Pediatr 35:426, 1980.

Index to Tables of Malformations and Associated Syndromes

Topic

Table

Page

Topic

Acrorenal disorders

Table 28-6

1168

Bone density, increased

Adactyly

Table 21-13

985

Ambiguous genitalia Amelia Amniotic bands Anencephaly Anorectal atresia

Page

Table 20-26

912

Table 20-27

913

Table 29-11

1274

Table 22-3

1018

Table 30-2

1290

Brachycephaly

Table 7-1

224

Table 20-5

850

Brachydactyly

Table 21-11

970

872

Brain malformations and metabolic disorders

Table 1-18

70

Table 1-19

71

Table 20-13 Table 20-14

874

Table 16-1

722

Branchial cleft, anomalies of

Table 24-3

1070

Table 16-3

735

Breast, absent

Table 23-8

1051

Table 26-2

1119

Breast, hypoplastic

Table 23-8

1052

Cardiac defects, conotruncal

Table 2-3

Anus, atresia of

Table 26-2

1119

Aorta, coarctation of

Table 3-3

134

Aortic arch, interrupted

Table 3-1

122

Aprosencephaly

Table 15-3

526

Arachnoid cysts

Table 15-20

693

Areola, absent

Table 23-8

1052

Areola, hypoplastic

Table 23-8

1052

Arhinencephaly

Table

Table 11-3

387

Table 15-4

531

Asplenia

Table 5-3

191

Asymmetry of the facial skeleton

Table 8-9

294

Atelencephaly

Table 15-3

526

Atrial septal defect

Table 2-7

112

Atrioventricular septal defects

Table 2-4

Auricle, protruding

Cardiovascular malformations

99

Table 2-3

99

Table 2-4

102

Table 2-5

105

Table 2-6

109

Table 2-7

113

Table 2-8

115

Table 2-9

116

Table 3-1

122

Table 3-2

131

Table 3-3

131

Carpal coalition

Table 20-9

858

Cataracts

Table 9-4

316

Table 9-5

317

102

Cavum septum pellucidum

Table 15-9

606

Table 10-9

347

Cerebellar hypoplasia

Table 1-18

70

Auricular pits

Table 10-10

353

Table 15-17

657

Auricular tags

Table 10-10

353

Cerebro-renal-digital disorders

Table 28-8

1175

Basilar impression of skull

Table 7-14

263

Chiari malformations

Table 15-21

706

Bifid epiglottis

Table 6-1

202

Clavicle, altered shape of

Table 19-2

808

Bone density, decreased

Table 20-28

915

Clavicle, hypoplasia of,

Table 19-1

806

Table 20-29

916

Cleft, branchial

Table 24-3

1070

Table 22-3

1016

Cleft, facial

Table 8-5

280

1473

1474

Index to Tables of Malformations

Topic

Table

Cleft lip, midline

Table 12-1

Page

Topic

Table

394

Eye, malformations of

Table 9-1

Page

298

Cleft lip, with or without cleft palate

Table 12-2

396

Eye, microphthalmia, classification of

Table 9-3

301

Cleft palate

Table 12-5

401

Facial asymmetry

Table 8-9

294

Clitoromegaly

Table 30-6

1302

Facial clefting

Table 8-5

280

Cloverleaf skull

Table 7-5

235

Facial skeleton, asymmetry of

Table 8-9

294

Coarctation of aorta

Table 3-3

134

Female genitalia, hypoplasia of external

Table 30-7

1304

Coloboma, ocular

Table 9-3

301

Female genitalia, Mu¨llerian aplasia

Table 30-3

1292

Colpocephaly

Table 15-13

638

Female genitalia, Mu¨llerian fusion

Table 30-4

1296

Connective tissue disorders

Table 31-9

1326

Fetal cystic hygroma

Table 4-2

166

Conotruncal cardiac defects

Table 2-3

Constriction rings

Table 20-13

Floppy infant

Table 20-33

924

872

99

Follicular keratosis

Table 31-7

1324

Contractures, multiple congenital

Table 20-14

874

Fontanel, delayed closure of

Table 7-7

239

Table 20-35

927

Fontanel, large

Table 7-7

Corpus callosum, absence of

Table 1-18

70

239

Gallbladder, agenesis of

Table 27-4

1141

Table 15-7

583

Coxa vara

Table 19-11

834

Cranial bones, defective ossification of

Table 7-10

249

Globodontia

Table 14-13

453

Cranial bones, sclerosis of

Table 7-12

255

Gonadal dysgenesis

Table 30-1

1285

Cranial bones, thick

Table 7-11

252

Growth, excess prenatal, onset of

Table 33-6

1373

Cranial bones, thin

Table 7-10

249

Gynecomastia

Table 23-11

1060

Cranial sutures, wide

Table 7-6

237

Hearing loss syndromes

Table 10-14

370

Craniosynostosis

Table 7-1

224

Hemiatrophy

Table 33-5

1371

Table 7-2

227

Hemihyperplasia

Table 33-3

1367

Table 7-3

227

Hemihypertrophy

Table 20-25

907

Cup ear

Table 10-8

345

Table 33-3

1367

Cyst, arachnoid

Table 15-20

693

Hemihypoplasia

Table 33-4

1370

Genitalia, ambiguous

Table 27-11

1274

Table 30-2

1290

Cyst, septum pellucidum

Table 15-9

606

Hernia, diaphragmatic

Table 6-7

214

Cystic hygroma, fetal

Table 4-2

166

Hernia, umbilical

Table 23-3

1033

Dandy-Walker malformation

Table 15-18

680

Holoprosencephaly

Table 1-18

70

Dental cusps, supernumerary

Table 14-13

453

Table 11-2

381

Diaphragmatic hernia

Table 6-7

214

Ductus arteriosis

Table 3-2

131

Horseshoe kidney

Table 15-4

531

Table 28-20

1230

Duodenum, atresia of

Table 24-14

1091

Hydranencephaly

Table 15-14

641

Duodenum, stenosis of

Table 24-14

1091

Hydrocephalus

Table 15-11

614

Ear, cup

Table 10-8

345

Hydrops fetalis

Table 1-17

69

Ear, lop

Table 10-8

345

Hypermobility of joints

Table 20-34

925

Ear, middle, malformations of

Table 10-11

360

Hypertelorism

Table 8-3

Ear pits

Table 10-10

353

Hypertrichosis

Table 31-13

1335

Ear tags

Table 10-10

353

Table 31-14

1335 1260

276

Enamel dysplasia of teeth

Table 14-16

461

Hypospadias

Table 29-4

Encephalocele

Table 16-1

722

Hypotelorism

Table 8-2

Table 16-3

735

Hypotrichosis

Table 31-12

Endocrine features, chromosomal disorders with

Table 32-5

1348

Interrupted aortic arch

Table 3-1

122

Endocrine features, genetic syndromes with

Table 32-4

1347

Intestine, atresia of

Table 25-2

1102

Endocrine features, tumor syndromes with

Table 32-3

1346

Intestine, malrotation of

Table 25-5

1110

Endocrine organs, disorders of

Table 32-1

1340

Intestine, polyps of

Table 25-6

1113

Table 32-2

1345

Kidney, horseshoe

Table 28-20

1230

Epiglottis, bifid

Table 6-1

202

Esophagus, atresia of

Table 24-6

1075

Eye, coloboma of

Table 9-3

301

272 1335

Kleeblattscha¨del

Table 7-5

236

Larynx, malformations of

Table 6-2

204

Laterality defects

Table 5-2

190

Index to Tables of Malformations

Topic

Table

Page

Topic

1475

Table

Page

Left ventricular outflow tract obstruction

Table 2-6

109

Neuronal ectopias

Table 15-6

Limb deficiencies, intercalary

Table 20-2

842

Neuronal heterotopias

Table 1-18

70

Limb deficiencies, longitudinal

Table 20-3

843

Table 15-6

559

Limb deficiencies, transverse

Table 20-6

852

Nipples, absent

Table 23-8

1052

Limb overgrowth

Table 20-22

902

Nipples, hypoplastic

Table 23-8

1052

Table 20-23

905

Nipples, supernumerary

Table 23-9

1055

Table 12-1

394

Nipples, widely spaced

Table 23-10

1059

Table 12-2

396

Obesity, postnatal onset

Table 33-7

1374

Table 1-18

70

Ocular coloboma

Table 9-3

301

Table 1-19

71

Ocular malformations

Table 9-1

298

Table 15-5

551

Odontoid aplasia

Table 19-6

820

Liver, dysplasia of

Table 27-2

1134

Odontoid hypoplasia

Table 19-6

820

Long bones, bowing of

Table 20-15

884

Oligodactyly

Table 21-13

985

Table 20-16

890

Omphalocele

Table 23-4

1036

Optic nerve hypoplasia

Table 9-6

321

Orbital hypertelorism

Table 8-3

276

Orbital hypotelorism

Table 8-2

272

Osteolysis

Table 20-30

917

Table 22-3

1020

Osteorenal disorders

Table 28-7

1172

Pachygyria

Table 1-18

70

Table 15-6

559

Table 12-5

401

Lip, cleft Lissencephaly

Long bones, synostosis of

Table 20-12

861

Lop ear

Table 10-8

345

Lymphatic dysplasia

Table 4-1

153

Lymphedema

Table 4-1

153

Macrocephaly

Table 15-2

513

Macrodactyly

Table 20-24

906

Macrodontia

Table 14-11

452

Macrosomia

Table 20-22

902

Table 33-6

1373

559

Macrotia

Table 10-7

339

Palate, cleft

Malocclusion

Table 14-15

457

Palmar plantar keratoderma

Table 31-6

1324

Malrotation of intestine

Table 25-5

1110

Pancreatic dysplasia

Table 27-6

1155

Meatal atresia without microtia

Table 10-6

337

Patella, anomalies of

Table 20-31

921

Megacolon

Table 25-4

1107

Table 20-32

921

Meningocele, anterior

Table 17-2

780

Patent ductus arteriosus

Table 3-2

131

Meningocele, lateral

Table 17-2

780

Pectus carinatum

Table 19-4

815

Meromelia

Table 20-2

842

Pectus excavatum

Table 19-3

814

Table 20-3

843

Pelvic bones, anomalies of

Table 19-10

831

Table 20-6

852

Polydactyly

Table 21-3

939

Metacarpal synostosis

Table 20-10

859

Table 21-4

941

Metatarsal synostosis

Table 20-10

859

Table 21-5

942

Metopic suture synostosis

Table 7-4

228

Table 21-6

943

Table 8-1

269

Table 21-7

943

Microcephaly

Table 15-1

474

Polymicrogyria

Table 1-18

70

Microdontia

Table 14-10

448

Table 15-6

559

Micrognathia

Table 8-8

290

Polysplenia

Table 5-3

191

Microphthalmia

Table 9-3

301

Porencephaly

Table 15-15

646

Microtia

Table 10-4

333

Preauricular pits

Table 10-10

353

Middle ear, malformations of

Table 10-11

360

Preauricular tags

Table 10-10

353

Middle limb segment, longitudinal deficiencies of

Table 20-3

843

Pseudohermaphroditism

Table 29-11

1274

Midface hypoplasia

Table 8-7

285

Table 30-2

1290

Midface retrusion

Table 8-7

285

Pulmonary agenesis

Table 6-5

210

Mu¨llerian aplasia

Table 30-3

1292

Pulmonary aplasia

Table 6-5

210

Mu¨llerian fusion

Table 30-4

1296

Pulmonary lobar aplasia

Table 6-5

210

Neural tube defect

Table 16-1

722

Pulmonary stenosis

Table 2-5

105

Table 16-3

735

Pulmonary venous connection, anomalous

Table 2-9

116

1476

Index to Tables of Malformations

Topic

Table

Page

Topic

Table

Page

Pyloric stenosis

Table 24-10

1083

Teeth, eruption defects

Table 14-20

464

Rectoanal atresia

Table 26-2

1119

Teeth, incisor abnormalities

Table 14-12

453

Renal agenesis

Table 28-12

1186

Teeth, supernumerary

Table 14-7

445

Renal dysplasia

Table 28-18

1207

Testicular failure

Table 23-11

1060

Renal ectopia

Table 28-19

1224

Testis, absent

Table 29-10

1271

Renal hypoplasia

Table 28-13

1192

Testis, small

Table 29-9

1270

Renal-hepatic-pancreatic disorders

Table 28-9

1178

Thumb, triphalangeal

Table 21-6

943

Rib anomalies

Table 19-5

816

Tooth agenesis

Table 14-2

432

Schizencephaly

Table 15-15

646

Table 14-3

432

Septal defect, ventricular

Table 2-8

115

Table 14-4

433

Septum pellucidum, absence of

Table 15-9

606

Table 14-5

439

Septum pellucidum, cysts of

Table 15-9

606

Tooth eruption defect

Table 14-20

464

Short stature

Table 20-20

898

Tooth, enamel dysplasia

Table 14-16

461 208

Skeletal dysplasia

Table 22-2

1001

Trachea. stenosis of

Table 6-4

Table 22-3

1003

Trigonocephaly

Table 7-4

228

Skull, basilar impression of

Table 7-14

263

Table 8-1

269

Skull, hyperostosis of

Table 7-12

255

Triphalangeal thumb

Table 21-6

943

Skull, sclerosis of

Table 7-12

255

Tumor syndromes, with endocrine features

Table 32-2

1346

Spina bifida

Table 16-1

722

Tumors, vascular

Table 31-11

1327

Table 16-3

735

Umbilical hernia

Table 23-3

1033

Stature, short

Table 20-20

898

Urethral agenesis

Table 28-21

1239

Stature, tall

Table 20-21

901

Urethral stenosis

Table 28-23

1243

Stomach, malposition of

Table 24-12

1088

Vaginal atresia

Table 30-5

1299

Symphalangism

Table 20-11

860

Vascular malformations

Table 31-10

1327

Syndactyly

Table 21-9

956

Vascular tumors

Table 31-11

1327

Synostosis of long bones

Table 20-12

861

Ventricular outflow tract obstruction, left

Table 2-6

109

Syringomyelia

Table 17-1

771

Ventricular septal defect

Table 2-8

115

Tall stature

Table 20-21

901

Vertebrae, coronal cleft of

Table 19-9

828

Tarsal coalition

Table 20-9

858

Vertebrae, formation defects of

Table 19-7

822

Taurodontia

Table 14-14

454

Vertebrae, segmentation defects of

Table 19-7

822

Teeth, agenesis of

Table 14-2

432

Vertebral body contours, altered

Table 19-8

826

Table 14-3

432

Wormian bones

Table 7-9

245

Table 14-4

433

Zygoma, absence of

Table 8-6

282

Table 14-5

439

Zygoma, hypoplasia of

Table 8-6

282

Table 14-16

461

Teeth, enamel dysplasia of

Subject Index

Page numbers followed by t indicate tables. Aarskog syndrome, 276 Abdominal muscles, deficiency of, 799 Abdominal wall, 1023 anomalies of, 797, 1023 deficiency of muscles, 797, 799 embryogenesis of, 1023 Ablepharon, 308 ABO incompatibility, 57 Absence of corpus callosum, 581 syndromes with, 70t, 583t Acalvaria, 716 Acanthosis nigricans and craniosynostosis, 225 Acardia, 1396 Accessory bones, 876, 877 Accessory breast tissue, 1056 Accessory digits, 1310 Accessory muscle tissue, 800 Accessory scrotum, 1267 Accessory spleen, 196 Accessory tragi, 1309 Acetabular dysplasia, 830 Achalasia, 1079 syndromes with, 1080 Acheiropody, 988 Achondrogenesis, 1005, 1006, 1009 Achondroplasia, 513, 1005 growth in, 67 Acordia, 1428 Acrania, 716 Acrocephaly, 226 syndromes with, 224 Acrodysostosis, 970, 1014 Acromelic dysplasias, 1014 Acromesomelic dysplasias, 1013 Acronyms, use of, 10 Acrorenal disorders, 1167, 1168t Adactyly, 984 entities with, 985t Adams-Oliver syndrome, 985 Adenylosuccinase deficiency, 657

Adrenal gland, 1340 congenital hyperplasia of, 1289, 1346 hyperplasia of, 1287, 1340, 1342, 1346 hypoplasia of, 1340 Adrenogenital syndrome, 1340 Adult polycystic kidney disease, 1134 AEC syndrome, 1334 Aganglionic duodenum, 1094 Aganglionic megacolon, 1106 Agenesis of corpus callosum, 581 diagnosis of, 582 EEG findings in, 593 embryogenesis of, 596 genes associated with, 597 intracerebral cysts and, 582 pathogenesis of, 596 prenatal diagnosis of, 593 presenting signs in, 582 prevalence of, 595 prognosis of, 597 syndromes with, 583 teratogen exposures and, 598 treatment of, 598 types of, 582 Aglossia, 406, 791 Agnathia, 287, 340 Agnathia-holoprosencephaly, 287, 340 Agonadism, 1268 syndromes with, 1271 Alagille syndrome, 1136, 1186 Albinism, 1330 Albright hereditary osteodystrophy, 970, 1353 Alcohol, prenatal, syndrome, 474 Alcohol, prenatal exposure to, 41, 474 Allantoic artery, 1459 Allantoic duct cysts, 1419 Allantoic duct remnants, 1419 Alobar holoprosencephaly, 528, 536 Alopecia, 1335

Amastia, 1051 syndromes with, 1052 Ambiguous genitalia, 1287 associated anomalies, 1287 cause of, 1288 incidence of, 1289 laboratory evaluation, 1287 syndromes with, 1274t, 1290t treatment, 1289 Amelia, 839 conditions with, 850t Amelogenesis imperfecta, 459 classification of, 460 Aminoacidopathies, 52 Aminopterin, prenatal exposure to, 43 Amniocele, 1034 Amniocentesis, 58 Amnion disruption, 54 Amnion rupture, 872 craniofacial involvement, 872 Amniotic bands, 54, 852, 871, 985 associated anomalies, 872t, 874t Amputation of limbs, 872 Amyoplasia, 926, 929 Amyoplasia congenita, 92 Amyotonia, congenital, 788 Androgen insensitivity, 1257 Androgens, prenatal exposure to, 45, 51 Anencephaly, 715 geographic/secular rates, 729 syndromes with, 722t, 735t Aneuploidies, 17 Aneurysm of umbilical cord, 1470 Angelman syndrome, 475 Angioma, 140, 1322, 1326 Angiotensin-converting enzyme inhibitors, 46 Anhidrotic ectodermal dysplasia, 1333 Animal models, 13 (see also Mouse models) for agnathia, 287

for for for for for for for for for

amniotic bands, 875 cardiovascular anomalies, 85 ear, 358 fetal cystic hygroma, 165 gastroschisis, 1040 heart development, 85 hydranencephaly, 640 hydrocephalus, 626 intestinal lymphangiectasia, 156 for intraspinal cysts, 765 for left ventricular outflow tract anomalies, 108 for limb deficiencies, 842 for limb development, 835 for lymphatic anomalies, 151, 156 for lymphedema, 151 for neural tube defects, 733, 734 for neuronal migration defects, 547 for situs inversus, 189, 1361 for spleen, 183 for split cord malformation, 776 for twins, 1382 Aniridia, 314 Ankyloglossia, 410 Ankyloglossum superius, 409 Ankylosis of tongue and palate, 409 Annular pancreas, 1151 anomalies associated with, 1151 Anodontia, 432 Anomalad, 13 Anomalies (see Malformations) Anomalous drainage of the inferior vena cava, 137 Anophthalmia, 299 Anorchia, 1268 Anorectal malformations, 1115, 1119t surgical treatment of, 1120 Anotia, 331 associated defects with, 332 prevalence of, 332 1477

1478 Anterior chamber cleavage syndrome, 311 Anterior hernia, 214 Anterior pituitary gland, disorders of, 894, 900, 1340 Anterior polar cataract, 316 Anterior segment dysgenesis of the eye, 311 Antibodies, maternal, 57 Anticoagulants, prenatal exposure to, 48 Anticonvulsants, prenatal exposure to, 42 Antley-Bixler syndrome, 224 Anus, 1115 associated anomalies, 1118 atresia of, 1116 syndromes with, 1119t development of, 1115 imperforate, 1116 Aorta, coarctation of, 108, 133 syndromes associated with, 134t Aortic arch, 121 anomalies of, 127 cervical, 125 double, 125 double-lumen, 126 interrupted, 100, 108, 121 syndromes with, 122t persistent fifth, 127 right, 123 type B, interrupted, 100 Aortic atresia, 107 Aortic stenosis, 107 Aortic valve, absent, 107 Aortic valvular stenosis, 107 Aortopulmonary septal defect, 119 Aortopulmonary window, 119 Apert syndrome, 224, 956 Aphallia, 1265 Apical ectodermal ridge, 835, 936 Apical dystrophy, 976 Aplasia, definition of, 11 cutis congenita, 246, 1311 deep venous system, 139 foramen of Monro, 613 heminasal, 374 Mu¨llerian, 1291 Applepeel intestinal atresia, 1099 Aprosencephaly, 525 associated anomalies, 526 clinical presentation, 525 definition, 525 diagnosis, 525 prevalence, 527 prognosis, 527 syndromes with, 526t Aqueductal atresia, congenital, 613 Aqueductal stenosis, 613, 624 congenital, 613 Arachnodactyly, contractural, 931 Arachnoid cysts, 689 compression of, 694 etiology of, 692 location of, 690 rupture of, 694 syndromes with, 693t Arachnoid diverticulum, 766

Subject Index Arachnoid granulations, 625 Areola, absent, 1051, 1052t hypoplastic, 1051, 1052t Arhinencephaly, 386, 528 syndromes with, 387t, 531t Arhinia, 374 unilateral, 374 Arnold-Chiari malformation (see Chiari malformation) Arteriohepatic dysplasia, 1136 Arteriovenous fistula, umbilical, 1469 Arteriovenous malformation, 141, 1326, 1469 Artery variants, 119, 121 innominate, 128 subclavian, 124, 129 of umbilical cord, 1457, 1459 Arthrogryposis, 788, 925 causes of, 788, 926 disorders with, 788, 927 distal, 930 Ash leaf spot, 1331 Asphyxiating thoracic dystrophy, 939 Asplenia, 185 malformations associated with, 188 phenotype, 187 syndromes with, 191t Association, definition of, 9 Asternia, 1025 Asymmetric crying facies, 791 Asymmetric gonadal dysgenesis, 1284 Asymmetric growth, 1365 Asymmetric limb overgrowth, syndromes with, 905 Asymmetry, 1359 embryogenesis, 1359 generalized overgrowth, 1372 hemiatrophy, 1369 hemihyperplasia, 1366 hemihypoplasia, 1369 Kartagener syndrome, 1363 laterality sequences, 1361 patterns of, 1365 Asymmetry of facial skeleton, 292 syndromes with, 294t Atavisms, muscle, 800 Atelencephaly, 525 associated anomalies, 526 clinical presentation, 525 definition, 525 diagnosis, 526 prevalence, 527 prognosis, 527 syndromes with, 526t Atelosteogenesis, 1012 Athelia, 1051 syndromes with, 1052t Atlanto-axial instability, 818 syndromes with, 820 subluxation, 818 Atlas, occipitalization of, 813 Atretic cephalocele, 721 Atrioventricular canal, 87 defects of, 101 septal defects of, 101 complete, 101

endocardial, 101 partial, 101 syndromes associated with, 102t transitional, 101 treatment of, 103 septation of, 88 Atrioventricular valve defect, 101 Atrium, 87 common, 101 septal defects of, 112, 112t septation of, 87 Atrophy, definition of, 12 ATR-X syndrome, 475, 1260 Auditory meatus abnormalities, 368 Auricle (see Ear, external) Auricular appendages, 351 Auricular fistulas, 353 Auricular pits, 353 associated defects, 354 prevalence, 354 syndromes with, 353 Auricular tags, 351 prevalence, 352 removal, 353 syndromes with, 353t Autosomal dominant phenotype, 29 characteristics of, 29 Autosomal recessive phenotype, 31 characteristics of, 31 Axenfeld anomaly, 311 Axenfeld-Rieger syndrome, 311 Axial skeletal dysplasias, 1011 Axis, hypoplasia, 818, 820 Azygous vein, 137 Bacterial infections and pregnancy, 38 Baller-Gerold syndrome, 224 Banana sign, 704, 719 Bannayan-Riley-Ruvalcaba syndrome, 513, 1373 Bardet-Biedl syndrome, 939, 970, 1134, 1257 Basal foramina, anomalies of, 261 Basilar impression, 261 syndromes with, 263t Bathrocephaly, 275, 264 Beare-Stevenson syndrome, 224, 1373 Becker nevus, congenital, 1317 Beckwith-Wiedemann syndrome, 1347, 1367, 1373 Benign hypermobility syndrome, 922 Bicuspid aortic valve, 107 Biemond syndrome, 1257 Bifactorial causation, 32 Bifid clitoris, 1302 Bifid cranium, 243 Bifid epiglottis, 201 syndromes with, 202 Bifid nose, 376 Bifid sternum, 810 Bifid tongue, 408 Bifurcation of femur, 877 Bifurcation of humerus, 877 Bilateral inferior vena cava, 118

left-sidedness, 185 periventricular nodular heterotopia, 569 right-sidedness, 185 superior vena cava, 117 Bile ducts, 1124 anomalies of, 1136 atresia of, 1136 development of, 1124 hypoplasia, 1136 paucity of, 1136 Biliary atresia, extrahepatic, 1142 Biliary system, cysts of, 1145 Biliary tree structure, variation in, 1149 Binder syndrome, 382 Bing-Siebenman dysplasia, 368 Biochemical testing, 68 Birth defects (see Malformations) Bladder, 1232 agenesis of, 1232 anomalies of, 1232 congenital dilation of, 1233 exstrophy of, 1233 megacystis, 1233 Bladder exstrophy, 1042 association with malformations, 1043 etiology of, 1043 prenatal diagnosis, 1045 prognosis, 1044 treatment, 1044 variants of, 1043 Blepharophimosis, 305 Blepharophimosis, ptosis, and epicanthus inversus syndrome, 305, 1347 Block vertebra, 819 Blomstrand dysplasia, 1005 Bloom syndrome, 1347 Bochdalek hernia, 214 Body wall defects, 1023 (see also Ventral wall of the trunk) genes associated with, 1023 pathogenic mechanisms, 1024 Bone density, decreased, 914 conditions with, 915t, 916t, 1016t Bone density, increased, 910 conditions with, 912t, 913t, 1018t Bone dysplasias, 997 (see also Skeletal dysplasias) classification of, 1003 Bones, accessory, 876, 877 bowing of long, 882 duplications, 876 facial, 267 excessive partition, 876 Bo¨rjeson-Forssman-Lehmann syndrome, 476, 1347, 1356 Bowing of long bones, 882 cause of, 883 syndromes with, 884 Brachycephaly, 223 syndromes with, 224t Brachydactyly, 968 A-1, 969 A-2, 975

Subject Index A-3, 974 B, 975 Bell classification, 968 C, 976 classification of, 968 D, 979 E, 980 Farabee type, 969 Fitch classification, 968 IHH gene and, 974 Mohr-Wriedt type, 969, 975 skeletal dysplasias with, 974 syndromes with, 970 treatment, 981 Brachymesophalangy, 969, 974 Brachymetacarpy/brachymetapody, 980 Brain, 469 agenesis of corpus callosum, 581 syndromes with, 583 aprosencephaly/atelencephaly, 525 syndromes with, 526 arhinencephaly, 528 syndromes with, 531 cerebellar anomalies, 654 syndromes with, 657 Chiari malformations, 700 syndromes with, 705 colpocephaly, 636 syndromes with, 638 cortical development malformations, 546 cystic malformations of, 604, 677 syndromes with, 606, 680, 693 ectopias, syndromes with, 559 focal cortical dysplasia, 572 heterotopias, 568 syndromes with, 559 holoprosencephaly, 528 syndromes with, 531 hydranencephaly, 639 syndromes with, 641 hydrocephaly, 610 syndromes with, 614 lissencephaly, 547 syndromes with, 551 macrocephaly, syndromes with, 513 megalencephaly, 511 microcephaly, 470 syndromes with, 474 pachygyria, 556 syndromes with, 559 polymicrogyria, syndromes with, 559 porencephaly, 645 syndromes with, 646 segmental nature of, 469 size, 470 and spinal cord, 715 tissue in tongue, 416 Branchial arches, 327 Branchial clefts, 1069 cysts, 1069, 1309 fistula, 1069 remnants of branchial apparatus, 1069 sinus, 1069, 1309

Branchial cleft cysts, syndromes with, 1070t Branchial cleft fistula, syndromes with, 1070t Branchial cleft sinus, syndromes with, 1070t Branchio-oto-renal syndrome, 327, 1186 Breakage, chromosomal, 21 Breasts, 1049 absence of, 1051 syndromes with, 1051t accessory, 1056 development of, 1049 embryogenesis of, 1049 enlarged, 1053 hyperplasia of, 1053 hyperplasia of, virginal, 1054 hypertrophy of, 1055 hypertrophy of, neonatal, 1053 hypertrophy of, pregnancy, 1055 hypoplastic, syndromes with, 1052t supernumerary, 1055 Breech head, 257 Bronchi, 211 compression of, 125, 128, 129 Bronchial stenosis, 213 Bronchogenic cyst, 1309 Bullae, 1319, 1325 Cacchi-Ricci disease, 1217 Cafe´ au lait spots, 1331 Caffey infantile hyperostosis, 1018 Calcium deficiency, prenatal, 53 Calcium sensing receptor defects, 1353 Callosal dysgenesis, 581 Campomelic dysplasia, 885, 1015, 1274 Camurati-Engelmann dysplasia, 1018 Cantrell pentalogy, 1027 Capillary hemangiomas, 1323 syndromes with, 1327 Capillary malformations, 142, 1323 Capillary-venous malformation, 142 Caput succedaneum, 262 Carbamazepine, prenatal exposure to, 43 Carbimazole, prenatal exposure to, 47 Cardiac defects, conotruncal, 97, 99t Cardiac development, 85 embryology, 85 neural crest contribution, 87 Cardiff modification, 13 Cardiorespiratory organs, 83 heart, 85 lower respiratory organs, 201 lymphatic system, 145 spleen, 183 systemic vasculature, 121 Cardiovascular system malformations, 85, 121 abnormal systemic venous connections, 118

anomalies of ductus arteriosus, 118 anomalies of pulmonary veins, 115, 116t aortopulmonary septal defect, 119 associated anomalies, 90 associated with laterality defect, 94 atrial septal defects, 112, 113t atrioventricular septal defects, 101, 102t cause of, 90 as cause of death, 90 chromosomal causes of, 90, 100 coarctation of aorta, 108, 133, 134t conotruncal defects, 97, 99t coronary arteries, anomalies of, 119 detection of, 90 diagnosis of, 90 ductus arteriosus, anomalies of, 118 epidemiology of, 88 frequency of, 88 gender differences, 90 heterotaxy, 93 hypoplastic left heart, 107 interrupted aortic arch, 100, 108, 121, 122t outflow tract anomalies, 88 pericardium, anomalies of, 120 prenatal diagnosis of, 90 prevalence of, 89 prevention of, 90 pulmonic stenosis, 104, 105t pulmonary veins, anomalies of, 115, 116t recurrence rate, 90 septal defects atrial, 112 ventricular, 114 single ventricle, 95 systemic venous connections, abnormal, 118 teratogenic causes of, 90 ventricular outflow tract obstruction defects left, 107, 109t right, 103 ventricular septal defects, 114, 115t Caroli disease, 1131, 1134 Carpal coalition, 859 syndromes with, 858t Carpal partition, 877 Carpenter syndrome, 224, 956 Carpotarsal osteolysis, 916, 917, 1020 Cartilage, disorganized development of, 1019 disorders with, 1019 Cartilage hair hypoplasia, 1005 Cartilaginous exostoses, 1020 Cartilaginous models, 836 Cataracts anterior polar, 316 classification of, 315 congenital, 316, 316t

1479 developmental, 317, 317t lamellar, 318 nuclear, 316 posterior lentiglobus, 318 zonular, 318 Caudal dysgenesis, 829 Caudal fold failure, 1024 Caudal regression, 49, 757, 829 teratogenic causes of, 49 Cavernous hemangiomas, 1322 syndromes with, 1327 Cavum septum pellucidum, 604 syndromes with, 606t Cavum vergae, 604 Cebocephaly, 528 Cementum dysplasia, 463 Cenani-Lenz syndrome, 962 Centers for Disease Control Modification of ICD codes, 13 Central limb deficiency, 840 Central nervous system, 469 cysts of, 604, 645, 677, 689, 697, 698 development of, 469 malformations of, 470 Central polydactyly, 948 syndromes with, 943 Centromere separation, 22 Centromeric division, premature, 22 Cephalhematoma, 262 Cephalic fold failure, 1024 Cephalocele, 715, 720, 742 location of, 720 prognosis of, 742 Cerebellum, anomalies of, 654 agenesis, 654, 667 aplasia, 668 atrophy, 655 Dandy-Walker malformation, 677 development of, 670 diagnosis of, 655 dysplasia of, 668 etiology, 670 hypertrophy, 668 hypoplasia, 654, 668 syndromes with, 70t, 657t prognosis, 671 syndromes with, 70t, 657t vermis aplasia of, 666 Cerebral cortex, morphogenesis of, 546 Cerebrocostomandibular syndrome, 290, 477, 816 Cerebro-oculo-facio-skeletal syndrome, 290, 477 Cerebro-renal-digital disorders, 1174, 1175t Cervical aortic arch, 125 Cervical atresia, 1297 Cervical clefts, midline, 1310 Cervical rib, 813 Cervicoaural fistula, 1069 Cervix, atresia of, 1297 hypoplasia of, 1297 Chalasia, 1080

1480 CHARGE syndrome, 658, 1186, 1257, 1356 Chediak-Higashi syndrome, 1330 Chemical influences, prenatal, 40 Cherubism, 1020 Chiari malformations, 700 clinical outcomes of treatment, 709 pathogenesis, 708 postoperative complications, 709 prognosis, 708 syndromes with, 706t treatment, 708 types, 701 CHILD syndrome, 1313, 1370 Chlamydia infection and pregnancy, 38 Chlorobiphenyls, prenatal exposure to, 48 Choanal atresia of nose, 377 syndromes with, 377 Choanal stenosis of nose, 377 syndromes with, 377 Choledochal cysts, 1145 Cholesteatoma, congenital, 364 Chondrodysplasia punctata, 828, 1004 Chondroma of tongue, 417 Chondroosseous dysplasias (see Skeletal dysplasias) Chorionic villus sampling, 59 Choristoma, 414, 146 epibulbar, 306 of tongue, 414, 416, 417 Choroid plexus cysts, 698 Chromosome aberrations 22q11 deletion, 100 aneuploidies, 17 breakage, 22 centromere separation, 22 deletions, 16, 18 duplications, 16, 18 and endocrine disorders, 1358 fragile sites, 21 fragile X syndrome, 21 heterodisomy, 22 inversions, 19 isochromosomes, 20 isodisomy, 22 microdeletions, 19 monosomies, 17 mosaicism, 17 numerical abnormalities, 17 paracentric inversions, 20 pericentric inversions, 19 premature centromeric division, 20 prevalence of, 15, 17 ring chromosome, 18 structural, 18 translocations, 18 trisomies, 17 uniparental disomy, 22 Chromosome analysis, 68 indications for, 68 molecular studies, 69 Chylothorax, 157

Subject Index Chylous ascites, 157 Chylous diseases, 157 Cigarette smoking, maternal, 41 Ciliary apparatus, abnormalities in, 189 Classification of malformations, 13 by cause, 13 by morphologic alteration, 13 by regional anatomy, 13 by system, 13 Clavicle abnormal shape of, 807, 808t anomalies of, 807 syndromes with, 808 aplasia of, 806 conditions with, 806t hypoplasia of, 806 conditions with, 806t pseudoarthrosis of, 807 Clefts branchial, 1069, 1070t facial, 278, 280t, 392 pathogenesis of, 393 lips, 393 genes causing, 395 median, 393, 394t prevalence of, 397 syndromes with, 396t midline cervical (vertebral), 1312 midline facial, 278 palate, 392, 400 appearance, 400 genes causing, 402 prenatal diagnosis, 400 syndromes with, 401t skin, 1309 sternum, 810 submucous, 400 tongue, 408 of the vertebrae, 825, 826 Cleidocranial dysplasia, 276, 806, 1015 Clitoris, 1300 agenesis of, 1302 duplication of, 1302 enlargement of, 1301 hypertrophy of, 1301 Clitoromegaly, 1301 syndromes with, 1302t Cloacal exstrophy, 1046 etiology of, 1046 and gender assignment, 1048 incidents of, 1047 prognosis, 1048 treatment, 1048 variants, 1046 Closed-lip schizencephaly, 648 Cloverleaf skull configuration, 235 syndromes with, 235t Coalition of bones, 857 Coarctation of aorta, 108, 133 syndromes associated with, 134t Cocaine, prenatal exposure to, 41 Cochlea aplasia of, 367 hypoplasia of, 367 malformations of, 366 Cochleosaccular dysplasia, 368

Coding of malformations, 14 Coffin-Siris syndrome, 971 Coloboma, classification of, 301t eyelid, 306 nostril, 376 uveal, 300, 301t Colon agenesis of, 1099 atresia of, 1099 duplication of, 1103 polyps, 1112 multiple, 1112 Colpocephaly, 636 clinical spectrum of, 637 recurrence, 637 syndromes with, 638t treatment, 639 Comparative genomic hybridization, molecular studies using, 69 Complete labyrinthine aplasia, 366 Complete situs inversus, 185, 1361 Complete syndactyly, 961 Complex, definition of, 9 Conduction system, 88 Congenital, definition of, 10 Conjoined twins, 1396 incidence of congenital malformations, 1400 malformations observed in, 1400 Connectional terms, definition of, 9 Connective tissue, developmental disorders of, 1321, 1326t Conotruncal defects, 97 syndromes associated with, 99t Conoventricular ventricular septal defect, 99 Conradi-Hunermann syndrome, 1313 Constricted ear, 345 Constriction rings, 871 acquired, 873 cause of, 873 entities associated with, 872t, 874t Contiguous gene phenotype, 32 Continuous traits, 6, 32 Contractural arachnodactyly, 931 Contractures, multiple congenital, 788, 926, 927t Cornea, mesodermal dysgenesis of, 311 Corneal anomalies, congenital, 309 Cornea plana, 309 Cornelia de Lange syndrome, 971, 985 Coronal clefts of the vertebrae, 826 syndromes with, 826, 828 Coronary arteries, anomalies of, 119 Coronary sinus, anomalies of, 118 atrial septal defect, 112 Corpus callosum, agenesis of, 70, 581 syndromes with, 70t, 583t Corrected transposition of the great vessels, 94 Cortex, development of, 546 dysplasias of, 572

ectopias, syndromes with, 559 heterotopias, 568 syndromes with, 559 malformations of, 546 transmantle dysplasia of, 546 Corticosteroids, prenatal exposure to, 46 Cor triatriatum, 117 Coxa valga, 833 Coxa vara, 833 conditions with, 834t CPHD, X-linked, 1352 Cranial bones, 221 anomalies of, 221 deformations of, 258 hyperostosis of, 254 sclerosis of, 254, 255t sutures of, 221 thick, 251, 252t thin, 248, 249t Cranial dermal sinus, 242 Cranial sutures, wide, 237t Craniofacial structures, 219 ear, 327 eye, 297 facial bones, 267 lips, 391 nose, 373 skull, 221 teeth, 425 tongue, 405 Craniofrontonasal dysplasia, 276, 807 Craniolacunae, 248 Craniometaphyseal dysplasia, 1019 Craniorhiny, 382 Craniosynostosis, 221 chromosomal anomalies, 227 secondary, 227 syndromes with, 224t, 227t Craniotabes, 249 Cranium (see Skull) Creases, ear lobe, 355 Cretinism, 1345, 1354 muscle hypertrophy in, 787 Crouzon syndrome, 225 Crus of helix, prominent, 350 Cryptophthalmia, 303 Cryptophthalmia syndrome, 304 Cryptophthalmos, 303 Cryptorchidism, 1267 incidence, 1268 prognosis/treatment, 1268 Cryptotia, 338 Cup ear, 344 syndromes with, 345t Cupid’s bow vertebrae, 824 Currarino triad, 830 Cushing syndrome, maternal, 51 Cutaneous markers of spinal cord dysraphism, 1310 Cutaneous structures, 1307 (see also Skin) Cutis aplasia, 1311 Cutis laxa, 1321 Cutis marmorata, 1323 telangiectatica congenital, 1323 CVM, 85

Subject Index CVS, 59 Cyclopia, 302, 528 Cystic adenomatoid malformation, 211 Cystic dilation of renal tubules, 1217 Cystic diseases of the kidney, 1194 Bernstein and Gardner classification, 1195 Potter classification, 1195 Cystic hygroma, fetal, 163 syndromes with, 166t Cystic malformations of brain, 604, 677 syndromes with, 606, 680, 693 Cysts arachnoid, 689, 693t, 766 arachnoid diverticulum, 766 of biliary system, 1145 of brain, 604, 677 branchial cleft, 1069, 1309 bronchogenic, 1309 choledochal, 1145 choroid plexus, 698 dermoid, 418, 757, 765, 1309 enterogenous, 1077 ependymal/glioependymal, 697 epidermoid, 757, 765 extradural, 767 gallbladder, 1146 intestines, 1104 intraspinal, 764 kidneys, 1195 lined with respiratory epithelium, 416 median raphe of penis, 1310 neurenteric, 762 nonneurenteric, 764 pancreatic, 1154 septum pellucidum, 605, 606t skin, 1309 spine, 764 tailgut, 783 thyroglossal duct, 1309 tongue, 414, 416, 418 umbilical cord, 1418, 1419, 1421, 1424 Cytomegalovirus, prenatal infection with, 36 Dandy-Walker malformation, 677 diagnosis, prenatal, 685 embryopathology, 684 intellect, 685 pathogenetic mechanisms, 684 prevalence, 683 prognosis, 684 syndromes with, 680t treatment, 685 Dandy-Walker variant, 677 Darwinian tubercle, 350 Deafness, 357, 369, 370 mouse models for human, 328 nonsyndromic, genes for, 328 syndromic genes, 329 Deciduous teeth, 425 average size of, 447

Decreased fetal movement, 926 Deep vein abnormalities, 139 Deformations, definition of, 7 DeLange syndrome, 479 Delayed closure of fontanels, 238 syndromes with, 239 Deletions, chromosomal, 18 Dens invaginatus, 452 Dental dysplasias, 458, 461, 464 Dental eruption, 425 abnormalities of, 464 Dental hypoplasia, 459 Dental malocclusion, 456 syndromes with, 457 Dentin dysplasia, 461 Dentinogenesis imperfecta, 461 classification of, 462 Dentition, patterning of, 426 Depakene, prenatal exposure to, 42 Dermal melanocytosis, 1332 Dermal sinus, 757 Dermis, 1307 Dermoid cyst, 765, 1309 congenital, 418 of the nose, 388 and primary tethered cord, 757 of the tongue, 418 Deviation of nasal septum, 386 Dextro-transposition of great arteries, 97 Diabetes mellitus, maternal, 49 Diaphragmatic defects, 799 hernia, 214t, 799 Diaphyseal dysplasias, 1010 Diastematomyelia, 773 Diastrophic dysplasia, 931, 1005 Diencephalon, 469 Diethylstilbestrol, prenatal exposure to, 46 DiGeorge syndrome, 99 Digits, anomalies of, 839, 957, 872, 876, 903, 916, 937, 954, 968, 984 Dilacerations, 452 Dilantin, prenatal exposure to, 42 Diphallia, 1264 Diphenylhydantoin, prenatal exposure to, 42 Diplomyelia, 773 Dislocated hip, 830 Dislocation of the patella, 921 Disruptions, definition of, 7 of umbilical cord, 1425 Distal arthrogryposis, 930 Distal symphalangism, 863 Distichiasis, 153, 306 Diverticulum, of bladder, 1232 of the duodenum, 1093 of esophagus, 1078 of stomach, 1085 Dizygotic twins, 1377 Dolichocephaly, 222 syndromes with, 224 Dominant phenotypes, 24 autosomal, 29 expressivity in, 31 genetic heterogeneity of, 30 penetrance of, 31

pleiotropy in, 29 X-linked, 29 Double aortic arch, 125 Double-lumen aortic arch, 126 Double-outlet right ventricle, 98 Double tongue, 412 Drug influences, prenatal, 40 Dubowitz syndrome, 971 Ductal plate malformations, 1131 syndromes with, 1134 Ductus arteriosus, anomalies of, 118, 131t Duodenum, 1089 aganglionic, 1094 anomalies of, 1089 atresia of, 1090 syndromes with, 1091t congenital aganglionic, 1094 diverticula of, 1093 duplication of, 1092 extrinsic vascular obstruction of, 1095 hernia, 1095 malrotation of, 1090 obstruction of, 1095 stenosis of, 1090 syndromes with, 1091t Duplications, chromosomal, 18 Dyggve-Melchior-Clausen dysplasia, 1010t Dyschondrosteosis, 885, 1013t Dysgenesis, callosal, 581 Dysgenesis, mixed gonadal, 1284 Dysgenesis, ovarian, 1282 Dysgenetic kidney, 1205 syndromes with, 1207 Dysmorphology, definition of, 61 Dysosto-dysplasias, 997 Dysostoses, 997 Dysplasia, definition of, 11 with abnormal bone density, 1016t, 1018t acromelic, 1014t acromesomelic, 1013t axial, 1011t Bing-Siebenman, 368 Blomstrand, 1005t campomelic, 885, 1015t, 1274 Camurati-Engelmann, 1019t cleidocranial, 806, 1015t of cochlea, 366 craniometaphyseal, 1019t with decreased bone density 914, 916t, 1016t of dental cementum, 464 of dental enamel, 458 of dentin, 461 diaphyseal, 1010t diastrophic, 1005t with disorganized cartilagenous components, 1019t with disorganized fibrous components, 1019t Dyggve-Melchior-Clausen, 1010t dyssegmental, 1009t endochondral, 1003t epimetaphyseal, 1005t epiphyseal, 1003t

1481 frontometaphyseal, 1011t geleophysic, 1014t Greenberg, 1003t with increased bone density, 1018t Jansen metaphyseal, 1005t of liver, 1131 syndromes with, 1134 membranous bone, 1015t mesomelic, 1013t metaphyseal, 1004t metatropic, 828 microcephalic osteodysplastic, 1011t with osteolysis, 1020t of pancreas, 1154 rhizomelic, 1012t Robinow, 1013t Schmid metaphyseal, 1005t septo-optic, 1257 skeletal, 997 spondyloepimetaphyseal, 1009t spondyloepiphyseal, 1006t spondylometaphyseal, 1009t transmantle, 574 trichorhinophalangeal, 1014t vestibulocochlear, 366 Dysplasia epiphysealis hemimelica, 1019t Dyssegmental dysplasia, 1009t Dystrophy, definition of, 12 asphyxiating thoracic, 939 of muscles, 786 Ear, 327 external, 329 anatomy of, 330 anotia, 331 atresia of auditory canal, 336 syndromes with, 337 crus of the helix, prominent, 350 cryptotia, 338 cup, 345, 345t Darwinian tubercle, 350 deformation of, 356 duplication of auditory meatus, 340 embryogenesis, 327 helix, crus of, 350 large, 338 lobe creases/pits, 355 lobular defects, 350 lop, 345, 345t low-set, 342 microtia, 331 Mozart, 349 otocephaly, 340 pits, 353, 353t polyotia, 339 posteriorly rotated, 344 protruding, 346 prevalence of, 348 syndromes with, 347 reconstruction, 334 size of, 335, 338 small, 335 Stahl, 348

1482 Ear (continued) stenosis of auditory canal, 336 synotia, 340 tags, 351, 353t inner, 327, 366 dysplasias of, 366 classification of, 367 embryogenesis, 327 hearing loss, prelingual, 369 hearing loss syndromes, 370 genes causing, 370 lobe, 350 creases, 355 defects of, 350 pits, 355 middle, 327, 356 aplasia of, 358 cholesteatoma, 364 embryogenesis, 327 fusion defects of, 359 hearing loss, 357 hypoplasia of, 358 incus, malformations of, 361, 362 jugular bulb, highly placed, 365 malformations in animals, 358 malformations of, 358 syndromes with, 360t oval window, absence of, 364 stapedial artery, persistence of, 365 stapes, malformations of, 362, 363 surgical reconstruction of, 358 Ebstein anomaly, 103 Echocardiography, 90 Ectodermal dysplasia, 1333 Ectopia cordis, 1027 and chromosomal aneuploidy, 1027 embryology of, 1027 prognosis, 1028 treatment, 1028 Ectopias of cortical development, 546 syndromes with, 559 Ectrodactyly, 988 Ectropion, congenital, 308 EEC syndrome, 1334 Ehlers-Danlos syndrome, 1321 Elejalde syndrome, 1330, 1373 Electrocardiogram, 90 Ellis-van Creveld syndrome, 939, 1005 Embryonic growth, assessment of, 59 Embryonic staging, 10 Enamel dysplasias, 458 syndromes with, 461t Encephalocele, 720 anomalies associated with, 721 atretic, 721 incidence of, 729 involving the nose, 388 prognosis of, 742

Subject Index syndromes with, 722t, 735t transsphenoidal, 720 Encephaloclastic porencephaly, 647 prognosis with, 648 Encephalocraniocutaneous lipomatosis, 1317 Enchondromatosis, 1020 Endocardial cushion defects, 101 Endocrine features, chromosomal disorders with, 1348, 1348t, 1358 genetic syndromes with, 1347t tumor syndromes with, 1346t Endocrine organs, 1339 adrenal hyperplasia, 1346 Albright hereditary osteodystrophy, 1353 animal models of disorders of, 1345 calcium sensing receptor defects, 1353 chromosomal disorders of, 1358 disorders involving multiple systems, 1344 disorders of, 1340t, 1345t short stature, disorders of, 1349 thyroid defects, 1354 tumor syndromes, 1346, 1346t, 1355 Enteric system, 1097 cysts, 1104 patency of, 1098 rotation of, 1097 Enterogenous cysts of esophagus, 1077 of tongue, 414 Entropion, congenital, 308 Environmental causes of malformations, 33 bacteria, 38 drug/chemical exposure, 40 fungi, 39 hormonal influence, 49 hyperthermia/hypothermia, 35 immunologic influence, 56 infection, 36 isotopes, 35 leptospirosis/Lyme disease, 39 magnetic fields, 35 malaria, 40 mechanical influence, 53 microwaves, 35 nutrient deficiency, 52 prion diseases, 40 protozoa, 40 radiation, 34, 35 radiowaves, 35 shortwaves, 35 teratogens, 33 ultrasound, 35 viruses, 36 Eosinophilic granuloma, 1357 Ependymal cyst, 697 Epiblepharon, 308 Epibulbar choristoma, 306 Epicanthus, 308 Epidermal appendages, 1308 malformations of, 1333

Epidermal atrophy, 1310 Epidermal nevus, 1315 Epidermis, 1307 Epidermoid cyst, 765 and primary tethered cord, 757 of tongue, 416 Epidermolysis bullosa, 1319 gene mutations in, 1325 Epigenetic phenomena, 15 Epiglottis, bifid, 201, 202t Epimetaphyseal dysplasia, 1005 Epiphyseal dysplasia, 1003, 1005 Epispadias, 1261 incidence of, 1262 prognosis, 1262 Epispadias, female, 1302 Eponyms, use of, 10 Esophagus, 1071 achalasia, 1079 anomalies of, 1073 atresia of, 1073 and associated anomalies, 1075 syndromes with, 1075t types of, 1074 chalasia, 1080 cysts, 1077 diverticula, 1078 duplications of, 1077 gastric mucosa in, 1079 rings, 1076 short, congenital, 1079 stenosis of, 1073 webs, 1076 Estrogen, prenatal exposure to, 51 Ethmocephaly, 528 Etiology, definition of, 11 Etretinate, prenatal exposure to, 45 Eventration of the diaphragm, 214 Examination, in postnatal diagnosis, 61 Exomphalos, 1034 Expressivity, 31 Exstrophy of bladder, 1042 Exstrophy of cloaca, 1046 External auditory meatus, 337 duplication of, 340 External ear (see Ear, external) External genitalia, female, 1305 absence of, 1303 duplication of, 1304 hyperplasia of, 1304 hypoplasia of, 1303 syndromes with, 1304 inversion of, 1304 Extradural cyst, 767 Extrahepatic biliary atresia, 1142 association with other anomalies, 1143 pathogenesis of, 1142 Extrahepatic ducts, anomalies of, 1147 Extraocular muscles, agenesis of, 792 Extrophia splanchnica, 1046 Eye, 297 aniridia, 314 anophthalmia, 299

anterior segment dysgenesis of, 311 blepharophimosis, 305 cataracts, congenital, 316 coloboma, 300, 301t corneal anomalies, 309 cryptophthalmos, 303 cyclopia, 302, 528 embryology of, 297 eyelids, anomalies of, 306 fetal vasculature, persistence of, 318 iris, hypoplasia of, 314 malformation syndromes of, 298t microphthalmia, 300 classification of, 301t morning glory disc anomaly, 322 optic nerve, hypoplasia of, 320 optic pit, 324 Peters anomaly, 313 synophthalmia, 302 telecanthus, 306 Eyelid, 306 anomalies of, 306 coloboma of, 306 retraction of, 309 Facial bones, 267 agnathia, 287 anomalies of, 267, 392 asymmetry of, 292 syndromes with, 294t embryology of, 267 interpupillary measurements, 271 metopic sutural synostosis, 268 syndromes with, 269 micrognathia, 288 syndromes with, 290 midface anomalies, 283 syndromes with, 285 midline clefting, 278 orbital hypertelorism, 273 syndromes with, 276 orbital hypotelorism, 270 syndromes with, 273 zygoma, anomalies of, 280 syndromes with, 282 Facial clefting, 278, 280t, 392, 394t, 396t midline, 278 pathogenesis of, 393 Facial muscle deficiency, 791 Facial skeleton (see Facial bones) Facio-auriculo-vertebral spectrum, 294 Fallopian tube, absence of, 1294 False ribs, 812 Familial nephronophthisis, 1215 Familial medullary cystic disease, 1215 Fanconi anemia, 985, 1356 Farabee brachydactyly, 969 Feet, 935 adactyly, 984 syndromes with, 985 anomalies of, 937, 954, 968, 984

Subject Index brachydactyly, 968 classification of, 968 skeletal dysplasias with, 974 syndromes with, 970 embryology of, 935 malformations of, 937, 954, 968, 984 mirror, 949 oligodactyly, 984 syndromes with, 985 polydactyly, 937 classification of, 937, 938 syndromes with, 939 syndactyly, 954 classification of, 937, 954 syndromes with, 956 Female epispadias, 1304 Female genital system, 1279 ambiguous genitalia, 1287 cervix, atresia of, 1297 clitoris, agenesis of, 1300 duplication of, 1302 hypertrophy of, 1301 embryogenesis of, 1279 external genitalia, absence of, 1303 hyperplasia of, 1304 hypoplasia of, 1303, 1304t Fallopian tube, absence of, 1294 fusion, incomplete, 1294, 1296t genes and development, 1280 gonadal dysgenesis, 1284 hermaphroditism, 1286 hymen, imperforate, 1303 labia, fusion of, 1303 longitudinal vaginal septum, 1300 Mu¨llerian aplasia, 1291, 1292t ovarian dysgenesis, 1281 structures, anomalies of, 1294 transverse vaginal septum, 1299 vagina, atresia of, 1298 Femoral deficiencies, 842, 849 hypoplasia-unusual facies syndrome, 843 Femur absent, 842 bifurcation of, 877 deficiency of, 840, 842 hypoplastic, 842, 843, 849 Fetal akinesia deformation sequence, 931 Fetal alcohol syndrome, 41, 474 Fetal brain disruption, 481 Fetal cystic hygroma, 163 syndromes with, 166t Fetal growth, assessment of, 59 Fetal movement, decreased, 926 Fetal period, 11 Fetus amorphus, 1394 Fetus papyraceus, 1387, 1388 Fibrodysplasia ossificans progressiva, 1020t Fibroids, 54 Fibrous dysplasia, 1020t Fibrous hamartoma of infancy, 1318

Fibula, anomalies of, 839 bowing of, 842, 885 deficiency of, 842, 843, 849 Field defect concept, 9 Filum, thickened, 757 FISH, molecular studies using, 69 Fissured tongue, 408 Fistula, 1069 branchial, 1069 Floating ribs, 812 Floppy infant, causes of, 923, 924t Fluconazole, prenatal exposure to, 49 Fluorescence in situ hybridization, 69 Focal cortical dysplasia, 572 Focal dermal hypoplasia, 1313, 1370 Folic acid, 52, 743 food fortification, 52 neural tube defect prevention, 52 other malformation prevention, 52 periconceptional use, 52 Follicular keratosis, 1324, 1324t Fontanels, 221, 238 anomalies of, 238 delayed closure of, 238, 239t extra, 238 of Gerdy, 238 interparietal, 238 large, 239, 239t obeliac, 238 sagittal, 238 small, 238 time of closure, 238 Foramen magnum, anomalies of, 260 Foramen of Monro, aplasia of, 613 Foramina, parietal, 243 syndromes with, 243 Forebrain, 469 Foregut, 1065, 1067, 1071, 1081, 1089 anomalies of, 1068, 1073, 1082, 1090 duplications of, 1077, 1086, 1092 embryogenesis of, 1065 Forelock, white, 1330 Fortification, folic acid, 743 Fourth ventricular roof malformations, 677 Fragile sites, 20 Fragile X syndrome, 21, 515 Fraser syndrome, 1186, 1290 Freeman-Sheldon syndrome, 931 Frontoethmoid cephalocele, 720 Frontometaphyseal dysplasia, 1011t Frontonasal dysplasia, 382 Fryns syndrome, 1260 Fukuyama syndrome, 551 Fungal, prenatal infection and pregnancy, 40 Fused kidneys, 1223, 1228 syndromes with, 1225, 1230 Fused pelvic kidney, 1223 Gallbladder, 1124 agenesis of, 1139

anomalies associated with, 1140 syndromes with, 1141t anomalies of, 1147 cysts of, 1146 development of, 1124 duplication, 1149 positional alterations, 1148 septation, 1148 structural variation, 1147 Gardner syndrome, 1113 Gastric duplication, 1086 Gastric mucosa, ectopic, 1077, 1094, 1112 Gastric musculature, defects of, 1086 Gastrointestinal system, 1065 branchial cleft anomalies, 1069 syndromes with, 1070 duodenum, 1089 anomalies of, 1090 esophagus, 1071 anomalies of, 1073 genes affecting development, 1066 pharynx, 1067 anomalies of, 1068, 1071 stomach, 1081 anomalies of, 1082 Gastroschisis, 1038 associated anomalies, 1039 incidence of, 1040 pathogenesis of, 1040 prenatal diagnosis of, 1040 prognosis of, 1040 treatment of, 1040 GBBB syndrome, 276, 1260 Geleophysic dysplasia, 1014t Gender differences, development of, 89 Gene, 22 as cause of malformations, 25 contiguous phenotypes, 32 dominant phenotypes, 24 germ line mosaicism, 32 mosaicism, 31 mutations, 22, 24 nonsyndromic deafness, 328 number of, 24 polygenic phenotypes, 32 recessive phenotypes, 31 syndromic deafness, 329 X-linked phenotypes, deafness, 328 Genetic counseling, 71 Genetic heterogeneity, 29 Genitalia, abnormal, X-linked, 551 Genitalia, ambiguous, 1287 syndromes with, 1274t, 1290t Genitalia, differentiation, 1252 duct development, 1254 Genital system, female, 1279 (see also Female genital system) Genital system, male, 1253 (see also Male genital system) Genocopy, definition of, 30 Genotype, definition of, 23

1483 Germ line mosaicism, 31 Gigantism, 1374 Gigantomastia, 1053 Glenoid hypoplasia, 809 syndromes with, 810 Glial formation, disorders of, 546 Glioependymal cysts, 697 Glioma of the nose, 388 Globodontia, 452 syndromes with, 453 Glomulovenous malformations, 1325 Glossopalatine ankylosis, 409 Glutaric-aciduria type II, 1134 Gluteal-lower leg anomaly, 796 Goiter, 1343 Gonadal dysgenesis, 1284 incidence of, 1284 prognosis, 1285 risk for gonadoblastoma, 1284 syndromes with, 1285t treatment, 1285 Gonads, disorders of, 1341 female genital system, 1281 male genital system, 1255 Graft-versus-host disease, prenatal, 58 Great arteries, transposition of, 97 Greenberg dysplasia, 1003 Gregor Mendel, 22 Greig cephalopolysyndactyly syndrome, 942 Griscelli syndrome, 1330 Growth anomalies of, 894, 900 asymmetric, 902, 1365 in childhood, 65 curves, 65 excess, syndromes with, 901 excessive, 900, 903 in individuals with skeletal dysplasias, 65 in infancy, 65 of muscle, 785, 786 overgrowth, 1372, 1373t Growth hormone, deficiency, 1350 pathway, 1349 receptor defects, 1350 receptor dysfunction, 1351 receptor releasing hormone, 1350 Growth plate, in skeletal dysplasias, 836 G syndrome, 276, 1260 Gynecomastia, 1059 adolescent, 1059 drugs causing, 1061 enzyme defects, 1060 neoplasms causing, 1060 syndromes with, 1060t Hair, abnormalities of, 1334 Hajdu-Cheney syndrome, 917, 1020t Hallermann-Streiff syndrome, 382 Hamartoma cutaneous, 1315 smooth muscle, 1317 of tongue, 419, 420

1484 Handed asymmetry, 1359 Hands, 935 adactyly, 984 syndromes with, 985 anomalies of, 937, 954, 968, 984 brachydactyly, 968 classification of, 968 skeletal dysplasias with, 974 syndromes with, 970 embryology of, 935 malformations of, 937, 954, 968, 984 mirror, 949 oligodactyly, 984 syndromes with, 985 polydactyly, 937 classification of, 937, 938 syndromes with, 939 syndactyly, 954 classification of, 937, 954 syndromes with, 956 Hand-Schuler-Christian disease, 1357 Harlequin fetus, 1322 Hearing loss, 357 nonsyndromic, 370 prelingual, 369 syndromes, 370t Heart malformations, 85, 121 abnormal systemic venous connections, 118 aortopulmonary septal defect, 119 associated anomalies, 90 associated with laterality defect, 94 atrial septal defects, 112 syndromes with, 113 atrioventricular septal defects, 101 syndromes with, 102 cause of, 90 as cause of death, 90 chromosomal causes of, 90, 100 conotruncal defects, 97 syndromes with, 99 coronary arteries, anomalies of, 119 detection of, 90 diagnosis of, 90 ductus arteriosus, anomalies of, 118 epidemiology of, 88 frequency of, 88 gender differences, 90 heterotaxy, 93 hypoplastic left heart, 107 outflow tract anomalies, 88 pericardium, anomalies of, 120 prenatal diagnosis of, 90 prevalence of, 89 prevention of, 90 pulmonary veins, anomalies of, 116 syndromes with, 117 recurrence rate, 90 septal defects atrial, 112 ventricular, 114

Subject Index single ventricle, 95 systemic venous connections, abnormal, 118 teratogenic causes of, 90 ventricular outflow tract obstruction defects, 103, 107 syndromes with, 109 ventricular septal defects, 114 syndromes with, 115 Hemangiomas congenital, 1327 infantile, 1327 of the nose, 386 syndromes with, 1327 of the tongue, 420 umbilical cord, 1455 Hematoma, umbilical cord, 1436 Hemiatrophy, 1369 syndromes with, 1371t Hemifacial microsomia syndrome, 294, 1370 Hemihyperplasia, 1366 syndromes with, 1367t Hemihypertrophy, 902, 905, 1366 syndromes with, 907t, 1367t Hemihypoplasia, 1369 syndromes with, 1370t Hemimegalencephaly, 512 Heminasal aplasia, 374 Hemivertebrae, 819 Hemochromatosis, 1357 Hepatic cystic dysplasia, 1131 Hepatic fibrosis, 1132 Hepatic lobation, anomalies of, 1127 Hepatic lymphangioma, 176 Hepatic shape, anomalies of, 1127 Hereditary hemorrhage telangiectasia, 141 Hereditary neurocutaneous vascular malformation, 141 Hermaphroditism, 1286 Hernia diaphragmatic, 214, 214t inguinal, 1277 incidence of, 1278 treatment, 1278 umbilical, 1031, 1033t umbilical cord, 1437 Herpes gestationis, 51 Herpesvirus, 36 HESX1 mutations, 1351 Heterodisomy, 22 Heterogeneity, genetic, 30 Heterotaxy, 93 Heterotopias of cortical development, 568 bilateral periventricular nodular, 569 diagnosis, 569 marginal glioneuronal, 570 nodular, 569 prevalence, 570 prognosis, 571 seizures, 569 syndromes with, 559

Heterotopic gastric mucosa, 1079 Heterotopic pancreas, 1157 Hindbrain, 469 Hip, developmental dysplasia of, 830 Hip, dislocation of, 830 Hirschsprung disease, 1106 Histiocytosis X, 1357 Holmes heart, 96 Holoanencephaly, 716 Holoprosencephaly, 381, 528 and absence of corpus callosum, 537 and agnathia, 287, 340 alobar, 528, 536 causes of, 539 conditions with, 70t, 381t, 531t cortical thickness in, 536 definition of, 528 developmental delay and, 542 diabetes insipidus in, 541 embryogenesis of, 540 facial abnormalities with, 528 feeding difficulties in, 542 lobar, 528, 536 MRI/CT in, 537 neural tube defects and, 539 non-facial malformations and, 541 pathogenesis of, 540 pituitary dysfunction in, 537 prenatal diagnosis of, 537 prevalence of, 538 prognosis of, 541 semilobar, 528, 536 syndromes with, 70t, 381t, 531t temperature instability in, 541 twinning and, 539 Holt-Oram syndrome, 985 Hormonal influences, prenatal, 49 Horseshoe kidney, 1228 associated anomalies, 1229 prevalence, 1229 prognosis, 1229 syndromes with, 1230 Human immunodeficiency virus, 38 Humeroradial synostosis, 864 Humerus bifurcation of, 877 deficiency of, 840, 842t Hydranencephaly, 639 congenital rhabdoid tumor, 643 prenatal infections, 643 prognosis, 643 syndromes with, 641t unilateral, 640 vascular disruptive pathogenesis, 640 Hydrocephalus, 610, 719 animal models of, 626 causes of, 611 classification of, 610 clinical signs in, 612 definition of, 610 neuroimaging in, 612 prevalence of, 624 prognosis in, 626

secondary, 611 skeletal dysplasias with, 625 syndromes with, 614t treatment of, 626 ultrasonography of, 612 venous congestion, 611 Hydrolethalus, 587 Hydromyelia, 768 Hydrops fetalis, 56 metabolic causes of, 69t 11b-Hydroxylase deficiency, 1289 17a-Hydroxylase deficiency, 1289 21-Hydroxylase deficiency, 1289 3b-Hydroxysteroid dehydrogenase deficiency, 1289 Hyperekplexia, 787 Hyperextensible skin, 1321 Hyperkeratosis, 1319 Hypermobile joints, 922 conditions with, 925t Hypermobility syndrome, benign, 923 Hyperostosis of the skull, 254, 910 syndromes with, 255, 912 Hyperparathyroidism, maternal, 51 Hyperphalangy, 877 Hyperphenylalaninemia, maternal, 487 Hyperpigmentation, cutaneous, 1331 Hyperplasia, congenital adrenal, 1289 Hyperplasia, definition of, 11 Hypertelorism, 273 ocular, 273 orbital, 273, 306 syndromes with, 276 Hypertelorism-hypospadias syndrome, 276t Hyperthermia, 35 Hypertrophy, 1359 (see also Asymmetry) Hyperthyroidism, maternal, 49 Hyperthyroxinemia, syndromes with, 1343 Hypertrichosis, 1335, 1335t Hypertrophia musculorum vera, 786 Hypertrophic pyloric stenosis, 1082 Hypertrophy, definition of, 12 Hypochondrogenesis, 1006 Hypochondroplasia, 1005 Hypodontia, 431 syndromes with, 432, 433 Hypogenesis, callosal, 581 Hypoglossia, 406 Hypohidrotic ectodermal dysplasia, 1333 Hypomastia, 1051 syndromes with, 1052 Hypomelanosis of Ito, 484 Hypomelanotic macule, 1331 Hypoparathyroidism, maternal, 51 Hypophosphatemic rickets, 1017t Hypopigmentation, 1329

Subject Index Hypoplasia, definition of, 11 Hypospadias, 1258 incidence of, 1260 syndromes with, 1260t treatment of, 1260 Hypotelorism, 270 and holoprosencephaly, 530 orbital, 270 syndromes with, 272t Hypothalamus, disorders of, 1340, 1349 Hypothermia during pregnancy, 35 Hypothyroidism maternal, 49 and muscle hypertrophy, 787 Hypotonia, conditions with, 924 Hypotrichosis, 1335, 1335t Hypotrophy, definition of, 12 Ichthyoses, 1319 classification of, 1323 disorders with, 1322 Ichthyosiform dermatoses, 1322 Ileal atresia, 1099 Iliac horn, 831 Iliac vein compression, 139 Ilium, anomalies of, 831 Imaging, 66, 69 Immotile cilia syndrome, 189 Immunologic influences, prenatal, 56 Imperforate anus, 1118 Imperforate hymen, 1303 Imprinting, 15 Inactivation, chromosome, 15 Inborn errors of metabolism, 70 with brain malformations, 70 and dysmorphic features, 71 and malformations, 71 Incomplete Mu¨llerian fusion, 1294 syndromes with, 1296 Incomplete partition dysplasia of inner ear, 367 Incontinentia pigmenti, 1312, 1371 Increased bone density, 910 syndromes with, 912 Incudostapedial disconnection, 362 Incus, 361 aplasia of, 361 fusion defects of, 362 hypoplasia of, 361 malformations of, 361 Infantile cataracts, 317 Infantile hypertrophic pyloric stenosis, 1082 Infantile polycystic kidney disease, 1198 Inferior rectus muscle, agenesis of, 792 Inferior vena cava, absence of, 138 bilateral, 118 double, 137 interrupted, 118 with azygous continuation, 137 left, 137 variants, 137 Influenza, prenatal exposure to, 37 Ingestional dysplasia of enamel, 459

Inguinal hernia, 1277 incidence of, 1278 treatment, 1278 Iniencephaly, 715, 718 prognosis in, 738 Inlet defects, of ventricle, 114 Inner canthal measurement, 271 Inner ear (see Ear, inner) Innominate artery, 128 Intercalary limb deficiency, 840 syndromes with, 842 Internal auditory meatus, anomalies of, 368 International Classification of Diseases Codes, 13 Interparietal fontanel, 238 Interpupillary measurement, 271 Interrupted aortic arch, 121 syndromes with 122t type A, 108 type B, 100 Intestines, 1097 agenesis of, 1099 atresia of, 1099 apple peel, 1099 etiology, 1100 location of, 1102 prognosis, 1100 syndromes with, 1102t treatment, 1100 cysts, 1104 duplications, 1104 large, 1097 lymphangiectasia, 155 malrotation, 1109 conditions with, 1110t Meckel diverticulum, 1111 megacolon, 1105 conditions with, 1107t polyps, 1111 syndromes with, 1113t small, 1097 stenosis, 1099 vascular anomalies, 1115 Intracranial arteriovenous malformation, 141 Intrahepatic biliary ducts, 1136 atresia, 1136 hypoplasia, 1136 paucity of, 1136 Intraspinal neurenteric cyst, 762, 764 Inversions, chromosomal, 19, 20 Iodides, prenatal exposure to, 47 Iodine deficiency and pregnancy, 53 Iris, hypoplasia of, 314 mesodermal dysgenesis of, 311 Iris dental dysplasia, 1357 Iron deficiency and pregnancy, 53 Ischium, anomalies of, 832 Isochromosomes, 20 Isodisomy, 22 Isoimmunization, prenatal, 56 ABO, 57 platelet, 57 Rh, 56 Isolated subclavian arteries, 130

Isomerism, 185 Isotopes, prenatal exposure to, 35 Isotretinoin, prenatal exposure to, 45 Ives microcephaly-micromelia, 485 Jackson-Weiss syndrome, 225 Jansen metaphyseal dysplasia, 1005 Jejunal atresia, 1099 Jeune syndrome, 939 Johanson-Blizzard syndrome, 384, 1347 Joint contractures, multiple, 926 syndromes with, 927 Joint hypermobility, 922 conditions with, 925 Jugular bulb, highly placed, 365 Jugular lymphatic obstruction sequence, 164 Juvenile polyps, 1112 Kabuki syndrome, 485 Kallmann syndrome, 1187, 1257 Kartagener syndrome, 1363 frequency of, 1364 gene loci for, 1364 prognosis of, 1365 signs and symptoms in, 1364 Kasabach-Merritt syndrome, 1328 Keratinization, disorders of, 1319 and gene mutations, 1320 Keratoderma, 1319 palmar plantar, 1324 Keratosis, follicular, 1324 Kidney cystic diseases of, 1134, 1194, 1215, 1219 dysgenetic, 1205 syndromes with, 1207 dysplastic, 1205 embryogenesis of, 1161 fused, 1223, 1228 horseshoe, 1228 associated anomalies, 1229 prevalence, 1229 prognosis, 1229 syndromes with, 1230t hypoplastic, 1190 sponge, medullary, 1217 supernumerary, 1222 Killian/Teschler-Nicola syndrome, 276 Kleeblattscha¨del, 235 syndromes with, 236t Klinefelter syndrome, 1358 Klippel-Feil anomaly, 821 Klippel-Trenaunay syndrome, 1327 Klippel-Trenaunay-Weber syndrome, 140 Kniest dysplasia, 1006 Knots, umbilical cord, 1441 Kocher-Debre´-Se´me´laigne syndrome, 787 Kok syndrome, 787 Labia minora, fusion of, 1287, 1303 Laboratory testing and malformations, 66

1485 biochemical, 68 chromosomal, 68, 69 FISH, 69 molecular, 69 Labyrinthine aplasia, 366 Lamellar cataracts, 318 Lamellar ichthyoses, 1322 Large intestine, 1097 (see Intestines) Laron dwarfism, 1251 Larsen syndrome, 1012 Laryngeal abnormalities, 202 syndromes associated with, 204 Laryngotracheoesophageal cleft, 205 Larynx, 202 anomalies of , 202, 204t atresia of, 202 stenosis of, 202 web, 203 Lateral fold failure, 1024 Laterality defects, 93, 190, 190t, 1361 cardiovascular malformations associated with, 93 chromosome abnormalities in, 95, 190 clinical features in, 93, 1362 etiology/distribution of, 94 evaluation of, 94 gene mutations in, 94 malformations associated with, 94 prevalence of, 94 prognosis, treatment, prevention, 95 Lateral rectus muscle, agenesis of, 792 Laurence-Moon syndrome, 1257 Lax skin, 1321, 1326 Left heart syndrome, hypoplastic, 107 Left renal vein compression, 138 Left-sidedness, 1361 bilateral, 185 Left subclavian artery, 124, 130 Left superior vena cava, persistent, 136 Left ventricular outflow tract obstructive defects, 106, 109t Lemon sign, 719 Lentigines, 1331 syndromes with, 1331 Lentiglobus, posterior, 318 Lenz microphthalmia, 486, 1187 Leprechaunism, 486 Leptospirosis, 39 Letterer-Siwe disease, 1357 Limb-body wall complex, 852 Limb deficiency, 839, 984, 991 associated anomalies, 849 causes of, 842 intercalary, 840, 842t longitudinal, 840, 843t prevalence of, 853 terminal, 840 transverse, 840, 852t treatment of, 849 vascular basis for, 846

1486 Limb-mammary syndrome, 985 Limb overgrowth, 902 asymmetric, 905 segmental, 906 syndromes with, 902t, 905t Limb reduction defects, incidence of, 853 Limbs, 835 accessory, 876 anomalies of, 839, 857, 872, 876, 882, 894, 900, 903, 910, 914, 916, 920, 923, 926, 937, 954, 968, 984 arthrogryposis, 925 differential diagnosis, 927 bone density, 910, 914 conditions with decreased, 915, 916 conditions with increased, 912, 913 bowing of, 882 syndromes with, 884, 890 constriction rings, 871 syndromes with, 872 deficiencies of, 839, 984, 991 duplications, 876, 880 embryology of, 835 excessive partition of, 876 hypermobile joints, 922 causes of, 923 conditions with, 925 hypertrophy of, 903 molecular embryology of, 837 osteolysis, 916 syndromes with, 917 overgrowth, 902 syndromes with, 905 patella, anomalies of, 919 conditions with, 920, 921 rays of, 835, 840, 988 segments of, 836, 840 short stature, 894 major types of, 895 syndromes with, 898 synostosis, 856 syndromes with, 859 tall stature, 900 syndromes with, 901 and thalidomide, 44, 846 Lines of Blaschko, 1312 Lingual frenulum, absence of, 406 Lingual pigmentations, 324 Lingual thyroid, 413 Lingua plicata, 408 Lipomas, 757 Lipomyelocele, 757, 758 Lipomyeloschisis, 757 Lips, 391 cleft, 392, 393, 394 genes causing, 395 prevalence of, 397 syndromes with, 394t, 396t embryogenesis of, 391 pits, 1310 Lissencephaly, 547, 551 with ambiguous genitalia, X-linked, 1290

Subject Index ARX and, 555 Doublecortin (DCX) and, 553 LIS1 and, 550 prognosis in, 556 RELN and, 554 syndromes with, 70t, 71t, 551t Lithium, prenatal exposure to, 47 Liver, 1123 accessory lobe, 1129 anomalies of, 1127 development of, 1123 dysplasias of, 1131 syndromes with, 1134t ectopic, 1129 hypoplasia, 1128 left lobe, absence of, 1128 malposition, 1129 right lobe, absence of, 1128 Lobar emphysema, 213 Lobar holoprosencephaly, 528, 536 Lobule of the ear, 327, 330 creases in, 355 defects of, 350 pits in, 355 London Dysmorphology Database, 14 Long bones, 835 bowing of, 882 etiology of, 888 prognosis, 890 syndromes with, 884t, 890t treatment, 890 deficiency of, 839, 984, 991 duplications of, 876, 880 dysplasias affecting, synostosis of, 856, 861t Longitudinal limb deficiency, 839, 840 of middle segment, 843 syndromes with, 843 Long umbilical cord, 1431 Looping defects, 87 Loops, umbilical cord, 1443 Loose skin, 1321, 1326 Lop ear, 344 syndromes with, 345t Lower limbs, duplication of, 880 Lower respiratory organs, 201 bifid epiglottis, 201 cystic adenomatoid malformation, 211 diaphragmatic hernia, 214 syndromes with, 215 laryngeal anomalies, 202 syndromes with, 204 laryngotracheoesophageal cleft, 205 lobar emphysema, 213 pulmonary agenesis/aplasia, 209 syndromes with, 210 pulmonary hypoplasia, 213 tracheal agenesis, 206 tracheal cartilaginous sleeve, 209 tracheal stenosis, 207 patterns of malformations, 208 tracheoesophageal fistula, 209 Low-set ears, 342

LSD, prenatal exposure to, 42 Lu¨ckenscha¨del, 248 Lujan marfanoid syndrome, 516 Lungs, 209 agenesis of, 209 syndromes with, 210 aplasia of, 209 syndromes with, 210 anomalies of, 209 development of, 211 hypoplasia of, 213 lymphangiectasia, 161 pulmonary artery, absent, 104 stenosis of, 104 syndromes with, 104 Lupus erythematosus, maternal, 57 Lyme disease and pregnancy, 39 Lymphangiectasia, 155, 159 cystic renal, 156 intestinal, 155 pulmonary, 161 Lymphangioleiomyomatosis, 180 Lymphangioma, 159, 169 of abdomen, 175 of anterior neck, 174 of bone, 177 capillary, 170 cavernous, 170 cystic, 170 of eye, 172 of genitalia, 176 of kidney, 176 of larynx, 173 of lung, 175 of neck, 174 of oral cavity, 173 of pharynx, 173 of salivary gland, 173 of skin, 178 of spleen, 176 of thorax, 175 of tongue, 419 treatment of, 172 Lymphangiomatosis, systemic, 177 Lymphangiosarcoma, 154 Lymphatic anomalies, 145 categories of, 147 Lymphatic dysplasia, generalized, 158 syndromes with, 153t Lymphatic malformations, 146, 1326 Lymphatic system, 145 anomalies of, 146 dysplasia of, syndromes with, 146, 153t embryogenesis of, 145 fetal cystic hygroma, 163 syndromes with, 166 hyperplasia of, 147 hypoplasia of, 147 lymphangioleiomyomatosis, 180 lymphangioma, 169 pulmonary lymphangiectasia, 161 Lymphedema, 148, 1326 animal models of, 151

and cerebral arteriovenous anomaly, 141 syndromes with, 153t treatment of, 154 Lymph nodes, anomalies of, 147 Lysergic acid diethylamide, prenatal exposure to, 42 Macrocephaly, 511 syndromes with, 513t Macrodactyly, 903 entities with, 906t Macrodontia, 451 syndromes with, 452t Macroglossia, 407 causes of, 407 classification of, 407 Macrosomia, 1372 syndromes with, 902t, 1373 Macrotia, 338 prevalence of, 338 syndromes with, 339t Maffucci syndrome, 140, 1367 Magnetic fields and pregnancy, 35 Magnetic resonance imaging and pregnancy, 69 Malar bones, hypoplasia of, 280 Malaria infection and pregnancy, 40 Male genital system, 1251 cryptorchidism, 1267 embryogenesis of, 1251 epispadias, 1261 genes and development of, 1253 genital duct development, 1254 hypospadias, 1258 syndromes with, 1260 inguinal hernia, 1277 megalourethra, 1263 micropenis, 1255 Mu¨llerian ducts, persistent, 1276 penis, malformations of, 1262, 1264, 1265 penoscrotal development, 1252 pseudohermaphroditism, 1272 scrotum, anomalies of, 1267 splenogonadal fusion, 1277 testes development of, 1251 malformations of, 1268, 1271 Wolffian duct malformations, 1276 Male pseudohermaphroditism, 1272 Malformations of anus, 1115 arteriovenous, 141, 1326 brain, 469, 715 capillary, 142, 1323 of cardiorespiratory organs, 83 of cardiovascular system, 85 causes of, 14 chance, role for, 58 chromosome aberrations and, 14 classification of, 13 coding of, 14 concurrence of minor and major, 7, 8

Subject Index connectional terms, 9 continuous traits, 33 of craniofacial structures, 219 of cranium, 221 of cutaneous structures, 1307 detection of, 58 disclosure of, 71 of duodenum, 1089 of ear, 327 of endocrine organs, 1339 environmental causes of, 33 of esophagus, 1071 evaluation of, 3, 58 of external ear, 329 of eye, 297 of facial bones, 267 of feet, 935 of female genital system, 1279 of gallbladder, 1123 gastrointestinal, 1021 gene loci of, 25 gene mutations and, 22 genes that cause, 25 genetic causes of, 14 of genital system, female, 1279 of genital system, male, 1251 glomulovenous, 1325 of hands, 935 heart, 85 incidence of, 33 of inner ear, 366 of intestines, 1097 of limbs, 835 of lips, 391 of liver, 1123 of lower respiratory organs, 201 lymphatic, 145 major, 5, 7 of male genital system, 1251 management of, 58 of middle ear, 356 minor, 5, 7, 8 multifactorial causation of, 33 of muscle, 783 naming of, 10 of neuromuscular system, 467 in newborn infants, 3 nomenclature, 6, 12 of nose, 373 of pancreas, 1123 of pectoral girdle, 805 of pelvic girdle, 805 of pharynx, 1067 postnatal diagnosis of, 60 prenatal diagnosis of, 58 prevalence of, 3, 4, 5, 7, 8 of rectum, 1115 of ribs, 805 role for chance in, 58 of skeletal system, 803, 997 of skin, 1307 of skull, 221 of spine, 715, 757, 805 of spinal cord, 715, 757 of spleen, 183 in stillbirths, 3 of stomach, 1081 of teeth, 425

as of in of of

threshold traits, 33 tongue, 405 twins, 1377 umbilical cord, 1413 upper gastrointestinal system, 1065 of urinary tract, 1161 of urogenital system, 1157 vascular, 140, 1322 of vasculature, systemic, 121 venous, 140, 1324 of ventral wall, 1023 Malformation syndromes, 25 gene loci of, 25 genes that cause, 25 growth in individuals with, 65 Malignancy predisposition, 1375 Malleus, 358 aplasia of, 358 fusion defects of, 359 hypoplasia of, 358 malformations of, 358 Malocclusion, 456 syndromes with, 457t Malposition of the stomach, 1087 syndromes with, 1088 Malrotation of duodenum, 1090 Malrotation of intestine, 1109 conditions with, 1110t Mammary gland, development of, 1049 Marble bone disease, 910, 913 Marfan syndrome, 1321 Marijuana, prenatal exposure to, 41 Marshall-Smith syndrome, 1373 MASA (X-linked hydrocephaly spectrum) syndrome, 588, 619 Maternal hyperphenylalaninemia, 487 Maternal serum screening, 58 Mayer-Rokitansky-Kuster-Hauser syndrome, 1292 McCune-Albright syndrome, 1018, 1367 McKusick-Kaufman syndrome, 939 Measurements methods of, 65 standards of, 61 Meatal atresia, syndromes with, 337t Mechanical influences, prenatal, 53 Meckel diverticulum, 1111 Meckel-Gruber syndrome, 726, 939 Meckel syndrome, 1134 Median cleft lip, 393 Median raphe cyst of penis, 1310 Median rhomboid glossitis, 411 Mediastinal cysts of foregut, 1077 Medullary cystic kidney disease, 1215 prognosis of, 1216 symptoms of, 1215 Medullary sponge kidney, 1217 incidence of, 1218 prognosis of, 1218 Mega cisterna magna, 677 Megacolon, 1105 aganglionic, 1106

conditions with, 1107t psychogenic, 1108 Megacystis, 1146 Megacystis-microcolon-intestinal hypoperistalsis syndrome, 1093 Megaduodenum, 1094 Megalencephaly, 511 among children with autism, 512 and associated manifestations, 512 benign, 512 causes of, 520 definition of, 511 diagnosis of, 511 hemimegalencephaly, 512 prevalence of, 520 prognosis in, 520 syndromes with, 513 treatment of, 521 unilateral, 512 Megalocornea, 310 Megalourethra, 1263 Megalymphatics, 147 Melanocytes, 1307 Melanocytic nevi, 1332 Melanocytosis, dermal, 1332 Melnick-Needles syndrome, 1010 Membranous bone dysplasias, 1015t Membranous ventricular septal defect, 114 Mendel, 22 Meningocele, 715, 719, 778 anterior, 778 syndromes with, 780t and associated malformations, 779 lateral, 778 syndromes with, 780t in Marfan syndrome, 780 in neurofibromatosis, 780 syndromes with, 780t treatment of, 781 Meningomyelocele, 715 Mercury, prenatal exposure to, 47 Mermaid malformation, 866 Meroanencephaly, 717 Meromelia, 840 syndromes with, 842t, 843t, 852t Mesencephalon, 469 Mesenchymoma, of tongue, 420 Mesoaxial polydactyly, 948 syndromes with, 943 Mesodermal dysgenesis of cornea/ iris, 311 Mesomelic bowing, syndromes with, 890 Mesomelic dysplasias, 1013t Metabolic disorders, 68 Metabolism, inborn errors of, 70, 71 with brain malformations, 70 with malformations/dysmorphic features, 71 Metabolism, water, 1343, 1354 Metacarpal segmentation, 877 Metacarpophalangeal synostosis, 859

1487 Metaphyseal dysplasias, 1004 Metatarsophalangeal synostosis, 859 Metatropic dysplasia, 828, 1009 Methotrexate, prenatal exposure to, 43 Metopic sutural synostosis, 268 syndromes with, 228t, 269t Michel dysplasia, 366 Micrencephaly, 470 Microarrays, molecular studies using, 69 Microblepharon, 308 Microcephalic osteodysplastic dysplasia, 1011t Microcephaly, 470 autosomal dominant, 473 autosomal recessive, 473 causes of, 473 classification of, 472 definition, 470 degenerative conditions and, 497 developmental delay and, 499 diagnosis of, 470 disruptive causes, 497 etiology of, 472 and holoprosencephaly, 530 oligogyric, 471 prenatal detection of, 499 prevalence of, 498 prognosis of, 498 simplified gyral pattern in, 471 spastic diplegia in, 473 syndromes with, 474t teratogenic causes of, 498 timing of onset of, 472 Microcornea, 310 Microdeletions, chromosomal, 19 Microdontia, 446 syndromes with, 448t Microgastria, 1084 Microglossia, 406 Micrognathia, 288 syndromes with, 290t Microorchia, 1268 Micropenis, 1255 prognosis, 1257 syndromes with, 1257 treatment, 1257 Microphthalmia, 300 classification of, 301t Microtia, 331 and associated defects, 332 classification of, 331 etiology of, 332 prevalence of, 332 syndromes with, 333t Microwaves, prenatal exposure to, 35 MIDAS syndrome, 1313 Midbrain, 469 Middle ear (see Ear, middle) Midface hypoplasia, 283 syndromes with, 285t Midface retrusion, 283 syndromes with, 285t Midline cervical clefts, 1310

1488 Midline facial clefts, 278 syndromes with, 280 Miller-Dieker syndrome, 551 Miller syndrome, 282 Milroy disease, 151, 154 Mineral metabolism, disorders of, 1342, 1353 Mirror feet, 949 Mirror hands, 949 Misoprostol, prenatal exposure to, 43 Mitral valve atresia, 107 Mitral valve stenosis, 107 Mixed type hamartoma of tongue, 420 MLS syndrome, 1313 Mobility of tongue, 421 Mo¨bius syndrome, 794 Molar tooth sign, 656 Molecular testing and malformations, 69 Mondini-Alexander dysplasia, 367 Monosomies, chromosomal, 17 Monozygotic twins, 1378 Monster, 12 Monstrosity, 12 Morgagni hernia, 214 Morning glory disc anomaly, 322 Morquio (MPS IV) syndrome, 820 Mosaicism, chromosomal, 17, 31 cutaneous, 1312 pigment, 1330 X-chromosome disorders, 1313 Mouse models (see also Animal models) for abdominal wall defects, 1024 for absence of zygoma, 281 for agenesis of corpus callosum, 596 for anal development, 1115 for aprosencephaly, 527 for Arnold-Chiari malformation, 707 for asymmetry, 1359 for cardiovascular system, 85 for cerebellar anomalies, 670 for cortical development, 546 for dental patterning, 426 for ear malformations, 328 for female genital system, 1280 for fetal cystic hygroma, 167 for gastrointestinal system, 1065 for heart development, 85 for holoprosencephaly, 540 for human deafness, 328 for hydrocephalus, 626 for laterality defects, 1359 for limb anomalies, 881 for limb deficiencies, 842 for limb development, 936 for lissencephaly, 550, 554, 555 liver, malposition, 1130 for midline facial clefting, 279 for neural tube defects, 733, 734 for neuronal heterotopia, 571 for neuronal migration, 547, 550 for oligodactyly, 991 for omphalocele, 1035

Subject Index for for for for for for for for for

polyasplenia, 189 rectal development, 1115 situs inversus, 189, 1361 spleen, 183 split hand/split foot, 991 tooth agenesis, 321 twins, 1382 urethral obstruction, 1238 ventral wall of the trunk defects, 1024 Movements, of tongue, 421 Mozart ear, 349 Mucoid degeneration of Wharton’s jelly, 1424 Mucolipidosis, 253, 1007 Mucopolysaccharidosis, 253, 1007 Mucosal heterotopia of stomach, 1088 Muenke syndrome, 225 Mu¨llerian aplasia, 1291 syndromes with, 1292t Mu¨llerian ducts, persistent, 1276 Mu¨llerian fusion, incomplete, 1294 syndromes with, 1296t Mu¨llerian structures, isolated anomalies of, 1294t Multicentric osteolysis, 917 Multicystic dysplastic kidney, 1205 syndromes with, 1207 Multicystic kidney, 1205 syndromes with, 1207 Multifactorial causation, 32 characteristics of, 33 Multiple cartilaginous exostoses, 1018 Multiple congenital contractures, 925 causes of, 926 disorders with, 927 Multiple epiphyseal dysplasia, 1003, 1005 Multiple pterygium syndrome, 930 Mumps, prenatal infection with, 37 MURCS association, 1187, 1292 Muscle, 783 abdominal, isolated deficiency of, 799 abnormalities of, 790 in chromosomal disorders, 801 absence of, 790 accessory tissue, 800 aglossia, 791 asymmetric crying face, 791 atavisms, 800 deficiency of, 788, 926 deficiency of esophageal, 792 deficiency of eye, 792 dysplasia, 786 dystrophy, 786 effect on morphogenesis, 783 embryology of, 784 facial deficiency of, 791 hypertrophy of, 785 hypoplasia of, 788 inactivity/immobilization of, 785 isolated deficiencies of, 790

localized abnormalities of, 790 mass, decreased, 788 mass, increased, 786 pectoralis, defects of, 793 Poland anomaly, 794 Poland-Mo¨bius syndrome, 795 shoulder girdle, defects of, 793 terminology used, 784 Muscle-eye-brain syndrome, 551, 662 Muscular dystrophy, 786 Muscular ventricular septal defects, 114 Myasthenia gravis, maternal, 57, 931 Mycoplasma infection and pregnancy, 38 Myelocystocele, 719, 776 Myeloschisis, 715, 719 Myopathy, nemaline, 789 Myotonic dystrophy, maternal, 931 Nager syndrome, 282 Nails, defects of, 1337 Nail-patella syndrome, 920, 1337 Natal dysplasia, 459 Natal teeth, 465 Nemaline myopathy, 789 Neck masses, 1069 Neoplasia predisposition, 1375 Neoplasms, development of, 1375 of umbilical cord, 1454 Neoplastic potential of overgrowth syndromes, 1375 Nephronophthisis, 1215 prognosis, 1216 symptoms, 1215 Netherton syndrome, 1322 Neu-Laxova syndrome, 1322 Neural crest, 88, 267, 1330 contribution to cardiac development, 88 Neural tube, closure of, 715 Neural tube defects, 52, 715 causes of, 732 complications of, 738 epidemiology of, 729, 733 environmental factors and, 733, 735 folic acid prevention, 743 genetic factors and, 734 geographic differences, 728 maternal age and, 731 mouse models of, 733, 734 parity in, 731 prenatal diagnosis of, 744 prevention of, 737, 743 rates of, 729 recurrence rates of, 737 reproductive history and, 731 seasonal variations in, 730 secular changes in, 728 sex ratio in, 729 socioeconomic factors in, 730 syndromes with, 722t, 735t treatment of, 737 ultrasound findings and, 719 Neurenteric cyst of spine, 762

Neurenteric malformation of spine, 762 etiology, 763 prognosis, 764 Neurofibromatosis, 517, 1357 Neuromuscular systems, 467 Neuronal ectopia, syndromes with, 559t Neuronal formation, disorders of, 546 Neuronal heterotopia, 568 syndromes with, 70t, 559t Neuronal migration, anomalies of, 546 syndromes with, 559 Nevo syndrome, 1373 Nevus, 1315 comedonicus, 1316 congenital Becker, 1317 connective tissue, 1317 epidermal, 1315 flammeus, 1323 lipomatosus cutaneous superficialis, 1317 pigmented, 1315 porokeratotic eccrine, 1317 port-wine, 1323 sebaceous, 1315, 1316 storkbite, 1323 Nipples, absence of, 1052 hypoplastic, 1052, 1052t supernumerary, 1055, 1055t syndromes with, 1052 widely spaced, 1058 syndromes with, 1059t Nodular heterotopias, 569 Nomenclature of malformations, 6 Noonan syndrome, 105, 167, 276 Nose, 373 anatomy of, 373 anomalies of, 373 aplasia, heminasal, 374 arhinencephaly, 386 syndromes with, 387 arhinia, 374 atresia, choanal, 377 syndromes with, 377 atresia of nostril, 377 bifid, 376 coloboma of nostril, 376 dermoid cyst of, 388 development of, 373 distinctive, 381 encephalocele affecting, 388 formation of, 373 glioma of, 388 hemangioma of, 386 malformations of, 373 nasal septum, deviation of, 386 polyrhinia, 378 proboscis, 378 septum, deviation of, 386 small, 375 stenosis, choanal, 377 syndromes with, 377 syndromic, 382 turbinate deformity, 386

Subject Index Nostril, 377 atresia, 377 coloboma, 376 NTD (see Neural tube defects) Nuccal lymphangioma, 169 Nuclear cataract, 316 Nutrient deficiencies, prenatal, 52 Obesity, postnatal-onset, 1372 syndromes with, 1374t Obstructive cystic disease of kidneys, 1219 Occipital horn, 265 Occipitalization of the atlas, 813 Occult spinal dysraphism, 757 prevalence of, 759 prognosis, 760 treatment, 760 Ocular hypertelorism, 273 Ocular hypotelorism, 270 Ocular lymphangioma, 172 Ocular malformations. See Eye. Oculodentodigital dysplasia, 960 Odontoid aplasia, 818 conditions with, 820t Odontoid hypoplasia, 818 conditions with, 820t OEIS complex, 1046 Oligodactyly, 984 entities with, 985t teratogenic causes of, 987 Oligogyric microcephaly, 471 Oligohydramnios, 55 Oligomeganephronia, 1191 Omphalocele, 1034 and associated anomalies, 1034 familial recurrence of, 1035 incidence of, 1035 prenatal diagnosis of, 1037 surgical repair of, 1037 syndromes with, 1036t Omphalomesenteric artery disruption, 1467 Omphalomesenteric duct anomalies, 1030, 1421 Open-lip schizencephaly, 648 Opitz syndrome, 276, 1260 Optic nerve hypoplasia, 320, 321t Optic pit, 324 Oral cavity anomalies of palate, 392, 400 anomalies of teeth, 452 anomalies of tongue, 405 Oral-facial-digital syndrome, 942, 957, 1314 Orbital hypertelorism, 273, 306 syndromes with, 276t Orbital hypotelorism, 270 syndromes with, 272t Oromandibular-limb hypogenesis syndrome, 406 Osler-Weber-Rendu syndrome, 141 Osseous atresia, 326 Ossicular chain, malformations of, 358, 359, 361, 362, 363 Ossicular malformations, 357 classification of, 357

Ossification centers, of long bones, appearance of, 850 Ossification of patella, abnormal, 921 Ossification of sternum, abnormal, 1026 Osteogenesis imperfecta, 1016t Osteolysis, 916, 1020t carpotarsal, 916, 917t, 1020t multicentric, 917 phalangeal, 917 syndromes with, 917t, 1020t Osteoma cutis, 1321 Osteoma of tongue, 417 Osteopenia, 914 Osteopetrosis, 910, 913, 1017 Osteoporosis, 914, 916 Osteo-renal disorders, 1171, 1172t Ostium primum defect, 112 Otocephaly, 340 prevalence of, 341 Oto-palato-digital syndrome, 276, 972, 1010 Outer canthal measurement, 271 Oval window, absence of, 364 Ovarian dysgenesis, 1281 Overgrowth, generalized, 1372 association with neoplasms, 1375 etiology, 1374 Overgrowth, prenatal onset, 1372 syndromes with, 1373 Overgrowth of limbs, 902 Oxycephaly, 226 syndromes with, 224 Oxygen deficiency, prenatal, 52 Pachygyria, 556 prevalence of, 558 recurrence of, 558 syndromes with, 70t, 559t Palate, 530 ankylosis of, 409 cleft, 392, 400 genes causing, 402 submucous, 400 syndromes with, 401t formation of, 392 Pallister-Hall syndrome, 940, 1348, 1357 Palmar plantar keratodermas, 1324t Pancreas, 1125, 1150 annular, 1150 and associated anomalies, 1151 anomalies of, 1150 cysts, 1154 syndromes with, 1156, 1155t development of, 1125 divisum, 1150, 1151 ductal variants of, 1152 dysplasia of, 1154 syndromes with, 1156 ectopia of, 1157 heterotopia of, 1157 polycystic disease and, 1154 structural variation in, 1150 Paracentric inversions, chromosomal, 19

Paradione, prenatal exposure to, 42 Paraduodenal hernia, 1095 Paraesophageal hernia, 214 Paramethadione, prenatal exposure to, 42 Parathyroid gland, disorders of, 1342, 1353 and pregnancy, 51 Parietal foramina, 240, 243 syndromes with, 243 Parry-Romberg syndrome, 1371 Patella, absent, conditions with, 920 agenesis of, 920 anomalies of, 919, 921t dislocation of, 921 hypoplasia of, 920 hypoplastic, conditions with, 921 ossification of, 921 Patent ductus arteriosus, 118, 130 syndromes associated with, 131t Pathogenesis, definition of, 11 Paucity of the interlobular bile ducts, 1136 Pectoral girdle, 805 atlas, occipitalization of, 813 clavicle, anomalies of, 807 aplasia/hypoplasia, 806 pseudarthrosis, 807 coxa valga/vara, 833 syndromes with, 834 development of, 805 Glenoid hypoplasia, 809 hip dysplasia, 830 Klippel-Feil anomaly, 821 odontoid aplasia/hypoplasia, 818 syndromes with, 820 pelvic bones, anomalies of, 830 syndromes with, 831 rib anomalies, 812 cervical, 813 sacral agenesis, 829 spondylolysis, 827 Sprengel anomaly, 807 sternum, anomalies of, 810 vertebra, defects of, 819 clefts of, 823, 825, 826, 828 syndromes with, 822, 826 Pectoral muscles, defects of, 793 Pectus carinatum, 811 conditions with, 815t Pectus excavatum, 811 conditions with, 814t Pedunculated postminimus, 938 Pelvic bones, anomalies of, 830 conditions with, 831t Pelvic girdle, 805 development of, 805 Pemphigus vulgaris, maternal, 57 Pena-Shokeir syndrome (fetal akinesia sequence), 931 Pendred syndrome, 1355 Penetrance, definition of, 30 Penis buried, 1256 concealed, 1262 duplication of, 1264 hidden, 1256, 1262

1489 length of, 1256 median raphe cyst of, 1310 Penoscrotal development, 1252 Penoscrotal transposition, 1265 Percutaneous umbilical blood sampling, 59 Pericardial constriction, 120 Pericardium, anomalies of, 120 Pericentric inversions, chromosomal, 19 Perimembranous ventricular septal defect, 113 Peripheral pulmonary artery stenosis, 104 Perisylvian polymicrogyria, bilateral, 566 Periureteral venous ring, 138 Periventricular nodular heterotopia, 569 Permanent teeth, 425 average size of, 447 Persistence of fetal vasculature, 318 Persistent hyperplastic primary vitreous, 318 Persistent left superior vena cava, 117, 136 Persistent Mu¨llerian ducts, 1276 Peters anomaly, 313 Peters-plus syndrome, 313 Peutz-Jeghers syndrome, 1112 Pfeiffer syndrome, 226 Phalangeal osteolysis, 917 Pharyngeal arches, derivatives of, 1068 clefts, derivatives of, 1068 diverticula, 1071 pouches, derivatives of, 1068 Pharynx, 1067 branchial cleft anomalies, 1069 syndromes with, 1070 pharyngeal diverticula, 1071 Phenocopy, 30 Phenotype, definition of, 9, 23 autosomal dominant, 29 autosomal recessive, 31 contiguous gene, 32 dominant, 24 polygenic, 32 recessive, 31 X-linked dominant, 29 Phenylketonuria, maternal, 52 Photogrammetry, 65 Photography, 69 Phytoestrogens, prenatal exposure to, 52 Pictures of Standard Syndromes and Undiagnosed Malformations (POSSUM), 14 Piebaldism, 1329 Pigmentation, cafe´ au lait, 1331 Pigmentation anomalies, 1329 Pigmented fungiform papillae, 423 Pigmented nevi, 1315, 1332 Pigment mosaicism, 1330 Pit, auricular, 353 ear lobe, 355

1490 Pituitary gland, anterior, disorders of, 894, 900, 1340, 1349 Pituitary gland, development of, 1349 Pituitary gland, posterior, disorders of, 1343, 1356 Pituitary hypoplasia, 1341, 1343, 1349, 1354 Pituitary insufficiency, 1341, 1343, 1349, 1354 PKD gene, 1200 Placenta, of twins, 1377 dichorionic diamniotic, 1378 monochorionic diamniotic, 1378 monochorionic monoamniotic, 1378 Plagiocephaly, 226 syndromes with, 224 Platelet isoimmunization, 57 Platyspondyly, 823, 1006, 1008, 1009 Pleiotropy, 29 Poland anomaly, 794, 852, 1370 Poland-like gluteal-lower leg anomaly, 796 Poland-Mo¨bius syndrome, 795, 852 Polar body twinning, 1380 Polyanomaly, definition of, 13 Polyasplenia, 185 Polycystic kidney disease, adult, 1134 Polycystic kidney disease, autosomal dominant, 1200 and cardiovascular abnormalities, 1201 changes in liver, 1201 clinical symptoms of, 1201 complications of, 1201 incidence of, 1202 management of, 1203 physical findings in, 1201 PKD gene and, 1202 prenatal diagnosis, 1201 prognosis, 1203 Polycystic kidney disease, autosomal recessive, 1134, 1197 clinical presentation of, 1198 incidence of, 1199 liver histology in, 1199 pathology of, 1199 PKHD1 gene and, 1199 prognosis, 1200 Polycystic liver disease, 1132 Polydactyly, 937 classification of, 937, 938 of index finger, 946 mesoaxial, 948 syndromes with, 943t mirror, 949 postaxial, 937 syndromes with, 939t preaxial, 940 syndromes with, 941t short rib, 940, 1005, 1135 treatment of, 950 triphalangeal thumb, 942

Subject Index Polygenic phenotype, 32 Polymastia, 1055 Polymicrogyria, 558 clinical signs, 566 prevalence, 567 prognosis, 568 syndromes with, 70t, 559t types of, 565 Polyorchidism, 1271 Polyotia, 339 Polyps colon, 1112 intestinal, 1111 syndromes with, 1113t umbilical, 1445 Polyrhinia, 378 Polysplenia, 185 malformations associated with, 188 phenotype, 187 syndromes with, 191t Polysyndactyly, 947 Haas type, 960 Polythelia, 1056 malformations associated with, 1056 Pontocerebellar anomalies, 669 Porencephaly, 645 cause of, 645 developmental, 647 encephaloclastic, 639, 647 pathogenesis, 652 prognosis in, 652 simple, 651 syndromes with, 646t transillumination of skull, 651 Porokeratotic eccrine nevus, 1317 Portal vein, congenital absence of, 138 Port-wine nevus, 1323 Port-wine stains, 1323 POSSUM, 14 Postaxial deficiency, 992 Postaxial limb deficiency, 840 Postaxial polydactyly, 937 syndromes with, 939 Posterior lentiglobus, 318 Posteriorly rotated ears, 344 Posterior pituitary, disorders of, 1343, 1356 Posterior urethral valves, 1242 syndromes with, 1244 Posterolateral hernia, 214 syndromes with, 215 Postnatal diagnosis, approach to, 60 Postnatal-onset obesity, syndromes with, 1374 Potter facies, 55 Potter syndrome, 1183 Prader-Willi syndrome, 491, 1257, 1358 Preauricular pits, 353, 353t, 1309 Preauricular sinus, 1309 Preauricular tags, 351, 353t, 1309 Preaxial deficiency, 991 Preaxial limb deficiency, 840

Preaxial polydactyly, 940 syndromes with, 941 type I, 940 type II, 942 type III, 946 type IV, 947 Precaliceal canalicular ectasia, 1217 Prelingual hearing loss, 369 syndromes with, 370 Premature centromeric division, 22 Premature metopic sutural synostosis, 268 Premature thelarche, 1063 incidence of, 1063 Premaxillary agenesis, 528 Prenatal alcohol syndrome, 41, 474 Prenatal diagnosis, 58 Prenatal environmental influences, 33 chemical, 40 drug, 40 hormonal, 49 immunologic, 56 infection, 36 mechanical, 53 nutrient deficiencies, 52 Prenatal overgrowth, 1373 Prenatal rubella syndrome, 37 Primary ciliary dyskinesia, 189 Primary growth excess, prenatal, 1372 syndromes with, 1373 Primary ossification centers, 850 Primary pulmonary hypoplasia, 213 Primary tethered cord, 757 age at diagnosis, 757 associated findings, 758 caudal dysgenesis, 759 neural arch anomalies, 759 neuroimaging, 759 prevalence of, 759 prognosis, 760 signs of, 757 treatment, 760 Prion diseases and pregnancy, 40 Proboscis, 378 Progesterone, prenatal exposure to, 51 Progestins, prenatal exposure to, 46 Prominent crus of the helix, 350 Propylthiouracil, prenatal exposure to, 46 Prosencephalon, 469 Proteus syndrome, 140, 1327, 1367, 1373 Protozoal infections and pregnancy, 40 Protruding ear, 346 prevalence of, 348 syndromes with, 347 Proximal symphalangism, 862 Prune belly syndrome, 797, 1238 etiology/pathogenesis of, 1238 Pseudoachondroplasia, 1003 Pseudoarthrosis, 880 Pseudoautosomal regions, X chromosome, 15

Pseudocyst of umbilical cord, 1424 Pseudogynecomastia, 1059 Pseudohermaphroditism, male, 1272 cause of, 1272 classification of, 1272 prognosis, 1273 syndromes with, 1274t, 1290t treatment, 1273 Pseudohypoparathyroidism, 1342, 1353 Pseudoxanthoma elasticum, 1321 Psychogenic megacolon, 1108 Pterygium, multiple, 926, 930 Pulmonary organs, 201 agenesis of, 209 syndromes with, 210t anomalies of, 209 aplasia of, 209 syndromes with, 210t development of, 211 hypoplasia of, 213 lymphangiectasia, 161 pulmonary artery, absent, 104 stenosis of, 104 syndromes with, 105t Pulmonary valve, atresia of, 104 Pulmonary veins, anomalies of, 115 stenosis of, 117 Pulmonary venous connection, 116 anomalous, 115 syndromes associated with, 116t Pulp dysplasia, 461 Pyknodysostosis, 1019t Pyloric stenosis, 1082 syndromes with, 1083t Rachischisis, 715 Radiation, prenatal exposure to, 34 Radiocephalometry, 65 Radiographic procedures and pregnancy, 35 Radioulnar synostosis, 865 Radiowaves, prenatal exposure to, 35 Radius, bowing of, 882, 885 deficiency of, 840 Random asymmetry, 93, 185, 1361 Rapp-Hodgkin syndrome, 1334 Recessive phenotypes, 31 Reciprocal translocations, 18, 20 Rectoanal atresias, 1116 malformations associated with, 1118 syndromes with, 1119t Rectum, 1115 associated anomalies, 1118 atresia of, 1116 syndromes with, 1121t development of, 1115 duplication of, 1122 etiology of, 1120 and other anomalies, 1120 Remnants of allantoic duct, 1419 Renal agenesis, 1184 associated congenital defects, 1184 prenatal diagnosis, 1188

Subject Index syndromes with, 1186t unilateral, 1184 Renal cystic disease, 1195 Potter classification, 1195 secondary to obstruction, 1219 sonographic appearance of, 1197 Renal cysts, 1195 classification of, 1196 Renal dysplasia, 1205 associated defects, 1206 clinical signs, 1206 etiology, 1211 incidence of, 1206 prognosis, 1212 syndromes with, 1207t Renal ectopia, 1223 associated anomalies, 1224 syndromes with, 1224t Renal-hepatic-pancreatic disorders, 1177, 1178t Renal hypoplasia, 1190 prognosis, 1191 syndromes with, 1192t Renal vein compression, 138 Renpenning syndrome, 492 Retinoic acid, prenatal exposure to, 45 Retraction, congenital eyelid, 308 Retrusion of midface, 283 syndromes with, 285 Rett syndrome, 492 Rh isoimmunization during pregnancy, 56 Rhizomelic dysplasias, 1012t Rhombencephalon, 469 Rhombencephalosynapsis, 656 Ribs, 805 anomalies of, 811, 812 conditions with, 813, 816t aplasia of, 816 broad, 817 cervical, 813 development of, 805 extra, 812, 816 short, 816 thin, 817 Rickets, hypophosphatemic, 1017t Rieger anomaly, 311 Right aortic arch, 123 aberrant left subclavian artery, 124 mirror-image branching, 123 Right-sidedness, 1361 bilateral, 185 Right subclavian artery, aberrant, 129 Ring chromosomes, 18 Robertsonian translocations, 18 Roberts syndrome, 842, 844 Robinow syndrome, 277, 1013 Rokitansky syndrome, 1187 Rubella, prenatal, 105, 492 Rubella and pregnancy, 37 Rubeola and pregnancy, 37 Rubinstein-Taybi syndrome, 493, 973 Russell-Silver syndrome, 1348, 1370

Sacral agenesis, 829 Sacral dysgenesis, 759, 829 Sacral meningocele, 776 Sacral teratoma, 764 Sacrum, absence of, 829 Saethre-Chotzen syndrome, 226, 294 Sagittal fontanel, 238 Salt losing adrenal hyperplasia, 1289 Scalp vertex aplasia, 246 Scaphocephaly, 222 syndromes with, 224 Scheibe dysplasia, 368 Schizencephaly, 639, 648 and arachnoid cysts, 650 incidence of, 650 neuroimaging findings, 649 and septo-optic dysplasia, 650 syndromes with, 646t unilateral, 651 Schmidt metaphyseal dysplasia, 1005 Schwartz-Jampel syndrome, 1009 Sclerocornea, 310 Sclerosis of bone, 910 syndromes with, 912, 913 Sclerosis of skull, 254 syndromes with, 255 Sclerosteosis, 253 Scoliosis, 819 syndromes with, 822 Scrotal tongue, 408 Scrotum, accessory/ectopic, 1267 Seckel syndrome, 493 Secondary craniosynostosis, conditions with, 227 Secundum atrial septal defect, 112 syndromes associated with, 113 Segmental limb overgrowth, syndromes with, 905 Sella turcica, anomalies of, 259 Semicircular canal abnormalities, 368 Semilobar holoprosencephaly, 528, 536 Sensorineural deafness, syndromes with, 369 Septal defects, 112, 113 aortopulmonary, 119 atrial, 112 atrioventricular, 101 ventricular, 114, 115t Septo-optic dysplasia, 1257 and schizencephaly, 650 Septum pellucidum, 604 absence of, 604 cavum, 604 cyst, 605, 606t signs and symptoms, 605 syndromes with cyst, cavum, absent, 606t Sequence, definition of, 9, 13 Sesamoid bones, 876, 877 Sex hormones, overproduction of, 51 Sex reversal, 46,XY, 1272

Sexual development, disorders of, 1341 female genital system, 1281 male genital system, 1255 Short rib polydactyly, 940, 1005, 1135 Short stature, 894 conditions with, 898t, 1340, 1349 major types of, 895 prognosis in, 897 treatment of, 897 Short umbilical cord, 1429 syndrome, 1430 Shortwaves and pregnancy, 35 Shovel-shaped incisors, 452 syndromes with, 453 Shprintzen syndrome (see Velocardiofacial syndrome) Silver-Russell syndrome, 1348, 1370 Simple porencephaly, 651 Simpson-Golabi-Behmel, 940, 1373 Single maxillary central incisor, 530 Single umbilical artery, 1459 type I, 1459 type II, 1461 type III, 1462 Single ventricle, 96 prevalence of, 96 Sinus venosus atrial septal defect, 112 Sirenomelia, 866 Situs ambiguus, 94, 186, 1361 Situs inversus, 94, 185, 1361 in conjoined twins, 1400 Situs solitus, 93, 185 Sjo¨gren-Larsson syndrome, 1322 Skeletal dysplasias, 997t, 1001t, 1003t with abnormal bone density, 1016t, 1018t acromelic, 1014t acromesomelic, 1013t axial, 1011t with brachydactyly, 974 cartilaginous, 1019t classification of, 1003 diaphyseal, 1010 with decreased bone density, 1016t with disorganized cartilaginous components, 1019t with disorganized fibrous components, 1019t with epimetaphyseal involvement, 1005t with epiphyseal involvement, 1003t etiopathogenesis, 997 recognizable by fetal sonography, 1001 generalized endochondral, 1003 growth in individuals with, 65 and hydrocephalus, 625 with increased bone density, 1018t localized, 1011t membranous, 1015t mesomelic, 1013t

1491 with metaphyseal involvement, 1004t with osteolysis, 1020t postnatal diagnosis of, 999 prenatal diagnosis of, 998 prevalence of, 997 radiographs in, 1000 rhizomelic, 1012t spondyloepimetaphyseal, 1009t spondyloepiphyseal involvement, 1006t spondylometaphyseal involvement, 1008t Skeleton, disorganized development of fibrous components of, 1018 disorders with, 1018 Skin, 1307 absence of, 1311 anatomy of, 1307 aplasia cutis congenita, 1311 appendages of, 1333 bullae, 1319 clefts, 1309 cysts, 1309 development of, 1307 dimples, 1309 and disorders of connective tissue, 1321 and disorders of keratinization, 1319 epidermal appendages, 1333 epidermolysis bullosa, 1319 hamartomas, 1315 hyperextensible, 1321 lines of Blaschko, 1312 loose, 1321 and mosaicism, 1312 pigmentation anomalies of, 1329 sinuses of, 1309 tags of, 1309 tails, 1309 thickened, 1319 vascular malformations of, 1322 Skin vesicles, 1312 Skull, 221 and abnormal fetal position, 258 anomalies, miscellaneous, 264 basal foramina, anomalies of, 261 basilar impression of, 261 syndromes with, 263t bathrocephaly, 257 bifid, 243 breech head, 257 caput succedaneum, 262 cephalohematoma of, 262 craniosynostosis, 221 chromosome anomalies with, 227 secondary, 227 syndromes with, 224 craniotabes, 249 cranium bifidum, 243 dermal sinus, 242 embryology, 221 fontanels, anomalies of, 238 syndromes with, 239

1492 Skull (continued) foramen magnum, anomalies of, 260 hyperostosis of, 254 syndromes with, 255t Kleeblattscha¨del, 235 syndromes with, 236 parietal foramina of, 243 scalp vertex aplasia, 246 sclerosis of, 254 syndromes with, 255t sella turcica, anomalies of, 259 sutures of, 221 thick, 251 syndromes with, 252 thin, 248 syndromes with, 249 trigonocephaly, syndromes with, 228 undermineralization of, 248 and vertex birth molding, 254 wide sutures, 237 syndromes with, 237 Wormian bones, 245 syndromes with, 245 Slipped capital femoral epiphysis, 833 Small intestine, (see Intestines) Smith-Lemli-Opitz, 494, 1257, 1290 Solid cystic dysplasia of kidneys, 1205 syndromes with, 1207 Solitary polyps of colon, 1112 Sonographic imaging and pregnancy, 69 Sotos syndrome, 519, 1373 Spectrum, definition of, 9 Spina bifida, 715, 718 complications, 740 geographic rates, 729 level of, 718 mortality rate, 738 neurologic impairment in, 719 occulta, 719 secular rates of, 729 syndromes with, 722t, 735t treatment of, 738 Spinal cord, 757 anomalies of, 715, 757, 762, 764, 768, 773, 776, 778 cysts of, 762, 764 myelocystocele, 776 neural tube closure, 715 neural tube defects, 715 environmental factors, 735 rates of, 729 syndromes with, 722 neurenteric malformations, 762 syringomyelia, 768 syndromes with, 771 tethered, 757 Spinal cord dysraphism, cutaneous markers of, 1310 Spine, 805 anomalies of, 715, 819 development of, 805 Spirochetal infection and pregnancy, 38

Subject Index Spleen, 183 accessory, 196 asplenia, 187 syndromes with, 188, 191 embryology of, 183 fusion of, 197 polyasplenia, 185 syndromes with, 188, 191 positional alterations of, 195 structural variation of, 196 Splenogonadal fusion, 199, 852, 1277 Split cord malformation, 757, 773 anorectal malformations, 758 congenital scoliosis, 758 diagnosis, 774 duplication of cord, 758 prognosis, 776 treatment, 776 Split hand/foot, 988, 986 associated malformations, 990 gene loci, 991 nonsyndromic, 990 syndromic, 990 Split notochord syndrome, 762 Spondyloepimetaphyseal dysplasia, 1009t Spondyloepiphyseal dysplasia, 1006t Spondylolisthesis, 827 Spondylolysis, 827 Spondylometaphyseal dysplasia, 1008t Stahl ear, 348 Standards of growth measurements, 61 Stapedial artery, persistence of, 365 Stapes, 362 aplasia of, 362 congenital fixation of, 363 hypoplasia of, 362 malformations of, 362 Startle disease, 787 Stature, short, 894 conditions with, 898t diagnosis, 894 etiology of, 895 major types of, 895 prognosis in, 897 radiographic assessment of, 894 treatments for, 897 Stature, tall, 900 conditions with, 901t etiology of, 900 treatments for, 900 Sternum, 810, 1025 anomalies of, 810, 1025 bifid, 810 cleft, 810, 1025 embryonic development, 805, 810, 1026 fusion of, 1026 Stickler syndrome, 291, 1006 Stippled epiphyses, syndromes with, 1004 Stomach, 1081 anomalies of, 1081 atresia of, 1084

development of, 1081 diverticula of, 1085 duplication of, 1086 gastric musculature defects, 1086 hypertrophic pyloric stenosis, 1082 syndromes with, 1083 malposition of, 1087, 1088t microgastria, 1084 mucosal heterotopia, 1088 stenosis of, 1084 Storkbite nevus, 1323 Strawberry hemangiomas, 1327 Streak gonads, 1281 Structural chromosomal abnormalities, 18 Stub thumb, 979 Sturge-Weber syndrome, 1327 Subaortic stenosis, 107 Subclavian artery, 124 aberrant, 129, 130 variants, 129 Subglottic stenosis, 203 Submucous clefts, 400 Superfecundation, 1380 Superfetation, 1380 Superior oblique tendon, agenesis of, 792 Superior rectus muscle, agenesis of, 792 Superior vena cava, 118, 136 bilateral, 117 Supernumerary breasts, 1055 Supernumerary dental cusps, 452 syndromes with, 453 Supernumerary dental roots, 452 Supernumerary kidney, 1222 Supernumerary nipples, 1055, 1310 conditions with, 1057 Supernumerary teeth, 444 syndromes with, 445 Supraumbilical raphe, 1310 Supravalvar aortic stenosis, 107 Symbrachydactyly, 963 Symmastia, 1055 Symmelia, 857 Symphalangism, 857 conditions with, 860t distal, 863 proximal, 862 Syndactyly, 856, 954 Cenani-Lenz, 962 classification of, 954 complete, 961 HOX genes and, 958 symbrachydactyly, 963 syndromes with, 956 treatment of, 965 type I, 954 type II, 955 type III, 959 type IV, 960 type V, 960 Syndrome, definition of, 9 communities of, 10 naming of, 10 Synophthalmia, 302

Synostosis, 856 etiology, 857 humeroradial, 864 of long bones, syndromes with, 861t of metacarpals, syndromes with, 859t metacarpophalangeal, 859 of metatarsals, syndromes with, 859t metatarsophalangeal, 859 of metopic suture, 268, 269t radioulnar, 865 tibiofibular, 866 Synotia, 340 prevalence of, 341 Synpolydactyly, 955 Syphilis, prenatal, 8 Syringomyelia, 768 associated abnormalities, 770 communicating, 768 noncommunicating, 768 pathophysiology of, 770 prognosis, 771 signs and symptoms, 769 syndromes with, 771t treatment, 771 Systemic lymphangiomatosis, 177 Systemic vasculature, 121 anomalies of aortic arch, 128 cervical, 125 double, 125 double lumen, 126 interrupted, 121 other anomalies, 128 right, 123 syndromes with, 122 artery variants, 128 coarctation of aorta, 133 syndromes with, 134 deep vein abnormalities, 139 inferior vena cava, 137 patent ductus arteriosus, 130 syndromes with, 131 persistent left superior vena cava, 138 vascular malformations, 140 venous variants, 138 Systemic venous connection, 117 Systemized Nomenclature of Medicine, 13 Tags, preauricular, 351 Tailgut cyst, 782 Tall stature, 900 conditions with, 901t etiology, 900 treatment, 900 Talon cusps, 452 Tarsal coalition, 859 syndromes with, 858t Tarsal partition, 877 Tarsal segmentation, 877 Taurodontia, 452 syndromes with, 454t Tectocerebellar dysraphia, 656 Teebi syndrome, 277

Subject Index Teeth, 425 abnormalities of, 452 agenesis of, 431 frequency of, 439 syndromes with, 432t, 433t, 439t anatomy of, 426 cementum dysplasia, 463 cusps, supernumerary, 453t deciduous, 425 dentin, dysplasia of, 461 dentition, patterning of, 426 development of, 427 dilacerations, 452 enamel dysplasia, 458, 461t eruption, abnormalities of, 463, 464t globodontia, syndromes with, 453 hypoplasia, 459 macrodontia, 451 malocclusion of, 456 microdontia, 446 parts of, 426 permanent, 425 shape of, 452 size of, 447 supernumerary, 444 syndromes with, 445t taurodontia, syndromes with, 454 Tegretol, prenatal exposure to, 43 Telecanthus, 273, 306 Teratogen, definition of, 11, 33, 41 Teratogenicity alcohol, 41, 474 aminopterin, 43 androgens, 45, 51 angiotensin converting enzyme inhibitor, 46 anticoagulants, 48 anticonvulsants, 42 bacterial infections, 38 carbamazepine, 43 carbimazole, 47 chemical, 40 chlorobiphenyls, 48 cocaine, 41 corticosteroids, 46 cytomegalovirus, 36 Depakene, 42 diethylstilbestrol, 46 Dilantin, 42 diphenylhydantoin, 42 estrogen, 51 etretinate, 45 hormones, 49 hydantoin, 42 infections, 36 influenza, 37 iodine deficiency, 53 iron deficiency, 53 isotopes, 35 isotretinoin, 45 lithium, 47 LSD, 42 magnetic fields, 35 magnetic resonance imaging, 69 marijuana, 41 mercury, 47

methotrexate, 43 microwaves, 35 mineral deficiency, 53 misoprostol, 43 mumps, 37 oxygen deficiency, 52 Paradione, 42 paramethadione, 42 phytoestrogens, 52 progesterone, 51 progestins, 46 propylthiouracil, 46 protozoal infection, 40 rubella, 37 spirochetes, 38 syphilis, 8 Tegretol, 43 thalidomide, 44 Tridione, 42 trimethadione, 42 valproate, 42 valproic acid, 42 viral infections, 36 Vitamin A, 45 Vitamin D, 45 vitamin deficiency, 53 vitamin K antagonist, 48 warfarin, 48 Teratoma intraspinal, 764 of tongue, 421 of umbilical cord, 1456 Terminal limb deficiency, 840 Terminal transverse deficiency, 840, 984 management of, 994 teratogenic causes of, 987 Terminology, negative, 12 Testes, 1251 absent, 1268, 1271 descent of, 1251 development of, 1251 ectopic, 1272 small, 1268 conditions with, 1270 supernumerary, 1271 undescended, 1267 Testicular failure, 1060, 1256, 1268 syndromes with, 1060t, 1270t, 1271t Testosterone synthesis, failure of, 1060, 1256 enzyme defects, 1060 Tethered cord, 757 and associated findings, 758 incidence of, 759 pathogenesis of, 758 prognosis of, 760 treatment of, 760 Tetralogy of Fallot, 98 with absent pulmonary valve, 98 with pulmonary atresia, 98 variants of, 98 TGA (see Transposition of great arteries) Thalidomide, prenatal exposure to, 44, 846

Thelarche, premature, 1063 incidence of, 1063 Thick cranial bones, 251 syndromes with, 252 Thickened filum, 757 Thin cranial bones, 248 syndromes with, 249 Thioureas, prenatal exposure to, 46 Third ventricle, stenosis of, 613 Thoracic lymphangioma, 175 Thoracic wall, 1023 anomalies of, 1025, 1027 embryogenesis of, 1023 Threshold traits, definition of, 33 Thrombocytopenia-absent radius syndrome, 845 Thumb, stub, 979 Thyroglossal duct cysts, 1309 Thyroid antibodies, 57 Thyroid defects, 1354 biosynthetic defects, 1354 Thyroid gland, disorders of, 894, 1354 and pregnancy, 49, 57 tumors of, 1355 Thyroid hormone resistance, 1355 Thyroid-releasing hormone receptor deficiency, 1355 Thyroid-stimulating hormone deficiency, 1355 Thyroid-stimulating hormone receptor deficiency, 1355 Tibia, bowing of, 882, 884t Tibia, deficiency of, 842, 843, 849 Tibiofibular synostosis, 866 Tongue, 405 aglossia, 406 ankyloglossia, 410 ankylosis of, 409 bifid, 408 brain tissue in, 416 chondroma, 417 choristoma of, 414, 416, 417 curling, 422 cyst of, 414, 416 dermoid cyst of, 418 double, 412 embryogenesis of, 405 fissured, 408 hamartoma of, 419, 420 hemangioma of, 420 hyperextensible, 422 hypertrophy, 787 hypoglossia, 406 lingual frenulum, absence of, 406 lingual thyroid, 413 lingua plicata, 408 lymphangioma of, 419 macroglossia, 407 median rhomboid glossitis, 411 mesenchymoma of, 420 microglossia, 406 movements of, 421 muscles, 405 osteoma, 417 pigmentation of, 423 scrotal, 408 teratoma of, 421

1493 tie, 410 trefoiling, 422 upfolding, 422 Tooth, agenesis of, 431 isolated, 432 syndromes with, 432t, 433t, 439t Tooth, eruption abnormalities, 463 syndromes with, 464t Tooth shape, abnormalities of, 452 Total anomalous pulmonary venous return, 116 Tower skull, 226 Toxoplasma Gondii, 40 Trachea agenesis of, 206 cartilaginous sleeve, 209 compression of, 128, 129 stenosis of, 207 syndromes with, 208 Tracheoesophageal fistula, 209, 1073 associated anomalies, 1075 syndromes with, 1075 types of, 1074 Translocations, 18 Reciprocal, 18 Robertsonian, 18 Transmantle dysplasia of cortex, 574 Transposition of great arteries, 97 Transsphenoidal encephalocele, 720 Transverse limb deficiency, 840 syndromes with, 852 TRAP sequence, 1395 Treacher Collins syndrome, 282, 291 Trefoiling of tongue, 421 Treponema pallidum, 38 Trichorhinophalangeal syndrome, 1013 Tricuspid atresia, 103 Tridione, prenatal exposure to, 42 Trigonocephaly, 227 and holoprosencephaly, 530 syndromes with, 228t, 269t Trimethadione, prenatal exposure to, 42 Triphalangeal thumb, 942 syndromes with, 943t Triplets, mortality, in, 1385 Triploid/diploid mixoploidy syndrome, 1367 Trisomies, chromosomal, 17 Trisomy 8 mosaicism, 1373 Truncus arteriosus, 97 TSH deficiency, 1355 TSHR deficiency, 1355 Tuberous sclerosis, 1331 Tumors adrenal, 1287, 1346 with endocrine features, 1339, 1346t intraspinal, 784 umbilical cord, 1454, 1456 vascular, 1322 and associated syndromes, 1327t Turbinate deformity, 386 Turner hypoplasia, 459

1494 Turner syndrome, 134, 166, 1281, 1358 Turricephaly, 226 syndromes with, 224 Twinning, 1377 (see also Twins) Twin placentas, vascular anastomoses in, 1390 Twin reversed arterial perfusion sequence, 1395 Twins, 54, 1377 animal models of, 1380 birth weight of, 1384 causes of, 1385 conjoined, 1396 deformations in, 1404 determination of zygosity, 1381 disruptions in, 1394, 1402 dizygotic, 1377 growth, 1384 incidence, 1382 malformations in, 1401 monozygotic, 1377 perinatal morbidity/mortality of, 1389 placentation, 1377 polar body, 1380 risk of structural anomalies, 1401 sex ratio, 1383 spontaneous abortions of, 1385 structural defects in, 1401 superfetation, 1378 transfusion syndrome, 1391 vanishing twin, 1385 vascular anastomoses in placentas, 1390 zygosity, 1377, 1381 Twin transfusion syndrome, 1393 Type A interrupted aortic arch, 108 Type B interrupted aortic arch, 100 Ulceration of umbilical cord, 1453 Ulna, bowing of, 882, 885 deficiency of, 842 Ulnar-mammary syndrome, 986 Ultrasonography, prenatal diagnosis, 58 Ultrasound, 35 Umbilical aneurysms, 1470 Umbilical artery (allantoic), single, 1459 with persistent right umbilical vein, 1462 Umbilical artery (vitelline), single, 1461 with persistent right umbilical vein, 1462 Umbilical cord, 1413 agenesis, 1428 amnion cysts, 1418 anatomy of, 1413 anomalies of, 1415 antenatal separation of, 1449 arteriovenous fistulas, 1469 calcifications of, 1417 cord-to-cord entanglements, 1434 cystic mucoid degeneration of, 1424

Subject Index cysts, 1418, 1419, 1421, 1424 development of, 1028 diameter, 1426 diameter, abnormalities of, 1431 dimensional abnormalities of, 1426 disruption, 1425 embryogenesis of, 1413 encirclements, 1443 entanglements, 1434 growth of, 1415 helical ulceration, 1453 hemangiomas, 1455 hematoma, 1436 hernia, 1437 insertion, anomalies of, 1439 knots, 1441 length, 1426 long, 1431 loops, 1443 neoplasms, 1454 polyp, 1445 position, abnormalities of, 1448 postnatal separation of, 1450 pseudocyst, 1424 short, 1429 spiraling of umbilical arteries, 1413 structural organization of, 1413 teratoma, 1456 torsion abnormalities, 1451 vascular anomalies of, 1457 vascular helix anomalies of, 1466 Umbilical hernia, 1031 incarceration of, 1032 incidence of, 1032 prognosis, 1032 syndromes with, 1033t treatment, 1032 Umbilical nodules, 1030 Umbilical placement, anomalies of, 1439 Umbilical polyp, 1030, 1310, 1445 Umbilical varicosities, 1470 Umbilical veins, anomalies of, 1463 Umbilicus, 1028 abnormalities of, conditions with, 1029 anomalies of, 1028 morphology of, 1029 position or shape of, 1028 Undermasculinization, 1272 Undermineralization of the skull, 248 syndromes with, 249 Unilateral hemispheric agenesis/ hypoplasia, 667 Unilateral renal agenesis, 1184 incidence of, 1188 Uniparental disomy, 22 Univentricular AV connection, 96 Upper gastrointestinal system, 1065 formation of, 1065 homeotic genes, 1065, 1066 Urachal anomalies, 1234 associated genitourinary anomalies, 1235 symptoms, 1237

Ureter, 1232 duplication of, 1233 Urethra, agenesis of, 1237 associated genitourinary anomalies, 1237 prenatal detection of, 1238 prognosis of, 1238 syndromes with, 1239t Urethra, atresia of, 1237 associated genitourinary anomalies, 1237 prenatal detection of, 1238 prognosis of, 1238 syndromes with, 1239t Urethra, duplication of, 1247 Urethra, stenosis of, 1241 syndromes with, 1243t Urethral valves, posterior, 1241 associated anomalies, 1242 classification of, 1242 obstruction due to, 1245 prognosis of, 1245 syndromes with, 1243t treatment of, 1245 Urinary tract, 1161 anomalies of, 1164, 1166 in chromosomal disorders, 1179t frequency of, 1164, 1167t teratogenic, 1180t bladder, anomalies of, 1232 cystic diseases, 1194, 1215, 1217, 1219 embryogenesis, 1161 key genes in, 1165t molecular aspects of, 1163 kidney disorders, 1194, 1200, 1202, 1217, 1219, 1224, 1228 Potter classification, 1195 renal anomalies, 1184, 1190, 1195, 1207 disorders with, 1186t, 1192t, 1193t, 1195, 1207 renal ectopia, 1223 disorders with, 1225 urachal anomalies, 1235 ureters, anomalies of, 1232 urethra, anomalies of, 1237, 1242, 1247 syndromes with, 1239, 1244 Urogenital system organs, 1157 Uropathy, obstructive, 1219 Urorectal septum malformation, 1188 Uterus, malformations of, 54 Uveal coloboma, 300 VACTERL association, 986 Vaginal atresia, 1298 syndromes with, 1299 Vaginal septum, longitudinal, 1300 Vaginal septum, transverse, 1299 Valproate, prenatal exposure to, 42 Valproic acid, prenatal exposure to, 42 Valvulogenesis, 88 Van der Woude syndrome, 1310

Vanishing twin, 1386 Varicella-zoster virus, 37 Varicosity of umbilical cord, 1470 Vascular anomalies of the intestine, 1092, 1099 of placenta, 1390 in twins, 1390 of umbilical cord, 1457 Vascular compression, of trachea, 128, 129 Vascular compromise, 54 Vascular malformations, 140, 1322 and associated syndromes, 1327t lymphatic, 1326 Vascular obstruction of duodenum, 1095 Vascular ring, 125 Vascular tumors, 1322 and associated syndromes, 1327t Vasculature, systemic (see Cardiovascular system malformations) Vein valve aplasia, 139 Velocardiofacial syndrome, 99, 100, 396, 401 Vena cava, anomalous drainage of, 137 inferior, 118 superior, 117 Venous malformation, 140, 1324 Venous ring, periureteral, 138 Venous variants, miscellaneous, 138 Ventral wall of the trunk, 1023 amastia/hypomastia, 1051 conditions with, 1052 bladder, exstrophy of, 1042 variants of, 1043 breasts, anomalies of, 1049, 1051 syndromes with, 1052 Cantrell pentalogy, 1027 cloaca, exstrophy of, 1046 defects of, 797, 1023 ectopia cordis, 1027 embryogenesis of, 1023 gastroschisis, 1038 gynecomastia, 1059 conditions with, 1060 drugs causing, 1062 muscle deficiency of, 797, 799 omphalocele, 1034 syndromes with, 1036 omphalomesenteric duct anomalies, 1030 pathogenic mechanisms, 1024 premature thelarche, 1063 sternal defects, 1025 umbilical anomalies, 1028, 1031 conditions with, 1029, 1033 Ventricle, common, 96 Ventricular inversion, 94 Ventricular outflow tract obstruction, 103, 107 syndromes with, 109t Ventricular septal defects, 113 syndromes associated with, 115t Vermis aplasia/hypoplasia/ dysplasia, 666

Subject Index Vertebra, 819 beaked, 823 biconcave, 823 coronal clefts of, 826 syndromes with, 826, 828t defects of, 819 syndromes with, 822t hook, 823 sagittal clefts of, 825 scalloped, 824 segmentation defects of, 819 syndromes with, 822t Vertebral body, altered contour, 823 conditions with, 826t Vertex birth molding, 254 Vesicles, 1312 Vesicointestinal fissure, 1046 Vestibular aqueduct abnormalities, 368 Vestibular dysplasias, 366 Vestibulocochlear dysplasias, 366 classification, 367 Viral infections and pregnancy, 36 cytomegalovirus, 36 herpes virus, 36 human immunodeficiency, 38 influenza, 37

mumps, 37 parvovirus, 38 rubella, 37 rubeola, 37 varicella-zoster, 37 Virilizing adrenal hypoplasia, 1289 Visceral heterotaxia, 93, 190, 1361 Visceral situs, 93, 190, 1361 Vitamin A, prenatal exposure to, 45 Vitamin D, deficiency, 53 prenatal exposure to, 45 Vitamin deficiency, 53 Vitamin K antagonists, prenatal exposure to, 48 Vitelline artery, 1461 disruption, 1467 remnants of, 1465 Vitelline cysts, 1421 Vitelline remnants, 1421, 1465 Waardenburg syndrome, 1330 WAGR syndrome, 1290 Walker-Warburg syndrome, 552 Wandering spleen, 195 Warfarin, prenatal exposure to, 48 Water homeostasis, abnormalities in, 1354

Water metabolism, disorders of, 1343, 1354 Weaver syndrome, 1373 Weber syndrome, 1367 Web neck, 163 Weill-Marchesani syndrome, 1014 Wharton’s jelly, 1413 Whistling face syndrome, 931 White forelock, 1330 Wide cranial sutures, 237 syndromes with, 237 Widely spaced nipples, 1058 syndromes with, 1059 Wildervanck syndrome, 823 Williams syndrome, 496 Wolffian duct malformations, 1278 Wormian bones, 245 syndromes with, 245t X-chromosome mosaicism, disorders, 1313 XK-aprosencephaly syndrome, 526, 527 XLAG syndrome, 1290 X-linked abnormal genitalia, 551 X-linked CPHD, 1352

1495 X-linked dominant chondrodysplasia punctata, 1313 X-linked dominant phenotype, 29 characteristics of, 29 X-linked hydrocephaly spectrum (MASA), 619 X-linked lissencephaly with ambiguous genitalia, 1290 X-linked recessive phenotype, 31 characteristics of, 31 Yolk sac, 1413 Zellweger syndrome, 593, 1135 Zone of polarizing activity, 835, 936 Zonular cataracts, 318 Zygodactyly, 954 Zygoma, absence of, 280 syndromes with, 282t Zygoma, hypoplasia of, 280 syndromes with, 282t Zygosity, 1377, 1381 determination of, 1381